U.S. patent application number 15/706797 was filed with the patent office on 2018-01-11 for pesticidal compositions and processes related thereto.
This patent application is currently assigned to Dow AgroSciences LLC. The applicant listed for this patent is Dow AgroSciences LLC. Invention is credited to John Herbert, James E. Hunter, Paul R. LePlae, JR., William C. Lo, Gerald B. Watson.
Application Number | 20180009737 15/706797 |
Document ID | / |
Family ID | 54769037 |
Filed Date | 2018-01-11 |
United States Patent
Application |
20180009737 |
Kind Code |
A1 |
LePlae, JR.; Paul R. ; et
al. |
January 11, 2018 |
PESTICIDAL COMPOSITIONS AND PROCESSES RELATED THERETO
Abstract
This disclosure relates to the field of molecules having
pesticidal utility against pests in Phyla Nematoda, Arthropoda,
and/or Mollusca, processes to produce such molecules and
intermediates used in such processes, compositions containing such
molecules, and processes of using such molecules against such
pests. These molecules may be used, for example, as nematicides,
acaricides, insecticides, miticides, and/or molluscicides. This
document discloses molecules having the following formula ("Formula
One"). ##STR00001##
Inventors: |
LePlae, JR.; Paul R.;
(Brownsburg, IN) ; Hunter; James E.;
(Indianapolis, IN) ; Watson; Gerald B.;
(Zionsville, IN) ; Lo; William C.; (Fishers,
IN) ; Herbert; John; (Brownsburg, IN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dow AgroSciences LLC |
Indianapolis |
IN |
US |
|
|
Assignee: |
Dow AgroSciences LLC
Indianapolis
IN
|
Family ID: |
54769037 |
Appl. No.: |
15/706797 |
Filed: |
September 18, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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15488732 |
Apr 17, 2017 |
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15706797 |
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14733057 |
Jun 8, 2015 |
9676704 |
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15488732 |
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62009448 |
Jun 9, 2014 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N 37/36 20130101;
C07C 317/44 20130101; A01N 33/08 20130101; C07C 323/60 20130101;
A01N 37/34 20130101; A01N 37/20 20130101; C07C 233/83 20130101;
C07C 225/16 20130101; A01N 37/18 20130101; C07C 243/38 20130101;
C07B 2200/07 20130101; A01N 41/10 20130101; C07C 317/28 20130101;
A01N 53/00 20130101; C07C 2601/02 20170501; C07C 233/78 20130101;
A01N 37/44 20130101; C07C 323/41 20130101; A01N 37/28 20130101;
C07C 255/19 20130101; A01N 37/26 20130101; C07C 255/46
20130101 |
International
Class: |
C07C 225/16 20060101
C07C225/16; A01N 33/08 20060101 A01N033/08; C07C 317/28 20060101
C07C317/28; C07C 323/41 20060101 C07C323/41 |
Claims
1. A molecule having the following formula ##STR00301## wherein:
(a) R1, R2, R3, R4, and R5, are, each independently, H, F, Cl, Br,
I, CN, C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.1-C.sub.6)haloalkoxy; (b) R6 is
(C.sub.1-C.sub.6)haloalkyl; (c) R7 is H; (d) R8 is H,
(C.sub.1-C.sub.6)alkyl, or (C.sub.1-C.sub.6)haloalkyl; (e) R9 is H,
F, Cl, Br, I, (C.sub.1-C.sub.6)alkyl, or
(C.sub.1-C.sub.6)haloalkyl; (f) R10 is F, Cl, Br, I,
(C.sub.1-C.sub.6)alkyl, or (C.sub.1-C6)haloalkyl; (g) R11 and R12
are, each independently, H, F, Cl, Br, I, (C.sub.1-C.sub.6)alkyl,
or (C.sub.1-C.sub.6)haloalkyl; (h) L is (1) a linker that is a bond
connecting the two nitrogen atoms, or (2) a (C.sub.1-C.sub.6)alkyl
that is optionally substituted with one or more substituents,
wherein each substituent is independently selected from F, Cl, Br,
I, CN, OH, oxo, (C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I; (I) R13 is (1) an H, or (2) a (C.sub.1-C.sub.6)alkyl
that is optionally substituted with one or more substituents,
wherein each substituent is independently selected from F, Cl, Br,
I, CN, OH, oxo, (C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I; and (j) R14 is independently selected from
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, or
(C.sub.2-C.sub.3)alkynyl, wherein each said alkyl, haloalkyl,
cycloalkyl, alkenyl, and alkynyl has one or more substituents
selected from F, Cl, Br, I, CN, NO.sub.2, OH, oxo,
(C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I.
2. A molecule according to claim 1 wherein: (a) R1 is H; (b) R2 is
H, F, Cl, or Br; (c) R3 is H, F, Cl, or Br; (d) R4 is H, F, Cl, or
Br; (e) R5 is H; (f) R6 is (C.sub.1-C.sub.8)haloalkyl; (g) R7 is H;
(h) R8 is H; (I) R9 is H; (j) R10 is selected from a group
consisting of F, Cl, Br, I, (C.sub.1-C.sub.6)alkyl, and
(C.sub.1-C.sub.6)haloalkyl; (k) R11 is H; (I) R12 is H; (m) L is
(1) a linker that is bond connecting the two nitrogen atoms, or (2)
a (C.sub.1-C.sub.6)alkyl; (n) R13 is (1) an H, or (2) a
(C.sub.1-C.sub.8)alkyl; (o) R14 is independently selected from
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C.sub.3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, or
(C.sub.2-C.sub.8)alkynyl, wherein each said alkyl, haloalkyl,
cycloalkyl, alkenyl, and alkynyl has one or more substituents
selected from F, Cl, Br, I, CN, NO.sub.2, OH, oxo,
(C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I.
3. A molecule according to claim 1 wherein: (a) R1 is H; (b) R2 is
Cl or Br; (c) R3 is H, F, Cl, or Br; (d) R4 is Cl or Br; (e) R5 is
H; (f) R6 is (C.sub.1-C.sub.8)haloalkyl; (g) R7 is H; (h) R8 is H;
(I) R9 is H; (j) R10 is Br, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl; (k) R11 is H; (I) R12 is H; (m) L is
(1) a linker that is bond connecting the two nitrogen atoms, or (2)
a (C.sub.1-C.sub.6)alkyl; (n) R13 is (1) an H, or (2) a
(C.sub.1-C.sub.8)alkyl; (o) R14 is (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl, (C.sub.3-C.sub.8)cycloalkyl, or
(C.sub.2-C.sub.8)alkenyl, wherein each said alkyl or cycloalkyl is
substituted with CN, SCH.sub.3, S(O)CH.sub.3, or
S(O).sub.2CH.sub.3.
4. A molecule according to claim 1 wherein said molecule is
selected from one of the following molecules TABLE-US-00015 No.
Structure F1 ##STR00302## F2 ##STR00303## F3 ##STR00304## F4
##STR00305## F5 ##STR00306## F6 ##STR00307## F7 ##STR00308## F8
##STR00309## F9 ##STR00310## F10 ##STR00311## F11 ##STR00312## F12
##STR00313## F13 ##STR00314## F14 ##STR00315## F15 ##STR00316## F16
##STR00317## F17 ##STR00318## F18 ##STR00319## F19 ##STR00320## F20
##STR00321## F21 ##STR00322## F22 ##STR00323## F23 ##STR00324##
5. A molecule according to claim 1 wherein said molecule is
selected from one of the following molecules TABLE-US-00016 No.
Structure P1 ##STR00325## P2 ##STR00326## P3 ##STR00327## P4
##STR00328## P5 ##STR00329## P6 ##STR00330## P7 ##STR00331## P8
##STR00332## P9 ##STR00333## P10 ##STR00334## P11 ##STR00335## P12
##STR00336## P13 ##STR00337## P14 ##STR00338## P15 ##STR00339## P16
##STR00340## P17 ##STR00341## P18 ##STR00342## P19 ##STR00343## P20
##STR00344## P21 ##STR00345## P22 ##STR00346## P23 ##STR00347## P24
##STR00348## P25 ##STR00349## P26 ##STR00350## P27 ##STR00351## P28
##STR00352## P29 ##STR00353## P30 ##STR00354## P31 ##STR00355## P32
##STR00356## P33 ##STR00357## P34 ##STR00358## P35 ##STR00359## P36
##STR00360## P37 ##STR00361## P38 ##STR00362## P39 ##STR00363## P40
##STR00364## P41 ##STR00365## P42 ##STR00366## P43 ##STR00367## P44
##STR00368## P45 ##STR00369## P46 ##STR00370## P47 ##STR00371## P48
##STR00372## P49 ##STR00373## P50 ##STR00374## P51 ##STR00375## P52
##STR00376## P53 ##STR00377## P54 ##STR00378##
6. A pesticidal composition comprising a molecule according to
claim 1 and further comprising one or more compounds having a mode
of action selected from: Acetylcholinesterase (AChE) inhibitors;
GABA-gated chloride channel antagonists; Sodium channel modulators;
Nicotinic acetylcholine (nAChR) agonists; Nicotinic acetylcholine
receptor (nAChR) allosteric activators; Chloride channel
activators; Juvenile hormone mimics; Miscellaneous non-specific
(multi-site) inhibitors; Selective homopteran feeding blockers;
Mite growth inhibitors; Microbial disruptors of insect midgut
membranes; Inhibitors of mitochondrial ATP synthase; Uncouplers of
oxidative phosphorylation via disruption of the proton gradient;
Nicotinic acetylcholine receptor (nAChR) channel blockers;
Inhibitors of chitin biosynthesis, type 0; Inhibitors of chitin
biosynthesis, type 1; Moulting disruptor, Dipteran; Ecdysone
receptor agonists; Octopamine receptor agonists; Mitochondrial
complex III electron transport inhibitors; Mitochondrial complex I
electron transport inhibitors; Voltage-dependent sodium channel
blockers; Inhibitors of acetyl CoA carboxylase; Mitochondrial
complex IV electron transport inhibitors; Mitochondrial complex II
electron transport inhibitors; and Ryanodine receptor
modulators.
7. A process comprising applylng a pesticidal composition
comprising a molecule according to claim 1 to a locus to control a
pest, in a sufficient amount to control said pest.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of, and claims the
benefit of, U.S. non-provisional application Ser. No. 15/488,732,
which was filed on 17 Apr. 2017, which is a continuation of, and
claims the benefit of, U.S. non-provisional application Ser. No.
14/733057, which was filed on 8 Jun. 2015, which claims the benefit
of, and priority from, U.S. provisional application Ser. No.
62/009448, which was filed on 9 Jun. 2014. The entire disclosures
of these applications is hereby incorporated by reference into this
application.
FIELD OF THE DISCLOSURE
[0002] The invention disclosed in this document is related to the
field of processes to produce molecules that are useful as
pesticides (e.g., acaricides, insecticides, molluscicides, and
nematicides), such molecules, and processes of using such molecules
to control pests.
BACKGROUND OF THE DISCLOSURE
[0003] Pests cause millions of human deaths around the world each
year. Furthermore, there are more than ten thousand species of
pests that cause losses in agriculture. The world-wide agricultural
losses amount to billions of U.S. dollars each year.
[0004] Termites cause damage to all kinds of private and public
structures. The world-wide termite damage losses amount to billions
of U.S. dollars each year.
[0005] Stored food pests eat and adulterate stored food. The
world-wide stored food losses amount to billions of U.S. dollars
each year, but more importantly, deprive people of needed food.
[0006] There is an acute need for new pesticides. Certain pests are
developing resistance to pesticides in current use. Hundreds of
pest species are resistant to one or more pesticides. The
development of resistance to some of the older pesticides, such as
DDT, the carbamates, and the organophosphates, is well known. But
resistance has even developed to some of the newer pesticides, for
example, imidadoprid.
[0007] Therefore, for many reasons, including the above reasons, a
need exists for new pesticides.
[0008] DeMassey et al. discloses the following structure. For more
detail, refer to US 2002/0068838.
##STR00002##
DEFINITIONS
[0009] The examples given in the definitions are generally
non-exhaustive and must not be construed as limiting the invention
disclosed in this document. It is understood that a substituent
should comply with chemical bonding rules and steric compatibility
constraints in relation to the particular molecule to which it is
attached.
[0010] "Alkenyl" means an acyclic, unsaturated (at least one
carbon-carbon double bond), branched or unbranched, substituent
consisting of carbon and hydrogen, for example, vinyl, allyl,
butenyl, pentenyl, and hexenyl.
[0011] "Alkenyloxy" means an alkenyl further consisting of a
carbon-oxygen single bond, for example, allyloxy, butenyloxy,
pentenyloxy, hexenyloxy.
[0012] "Alkoxy" means an alkyl further consisting of a
carbon-oxygen single bond, for example, methoxy, ethoxy, propoxy,
isopropoxy, butoxy, isobutoxy, and tert-butoxy.
[0013] "Alkyl" means an acyclic, saturated, branched or unbranched,
substituent consisting of carbon and hydrogen, for example, methyl,
ethyl, (C3)alkyl which represents n-propyl and isopropyl),
(C4)alkyl which represents n-butyl, sec-butyl, isobutyl, and
tert-butyl.
[0014] "Alkynyl" means an acyclic, unsaturated (at least one
carbon-carbon triple bond), branched or unbranched, substituent
consisting of carbon and hydrogen, for example, ethynyl, propargyl,
butynyl, and pentynyl.
[0015] "Alkynyloxy" means an alkynyl further consisting of a
carbon-oxygen single bond, for example, pentynyloxy, hexynyloxy,
heptynyloxy, and octynyloxy.
[0016] "Aryl" means a cyclic, aromatic substituent consisting of
hydrogen and carbon, for example, phenyl, naphthyl, and
biphenyl.
[0017] "Cycloalkenyl" means a monocyclic or polycyclic, unsaturated
(at least one carbon-carbon double bond) substituent consisting of
carbon and hydrogen, for example, cyclobutenyl, cyclopentenyl,
cyclohexenyl, norbomenyl, bicyclo[2.2.2]octenyl,
tetrahydronaphthyl, hexahydronaphthyl, and octahydronaphthyl.
[0018] "Cycloalkenyloxy" means a cydoalkenyl further consisting of
a carbon-oxygen single bond, for example, cyclobutenyloxy,
cyclopentenyloxy, norbomenyloxy, and bicyclo[2.2.2]octenyloxy.
[0019] "Cycloalkyl" means a monocyclic or polycyclic, saturated
substituent consisting of carbon and hydrogen, for example,
cyclopropyl, cyclobutyl, cyclopentyl, norbornyl,
bicyclo[72.2.2]octyl, and decahydronaphthyl.
[0020] "Cycloalkoxy" means a cycloalkyl further consisting of a
carbon-oxygen single bond, for example, cyclopropyloxy,
cyclobutyloxy, cyclopentyloxy, norbornyloxy, and
bicyclo[2.2,2]octyloxy.
[0021] "Halo" means fluoro, chloro, bromo, and iodo.
[0022] "Haloalkoxy" means an alkoxy further consisting of, from one
to the maximum possible number of identical or different, halos,
for example, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy,
chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, and
pentafluoreethoxy.
[0023] "Haloalkyl" means an alkyl further consisting of, from one
to the maximum possible number of, identical or different, halos,
for example, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl,
chloromethyl, trichloromethyl, and 1,1,2,2-tetrafIuoroethyl.
[0024] "Heterocyclyl" means a cyclic substituent that may be fully
saturated, partially unsaturated, or fully unsaturated, where the
cyclic structure contains at least one carbon and at least one
heteroatom, where said heteroatom is nitrogen, sulfur, or oxygen.
In the case of sulfur, that atom can be in other oxidation states
such as a sulfoxide and sulfone. Examples of aromatic heterocyclyls
include, but are not limited to, benzofuranyl, benzoisothiazolyl,
benzoisoxazolyl, benzoxazolyl, benzothienyl, benzothiazolyl,
cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoindolyl,
isoquinolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolinyl,
oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl, pyrazolyl,
pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,
quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl,
thienyl, triazinyl, and triazolyl. Examples of fully saturated
heterocyclyls include, but are not limited to, piperazinyl,
piperidinyl, morpholinyl, pyrrolidinyl, oxetanyl,
tetrahydrofuranyl, tetrahydrothienyl and tetrahydropyranyl.
[0025] Examples of partially unsaturated heterocyclyls include, but
are not limited to, 1,2,3,4-tetrahydroquinolinyl,
4,5-dihydro-oxazolyl, 4,5-dihydro-1H-pyrazolyl,
4,5-dihydro-isoxazolyl, and 2,3-dihydro-[1,3,4]-oxadiazolyl.
[0026] Additional examples include the following
##STR00003##
DETAILED DESCRIPTION OF THE DISCLOSURE
[0027] This document discloses molecules having the following
formula ("Formula One"):
##STR00004##
wherein:
[0028] (a) R1, R2, R3, R4, and R5, are, each independently, H, F,
Cl, Br, I, CN, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)haloalkyl,
(C.sub.1-C.sub.6)alkoxy, or (C.sub.1-C.sub.6)haloalkoxy;
[0029] (b) R6 is (C.sub.1-C.sub.6)haloalkyl;
[0030] (c) R7 is H;
[0031] (d) R8 is H, (C.sub.1-C.sub.6)alkyl, or
(C.sub.1-C.sub.6)haloalkyl;
[0032] (e) R9 is H, F, Cl, Br, I, (C.sub.1-C.sub.6)alkyl, or
(C.sub.1-C.sub.6)haloalkyl;
[0033] (f) R10 is F, Cl, Br, I, (C.sub.1-C.sub.6)alkyl, or
(C.sub.1-C.sub.6)haloalkyl;
[0034] (g) R11 and R12 are, each independently, H, F, Cl, Br, I,
(C.sub.1-C.sub.6)alkyl, or (C.sub.1-C.sub.6)haloalkyl;
[0035] (h) Lis [0036] (1) a linker that is a bond connecting the
two nitrogen atoms, or [0037] (2) a (C.sub.1-C.sub.6)alkyl that is
optionally substituted with one or more substituents, wherein each
substituent is independently selected from F, Cl, Br, I, CN, OH,
oxo, (C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I;
[0038] R13 is [0039] (1) an H, or [0040] (2) a
(C.sub.1-C.sub.6)alkyl that is optionally substituted with one or
more substituents, wherein each substituent is independently
selected from F, Cl, Br, I, CN, OH, oxo, (C.sub.1-C.sub.6)alkoxy,
S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl,
S(O).sub.2(C.sub.1-C.sub.6)alkyl, and N((C1-C.sub.6)alkyl).sub.2
wherein each (C.sub.1-C.sub.6)alkyl is independently selected, and
wherein each said alkyl or alkoxy has one or more substituents
independently selected from H, F, Cl, Br, and I; and
[0041] (j) R14 is independently selected from
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.8)haloalkyl,
(C3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, or
(C.sub.2-C.sub.8)alkynyl, wherein each said alkyl, haloalkyl,
cycloalkyl, alkenyl, arid alkynyl has one or more substituents
selected from F, Cl, Br, I, CN, NO.sub.2, OH, oxo,
(C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)alkyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I.
[0042] In another embodiment of this invention R1 is H. This
embodiment may be used in combination with the other embodiments of
R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and L.
[0043] In another embodiment of this invention R2 is Cl or Br. This
embodiment may be used in combination with the other embodiments of
R1, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and L.
[0044] In another embodiment of this invention R3 is H, F, Cl, or
Br. This embodiment may be used in combination with the other
embodiments of R1, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13,
R14, and L.
[0045] In another embodiment of this invention R4 is Cl or Br. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, and L.
[0046] In another embodiment of this invention R5 is H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, and L.
[0047] In another embodiment of this invention R2, R3, and R4 are
Cl. This embodiment may be used in combination with the other
embodiments of R1, R5, R6, R7, R8, R9, R10, Ril, R12, R13, R14, and
L.
[0048] In another embodiment of this invention R1 and R5 are H.
This embodiment may be used in combination with the other
embodiments of R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14,
and L.
[0049] In another embodiment of this invention R1 and R5 are H, and
R2, R3, and R4 are Cl. This embodiment may be used in combination
with the other embodiments of R6, R7, R8, R9, R10, R11, R12, R13,
R14, and L.
[0050] In another embodiment of this invention R6 is CF.sub.3. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, and L.
[0051] In another embodiment of this invention R7 H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, R14, and L.
[0052] In another embodiment of this invention R8 is H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R6, R7, R9, R10, R11, R12, R13, R14, and L.
[0053] In another embodiment of this invention R9 is H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R6, R7, R8, R10, R11, R12, R13, R14, and L.
[0054] In another embodiment of this invention R.10 is Br,
CH.sub.3, or CF.sub.3. This embodiment may be used in combination
with the other embodiments of R1, R2, R3, R4, R5, R6, R7, R8, R9,
R11, R12, R13, R14, and L.
[0055] In another embodiment of this invention R11 is H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, and L.
[0056] In another embodiment of this invention R12 is H. This
embodiment may be used in combination with the other embodiments of
R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R13, R14, and L.
[0057] In another embodiment L is --CH.sub.2--, --CHCH.sub.3CH--,
--CH(CH.sub.2CH.sub.3)--, or --CH.sub.2CH.sub.2--. This embodiment
may be used in combination with the other embodiments of R1, R2,
R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, and R14.
[0058] In another embodiment of this invention R13 is H or
CH.sub.3. This embodiment may be used in combination with the other
embodiments of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R.11, R12,
R14, and L.
[0059] In another embodiment of this invention R14 is
(C.sub.1-C.sub.6)alkyl or (C.sub.3-C.sub.6)cycloalkyl that is
substituted with one or more substituents selected from CN,
S(C.sub.1-C.sub.6)alkyl, S(O)(C.sub.1-C.sub.6)alkyl, and
S(O).sub.2(C.sub.1-C.sub.6)alkyl. This embodiment may be used in
combination with the other embodiments of Ri, R2, R3, R4, R5, R6,
R7, R8, R9, R10, R11, R12, R13, and L.
[0060] In another embodiment of this invention R14 is CF3,
CH.sub.2CF.sub.3, CH.sub.2CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CH.sub.2CF.sub.3,
CH.sub.2CH.sub.2CH(CF.sub.3)CH.sub.3, CH(CH.sub.3)CH.sub.2CF.sub.3,
C(CH.sub.3).sub.2CF3, C(CH.sub.3).sub.2CH.sub.2CF.sub.3, CH3,
CH.sub.2CH.sub.3, CH.sub.2CH.sub.2CH.sub.3,
CH.sub.2CH.sub.2CH.sub.2CH3,CH.sub.2CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH(CH.sub.3).sub.2, CH.sub.2CH(CH.sub.3).sub.2,
CH.sub.2CH.sub.2CH(CH.sub.3).sub.2, C(CH.sub.3).sub.3,
CH.sub.2C(CH.sub.3).sub.3, CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
CH.sub.2CH.sub.2CH.sub.2C(CH.sub.3).sub.3, cyclopropyl,
CH.dbd.CH.sub.2, CH.dbd.CH(CH.sub.3), CH.dbd.C(CH.sub.3).sub.2,
CH.sub.2CH.dbd.CH.sub.2, CH.sub.2CH.dbd.CH(CH.sub.3),
CH(CH.sub.3).dbd.CH.sub.2, C(CH.sub.3).dbd.CH(CH.sub.3),
C.ident.CH, CH.sub.2C.ident.CH, CH.sub.2CN, CH.sub.2CH.sub.2CN,
CH.sub.2SCH.sub.3, CH.sub.2CH.sub.2SCH.sub.3, CH.sub.2S(O)CH.sub.3,
CH.sub.2CH.sub.2S(O)CH.sub.3, CH.sub.2S(O).sub.2CH.sub.3,
CH.sub.2CH.sub.2S(O).sub.2CH.sub.3. This embodiment may be used in
combination with the other embodiments of R1, R2, R3, R4, R5, R6,
R7, R8, R9, R10, R11, R12, R13, and L.
[0061] In another embodiment of this invention:
[0062] (a) R1 is H;
[0063] (b) R2 is H, F, Cl, or Br;
[0064] (c) R3 is H, F, Cl, or Br;
[0065] (d) R4 is H, F, Cl, or Br;
[0066] (e) R5 is H;
[0067] (f) R6 is (C.sub.1-C.sub.8)haloalkyl;
[0068] (g) R7 is H;
[0069] (h) R8 is H;
[0070] (i) R9 is H;
[0071] (j) R10 is selected from a group consisting of F, Cl, Br, I,
(C.sub.1-C.sub.6)alkyl, and (C.sub.1-C.sub.6)haloalkyl;
[0072] (k) R11 is H;
[0073] (I) R12 is H;
[0074] (m) L is [0075] (1) a linker that is bond connecting the two
nitrogen atoms, or [0076] (2) a (C.sub.1-C.sub.6)alkyl;
[0077] (n) R13 is [0078] (1) an H, or [0079] (2) a
(C.sub.1-C.sub.8)alkyl;
[0080] (o) R14 is independently selected from
(C.sub.1-C.sub.8)alkyl, (C.sub.1-C.sub.6)haloalkyl
(C3-C.sub.8)cycloalkyl, (C.sub.2-C.sub.8)alkenyl, or
(C.sub.2-C.sub.8)alkynyl, wherein each said alkyl, haloalkyl,
cycloalkyl, alkenyl, and alkynyl has one or more substituents
selected from F, Cl, Br, I, CN, NO.sub.2, OH, oxo,
(C.sub.1-C.sub.6)alkoxy, S(C.sub.1-C.sub.6)akyl,
S(O)(C.sub.1-C.sub.6)alkyl, S(O).sub.2(C.sub.1-C.sub.6)alkyl, and
N((C.sub.1-C.sub.6)alkyl).sub.2 wherein each (C.sub.1-C.sub.6)alkyl
is independently selected, and wherein each said alkyl or alkoxy
has one or more substituents independently selected from H, F, Cl,
Br, and I.
[0081] In another embodiment of this invention:
[0082] (a) R1 is H;
[0083] (b) R2 is Cl or Br;
[0084] (c) R3 is H, F, Cl, or Br;
[0085] (d) R4 is Cl or Br;
[0086] (e) R5 is H;
[0087] (f) R6 is (C.sub.1-C.sub.8)haloalkyl;
[0088] (g) R7 is H;
[0089] (h) R8 is H;
[0090] (i) R9 is H;
[0091] (j) R10 is Br, (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.8)haloalkyl;
[0092] (k) R11 is H;
[0093] (I) R12 is H;
[0094] (m) L is [0095] (1) a linker that is bond connecting the two
nitroaen atoms, or [0096] (2) a (C.sub.1-C.sub.6)alkyl;
[0097] (n) R13 is [0098] (1) an H, or [0099] (2) a
(C.sub.1-C.sub.8)alkyl;
[0100] (o) R14 is (C.sub.1-C.sub.8)alkyl,
(C.sub.1-C.sub.6)haloalkyl, (C3-C3)cycloalkyl, or
(C.sub.2-C.sub.8)alkenyl, wherein each said alkyl or cycloalkyl is
substituted with CN, SCH.sub.3, S(O)CH.sub.3, or
S(O).sub.2CH.sub.3.
Preparation of Benzyl Bromides
[0101] Benzyl alcohol 1-3, wherein R1, R2, R3, R4, R5, R6, and R7
are as previously disclosed, may be prepared in several ways.
Treatment of ketones 1-1, wherein R1, R2, R3, R4, R5, and R6 are as
previously disclosed with a reducing agent, such as sodium
borohydride, in the presence of a base, such as aqueous sodium
hydroxide, in a polar protic solvent, such as methanol at about
-10.degree. C. to about 10.degree. C. to provide benzyl alcohol 1-3
(Scheme 1, step a). Alternatively, aldehydes 1-2, wherein R1, R2,
R3, R4, R5, and R7 are as previously disclosed, may be allowed to
react with trifluorotrimethylsilane in the presence of a catalytic
amount of tetrabutylammonium fluoride in a polar aprotic solvent,
such as tetrahydrofuran (Scheme 1, step b) to provide benzyl
alcohol 1-3. Subsequently, benzyl alcohol 1-3 may be converted into
benzyl halide 1-4, wherein Y is Br, Cl, or I, and R1, R2, R3, R4,
R5, R6, and R7 are as previously disclosed, by treatment with a
halogenating reagent, such as N-bromesuccinimide, and
triethylphosphite in a non-reactive solvent, such as
dichloromethane at about 40.degree. C. to provide benzyl halide
1-4, Y is Br; or such as thionyl chloride, and pyridine in a
hydrocarbon solvent, such as toluene at about 110.degree. C. to
provide benzyl halide 1-4, where Y is Cl (Scheme 1, step c).
##STR00005##
Preparation of Vinylbenzoic Acids and Esters
[0102] Halobenzoic acids 2-1, wherein R9, R10, R11, and R12 are as
previously disclosed may be converted to vinylbenzoic acid ester
2-3, wherein R8, R9, Rio, R11, and R12 are as previously disclosed
or vinylbenzoic acids 2-4, wherein R8, R9, R10, R11, and R12 are as
previously disclosed. Halobenzoic acid 2-1, may be treated with a
base, such as n-butylithium, and dimethylformamide in a polar,
aprotic solvent, such as tetrahydrofuran, at a temperature of about
-78.degree. C. (Scheme 2, step a). The resulting formyl benzoic
acid may be treated with an acid, such as sulfuric acid, in the
presence of an alcohol, such as ethyl alcohol, to provide formyl
benzoic acid ethyl ester 2-2 (Scheme 2, step b). Vinyl benzoic acid
ester 2-3 may be accessed via reaction of 2-2, with a base, such as
potassium carbonate, and methyl triphenylphosphonium bromide in a
polar aprotic solvent, such as 1,4-dioxane, at about ambient
temperature (Scheme 2, step c). Alternatively, halobenzoic acid 2-I
may be treated with di-tert-butyl dicarbonate in the presence of a
base, such as triethylamine and a catalytic amount of
4-(dimethylamino)pyridine in a polar aprotic solvent, such as
tetrahydrofuran, at about ambient temperature (Scheme 2, step d).
The resulting benzoic acid tort-butyl ester may be treated with
vinyl boronic anhydride pyridine complex in the presence of a
palladium catalyst, such a tetrakis(triphenylphospine)palladium(0),
and a base,
##STR00006##
such as potassium carbonate, in a non-reactive solvent such as
toluene at about 110.degree. C., to provide vinyl benzoic acid
ester 2-3 (Scheme 2, step e).
[0103] Halobenzoic acid 2-1 may be treated directly with a
vinyltrifluoroborate in the presence of a palladium catalyst, such
as [1,1'-bis(diphenylphosphino) ferrocene]dichloropalladium(II) and
a base, such as potassium carbonate, in a non-reactive solvent such
as dimethylsulfoxide at temperatures ranging from about 80.degree.
C. to about 140.degree. C., to provide vinyl benzoic acids 2-4
(Scheme 2, step f).
Preparation of Diphenyl Allylbenzoic Acids
[0104] Benzyl halides 1-4 and vinylbenzoic acid esters 2-3 may be
treated with copper(I) chloride and 2,2-bipyridyl in a solvent,
such as 1,2-dichlorobenzene, at a temperature of about 180.degree.
C. to provide diphenyl allylbenzoic esters 3-1, wherein R1, R2, R3,
R4, R5, R6, R7, R8, R9, R10, R11, and R12 are as previously
disclosed (Scheme 3, step a). Diphenyl allylbenzoic esters 3-1 may
be then converted to diphenyl allylbenzoic acids 3-2, wherein R1,
R2, R3, R4, R5, R6, R7, R8, R9, R10R11, and R12 are as previously
disclosed. Treatment of diphenyl allylbenzoic esters 3-1, with an
acid, such as about 11 N aqueous hydrochloric acid, in a polar
aprotic solvent, such as 1,4-dioxane, at about 100.degree. C. may
provide diphenyl aliylbenzoic acids 3-2 (Scheme 3, step b),
##STR00007##
[0105] Alternatively, benzyl halides 1-4 and vinylbenzoic acids 2-4
may be treated with copper(I) chloride and 2,2-bipyridyl in a
solvent, such as 1,2-dichlorobenzene or N-methylpyrolidine, at
temperatures between about 60.degree. C. and about 180.degree. C.
to provide diphenyl allylbenzoic acids 3-2 (Scheme 3, step c).
Preparation of Diacylamines
[0106] Diacylamines 4-3, wherein R1, R2, R3, R4, R5, R6, R7, R8,
R9, R10, R11, R12, R13, R14, and L are as previously disclosed may
be prepared by treatment with acylamine salts 4-2, wherein R13,
R14, and L are as previously disclosed, and activated carboxylic
acids 4-1, wherein X is an activating group, and R1, R2, R3, R4,
R5, R6, R7, R8, R9, R10, R11, and R12 are as previously disclosed,
with a base, such as potassium bicarbonate, triethylamine,
diisopropylethylamine, or preferably 4-methylmorpholine in an
anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,
1,2-dichloroethane, dimethylformamide, or any combination thereof,
at temperatures between about 0.degree. C. and about 120.degree. C.
(Scheme 4, step a).
[0107] Activated carboxylic acids 4-1 may be an acid halide, such
as an acid chloride, an acid bromide, or an acid fluoride; a
carboxylic ester, such as a para-nitrophenyl ester, a
pentafluorophenyl ester, an ethyl (hydroxylminio)cyanoacetate
ester, a methyl ester, an ethyl ester, a benzyl ester, an
N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl ester, or a
hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acid
anhydride; or a thioester. Acid chlorides are most preferred and
may be prepared from the corresponding carboxylic acids by
treatment with a dehydrating chlorinating reagent, such as oxalyl
chloride or thionyl chloride both with or without catalytic
dimethylformamide. Activated carboxylic esters 4-1 may be prepared
from carboxylic acids in situ with a uronium salt, such as
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), or
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni-
um hexafluorophosphate (COMU). Activated carboxylic esters 4-1 may
also be prepared from carboxylic acids in situ with a phosphonium
salt such as benzotriazol-1-yl-oxytripyrrolidinophosphonium
hexafluorophosphate (PyBop). Activated carboxylic esters 4-1 may
also be prepared from carboxylic acids in situ with a coupling
reagent such as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or
dicyclohexylcarbodiimide in the presence of a triazolol such as
hydroxybenzotriazole.cndot.monohydrate (HOBt) or
1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared
with a dehydrating carbodimide such as 1-(3-dimethylamino
propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide.
##STR00008##
[0108] Diacylamines 4-3, wherein R14 contains a sulfide may be
oxidized to the corresponding sulfoxide and sulfone by treatment
with one equivalent of sodium perborate in a protic solvent such as
acetic acid (sulfoxide) or two equivalents of sodium perborate
(sulfone). Preferably, the oxidation will be performed at
temperatures between about 40.degree. C. to about 100.degree. C.
using 1.5 equivalents of sodium perborate to provide
chromatographically separable mixtures of sulfoxide and sulfone
diacylaminals 4-3, wherein R14 contains a sulfoxide or sulfone.
[0109] Alternatively, diacylamines 5-3, wherein R1, R2, R3, R4, R5,
R6, R7, R8, R9, R10, R11, R12, R14, and L are as previously
disclosed may be prepared by treatment of acylamine salts 5-1,
wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, and L
are as previously disclosed, with activated carboxylic acids 5-2,
wherein X is an activating group and R14 is as previously
disclosed, with a base, such as potassium bicarbonate,
triethylamine, diisopropylethylamine, or preferably
4-methylmorpholine in an anhydrous aprotic solvent such as
dichloromethane, tetrahydrofuran, 1,2-dichloroethane,
dimethylformamide, or any combination thereof, at temperatures
between about 0.degree. C. and about 120 PC (Scheme 5, step a).
[0110] Activated carboxylic acids 5-2 may be an acid halide, such
as an acid chloride, an acid bromide, or an acid fluoride; a
carboxylic ester, such as a para-nitrophenyl ester, a
pentafluorophenyl ester, an ethyl (hydroxylminio)cyanoacetate
ester, a methyl ester, an ethyl ester, a benzyl ester, an
N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-yl ester, or a
hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acid
anhydride; or a thioester. Acid chlorides are most preferred and
may be prepared from the corresponding carboxylic acids by
treatment with a dehydrating chlorinating reagent, such as oxalyl
chloride or thionyl chloride. Activated carboxylic esters 5-2 may
be prepared from carboxylic acids in situ with a uronium salt, such
as
1-[bis(dimethylamino)methylene[-1H-1,2,3-triazolo[4,5-b]pyridinium
3-oxid hexafluorophosphate (HATU),
O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium
hexafluorophosphate (HBTU), or
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)
dimethylamino-morpholine-carbenium hexafluorophosphate (COMU).
Activated carboxylic esters 5-2 may also be prepared from
carboxylic acids in situ with a phosphonium salt such as
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(PyBop). Activated carboxylic esters 5-2 may also be prepared from
carboxylic acids in situ with a coupling reagent such as
1-(3-dimethylamino propyl)-3-ethylcarbodiimide, or
dicyclohexylcarbodiimide in the presence of a triazolol such as
hydroxybenzotriazole.cndot.monohydrate (HOBt) or
1-hydroxy-7-azabenzotriazole (HOAt). O-Acylisoureas may be prepared
with a dehydrating carbodimide such as 1-(3-dimethylamino
propyl)-3-ethylcarbodiimide or dicyclohexylcarbodiimide.
##STR00009##
[0111] Carboxylic acid precursors to and activated carboxylic acids
5-2, wherein R14 contains a sulfide may be oxidized to the
corresponding sulfoxide or sulfone by treatment with one equivalent
of sodium perborate in a erotic solvent such as acetic acid
(sulfoxide) or two equivalents of sodium perborate (sulfone).
Preferably, the oxidation will be performed at temperatures between
about 40.degree. C. to about 100.degree. C. using 1.5 equivalents
of sodium perborate to provide chromatographically separable
mixtures of sulfoxide and sulfone.
[0112] Additionally, diacylamines 4-3 may be prepared by treating
acylamines 5-3 with an alkylating reagent R13-Z, wherein R13 is not
H and is as previously disclosed and Z is a leaving group, such as
a halogen or sulfonate, wherein R13-Z is an alkyl halide, such as
iodomethane, or an activated alcohol, such as ethyltriflate in the
presence of a base, such as sodium hydride, cesium carbonate,
silver oxide, potassium hydride, tetrabutylammonium fluoride, or
potassium carbonate in a polar aprotic solvent such as
dimethylformamide, tetrahydrofuran, acetone, acetonitrile,
dimethylsulfoxide, or glyme. Alternatively, the alkylation of
acylamines 5-3 may be conducted in a biphasic manner using an
alkali metal hydroxide base, such as sodium hydroxide, in water, a
phase-transfer catalysts, such as a tetraalkylammonium salt, in an
organic solvent such as toluene or dichloromethane at temperatures
ranging from about 0.degree. C. and about 120.degree. C. (Scheme 6,
step a).
##STR00010##
[0113] Diacylamines 5-3, wherein R14 contains a sulfide may be
oxidized to the corresponding sulfoxide and sulfone by treatment
with one equivalent of sodium perborate in a protic solvent such as
acetic acid (sulfoxide) or two equivalents of sodium perborate
(sulfone). Preferably, the oxidation will be performed at
temperatures between about 40.degree. C. to about 100.degree. C.
using 1.5 equivalents of sodium perborate to provide
chromatographically separable mixtures of sulfoxide and sulfone
diacylamines 5-3, wherein R14 contains a sulfoxide or sulfone.
Preparation of Acylamine Salt 5-1 Precursors
[0114] Amides 7-2, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, Rio,
R11, R12, and L are as previously disclosed are novel intermediates
which may be used in the preparation of acylamine salts 5-1. Amides
7-2 may be prepared by reacting alpha-amino amides 7-1, wherein L
is as previously disclosed, and an activated carboxylic acid 4-1
with a base, such as potassium bicarbonate, triethylamine,
diisopropylethylamine, or preferably 4-methylmorpholine in an
anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,
1,2-dichloroethane, dimethylformamide, or any combination thereof,
at temperatures between about 0.degree. C. and about 120.degree. C.
(Scheme 7, step a).
##STR00011##
Preparation of Acylamine Salts 5-1
[0115] Acylamines 5-1 may be prepared from amides 7-2 by conversion
of the primary amide nitrogen to a nitrene-iike species, resulting
in nitrogen migration, followed by isocyanate formation. Hydrolysis
of the intermediate isocyanate with aqueous acid, such as
hydrochloric acid may provide acylamine salts 5-1 (Scheme 8, step
a). When an acid weaker than aqueous hydrochloric acid is employed,
anion exchange may be achieved by treatment with hydrochloric acid
to provide acylamine salts 5-1. Preferably amide 7-2 may be treated
with iodobenzene bis(trifluoroacetate) in a solvent mixture
consisting of about two parts acetonitrile and about one part
deionized water at temperatures between about 0.degree. C. and
about 120.degree. C. The resulting trifluoroacetate salt may be
converted to the chloride salt by the addition of hydrochloric acid
followed by evaporation of volatiles.
Preparation of Acylamine Salts 4-2
[0116] Acylamine salts 4-2 may be prepared according to those
reactions outlined in Scheme 9, Scheme 10, and Scheme 11. Treatment
carboxylic acids 9-1, wherein X is OH, and R13, R14, and L are as
previously disclosed, or the corresponding activated acids 9-1,
wherein X is an activating group as previously described may be
reacted with a nitrogen nucleophile to provide amides and amide
derivatives 9-2, wherein Y2 is H, N2, NH tert-butoxycarbonyl, or
OH) and R13, R14, arid L are as previousiy disclosed. The resultant
amides and amide derivatives 9-2 may be converted to acylamine
salts 4-2 by the formation of the corresponding nitrene-like
species, resulting in nitrogen migration, and subsequent hydrolysis
of the resultant isocyanate.
##STR00012##
[0117] Activated amido acids 9-1, wherein X, R13, R14, and L are as
previously disclosed, may be treated with ammonia (Scheme 9, step
a) to provide carboxamides 9-2, wherein Y2 is H. Carboxamides 9-2,
wherein Y2 is H, may be converted to acylamine 4-2 via the Hoffman
rearrangement followed by acidification with hydrochloric acid or
preferably by treatment with iodobenzene bis(trifluoroacetate) in a
solvent mixture consisting of about one part acetonitrile and about
one part deionized water at temperatures between about 0.degree. C.
and about 120.degree. C. (Scheme 9, step e). The resulting
trifluoroacetate salt may be converted to the chloride salt by the
addition of hydrochloric acid followed by evaporation of
volatiles.
[0118] Amido acids 9-1, wherein X is OH, and R13, R14, and L are as
previously disclosed, may be treated with an azide source such as
diphenylphosphoryl azide in the presence of a base, such as proton
sponge or triethylamine (Scheme 9, step b) to provide acyl azides
9-2, wherein Y2 is N2. Alternatively, activated am do acids 9-1,
wherein X is as described above, may be treated with an azide
source, such as sodium azide (Scheme 9, step b) to provide acyl
azides 9-2, wherein Y2 is N2. Acyl azides 9-2, may be heated to
about 40.degree. C. to about 110.degree. C. in an aprotic solvent,
such as acetonitrile, toluene, 1,2-dichloroethane, tetrahyrafuran,
or 1,4-dioxane to affect a Curtius Rearrangement resulting in the
formation of a non-isolated isocyanate that may be treated with
aqueous hydrochloric acid to provide acylamine salts 4-2.
Alternatively, the isocyanate may be treated with an alcohol, such
as tert-butanol, para-methoxy benzyl alcohol, or benzyl alcohol to
provide an acid labile carbamate, which after purification may be
decomposed under acidic conditions to provide acylamine salts 4-2
(Scheme 9, step f).
##STR00013##
[0119] Activated amido acids 9-1, wherein X, R13, R14, and L are as
previously disclosed, may be treated with protected hydrazines
(Scheme 9, step c), such as tert-butyl carbazate in the presence of
a base, such as 4-methylmorpholine, to provide protected hydrazides
9-2, wherein Y2 is NH tert-butoxycarbonyl. Protected hydrazides 9-2
may be deprotected by treatment with acids such as hydrochloric
acid or trifluoroacetic acid in aprotic solvents such as
1,4-dioxane or dichloromethane. The resulting hydrazide salts 9-2,
wherein Y2 is NH.sub.3Cl, may be neutralized to provide hydrazide
9-2, wherein Y2 is NH.sub.2. Hydrazides 9-2 may then be diazotized
with reagents such as nitric acid or isobutyl nitrite to produce
isocyanates that may be converted to acylamine salts 4-2 (Scheme 9,
step g).
[0120] Activated amido acids 9-1, wherein X, R13, R14, and L are as
previously disclosed, may be treated with hydroxylarmine (Scheme 9,
step d) to provide hydroxamic acids 9-2, wherein Y2 is OH.
Hydroxamic acids 9-2 may be acylated with activated carboxylic
acids, wherein activated carboxylic acids are as previously
disclosed, to provide the O-acyl hydroxamic acids 9-2, wherein Y2
is O-acyl, which may be converted to isocyanates by treatment with
heat or the addition of base to produce isocyanates that may be
converted to acylamine salts 4-2 (Scheme 9, step h).
[0121] Carbamate acids 10-1, wherein R13 and L are as previously
disclosed, may be treated with an alkylating reagent R13-Z, wherein
R13 is not H and is as previously disclosed and Z is a leaving
group, such as a halogen or sulfonate, wherein R13-Z is an alkyl
halide, such as iodomethane, or an activated alcohol, such as
ethyltriflate, in the presence of a base, such as sodium hydride,
cesium carbonate, silver oxide, potassium hydride,
tetrabutylammonium fluoride, or potassium carbonate in a polar
aprotic solvent such as dimethylformamide, tetrahydrofuran,
acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively,
the alkylation of carbamate acids 10-1 may be conducted in a
biphasic manner using an alkali metal hydroxide base, such as
sodium hydroxide, in water, a phase-transfer catalysts, such as a
tetraalkylammonium salt, in an organic solvent such as toluene or
dichloromethane at temperatures ranging from about 0.degree. C. to
about 120.degree. C. (Scheme 10, step a).
[0122] The resultant carbamate acids 10-2, wherein R13 and L are as
previously disclosed may be treated with an azide source such as
diphenylphosphoryl azide in the presence of a base, such as proton
sponge or triethylamine (Scheme 10, step b) to provide an acyl
azide which may in turn be heated from about 40.degree. C. to about
110.degree. C. in an aprotic solvent, such as acetonitrile,
toluene, 1,2-dichloroethane, tetrahydrofuran, or 1,4-dioxane to
effect a Curtius Rearrangement resulting in the formation of an
isocyanate (Scheme 10, step c). Treatment of the resultant
isocyanate with benzyl alcohol may provide a differentially
protected dicarbamate (Scheme 10, step d). Deprotection of the
tert-butylcarbamate may be achieved by treatment with an acid, such
as hydrochloric acid or trifluoroacetic acid, in a polar aprotic
solvent, such as 1,4-dioxane or dichloromethane, at temperatures
between about 0.degree. C. and about 65.degree. C., to provide
benzyl carbamate amine salts 10-3, wherein R13 and L are as
previously disclosed (Scheme 10, step e).
[0123] Benzyl carbamate amine salts 10-3 may treated with activated
carboxylic acids 5-2 in the presence of a base, such as potassium
bicarbonate, triethylamine, diisopropylethylamine, or preferably
4-methylrnorpholine in an anhydrous aprotic solvent such as
dichloromethane, tetrahydrofuran, 1,2-dichloroethane,
dimethylformarnide, or any combination thereof, at temperatures
between about 0.degree. C. and about 120.degree. C. (Scheme 10,
step f). The resultant carbamate acylamine may be treated with a
source of hydrogen and a transition metal catalyst, such as
palladium on carbon to provide acylamine salts 4-2 (Scheme 10, step
g).
##STR00014##
[0124] Carbamate acids 10-1 may be treated with an alkylating
reagent R15-Z, wherein R15 is (C.sub.1-C.sub.8)alkenyl and Z is a
leaving group, such as a halogen or a sulfonate, wherein R15-Z is
an alkenyl halide, such as allyl bromide, or an activated alcohol,
such as crotyltriflate in the presence of a base, such as sodium
hydride, cesium carbonate, silver oxide, potassium hydride,
tetrabutylammonium fluoride, or potassium carbonate in a polar
aprotic solvent such as dimethylforrnarnide, tetrahydrofuran,
acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively,
the alkylation of amide esters 10-1 may be conducted in a biphasic
manner using an alkali metal hydroxide base, such as sodium
hydroxide, in water, a phase-transfer catalysts, such as a
tetraalkylammonium salt, in an organic solvent such as toluene or
dichloromethane at temperatures ranging from about 0.degree. C. to
about 100.degree. C. (Scheme 11, step a).
[0125] The resultant carbamate acids 11-2, wherein R15 and L are as
previously disclosed may be treated with an azide source such as
diphenylphosphoryl azide in the presence of a base, such as proton
sponge or triethylamine (Scheme 11, step b) to provide an acyl
azide which may in turn be heated to about 40.degree. C. to about
110.degree. C. in an aprotic solvent, such as acetonitrile,
toluene, 1,2-dichloroethane, tetrahydrofuran, or 1,4-dioxane to
effect a Curtius Rearrangement resulting in the formation of an
isocyanate (Scheme 11, step c). Treatment of the resultant
isocyanate with benzyl alcohol may provide a differentially
protected dicarbamate (Scheme 11, step d). Deprotection of the
tert-butylcarbamate may be achieved by treatment with an acid, such
as hydrochloric acid or trifluoroacetic acid, in a polar aprotic
solvent, such as 1,4-dioxane or dichloromethane, at temperatures
between about 0.degree. C. and about 65.degree. C., to provide
benzyl carbamate aminal salts 11-3, wherein L and R15 are as
previously disclosed (Scheme 11, step e).
[0126] Benzyl carbamate amine salts 11-3 may be treated with
activated carboxylic acids 5-2 in the presence of a base, such as
potassium bicarbonate, triethylamine, diisopropylethylamine, or
preferably 4-methylmorpholine in an anhydrous aprotic solvent such
as dichloromethane, tetrahydrofuran, 1,2-dichloroethane,
dimethylformamide, or any combination thereof, at temperatures
between about 0.degree. C. and about 120.degree. C. (Scheme 11,
step f). The resultant carbamate acylaminal may be treated with a
source of hydrogen and a transition metal catalyst, such as
palladium on carbon to provide acylamine salts 4-2 (Scheme 11, step
g).
##STR00015##
Preparation of Amido Acids 9-1
[0127] Amido esters 12-2, wherein R13 and L are as previously
disclosed may be prepared by treating amino esters 12-1, wherein Y3
is O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl and L
is as previously disclosed, with activated carboxylic acids 5-2
with a base, such as potassium bicarbonate, triethylamine,
diisopropylethylamine, or preferably 4-methylmorpholine in an
anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,
1,2-dichloroethane, dimethylformamide, or any combination thereof,
at temperatures between about 0.degree. C. and about 120.degree. C.
(Scheme 12, step a).
##STR00016##
[0128] Amido esters 12-2 may be treated with an alkylating reagent
R13-Z, wherein R13 is not H and as previously disclosed and Z is a
leaving group, such as a halogen or a sulfonate, wherein R13-Z is
an alkyl halide, such as iodomethane or an activated alcohol, such
as ethyltriflate in the presence of a base, such as sodium hydride,
cesium carbonate, silver oxide, potassium hydride,
tetrabutylammonium fluoride, or potassium carbonate in a polar
aprotic solvent such as dimethylformamide, tetrahydrofuran,
acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively,
the alkylation of amido esters 12-2 may be conducted in a biphasic
manner using an alkali metal hydroxide base, such as sodium
hydroxide, in water, a phase-transfer catalyst, such as a
tetraalkylammonium salt, in an organic solvent such as toluene or
dichloromethane at temperatures ranging from about 0.degree. C. to
about 120.degree. C. (Scheme 12, step b) .
[0129] The resultant alkylated amido esters, when Y3 is
O(C.sub.1-C.sub.8)alkyl, may be treated with an acid, such as about
11 N aqueous hydrochloric acid, in a polar aprotic solvent, such as
1,4-dioxane, at about 100.degree. C. to provide amido acids 9-1.
Alternatively, alkylated amide esters, when Y3 is O-tert-butyl, may
be treated with hydrochloric acid in 1,4-dioxane, Alkylated amido
esters, when Y3 is O(C.sub.1-C.sub.8)alkyl may be treated with an
alkali base, such as lithium hydroxide, in a polar solvent, such as
1,4-dioxane, tetrahydrofuran, methanol, water, or mixtures thereof,
at temperatures between 0.degree. C. and about 140.degree. C. to
provide amido acids 9-1. The alkylated amido esters, when Y3 is
O(C.sub.1-C.sub.8)alkylphenyl may be treated with a source of
hydrogen and a transition metal catalyst, such as palladium on
carbon to provide amido acids 9-1 (Scheme 12, step c).
[0130] Amido acids 9-1 may be prepared in alternate sequences to
the sequence discussed above. Step b may be initially performed to
provide substituted amine esters 12-3, wherein Y3 is
O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and R13
and L are as previously disclosed, before steps a and steps c are
performed to provide amido acids 9-1.
[0131] Substituted amine esters 12-3, wherein R13 is as previously
disclosed, may be prepared by treating amino esters 12-1 with
R16-C(O)H or R16-C(O)(C.sub.1-C.sub.8)alkyl, wherein R16 is not H,
in the presence of a reductant, such as sodium borohydride or
sodium cyanoborohydride, in protic solvents such as methanol or
ethanol in the presence of weak organic acids, such acetic acid.
Alternatively, the imine intermediate resulting from condensation
of the amine and the carbonyl may be reduced by a source of
hydrogen and a transition metal catalyst, such as palladium on
carbon to provide substituted amine esters 12-3, when Y3 is
O(C.sub.1-C.sub.8)alkyl (Scheme 12, step d).
[0132] Amido acids 9-1 may be prepared in a two-step sequence, by
first treating substituted amine esters 12-3 with activated
carboxylic adds 5-2 with a base, such as potassium bicarbonate,
triethylamine, diisopropylethylamine, or preferably
4-methylmorpholine in an anhydrous aprotic solvent such as
dichloromethane, tetrahydrofuran, 1,2-dichloroethane,
dimethylformamide, or any combination thereof, at temperatures
between about 0.degree. C. and about 120.degree. C. (Scheme 12,
step e).
[0133] Secondly, the resultant amido esters, when Y3 is
O(C.sub.1-C.sub.8)alkyl may be treated with an acid, such as about
11 N aqueous hydrochloric acid, in a polar aprotic solvent, such as
1,4-dioxane, at about 100.degree. C. to provide amido acids 9-1.
Alternatively, amido esters, when Y3 is Otert-butyl, may be treated
with hydrochloric acid in 1,4-dioxane. Amido esters, when Y3 is
O(C.sub.1-C.sub.8)alkyl may be treated with an alkali base, such as
lithium hydroxide, in a polar solvent, such as 1,4-dioxane,
tetrahydrofuran, methanol, water, or mixtures thereof, at
temperatures between 0.degree. C. and about 100.degree. C. to
provide amido acids 9-1. Finally, acylated amido esters, when Y3 is
O(C.sub.1-C.sub.8)alkylphenyl may be treated with a source of
hydrogen and a transition metal catalyst, such as palladium on
carbon to provide amido acids 9-1 (Scheme 12, step f).
[0134] Amido adds 12-2 may be prepared by treating amino esters
12-1 with an activated carboxylic acid 5-2 with a base, such as
potassium bicarbonate, triethylamine, diisopropylethylamine, or
preferably 4-methylmorpholine in an anhydrous aprotic solvent such
as dichloromethane, tetrahydrofuran, 1,2-dichloroethane,
dimethylformamide, or any combination thereof, at temperatures
between about 0.degree. C. and about 120.degree. C. (Scheme 13,
step a).
##STR00017##
[0135] Amido esters 12-2 may be treated with an alkylating reagent
R15-Z, wherein R15 is (C.sub.1-C.sub.8)alkenyl and Z is a leaving
group, such as a halogen or a sulfonate, wherein R15-Z is an alkyl
halide, such as allyl bromide, or an activated alcohol, such as
crotyltrifiate in the presence of a base, such as sodium hydride,
cesium carbonate, silver oxide, potassium hydride,
tetrabutylammonium fluoride, or potassium carbonate in a polar
aprotic solvent such as dimethylformamide, tetrahydrofuran,
acetone, acetonitrile, dimethylsulfoxide, or glyme. Alternatively,
the alkylation of amido esters 12-2 may be conducted in a biphasic
manner using an alkali metal hydroxide base, such as sodium
hydroxide, in water, a phase-transfer catalysts, such as a
tetraalkylammonium salt, in an organic solvent such as toluene or
dichloromethane at temperatures ranging from about 0.degree. C. to
about 100.degree. C. (Scheme 13, step b). The alkene present in R15
may be subsequently reduced by a source of hydrogen and a
transition metal catalyst, such as palladium on carbon. In
alkylated amido esters when Y3 is O(C.sub.1-C.sub.8)alkylphenyl
reduction of the alkene may also lead to concomitant reduction of
the ester to provide amido acids 9-1 (Scheme 13, step c).
[0136] Alkylated amido esters, when Y3 is O(C.sub.1-C.sub.8)alkyl
may be treated with an acid, such as about 11 N aqueous
hydrochloric acid, in a polar aprotic solvent, such as 1,4-dioxane,
at about 100.degree. C. to provide amido acids 9-1. Alternatively,
amido esters, when Y3 is Otert-butyl, may be treated with
hydrochloric acid in 1,4-dioxane. Alkylated amido esters, when Y3
is O(C.sub.1-C.sub.8)alkyl may be treated with an alkali base, such
as lithium hydroxide, in a polar solvent, such as 1,4-dioxane,
tetrahydrofuran, methanol, water, or mixtures thereof, at
temperatures between 0.degree. C. and about 100.degree. C. to
provide amido acids 9-1 (Scheme 10, step d).
[0137] Amido acids 9-1 may be prepared in alternate sequences to
the sequence discussed above. Step b may be initially performed to
provide substituted amine esters 13-1, wherein Y3 is
O(C.sub.1-C.sub.8)alkyl or O(C.sub.1-C.sub.8)alkylphenyl, and R15
and L are as previously disclosed, before steps a and steps c, or
steps a, steps c, and steps d are performed to provide 9-1.
EXAMPLES
[0138] The examples are for illustration purposes and are not to be
construed as limiting the invention disclosed in this document to
only the embodiments disclosed in these examples.
[0139] Starting materials, reagents, and solvents that were
obtained from commercial sources were used without further
purification. Anhydrous solvents were purchased as Sure/Sea.TM.
from Aldrich and were used as received. Melting points were
obtained on a Thomas Hoover Unimelt capillary melting point
apparatus or an OptiMelt Automated Melting Point System from
Stanford Research Systems and are uncorrected. Molecules are given
their known names, named according to naming programs within ISIS
Draw, ChemDraw, or ACD Name Pro. If such programs are unable to
name a molecule, the molecule is named using conventional naming
rules. .sup.1NMR spectral data are in ppm (.delta.) and were
recorded at 300, 400, or 600 MHz, and .sup.13C NMR spectral data
are in ppm (.delta.) and were recorded at 75, 100, or 150 MHz,
unless otherwise stated.
Example 1
Preparation of 1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene
(C2)
##STR00018##
[0141] Step 1 Method A.
1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (C1). To a stirred
solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone
(procured from Rieke Metals, UK; 5.00 g, 20.5 mmol) in methanol
(100 mL) at 0.degree. C. were added sodium borohydride (3.33 g,
92.5 mL) and aqueous sodium hydroxide (1 N; 10 mL). The reaction
mixture was warmed to 25.degree. C. and stirred for 2 hours. After
the reaction was deemed complete by thin layer chromatography,
saturated aqueous ammonium chloride was added to the reaction
mixture, and the mixture was concentrated under reduced a pressure.
The residue was diluted with diethyl ether and washed with water
(3.times.50 mL). The organic layer was dried over sodium sulfate
and concentrated under reduced pressure to afford the title
compound as a liquid (4.00 g, 79%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.41 (m, 3H), 5.00 (m, 1H), 2.74 (s, 1H); ESIMS
m/z 242.97 ([M-H].sup.-).
[0142] Step 1 Method B.
1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanol (C1). To a stirred
solution of 3,5-dichlorobenzaldehyde (10 g, 57 mmol) in
tetrahydrofuran (250 mL) were added trifluoromethyltrimethylsilane
(9.8 g, 69 mmol) and a catalytic amount of tetrabutylammonium
fluoride. The reaction mixture was stirred at 25.degree. C. for 8
hours. After the reaction was deemed complete by thin layer
chromatography, the reaction mixture was diluted with hydrochloric
acid (3 N) and then was stirred for 16 hours. The reaction mixture
was diluted with water and was extracted with ethyl acetate (3
times). The combined organic extracts were washed with brine, dried
over sodium sulfate, and concentrated under reduced pressure to
afford the title compound as a liquid (8.4 g, 60%).
[0143] Step 2. 1-(1-Bromo-2,2,2-trifluoreethyl)-3,5-dichlorobenzene
(C2). To a stirred solution of
1-(3,5-dichlorophenyI)-2,2,2-trifluoroethanol (C1) (4.00 g, 16.3
mmol) in dichloromethane (50 mL), were added N-bromosuccinimide
(2.90 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol),
and the resultant reaction mixture was heated at reflux for 18
hours. After the reaction was deemed complete by thin layer
chromatography, the reaction mixture was cooied to 25.degree. C.
and was concentrated under reduced pressure. Purification by flash
column chromatography using 100% pentane as eluent afforded the
title compound as a liquid (2.00 g, 40%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306
([M].sup.+).
[0144] The following compounds were made in accordance with the
procedures disclosed in Step 1 Method A of Example 1.
1-(3,5-difluorophenyl)-2,2,2-trifluoroethanol (C3)
##STR00019##
[0146] The product was isolated as a colorless oil (0.2 g, 75%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (m, 2H), 6.88 (m,
1H), 5.06 (m, 1H), 2.66 (s, 1H); ESIMS m/z 212 ([M].sup.+).
1-(4-Chlorophenyl)-2,2,2-trifluoroethanol (C4)
##STR00020##
[0148] The product was isolated as a colorless oil (5.0 g, 99%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.44-7.38 (m, 4H), 5.05
(m, 1H), 2.55 (s, 1H); ESIMS m/z 210 ([M].sup.+).
2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol (C5)
##STR00021##
[0150] The product was isolated as a pale yellow liquid: .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (d, J=8.8 Hz, 2H), 6.95 (m,
J 32 8.8 Hz, 2H), 5.00 (m, 1H), 3.82 (s, 3H), 2.44 (s, 1H); ESIMS
m/z 206 ([M].sup.+).
2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol (C6)
##STR00022##
[0152] The product was isolated as a colorless oil (5 g, 99%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48-7.45 (m, 2H),
7.13-7.07 (m, 2H), 5.06 (m, 1H), 2.53 (s, 1H); ESIMS m/z 194
([M].sup.+).
2,2,2-Trifluoro-1-(p-tolyl)ethanol (C7)
##STR00023##
[0154] The product was isolated as colorless oil (5.0 g, 99%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.37 (d, J=8.0 Hz, 2H),
7.23 (d, J=8.0 Hz, 2H), 5.02 (m, 1H), 2.46 (m, 1H), 2.37 (s, 3H);
ESIMS m/z 190 ([M].sup.+).
2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol (C8)
##STR00024##
[0156] The product was isolated as a colorless viscous oil (2.8 g,
93%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41 (m, 1H), 7.25
(m, 2H), 7.14 (m, 1H), 5.06 (m, 1H), 2.60 (s, 1H); ESIMS m/z 194
([M].sup.+).
2,2,2-Trifluoro-1-(2-fluorophenyl)ethanol (C9)
##STR00025##
[0158] The product was isolated as a colorless oil (2.5 g, 99%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.40 (m, 1H), 7.43
(m,1H), 7.24 (m, 1H), 7.13 (m, 1H), 5.42 (m, 1H), 2.65 (s, 1H);
ESIMS m/z 194 ([M].sup.+).
[0159] The following compounds were made in accordance with the
procedures disclosed in Step 1 Method B of Example 1.
2,2,2-Trifluoro-1-(3,4,5-trichlorophenyl)ethanol (C10)
##STR00026##
[0161] The product was isolated as a pale yellow liquid (0.500 g,
65%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (s, 2H), 5.00
(m, 1H), 2.80 (s, 1H); ESIMS m/z 278 ([M+H].sup.+); IR (thin film)
3420, 1133, 718 cm.sup.-1.
1-(3,5-Dichloro-4-fluorophenyl)-2,2,2-trifluoroethanol (C11)
##STR00027##
[0163] The product was isolated as a pale yellow liquid (0.500 g,
65%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.41 (s, 2H), 5.00
(m, 1H), 2.80 (s, 1H); ESIMS m/z 262 ([M+H].sup.+); IR (thin film)
3420, 1133, 718 cm.sup.-1.
1-(3,4-DichlorophenyI)-2,2,2-trifluoroethanol (C12)
##STR00028##
[0165] The product was isolated as a pale yellow liquid (0.500 g,
65%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.60 (s, 1H), 7.51
(m, 1H), 7.35 (m, 1H), 5.01 (m, 1H), 2.60 (s, 1H); EIMS m/z 244
([M].sup.+).
1-(3-Chlorophenyl)-2,2,2-trifluoroethanol (C13)
##STR00029##
[0167] The produce was isolated as a colorless viscous oil (1.5 g,
75%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (s, 1H),
7.42-7.35 (m, 3H), 5.02 (m, 1H), 2.65 (br s, 1H).
2,2,2-Trifluoro-1-phenylethanol (C14)
##STR00030##
[0169] The product was isolated (10 g, 80%): .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.48 (m, 2H), 7.40 m, 3H), 5.02 (m, 1H), 2.65
(d, J=7.1 Hz, 1H).
1-(3,5-Dimethylphenyl)-2,2,2-trifluoroethanol (C15)
##STR00031##
[0171] The product was isolated as an off white solid: .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.05 (s, 2H), 7.02 (s, 1H), 4.95 (m,
1H), 2.32 (s, 6H); ESIMS m/z 204 ([M]).sup.-).
1-(2,4-Dichlorophenyl)-2,2,2-trifluoroethanol (C16)
##STR00032##
[0173] The product was isolated as an off white powder (5.3 g,
61%): mp 49-51.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.62-7.66 (d, 1H), 7.42-7.44 (d, 1H), 7.32-7.36 (d, 1H),
5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244 ([M].sup.+).
1-(2,3-Dichlorophenyl)-2,2,2-trifluoroethanol (C17)
##STR00033##
[0175] The produce was isolated as a pale yellow oil (5.2 g, 60%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62-7,64 (d, 1H),
7.52-7.54 (m, 1H), 7.29-7.33 (t, 1H), 5.6-5.76 (m, 1H), 2.7 (s,
1H); ESIMS m/z 244 ([M].sup.+).
1-(2,5-Dichlorophenyl)-2,2,2-trifluoroethanol (C19)
##STR00034##
[0177] The product was isolated as a yellow oil (4.1 g, 60%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68-7.7 (s, 1H),
7.3-7.37 (m, 2H), 5.51-5.6 (m, 1H), 2.7 (s, 1H); ESIMS m/z 244
([M].sup.+).
1-(3,5-Bis(trifluoromethyl)phenyl)-2,2,2-trifluoroethanol (C20)
##STR00035##
[0179] The product was isolated (3.8 g, 60%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.98 (m, 3H), 5.25 (m, 1H), 3.2 (br, 1H); ESIMS
m/z 312 ([M].sup.+).
2,2,2-Trifluora-1-(2,3,5-trichlorophenyl)ethanol (C21)
##STR00036##
[0181] The product was isolated as a white solid (4.0 g, 60%): mp
113-115.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62
(d, 1H), 7.50 (d, 1H), 5.60-5.70 (m, 1H), 2.75 (s, 1H); ESIMS m/z
278 ([M+]).
1-(3-Chloro-5-trifluoromethyI)phenyl)-2,2,2-trifluoroethanol
(C22)
##STR00037##
[0183] The product was isolated as a pale yellow oil (2.0 g, 50%):
NMR (400 MHz, CDCl.sub.3) .delta. 7.51 (m, 3H), 5.08 (m, 1H), 2.81
(s, 1H); ESIMS m/z 278 ([M].sup.+).
1-(3,5-Dichloro-4-methoxyphenyl)-2,2,2-trifluoroethanol (C23)
##STR00038##
[0185] The produce was isolated as an off white solid (0.8 g, 60%);
mp 92-95.degree. C.: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41
(s, 2H), 5.00 (m, 1H), 3.89 (s, 3H), 2.64 (in, 1H); ESIMS m/z 274
([M].sup.+).
[0186] The following compounds were made in accordance with the
procedures disclosed in Step 1 Method B of Example 1 above.
1-(3,5-Dibromophenyl)-2,2,2-trifluoroethanol (C24)
##STR00039##
[0188] The title molecule was isolated as a colorless liquid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.67 (s, 1H), 7.58 (s,
2H), 5.08-5.02 (m, 1H), 4.42 (bs, 1H); EIMS m/z 333.7 ([M].sup.+);
IR (thin film) 3417, 2966, 1128, 531 cm.sup.-1.
1-(4-Bromo-3,5-dichlorophenyl)-2,2,2-trifluoroethanol (C25)
##STR00040##
[0190] The product was isolated as a colorless liquid: .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 7.75 (s, 2H), 7.24 (d, J=6.0 Hz,
1H), 5.34-5.29 (m, 1H); EIMS m/z 321.88 ([M].sup.+); IR (thin film)
3420, 1706, 1267, 804, 679 cm.sup.-1.
1-(3,5-Dibromo-4-chlorophenyl)-2,2,2-trifluoroethanol (C26)
##STR00041##
[0192] The product was isolated as a pale yellow gum: .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 7.89 (s, 2H), 7.20 (d, J=6.0 Hz,
1H) 5.34-5.30 (m, 1H); EIMS m/z 366.0 ([M].sup.+).
[0193] The following compounds were made in accordance with the
procedures disclosed in Step 2 of Example 1.
5-(1-Bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (C27)
##STR00042##
[0195] The product was isolated as a colorless oil (0.300 g, 60%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.59 (s, 2H), 5.00 (m,
1H); EIMS m/z 340 ([M].sup.+).
5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-fluorobenzene
(C28)
##STR00043##
[0197] The product was isolated as a colorless oil (0.320 g, 60%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.45 (s, 2H), 5.00 (m,
1H); EIMS m/z 324 ([M].sup.+).
4-(1-Bromo-2,2,2-trifluoroethyl)-1,2-dichlorabenzene (C29)
##STR00044##
[0199] The product was isolated as a colorless oil (0.300 g, 60%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.63 (s, 1H), 7.51 (m,
1H), 7.35 (m, 1H), 5.01 (m, 1H); EMS m/z 306 ([M].sup.+).
1-(1-Bromo-2,2,2-trifluoroethyl)-3-chlorobenzene (C30)
##STR00045##
[0201] The produce was isolated (0.14 g, 22%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.50 (br s, 1H), 7,42-7.35 (m, 3H), 5.07
(m, 1H).
(1-Bromo-2,2,2-trifluoroethyl)benzene (C31)
##STR00046##
[0203] The product was isolated as a liquid (8.0 g, 60%): .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (m, 2H), 7.40 (m, 3H), 5.00
(q, J=7.5 Hz, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-dimethylbenzene (C32)
##STR00047##
[0205] The product was isolated and carried on crude (3.0 g,
51%).
1-(1-Bromo-2,2,2-trifluoroethyl)-2,4-dichlorobenzene (C33)
##STR00048##
[0207] The product was isolated (3.2 g, 50%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7,62-7.72 (m, 1H), 7.4-7.42 (m, 1H), 7.3-7.38
(m, 1H), 5.7-5.8 (m, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-2,3-dichlorobenzene (C34)
##STR00049##
[0209] The product was isolated as an oil (8.7 g, 60%): .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.62-7.71 (m, 1H), 7.44-7.52 (m, 1H),
7.27-7.3 (s, 1H), 5.81-5.91 (m, 1H).
2-(1-Bromo-2,2,2-trifluoroethyl)-1,4-dichlorobenzene (C35)
##STR00050##
[0211] The product was isolated (3.0 g, 60%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.7-7.78 (m, 1H), 7.3-7.4 (m, 2H), 5.7-5.8 (m,
1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-bis(trifluoromethyl)benzene
(C36)
##STR00051##
[0213] The product was prepared and carried on crude.
1-(1-Bromo-2,2,2-trifluoroethyl)-2,3,5-trichlorobenzene (C37)
##STR00052##
[0215] The product was isolated (2.9 g, 60%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.70 (d, 1H), 7.50 (d, 1H), 5.72-5.82 (m,
1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-3-chloro-5-(trifluoromethyl)benzene
(C38)
##STR00053##
[0217] The product was isolated as an oil (2.0 g, 40%): ESIMS m/z
342 ([M].sup.+).
5-(1-Bromo-2,2,2-trifluoroethyl)-1,3-dichloro-2-methoxybenzene
(C39)
##STR00054##
[0219] The product was isolated as a colorless liquid (0.6 g,
57%).
1-(1-Bromo-2,2,2-trifluoroethyl)-3,5-difluorobenzene (C40)
##STR00055##
[0221] The product was isolated (3.2 g, 50%); .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.05 (m, 2H), 6.86 (m, 1H), 5.03 (q, J=7.4 Hz,
1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-4-chlorobenzene (C41)
##STR00056##
[0223] The product was isolated (3.0 g, 46%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.45 (d, J=8.2 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H),
5.10 (q, J=7.2 Hz, 1H).
1-(1-Bromo-2,2,2-trifluoroethyl)-4-methoxybenzene (C42)
##STR00057##
[0225] The product was isolated (3.8 g, 62%).
1-(1-Bromo-2,2,2-trifluoroethyl)-4-fluorobenzene (C43)
##STR00058##
[0227] The produce was prepared and carried on as crude
intermediate.
1-(1-Bromo-2,2,2-trifluoroethyl)-4-methylbenzene (C44)
##STR00059##
[0229] The product was isolated (3.0 g, 45%).
1-(1-Bromo-2,2,2-trifluoroethyl)-3-fluorobenzene (C45)
##STR00060##
[0231] The product was isolated (2.0 g, 61%).
1-(1-Bromo-2,2,2-trifluoroethyl)-2-fluorobenzene (C46)
##STR00061##
[0233] The product was isolated (2.0 g, 61%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.61 (m, 1H), 7.40 (m, 1H), 7.23 (m, 1H), 7.10
(m, 1H), 5.40 (m, 1H); GCMS m/z 255 ([M].sup.+).
1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)benzene (C47)
##STR00062##
[0235] The title molecule was isolated as a colorless liquid:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta.7.71 (s, 1H), 7,59 (s,
2H), 5.04-4.97 (m, 1H); EIMS m/z 394.6 ([M].sup.+); IR (thin film)
1114, 535 cm.sup.-1.
2-6Bromo-5-(1-bromo-2,2,2-trifluoroethyl)-1,3-dichlorobenzene
(C48)
##STR00063##
[0237] The title molecule was isolated as a colorless liquid:
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.79 (s, 2H), 6.27-6.21
(m, 1H); EIMS m/z 383.9 ([M].sup.+); IR (thin film) 2924, 1114,
749, 534 cm.sup.-1.
1,3-Dibromo-5-(1-bromo-2,2,2-trifluoroethyl)-2-chlorobenzene
(C49)
##STR00064##
[0239] The title molecule was isolated as a pale yellow liquid:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.97 (s, 2H), 6.27-6.19
(m, 1H); EIMS m/z 428.0 ([M].sup.+).
Example 3
Preparation of ethyl 2-methyl-4-vinylbenzoate (C52)
##STR00065##
[0241] Step 1. 4-Formyl-2-methylbenzoic acid (C50). To a stirred
solution of 4-bromo-2-methylbenzoic acid (10.0 g, 46.4 mmol) in dry
tetrahydrofuran (360 mL) at -78.degree. C. was added n-butyllithium
(1.6 M solution in hexane, 58.2 mL, 93.0 mmol) and
dimethylformamide (8 mL). The reaction mixture was stirred at
-78.degree. C. for 1 hour then was warmed to 25.degree. C. and
stirred for 1 hour. The reaction mixture was quenched with
hydrochloric acid (1 N) and extracted with ethyl acetate. The
combined ethyl acetate extracts were washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure. The
residue was washed with n-hexane to afford the title compound as a
solid (3.00 g, 40%): mp 196-198.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d5) .delta. 13.32 (br s, 1H), 10.05 (s, 1H), 7.98 (m, 1H),
7.84 (m, 2H), 2.61 (s, 3H); ESIMS m/z 163 ([M-H].sup.-).
[0242] Step 2. Ethyl4-formyl-2-methylbenzoate (C51). To a stirred
solution of 4-formyl-2-methylbenzoic acid (C50) (3.00 g, 18.2 mmol)
in ethyl alcohol (30 mL) was added sulfuric acid (2 mL), and the
reaction mixture was heated at 80.degree. C. for 18 hours. The
reaction mixture was cooled to 25.degree. C. and concentrated under
reduced pressure. The residue was diluted with ethyl acetate and
washed with water. The combined ethyl acetate extracts were washed
with brine, dried over sodium sulfate and concentrated under
reduced pressure to afford the title compound as a solid (2.80 g,
80%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 10.05 (s, 1H), 8.04
(m, 1H), 7.75 (m, 2H), 4.43 (m, 2H), 2.65 (s, 3H), 1.42 (m,
3H).
[0243] Step 3. Ethyl2-methyl-4-vinylbenzoate (C52). To a stirred
solution of ethyl 4-formyl-2-methylbenzoate (C51) (2.8 g, 4.0 mmol)
in 1,4-dioxane (20 mL) were added potassium carbonate (3.0 g, 22
mmol) and methyltriphenyl phosphonium bromide (7.8 g, 22 mmol) at
25.degree. C. Then the reaction mixture was heated at 100.degree.
C. for 18 hours. After the reaction was deemed complete by thin
layer chromatography, the reaction mixture was cooled to 25.degree.
C. and filtered, and the filtrate was concentrated under reduced
pressure. The crude compound was purified by flash column
chromatography using 25-30% ethyl acetate/hexanes as eluent to
afford the title compound as a solid (2.0 g, 72%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.86 (m, 1H), 7.27 (m, 2H), 6.68 (dd,
J=17.6, 10.8 Hz , 1H), 5.84 (d, J=17.6 Hz, 1H), 5.39 (d, J=10.8 Hz,
1H), 4.39 (m, 2H), 2.60 (s, 3H), 1.40 (m, 3H); ESIMS m/z 191
([M-H].sup.-); IR (thin film) 2980, 1716, 1257 cm.sup.-1.
Example 4
Preparation of tert-butyl 2-chloro-4-vinylbenzoate (C54)
##STR00066##
[0245] Step 1. tert-Butyl 4-bromo-2-chlorobenzoate (C53). To a
stirred solution of 4-bromo-2-chlorobenzoic acid (5.00 g, 21.4
mmol) in tetrahydrofuran (30 mL) was added di-tert-butyl
dicarbonate (25.5 g, 25.6 mmol), triethylamine (3.20 g, 32.0 mmol)
and 4-dimethylaminopyridine (0.780 g, 6.40 mmol), and the reaction
mixture was stirred at 25.degree. C. for 18 hours. The reaction
mixture was diluted with ethyl acetate and washed with water. The
combined organic layer was washed with brine, dried over sodium
sulfate, and concentrated under reduced pressure. The residue was
purified by flash column chromatography using 2-3% ethyl
acetate/hexanes as eluent to afford the title compound as a liquid
(3.20 g, 51%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.62 (m,
2H), 7.44 (d, J=8.4 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 290
([M].sup.+); IR(thin film) 1728 cm.sup.-1.
[0246] Step 2. tert-Butyl 2-chloro-4-vinylbenzoate (C54). To a
stirred solution of tert-butyl 4-bromo-2-chlorobenzoate (C53) (1.6
g, 5.5 mmol) in toluene (20 mL) was added
tetrakis(triphenylphospine)palladium(0) (0.31 mg, 0.27 mmol),
potassium carbonate (2.3 g, 17 mmol) and vinylboronic anhydride
pyridine complex (2.0 g, 8.3 mmol) and the reaction mixture was
heated to reflux for 16 hours. The reaction mixture was filtered,
the filtrate was washed with water and brine, dried over sodium
sulfate, and concentrated under reduced pressure. Purification by
flash column chromatography using 5-6% ethyl acetate/hexanes as
eluent afforded the title compound as a liquid (0.60 g, 46%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.72 (d, J=8.1 Hz, 1H),
7.44 (m, 1H), 7.31 (d, J=8.0 Hz, 1H), 6.69 (dd, J=17.6, 10.8 Hz ,
1H) , 5.85 (d, J=17.6 Hz, 1H), 5.40 (d, J=10.8 Hz, 1H), 1.60 (s,
9H); ESIMS m/z 239 ([M+H].sup.+); IR (thin film) 2931, 1725, 1134
cm.sup.-1.
[0247] The following compounds were made in accordance with the
procedures disclosed in Step 1 of Example 4.
tert-Butyl 2-bromo-4-iodobenzoate (C55)
##STR00067##
[0249] The product was isolated as a colorless oil (1.2 g, 50%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.01 (s, 1H), 7.68 (d,
J=8.4 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 1.59 (s, 9H); ESIMS m/z 382
([M+H].sup.+); IR(thin film) 1727 cm.sup.-1.
tert-Butyl 4-bromo-2-(trifluoromethyl)benzoate(C56)
##STR00068##
[0251] The product was isolated as a colorless oil (1 g, 52%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (s, 1H), 7.73 (d,
J=8.4 Hz, 1H), 7.62 (d, J=8.4 Hz, 1H), 1.57 (s, 9H); ESIMS m/z 324
([M+H].sup.+); IR (thin film) 1725 cm.sup.-1.
[0252] The following compounds were made in accordance with the
procedures disclosed in Step 2 of Example 4.
tert-Butyl 2-bromo-4-vinylbenzoate (C57)
##STR00069##
[0254] The product was isolated as a colorless oil (1 g, 52%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.68 (m, 2H), 7.36 (d,
J=8.0 Hz, 1H), 6.68 (dd, J =:17.6, 10.8 Hz , 1H), 5.84 (d, J=17.6
Hz, 1H), 5.39 (d, J=10.8 Hz, 1H), 1.60 (s, 9H); ESIMS m/z 282
([M+H].sup.+); IR (thin film) 2978, 1724, 1130 cm.sup.-1.
tert-Butyl 2-(trifluoromethyl)-4-vinylbenzoate (C58)
##STR00070##
[0256] The product was isoiated as a colorless oil (1.2 g, 50%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.71 (d, J=6.4 Hz, 2H),
7.59 (d, J=7.6 Hz, 1H), 6.77 (dd, J=17.6, 10.8 Hz , 1H), 5.89 (d,
J=17.6 Hz, 1H), 5.44 (d, J=10.8 Hz, 1H), 1.58 (s, 9H); ESIMS m/z
272 ([M+H].sup.+); IR (thin film) 2982, 1727, 1159 cm.sup.-1.
Example 5
Preparation of tert-butyl 2-cyano-4-vinylbenzoate (C59)
##STR00071##
[0258] To a stirred solution of tert-butyl 2-bromo-4-vinylbenzoate
(C57) (0.5 g, 1.8 mmol) in dimethylformamide (20 mL) was added
copper(I) cyanide (0.23 g, 2.7 mmol), and the reaction mixture was
heated at 140.degree. C. for 3 hours. The reaction mixture was
cooled to 25.degree. C., diluted with water, and extracted with
ethyl acetate. The combined organic layer was washed with brine,
dried over sodium sulfate, and concentrated under reduced pressure.
The residue was purified by flash column chromatography using 15%
ethyl acetate; hexanes as eluent to afford the title compound as a
white solid (0.30 g, 72%): mp 51-53.degree. C.; .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 8.03 (s, 1H), 7.77 (s, 1H), 7.64 (d, J=8.4
Hz, 1H), 6.75 (dd, J=17.6, 10.8 Hz , 1H), 5.93 (d, J=17.6 Hz, 1H),
5.51 (d, J=10.8 Hz, 1H), 1.65 (s, 9H); ESIMS m/z 230 ([M+H].sup.+);
IR (thin film) 2370, 1709, 1142 cm.sup.-1.
Example 6
Preparation of ethyl 2-bromo-4-iodobenzoate (C60)
##STR00072##
[0260] To a stirred solution of 4-iodo-2-bromobenzoic acid (5.00 g,
15.3 mmol) in ethyl alcohol (100 mL) was added sulfuric acid (5
mL), and the reaction mixture was heated at 80.degree. C. For 18
hours. The reaction mixture was cooled to 25.degree. C. and
concentrated under reduced pressure. The residue was diluted with
ethyl acetate (2.times.100 mL) and washed with water (100 mL). The
combined ethyl acetate extracts were washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure to afford
the compound as a pale yellow solid (5.00 g, 92%): NMR (400 MHz,
DMSO-d.sub.6) .delta. 8.04 (d, J=1.2 Hz, 1H), 7.71 (d, J=7.6 Hz,
1H), 7.51 (d, J=8.4 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 1.41 (t, J=7.2
Hz, 3H).
[0261] The following compounds were made in accordance with the
procedures disclosed in Example 6.
Ethyl4-bromo-2-chlorobenzoate (C61)
##STR00073##
[0263] The title compound was isolated as an off-white solid (2.0
g, 80%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.25 (d, J=1.2
Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 4.65 (q,
J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H).
Ethyl4-bromo-2-methylbenzoate (C62)
##STR00074##
[0265] The title compound was isolated as a pale yellow liquid (3.0
g, 83%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.4
Hz, 1H), 7.41 (s, 1H), 7.39 (d, J=8.4 Hz, 1H), 4.42 (q, J=7.2 Hz,
2H), 2.60 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ESIMS m/z 229
([M+H].sup.30 ); IR (thin film) 1725 cm.sup.-1.
Ethyl4-bromo-2-fluorolbenzoate (C63)
##STR00075##
[0267] The title compound was isolated as a colorless liquid (9.0
g, 79%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.84 (t, J=8.4
Hz, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.58 (d, J=1.6 Hz, 1H), 4.34 (q,
J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); ESIMS m/z 247 ([M+H].sup.+),
IR (thin film) 1734 cm.sup.-1.
Example 7
Preparation of ethyl 4-bromo-2-ethylbenzoate (C64)
##STR00076##
[0269] To a stirred solution of 4-bromo-2-fluorobenzoic acid (2.0
g, 9.2 mmol) in tetrahydrofuran (16 mL), was added ethyl magnesium
bromide (1.0 M in tetrahydrofuran, 32 mL, 32.0 mmol) dropwise at
0.degree. C. and the resultant reaction mixture was stirred at
ambient temperature for 18 hours. The reaction mixture was quenched
with hydrochloric acid (2 N) and extracted with ethyl acetate. The
combined ethyl acetate layer was dried over anhydrous sodium
sulfate and concentrated under reduced pressure to afford crude
4-bromo-2-ethylbenzoic acid as a colorless liquid that was used in
the next step without purification (0.40 g): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.64 (d, J=8.4 Hz, 1H), 7.47 (m, 1H), 7.43 (m,
1H), 2.95 (q, J=4.0 Hz, 2H), 1.32 (t, J=4.0 Hz, 3H); ESIMS m/z 229
([M+H].sup.+).
[0270] Alternatively, the title compound was synthesized from
4-bromo-2-ethylbenzoic acid in accordance to the procedure in
Example 6 and isolated as a colorless liquid (0.15 g, 68%): .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 7.90 (d, J=8.4 Hz, 1H), 7.47
(m, 2H), 4.40 (q, J=7.2 Hz, 2H), 3.06 (q, J=7.6 Hz, 2H), 1.42 (t,
J=7.2 Hz, 3H), 1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 227 ([M-H].sup.-);
IR (thin film) 3443, 1686, 568 cm.sup.-1.
Example 8
Preparation of ethyl 2-bromo-4-vinylbenzoate (C65)
##STR00077##
[0272] To a stirred solution of ethyl 2-bromo-4-iodobenzoate (C60)
(5.00 g, 14.3 mmol) in tetrahydrofuran/water (100 mL, 9:1) was
added potassium vinyltrifluoroborate (1.89 g, 14.3 mmol), cesium
carbonate (18.3 g, 56.1 mmol), and triphenylphosphine (0.220 g,
0.850 mmol). The reaction mixture was degassed with argon for 20
minutes, then charged with dichloropaliadium(II) (0.0500 g,0.280
mmol). The reaction mixture was heated to reflux for 16 hours. The
reaction mixture was cooled to ambient temperature and filtered
through a Celite.RTM.) bed arid washed with ethyl acetate. The
filtrate was again extracted with ethyl acetate arid the combined
organic layers washed with water and brine, dried over sodium
sulfate, and concentrated under reduced pressure to afford crude
compound. The crude compound was purified by flash column
chromatography using 2% ethyl acetate/petroleum ether as eluent to
afford the title compound as a light brown gummy material (2.00 g,
56%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.78 (d, J=8.4 Hz,
1H), 7.71 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 6.69 (dd,
J=17.6, 10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz,
1H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=3.6 Hz, 3H); ESIMS m/z 255
([M+H].sup.+); IR (thin film) 1729 cm.sup.-1.
[0273] The following compounds were made in accordance with the
procedures disclosed in Example 8.
Ethyl2-methyl-4-vinylbenzoate (C66)
##STR00078##
[0275] The title compound was isolated as a colorless liquid (0.8
g, 80%); .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.89 (d, J=8.4
Hz, 1H), 7.27 (m, 2H), 6.79 (dd, J=17.6, 10.8 Hz, 1H), 5.86 (d,
J=17.6 Hz, 1H), 5.42 (d, J=11.2 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H),
2.60 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 191 ([M+H].sup.+);
IR (thin film) 1717, 1257 cm.sup.-1.
Ethyl2-fluoro-4-vinylbenzoate (C67)
##STR00079##
[0277] The title compound was isolated as a pale yellow liquid (2.0
g, 50%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 7.87 (t, J=8.0
Hz, 1H), 7.51(d, J=16.0 Hz, 1H), 7.48 (d, J =16.0 Hz, 1H), 6.82
(dd, J=17.6, 10.8 Hz, 1H), 6.09 (d, J=17.6 Hz, 1H), 5.50 (d, J
=10.8 Hz, 1H), 4.35 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H);
ESIMS m/z 195 ([M+H]'.sup.+); IR (thin film) 1728 cm.sup.-1.
Example 9
Preparation of ethyl 2-chloro-4-vinylbenzoate (C68)
##STR00080##
[0279] To a stirred solution of ethyl 2-chloro-4-bromobenzoate
(C61) (2.00 g, 7.63 mmol) in dimethylsulfoxide (20 mL) was added
potassium vinyltrifluoroborate (3.06 g, 22.9 mmol), and potassium
carbonate (3.16 g, 22.9 mmol). The reaction mixture was degassed
with argon for 30 minutes. Bistriphenylphosphine(diphenylphosphino
ferrocene)paliadium(II) dichloride (0.270 g, 0.380 mmol) was added
and the reaction mixture was heated to 80.degree. C. for 1 hour.
The reaction mixture was diluted with water (100 mL), extracted
with ethyl acetate (2.times.50 mL), washed with brine, dried over
sodium sulfate, and concentrated under reduced pressure to obtain
the compound as brown gummy material (1.10 g, 69%); .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.81 (d, J=8.4 Hz, 1H), 7.46 (s, 1H),
7.33 (d, J=8.4 Hz, 1H), 6.70 (dd, J=17.6, 11.2 Hz, 1H), 5.87 (d,
j=17,6 Hz, 1H), 5.42 (d, J=10.8 Hz, 1H), 4.41 (q, J=7.2 Hz,2H),
1.43 (t, J=7.2 Hz, 3H); ESIMS m/z 211 ([M+H].sup.+); IR (thin film)
1729, 886 cm.sup.-1.
[0280] The following compounds were made in accordance with the
procedures disclosed in Example 9.
Ethyl2-ethyl-4-vinylbenzoate (C69)
##STR00081##
[0282] The title compound was isolated as a colorless liquid (1.0
g, 66%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85 (m, 1H),
7.29 (m, 2H), 6.76 (d, J=10.8 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H),
5.36 (d, J=10.5 Hz, 1H), 4.41 (q, J=7.2 Hz, 2H), 3.10 (q, J=7.2 Hz,
2H), 1.40 (t, J=7.2 Hz, 3H), 1.30 (t, J=7.2 Hz, 3H); ESIMS m/z 205
([M+H].sup.+); IR (thin film) 1720, 1607, 1263 cm.sup.-1.
Methyl 2-methoxy-4-vinylbenzoate (C70)
##STR00082##
[0284] The title compound was isolated as a pale yellow liquid (1.2
g, 75%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.0
Hz, 1H), 7.04 (d, J=1.2 Hz, 1H), 6.97 (s, 1H), 6.74 (dd, J=11.2,
11.2 Hz, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.39 (d, J=17.6 Hz, 1H) 3.93
(s, 3H), 3.91 (s, 3H); ESIMS m/z 193 ([M+H].sup.+); IR (thin fiim)
1732 cm.sup.-1,
Example 10
Preparation of (E)-ethyl
4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate
(C71)
##STR00083##
[0286] To a stirred solution of ethyl 2-methyl-4-vinylbenzoate
(C66) (2.00 g, 10.5 mmol) in 1,2-dichlorobenzene (25 mL) were added
1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichlorobenzene (C2) (6.44 g,
21.0 mmol), copper(I) chloride (0.208 g, 21.0 mmol) and
2,2'-bipyridyl (0.650 g, 4.10 mmol). The reaction mixture was
degassed with argon for 30 minutes and then stirred at 180.degree.
C. for 24 hours. After the reaction was deemed complete by thin
layer chromatography, the reaction mixture was cooled to 25.degree.
C. and filtered, and the filtrate was concentrated under reduced
pressure. Purification by flash column chromatography using 25-30%
ethyl acetate/petroleum ether as eluent afforded the title compound
as a solid (1.70 g, 40%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.91 (d, J=8.0 Hz, 1H), 7.37 (m, 1H), 7.27-7.24 (m, 4H), 6.59 (d,
J=16.0 Hz, 1H), 6.59 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz,
2H), 4.08 (m, 1H), 2.62 (s, 3H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z
415 ([M-H].sup.-); IR (thin film) 1717, 1255, 1114 cm.sup.-1.
[0287] The following compounds were made in accordance with the
procedures disclosed in Example 10.
(E)-Ethyl4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(triflu-
oromethyl)-benzoate (C72)
##STR00084##
[0289] The product was isolated as a pale brown gummy liquid (0.500
g, 40%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.0
Hz, 1H), 7.71 (m, 1H), 7.61 (d, J=7.6 Hz, 1H),7.42 (s, 2H), 6.70
(d, J=16.0 Hz, 1H), 6.57 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.2
Hz, 2H), 4.19 (m, 1H), 1.40 (t, J=7.6 Hz, 3H); ESIMS m/z 503
([M-H].sup.-); IR (thin film) 1730, 1201, 1120, 749 cm.sup.-1.
(E)-Ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenz-
oate (C73)
##STR00085##
[0291] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.38 (s, 1H), 7.26
(s, 3H), 7.21 (d, J=8.4 Hz, 1H), 7.16 (d, J=11.6 Hz, 1H), 6.59 (d,
J=16.0 Hz, 1H), 6.47 (dd, J=,16.0, 8.0 Hz, 1H), 4.41 (q, J=6.8 Hz,
2H), 4.18 (m, 1H), 1.41 (t, J=6.8 Hz, 3H); ESIMS m/z 419
([M-H].sup.-); IR (thin film) 1723, 1115, 802 cm.sup.-1.
(E)-Ethyl4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-bromobenzo-
ate (C74)
##STR00086##
[0293] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.0 Hz,
1H), 7.67 (s, 1H), 7.38 (m, 2H), 7.26 (m, 2H), 6.56 (d, J=16.0 Hz,
1H), 6.45 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q, J=7.2 Hz, 2H), 4.39
(m, 1H), 1.42 (t, J=7.2 Hz, 3H); ESIMS m/z 481 ([M-H].sup.-); IR
(thin film) 1727, 1114, 801, 685 cm.sup.-1.
(E)-Ethyl2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)
but-1-enyl)benzoate (C75)
##STR00087##
[0295] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.0 Hz,
1H), 7.67 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.36 (d, J=1.6 Hz, 1H),
6.56 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0, 7.6 Hz, 1H), 4.42 (q,
J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z 515
([M-H].sup.-); IR (thin film) 1726, 1115, 808, 620 cm.sup.-1.
(E)-Ethyl2-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)
but-1-enyl)benzoate (C76)
##STR00088##
[0297] The title compound was isolated as a light brown gummy
material: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.90 (d, J=8.8
Hz, 1H), 7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d,
J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz,
2H), 4.19 (m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H).
(E)-Ethyl2-chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)
but-1-enyl)benzoate (C77)
##STR00089##
[0299] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.87 (d, J=8.0 Hz,
1H), 7.46 (d, J=1.6 Hz, 1H), 7.40 (s, 2H), 7.31 (d, J=1.6 Hz, 1H),
6.57 (d, J=16.0 Hz, 1H), 6.44 (dd, J=16.0 Hz., 8.0 Hz, 1H), 4.42
(q, J=6.8 Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=6.8 Hz, 3H); ESIMS m/z
471 ([M-H].sup.-); IR (thin film) 1726, 1115, 809, 3072
cm.sup.-1.
(E)-Ethyl4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(triflu-
oromethyl)benzoate (C78)
##STR00090##
[0301] The title compound was isolated as a pale brown liquid (1.0
g, 46,3%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.0
Hz, 1H), 7.71 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.41 (s, 2H) 6.65
(d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 8.0 Hz, 1H), 4.42 (q, J=7.6
Hz, 2H), 4.15 (m, 1H), 1.42 (t, J=7.6 Hz, 3H); ESIMS m/z 503
([M-1-1].sup.-); IR (thin film) 1730, 1202, 1120, 750
cm.sup.-1.
(E)-Ethyl2-chloro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1--
enyl)benzoate (C79)
##STR00091##
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (d, J=6.0 Hz,
1H), 7.46 (d, J=1.8 Hz, 2H), 7.34 (m, 1H), 7.24 (m, 1H), 6.57 (d,
J=16.2 Hz, 1H), 6.45 (dd, J=16.2, 7.2 Hz, 1H), 4.43 (q, J=7.2 Hz,
2H), 4.13 (m, 1H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 455
([M/H].sup.+); IR (thin film) 1728, 1115, 817 cm.sup.-1.
(E)-Ethyl2-fluoro-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1--
enyl)benzoate (C80)
##STR00092##
[0305] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.93 (t, J=7.6 Hz,
1H), 7.34 (d, J=5.6 Hz, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.16 (d,
J=11.6 Hz, 1H), 6.59 (d, J=16.0 Hz, 1H), 6.49 (dd, J=16.0, 7.6 Hz,
1H), 4.42 (q, J=7.6 Hz, 2H), 4.13 (m, 1H), 1.41 (t, J=7.6 Hz, 3H);
ESIMS m/z 436.81([M-H].sup.-); IR (thin fiim) 1725 cm.sup.-1.
(E)-Ethyl2-bramo-4-(3-(3,5-dichloro-4-fluoraphenyl)-4,4,4-trifluorobut-1-e-
nyl)benzoate (C81)
##STR00093##
[0307] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.94 (d, J=8.0 Hz,
1H), 7.67 (s, 1H), 7.36 (m, 3H), 6.56 (d, J=15.6 Hz, 1H), 6.44 (dd,
J=15.6, 8.0 Hz, 1H), 4.42 (q, J=6.8 Hz, 2H), 4.10 (m, 1H), 1.42 (t,
J=6.8 Hz, 3H); ESIMS m/z 499 ([M-H].sup.-); IR (thin film) 1726,
1114, 820, 623 cm.sup.-1.
(E)-Ethyl2-methyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1--
enyl)benzoate (C82)
##STR00094##
[0309] The title compound was isolated as a brown semi-solid:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.90 (d, J=8.8 Hz, 1H),
7.34 (d, J=6.0 Hz, 2H), 7.25 (d, J=7.2 Hz, 2H), 6.59 (d, J=16.0 Hz,
1H), 6,42 (dd, J=16.0 Hz, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 4.19
(m, 1H), 2.63 (s, 3H), 1.41 (t, J=7.2 Hz, 3H); ESIMS m/z 433
([M-H].sup.-); IR (thin film) 1715 cm.sup.-1.
(E)-Methyl2-methoxy-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut--
1-enyl)benzoate (C83)
##STR00095##
[0311] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7,80 (d, J=8.4 Hz,
1H), 7.35 (d, J=6.0 Hz, 2H), 7.03 (d, J=1.2 Hz, 1H), 6.92 (s, 1H),
6.59 (d, J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.13 (m,
1H), 3.93 (s, 3H), 3.88 (s, 3H); ESIMS m/z 437 ([M+H].sup.+); IR
(thin film) 1724 cm.sup.-1.
(E)-Ethyl2-ethyl-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-e-
nyl)benzoate (C84)
##STR00096##
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.85 (d, J=8.0 Hz,
1H), 7.35 (d, J=9.6 Hz, 2H), 7.26 (m, 1H), 7.24 (m, 1H), 6.60 (d,
J=15.6 Hz, 1H), 6.42 (dd, J=15.6, 8.0 Hz, 1H), 4.38 (q, J=7.2 Hz,
2H), 4.14 (m, 1H), 3.01 (q, J=7.6 Hz 2H), 1.41 (t, J=7.2 Hz, 3H),
1.26 (t, J=7.6 Hz, 3H); ESIMS m/z 447 ([M-H].sup.-); IR (thin film)
1715, 1115, 817 cm.sup.-1.
Example 11
Preparation of
(E)-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyI)-2-methylbenzoic
acid (C85)
##STR00097##
[0315] To a stirred solution of (E)-ethyl
4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoate
(C71) (1.7 g, 4.0 mmol) in 1,4-dioxane (10 mL) was added
hydrochloric acid (11 N, 30 mL), and the reaction mixture was
heated at 100.degree. C. for 48 hours. The reaction mixture was
cooled to 25.degree. C. and concentrated under reduced pressure.
The residue was diluted with water and extracted with chloroform.
The combined organic layer was dried over sodium sulfate and
concentrated under reduced pressure. The crude compound was washed
with n-hexane to afford the title compound as a white solid (0.70
g, 50%): mp 142-143.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 12.62 (br s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.66 (s, 3H),
7.52-7.44 (m, 2H), 6.89 (dd, J=16.0, 8.0 Hz, 1H), 6.78-6.74 (d,
J=16.0 Hz, 1H), 4.84 (m, 1H), 2.50 (s, 3H); ESIMS m/z 387
([M-H].sup.-); IR (thin flim) 3448, 1701, 1109, 777 cm.sup.-1.
[0316] The following compounds were made in accordance with the
procedures disclosed in Example 11.
(E)-2-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoi-
c acid (C86)
##STR00098##
[0318] The product was isolated as a pale brown gummy liquid (1 g,
46%): .sup.1H NMR (400 MHz, CDCl3) .delta. 7.97 (d, J=8.0 Hz, 1H),
7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68 (d, J=16.0 Hz, 1H),
6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H), 2.50 (s, 3H); ESIMS
m/z 423 ([M-H].sup.-).
(E)-2-Chloro-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoi-
c acid (C87)
##STR00099##
[0320] The produce was isolated as an off-white semi-solid (1 g,
45%): .sup.1H NMR (400 MHz, CDCl3) .delta. 7.99 (d, J=8.4 Hz, 1H),
7.50 (m, 1H), 7.40 (s, 1H), 7.36 (m, 2H), 6.59 (d, J=15.6 Hz, 1H),
6.48 (dd, J=15.6, 7.6 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 443
([M-H].sup.-); IR (thin film) 3472, 1704, 1113, 808 cm.sup.-1.
(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic
acid (C88)
##STR00100##
[0322] The product was isolated as a brown solid (1 g, 45%): mp
70-71.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.99
(d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.40 (m, 3H), 6.58 (d, J=16.0 Hz,
1H), 6.48 (dd, J=16,0, 8.0 Hz, 1H), 4.14 (m, 1H); ESIMS m/z 485
([M-H].sup.-); IR (thin film) 3468, 1700 cm.sup.-1.
(E)-2-Cyano-4-(4,4,4-trifluora-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic
acid (C89)
##STR00101##
[0324] The product was isoated as an off-white solid (0.500 g,
45%): mp 100-101.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.90 (s, 1H), 7.85 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.0 Hz,
1H), 7.65 (br s, 1H), 7.42 (s, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58
(dd, J=16.0, 8.0 Hz, 1H), 4.19 (m, 1H); ESIMS m/z 432
([M-H].sup.-).
E)-4-(3-(3,4-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methylbenzoic
acid (C90)
##STR00102##
[0326] The product was isolated as a pale brown liquid (0.500 g,
46%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.03 (m, 1H), 7.49
(m, 2H), 7.29 (m, 1H), 7.22 (m, 2H), 6.73 (d, J=16.0 Hz, 1H), 6.58
(dd, J=16.0, 7.8 Hz, 1H), 4.16 (m, 1H), 2.64 (s, 3H); ESIMS m/z 387
([M-H].sup.-); IR (thin film) 3428, 1690, 1113, 780 cm.sup.-1.
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-
benzoic acid (C91)
##STR00103##
[0328] The product was isolated as a white solid (500 mg, 50%): mp
91-93.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.02
(d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H), 7.30 (m, 3H), 6.61 (d,
J=16.0 Hz, 1H), 6.48 (dd, J=16.0, 8.0 Hz, 1H), 4.13 (m, 1H), 2.65
(s, 3H); ESIMS m/z 407 ([M-H].sup.-).
(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluorome-
thyl)benzoic acid (C92)
##STR00104##
[0330] The product was isolated as a white solid (500 mg, 45%): mp
142-143.degree. C.; .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.97
(d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 1H), 7.41 (s, 2H), 6.68
(d, J=16.0 Hz, 1H), 6.53 (dd, J=16.0, 8.0 Hz, 1H), 4.16 (m, 1H);
ESIMS m/z 475 ([M-H].sup.-).
(E)-2-Bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)benzoic
acid (C93)
##STR00105##
[0332] The title compound was isolated as a brown solid (0.8 g,
28%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 13.42 (br, 1H),
7.98 (d, J=1.5 Hz, 1H), 7.94 (m, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.65
(m, 1H), 7.06 (dd, J=15.9, 9.0 Hz, 1H), 6.80 (d, J=15.9 Hz, 1H),
4.91 (m, 1H); ESIMS m/z 485 ([M-H].sup.-); IR (thin film) 3469,
1700 cm.sup.-1.
(E)-2-Bromo-4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)b-
enzoic acid (C94)
##STR00106##
[0334] The title compound was isolated as a yellow liquid (0.3 g,
crude): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.79 (d, J=8.1
Hz, 1H), 7.67 (s, 1H), 7.34 (m, 3H), 6.56 (d, J=15.9 Hz, 1H), 6.45
(dd, J=15.9, 7.6 Hz, 1H), 4.43 (m, 1H); ESIMS m/z 471
([M-H].sup.-).
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-ethylb-
enzoic acid (C95)
##STR00107##
[0336] The title compound was isolated as a brown gummy material
(0.2 g, crude): `H NMR (300 MHz, DMSO-d5) .delta. 12.5 (br, 1H),
7.85 (d, J=6.3 Hz, 2H), 7.75 (d, J=8.1 Hz, 1H), 7.52 (m, 2H), 6.96
(dd, J=8.7, 8.7 Hz, 1H), 6.78 (d, J=15.6 Hz, 1H), 4.80 (m, 1H),
4.06 (q, J=7.2 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H); ESIMS m/z 419
([M-H].sup.-).
(E)-2-Chloro-4-(3-(3,5-dichloro-4-fluoraphenyl)-4,4,4-trifluorobut-1-enyl)-
benzoic acid (C96)
##STR00108##
[0338] The title compound was isolated as a yellow liquid (0.7 g,
95%): .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.85 (d, J=6.0 Hz,
1H), 7.46 (d, J=1.8 Hz, 1H), 7.41 (s, 3H), 6.57 (d, J=16.0 Hz, 1H),
6.45 (dd, J=16.0 Hz, 1H), 6.45 (dd, J=16.0, 8.0 Hz, 1H); 4.16 (m,
1H); ESIMS m/z 455 ([M+H].sup.+); IR (thin film) 1728, 1115, 817
cm.sup.-1.
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-methyl-
benzoic acid (C97)
##STR00109##
[0340] The title compound was isolated as a light brown gummy
material (0.7 g, 38%): mp 91-93.degree. C.; .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.02 (d, J=8.0 Hz, 1H), 7.35 (d, J=5.6 Hz, 1H),
7.30 (m, 3H), 6.10 (d, J=16.0 Hz, 1H), 6.46 (dd, J=16.0, 8.0 Hz,
1H), 4.03 (m, 1H), 2.65 (s, 3H); ESIMS m/z 407 ([M-H].sup.-).
(E)-4-(3-(3,5-Dichlorophenyl)-4,4,4-trifluorobut-1-enyl)-2-fluorobenzoic
acid (C98)
##STR00110##
[0342] The title compound was isolated as a light drown liquid (0.3
g, crude): ESIMS m/z 393 ([M-H].sup.-).
(E)-2-Bromo-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-enyl)benzoic
acid (C99)
##STR00111##
[0344] The title compound was isolated as a light brown liquid
(0.35 g, crude): ESIMS m/z 452 ([M-H].sup.-).
(E)-4-(3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-meth-
ylbenzoic acid (CA1)
##STR00112##
[0346] The title compound was isolated as a dark brown glass (0.900
g, 80%): .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.05 (d, J=8.1
Hz, 1H), 7.40 (s, 2H), 7.30 (dd, J=8.2, 1.7 Hz, 1H), 7.28 (d, J=1.6
Hz, 1H), 6.60 (d, J=15.8 Hz, 1H), 6.44 (dd, J=15.9, 8.0 Hz, 1H),
4.11 (p, J=8.6 Hz, 1H), 2.66 (s, 3H); .sup.19F NMR (471 MHz,
CDCl.sub.3) .delta. -68.63 (d, J=8.8 Hz); ESIMS m/z 466
([M-H].sup.-).
(E)-4-(3-(3,5-Dibromo-4-chlorophenyI)-4,4,4-trifluorobut-1-en-1-yl)-2-meth-
ylbenzoic acid (CA2)
##STR00113##
[0348] The title compound was isolated as a yellow glass (0.900 g,
68%): .sup.1H NMR (500 MHz, CDCl.sub.3) .delta. 8.05 (d, J=8.1 Hz,
1H), 7.62 (s, 2H), 7.30 (dd, J=8.3, 1.7 Hz, 1H), 7.28 (d, J=1.5 Hz,
1H), 6.60 (d, J=15.8 Hz, 1H), 6.43 (dd, J=15.9, 8.0 Hz, 1H), 4.10
(p, J=8.6 Hz, 1H), 2.67 (s, 3H); .sup.19F NMR (471 MHz, CDCl.sub.3)
.delta. -68.63 (d, J=8.8 Hz); ESIMS m/z 510 ([M-H].sup.-).
(E)-4-(3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methylbenzoic
acid (CA3)
##STR00114##
[0350] The title compound was isolated as a red solid (16.2 g,
82%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (d, J=8.1 Hz,
1H), 7.68 (t, J=1.7 Hz, 1H), 7.47 (d, J=1.7 Hz, 2H), 7.33-7.26 (m,
2H), 6.60 (d, J=15.8 Hz, 1H), 6.45 (dd, J=15.9, 8.0 Hz, 1H), 4.10
(p, J=8.7 Hz, 1H), 2.67 (s, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -68.54; ESIMS m/z 477 ([M-H].sup.-).
Example 12
Preparation of
(E)-4-(3-(35-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trifl-
uoromethoxy)benzoic acid (C101)
##STR00115##
[0352] Step 1. 2-(Trifluoromethoxy)-4-vinylbenzoic acid (C100): To
a stirred solution of 4-bromo-2-(trifluoromethoxy)benzoic acid
(1.00 g, 3.67 mmol) in dimethylsulfoxide (20 mL) was added
potassium vinyltrifluoroborate (1.47 g, 11.0 mmol), and potassium
carbonate (1.52 g, 11.0 mmol). The reaction mixture was degassed
with argon :for 30 minutes. Bistriphenylphosphine(diphenylphosphino
ferrocene)paliadium(II) dichloride (0.130 g, 0.180 mmol) was added
and the reaction mixture was heated to 80.degree. C. for 1 hour.
The reaction mixture was diluted with water (100 mL), extracted
with ethyl acetate (2.times.50 mL), washed with brine, and dried
over sodium sulfate. Concentration under reduced pressure furnished
the crude compound which was purified by flash column
chromatography to afford the product as pale yellow gummy material
(0.400 g, 47%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.05 (d,
J=8.1 Hz, 1H), 7.44 (d, J=1.8 Hz, 1H), 7.35 (s, 1H), 6.78 (dd,
J=17.4.1, 11.1 Hz, 1H), 5.92 (d, J =17.4 Hz, 1H), 5.51 (d, J=10.8
Hz, 1H); ESIMS m/z 233 ([M+H].sup.+).
[0353] Step 2.
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-enyl)-2-(trif-
luoromethoxy)benzoic acid (C101): To a stirred solution of
2-(trifluoromethoxy)-4-vinylbenzoic acid (0.356 g, 1.53 mmol) in 1N
methyl pyrrolidine (5.0 mL) was added
1-(1-bromo-2,2,2-trifluoroethyl)-3,5-dichloro 4-fluorobenzene (1.0
g, 3.07 mmol), copper(I) chloride (CuCl; 0.03 g, 0.307 mmol) and
2,2 bipyridyl (0.095 g, 0.614 mmol). The reaction mixture was
stirred at 150.degree. C. for 1 h. After the reaction was complete
by TLC, the reaction mixture was diluted with water (100 mL) and
extracted with ethyl acetate (2.times.50 mL). The combined organic
layers were washed with brine, dried over sodium sulfate and
concentrated under reduced pressure to obtain the crude compound
which was purified by flash column chromatography to afford the
product as pale yellow gummy material (0.3 g, 21%): .sup.1H NMR
(400 MHz, CDCI.sub.3) .delta. 8.08 (d, J=8.0 Hz, 1H), 7.45 (d,
J=1.6 Hz, 1H), 7.35 (s, 3H), 6.63 (d, J=16.0 Hz, 1H), 6.50 (dd,
J=16.0, 8.0 Hz, 1H), 4.15 (m, 1H); ESIMS m/z 474.81
([M-H].sup.-).
[0354] The following molecules were made in accordance with the
procedures disclosed in Step 2 in Example 12.
(E)-4-(3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromet-
hyl)benzoic add (C102)
##STR00116##
[0356] The title molecule was isolated as a brown solid: .sup.1H
NMR (300 MHz, DMSO-d.sub.6) .delta.13.5 (bs, 1H), 8.03 (s, 1H),
7.95-7.85 (m, 4H), 7.81 (d, J=7.8 Hz, 1H), 7.14 (dd, J=15.6, 9.6
Hz, 1H), 6.90 (d, J=15.9 Hz, 1H), 4.86-4.79 (m, 1H); ESIMS m/z 529
([M-H].sup.+); IR (thin film) 3437, 1707, 1153, 555 cm.sup.-1.
(E)-4-(3-(3,5-Dibroma-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tri-
fluoromethyl)benzoic acid (C103)
##STR00117##
[0358] Isolated as a brown gum: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta., 13.36 (bs, 1H) 8.05(s, 2H), 7.95 (d, J=8.1 Hz, 1H),
7.87-7.67 (m, 2H), 7.14 (dd, J=9.0, 15.6 Hz, 1H), 6.96 (d, J=15.6
Hz, 1H), 4.88-4.82 (m, 1H); ESIMS m/z 565 ([M+H].sup.+).
(E)-4-(3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tri-
fluoromethyl)benzoic add (C104)
##STR00118##
[0360] Isolated as a brown gum: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 13.6 (bs, 1H) 8.03 (s, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.88
(s, 2H), 7.81 (d, J=8.1 Hz, 1H), 7.13 (dd, J=16.2, 7.5 Hz, 1H),
6.91 (d, J=15.9 Hz, 1H), 4.89-4.83 (m, 1H); ESIMS m/z 532
([M+H].sup.+).
(E)-4-(3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tr-
ifluoromethyl)benzoic acid (C105)
##STR00119##
[0362] The title molecule was isolated as an off white solid: mp
140-143.degree. C.; .sup.1H NMR (400 MHz, DMSO-d6) .delta. 13.60
(bs, 1H), 8.02 (s, 1H), 7.94-7.90 (m, 1H), 7.88-7.86 (m, 2H),
7.81-7.79 (m, 1H), 7.12 (dd, J=15.6, 8.8 Hz, 1H), 6.89 (d, J=15.6
Hz, 1H), 4.86-4.81 (m, 2H); ESIMS m/z 459 ([M-H].sup.-).
Example 13
Preparation of
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluo-
romethyl)benzoyl chloride (C106)
##STR00120##
[0364] To a round-bottomed flask (500 mL) equipped with a drylng
tube, a magnetic stir bar, and
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2-(trifluoror-
methyl) benzoic acid (C92) (8.70 g, 18.2 mmol) was added
dichloromethane (30 mL). To this stirred solution oxalyl dichloride
(3.12 mL, 36.4 mmol) was added and the reaction was left to stir
for 65 hours. The solution was concentrated under reduced pressure
and the resulting red oil was diluted with cyclohexane and
concentrated under reduced pressure. The resulting red oil was
placed in a 40.degree. C. vacuum oven for 18 hours provided the
title compound as a red gum (8.28 g, 92%): .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.05 (d, J=8.2 Hz, 1H), 7.83-7.75 (m, 1H), 7.70
(dd, J=8.2, 1.7 Hz, 1H), 7.42 (s, 2H), 6.67 (d, J=16.0 Hz, 1H),
6.55 (dd, J=15.9, 7.6 Hz, 1H), 4.16 (p, J=8.5 Hz, 1H); .sup.19F NMR
(376 MHz, CDCl.sub.3) .delta. -59.59, -68.47; .sup.13C NMR (101
MHz, CDCl.sub.3) .delta. 165.62 , 140.39 , 135.01 , 134.03, 133.68
(q, J=1.8 Hz), 133.18 (q, J=1.8 Hz), 132.29 , 132.20 , 129.63 ,
129.13 (q, J=33.4 Hz), 129.09, 126.32 (q, J=2.4 Hz), 125.67 (q,
J=281.4 Hz), 125.28 (q, J=5.6 Hz), 122.45 (q, J=274.1 Hz), 52.38
(q, J=28.9 Hz).
Example 14
Preparation of
N--((R)-1-amino-1-oxopropan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlo-
rophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C107)
##STR00121##
[0366] To a vial (30 mL) containing a magnetic stir bar and
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluo-
romethyl)benzoyl chloride (C106) (0.980 g, 1.98 mmol) was added
1,2-dichloroethane (7.9 mL) to give a brown solution.
(R)-2-Aminopropanamide.cndot.hydrochloride (0.295 g, 2.37 mmol) and
4-methylmorpholine (0.652 mL, 5.93 mmol) were added and the vial
was capped and left to stir overnight. The reaction was diluted
with ethyl acetate (100 mL) and citric acid (5%, 100 mL). The
layers were separated and the organic layer was washed with an
additional citric acid (5%, 100 mL), water (100 mL), saturated
aqueous sodium bicarbonate (100 mL), and brine (20 mL). The organic
phase was dried with sodium sulfate, filtered, and concentrated to
give a red/brown oil. The oil was purified by flash column
chromatography using 0-100% ethyl acetate/hexanes as eluent. The
title compound was isolated as a beige solid (0.479 g, 44%):
.sup.1H NMR (400 MHz, CDCl3) .delta. 7.68 (s, 1H), 7.58 (dd, J=8.0,
1.7 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 6.73 (d, J=7.4
Hz, 1H), 6.62 (d, J=15.9 Hz, 1H), 6.52 (s, 1H), 6.44 (dd, J=15.9,
7.8 Hz, 1H), 5.64 (s, 1H), 4.78 (p, J=7.1 Hz, 1H), 4.21 (m, 1H),
1.50 (d, J=6.9 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-59.02, -68.56; ESIMS m/z 549 ([M+H]+).
Example 15
Preparation of
(E)-N-(2-amino-2-oxoethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)bu-
t-1-en-1-yl)-2-(trifluoromethyl)benzamide (C108)
##STR00122##
[0368] Into a vial (30 mL) equipped with a magnetic stir bar was
added 2-aminoacetamide.cndot.hydrochloride (0.555 g, 5.02 mmol),
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluo-
romethyl)benzoic acid (C106) (2.00 g, 4.19 mmol),
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni-
um hexafluorophosphate (2.15 g, 5.02 mmol) and 1,2-dichloroethane
(15 mL). 4-Methylmorpholine (1.38 mL, 12.6 mmol) was added to this
brown solution and the reaction was capped and left to stir
overnight. The reaction was diluted with ethyl acetate (150 mL) and
(100 mL). The layers were separated and the organic layer was
washed with an additional hydrochloric acid (1 M, 100 mL), water
(100 mL), saturated aqueous sodium bicarbonate (100 mL), and brine
(20 mL). The organic phase was dried with magnesium sulfate,
filtered, and concentrated to give a red/brown oil. The oil was
purified by flash column chromatography using 0-100% ethyl
acetate/hexanes. The title compound was isolated as a beige solid
(1.62, 72%): .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.72-7.67
(m, 1H), 7.61 (dd, J=8.0, 1.7 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.42
(s, 2H), 6.71 (t, J=5.1 Hz, 1H), 6.63 (d, J=15.9 Hz, 1H), 6.45 (dd,
J=15.9, 7.8 Hz, 1H), 6.24 (s, 1H), 5.56 (s, 1H), 4.19 (d, J=5.0 Hz,
2H), 4.16-4.08 (m, 1H); .sup.19F NMR (376 MHz, CDCl.sub.3) .delta.
-59.15, -68.56; ESIMS m/z 535 ([M+H].sup.+).
[0369] The following compound was prepared in accordance to the
procedure in Example 15.
N--((R)-1-Amino-1-oxobutan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichloro-
phenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C109)
##STR00123##
[0371] The title compound was prepared with
(R)-2-aminobutanamidehydrochloride in place of
2-aminoacetamide.cndot.hydrochloride (2.87, 71%): .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.70 -7.65 (m, 1H), 7.57 (dd, J=8.0, 1.7
Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.42 (s, 2H), 6.74 (dd, J=7.8, 1.4
Hz, 1H), 6.62 (d, J=15.9 Hz, 1H), 6.57-6.49 (m, 1H), 6.44 (dd,
J=15.9, 7.8 Hz, 1H), 5.72 (s, 1H), 4.71 (dt, J=7.7, 6.3 Hz, 1H),
4.19-4.05 (m, 1H), 1.99 (ddd, J=13.7, 7.4, 6.1 Hz, 1H), 1.85-1.70
(m, 1H), 1.01 (t, J=7.4 Hz, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -59.11, 68.57; ESIMS m/z 561([M-H].sup.-).
Example 16
Preparation of
N--((R)-1-aminoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride
(C110)
##STR00124##
[0373] To a vial (5 mL) wrapped in aluminium foil containing a
magnetic stir vane and
N--((R)-1-amino-1-oxopropan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlo-
rophenyl)but-1-en-1-yl)-2-(trifluorormethyl)benzamide (C107) (0.050
g, 0.091 mmol) was added acetonitrile (0.400 mL) and water (0.200
mL) to give a pale beige solution.
[I,I-Bis(trifluoroacetoxy)iodo]benzene (0.039 g, 0.091 mmol,
freshly prepared as described in J. Org. Chem., 1984, 49,
4272-4276) was added and the reaction was left to stir for 2.5
hours. The crude reaction mixture was adsorbed onto Celite.RTM. (5
g) and was purified by reverse phase chromatography (C-18) using
10-100% acetonitrile/water as eluent. The title compound was
isolated as an off-white solid (0.031 g, 66%): .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 9.49 (d, J=7.3 Hz, 1H), 8.44 (s, 3H),
8.05 (s, 1H), 7.97 (dt, J=8.4, 1.8 Hz, 1H), 7.94 (s, 2H), 7.61 (d,
J=8.0 Hz, 1H), 7.10 (dd, J=15.8, 9.1 Hz, 1H), 6.90 (d, J=15.8 Hz,
1H), 5.13 (p, J=6.6 Hz, 1H), 4.90 (p, =9.4 Hz, 1H), 1.45 (d, J=6.5
Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta. -57.73,
-67.93; ESIMS m/z 519 ([M-H].sup.-).
[0374] The following compounds were prepared in accordance to the
procedure in Example 16.
N--((R)-1-Aminapropyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yI)-2-(trifluoromethyl)benzamide.cndot.hydrochloride
(C111)
##STR00125##
[0376] The title compound was prepared with
N--((R)-1-amino-1-oxobutan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlor-
ophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C109) in place
of
N--((R)-1-amino-1-oxopropan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlo-
rophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C107) (0.910
g, 30%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.39 (dd,
J=8.2, 1.4 Hz, 1H), 8.57-8.43 (m, 3H), 8.05 (t, J=1.7 Hz, 1H), 7.98
(dd, J=8.1, 1.9 Hz, 1H), 7.93 (s, 2H), 7.61 (d, J=8.0 Hz, 1H), 7.09
(dd, J=15.8, 9.1 Hz, 1H), 6.89 (d, J=15.7 Hz, 1H), 4.91 (m, 2H),
1.81 (m, 2H), 0.93 (t, J=7.3 Hz, 3H); .sup.19F NMR (376 MHz,
DMSO-d.sub.6) .delta. -57.80, -67.93; ESIMS m/z 533
([M-H].sup.-)
(E)-N-(Aminomethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-
-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C112)
##STR00126##
[0378] The title compound was prepared with
(E)-N-(2-amino-2-oxoethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)bu-
t-1-en-1-yl)-2-(trifluoromethyl)benzamide (C108) used in place of
N--((R)-1-amino-1-oxopropan-2-yl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlo-
rophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamde (C107) (0.710
g, 50%): .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.27 (t, J=6.0
Hz, 1H), 8.03 (d, J=1.6 Hz, 1H), 7.95 (dd, J=8.2, 1.9 Hz, 1H), 7.93
(s, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.09 (dd, J=15.8, 9.1 Hz, 1H),
6.89 (d, J=15.7 Hz, 1H), 6.52 (s, 3H), 4.88 (p, J=9.3 Hz, 1H), 4.26
(d, J=6.0 Hz, 2H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-57.74, -67.95; ESIMS m/z 505 ([M-H].sup.-).
Example 17
Preparation of
N--((R)-1-hexanamidoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichloropheny-
l)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F3)
##STR00127##
[0380] Into a vial (4 mL) equipped with a magnetic stir vane were
placed dry dichloromethane (1.5 mL),
N--((R)-1-aminoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C110)
(0.100 g, 0.180 mmol) and hexanoyl chloride (0.0380 mL, 0.270
mmol). To this solution was added 4-methylmorpholine (0.0500 mL,
0.450 mmol). The resulting suspension was stirred overnight. The
reaction mixture was diluted with ethyl acetate (20 mL) and citric
acid (5%, 20 mL). The layers were separated and the aqueous phase
was extracted with additional ethyl acetate. The pooled organic
layers were dried with sodium sulfate, filtered, and concentrated.
The resulting material was purified by flash column chromatography
using 0-100% ethyl acetate/hexanes as eluent. The title compound
was isolated as an off-white foam (0.0860 g, 78%).
[0381] The following compounds were prepared in accordance to the
procedure in Example 17.
N--((R)-1-(4-Methylpentanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-tric-
hlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F4)
##STR00128##
[0383] The title compound was prepared using 4-methypentanoyl
chloride and isolated as an off-white foam/glass (0.037 g,
34%).
N--((R)-1-Pentanamidoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichloropheny-
l)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F5)
##STR00129##
[0385] The title compound was prepared using pentanoyl chloride and
isolated as an off-white foam/solid (0.028 g, 26%).
N--((R)-1-(3-Methylbutanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trich-
lorophenyl)but-1-en-1-yl)-2-(trifluoramethyl)benzamide (F6)
##STR00130##
[0387] The title compound was prepared using 3-methylbutanoyl
chloride and isolated as an off-white foam (0.038 g, 35%).
N--((R)-1-(Cyclopropanecarboxamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5--
trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(F7)
##STR00131##
[0389] The title compound was prepared using cyclopropanecarbonyl
chloride and isolated as a colorless glass/foam (0.145 g, 55%).
N--((R)-1-(3-Methylbut-2-enamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-tr-
ichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F8)
##STR00132##
[0391] The title compound was prepared using 3-methylbut-2-enoyl
chloride and isolated as a colorless glass/foam (0.096 g, 55%).
Example 18
Preparation of
4-((E)-4,4,4-trifluoro-3-(3,4,5-trichloropheny)but-1-en-1-yl)-2-(trifluor-
omethyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide
(F2)
##STR00133##
[0393] Into a vial (5 mL) equipped with a magnetic stir vane was
placed
N--((R)-1-aminoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C110)
(0.117 g, 0.210 mmol) and 1,2-dichloroethane (3 mL).
3,3,3-Trifluoropropanoyl chloride (0.0390 g, 0.266 mmol) was added
and two minutes later 4-methylmorpholine (0.0690 mL, 0.631 mmol)
was added. The reaction was vortexed 5 times over a 2 minute
period. After the second vortex, the solution became cloudy. The
reaction was left to stir for an additional 1.5 hours. Purification
by flash column chromatography using 0-100% ethyl acetate/hexanes
as eluent. The title compound was isolated as an off-white solid
(0.060 g, 46%).
[0394] The following compounds were prepared in accordance to the
procedure in Example 18.
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-1-yl)-N--((R)-1-
-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide
(F1)
##STR00134##
[0396] The title compound was prepared using
4,4,4-trifluorobutanoyl chloride and isolated as an off-white solid
(0.066 g, 65%).
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N--((R)-1-(-
4,4,4-trifluorobutanamido)propyl)-2-(trifluoromethyl)benzamide
(F12)
##STR00135##
[0398] The title compound was prepared using
N--((R)-1-aminopropyI)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)bu-
t-1-en-1-yl)-2-(trifluoromethyl)benzarnide.cndot.hydrochloride
(C111) and 4,4,4-trifluorobutanoyl chloride and isolated as a white
solid (0.084 g, 49%),
(E)-4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-((4,4,4-t-
rifluorobutanamido)methyl)-2-(trifluoromethyl)benzamide (F13)
##STR00136##
[0400] The title compound was prepared using
(E)-N-(aminomethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en--
1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C112) and
4,4,4-trifluorobutanoyl chloride and isolated as a pale yellow
solid (0.040 g, 20%).
N--((S)-1-Pivalamidoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl-
)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F19)
##STR00137##
[0402] The title compound was prepared using pivaloyl chloride and
isolated as a white solid (0.104 g, 64%).
Example 19
Preparation of
N--((S)-1-(1-cyanocyclopropanecarboxamido)ethyl)-4-((E)-4,4,4-trifluoro-3-
-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(F14)
##STR00138##
[0404] Into a vial (5 mL) equipped with a magnetic stir vane was
placed 1-cyanocyclopropanecarboxylic acid (0.052 g, 0.47 mmol) and
1,2-dichloroethane (1.3 mL). Oxalyl chloride (0.040 mL, 0.47 mmol)
and dimethylformamide (.about.1 drop) were added and the reaction
was left to stir at room temperature for 3 hours.
N--((R)-1-aminoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C110)
(0.15 g, 0.27 mmol) and 4-methylmorpholine (0.089 mL, 0.81 mmol)
were added and the reaction was capped, vortexed and left to stir.
Purification by flash column chromatography using 0-100% ethyl
acetate/hexanes as eluent. The title compound was isolated as a
colorless foam (0.135 g, 82%),
[0405] The following compounds were prepared in accordance to the
procedure in Example 19.
N--((R)-1-(3,3-Dimethylbutanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-t-
richlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(F15)
##STR00139##
[0407] The title compound was prepared using 3,3-dimethylbutanoic
acid and isolated as a colorless glass (0.109 g, 65%).
N--((R)-1-(4,4-Dimethylpentanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5--
trichlorophenyl)but-1-en-1-yl)-2-(trifluoramethyl)benzamide
(F17)
##STR00140##
[0409] The title compound was prepared using 4,4-dimethylpentanoic
acid and isolated as a colorless foam (0.104 g, 61%).
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-((1R)-1-(-
4,4,4-trifluoro-3-methylbutanamido)ethyl)-2-(trifluoromethyl)benzamide
(F16)
##STR00141##
[0411] The title compound was prepared using
4,4,4-trifluoro-3-methylbutanoic acid and isolated as a white solid
(0.105 g, 59%).
N--((R)-1-(5,5-Dimethylhexanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-t-
richlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(F18)
##STR00142##
[0413] The title compound was prepared using 5,5-dimethylhexanoic
acid and isolated as a white solid (0.100 g, 57%).
N--((R)-1-(4,4,4-Trifluoro-2-methylbutanamido)ethyl)-4-((E)-4,4,4-trifluor-
o-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P30)
##STR00143##
[0415] Isolated as a colorless glass (0.0% g, 24%).
N--((S)-1-(3,3,3-Trifluoro-2,2-dimethylpropanamido)ethyl)-4-((E)-4,4,4-tri-
fluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamid-
e (P33)
##STR00144##
[0417] Isolated as a white solid (0.101 g, 51%).
Example 20: Preparation of
N--((R)-1-(3-cyanopropanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-tric-
hlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F9)
##STR00145##
[0419] Into a vial (4 mL) equipped with a stir vane was placed
3-cyanopropanoic acid (0.080 g, 0.81 mmol)),
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni-
um hexafluorophosphate (0.37 g, 0.86 mmol), and 4-methylmorpholine
(0.14 9, 1.3 mmol). Dimethylformamide (1 mL) was added and the
reaction was stirred at room temperature for 5 minutes.
N--((R)-1-Aminoethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-
-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride (C110)
(0.30 g, 0.54 mmol) was dissolved in dimethylformamide (0.5 mL) and
was added drop-wise. The mixture was then stirred at room
temperature overnight. The resulting solution was diluted with
ethyl acetate (.about.20 mL) and was washed with water. The organic
layer was dried with sodium sulfate, filtered, and concentrated.
The resulting material was purified via flash column chromatography
using 35% ethyl acetate/hexanes as eluent to provide the title
compound as a brown glass/foam (0.073 g, 23%).
[0420] The following compounds were prepared in accordance to the
procedure in Example 20.
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluor-
omethyl)-N--((R)-1-(5,5,5-trifluoropentanamido)ethyl)benzamide
(F10)
##STR00146##
[0422] The title compound was prepared using
5,5,5-trifluoropentanoic acid and isolated as a colorless
glass/foam (0.173 g, 49%).
N--((R)-1-(2-Cyanoacetamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlo-
rophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide (F11)
##STR00147##
[0424] The title compound was prepared using 2-cyanoacetic acid and
isolated as an off-white foam/glass (0.132 g, 42%).
Example 21
Preparation of (E)-tert-butyl
methyl(2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(t-
rifluoromethyl)benzamido)ethyl)carbamate (C113)
##STR00148##
[0426] Into a round-bottomed flask (250 mL) was added
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluo-
romethyl)benzoic acid (C92) (0.75 g, 1.6 mmol), tert-butyl
(2-aminoethyl)(methyl)carbamate (0.56 mL, 3.1 mmol),
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.24 g, 1.6 mmol), and
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate(V) (0.60 g, 1.6 mmol) and acetonitrile (27 mL)
under nitrogen. N-Ethyl-N-isopropylpropan-2-amine (0.55 mL, 3.1
mmol) was then added dropwise and the reaction was allowed to stir
at room temperature overnight. The reaction mixture was then
filtered through a silica gel frit, concentrated, purified by flash
column chromatography using ethyl acetate/hexanes as eluent to
provide the title compound as a light brown foam (0.40 g, 38%):
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.66 (s, 1H), 7.57-7.46
(m, 2H), 7.42 (s, 2H), 6,74 (s, 1H), 6.61 (d, J=15.9 Hz, 1H), 6.42
(dd, J=15.9, 7.8 Hz, 1H), 4.12 (p, J=8.4 Hz, 1H), 3.60 (dt, J=6.1,
4.7 Hz, 2H), 3.48 (d, J=6.2 Hz, 2H), 2.92 (s, 3H), 1.40 (s, 9H);
.sup.19F NMR (376 MHz, CDCl.sub.3) .delta. -59.31, -68.58; ESIMS
m/z 633 ([M-H].sup.-).
Example 22
Preparation of
(E)-N-(2-(methylamino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-
but-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride
(C114)
##STR00149##
[0428] Into a round-bottomed flask (100 mL) under nitrogen was
added (E)-tert-butyl
methyl(2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(t-
rifluoromethyl)benzamido)ethyl)carbamate (C113) (0.770 g, 1.22
mmol) and dichloromethane (1.39 mL). Hydrochloric acid (4 M in
dioxane) (1.39 mL) was then added dropwise to the solution and the
solution was allowed to stir at room temperature overnight. The
reaction was concentrated to provide the title compound as a brown
foam (0.500 g, 51%): .sup.1H NMR (400 MHz, MeOH-d.sub.4) .delta.
7.90-7.81 (m, 2H), 7.70 (s, 2H), 7.63 (d, J=8.0 Hz, 1H), 6.91-6.75
(m, 2H), 4.64-4.50 (m, 1H), 3.66 (s, 4H), 2.78 (s, 3H) (NH not
observed); .sup.19F NMR (376 MHz, MeOH-d.sub.4) .delta. -60.51,
-70.47; ESIMS m/z 533 ([M-H].sup.-).
Example 23
Preparation of
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichloropheny)but-1-en-1-yl)-N-(2-(3,3,3-
-trifluoro-N-methylpropanamido)ethyl)-2-(trifluoromethyl)benzamide
(F20)
##STR00150##
[0430] Into a round-bottomed flask (100 mL) was added the
1H-benzo[d][1,2,3]triazol-1-ol hydrate (0.040 g, 0.26 mmol),
2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate(V) (0.10 g, 0.26 mmol),
(E)-N-(2-(methylamino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-
but-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride
(C114) (0.15 g, 0.26 mmol), 3,3,3-trifluoropropanoic acid (0.046
mL, 0.53 mmol), and acetonitrile (4.5 mL) under nitrogen. This was
then followed by dropwise addition of
N-ethyl-N-isopropylpropan-2-amine (0.14 mL, 0.79 mmol). The
resulting solution was allowed to stir overnight at room
temperature. The reaction mixture was filtered through silica gel
frit, concentrated, and then purified via flash column
chromatography to provide the title compound as a brown glass
(0.094 g, 50%).
Example 24
Preparation of
(E)-N-(2-(methylamino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-
but-1-en-1-yl)-2-(trifluoromethyl)benzamide (C115)
##STR00151##
[0432] Into a round-bottomed flask (100 mL) containing
(E)-N-(2-(methylamino)ethyl)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)-
but-1-en-1-yl)-2-(trifluoromethyl)benzamide.cndot.hydrochloride
(C114) (0.60 g, 1.1 mmol) was added dichloromethane (20 mL)
followed by saturated sodium bicarbonate (10 mL). This mixture was
allowed to stir for 10 minutes. The solution was extracted with
dichloromethane. The combined organic layers were dried,
concentrated, and purified by flash column chromatography using
methanol/dichloromethane as eluent to provide the title compound as
a yellow foam (0.30 g, 51%): .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.65 (s, 1H), 7.55 (d, J=7.9 Hz, 1H), 7.42 (d, J=3.3 Hz,
3H), 6.61 (d, J=15.9 Hz, 1H), 6.42 (dd, J=15.9, 7.9 Hz, 1H), 4.12
(p, J=8.7 Hz, 1H), 3.59 (q, J=5.4 Hz, 2H), 2.88 (t, J=5.5 Hz, 2H),
2.47 (s, 3H) (NH not observed); .sup.19F NMR (376 MHz, CDCl.sub.3)
.delta. -59.11, -68.60; ESIMS m/z 535 ([M+H].sup.+).
Example 25
Preparation of
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-(2-(2,2,-
2-trifluoro-N-methylacetamido)ethyl)-2-(trifluoromethyl)benzamide
(F21)
##STR00152##
[0434] Into a round-bottomed flask (100 mL) was added the
(E)-N-(2-(methylamine)ethy)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)b-
ut-1-en-1-yl)-2-(trifluoromethyl)benzamide (C115) (0.125 g, 0.234
mmol), tetrahydrofuran (0.781 mL), and dichloromethane (0.781 mL)
under nitrogen. This was followed by the dropwise addition of the
trifluoroacetic anhydride (0.0350 mL, 0.246 mmol). The reaction was
then allowed to stir at room temperature for 18 hours. The mixture
was diluted with dichloromethane, concentrated, and purified via
flash column chromatography using ethyl acetate/hexanes as eluent
to provide the title compound as a very light yellow glass/foam
(0.0720 g, 46%).
Example 26
Preparation of (E)-tert-butyl
1-methyl-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2--
(trifluoromethyl)benzoyl)hydrazinecarboxylate (C116)
##STR00153##
[0436] To N-ethyl-N-isopropylpropan-2-amine (1.21 mL, 7.08 mmol),
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(1,35 g, 2.60 mmol), tert-butyl N-amino-N-methyl-carbamate (0.380
g, 2.60 mmol) was added
(E)-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)--
2-(trifluoromethyl)benzoic acid (C92) (1.00 g, 2.36 mmol) in
dichloromethane (5 mL). The reaction was stirred at room
temperature for 12 hours. The reaction mixture was poured into
water and extracted with dichloromethane (20 mL). The separated
organic layer was washed with water, brine, dried over sodium
sulfate, filtered, and concentrated. The residue was purified via
flash column chromatography using 30% ethyl acetate/petroleum ether
as eluent to provide the title compound as a colorless liquid
(0.750 g, 49%): IR (thin film) 3418, 2928, 1714, 1160, 865
cm.sup.-1; .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.4 (s,
1H), 7.89 (s, 2H), 7.48-7.43 m, 2H), 733 (d, J=8.0 Hz, 1H), 6.90
(dd, J=15.6, 8.8 Hz, 1H), 6.76 (d, J=15.6 Hz, 1H), 4.86-4.82 (m,
1H), 2.38 (s, 3H), 1.45 (s, 9H); ESIMS m/z 603 ([M-H].sup.-).
Example 27
Preparation of
(E)-N'-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)--
2-(trifluoromethyl)benzohydrazide.cndot.hydrochloride (C117)
##STR00154##
[0438] To (E)-tert-butyl
1-methyl-2-(4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2--
(trifluoromethyl)benzoyl)hydrazinecarboxylate (C116) (1.0 g, 1.7
mmol) in dioxane (10 mL) was added hydrochloric acid (4 M in
dioxane) (10 mL). The solution was allowed to stir at room
temperature for 2 hours. The reaction was concentrated, washed with
pentane, filtered, and dried to provide the title compound as a
yellow solid (0.80 g, 89%): .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta.11.30 (bs, 2H), 8.09 (bs, 1H), 7.97 (d, J=6.6 Hz, 2H), 7.92
(s, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.14 (dd, J=15.9, 8.7 Hz, 1H),
6.91 (d, J=15.9 Hz, 1H), 4.90 (t, J=6.9 Hz, 1H), 2.73 (bs, 3H);
ESIMS m/z 505 ([M-H].sup.+).
Example 28
Preparation of
(E)-N'-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)--
2-(trifluoromethyl)-N'-(3,3,3-trifluoropropanoyl)benzohydrazide
(F22)
##STR00155##
[0440] To N-ethyl-N-isopropylpropan-2-amine (0.14 mL, 0.83 mmol),
benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate
(0.16 g, 0.30 mmol) was added
(E)-N-methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-
-(trifluoromethyl)benzohydrazide.cndot.hydrochloride (C117) (0.15
g, 0.28 mmol) and 3,3,3-trifluoropropanoic acid (0.046 mL, 0.53
mmol) in dichloromethane (5 mL). The reaction was stirred at room
temperature for 6 hours. The reaction mixture was then diluted with
dichloromethane and washed with water. The organic layer was dried
over sodium sulfate, filtered, and concentrated. The residue was
purified via flash column chromatography using 20% ethyl
acetate/petroleum ether as eluent to provide the title compound as
a pale yellow gum (0.15 g, 86%).
[0441] The following compounds were prepared in accordance to the
procedure in Example 28.
(E)-N'-Methyl-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-
'-(4,4,4-trifluorobutanoyl)-2-(trifluoromethyl)benzohydrazide
(F23)
##STR00156##
[0443] The title compound was prepared using
4,4,4-trifluorobutanoic acid and isolated as a pale yellow gum
(0.21 g, 91%).
Example 29
Preparation of 3,5-Dibromo-4-chlorobenzaldehyde (C121)
##STR00157##
[0445] Step 1. Methyl 4-amino-3,5-dibromobenzoate (C118):
Concentrated sulfuric acid (1.35 mL, 25.5 mmol) was added dropwise
to a stirred solution of 4-amino-3,5-dibromobenzoic acid (5.00 g,
17.0 mmol) in methanol (50 mL) at ambient temperature and the
reaction mixture was then stirred at 80.degree. C. for 8 hours. The
reaction mixture was allowed to cool to ambient temperature,
volatiles were evaporated, ice-water was added to the residue, and
extracted with ethyl acetate. The organic layer was washed with
aqueous sodium bicarbonate solution followed by brine and water,
dried (sodium sulfate), filtered, and concentrated to afford the
title compound as an off white solid (5.00 g, 95%): .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 7.91 (s, 2H), 6.20 (bs, 2H), 3.78
(s, 3H); ESIMS m/z 307 ([M].sup.+); IR (thin film) 3312 , 2953,
1726, 595 cm.sup.-1.
[0446] Step 2. Methyl 3,5-dibromo-4-chlorobenzoate (C119):
Copper(II) chloride (2.82 g, 21.0 mmol) in acetonitrile (30 mL) was
stirred at 80.degree. C. for 30 minutes. tert-Butylnitrite (2.70
mL, 23.0 mmol) was then added dropwise at the same temperature and
the mixture was stirred for another 10 minutes. Methyl
4-amino-3,5-dibromobenzoate (C118) (5.00 g, 16.0 mmol) in
acetonitrile (30 mL) was added dropwise to the reaction mixture and
stirred at 80.degree. C. for 30 minutes. The reaction mixture was
allowed to cool to ambient temperature and an aqueous ammonia
solution (20 mL) was added to the reaction mixture followed by
extraction with petroleum ether. The organic layer was washed with
brine followed by water, dried (sodium sulfate), filtered, and
concentrated to afford the title compound as an off white solid
(4.50 g, 84%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.21 (s,
2H), 3.94 (s, 3H); ESIMS m/z 326 ([M].sup.+); IR (thin film) 1732,
746 cm.sup.-1.
[0447] Step 3. (3,5-Dibromo-4-chlorophenyl)methanol (C120): Sodium
borohydride (1.53 g, 40.7 mmol) was added portionwise to a stirred
solution of methyl 3,5-dibromo-4-chlorobenzoate (C119) (4.45 g,
13.6 mmol) in methanol (50 mL) at 0.degree. C. The reaction mixture
was then stirred at ambient temperature for 8 hours. The volatiles
were evaporated and the residue was diluted with dichloromethane
and washed with brine followed by water. The organic layer was
dried (sodium sulfate), filtered, and concentrated to afford the
title compound as an off white solid (3.30 g, 80%): .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 7.71 (s, 2H), 5.49 (bs, 1H), 4.48
(d, J=4.5 Hz, 2H); ESIMS m/z 298 ([M].sup.+); IR (thin flim) 3460,
747, 534 cm.sup.-1.
[0448] Step 4. 3,5-Dibromo-4-chlorabenzaldehyde (C121): Pyridinium
chlorochormate (3.44 g, 15.9 mmol) was added in one portion to a
stirred solution of (3,5-dibromo-4-chlorophenyl)methanol (C120)
(3.2 g, 11.0 mmol) in chloroform (40 mL) at ambient temperature and
the reaction mixture was stirred overnight. The reaction mixture
was filtered through Celite.RTM., the Celite.RTM. pad was washed
with chloroform, and the filtrate was concentrated to afford the
title compound as an off white solid (2.00 g, 62%): mp
110-113.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
9.93 (s, 1H), 8.27 (s, 2H); ESIMS m/z 297 ([M].sup.+).
[0449] The following compounds were prepared in accordance to the
procedures in Example 29.
4-Bromo-3,5-dichlorobenzaldehyde (C125)
##STR00158##
[0450] Step 1. Methyl 4-amino-3, 5-dichlorobenzoate (C122)
[0451] The title compound was isolated as a white solid (7.5 g,
70%): .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.05 (s, 2H),
3.96 (s, 3H); ESIMS m/z 282 ([M].sup.+); IR (KBr); 1733, 762, 514
cm.sup.-1.
Step 2. Methyl 4-bromo-3, 5-dichlorobenzoate (C123)
[0452] The title compound was isolated as an off white solid (7.5
g, 77%); .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 8.02 (s, 2H),
3.94 (s, 3H); ESIMS m/z 282 ([M].sup.+); IR (thin film) 1733, 762,
514 cm.sup.-1.
Step 3. (4-Bromo-3,5-dichlorophenyl)methanol (C124)
[0453] The title compound was isolated as an off white solid which
was taken to next step without purification.
Step 4. 4-Bromo-3, 5-dichlorobenzaldehyde (C125)
[0454] The title compound was isolated as an off white solid (3.5
g, 67%): mp 125-128.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 9.96 (s, 1H), 8.10 (s, 2H); ESIMS m/z 252 ([M].sup.+).
Example 30
Preparation of
4-((E)-3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(t-
rifluoromethyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide
(P24)
##STR00159##
[0456] To a vial (50 mL) under a nitrogen atmosphere was added
(E)-2-bromo-4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)ben-
zoic acid (C88) (0.306 g, 0.626 mmol) and 1,2-dichloroethane (2
mL). Oxalyl dichloride (0.100 mL, 1.17 mmol) and
N,N-dimethylformamide (0.00400 mL, 0.0510 mmol) were added, and the
resulting suspension was stirred for 1 hour. The reaction mixture
was concentrated to remove any excess oxalyl chloride. The
resulting orange oil was diluted with 1,2-dichloroethane (5 mL) and
added to a vial (25 mL) containing
(S)--N-(1-aminoethyl)-3,3,3-trifluoropropanamide hydrochloride
(CA5) (0.168 g, 0.814 mmol). The reaction mixture was vortexed, and
4-methylmorpholine (0.172 mL, 1.57 mmol) was added. The reaction
vial was capped and vortexed several times over a 1 minute period.
The reaction mixture was allowed to stir with occasional vortexing
for 1 hour. The reaction mixture was concentrated under a stream of
nitrogen gas, dissolved in N,N-dimethylformamide:vvater (5:1, 3.2
mL), and partially purified via preparative C-18 reverse phase HPLC
purification using 5-95% acetonitrile (0.1% acetic acid) and water
(0.1% acetic acid) as eluent. The obtained material was dissolved
in methanol containing an excess of Amberlite IRA-65 weak anion
exchange resin in the free base form (IRA-67 free base), and the
mixture was vortexed and left to stand for 1 hour. The mixture was
gravity filtered, and the resin was washed with excess methanol.
The filtrate was concentrated to provide the desired compound as a
white solid (0.172 g, 39%).
[0457] The following compounds were prepared in accordance to the
procedures in Example 30.
4-((E)-3-(3,5-Dichloro-4-fluoraphenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tr-
ifluoromethyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide
(P1)
##STR00160##
[0459] Isolated as an amber glass (0.041 g, 10%).
4-((E)-3-(3,5-Dibroma-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tri-
fluoromethyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide
(P2)
##STR00161##
[0461] Isolated as an amber glass (0.223 g, 55%).
4-((E)-3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(trifluoromet-
hyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P3)
##STR00162##
[0463] Isolated as a brown amorphous solid (0.226 q, 52%).
4-((E)-3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-(tri-
fluoromethyl)-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide
(P4)
##STR00163##
[0465] Isolated as a brown amorphous solid (0.226 q, 52%).
4-((E)-3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-met-
hyl-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P5)
##STR00164##
[0467] Isolated as a pale yellow glass (0.215 g, 4g%).
4-((E)-3-(3,5-Dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-meth-
yl-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P6)
##STR00165##
[0469] Isolated as a pale orange glass (0.211 g, 49%).
4-((E)-3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methyl-N--((R-
)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P7)
##STR00166##
[0471] Isolated as a brown amorphous solid (0.226 g, 54%).
4-((E)-3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-meth-
yl-N--((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P8)
##STR00167##
[0473] Isolated as a pale yellow solid (0.148 g, 35%).
4-((E)-3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N--((-
R)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide
(P9)
##STR00168##
[0475] Isolated as a coloress glass (0,036 g, 8%).
4-((E)-3-(3,5-Dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N--((R-
)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide
(P10)
##STR00169##
[0477] Isolated as a pale ye low glass (0.171 g, 39%).
4-((E)-3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N--((R)-1-(4,4,-
4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide (P11)
##STR00170##
[0479] Isolated as an amber glass (0.181 g, 39%).
4-((E)-3-(4-Bromo-3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-N--((R-
)-1-(4,4,4-trifluorobutanamido)ethyl)-2-(trifluoromethyl)benzamide
(P12)
##STR00171##
[0481] Isolated as an orange glass (0.135 g, 29%).
4-((E)-3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-met-
hyl-N--((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P13)
##STR00172##
[0483] Isolated as a light yellow solid (0.197 g, 42%).
4-((E)-3-(3,5-Dibromo-4-chlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-meth-
yl-N--((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P14)
##STR00173##
[0485] Isolated as a white solid (0.104 a, 16%).
4-((E)-3-(3,5-Dibromophenyl)-4,4,4-trifluorobut-1-en-1-yl)-2-methyl-N--((R-
)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P15)
##STR00174##
[0487] Isolated as a beige solid (0.150 g, 33%).
4-((E)-3-(4-Bromo-3,5-dichloropheny-4,4,4-trifluorobut-1-en-1-yl)-2-methyl-
-N--((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P16)
##STR00175##
[0489] Isolated as a white solid (0.122 g, 20%).
2-Methyl-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N--
-((R)-1-(3,3,3-trifluoropropanamido)ethyl)benzamide (P22)
##STR00176##
[0490] Isolated as a beige solid (0.241 g, 52%).
2-Methyl-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N-
--((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P25)
##STR00177##
[0492] Isolated as a beige solid (0.157 g, 32%).
2-Bromo-4-((E)-4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N---
((R)-1-(4,4,4-trifluorobutanamido)ethyl)benzamide (P27)
##STR00178##
[0494] Isolated as a pale yellow solid (0.110 g, 24%).
N--((R)-1-(3-(Methylthio)propanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,-
5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoramethyl)benzamide
(P53)
##STR00179##
[0496] Isolated as a white foam (0,225 g, 36%).
N--((S)-1-(2-(Methylthio)acetamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4,5--
trichlorophenyl)but-1-en-1-yl)-2-(trifluoramethyl)benzamide
(P54)
##STR00180##
[0498] Isolated as a white foam (0.353 g, 55%).
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N--((R)-1-(-
4,4,4-trifluorobutanamido)ethyl)benzamide (FC1)
##STR00181##
[0500] Isolated as a yellow foam (0.0423 g, 40%, approximately 30%
pure).
4-((E)-4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-N--((R)-1-(-
3,3,3-trifluoropropanamido)ethyl)benzamide (FC2)
##STR00182##
[0502] Isolated as a white solid (0.052 g, 47%).
Example 31
Preparation of
N--((R)-1-(3-(methylsulfonyl)propanamido)ethyl)-4-((E)-4,4,4-trifluoro-3--
(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P47) and
N-((1R)-1-(3-(methylsulfinyl)propanamido)ethyl)-4-((E)-4,4,4-trifluor-
o-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P49)
##STR00183##
[0504] To a vial (25 mL) was added
N--((R)-1-(3-(methylthio)propanamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,4-
,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P53) (0.150 g, 0.241 mmol), sodium perborate tetrahydrate (0.0557
g, 0.362 mmol), and acetic acid (5 mL). The vial was capped, and
the reaction was stirred and heated at 55.degree. C. overnight. The
reaction mixture was concentrated under a stream of nitrogen gas.
Purification by flash column chromatography using 20-100% ethyl
acetate/hexanes followed by 0-40% methanol/dichloromethane as
eluent provided the title compound (P47) as a coloroless glass
(0.0630 g, 72%) and (P49) as a colorless glass (0.0360 g, 42%).
[0505] The following compounds were prepared in accordanceo the
procedures in Example 31.
N-((1S)-1-(2-(Methylsulfinyl)acetamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,-
4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P36)
##STR00184##
[0507] Isolated as a colorless glass (0.054 g, 34%).
N--((S)-1-(2-(Methylsulfonyl)acetamido)ethyl)-4-((E)-4,4,4-trifluoro-3-(3,-
4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)benzamide
(P43)
##STR00185##
[0509] Isolated as a colorless glass (0.138 g, 85%).
Example 32
Preparation of (S)--N-(1-aminoethyl)-4,4,4-trifluorobutanamide
hydrochloride (CA4)
##STR00186##
[0511] (S)--N-(1-Amino-1-oxopropan-2-yl)-4,4,4-trifluorobutanamide
(CA6) (3.00 g, 14.1 mmol) was dissolved in water (21 mL) and
acetonitrile (21 mL), after which
[I,I-bis(trifluoroacetoxy)iodo]benzene (6.08 g, 14.1 mmol) was
added. The reaction mixture was stirred in a flask wrapped in
aluminum foil overnight. The reaction mixture was then poured into
hydrochloric acid (1 N, 35 mL) and diethyl ether (35 mL). The
organic layer was separated, and the aqueous layer was azeotroped
(2.times.125 mL) with isopropanol. Purification by reverse phase
flash column chromatography using 20% acetonitrile/water as eluent
provided the title compound as a white, highly hygroscopic solid
(1.50 g, 48%): .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.11 (d,
J=7.4 Hz, 1H), 8.36 (s, 3H), 4.94 (p, J=6.6 Hz, 1H), 2.66-2.32 (m,
4H), 1.40 (d, J=6.5 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.about. -65.19; ESIMS m/z 185 ([M-H].sup.+).
[0512] The following compound was prepared in accordance to the
procedures in Example 32.
(S)--N-(1-Aminoethyl)-3,3,3-trifluoropropanamide hydrochloride
(CA5)
##STR00187##
[0514] Isolated as an off-white solid (2.8 g, 90%): mp 125.degree.
C. (dec.); .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 9.47 (d,
J=7.3 Hz, 1H), 8.48 (s, 3H), 4.96 (p, J=6.6 Hz, 1H), 3.44 (m, 2H),
1.42 (d, J=6.5 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6)
.delta. -61.28.
Example 33
Preparation of
(S)--N-(1-amino-1-oxopropan-2-yl)-4,4,4-trifluorobutanamide
(CA6)
##STR00188##
[0516] To a round bottomed flask (500 mL) was added sodium
bicarbonate (saturated solution, 54.6 mL, 60.1 mmol) and
(S)-2-aminopropanamide hydrochloride (3.74 g, 30.0 mmol). The
solution was allowed to stir until gas evolution ceased, after
which time trifluoroethanol (54.6 mL) was added.
3,3,3-Trifluoropropanocyl chloride (2.81 ml, 27.3 mmol) was added
in small portions (gas evolution). Addition rate was determined by
the rate of gas evolution. After addition was complete, the
reaction mixture was left to stir open to air at room temperature
overnight. Hydrochloric acid (2 M, .about.15 mL) was added until
gas evolution ceased, and the solution was concentrated. The
resulting slurry was diluted with ethyl acetate and water, the
layers were separated and the aqueous layer was extracted with
ethyl acetate (3.times.100 mL). The resulting organic layer was
dried over sodium sulfate, filtered, and concentrated to provide
the title compound as a white solid (3.30 g, 55%): .sup.1H NMR (300
MHz, DMSO-d.sub.6) .delta. 8.15 (d, J=7.6 Hz, 1H), 7.33 (s, 1H),
6.98 (s, 1H), 4.21 (p, J=7.2 Hz, 1H), 2.49-2.34 (m, 4H), 1.19 (d,
J=7.1 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d6) .delta. -61.46;
ESIMS m/z 197 ([M-H].sup.-).
[0517] The following compound was prepared in accordance to the
procedures in Example 33.
(S)--N-(1-Amino-1-oxopropan-2-yl)-3,3,3-trifluoropropanamide
(CA7)
##STR00189##
[0519] Isolated as a white solid (1.5 g, 39%): .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.38 (d, J=7.6 Hz, 1H), 7.43 (s, 1H),
7.04 (s, 1H), 4.25 (p, J=7.1 Hz, 1H), 3.32 (q, J=11.3 Hz, 2H), 1.20
(d, J=7.1 Hz, 3H); .sup.19F NMR (376 MHz, DMSO-d.sub.6) .delta.
-65.18.
[0520] The following prophetic molecules could be made in
accordance with the procedures disclosed above:
TABLE-US-00001 TABLE 1 Structure and Preparation Method for P
Series Compounds Prep. according to example No. Structure or
scheme: P1 ##STR00190## Example 18 P2 ##STR00191## Example 18 P3
##STR00192## Example 18 P4 ##STR00193## Example 18 P5 ##STR00194##
Example 18 P6 ##STR00195## Example 18 P7 ##STR00196## Example 18 P8
##STR00197## Example 18 P9 ##STR00198## Example 18 P10 ##STR00199##
Example 18 P11 ##STR00200## Example 18 P12 ##STR00201## Example 18
P13 ##STR00202## Example 18 P14 ##STR00203## Example 18 P15
##STR00204## Example 18 P16 ##STR00205## Example 18 P17
##STR00206## Scheme 4 P18 ##STR00207## Scheme 4 P19 ##STR00208##
Scheme 4 P20 ##STR00209## Scheme 4 P21 ##STR00210## Scheme 4 P22
##STR00211## Example 18 P23 ##STR00212## Example 18 P24
##STR00213## Example 18 P25 ##STR00214## Example 18 P26
##STR00215## Example 18 P27 ##STR00216## Example 18 P28
##STR00217## Examples 18, 19, 20, or 21 P29 ##STR00218## Examples
18, 19, 20, or 21 P30 ##STR00219## Examples 18, 19, 20, or 21 P31
##STR00220## Examples 18, 19, 20, or 21 P32 ##STR00221## Examples
18, 19, 20, or 21 P33 ##STR00222## Examples 18, 19, 20, or 21 P34
##STR00223## Examples 18, 19, 20, or 21 P35 ##STR00224## Examples
18, 19, 20, or 21 P36 ##STR00225## Examples 18, 19, 20, or 21 P37
##STR00226## Examples 18, 19, 20, or 21 P38 ##STR00227## Examples
18, 19, 20, or 21 P39 ##STR00228## Examples 18, 19, 20, or 21 P40
##STR00229## Examples 18, 19, 20, or 21 P41 ##STR00230## Examples
18, 19, 20, or 21 P42 ##STR00231## Examples 18, 19, 20, or 21 P43
##STR00232## Examples 18, 19, 20, or 21 P44 ##STR00233## Examples
18, 19, 20, or 21 P45 ##STR00234## Examples 18, 19, 20, or 21 P46
##STR00235## Examples 18, 19, 20, or 21 P47 ##STR00236## Examples
18, 19, 20, or 21 P48 ##STR00237## Examples 18, 19, 20, or 21 P49
##STR00238## Examples 18, 19, 20, or 21 P50 ##STR00239## Examples
18, 19, 20, or 21 P51 ##STR00240## Examples 18, 19, 20, or 21 P52
##STR00241## Examples 18, 19, 20, or 21 P53 ##STR00242## Examples
18, 19, 20, or 21 P54 ##STR00243## Examples 18, 19, 20, or 21
Example A
Bioassays on Beet Armyworm ("BAW") and Cabbage Looper ("CL")
[0521] BAW has few effective parasites, diseases, or predators to
lower its population. BAW infests many weeds, trees, grasses,
legumes, and field crops. In various places, it is of economic
concern upon asparagus, cotton, corn, soybeans, tobacco, alfalfa,
sugar beets, peppers, tomatoes, potatoes, onions, peas, sunflowers,
and citrus, among other plants. CEW is known to attack corn and
tomatoes, but it also attacks artichoke, asparagus, cabbage,
cantaloupe, collards, cowpeas, cucumbers, eggplant, lettuce, lima
beans, melon, okra, peas, peppers, potatoes, pumpkin, snap beans,
spinach, squash, sweet potatoes, and watermelon, among other
plants. CEW is also known to be resistant to certain insecticides.
CL feeds on a wide variety of cultivated plants and weeds. It feeds
readily on crucifers, and has been reported damaging broccoli,
cabbage, cauliflower, Chinese cabbage, collards, kale, mustard,
radish, rutabaga, turnip, and watercress. Other vegetable crops
injured include beet, cantaloupe, celery, cucumber, lima bean,
lettuce, parsnip, pea, pepper, potato, snap bean, spinach, squash,
sweet potato, tomato, and watermelon. CL is also known to be
resistant to certain insecticides. Consequently, because of the
above factors control of these pests is important. Furthermore,
molecules that control these pests are useful in controlling other
pests.
[0522] Certain molecules disclosed in this document were tested
against BAW and CEW and CL using procedures described in the
following examples. In the reporting of the results, the "BAW &
CL Rating Table" was used (See Table Section).
Bioassays on BAW (Spodoptera exigua)
[0523] Bioassays on BAW were conducted using a 128-well diet tray
assay. one to five second instar BAW larvae were placed in each
well (3 mL) of the diet tray that had been previously filled with 1
mL of artificial diet to which 50 .mu.g/cm.sup.2 of the test
compound (dissolved in 50 .mu.L of 90:10 acetone-water mixture) had
been applied (to each of eight wells) and then allowed to dry.
Trays were covered with a clear self-adhesive cover, and held at
25.degree. C., 14:10 light-dark for five to seven days. Percent
mortality was recorded for the larvae in each well; activity in the
eight wells was then averaged. The results are indicated in the
tables entitled "Table ABC: Assay Results (F)","Table ABCD: Assay
Results (C)", and "Table ABCDE: Assay Results (P)" (See Table
Section).
Bioassays on CL (Trichoplusia ni)
[0524] Bioassays on CL were conducted using a 128-well diet tray
assay. One to five second instar CL larvae were placed in each well
(3 mL) of the diet tray that had been previously filled with 1 mL
of artificial diet to which 50 .mu.g/cm.sup.2 of the test compound
(dissolved in 50 .mu.L of 90:10 acetone-water mixture) had been
applied (to each of eight wells) and then allowed to dry. Trays
were covered with a clear self-adhesive cover, arid held at
25.degree. C., 14:10 light-dark for five to seven days. Percent
mortality was recorded for the larvae in each well; activity in the
eight wells was then averaged. The results are indicated in the
table entitled "Table ABC: Assay Results (F)","Table ABCD: Assay
Results (C)", and "Table ABCDE: Assay Results (P)" (See Table
Section).
Example B
Bioassays on Green Peach Aphid ("GPA") (Myzus persicae).
[0525] GPA is the most significant aphid pest of peach trees,
causing decreased growth, shriveling of the leaves, and the death
of various tissues. It is also hazardous because it acts as a
vector for the transport of plant viruses, such as potato virus Y
and potato leafroil virus to members of the nightshade/potato
family Solanaceae, and various mosaic viruses to many other food
crops. GPA attacks such plants as broccoli, burdock, cabbage,
carrot, cauliflower, daikon, eggplant, green beans, lettuce,
macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress,
and zucchini, among other plants. GPA also attacks many ornamental
crops such as carnation, chrysanthemum, flowering white cabbage,
poinsettia, and roses. GPA has developed resistance to many
pesticides.
[0526] Certain molecules disclosed in this document were tested
against GPA using procedures described in the following example. In
the reporting of the results, the "GPA & YFM Rating Table" was
used (See Table Section).
[0527] Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5
cm) true leaves, were used as test substrate. The seedlings were
infested with 20-50 GPA (wingless adult and nymph stages) one day
prior to chemical application. Four pots with individual seedlings
were used for each treatment. Test compounds (2 mg) were dissolved
in 2 mL of acetone/MeOH (1:1) solvent, forming stock solutions of
1000 ppm test compound. The stock solutions were diluted 5X with
0.025% Tween 20 in water to obtain the solution at 200 ppm test
compound. A hand-held aspirator-type sprayer was used for spraylng
a solution to both sides of cabbage leaves until runoff. Reference
plants (solvent check) were sprayed with the diluent only
containing 20% by volume of acetone/MeOH (1:1) solvent. Treated
plants were held in a holding room for three days at approximately
25.degree. C. and ambient relative humidity (RH) prior to grading.
Evaluation was conducted by counting the number of live aphids per
plant under a microscope. Percent Control was measured by using
Abbott's correction formula (W. S. Abbott, "A Method of Computing
the Effectiveness of an Insecticide" J. Econ. Entomol. 18 (1925),
pp.265-267) as follows. Corrected % Control=100*(X-Y)/X where X=No.
of live aphids on solvent check plants and Y =No. of live aphids on
treated plants. The results are indicated in the table entitled
"Table ABC: Assay Results (F)" and "Table ABCD: Assay Results (C)"
(See Table Section).
Example C
Bioassays on Yellow Fever Mosquito "YFM" (Aedes aegypti).
[0528] YFM prefers to feed on humans during the daytime and is most
frequently found in or near human habitations. YFM is a vector for
transmitting several diseases. It is a mosquito that can spread the
dengue fever and yellow fever viruses. Yellow fever is the second
most dangerous mosquito-bome disease after malaria. Yellow fever is
an acute viral hemorrhagic disease and up to 50% of severely
affected persons without treatment will die from yellow fever.
There are an estimated 200,000 cases of yellow fever, causing
30,000 deaths, worldwide each year. Dengue fever is a nasty, viral
disease; it is sometimes called "breakbone fever" or "break-heart
fever" because of the intense pain it can produce. Dengue fever
kills about 20,000 people annually. Consequently, because of the
above factors control of this pest is important. Furthermore,
molecules that control this pest (YFM), which is known as a sucking
pest, are useful in controlling other pests that cause human and
animal suffering.
[0529] Certain molecules disclosed in this document were tested
against YFM using procedures described in the following paragraph.
in the reporting of the results, the "GPA & YFM Rating Table"
was used (See Table Section).
[0530] Master plates containing 400 .mu.g of a molecule dissolved
in 100 .mu.L of dimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm
solution) are used. A master plate of assembled molecules contains
15 .mu.L per well. To this plate, 135 .mu.L of a 90:10
water:acetone mixture is added to each well. A robot (Biomek.RTM.
NXP Laboratory Automation Workstation) is programmed to dispense 15
.mu.L aspirations from the master plate into an empty 96-well
shallow plate ("daughter" plate). There are 6 reps ("daughter"
plates) created per master. The created daughter plates are then
immediately infested with YFM larvae. The day before plates are to
be treated, mosquito eggs are placed in Millipore water containing
liver powder to begin hatching (4 g. into 400 mL). After the
daughter plates are created using the robot, they are infested with
220 .mu.L of the liver powder/larval mosquito mixture (about 1
day-old larvae). After plates are infested with mosquito larvae, a
non-evaporative lid is used to cover the plate to reduce drylng.
Plates are held at room temperature for 3 days prior to grading.
After 3 days, each well is observed and scored based on mortality.
The results are indicated in the table entitled "Table ABC: Assay
Results (F)" and "Table ABCD: Assay Results (C)" (See Table
Section).
Pesticidally Acceptable Acid Addition Salts, Salt Derivatives,
Solvates, Ester Derivatives, Polymorphs, Isotopes and
Radionuclides
[0531] Molecules of Formula One may be formulated into pesticidally
acceptable acid addition salts. By way of a non-limiting example,
an amine function can form salts with hydrochloric, hydrobromic,
sulfuric, phosphoric, acetic, benzoic, citric, malonic, salicylic,
malic, fumaric, oxalic, succinic, tartaric, lactic, gluconic,
ascorbic, maleic, aspartic, benzenesulfonic, methanesulfonic,
ethanesulfonic, hydroxymethanesulfonic, and hydroxyethanesulfonic
acids. Additionally, by way of a non-limiting example, an acid
function can form salts including those derived from alkali or
alkaline earth metals and those derived from ammonia and amines.
Examples of preferred cations include sodium, potassium, and
magnesium.
[0532] Molecules of Formula One may be formulated into salt
derivatives. By way of a non-limiting example, a salt derivative
can be prepared by contacting a free base with a sufficient amount
of the desired acid to produce a salt. A free base may be
regenerated by treating the salt with a suitable dilute aqueous
base solution such as dilute aqueous sodium hydroxide (NaOH),
potassium carbonate, ammonia, and sodium bicarbonate. As an
example, in many cases, a pesticide, such as 2,4-D, is made more
water-soluble by converting it to its dimethylamine salt.
[0533] Molecules of Formula One may be formulated into stable
complexes with a solvent, such that the complex remains intact
after the non-complexed solvent is removed. These complexes are
often referred to as "solvates." However, it is particularly
desirable to form stable hydrates with water as the solvent.
[0534] Molecules of Formula One may be made into ester derivatives.
These ester derivatives can then be applied in the same manner as
the invention disclosed in this document is applied.
[0535] Molecules of Formula One may be made as various crystal
polymorphs. Polymorphism is important in the development of
agrochemicals since different crystal polymorphs or structures of
the same molecule can have vastly different physical properties and
biological performances.
[0536] Molecules of Formula One may be made with different
isotopes. Of particular importance are molecules having .sup.2H
(also known as deuterium) in place of .sup.1H.
[0537] Molecules of Formula One may be made with different
radionuclides. Of particular importance are molecules having
.sup.14C.
Stereoisomers
[0538] Molecules of Formula One may exist as one or more
stereoisomers. Thus, certain molecules can be produced as racemic
mixtures. It will be appreciated by those skilled in the art that
one stereoisomer may be more active than the other stereoisomers.
Individual stereoisomers may be obtained by known selective
synthetic procedures, by conventional synthetic procedures using
resolved starting materials, or by conventional resolution
procedures. Certain molecules disclosed in this document can exist
as two or more isomers. The various isomers include geometric
isomers, diastereomers, and enantiomers. Thus, the molecules
disclosed in this document include geometric isomers, racemic
mixtures, individual stereoisomers, and optically active mixtures.
It will be appreciated by those skilled in the art that one isomer
may be more active than the others. The structures disclosed in the
present disclosure are drawn in only one geometric form for
clarity, but are intended to represent all geometric forms of the
molecule.
Combinations
[0539] Molecules of Formula One may also be used in combination
(such as, in a compositional mixture, or a simultaneous or
sequential application) with one or more compounds having
acaricidal, algicidal, avicidal, bactericidal, fungicidal,
herbicidai, insecticidal, molluscicidal, nematicidal, rodenticidal,
or virucidal properties. Additionally, the molecules of Formula One
may also be used in combination (such as, in a compositional
mixture, or a simultaneous or sequential application) with
compounds that are antifeedants, bird repellents, chemosterilants,
herbicide safeners, insect attractants, insect repellents, mammal
repelients, mating disrupters, plant activators, plant growth
regulators, or syneraists. Examples of such compounds in the above
groups that may be used with the Molecules of Formula One
are--(3-ethoxypropyl)mercury bromide, 1,2-dichloropropane,
1,3-dichloropropene, 1-methylcyclopropene, 1-naphthol,
2-(octylthio)ethanol, 2,3,5-tri-iodobenzoic acid, 2,3,6-TBA,
2,3,6-TBA-dimethylammonium, 2,3,6-TBA-lithium, 2,3,6-TBA-potassium,
2,3,6-TBA-sodium, 2,4,5-T, 2,4,5-T-2-butoxypropyl,
2,4,5-T-2-ethylhexyl, 2,4,5-T-3-butoxypropyl, 2,4,5-TB,
2,4,5-T-butometyl, 2,4,5-T-butotyl, 2,4,5-T-isobutyl,
2,4,5-T-isoctyl, 2,4,5-T-isopropyl, 2,4,5-T-methyl, 2,4,5-T-pentyl,
2,4,5-T-sodium, 2,4,5-T-triethylammonium, 2,4,5-T-trolamine, 2,4-D,
2,4-D-2-butoxypropyl, 2,4-D-2-ethylhexyl, 2,4-D-3-butoxypropyl,
2,4-D-ammonium, 2,4-DB, 2,4-DB-butyl, 2,4-DB-dimethylammonium,
2,4-DB-isoctyl, 2,4-DB-potassium, 2,4-DB-sodium, 2,4-D-butotyl,
2,4-D-butyl, 2,4-D-diethylammonium, 2,4-D-dimethylammonium,
2,4-D-diolamine, 2,4-D-dodecylammonium, 2,4-DEB, 2,4-DEP,
2,4-D-ethyl, 2,4-D-heptylammonium, 2,4-D-isobutyl, 2,4-D-isoctyl,
2,4-D-isopropyl, 2,4-D-isopropylammonium, 2,4-D-lithium,
2,4-D-meptyl, 2,4-D-methyl, 2,4-D-octyl, 2,4-D-pentyl,
2,4-D-potassium, 2,4-D-propyl, 2,4-D-sodium, 2,4-D-tefuryl,
2,4-D-tetradecylammonium, 2,4-D-triethylammonium,
2,4-D-tris(2-hydroxypropyl)ammonium, 2,4-D-trolamine, 2iP,
2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DB, 3,4-DP,
4-aminopyridine, 4-CPA, 4-CPA-potassium, 4-CPA-sodium, 4-CPB,
4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,
8-phenylmercurioxyquinoline, abamectin, abscisic add, ACC,
acephate, acequinocyl, acetamiprid, acethion, acetochlor,
acetophos, acetoprole, acibenzolar, acibenzolar-S-methyl,
acifluorfen, acifluorfen-methyl, acifluorfen-sodium, aclonifen,
acrep, acrinathrin, acrolein, acrylonitrile, acypetacs,
acypetacs-copper, acypetacs-zinc, alachlor, alanycarb, albendazole,
aldicarb, aldimorph, aldoxycarb, aldrin, allethrin, ailicin,
allidochlor, allosarnidin, alloxydim, alloxydim-sodium, ally!
alcohol, allyxycarb, alorac, alpha-cypermethrin, alpha-endosulfan,
ametoctradin, ametridione, ametryn, amibuzin, amicarbazone,
amicarthiazol, amidithion, amidoflumet, amidosulfuron, aminocarb,
aminocyclopyrachlor, aminocyclopyrachlor-methyl,
aminocyclopyrachlor-potassium, aminopyralid,
aminopyralid-potassium, aminopyralid-tris(2-hydroxypropyl)ammonium,
amiprofos-methyl, amiprophos, amisulbrom, amiton, amiton oxalate,
amitraz, amitrole, ammonium sulfamate, ammonium
.alpha.-naphthaleneacetate, amobam, ampropylfos, anabasine,
ancyrnidol, anilazine, anilolos, anisuron, anthraquinone, antu,
apholate, aramite, arsenous oxide, asornate, aspirin, asulam,
asulam-potassium, asularn-sodium, athidathion, atraton, atrazine,
aureofungin, avialycine, aviglycine hydrochloride, azaconazole,
azadirachtin, azafenidin, azamethiphos, azimsulfuron,
azinphos-ethyl, azinphos-methyl, aziprotryne, azithiram,
azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh,
barban, barium hexafluorosilicate, barium polysulfide, barthrin,
BCPC, beflubutamid, benalaxyl, benalaxyl-M, benazolin,
benazolin-dimethylammonium, benazolin-ethyl, benazolin-potassium,
bencarbazone, benclothiaz, bendiocarb, benfluralin, benfuracarb,
benfuresate, benodanil, benomyl, benoxacor, benoxafos, benquinox,
bensulfuron, bensulfuron-methyl, bensulide, bensultap, bentaluron,
bentazone, bentazone-sodium, benthiavalicarb,
benthiavalicarb-isopropyl, benthiazole, bentranil, benzadox,
benzadox-ammonium, benzalkonium chloride, benzamacril,
benzamacril-isobutyl, benzamorf, benzfendizone, bent pram,
benzobicyclon, benzofenap, benzofluor, benzohydroxamic acid,
benzoximate, benzoylprop, benzoylprop-ethyl, benzthiazuron, benzyl
benzoate, benzylademine, berberine, berberine chloride,
beta-cyfluthrin, beta-cypermethrin, bethoxazin, bicyclopyrone,
bifenazate, bifenox, bifenthrin, bifujunzhi, bilanafos,
bilanafos-sodium, binapacryl, bingqingxiao, bioallethrin,
bioethanomethrin, biopermethrin, bioresmethrin, biphenyl, bisazir,
bismerthiazol, bispyribac, bispyribac-sodium, bistrifluron,
bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeaux
mixture, boric acid, boscalid, brassinolide, brassinolide-ethyl,
brevicomin, brodifacoum, brofenvalerate, brofluthrinate, bromacil,
bromacil-lithium, bromacil-sodium, bromadiolone, bromethalin,
bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide,
bromocyclen, bromo-DDT, bromofenoxim, bromophos, bromophos-ethyl,
bromopropylate, bromothalonil, bromoxynil, bromoxynil butyrate,
bromoxynil heptanoate, bromoxynil octanoate, bromoxynil-potassium,
brompyrazon, bromuconazole, bronopol, bucarpolate, bufencarb,
buminafos, bupirimate, buprofezin, Burgundy mixture, busulfan,
butacarb, butachlor, butafenacil, butamifos, butathiofos,
butenachlor, butethrin, buthidazole, buthiobate, buthiuron,
butocarboxim, butonate, butopyronoxyl, butoxycarboxim, butralin,
butroxydim, buturon, butylamine, butylate, cacodylic acid,
cadusafos, cafenstrole, calcium arsenate, calcium chlorate, calcium
cyanamide, calcium polysulfide, caivinphos, cambendichlor,
carnphechlor, camphor, captafol, captan, carbamorph, carbanolate,
carbaryl, carbasulam, carbendazim, carbendazim benzenesulfonate,
carbendazim sulfite, carbetamide, carbofuran, carbon disulfide,
carbon tetrachloride, carbophenothion, carbosulfan, carboxazole,
carboxide, carboxin, carfentrazone, carfentrazone-ethyl,
carpropamid, cartap, cartap hydrochloride, carvacrol, carvone,
CDEA, cellocidin, CEPC, ceralure, Cheshunt mixture, chinomethionat,
chitosan, chlobenthiazone, chlomethoxyfen, chloralose, chloramben,
chloramben-ammonium, chloramben-diolamine, chloramben-methyl,
chloramben-methylammonium, chloramben-sodium, chloramine
phosphorus, chloramphenicol, chloraniformethan, chloranil,
chloranocryl, chlorantraniliprole, chlorazifop,
chlorazifop-propargyl, chlorazine, chlorbenside, chlorbenzuron,
chlorbicyclen, chlorbromuron, chlorbufam, chlordane, chlordecone,
chlordimeform, chlordimeform hydrochloride, chlorempenthrin,
chlorethoxyfos, chloreturon, chlorfenac, chlorfenac-ammonium,
chlorfenac-sodium, chlorfenapyr, chlorfenazole, chlorfenethol,
chlorfenprop, chlorfenson, chlorfensuiphide, chlorfenvinphos,
chlorfluazuron, chlorflurazole, chlorfluren, chlorfluren-methyl,
chlorflurenol, chlorflurenol-methyl, chloridazon, chlorimuron,
chlorimuron-ethyl, chlormephos, chlormequat, chlormequat chloride,
chlornidine, chlornitrofen, chlorobenzilate,
chlorodinitronaphthalenes, chloroform, chloromebuform,
chloromethiuron, chloroneb, chlorophacinone,
chlorophacinone-sodium, chloropicrin, chloropon, chloropropylate,
chlorothalonil, chlorotoluron, chloroxuron, chloroxynil,
chlorphonium, chlorphonium chloride, chlorphoxim, chlorprazophos,
chlorprocarb, chlorpropham, chlorpyrifos, chlorpyrifos-methyl,
chlorquinox, chlorsulfuron, chlorthal, chlorthal-dimethyl,
chlorthal-monomethyl, chlorthiamid, chlorthiophos, chlozolinate,
choline chloride, chromafenozide, cinerin I, cinerin II, cinerins,
cinidon-ethyl, cinmethylin, cinosulfuron, clobutide, cisanilide,
cismethrin, clethodim, climbazole, cliodinate, clodinairop,
clodinafop-propargyl, cloethocarb, clofencet, clofencet-potassium,
clofentezine, clofibric acid, clofop, clofop-isobutyl, clomazone,
clomeprop, cloprop, cloproxydim, clopyralid, clopyralid-methyl,
clopyralid-olamine, clopyralid-potassium,
clopyralid-tris(2-hydroxypropyl)ammonium, cloquintocet,
cloquintocet-mexyl, cloransulam, cloransulam-methyl, closantel,
clothianidin, clotrimazole, cloxyfonac, cloxyfonac-sodium, CMA,
codlelure, colophonate, copper acetate, copper acetoarsenite,
copper arsenate, copper carbonate, basic, copper hydroxide, copper
naphthenate, copper oleate, copper oxychloride, copper silicate,
copper sulfate, copper zinc chromate, coumachlor, coumafuryl,
coumaphos, coumatetralyl, coumithoate, coumoxystrobin, CPMC, CPMF,
CPPC, credazine, cresol, crimidine, crotamiton, crotoxyphos,
crufomate, cryolite, cue-lure, cufraneb, cumyluron, cuprobam,
cuprous oxide, curcumenol, cyanamide, cyanatryn, cyanazine,
cyanofenphos, cyanophos, cyanthoate, cyantraniliprole, cyazofamid,
cybutryne, cyclafuramid, cyclanilide, cyciethrin, cycloate,
cycloheximide, cycloprate, cycloprothrin, cyclosulfamuron,
cycloxaprid, cycloxydim, cycluron, cyenopyrafen, cyflufenamid,
cyflumetofen, cyfluthrin, cyhalofop, cyhalofop-butyl, cyhalothrin,
cyhexatin, cymiazole, cymiazole hydrochloride, cymoxanil,
cyometrinil, cypendazole, cypermethrin, cyperquat, cyperquat
chloride, cyphenothrin, cyprazine, cyprazole, cyproconazole,
cyprodinil, cyprofuram, cypromid, cyprosulfamide, cyromazine,
cythloate daimuron, dalapon, dalapon-calcium, dalapon-magnesium,
dalapon-sodium, daminozide, dayoutong, dazomet, dazomet-sodium,
DBCP, d-camphor, DCIP, DCPTA, DDT, debacarb, decafentin,
decarbofuran, dehydroacetic acid, delachlor, deltamethrin,
demephion, demephion-O, demephion-S, demeton, demeton-methyl,
demeton-O, demeton-O-methyl, demeton-S, demeton-S-methyl,
demeton-S-methylsulphon, desmedipham, desmetryn,
d-fanshiluquebingjuzhi, diafenthiuron, dialifos, di-ailate,
diamidafos, diatomaceous earth, diazinon, dibutyl phthalate,
dibutyl succinate, dicamba, dicamba-diglycolamine,
dicamba-dimethylammonium, dicamba-diolamine,
dicamba-isopropylammonium, dicamba-methyl, dicamba-olamine,
dicamba-potassium, dicamba-sodium, dicamba-trolamine, dicapthon,
dichlobenil, dichlofenthion, dichlofluanid, dichlone,
dichloralurea, dichlorbenzuron, dichlorflurenol,
dichlorflurenol-methyl, dichlormate, dichlormid, dichlorophen,
dichlorprop, dichlorprop-2-ethylhexyl, dichlorprop-butotyl,
dichlorprop-dimethylammonium, dichlorprop-ethylammonium,
dichlorprop-isoctyl, dichlorprop-methyl, dichlorprop-P,
dichlorprop-P-2-ethylhexyl, dichlorprop-P-dimethylammonium,
dichlorprop-potassium, dichlorprop-sodium, dichlorvos,
dichlozoline, diclobutrazol, diclocymet, diclofop, diclofop-methyl,
diclomezine, diclomezine-sodium, dicloran, diclosulam, dicofol,
dicoumarol, dicresyl, dicrotophos, dicyclanil, dicyclonon,
dieldrin, dienochlor, diethamquat, diethamquat dichloride,
diethatyl, diethatyl-ethyl, diethofencarb, dietholate, diethyl
pyrocarbonate, diethyltoluamide, difenacoum, difenoconazole,
difenopenten, difenopenten-ethyl, difenoxuron, difenzoquat,
difenzoquat metilsulfate, difethialone, diflovidazin,
diflubenzuron, diflufenican, diflufenzopyr, diflufenzopyr-sodium,
diflumetorim, dikegulac, dikegulac-sodium, dilor, dimatif,
dimefluthrin, dimefox, dimefuron, dimepiperate, dimetachlone,
dimetan, dimethacarb, dimethachlor, dimethametryn, dimethenamid,
dimethenamid-P, dimethipin, dimethirimol, dimethoate, dimethomorph,
dimethrin, dimethyl carbate, dimethyl phthalate, dimethylvinphos,
dimetilan, dimexano, dimidazon, dimoxystrobin, dinex,
dinex-diclexine, dingjunezuo, diniconazole, diniconazole-M,
dinitrarmine, dinobuton, dinocap, dinocap-4, dinocap-6, dinocton,
dinofenate, dinopenton, dinoprop, dinosaur, dinoseb, dinoseb
acetate, dinoseb-ammonium, dinoseb-diolamine, dinoseb-sodium,
dinoseb-trolamine, dinosulfon, dinotefuran, dinoterb, dinoterb
acetate, dinoterbon, diofenolan, dioxabenzofos, dioxacarb,
dioxathion, diphacinone, diphacinone-sodium, diphenamid, diphenyl
sulfone, diphenylamine, dipropalin, dipropetryn, dipyrithione,
diquat, diquat dibromide, disparlure, disul, disulfiram,
disulfoton, disul-sodium, ditalimfos, dithianon, dithicrofos,
dithioether, dithiopyr, diuron, d-limonene, DMPA, DNOC,
DNOC-ammonium, DNOC-potassium, DNOC-sodium, dodemorph, dodemorph
acetate, dodemorph benzoate, dodicin, dodicin hydrochloride,
dodicin-sodium, dodine, dofenapyn, dominicalure, doramectin,
drazoxolon, DSMA, dufulin, EBEP, EBP, ecdysterone, edifenphos,
eglinazine, eglinazine-ethyl, emamectin, emamectin benzoate, EMPC,
empenthrin, endosulfan, endothal, endothal-diammonium,
endothal-dipotassium, endothal-disodium, endothion, endrin,
enestroburin, EPN, epocholeone, epofenonane, epoxiconazole,
eprinomectin, epronaz, EPTC, erbon, ergocalciferol,
erlujixiancaoan, esdepallethrine, esfenvalerate, esprocarb,
etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor,
ethafluralin, ethametsulfuron, ethametsulfuron-methyl,
ethaprochlor, ethephon, ethidimuron, ethiofencarb, ethiolate,
ethion, ethiozin, ethiprole, ethirimol, ethoate-methyl,
ethofumesate, ethohexadiol, ethoprophos, ethoxyfen,
ethoxyfen-ethyl, ethoxyquin, ethoxysulfuron, ethychlozate, ethyl
formate, ethyl .alpha.-naphthaleneacetate, ethyl-DDD, ethylene,
ethylene dibromide, ethylene dichloride, ethylene oxide, ethylicin,
ethylmercury 2,3-dihydroxypropyl mercaptide, ethylmercury acetate,
ethylmercury bromide, ethylmercury chloride, ethylmercury
phosphate, etinofen, etnipromid, etobenzanid, etofenprox,
etoxazole, etridiazole, etrimfos, euaenol, EXD, famoxadone,
famphur, fenamidone, fenaminosulf, fenamiphos, fenapanil,
fenarimoi, fenasulam, fenazaflor, fenazaguin, fenbuconazole,
fenbutatin oxide, fenchlorazole, fenchlorazole-ethyl, fenchlorphos,
fenclorim, fenethacarb, fenfluthrin, fenfuram, fenhexamid,
fenitropan, fenitrothion, fenjuntong, fenobucarb, fenoprop,
fenoprop-3-butoxypropyl, fenoprop-butometyl, fenoprop-butotyl,
fenoprop-butyl, fenoprop-isoctyl, fenoprop-methyl,
fenoprop-potassium, fenothiocarb, fenoxacrim, fenoxanil,
fenoxaprop, fenoxaprop-ethyl, fenoxaprop-P, fenoxaprop-P-ethyl,
fenoxasulfone, fenoxycarb, fenpiclonil, fenpirithrin,
fenpropathrin, fenpropidin, fenpropimorph, fenpyrazamine,
fenpyroximate, fenridazon, fenridazon-potassium, fenridazon-propyl,
fenson, fensulfothion, fenteracol, fenthiaprop, fenthiaprop-ethyl,
fenthion, fenthion-ethyl, fentin, fentin acetate, fentin chloride,
fentin hydroxide, fentrazamide, fentrifanil, fenuron, fenuron TCA,
fenvalerate, ferbam, ferimzone, ferrous sulfate, fipronil,
flamprop, flamprop-isopropyl, flamprop-M, flamprop-methyl,
flamprop-M-isopropyl, flamprop-M-methyl, flazasulfuron,
flocourmafen, flometoquin, flonicamid, florasulam, fluacrypyrim,
fluazifop, fluazifop-butyl, fluazifop-methyl, fluazifop-P,
fluazifop-P-butyl, fluazinam, fluazolate, fluazuron, flubendiamide,
flubenzimine, flucarbazone, flucarbazone-sodium, flucetosulfuron,
fluchloralin, flucofuron, flucycloxuron, flucythrinate,
fludioxonil, fluenetil, fluensulfone, flufenacet, flufenerim,
flufenican, flufenoxuron, flufenprox, flufenpyr, flufenpyr-ethyl,
flufiprole, flumethrin, flumetover, flumetrahn, flumetsulam,
flumezin, flumiclorac, flumiclorac-pentyl, flumiaxazin,
flurnipropyn, flurnorph, fluometuron, fluopicolide, fluopyram,
fluorbenside, fluoridamid, fluoroacetarnide, fluorodifen,
fluorogycofen, fluoroglycofen-ethyl, fluoroimide, fluoromicline,
fluoronitrofen, fluothiuron, fluotrimazole, fluoxastrobin,
flupoxam, flupropacil, flupropadine, flupropanate,
flupropanate-sodium, flupyradifurone, flupyrsulfuron,
flupyrsulfuron-methyl, flupyrsulfuron-methyl-sodium,
fluquinconazole, flurazole, flurenol, flurenol-butyl,
flurenol-methyl, fluridone, flurochloridone, fluroxypyr,
fluroxypyr-butometyl, fluroxypyr-meptyl, flurphmidol, flursulamid,
flurtamone, flusilazoie, flusulfamide, fluthiacet,
fluthiacet-methyl, flutianii, flutoianil, flutriafol, fluvalinate,
fluxapyroxad, fluxofenim, folpet, fomesafen, fomesafen-sodium,
fonofos, foramsulfuron, forchlorfenuron, formaldehyde, formetanate,
formetanate hydrochloride, formothion, formparanate, formparanate
hydrochloride, fosamine, fosamine-ammonium, fosetyl,
fosetyl-aluminium, fosmethilan, fospirate, fosthiazate, fosthietan,
frontalin, fuberidazole, fucaojing, fucaomi, funaihecaoling,
fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr,
furathiocarb, furcarbanil, furconazole, furconazole-cis, furethrin,
furfural, furilazole, furmecyclox, furophanate, furyloxyfen,
gamma-cyhalothrin, garnma-HCH, genit, gibberellic acid,
gibberellins, gliitor, glufosinate, glufosinate- ammonium,
glufosinate-P, glufosinate-P-ammonium, glufosinate-P-sodium, gk
.sub.iodin, glyoxime, glyphosate, glyphosate-diammonium,
glyphosate-dimethylammonium, glyphosate-isopropylammonium,
glyphosate-monoammonium, glyphosate-potassium,
glyphosate-sesquisodium, glyphosate-trimesium, glyphosine,
gossyplure, grandlure, griseofulvin, guazatine, guazatine acetates,
halacrinate, halfenprox halofenozide, halosafen, halosulfuron,
halosulfuron-methyl, haloxydine, haloxyfop, haloxyfop-etotyl,
haloxyfop-methyl, haloxyfop-P, haloxyfop-P-etotyl,
haloxyfop-P-methyl, haloxyfop-sodium, HCH, hemel, hempa, HEAD,
heptachlor, heptenophos, heptopargil, heterophos,
hexachloroacetone, hexachlorobenzene, hexachlorobutadiene,
hexachlorophene, hexaconazole, hexaflumuron, hexaflurate, hexalure,
hexarnide, hexazinone, hexylthiofos, hexythiazox, HHDN, holosulf,
huancaiwo, huangcaolina, huanjunzuo, hydramethylnon, hydrargaphen,
hydrated lime, hydrogen cyanide, hydroprene, hymexazol, hyquincarb,
IAA, IBA, icaridin, imazalil, imazalil nitrate, imazalll sulfate,
imazamethabenz, imazamethabenz-methyl, imazamox, mazamox-ammonium,
imazapic, imazapic-ammonium, imazapyr, mazapyr-isopropylammonium,
imazaquin, imazaquin-ammonium, imazaquin-methyl, imazaquin-sodium,
imazethapyr, imazethapyr-ammonium, imazosulfuron, imibenconazole,
imicyafes, imidadoprid, imidaclothiz, iminoctadine, iminoctadine
triacetate, iminoctadine trialbesilate, imiprothrin, inabenfide,
indanofan, indazifiam, indoxacarb, inezin, iodobonil, odocarb,
iodomethane, iodosulfuron, iodosulfuron-methyl,
iodosulfuron-methyl-sodium, iofensulfuron, iofensulfuron-sodium,
ioxynil, ioxynil octanoate, ioxynil-lithium, ioxynil-sodium,
ipazine, ipconazole, ipfencarbazone, iprobenfos, iprodione,
iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, isamidofos,
isazofos, isobenzan, isocarbamid, isocarbophos, isocil, isodrin,
isofenphos, isofenphos-methyl, isolan, isomethiozin, isonoruron,
isopolinate, isoprocarb, isopropain, isoprothiolane, isoproturon,
isopyrazam, isopyrimol, isothioate, isotianil, isouron,
isovaledione, isoxaben, isoxachlortole, isoxadifen,
isoxadifen-ethyl, isoxaflutole, isoxapyrifop, isoxathion,
ivermectin, izopamfos, japonilure, japothrins, jasmolin I, jasmolin
II, jasmonic acid, jiahuangchongzong, jiajizengxiaolin,
jiaxiangjunzhi, jiecaowan, jiecaoxi, jodfenphos, juveniie hormone
I, juvenile hormone II, juvenile hormone III, kadethrin,
karbutilate, karetazan, karetazan-potassium, kasugamycin,
kasugamycin hydrochloride, kejunlin, kelevan, ketospiradox,
ketospiradox-potassium, kinetin, kinoprene, kresoxim-methyl,
kuicaoxi, lactofen, lambda-cyhalothrin, latilure, lead arsenate,
lenacil, lepimectin, leptophos, lindane, ineatin, linuron, irimfos,
litlure, loopure, lufenuron, lvdingjunzhi, lvxiancaolin,
lythidathion, MAA, malathion, maleic hydrazide, malonoben,
maitodextrin, MAMA, mancopper, mancozeb, mandipropamid, maneb,
matrine, mazidox, MCPA, MCPA-2-ethylhexyl, MCPA-butotyl,
MCPA-butyl, MCPA-dimethylammonium, MCPA-diolamine, MCPA-ethyl,
MCPA-isobutyl, MCPA-isoctyl, MCPA-isopropyl, MCPA-methyl,
MCPA-olamine, MCPA-potassium, MCPA-sodium, MCPA-thioethyl,
MCPA-trolamine, MCPB, MCPB-ethyl, MCPB-methyl, MCPB-sodium,
mebenil, mecarbam, mecarbinzid, mecarphon, mecoprop,
mecoprop-2-ethylhexyl, mecoprop-dimethylammonium,
mecoprop-diolamine, mecoprop-ethadyl, mecoprop-isoctyl,
mecoprop-methyl, mecoprop-P, mecoprop-P-2-ethylhexyl,
mecoprop-P-dimethylammonium, mecoprop-P-isobutyl,
mecoprop-potassium, mecoprop-P-potassium, mecoprop-sodium,
mecoprop-trolamine, medimeform, medinoterb, medinoterb acetate,
medlure, mefenacet, mefenpyr, mefenpyr-diethyl, mefluidide,
mefluidide-diolamine, mefluidide-potassium, megatomoic acid,
menazon, mepanipyrim, meperiluthrin, mephenate, mephosfolan,
mepiquat, mepiquat chloride, mepiquat pentaborate, mepronil,
meptyldinocap, mercuric chloride, mercuric oxide, mercurous
chloride, merphos, mesoprazine, mesosulfuron, mesosulfuron-methyl,
mesotrione, mesulfen, mesulfenfos, metaflumizone, metalaxyl,
metalaxyl-M, metaldehyde, metam, metam-ammonium, metamifop,
metamitron, metam-potassium, metam-sodium, metazachlor,
metazosulfuron, metazoxolon, metconazole, metepa, metflurazon,
methabenzthiazuron, methacrifos, methalpropalin, methamidophos,
methasulfocarb, methazole, methfuroxam, methidathion,
methiobencarb, methiocarb, methiopyrisulfuron, methiotepa,
methiozoin, methiuron, methocrotophos, methometon, methomyl,
methoprene, methoprotryne, methoquin-butyl, methothrin,
methoxychlor, methoxyfenozide, methoxyphenone, methyl apholate,
methyl bromide, methyl eugenol, methyl iodide, methyl
isothiocyanate, methylacetophos, methylchloroform methyldymron,
methylene chloride, methylmercury benzoate, methylmercury
dicyandiamide, methylmercury pentachlorophenoxide,
methylneodecanamide, metlram, rrietobenzuron, rrietobrornuron,
metofluthrin, metolachlor, metolcarb, metorninostrobin, metosulam,
metexadiazone, metexuron, metrafenone, metribuzin, metsulfovax,
metsulfuron, metsulfuron-methyl, mevinphos, mexacarbate, mieshuan,
milbemectin, milbemycin oxime, mlineb, mipafox, mirex, MNAF,
moguchun, molinate, molosultap, monalide, monisouron,
monochloroacetic acid, monocrotophos, monolinuron, monosulfuron,
monosulfuron-ester, monuron, monuron TCA, morfamquat, morfamquat
dichloride, moroxydine, moroxydine hydrochloride, morphothion,
morzid, moxidectin, MSMA, muscaiure, myclobutanii, myclozolin,
N-(ethylmercury)-p-toluenesulphonanilide, nabam, naftalofos, naled,
naphthalene, naphthaleneacetamide, naphthalic anhydride,
naphthoxyacetic acids, naproanilide, napropamide, naptalarn,
naptalam-sodiurn, natamycin, neburon, niclosamide,
niclosamide-olamine, nicosulfuron, nicotine, nifluridide,
nipyraclofen, nitenpyram, nithiazine, nitralin, nitrapyrin,
nitrilacarb, nitrofen, nitrofluorfen, nitrostyrene,
nitrothal-isopropyl, norbormide, norflurazon, nornicotine, noniron,
novaiuron, noviflumuron, nuarimol, OCH, octachlorodipropyl ether,
octhilinone, ofurace, omethoate, orbencarb, orfralure,
ortho-dichlorobenzene, orthosulfamuron, oryctaiure, orysastrobin,
oryzalin, osthol, ostramone, oxabetrinil, oxadiargyl, oxadiazon,
oxadixyl, oxamate, oxamyl, oxapyrazon, oxapyrazon-dimolarmine,
oxapyrazon-sodium, oxasulfuron, oxaziclomefone, oxine-copper,
oxolinic acid, oxpoconazole, oxpoconazole fumarate, oxycarboxin,
oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyfluorfen,
oxymatrine, oxytetracycline, oxytetracycline hydrochloride,
paclobutrazol, paichongding, para-dichlorobenzene, parafluron,
paraquat, paraquat dichloride, paraquat dimetilsulfate, parathion,
parathion-methyl, parinol, pebulate, pefurazoate, pelargonic acid,
penconazole, pencycuron, pendlmethalin, penflufen, penfluron,
penoxsulam, pentachlorophenol, pentanochlor, penthiopyrad,
pentmethrin, pentoxazone, perfluidone, permethrin, pethexamid,
phenarnacril, phenazine oxide, phenisopham, phenkapton,
phenmedipharn, phenmedipham-ethyl, phenobenzuron, phenothrin,
phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate,
phenylmercury chloride, phenylmercury derivative of pyrocatechol,
phenylmercury nitrate, phenylmercury salicylate, phorate,
phosacetim, phosalone, phosdiphen, phosfoian, phosfolan-methyl,
phosglycin, phosmet, phosnichlor, phosphamidon, phosphine,
phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide,
picloram, picloram-2-ethylhexyl, picloram-isoctyl, picloram-methyl,
picloram-olamine, picloram-potassiurn, picloram-triethylammonium,
picloram-tris(2-hydroxypropyl)ammonium, picolinafen, picoxystrobin,
pindone, pindone-sodium, pinoxaden, piperalin, piperonyl butoxide,
piperonyl cyclonene, piperophos, piproctanyl, piproctanyl bromide,
piprotal, pirimetaphos, pirimicarb pirimioxyphos, pirimiphos-ethyl,
pirimiphos-methyl, plifenate, polycarbamate, polyoxins, polyoxorim,
poiyoxorim-zinc, polythialan, potassium arsenite, potassium azide,
potassium cyanate, potassium gibberellate, potassium naphthenate,
potassium polysulfide, potassium thiocyanate, potassium
.alpha.-naphthaleneacetate, pp`-DDT, praliethrin, precocene I,
precocene II, precocene III, pretilachlor, primidophos,
primisulfuron, primisulfuron-methyl, probenazole, prochloraz,
prochloraz-manganese, proclonol, procyazine, procymidone,
prodiamine, profenofos, profluazol, profluralin, profluthrin,
profoxydim, proglinazine, proglinazine-ethyl, prohexadione,
prohexadione-calcium, prohydrojasmon, promacyl, promecarb,
prometon, prometryn, promurit, propachlor, propamidine, propamidine
dihydrochloride, propamocarb, propamocarb hydrochloride, propanil,
propaphos, propaquizafop, propargite, proparthrin, propazine,
propetamphos, propham, propiconazole, propineb, propisochlor,
propoxur, propoxycarbazone, propoxycarbazone-sodium, propyl isome,
propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin,
prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothiocarb
hydrochloride, prothioconazole, prothiofos, prothoate,
protrifenbute, proxan, proxan-sodium, prynachlor, pydanon,
pymetrozine, pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin,
pyraflufen, pyraflufen-ethyl, pyrafluprole, pyramat,
pyrametostrobin, pyraoxystrobin, pyrasulfotole, pyrazolynate,
pyrazophos, pyrazosulfuron, pyrazosulfuron-ethyl, pyrazothion,
pyrazoxyfen, pyresmethrin, pyrethrin I, pyrethrin II, pyrethrins,
pyribambenz-isopropyl, pyribarnbenz-propyl, pyribencarb,
pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol,
pyridalyl, pyridaphenthion, pyridate, pyridinitril, pyrifenox,
pyrifluquinazon, pyriftalid, pyrimethanil, pyrimidifen,
pyriminobac, pyriminobac-methyl, pyrimisulfan, pyrimitate,
pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen,
pyrithiobac, pyrithiobac-sodium, pyrolan, pyroquilon, pyroxasufone,
pyroxsulam, pyroxychlor, pyroxyfur, quassia, quinacetol, quinacetol
sulfate, quinalphos, quinalphos-methyl, quinonamid, quinclorac,
quinconazole, quinmerac, quinoclamine, quinonamid, quinothion,
quinoxyfen, quintiofos, quintozene, quizalofop, quizalofop-ethyl,
quizalofop-P, quizaiofop-P-ethyl, quizalofop-P-tefuryl, quwenzhi,
quylngding, rabenzazole, rafoxanide, rebemide, resmethrin,
rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rotenone,
ryania, saflufenacii, saijunmao, saisentong, salicylanilide,
sanguinarine, santonin, schradan, scilliroside, sebuthylazine,
secbumeton, sedaxane, selamectin, semiamitraz, semiamitraz
chloride, sesamex, sesamolin, sethoxydim, shuangjiaancaolin,
siduron, siglure, silafluofen, silatrane, silica gel, silthiofam,
simazine, simeconazole, simeton, simetryn, sintofen, SMA,
5-metolachlor, sodium arsenite, sodium azide, sodium chlorate,
sodium fluoride, sodium fluoroacetate, sodium hexafluorosilicate,
sodium naphthenate, sodium orthophenylphenoxide, sodium
pentachlorophenoxide, sodium polysulfide, sodium thiocyanate,
sodium .alpha.-naphthaleneacetate sophamide, spinetoram, spinosad,
spirodiclofen, spiromesifen, spirotetramat, spiroxamine,
streptomycin, streptomycin sesquisulfate, strychmine, sulcatol,
sulcofuron, sulcofuron-sodium, sulcotrione, sulfallate,
sulfentrazone, sulfiram, sulfluramid, sulfometuron,
sulfometuron-methyl, sulfosulfuron, sulfotep, sulfoxafior,
sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfuryl fluoride,
sulglycapin, sulprofos, suitropen, swep, tau-fluvalinate, tavron,
tazimcarb, TCA, TCA-ammonium, TCA-calcium, TCA-ethadyl,
TCA-magnesium, TCA-sodium, IDE, tebuconazole, tebufenozide,
tebufenpyrad, tebufloquin, tebupirimfos, tebutam, tebuthiuron,
tecloftalam, tecnazene, tecoram, teflubenzuron, tefluthrin,
tefuryltrione, tembotrione, temephos, tepa, TEPP, tepraloxydim,
terallethrin, terbacil, terbucarb, terbuchlor, terbufos,
terbumeton, terbuthylazine, terbutryn, tetcyclacis,
tetrachloroethane, tetrachlorvinphos, tetraconazole, tetradifon,
tetrafluron, tetramethrin, tetramethylfluthrin, tetramine,
tetranactin, tetrasul, thallium sulfate, thenylchlor,
theta-cypermethrin, thiabendazole, thiacloprid, thiadifluor,
thiamethoxam, thiapronil, thiazafluron, thiazopyr, thicrofos,
thicyofen, thidiazimin, thidiazuron, thiencarbazone,
thiencarbazone-methyl, thifensulfuron, thifensulfuron-methyl,
thifluzamide, obencarb, thiocarboxime, thiochlorfenphim,
thiocyclam, thiocyclam hydrochloride, thiocyclam oxalate,
thiodiazole-copper, thiodicarb, thiofanox, thiofluoximate,
thiohempa, thiomersal, thiometon, thionazin, thiophanate,
thiophanate-methyl, thioquinox, thiosemicarbazide, thiosultap,
thiosultap-diammonium, thiosultap-disodiurn, thiosultap-monosodium,
thiotepa, thiram, thuringiensin, tiadinil, tiaojiean, tiocarbazil,
tioclorim, tioxymid, tirpate, toiclofos-methyl, tolfenpyrad,
tolylfluanid, tolylmercury acetate, topramezone, tralkoxydim,
tralocythrin, traiomethrin, tralopyril, transfluthrin,
transpermethrin, tretamine, triacontanol, triadimefon, triadimenol,
triafamone, tri-aliate, triamiphos, triapenthenol, triarathene,
triarimol, triasulfuron, triazamate, triazbutil, triaziflam,
triazophos, triazoxide, tribenuron, tribenuron-methyl, tribufos,
tributyltin oxide, tricamba, trichlamide, trichlorfon,
trichlormetaphos-3, trichloronat, triclopyr, triclopyr-butotyl,
triclopyr-ethyl, triclopyr-triethylammonium, tricyclazole,
tridemorph, tridiphane, trietazine, trifenmorph, trifenofos,
trifloxystrobin, trifioxysulfuron, trifloxysulfuron-sodium,
triflurnizole, triflumuron, trifluralin, triflusulfuron,
triflusulfuron-methyl, trifop, trifop-methyl, trifopsime,
triforine, trihydroxytriazine, trimedlure, trimethacarb,
trimeturon, trinexapac, trinexapac-ethyl, triprene, tripropindan,
triptolide, tritac, triticonazole, tritosulfuron, trunc-call,
uniconazole, uniconazole-P, urbacide, uredepa, valerate,
validamycin, valifenalate, valone, vamidothion, vangard,
vaniliprole, vernolate, vinclozolin, warfarin, warfarin-potassium,
warfarin-sodium, xiaochongliulin, xinjunan, xiwojunan, XMC,
xylachlor, xylenols, xylylcarb, ylshijing, zarilamid, zeatin,
zengxiaoan, zeta-cypermethrin, zinc naphthenate, zinc phosphide,
zinc thiazole, zineb, zirarn, zolaprofos, zoxamide, zuomihuanglong,
.alpha.-chlorohydrin, .alpha.-ecdysone, .alpha.-multistriatin, and
.alpha.-naphthaleneacetic acid. For more information consult the
"COMPENDIUM OF PESTICIDE COMMON NAMES" located at alanwood net.
Also consult "THE PESTICIDE MANUAL" 14th Edition, edited by C D S
Tomlin, copyright 2006 by British Crop Production Council, or its
prior or more recent editions.
Biopesticides
[0540] Molecules of Formuia One may also be used in combination
(such as in a compositional mixture, or a simultaneous or
sequential application) with one or more biopesticides. The term
"biopesticide" is used for microbial biological pest control agents
that are applied in a similar manner to chemical pesticides.
Commonly these are bacterial, but there are also examples of fungal
control agents, including Trichoderma spp. and Ampelomyces
quisqualis (a control agent for grape powdery mildew). Bacillus
subtilis are used to control plant pathogens. Weeds and rodents
have also been controlied with microbial agents. One well-known
insecticide example is Bacillus thuringiensis, a bacterial disease
of Lepidoptera, Coieoptera, and Diptera. Because it has little
effect on other organisms, it is considered more environmentally
friendly than synthetic pesticides. Biological insecticides include
products based on:
[0541] 1. entomopathogenic fungi (e.g. Metarhizium anisopliae);
[0542] 2. entomopathogenic nematodes (e.g. Steinernema feltiae);
and
[0543] 3. entomopathogenic viruses (e.g. Cydia pomonella
granulovirus).
[0544] Other examples of entornopathogenic organisms include, but
are not limited to, baculoviruses, bacteria and other prokaryotic
organisms, fungi, protozoa and Microsproridia. Biologically derived
insecticides include, but not limited to, rotenone, veratridine, as
well as microbial toxins; insect tolerant or resistant plant
varieties; and organisms modified by recombinant DNA technology to
either produce insecticides or to convey an insect resistant
property to the genetically modified organism. In one embodiment,
the molecules of Formula One may be used with one or more
biopesticides in the area of seed treatments and soil amendments.
The Manual of Biocontrol Agents gives a review of the available
biological insecticide (and other biology-based control) products.
Copping L. G. (ed.) (2004). The Manual of Biocontrol Agents
(formerly the Biopesticide Manual) 3rd Edition. British Crop
Production Councii (BCPC), Farnham, Surrey UK.
Other Active Compounds
[0545] Molecules of Formula One may also be used in combination
(such as in a compositional mixture, or a simultaneous or
sequential application) with one or more of the following: [0546]
1.
3-(4-chloro-2,6-dimethylphenyl)-4-hydroxy-8-oxa-1-azaspiro[4,5]dec-3-en-2-
-one; [0547] 2.
3-(4'-chloro-2,4-dimethyl[1,1'-biphenyl]-3-yl)-4-hydroxy-8-oxa-1-azaspiro-
[4,5]dec-3-en-2-one; [0548] 3.
4-[[(6-chloro-3-pyridinyl)methyl]methylamino]-2(5H)-furanone;
[0549] 4.
4-[[(6-chloro-3-pyridinyl)methyl]cyclopropylamino]-2(51-1)-furanone;
[0550] 5.
3-chloro-N2-[(15)-1-methyl-2-(methylsulfonyl)ethyl]-N1-[2-methy-
l-4-[1,2,2,2-tetrafluoro-1-(trifluoromethypethyl)ethyl]phenyl]-1,2-benzene-
dicarboxamide; [0551] 6.
2-cyano-N-ethyl-4-fluoro-3-methoxy-benenesulfonamide; [0552] 7.
2-cyano-N-ethyl-3-methoxy-benzenesulfonamide; [0553] 8.
2-cyano-3-difluoromethoxy-N-ethyl-4-fluoro-benzenesulfonamide;
[0554] 9. 2-cyano-3-fluoromethoxy-N-ethyl-benzenesulfonamide;
[0555] 10.
2-cyano-6-fluoro-3-methoxy-N,N-dimethyl-benzenesulfonamide; [0556]
11. 2-cyano-N-ethyl-6-fluoro-3-methoxy-N-methyl-benzenesulfonamide;
[0557] 12.
2-cyano-3-difluoromethoxy-N,N-dimethylbenzenesulfon-amide; [0558]
13.
3-(difluoromethyl)-N-12-(3,3-dimethylbutyl)phenyI]-1-methyl-1H-pyrazole-4-
-carboxamide; [0559] 14.
N-ethyl-2,2-dimethylpropionamide-2-(2,6-dichloro-.alpha.,.alpha.,.alpha.--
trifluoro-p-tolyl) hydrazone; [0560] 15.
N-ethyl-2,2-dichloro-1-methylcyclopropane-carboxamide-2-(2,6-dichloro-.al-
pha.,.alpha.,.alpha.-trifluoro-p-tolyl) hydrazone nicotine; [0561]
16.
O-{(E-)-[2-(4-chloro-phenyl)-2-cyano-1-(2-trifluoromethylphenyl)-viny[}S--
methyl thiocarbonate; [0562] 17.
(E)-N1-[(2-chloro-1,3-thiazol-5-ylmethyl)]-N2-cyano-N1-methylacetamidine;
[0563] 18.
1-(6-chloropyridin-3-ylmethyl)-7-methyl-8-nitro-1,2,3,5,6,7-hexahydro-imi-
dazo[1,2-a]pyridin-5-ol; [0564] 19.
4-[4-chlorophenyl-(2-butylidine-hydrazono)methyl)]phenyl mesylate;
and [0565] 20.
N-Ethyl-2,2-dichloro-1-methylcyclopropanecarboxamide-2-(2,6-dichloro-alph-
a,alpha,alpha-trifluoro-p-tolyl)hydrazone.
Synergistic Mixtures
[0566] Molecules of Formula One may be used with certain active
compounds to form synergistic mixtures where the mode of action of
such compounds compared to the mode of action of the molecules of
Formula One are the same, similar, or different. Examples of modes
of action include, but are not limited to: acetylcholinesterase
inhibitor; sodium channel modulator; chitin biosynthesis inhibitor;
GABA and glutamate-gated chloride channel antagonist; GABA and
glutamate-gated chloride channel agonist; acetylcholine receptor
agonist; acetylcholine receptor antagonist; MET I inhibitor;
Mg-stimulated ATPase inhibitor; nicotinic acetylcholine receptor;
Midgut membrane disrupter; oxidative phosphorylation disrupter, and
ryanodine receptor (RyRs). Generally, weight ratios of the
molecules of Formula One in a synergistic mixture with another
compound are from about 10:1 to about 1:10, in another embodiment
from about 5:1 to about 1:5, and in another embodiment from about
3:1, and in another embodiment about 1:1.
Formulations
[0567] A pesticide is rarely suitable for application in its pure
form. It is usually necessary to add other substances so that the
pesticide can be used at the required concentration and in an
appropriate form, permitting ease of application, handling,
transportation, storage, and maximum pesticide activity. Thus,
pesticides are formulated into, for example, baits, concentrated
emulsions, dusts, emulsifiable concentrates, fumigants, gels,
granules, microencapsulations, seed treatments, suspension
concentrates, suspoemulsions, tablets, water soluble liquids, water
dispersible granules or dry flowables, wettable powders, and
ultra-low volume solutions. For further information on formulation
types see "Catalogue of Pesticide Formulation Types and
International Coding System" Technical Monograph no 2, 5th Edition
by CropLife International (2002).
[0568] Pesticides are applied most often as aqueous suspensions or
emulsions prepared from concentrated formulations of such
pesticides. Such water-soluble, water-suspendable, or emulsifiable
formulations are either solids, usually known as wettable powders,
or water dispersible granules, or liquids usually known as
emulsifiable concentrates, or aqueous suspensions. Wettable
powders, which may be compacted to form water dispersible granules,
comprise an intimate mixture of the pesticide, a carrier, and
surfactants. The concentration of the pesticide is usually from
about 10% to about 90% by weight. The carrier is usually selected
from among the attapulgite clays, the montmorillonite clays, the
diatomaceous earths, or the purified silicates. Effective
surfactants, comprising from about 0.5% to about 10% of the
wettable powder, are found among sulfonated lignins, condensed
naphthalenesulfonates, naphthalenesulfonates,
alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants
such as ethylene oxide adducts of alkyl phenols.
[0569] Emulsifiable concentrates of pesticides comprise a
convenient concentration of a pesticide, such as from about 50 to
about 500 grams per liter of liquid dissolved in a carrier that is
either a water miscible solvent or a mixture of water-immiscible
organic solvent and emulsifiers. Useful organic solvents include
aromatics, especially xylenes and petroleum fractions, especially
the high-boiling naphthalenic and olefinic portions of petroleum
such as heavy aromatic naphtha. Other organic solvents may also be
used, such as the terpenic solvents including rosin derivatives,
aliphatic ketones such as cyclohexanone, and complex alcohols such
as 2-ethoxyethanol. Suitable emulsifiers for emulsifiable
concentrates are selected from conventional anionic and non-ionic
surfactants.
[0570] Aqueous suspensions comprise suspensions of water-insoluble
pesticides dispersed in an aqueous carrier at a concentration in
the range from about 5% to about 50% by weight. Suspensions are
prepared by finely grinding the pesticide and vigorously mixing it
into a carrier comprised of water and surfactants. Ingredients,
such as inorganic salts and synthetic or natural gums may also be
added, to increase the density and viscosity of the aqueous
carrier. It is often most effective to grind and mix the pesticide
at the same time by preparing the aqueous mixture and homogenizing
it in an implement such as a sand mill, bail mill, or piston-type
homogenizer.
[0571] Pesticides may also be applied as granular compositions that
are particularly useful for applications to the soil. Granular
compositions usually contain from about 0.5% to about 10% by weight
of the pesticide, dispersed in a carrier that comprises clay or a
similar substance. Such compositions are usually prepared by
dissolving the pesticide in a suitable solvent and applylng it to a
granular carrier which has been pre-formed to the appropriate
particle size, in the range of from about 0.5 to about 3 mm. Such
compositions may also be formulated by making a dough or paste of
the carrier and compound and crushing and drylng to obtain the
desired granular particle size.
[0572] Dusts containing a pesticide are prepared by intimately
mixing the pesticide in powdered form with a suitable dusty
agricultural carrier, such as kaolin clay, ground volcanic rock,
and the like. Dusts can suitably contain from about 1% to about 10%
of the pesticide. They can be applied as a seed dressing or as a
foliage application with a dust blower machine.
[0573] It is equally practical to apply a pesticide in the form of
a solution in an appropriate organic solvent, usually petroleum
oil, such as the spray oils, which are widely used in agricultural
chemistry.
[0574] Pesticides can also be applied in the form of an aerosol
composition. In such compositions the pesticide is dissolved or
dispersed in a carrier, which is a pressure- generating propellant
mixture. The aerosol composition is packaged in a container from
which the mixture is dispensed through an atomizing valve.
[0575] Pesticide baits are formed when the pesticide is mixed with
food or an attractant or both. When the pests eat the bait they
also consume the pesticide. Baits may take the form of granules,
gels, flowable powders, liquids, or solids. They can be used in
pest harborages.
[0576] Fumigants are pesticides that have a relatively high vapor
pressure and hence can exist as a gas in sufficient concentrations
to kill pests in soil or enclosed spaces. The toxicity of the
fumigant is proportional to its concentration and the exposure
time. They are characterized by a good capacity for diffusion and
act by penetrating the pest's respiratory system or being absorbed
through the pest's cuticle. Fumigants are appiied to control stored
product pests under gas proof sheets, in gas sealed rooms or
buildings or in special chambers.
[0577] Pesticides can be microencapsuiated by suspending the
pesticide particles or droplets in plastic polymers of various
types. By altering the chemistry of the polymer or by changing
factors in the processing, microcapsules can be formed of various
sizes, solubility, wail thicknesses, and degrees of penetrability.
These factors govern the speed with which the active ingredient
within is released, which in turn, affects the residual
performance, speed of action, and odor of the product.
[0578] Oil solution concentrates are made by dissolving pesticide
in a solvent that will hold the pesticide in solution. Oil
solutions of a pesticide usually provide faster knockdown and kill
of pests than other formulations due to the solvents themselves
having pesticidal action and the dissolution of the waxy covering
of the integument increasing the speed of uptake of the pesticide.
Other advantages of oil solutions include better storage stability,
better penetration of crevices, and better adhesion to greasy
surfaces.
[0579] Another embodiment is an oil-in-water emulsion, wherein the
emulsion comprises oily globules which are each provided with a
lamellar liquid crystal coating and are dispersed in an aqueous
phase, wherein each oily globule comprises at least one compound
which is agriculturally active, and is individually coated with a
monolamellar or oligolamellar layer comprising: (1) at least one
non-ionic lipophilic surface-active agent, (2) at least one
non-ionic hydrophilic surface-active agent and (3) at least one
ionic surface-active agent, wherein the globules having a mean
particle diameter of less than 800 nanometers. Further information
on the embodiment is disclosed in U.S. patent publication
20070027034 published Feb. 1, 2007, having patent application Ser.
No. 11/495,228. For ease of use, this embodiment will be referred
to as "OIWE".
[0580] For further information consult "Insect Pest Management" 2nd
Edition by D. Dent, copyright CAB International (2000).
Additionally, for more detailed information consult "Handbook of
Pest Control--The Behavior, Life History, and Control of Household
Pests" by Arnold Mailis, 9th Edition, copyright 2004 by GIE Media
Inc.
Other Formulation Components
[0581] Generally, when the molecules disclosed in Formula One are
used in a formulation, such formulation can also contain other
components. These components include, but are not limited to, (this
is a non-exhaustive and non-mutually exclusive list) wetters,
spreaders, stickers, penetrants, buffers, sequestering agents,
drift reduction agents, compatibility agents, anti-foam agents,
cleaning agents, and emulsifiers. A few components are described
forthwith.
[0582] A wetting agent is a substance that when added to a liquid
increases the spreading or penetration power of the liquid by
reducing the interfacial tension between the liquid and the surface
on which it is spreading. Wetting agents are used for two main
functions in agrochemical formulations: during processing and
manufacture to increase the rate of wetting of powders in water to
make concentrates for soluble liquids or suspension concentrates;
and during mixing of a product with water in a spray tank to reduce
the wetting time of wettable powders and to improve the penetration
of water into water-dispersible granules. Examples of wetting
agents used in wettable powder, suspension concentrate, and
water-dispersible granule formulations are: sodium lauryl sulfate;
sodium dioctyl sulfosuccinate; alkyl phenol ethoxylates; and
aliphatic alcohol ethoxylates.
[0583] A dispersing agent is a substance which adsorbs onto the
surface of particles and helps to preserve the state of dispersion
of the particles and prevents them from reaggregating. Dispersing
agents are added to agrochemical formulations to facilitate
dispersion and suspension during manufacture, and to ensure the
particles redisperse into water in a spray tank. They are widely
used in wettable powders, suspension concentrates and
water-dispersible granules. Surfactants that are used as dispersing
agents have the ability to adsorb strongly onto a particle surface
and provide a charged or steric barrier to reaggregation of
particles. The most commonly used surfactants are anionic,
non-ionic, or mixtures of the two types. For wettable powder
formulations, the most common dispersing agents are sodium
lignosulfonates. For suspension concentrates, very good adsorption
and stabilization are obtained using polyelectrolytes, such as
sodium naphthalene sulfonate formaldehyde condensates.
Tristyrylphenol ethoxylate phosphate esters are also used.
Non-ionics such as alkylarylethylene oxide condensates and EO-PO
block copolymers are sometimes combined with anionics as dispersing
agents for suspension concentrates. in recent years, new types of
very high molecular weight polymeric surfactants have been
developed as dispersing agents.
[0584] These have very long hydrophobic `backbones` and a large
number of ethylene oxide chains forming the `teeth` of a `comb`
surfactant. These high molecular weight polymers can give very good
long-term stability to suspension concentrates because the
hydrophobic backbones have many anchoring points onto the particle
surfaces. Examples of dispersing agents used in agrochemical
formulations are: sodium lignosulfonates; sodium naphthalene
sulfonate formaldehyde condensates; tristyrylphenol ethoxylate
phosphate esters; aliphatic alcohol ethoxylates; alkyl ethoxylates;
EO-PO block copolymers; and graft copolymers.
[0585] An emulsifylng agent is a substance which stabilizes a
suspension of droplets of one liquid phase in another liquid phase.
Without the emulsifylng agent the two liquids would separate into
two immiscible liquid phases. The most commonly used emulsifier
blends contain alkylphenol or aliphatic alcohol with twelve or more
ethylene oxide units and the oil-soluble calcium salt of
dodecylbenzenesulfonic acid. A range of hydrophile-lipophile
balance ("HLB") values from 8 to 18 will normally provide good
stable emulsions. Emulsion stability can sometimes be improved by
the addition of a small amount of an EO-PO block copolymer
surfactant.
[0586] A solubilizing agent is a surfactant which will form
micelles in water at concentrations above the critical miceile
concentration. The micelles are then able to dissolve or solubilize
water-insoluble materials inside the hydrophobic part of the
micelle. The types of surfactants usually used for solubilization
are non-ionics, sorbitan monooleates, sorbitan monooleate
ethoxylates, and methyl oleate esters.
[0587] Surfactants are sometimes used, either alone or with other
additives such as mineral or vegetable oils as adjuvants to
spray-tank mixes to improve the biological performance of the
pesticide on the target. The types of surfactants used for
bioenhancement depend generally on the nature and mode of action of
the pesticide. However, they are often non-ionics such as: alkyl
ethoxylates; linear aliphatic alcohol ethoxylates; aliphatic amine
ethoxylates.
[0588] A carrier or diluent in an agricultural formulation is a
material added to the pesticide to give a product of the required
strength. Carriers are usually materials with high absorptive
capacities, while diluents are usually materials with low
absorptive capacities. Carriers and diluents are used in the
formulation of dusts, wettable powders, granules and
water-dispersible granules.
[0589] Organic solvents are used mainly in the formulation of
emulsifiable concentrates, oil-in-water emulsions, suspoemuisions,
and ultra-low volume formulations, and to a lesser extent, granular
formulations. Sometimes mixtures of solvents are used. The first
main groups of solvents are aliphatic paraffinic oils such as
kerosene or refined paraffins. The second main group (and the most
common) comprises the aromatic solvents such as xylene and higher
molecular weight fractions of C9 and C10 aromatic solvents.
Chlorinated hydrocarbons are useful as cosolvents to prevent
crystallization of pesticides when the formulation is emulsified
into water. Alcohols are sometimes used as cosolvents to increase
solvent power. Other solvents may include vegetable oils, seed
oils, and esters of vegetable and seed oils.
[0590] Thickeners or gelling agents are used mainly in the
formulation of suspension concentrates, emulsions and
suspoemulsions to modify the rheology or flow properties of the
liquid and to prevent separation and settling of the dispersed
particles or droplets. Thickening, gelling, and anti-settling
agents generally fall into two categories, namely water-insoluble
particulates and water-soluble polymers. It is possible to produce
suspension concentrate formulations using clays and silicas.
Examples of these types of materials, inciude, but are riot limited
to, montmorillonite, bentonite, magnesium aluminum silicate, and
attapuigite. Water-soluble polysaccharides have been used as
thickening-gelling agents for many years. The types of
polysaccharides most commonly used are natural extracts of seeds
and seaweeds or are synthetic derivatives of cellulose. Examples of
these types of materials include, but are not limited to, guar gum;
locust bean gum; carrageenan; alginates; methyl cellulose; sodium
carboxymethyl cellulose (SCMC); hydroxyethyl cellulose (HEC). Other
types of anti-settling agents are based on modified starches,
polyacrylates, polyvinyl alcohol and polyethylene oxide. Another
good anti-settling agent is xanthan gum.
[0591] Microorganisms can cause spoilage of formulated products.
Therefore preservation agents are used to eliminate or reduce their
effect. Examples of such agents include, but are not limited to:
propionic acid and its sodium salt; sorbic acid and its sodium or
potassium salts; benzoic acid and its sodium salt; p-hydroxybenzoic
acid sodium salt; methyl p-hydroxybenzoate; and
1,2-benzisothiazolin-3-one (BIT).
[0592] The presence of surfactants often causes water-based
formulations to foam during mixing operations in production and in
application through a spray tank. In order to reduce the tendency
to foam, anti-foam agents are often added either during the
production stage or before filling into bottles. Generally, there
are two types of anti-foam agents, namely silicones and
non-silicones. Silicones are usually aqueous emulsions of dimethyl
polysiloxane, while the non-silicone anti-foam agents are
water-insoluble oils, such as octanol and nonanol, or silica. In
both cases, the function of the anti-foam agent is to displace the
surfactant from the air-water interface.
[0593] "Green" agents (e.g., adjuvants, surfactants, soivents) can
reduce the overall environmental footprint of crop protection
formulations. Green agents are biodegradable and generally derived
from natural and/or sustainable sources, e.g. plant and animal
sources. Specific examples are: vegetable oils, seed oils, and
esters thereof, also alkoxylated alkyl polygiucosides.
[0594] For further information, see "Chemistry and Technology of
Agrochemical Formulations" edited by D. A. Knowles, copyright 1998
by Kluwer Academic Publishers. Also see "Insecticides in
Agriculture and Environment--Retrospects and Prospects" by A. S.
Perry, I. Yamamoto, I. Ishaaya, and R. Perry, copyright 1998 by
Springer-Verlag.
Pests
[0595] In general, the molecules of Formula One may be used to
control pests e.g. beetles, earwigs, cockroaches, flies. aphids,
scales, whiteflies, leafhoppers, ants, wasps, termites, moths,
butterflies, lice, grasshoppers, locusts, crickets, fleas, thrips,
bristletails, mites, ticks, nematodes, and symphylans.
[0596] In another embodiment, the molecules of Formula One may be
used to control pests in the Phyla Nematoda and/or Arthropoda.
[0597] In another embodiment, the molecules of Formula One may be
used to control pests in the Subphyla Chelicerata, Myriapoda,
and/or Hexapoda.
[0598] In another embodiment, the molecules of Formula One may be
used to control pests in the Classes of Arachnida, Symphyla, and/or
Insecta.
[0599] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Anoplura. A non-exhaustive list
of particular genera includes, but is not limited to, Haematopinus
spp., Hoplopleura spp., Linognathus spp., Pediculus spp., and
Polyplax spp. A non-exhaustive list of particular species includes,
but is not limited to, Haematopinus asini, Haematopinus suis,
Linognathus setosus, Linognathus ovillus, Pediculus humanus
capitis, Pediculus humanus humanus, and Pthirus pubis.
[0600] In another embodiment, the molecules of Formula One may be
used to control pests in the Order Coleoptera, A non-exhaustive
list of particular genera includes, but is not limited to,
Acanthoscelides spp., Agriotes spp., Anthonomus spp., Apion spp.,
Apogonia spp., Aulacophora spp., Bruchus spp., Cerosterna spp.,
Cerotorna spp., Ceutorhynchus spp., Chaetocnema spp., Colaspis
spp., Ctenicera spp., Curculio spp., Cyclocephala spp., Diabrotica
spp., Hypera spp., Ips spp., Lyctus spp., Megascelis spp.,
Meligethes spp., Otiorhynchus spp., Pantomorus spp., Phyllophaga
spp., Phyllotreta spp., Rhizotrogus spp., Rhynchites spp.,
Rhynchophorus spp., Scolytus spp., Sphenophorus spp., Sitophilus
spp., and Tribolium spp. A non-exhaustive list of particular
species includes, but is not limited to, Acanthoscelides obtectus,
Agrilus planipennis, Anoplophora glabripennis, Anthonomus grand's,
Ataenius spretulus, Atomaria linearis, Bothynoderes punctiyentris,
Bruchus pisorum, Callosobruchus rnaculatus, Carpophilus hemipterus,
Cassida vittata, Cerotorna trifurcata, Ceutorhynchus assimilis,
Ceutorhynchus napi, Conoderus scalaris, Conoderus stigmosus,
Conotrachelus nenuphar, Cotinis nitida, Crioceris asparagi,
Cryptolestes ferrugineus, Cryptolestes pusillus, Cryptolestes
turcicus, Cylindrocopturus adspersus, Deporaus marginatus,
Dermestes lardarius, Dermestes maculatus, Epilachna varivestis,
Faustinus tubae, Hylobius pales, Hypera postica, Hypothenemus
hampei, Lasioderma serricorne, Leptinotarsa decemlineata, Liogenys
fuscus, Liogenys suturalis, Lissorhoptrus oryzophilus, Maecolaspis
joliveti, Melanotus communis, Meligethes aeneus, Melolontha
melolontha, Oberea brevis, Oberea linearis, Oryctes rhinoceros,
Oryzaephilus mercator, Oryzaephilus surinamensis, Oulerna
melanopus, Oulerna oryzae, Phyllophaga cuyabana, PopiIlia japonica,
Prostephanus truncatus, Rhyzopertha dominica, Sitona lineatus,
Sitophilus granarius, Sitophilus oryzae Sitophilus zeamais,
Stegobium paniceum, Tribolium castaneum, Tribolium confusum,
Trogoderma variabile and Zabrus tenebrioides.
[0601] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Dermaptera.
[0602] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Blattaria. A non-exhaustive list
of particular species includes, but is not limited to, Blattella
germanica, Blatta orientalis, Parcoblatta pennsylvanica,
Periplaneta americana, Periplaneta australasiae, Periplaneta
brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis, and
Supella longipalpa.
[0603] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Diptera. A non-exhaustive list
of particular genera includes, but is not limited to, Aedes spp.,
Agromyza spp., Anastrepha spp., Anopheles spp., Bactrocera spp.,
Ceratitis spp., Chrysops spp., Cochliomyla spp., Contarinia spp.,
Culex spp., Dasineura spp., Delia spp., Drosophila spp., Fannia
spp., Hylemyla spp., Liriomyza spp., Musca spp., Phorbia spp.,
Tabanus spp., and Tipula spp. A non-exhaustive list of particular
species includes, but is not limited to, Agromyza frontella,
Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqa,
Bactrocera cucurbitae, Bactrocera dorsalis, Bactrocera invadens,
Bactrocera zonata, Ceratitis capitata, Dasineura brassicae, Delia
platura, Fannia canicularis, Fannia scalaris, Gasterophilus
intestinalis, Gracillia perseae, Haematobia irritans, Hypoderma
lineatum, Liriomyza brassicae, Melophagus ovinus, Musca autumnalls,
Musca domestica, Oestrus avis, OscineIla frit, Pegornya betae,
Psila rosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis
mendax, Sitodiplosis mosellana, and Stomoxys caldtrans.
[0604] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Herniptera A non-exhaustive list
of particular genera includes, but is not limited to, Adelges spp.,
Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp.,
Ceroplastes spp., Chionaspis spp., Chrysornphalus spp., Coccus
spp., Empoasca spp., Lepidosaphes spp., Lagyrrotomus spp., Lygus
spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Philaenus
spp., Phytocoris spp., Piezodorus spp., Planococcus spp.,
Pseudococcus spp., Rhopalosiphum spp., Saissetia spp., Therloaphis
spp., Toumeyella spp., Toxoptera spp., Trialeurodes spp., Triatoma
spp. and Unaspis spp. A non-exhaustive list of particular species
includes, but is not limited to, Acrosternum hilare, Acyrthosiphon
pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus
floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis
gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bemisia
argentifolii, Bemisia tabaci, Blissus leucopterus, Brachycorynella
asparagi, Brevennia rehi, Brevicoryne brassicae, Calocoris
norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimex
lectularius, Dagbertus fasciatus, Dichelops furcatus, Diuraphis
noxia, Diaphorina citri, Dysaphis plantaginea, Dysdercus
suturellus, Edessa meditabunda, Eriosoma lanigerum, Eurygaster
maura, Euschistus herds, Euschistus serus, Helopeltis antonii,
Helopeltis theivora, Icerya purchasi, Idioscopus nitidulus,
Laodelphax striatellus, Leptocorisa oratorius, Leptocorisa
varicornis, Lygus hesperus, Maconellicoccus hirsutus, Macrosiphum
euphorbiae, Macrosiphum granarium, Macrosiphum rosae, Macrosteles
quadrilineatus, Mahanarva frimbiolaya, Metopolophium dirhodurn,
Mictis longicornis, Myzus persicae, Nephotettix cinctipes,
Neurocolpus longirostris, Nezara viridula, Nilaparvata lugens,
Parlatoria pergandii, Pariatoria ziziphi, Peregrinus maidis,
Phylloxera vitifoliae, Physokermes piceae, Phytocoris californicus,
Phytocoris relativus, Piezodorus guildinii, Poecilocapsus lineatus,
Psallus vaccinicola, Pseudacysta perseae, Pseudococcus brevipes,
Quadraspidiotus perniclosus, Rhopalosiphum maidis, Rhopalosiphum
padi, Saissetia oleae, Scaptocoris castanea, Schizaphis graminum,
Sitobion avenae, Sogatella furcifera, Trialeurodes vaporariorum,
Trialeurocies abutiloneus, Unaspis yanonensis, and Zulia
entrerriana.
[0605] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Hymenoptera. A non-exhaustive
list of particular genera includes, but is not limited to,
Acromyrmex spp., Atta spp., Camponotus spp., Diprion spp., Formica
spp. Monomorium spp., Neodiprion spp., Pogonomyrmex spp., Polistes
spp., Solenopsis spp., Vespula spp., and Xylocopa spp. A
non-exhaustive list of particular species includes, but is not
limited to, Athalia rosae, Atta texana, Iridomyrmex humilis,
Monornorium minimum, Monornoriurn pharaonis, Solenopsis invicta,
Solenopsis gerninata, Solenopsis molesta, Solenopsis richtery,
Solenopsis xyloni, and Tapinoma sessile.
[0606] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Isoptera. A non-exhaustive list
of particular genera includes, but is not limited to, Coptotermes
spp., Cornitermes spp., Cryptotermes spp., Heterotermes spp.,
Kalotermes spp., Incisitermes spp., Macrotermes spp., Marginitermes
spp., Microcerotermes spp., Procornitermes spp., Reticulitermes
spp., Schedorhinotermes spp., and Zootermopsis spp. A
non-exhaustive list of particular species includes, but is not
limited to, Coptotermes curvignathus, Coptotermes frenchi,
Coptotermes formosanus, Heterotermes aureus Microtermes obesi,
Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermes
flavipes, Reticulitermes hageni, Reticulitermes hesperus,
Reticulitermes santonensis Reticulitermes speratus, Reticulitermes
tibialis and Reticulitermes virginicus.
[0607] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Lepidoptera. A non-exhaustive
list of particular genera includes, but is not limited to,
Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp.,
Caloptilia spp., Chilo spp., Chrysocielxis spp., Collas spp.,
Crambus spp., Diaphania spp.,
[0608] Diatraea spp., Earias spp., Ephestia spp., Epimecis spp.,
Feltie spp., Gortyna spp., Helicoverpa spp., Heliothis spp.,
Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma
spp., Peridroma spp., Phyllonorycter spp., Pseudaletia spp.,
Sesamia spp., Spodoptera spp., Synanthedon spp., and Yponomeuta
spp. A non-exhaustive list of particular species includes, but is
not limited to, Achaea janata, Adoxophyes orana,
[0609] Agrotis ipsilon, Alabama argi/lacea, Arnorbia cuneana,
Amye/ois transitella, Anacamptodes defectaria, Anarsia lineatella,
Anornis sabulifera, Anticarsia gernmatalis, Archips argyrospila,
Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota
cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua
reticulana, Carposina niponensis, Chilo suppressalis, Chilo
polychrysus, Chlumetia transversa, Choristoneura rosaceana,
Cnaphalocrocis medinalis, Conopomorpha cramerella, Cossus cossus,
Cydia caryana, Cydia funebrana, Cydia molesta, Cydia nigricana,
Cydia pomonella, Darna diducta, Diatraea saccharalis, Diatraea
grandiosella, Earias insulana, Earias vitteila, Ecdytolopha
aurantianum, Elasrnopalpus lignoselius, Ephestia cautelia, Ephestia
elutella, Ephestia kuehniella, Epinotia aporema, Epiphyas
postvittana, Erionota thrax, Eupoecilia ambiguelia, Euxoa
auxiliaris, Grapholita molesta, Hedylepta inthcata, Helicoverpa
armigera, Helicoverpa zea, Heliothis virescens, Hellula undalis,
Keiferia lycopersicella, Leucinodes orbonalis, Leucoptera
coffeella, Leucoptera malifoliella, Lobesia botrana, Loxagrotis
albicosta, Lymantria dispar, Lyonetia clerkella, Mahasena corbetti,
Mamestra brassicae, Maruca testulalis, Metisa plana, Mythimna
unipuncta, Neoleucinodes elegantalis, Nymphula depunctalis,
Operophtera brumata, Ostrinia nubilalis, Oxydia vesulia, Pandemis
cerasana, Pandemis heparana, Papilio demodocus, Pectinophora
gossypiella, Peridroma saucia, Perileucoptera coffeella,
Phthorimaea operculella, Phyllocnistis citrella, Pieris rapae,
Plathypena scabra, Plodia interpunctella, Plutella xylostella,
Polychrosis viteana, Prays endocarps, Prays oleae, Pseudaletia
unipuncta, Pseudoplusia includens, Rachiplusia nu, Scirpophaga
incertulas, Sesamia inferens, Sesamia nonagrioides, Setora nitens,
Sitotroga cerealella, Sparganothis pilleriana, Spodoptera exigua,
Spodoptera frugiperda, Spodoptera eridania, Thecia basilides,
Tineola bisselliella, Trichoplusia ni, Tuta absoluta, Zeuzera
coffeae, and Zeuzera pyrina.
[0610] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Mallophaga. A non-exhaustive
list of particular genera includes, but is not limited to,
Anaticola spp., Bovicola spp., Chelopistes spp., Goniodes spp.,
Menacanthus spp., and Trichodectes spp. A non-exhaustive list of
particular species includes, but is not limited to, Bovicola bovis,
Bovicola caprae, Bovicola ovis, Chelopistes meleagridis, Goniodes
dissimilis, Goniodes gigas, Menacanthus stramineus, Menopon
gallinae, and Trichodectes canis.
[0611] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Orthoptera. A non-exhaustive
list of particular genera includes, but is not limited to,
Melanoplus spp., and Pterophylla spp. A non-exhaustive list of
particular species includes, but is not limited to, Anabrus
simplex, Gryllotalpa africana, Gryllotalpa australis, Gryllotalpa
brachyptera, Gryllotalpa hexadactyla, Locusta migratoria,
Microcentrum retinerve, Schistocerca gregaria, and Scudderia
furcata.
[0612] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Siphonaptera. A non-exhaustive
list of particular species includes, but is not limited to,
Ceratophyllus gallinae, Ceratophyllus niger, Ctenocephalides canis,
Ctenocephalides fells, and Pulex irritans.
[0613] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Thysanoptera. A non-exhaustive
list of particular genera includes, but is not limited to,
Caliothrips spp., Frankliniella spp., Scirtothrips spp., and Thrips
spp. A non-exhaustive list of particular sp. includes, but is not
limited to, Frankliniella fusca, Frankliniella occidentalis,
Frankliniella schultzei, Frankliniella williamsi, Heliothrips
haemorrhoidalls, Rhipiphorothrips cruentatus, Scirtothrips citri,
Scirtothrips dorsalis, and Taeniothrips rhopalantennalis, Thrips
hawaiiensis, Thrips nigropilosus, Thrips orientalis, Thrips
tabaci.
[0614] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Thysanura. A non-exhaustive list
of particular genera includes, but is not limited to, Lepisma spp.
and Thermobia spp.
[0615] In another embodiment, the molecules of Formula One may be
used to control pests of the Order Acarina. A non-exhaustive list
of particular genera includes, but is not limited to, Acarus spp.,
Aculops spp., Boophilus spp., Demodex spp., Dermacentor spp.,
Epitrimerus spp., Eriophyes spp., Ixodes spp., Oligonychus spp.,
Panonychus spp., Rhizoglyphus spp., and Tetranychus spp. A
non-exhaustive list of particular species includes, but is not
limited to, Acarapis woodi, Acarus siro, Aceria mangiferae, Aculops
lycopersici, Aculus pelekassi, Acarapis schlechtendali, Amblyomma
americanum, Brevipalpus obovatus, Brevipalpus phoenicis,
Dermacentor variabilis, Dermatophagoides pteronyssinus,
Eotetranychus carpini, Notoedres cati, Oligonychus coffeae,
Oligonychus ilicis, Panonychus citri, Panonychus ulmi,
Phyllocoptruta oieivora, Poiyphagotarsonernus latus, Rhipicephalus
sanguineus, Sarcoptes scablei, Tegolophus perseaflorae Tetranychus
urticae, and Varroa destructor.
[0616] In another embodiment, the molecules of Formula One may be
used to control pest of the Order Symphyla. A non-exhaustive list
of particular sp. includes, but is not limited to, Scutigerella
immaculata.
[0617] In another embodiment, the molecules of Formula One may be
used to control pests of the Phylum Nematode. A non-exhaustive list
of particular genera includes, but is not limited to,
Aphelenchoides spp., Belonolaimus spp., Criconemella spp.,
Ditylenchus spp., Heterodera spp., Hirschmanniella spp.,
Hoplolaimus spp., Meloidogyne spp., Pratylenchus spp., and
Radopholus spp. A non-exhaustive list of particular sp. includes,
but is not limited to, Dirofilaria immitis, Heterodera zeae,
Meloidogyne incognita, Meloidogyne javanica, Onchocerca volvulus,
Radopholus similis and Rotylenchulus reniformis.
[0618] For additional information consult "HANDBOOK OF PEST
CONTROL--THE BEHAVIOR, LIFE HISTORY, AND CONTROL OF HOUSEHOLD
PESTS" by Arnold Mallis, 9th Edition, copyright 2004 by GIE Media
Inc.
Applications
[0619] Molecules of Formula One are generally used in amounts from
about 0.01 grams per hectare to about 5000 grams per hectare to
provide control. Amounts from about 0.1 grams per hectare to about
500 grams per hectare are generally preferred, and amounts from
about 1 gram per hectare to about 50 grams per hectare are
generally more preferred.
[0620] The area to which a molecule of Formula One is appiied can
be any area inhabited (or maybe inhabited, or traversed by) a pest,
for example: where crops, trees, fruits, cereals, fodder species,
vines, turf and ornamental plants, are growing; where domesticated
animals are residing; the interior or exterior surfaces of
buildings (such as places where grains are stored), the materials
of construction used in building (such as impregnated wood), and
the soil around buildings. Particular crop areas to use a molecule
of Formula One include areas where apples, corn, sunflowers,
cotton, soybeans, canola, wheat, rice, sorghum, barley, oats,
potatoes, oranges, alfalfa, lettuce, strawberries, tomatoes,
peppers, crucifers, pears, tobacco, almonds, sugar beets, beans and
other valuable crops are growing or the seeds thereof are going to
be planted. It is also advantageous to use ammonium sulfate with a
molecule of Formula One when growing various plants.
[0621] Controlling pests generally means that pest populations,
pest activity, or both, are reduced in an area. This can come about
when: pest populations are repulsed from an area; when pests are
incapacitated in or around an area; or pests are exterminated, in
whole, or in part, in or around an area. Of course, a combination
of these results can occur. Generally, pest populations, activity,
or both are desirably reduced more than fifty percent, preferably
more than 90 percent. Generally, the area is not in or on a human;
consequently, the locus is generally a non-human area.
[0622] The molecules of Formula One may be used in mixtures,
applied simultaneously or sequentially, alone or with other
compounds to enhance plant vigor (e.g. to grow a better root
system, to better withstand stressful growing conditions). Such
other compounds are, for example, compounds that modulate plant
ethylene receptors, most notably 1-methylcyclopropene (also known
as 1-MCP). Furthermore, such molecules may be used during times
when pest activity is low, such as before the plants that are
growing begin to produce valuable agricultural commodities. Such
times include the early planting season when pest pressure is
usually low.
[0623] The molecules of Formula One can be applied to the foliar
and fruiting portions of plants to control pests. The molecules
will either come in direct contact with the pest, or the pest will
consume the pesticide when eating leaf, fruit mass, or extracting
sap, that contains the pesticide. The molecules of Formula One can
also be appiied to the soil, and when applied in this manner, root
and stem feeding pests can be controlled. The roots can absorb a
molecule taking it up into the foliar portions of the plant to
control above ground chewing and sap feeding pests.
[0624] Generally, with baits, the baits are placed in the ground
where, for example, termites can come into contact with, and/or be
attracted to, the bait. Baits can also be applied to a surface of a
building, (horizontal, vertical, or slant surface) where, for
example, ants, termites, cockroaches, and flies, can come into
contact with, and/or be attracted to, the bait. Baits can comprise
a molecule of Formula One.
[0625] The molecules of Formula One can be encapsulated inside, or
placed on the surface of a capsule. The size of the capsules can
range from nanometer size (about 100-900 nanometers in diameter) to
micrometer size (about 10-900 microns in diameter).
[0626] Because of the unique ability of the eggs of some pests to
resist certain pesticides, repeated applications of the molecules
of Formula One may be desirable to control newly emerged
larvae.
[0627] Systemic movement of pesticides in plants may be utilized to
control pests on one portion of the plant by applylng (for example
by spraylng an area) the molecules of Formula One to a different
portion of the plant. For example, control of foliar-feeding
insects can be achieved by drip irrigation or furrow application,
by treating the soil with for example pre- or post-planting soil
drench, or by treating the seeds of a plant before planting.
[0628] Seed treatment can be applied to all types of seeds,
including those from which plants genetically modified to express
specialized traits will germinate. Representative examples include
those expressing proteins toxic to invertebrate pests, such as
Bacillus thuringiensis or other insecticidal toxins, those
expressing herbicide resistance, such as "Roundup Ready" seed, or
those with "stacked" foreign genes expressing insecticidal toxins,
herbicide resistance, nutrition-enhancement, drought resistance, or
any other beneficial traits. Furthermore, such seed treatments with
the molecules of Formula One may further enhance the ability of a
plant to better withstand stressful growing conditions. This
results in a healthier, more vigorous plant, which can lead to
higher ylelds at harvest time. Generally, about 1 gram of the
molecules of Formula One to about 500 grams per 100,000 seeds is
expected to provide good benefits, amounts from about 10 grams to
about 100 grams per 100,000 seeds is expected to provide better
benefits, and amounts from about 25 grams to about 75 grams per
100,000 seeds is expected to provide even better benefits.
[0629] It should be readily apparent that the molecules of Formula
One may be used on, in, or around plants genetically modified to
express specialized traits, such as Bacillus thuringiensis or other
insecticidal toxins, or those expressing herbicide resistance, or
those with "stacked" foreign genes expressing insecticidal toxins,
herbicide resistance, nutrition-enhancement, or any other
beneficial traits.
[0630] The molecules of Formula One may be used for controlling
endoparasites and ectoparasites in the veterinary medicine sector
or in the field of non-human animal keeping. The molecules of
Formula One are applied, such as by oral administration in the form
of, for example, tablets, capsules, drinks, granules, by dermal
application in the form of, for example, dipping, spraylng, pouring
on, spotting on, and dusting, and by parenteral administration in
the form of, for example, an injection.
[0631] The molecules of Formula One may also be employed
advantageously in livestock keeping, for example, cattle, sheep,
pigs, chickens, and geese. They may also be employed advantageously
in pets such as, horses, dogs, and cats. Particular pests to
control would be fleas and ticks that are bothersome to such
animals. Suitable formulations are administered orally to the
animals with the drinking water or feed. The dosages and
formulations that are suitable depend on the species.
[0632] The molecules of Formula One may also be used for
controlling parasitic worms, especially of the intestine, in the
animals listed above.
[0633] The molecules of Formula One may also be employed in
therapeutic methods for human health care. Such methods include,
but are limited to, oral administration in the form of, for
example, tablets, capsules, drinks, granules, and by dermal
application.
[0634] Pests around the world have been migrating to new
environments (for such pest) and thereafter becoming a new invasive
species in such new environment. The molecuies of Formula One may
also be used on such new invasive species to control them in such
new environment.
[0635] The molecules of Formula One may also be used in an area
where plants, such as crops, are growing (e.g. pre-planting,
planting, pre-harvesting) and where there are low levels (even no
actual presence) of pests that can commercially damage such plants.
The use of such molecules in such area is to benefit the plants
being grown in the area. Such benefits, may include, but are not
limited to, improving the health of a plant, improving the yleid of
a plant (e.g. increased biomass anti/or increased content of
valuable ingredients), improving the vigor of a plant (e.g.
improved piant growth anti/or greener leaves), improving the
quality of a plant (e.g. improved content or composition of certain
ingredients), and improving the tolerance to abiotic and/or biotic
stress of the plant.
[0636] Before a pesticide can be used or sold commercially, such
pesticide undergoes lengthy evaluation processes by various
governmental authorities (local, regional, state, national, and
international). Voluminous data requirements are specified by
regulatory authorities and must be addressed through data
generation and submission by the product registrant or by a third
party on the product registrant's behalf, often using a computer
with a connection to the World Wide Web. These governmental
authorities then review such data and if a determination of safety
is concluded, provide the potential user or seller with product
registration approval. Thereafter, in that locality where the
product registration is granted and supported, such user or seller
may use or sell such pesticide.
[0637] A molecule according to Formula One can be tested to
determine its efficacy against pests. Furthermore, mode of action
studies can be conducted to determine if said molecule has a
different mode of action than other pesticides. Thereafter, such
acquired data can be disseminated, such as by the intemet, to third
parties.
[0638] The headings in this document are for convenience only and
must not be used to interpret any portion hereof.
Table Section
TABLE-US-00002 [0639] TABLE 2 Structure and Preparation Method for
F Series Compounds Prep. according to No. Structure example F1
##STR00244## 18 F2 ##STR00245## 18 F3 ##STR00246## 17 F4
##STR00247## 17 F5 ##STR00248## 17 F6 ##STR00249## 17 F7
##STR00250## 17 F8 ##STR00251## 17 F9 ##STR00252## 20 F10
##STR00253## 20 F11 ##STR00254## 20 F12 ##STR00255## 18 F13
##STR00256## 18 F14 ##STR00257## 19 F15 ##STR00258## 19 F16
##STR00259## 19 F17 ##STR00260## 19 F18 ##STR00261## 19 F19
##STR00262## 18 F20 ##STR00263## 23 F21 ##STR00264## 25 F22
##STR00265## 28 F23 ##STR00266## 28
TABLE-US-00003 TABLE 3 Analytical Data for Compounds in Table 2
Mass No. (m/z) .sup.1H NMR .sup.19F NMR F1 ESIMS .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. .sup.19F NMR (376 MHz, m/z 643 7.79-7.69
(m, 1H), 7.61 (d, J = 8.1 Hz, 1H), CDCl.sub.3) .delta. ([M -
H].sup.-) 7.55 (d, J = 5.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, -59.34,
-66.97, -68.61. 1H), 7.40 (s, 2H), 7.34 (d, J = 7.9 Hz, 1H), 6.55
(dd, J = 16.0, 4.5 Hz, 1H), 6.39 (ddd, J = 15.9, 8.0, 2.6 Hz, 1H),
5.64 (h, J = 7.5 Hz, 1H), 4.10 (pd, J = 8.7, 3.0 Hz, 1H), 2.44-2.00
(m, 4H), 1.51 (d, J = 6.7 Hz, 3H) F2 ESIMS .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 8.27 (d, J = 17.8 Hz, .sup.19F NMR (376 MHz,
m/z 629 2H), 7.43-7.33 (m, 3H), CDCl.sub.3) .delta. ([M - H].sup.-)
7.28 (d, J = 8.3 Hz, 1H), 7.17 (dd, J = 7.8, 3.2 Hz, -59.63,
-63.29, 1H), 6.53-6.43 (m, 1H), 6.33 (ddd, J = 15.9, -68.60 8.0,
5.0 Hz, 1H), 5.89 (dq, J = 13.8, 6.2 Hz, 1H), 4.07 (hept, J = 8.3
Hz, 1H), 3.04 (p, J = 11.2 Hz, 1H), 2.87 (p, J = 10.5 Hz, 1H), 1.41
(d, J = 6.4 Hz, 3H) F3 ESIMS .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. .sup.19F NMR (376 MHz, m/z 617 7.69-7.63 (m, 1H), 7.57 (dd,
J = 8.0, 1.7 Hz, 1H), CDCl.sub.3) .delta. ([M - H].sup.-) 7.47 (d,
J = 8.0 Hz, 1H), 7.41 (s, 2H), -59.06, -68.57 6.91 (d, J = 7.4 Hz,
1H), 6.66-6.55 (m, 2H), 6.42 (dd, J = 15.9, 7.8 Hz, 1H), 5.42 (h, J
= 7.0 Hz, 1H), 4.12 (p, J = 8.4 Hz, 1H), 2.16 (dd, J = 8.3, 6.9 Hz,
2H), 1.68 (d, J = 6.7 Hz, 3H), 1.62 (q, J = 7.5 Hz, 2H), 1.38-1.22
(m, 4H), 0.93-0.85 (m, 3H) F4 ESIMS .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.68 (d, J = 12.0 Hz, .sup.19F NMR (376 MHz,
m/z 617 1H), 7.64-7.54 (m, 1H), DMSO- ([M - H].sup.-) 7.47 (d, J =
7.9 Hz, 1H), 7.41 (s, 2H), 6.86 (d, d.sub.6) .delta. -57.81, J =
7.4 Hz, 1H), 6.62 (dd, J = 15.9, 7.5 Hz, -67.95 1H), 6.55 (d, J =
7.6 Hz, 1H), 6.43 (dd, J = 15.9, 7.9 Hz, 1H), 5.42 (q, J = 7.2 Hz,
1H), 4.12 (p, J = 8.5 Hz, 1H), 2.22-2.13 (m, 2H), 1.69 (d, J = 6.8
Hz, 3H), 1.63-1.41 (m, 3H), 0.90 (d, J = 6.4 Hz, 6H) F5 ESIMS
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.66 (s, 1H), .sup.19F
NMR (376 MHz, m/z 603 7.57 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 27.1
Hz, DMSO- ([M - H].sup.-) 3H), 6.85 (d, J = 7.3 Hz, 1H), d.sub.6)
.delta. -57.81, 6.66-6.50 (m, 2H), 6.43 (dd, J = 15.9, -67.95 7.8
Hz, 1H), 5.42 (q, J = 7.2 Hz, 1H), 4.12 (p, J = 8.6 Hz, 1H),
2.22-2.13 (m, 2H), 1.69 (d, J = 6.8 Hz, 3H), 1.64-1.55 (m, 2H),
1.42-1.23 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) F6 ESIMS .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.66 (d, J = 1.5 Hz, .sup.19F NMR
(376 MHz, m/z 603 1H), 7.57 (d, J = 7.9 Hz, 1H), DMSO- ([M -
H].sup.-) 7.47 (d, J = 8.0 Hz, 1H), 7.41 (s, 2H), d.sub.6) .delta.
-57.81, 6.88 (d, J = 7.4 Hz, 1H), 6.61 (d, J = 15.9 Hz, -67.95 1H),
6.54 (d, J = 7.6 Hz, 1H), 6.43 (dd, J = 15.9, 7.8 Hz, 1H), 5.44 (p,
J = 7.0 Hz, 1H), 4.12 (p, J = 8.6 Hz, 1H), 2.17-2.00 (m, 2H), 1.69
(d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.2 Hz, 7H) F7 ESIMS .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.66 (d, J = 1.6 Hz, .sup.19F NMR
(376 MHz, m/z 589 1H), 7.57 (dd, J = 8.0, 1.7 Hz, CDCl.sub.3)
.delta. ([M + H].sup.+) 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.41 (s,
-59.06, -68.57 2H), 6.92 (d, J = 7.4 Hz, 1H), 6.79 (d, J = 7.6 Hz,
1H), 6.61 (d, J = 15.9 Hz, 1H), 6.42 (dd, J = 15.9, 7.8 Hz, 1H),
5.43 (h, J = 6.9 Hz, 1H), 4.12 (p, J = 8.5 Hz, 1H), 1.69 (d, J =
6.8 Hz, 3H), 1.36 (tt, J = 7.8, 4.5 Hz, 1H), 0.93 (dt, J = 4.6, 3.2
Hz, 2H), 0.77 (dt, J = 7.9, 3.4 Hz, 2H) F8 ESIMS .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. .sup.19F NMR (376 MHz, m/z 603 7.72-7.63
(m, 1H), 7.63-7.52 (m, 1H), 7.48 (d, J = 7.9 Hz, CDCl.sub.3)
.delta. ([M + H].sup.+) 1H), 7.41 (d, J = 1.2 Hz, 2H), rotomers
-59.04 6.95 (d, J = 7.4 Hz, 1H), 6.62 (dd, J = 15.9, & -59.08,
9.0 Hz, 1H), 6.43 (ddd, J = 16.0, -68.57 10.0, 7.9 Hz, 2H),
5.57-5.52 (m, 1H), 5.46 (h, J = 7.0 Hz, 1H), 4.13 (p, J = 8.5 Hz,
1H), 2.13 (d, J = 1.3 Hz, 3H), 1.85 (d, J = 1.4 Hz, 3H), 1.70 (d, J
= 6.8 Hz, 3H) F9 ESIMS .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.67 (s, 1H), .sup.19F NMR (376 MHz, m/z 602 7.59 (d, J = 7.9 Hz,
1H), 7.50 (d, J = 8.0 Hz, CDCl.sub.3) .delta. ([M + H].sup.+) 1H),
7.41 (s, 2H), 6.75 (t, J = 7.4 Hz, -59.02, -68.56 2H), 6.61 (d, J =
15.9 Hz, 1H), 6.43 (dd, J = 15.9, 7.8 Hz, 1H), 5.44 (q, J = 7.2 Hz,
1H), 4.17-4.07 (m, 1H), 2.67 (td, J = 7.1, 1.0 Hz, 2H), 2.55 (t, J
= 6.9 Hz, 2H), 1.70 (d, J = 6.8 Hz, 3H) F10 ESIMS .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.66 (s, 1H), .sup.19F NMR (376 MHz, m/z
659 7.57 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 7.9 Hz, CDCl.sub.3)
.delta. ([M + H].sup.+) 1H), 7.41 (s, 2H), 6.90 (s, 1H), -59.06,
-66.23, 6.72 (d, J = 7.9 Hz, 1H), 6.61 (d, J = 15.9 Hz, -68.57 1H),
6.43 (dd, J = 15.9, 7.8 Hz, 1H), 5.43 (h, J = 7.0 Hz, 1H), 4.12 (p,
J = 8.5 Hz, 1H), 2.30-2.22 (m, 2H), 2.20-2.02 (m, 2H), 1.89 (p, J =
7.4 Hz, 2H), 1.68 (d, J = 6.8 Hz, 3H) F11 ESIMS .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.66 (s, 1H), .sup.19F NMR (376 MHz, m/z
588 7.57 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, CDCl.sub.3)
.delta. ([M + H].sup.+) 1H), 7.41 (s, 2H), 7.34 (d, J = 7.4 Hz,
-58.97, -68.55 1H), 6.88 (d, J = 7.6 Hz, 1H), 6.61 (d, J = 16.0 Hz,
1H), 6.44 (dd, J = 15.9, 7.8 Hz, 1H), 5.51 (h, J = 6.9 Hz, 1H),
4.19-4.06 (m, 1H), 3.37 (s, 2H), 1.69 (d, J = 6.8 Hz, 3H) F12 ESIMS
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (d, J = 7.6 Hz,
.sup.19F NMR (376 MHz, m/z 659 1H), 8.31 (d, J = 7.7 Hz, 1H), DMSO-
([M + H].sup.+) 7.99 (d, J = 1.6 Hz, 1H), 7.95-7.86 (m, d.sub.6)
.delta. -57.83, 3H), 7.45 (d, J = 7.9 Hz, 1H), 7.05 (dd, J = 15.8,
-65.19, -67.95 9.1 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.39 (p, J =
7.3 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H), 2.50 (dt, J = 3.7, 1.9 Hz,
2H), 2.43-2.28 (m, 2H), 1.68 (dq, J = 11.6, 6.7 Hz, 2H), 0.88 (t, J
= 7.4 Hz, 3H) F13 ESIMS .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
9.13 (t, J = 5.9 Hz, .sup.19F NMR (376 MHz, m/z 629 1H), 8.78 (t, J
= 6.0 Hz, 1H), DMSO- ([M + H].sup.+) 7.98 (d, J = 1.6 Hz, 1H), 7.93
(s, 2H), d.sub.6) .delta. -57.82, 7.89 (dd, J = 8.0, 1.8 Hz, 1H),
7.45 (d, J = 8.0 Hz, -65.21, -67.95 1H), 7.06 (dd, J = 15.8, 9.1
Hz, 1H), 6.86 (d, J = 15.8 Hz, 1H), 4.85 (q, J = 9.4 Hz, 1H), 4.54
(t, J = 5.9 Hz, 2H), 2.61-2.28 (m, 4H) F14 ESIMS .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.70 (d, J = 7.3 Hz, .sup.19F NMR (376
MHz, m/z 612 1H), 8.28 (d, J = 7.6 Hz, 1H), DMSO- ([M - H].sup.-)
8.00 (d, J = 1.6 Hz, 1H), 7.93 (s, 2H), d.sub.6) .delta. -57.78,
7.92-7.87 (m, 1H), 7.53 (d, J = 8.0 Hz, -67.93 1H), 7.06 (dd, J =
15.7, 9.1 Hz, 1H), 6.87 (d, J = 15.7 Hz, 1H), 5.65 (h, J = 6.8 Hz,
1H), 4.85 (q, J = 9.5 Hz, 1H), 1.62-1.43 (m, 4H), 1.36 (d, J = 6.5
Hz, 3H) F15 ESIMS .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.72
(d, J = 7.4 Hz, .sup.19F NMR (376 MHz, m/z 617 1H), 8.05 (d, J =
7.5 Hz, 1H), DMSO- ([M - H].sup.-) 7.98 (d, J = 1.7 Hz, 1H), 7.93
(s, 2H), d.sub.6) .delta. -57.81, 7.92-7.85 (m, 1H), 7.45 (d, J =
8.0 Hz, -67.96 1H), 7.05 (dd, J = 15.7, 9.1 Hz, 1H), 6.86 (d, J =
15.7 Hz, 1H), 5.58 (h, J = 6.8 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H),
1.97 (d, J = 2.7 Hz, 2H), 1.31 (d, J = 6.5 Hz, 3H), 0.97 (s, 9H)
F16 ESIMS .sup.1H NMR (400 MHz, DMSO-d.sub.6) mixture of .sup.19F
NMR (376 MHz, m/z 657 diastereomers .delta. 8.89-8.72 (m, 1H),
DMSO- ([M - H].sup.-) 8.53-8.41 (m, 1H), 8.01-7.96 (m, 1H),
d.sub.6), mixture 7.93 (s, 2H), 7.92-7.86 (m, 1H), of 7.51-7.42 (m,
1H), 7.06 (dd, J = 15.8, 9.1 Hz, 1H), diastereomers 6.87 (d, J =
15.7 Hz, 1H), .delta. -57.84, -67.96, -72.25, 5.68-5.50 (m, 1H),
4.86 (p, J = 9.4 Hz, 1H), -72.26 2.88-2.70 (m, 1H), 2.46-2.38 (m,
1H), 2.22-2.11 (m, 1H), 1.39-1.28 (m, 3H), 1.11-1.03 (m, 3H) F17
ESIMS .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 8.70 (d, J = 7.2
Hz, .sup.19F NMR (376 MHz, m/z 631 1H), 8.16 (d, J = 7.5 Hz, 1H),
DMSO- ([M - H].sup.-) 7.98 (d, J = 1.8 Hz, 1H), 7.96-7.86 (m,
d.sub.6) .delta. -57.80, 3H), 7.45 (d, J = 8.0 Hz, 1H), 7.05 (dd, J
= 15.8, -67.95 9.1 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.55 (h, J =
6.7 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H), 2.11-2.00 (m, 2H), 1.47-1.37
(m, 2H), 1.31 (d, J = 6.5 Hz, 3H), 0.86 (s, 9H) F18 ESIMS .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. 8.71 (d, J = 7.2 Hz, .sup.19F
NMR (376 MHz, m/z 647 1H), 8.12 (d, J = 7.5 Hz, 1H), DMSO- ([M +
H].sup.+) 8.00-7.95 (m, 1H), 7.92 (s, 2H), d.sub.6) .delta. -57.78,
7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.45 (d, J = 7.9 Hz, -67.95 1H),
7.05 (dd, J = 15.8, 9.1 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.56
(h, J = 6.7 Hz, 1H), 4.86 (p, J = 9.5 Hz, 1H), 2.04 (t, J = 7.4 Hz,
2H), 1.46 (dtd, J = 9.7, 7.5, 4.5 Hz, 2H), 1.32 (d, J = 6.5 Hz,
3H), 1.18-1.09 (m, 2H), 0.85 (s, 9H) F19 ESIMS .sup.1H NMR (400
MHz, DMSO-d.sub.6) .delta. 8.57 (d, J = 7.3 Hz, .sup.19F NMR (376
MHz, m/z 603 1H), 7.99 (d, J = 1.6 Hz, 1H), DMSO- ([M - H].sup.-)
7.92 (s, 2H), 7.89 (dd, J = 8.1, 1.6 Hz, d.sub.6) .delta. -57.76,
1H), 7.58 (d, J = 7.7 Hz, 1H), 7.48 (d, J = 8.0 Hz, -67.95 1H),
7.05 (dd, J = 15.8, 9.1 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.59
(h, J = 6.8 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H), 1.34 (d, J = 6.5 Hz,
3H), 1.10 (s, 9H) F20 ESIMS .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. .sup.19F NMR (376 MHz, m/z 643 7.71-7.63 (m, 1H), 7.65-7.53
(m, 1H), 7.47 (d, J = 7.9 Hz, CDCl.sub.3) .delta. ([M - H].sup.-)
1H), 7.41 (s, 2H), -59.32, -62.60, 6.66-6.56 (m, 1H), 6.42 (dd, J =
16.0, 7.8 Hz, 1H), -68.59 6.42 (s, 1H), 4.12 (p, J = 8.8 Hz, 1H),
3.73-3.63 (m, 4H), 3.22 (q, J = 9.9 Hz, 2H), 3.13 (s, 3H) F21 ESIMS
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.67 (d, J = 1.6 Hz,
.sup.19F NMR (376 MHz, m/z 629 1H), 7.59 (dd, J = 7.9, 1.7 Hz,
CDCl.sub.3) .delta. ([M - H].sup.-) 1H), 7.45 (d, J = 7.9 Hz, 1H),
7.41 (s, -59.22, -68.59, 2H), 6.66-6.57 (m, 1H), 6.43 (dd, J =
15.9, -69.88 7.9 Hz, 1H), 6.18 (s, 1H), 4.12 (p, J = 8.8 Hz, 1H),
3.72 (d, J = 3.2 Hz, 4H), 3.25 (q, J = 1.5 Hz, 3H) F22 ESIMS
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.05 (bs, IR (thin m/z
615 1H), 8.11 (s, 1H), 7.98 (d, J = 8.4 Hz, film) 3256, ([M +
H].sup.+) 1H), 7.92 (s, 2H), 7.79 (s, J = 7.6 Hz, 1698, 1114, 1H),
7.15 (dd, J = 16.4, 9.6 Hz, 1H), 749 (cm.sup.-1) 6.92 (d, J = 16.0
Hz, 1H), 4.90-4.83 (m, 1H), 3.10 (s, 3H), 2.50 (s, 2H) F23 ESIMS
.sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.01 (bs, IR (thin m/z
629 1H), 8.10 (s, 1H), 7.99 (d, J = 8.4 Hz, film) 3436, ([M +
H].sup.+) 1H), 7.92 (s, 2H), 7.68 (s, J = 8.0 Hz, 1689, 1275, 1H),
7.15 (dd, J = 15.6, 8.8 Hz, 1H), 750 (cm.sup.-1) 6.92 (d, J = 15.6
Hz, 1H), 4.90-4.83 (m, 1H), 3.11 (s, 3H), 2.97 (s, 1H), 2.67-2.58
(m, 3H)
TABLE-US-00004 TABLE 4 Structure and Preparation Method for C
Series Compounds Prep. according to No. Structure example C113
##STR00267## 21 C115 ##STR00268## 24 C116 ##STR00269## 26
TABLE-US-00005 TABLE 5 Structure and Preparation Method for
Exemplified P Series Compounds Prep. according to No. Structure
example: P1 ##STR00270## 30 P2 ##STR00271## 30 P3 ##STR00272## 30
P4 ##STR00273## 30 P5 ##STR00274## 30 P6 ##STR00275## 30 P7
##STR00276## 30 P8 ##STR00277## 30 P9 ##STR00278## 30 P10
##STR00279## 30 P11 ##STR00280## 30 P12 ##STR00281## 30 P13
##STR00282## 30 P14 ##STR00283## 30 P15 ##STR00284## 30 P16
##STR00285## 30 P22 ##STR00286## 30 P24 ##STR00287## 30 P25
##STR00288## 30 P27 ##STR00289## 30 P30 ##STR00290## 19 P33
##STR00291## 19 P36 ##STR00292## 31 P43 ##STR00293## 31 P47
##STR00294## 31 P49 ##STR00295## 31 P53 ##STR00296## 30 P54
##STR00297## 30
TABLE-US-00006 TABLE 6 Analytical Data for Compounds in Table 5 No.
Mass (m/z) .sup.1H NMR .sup.19F NMR/IR P1 HRMS-ESI [M + H].sup.+
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd
for 8.90 (d, J = 7.3 Hz, 1H), 8.65 (d, J = 7.4 Hz, 1678 cm.sup.-1
C.sub.23H.sub.16Cl.sub.2F.sub.10N.sub.2O.sub.2, 1H), 8.02-7.97 (m,
1H), 613.0502; Found, 7.89 (dd, J = 10.3, 7.1 Hz, 3H), 7.45 (d, J =
7.9 Hz, 613.0494 1H), 7.05 (dd, J = 15.8, 9.2 Hz, 1H), 6.86 (d, J =
15.7 Hz, 1H), 5.58 (h, J = 6.8 Hz, 1H), 4.83 (p, J = 9.4 Hz, 1H),
3.27 (q, J = 11.3 Hz, 2H), 1.35 (d, J = 6.5 Hz, 3H) P2 HRMS-ESI [M
+ H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin
film) calcd for 8.89 (d, J = 7.4 Hz, 1H), 8.63 (d, J = 7.4 Hz, 1675
cm.sup.-1 C.sub.23H.sub.17Br.sub.2ClF.sub.9N.sub.2O.sub.2, 1H),
8.06 (s, 2H), 718.9176; Found, 8.01-7.97 (m, 1H), 7.93-7.87 (m,
1H), 718.9181 7.45 (d, J = 8.0 Hz, 1H), 7.06 (dd, J = 15.8, 9.2 Hz,
1H), 6.85 (d, J = 15.7 Hz, 1H), 5.57 (h, J = 6.8 Hz, 1H), 4.84 (p,
J = 9.4 Hz, 1H), 3.27 (q, J = 11.3 Hz, 2H), 1.35 (d, J = 6.5 Hz,
3H) P3 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. IR (thin film) calcd for 8.90 (d, J = 7.4 Hz, 1H), 8.64 (d,
J = 7.4 Hz, 1677 cm.sup.-1
C.sub.23H.sub.17Br.sub.2F.sub.9N.sub.2O.sub.2, 1H), 8.01-7.97 (m,
1H), 684.9567; Found, 7.93-7.88 (m, 2H), 7.85 (d, J = 1.7 Hz,
684.9570 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.06 (dd, J = 15.8, 9.2 Hz,
1H), 6.86 (d, J = 15.7 Hz, 1H), 5.58 (h, J = 6.8 Hz, 1H), 4.82 (p,
J = 9.5 Hz, 1H), 3.27 (q, J = 11.3 Hz, 2H), 1.35 (d, J = 6.5 Hz,
3H) P4 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. IR (thin film) calcd for 8.89 (d, J = 7.4 Hz, 1H), 8.63 (d,
J = 7.4 Hz, 1675 cm.sup.-1
C.sub.24H.sub.18Br.sub.2ClF.sub.9N.sub.2O.sub.2, 1H), 8.01-7.97 (m,
1H), 674.9679; Found, 7.92-7.84 (m, 3H), 7.45 (d, J = 7.9 Hz,
674.9681 1H), 7.05 (dd, J = 15.8, 9.1 Hz, 1H), 6.86 (d, J = 15.7
Hz, 1H), 5.57 (h, J = 6.8 Hz, 1H), 4.85 (p, J = 9.2 Hz, 1H), 3.27
(q, J = 11.5 Hz, 2H), 1.35 (d, J = 6.6 Hz, 3H) P5 HRMS-ESI [M +
H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film)
calcd for 8.62-8.54 (m, 2H), 7.84 (d, J = 6.3 Hz, 1672 cm.sup.-1
C.sub.23H.sub.19Cl.sub.2F.sub.7N.sub.2O.sub.2, 2H), 7.45 (d, J =
1.8 Hz, 1H), 559.0785; Found, 7.40 (dd, J = 8.0, 1.7 Hz, 1H), 7.29
(d, J = 7.9 Hz, 559.0794 1H), 6.84 (dd, J = 15.7, 9.1 Hz,1H), 6.72
(d, J = 15.7 Hz, 1H), 5.60 (h, J = 6.8 Hz, 1H), 4.80 (p, J = 9.4
Hz, 1H), 3.27 (q, J = 11.3 Hz, 2H), 2.33 (s, 3H), 1.35 (d, J = 6.5
Hz, 3H) P6 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.60 (d, J = 7.5 Hz,
1H), 8.57 (d, J = 7.2 Hz, 1672 cm.sup.-1
C.sub.23H.sub.19BrCl.sub.2F.sub.6N.sub.2O.sub.2, 1H), 7.85 (s, 2H),
7.45 (d, J = 1.7 Hz, 732.9332; Found, 1H), 7.40 (dd, J = 8.0, 1.7
Hz, 732.9342 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.83 (dd, J = 15.7, 9.0
Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H), 5.60 (h, J = 6.8 Hz, 1H), 4.81
(p, J = 9.4 Hz, 1H), 3.26 (q, J = 11.3 Hz, 2H), 2.33 (s, 3H), 1.35
(d, J = 6.5 Hz, 3H) P7 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.59 (d, J = 7.5 Hz,
1H), 8.56 (d, J = 7.2 Hz, 1656 cm.sup.-1
C.sub.23H.sub.21Br.sub.2F.sub.6N.sub.2O.sub.2, 1H), 7.89 (t, J =
1.7 Hz, 1H), 630.9850; Found, 7.82 (d, J = 1.7 Hz, 2H), 630.9858
7.47-7.43 (m, 1H), 7.40 (dd, J = 8.0, 1.7 Hz, 1H), 7.29 (d, J = 7.8
Hz, 1H), 6.83 (dd, J = 15.7, 9.1 Hz, 1H), 6.72 (d, J = 15.6 Hz,
1H), 5.60 (h, J = 6.8 Hz, 1H), 4.79 (p, J = 9.5 Hz, 1H), 3.27 (q, J
= 11.3 Hz, 2H), 2.33 (s, 3H), 1.35 (d, J = 6.5 Hz, 3H) P8 HRMS-ESI
[M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin
film) calcd for 8.60 (d, J = 7.5 Hz, 1H), 8.57 (d, J = 7.3 Hz, 1673
cm.sup.-1 C.sub.23H.sub.20Br.sub.2ClF.sub.6N.sub.2O.sub.2, 1H),
8.03 (s, 2H), 7.45 (d, J = 1.8 Hz, 664.9458; Found, 1H), 7.41 (dd,
J = 8.1, 1.7 Hz, 664.9465 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.84 (dd,
J = 15.7, 9.1 Hz, 1H), 6.72 (d, J = 15.7 Hz, 1H), 5.60 (h, J = 6.8
Hz, 1H), 4.81 (p, J = 9.5 Hz, 1H), 3.27 (q, J = 11.3 Hz, 2H), 2.33
(s, 3H), 1.35 (d, J = 6.5 Hz, 3H) P9 HRMS-ESI [M + H].sup.+ .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.78
(d, J = 7.2 Hz, 1H), 8.41 (d, J = 7.5 Hz, 1667 cm.sup.-1
C.sub.24H.sub.18Cl.sub.2F.sub.10N.sub.2O.sub.2, 1H), 8.00-7.96 (m,
1H), 627.0658; Found, 7.91-7.85 (m, 3H), 7.46 (d, J = 7.9 Hz,
627.0662 1H), 7.05 (dd, J = 15.8, 9.1 Hz, 1H), 6.86 (d, J = 15.8
Hz, 1H), 5.58 (h, J = 6.7 Hz, 1H), 4.84 (p, J = 9.4 Hz, 1H),
2.58-2.28 (m, 4H), 1.33 (d, J = 6.5 Hz, 3H) P10 HRMS-ESI [M +
H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film)
calcd for 8.77 (d, J = 7.2 Hz, 1H), 8.40 (d, J = 7.5 Hz, 1665
cm.sup.-1 C.sub.24H.sub.18Br.sub.2ClF.sub.9N.sub.2O.sub.2, 1H),
8.06 (s, 2H), 7.98 (d, J = 1.7 Hz, 732.9332; Found, 1H), 7.92-7.85
(m, 1H), 732.9342 7.45 (d, J = 8.0 Hz, 1H), 7.05 (dd, J = 15.8, 9.2
Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.57 (h, J = 6.7 Hz, 1H), 4.84
(p, J = 9.4 Hz, 1H), 2.52-2.29 (m, 4H),1.33 (d, J = 6.5 Hz, 3H) P11
HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
IR (thin film) calcd for 8.78 (d, J = 7.1 Hz, 1H), 8.41 (d, J = 7.4
Hz, 1665 cm.sup.-1 C.sub.24H.sub.19Br.sub.2F.sub.9N.sub.2O.sub.2,
1H), 7.98 (d, J = 1.6 Hz, 1H), 698.9723; Found, 7.93-7.87 (m, 2H),
7.86 (d, J = 1.7 Hz, 698.9721 2H), 7.45 (d, J = 7.9 Hz, 1H), 7.05
(dd, J = 15.8, 9.2 Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.58 (h, J =
6.8 Hz, 1H), 4.82 (p, J = 9.5 Hz, 1H), 2.57-2.28 (m, 4H), 1.33 (d,
J = 6.5 Hz, 3H) P12 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.78 (d, J = 7.2 Hz,
1H), 8.41 (d, J = 7.5 Hz, 1666 cm.sup.-1
C.sub.24H.sub.19BrCl.sub.2F.sub.9N.sub.2O.sub.2, 1H), 8.00-7.96 (m,
1H), 688.9836; Found, 7.88 (s, 3H), 7.46 (d, J = 7.9 Hz, 1H),
688.9845 7.05 (dd, J = 15.7, 9.1 Hz, 1H), 6.86 (d, J = 15.7 Hz,
1H), 5.58 (h, J = 6.8 Hz, 1H), 4.85 (p, J = 9.4 Hz, 1H), 2.54-2.29
(m, 4H), 1.33 (d, J = 6.5 Hz, 3H) P13 HRMS-ESI [M + H].sup.+
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd
for 8.47 (d, J = 7.3 Hz, 1H), 8.35 (d, J = 7.2 Hz, 1655 cm.sup.-1
C.sub.24H.sub.21Cl.sub.2F.sub.7N.sub.2O.sub.2, 1H), 7.84 (d, J =
6.2 Hz, 2H), 573.0941; Found, 7.45 (d, J = 1.8 Hz, 1H), 573.0911
7.42-7.37 (m, 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 15.7,
9.1 Hz, 1H), 6.72 (d, J = 15.7 Hz, 1H), 5.61 (h, J = 6.7 Hz, 1H),
4.80 (p, J = 9.4 Hz, 1H), 2.58-2.21 (m, 7H), 1.33 (d, J = 6.5 Hz,
3H) P14 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. IR (thin film) calcd for 8.46 (d, J = 7.3 Hz, 1H), 8.33 (d,
J = 7.2 Hz, 1660 cm.sup.-1
C.sub.24H.sub.18Br.sub.2ClF.sub.9N.sub.2O.sub.2, 1H), 8.03 (s, 2H),
7.44 (d, J = 1.7 Hz, 678.9615; Found, 1H), 7.39 (dd, J = 8.0, 1.7
Hz, 678.9623 1H), 7.29 (d, J = 7.8 Hz, 1H), 6.83 (dd, J = 15.7, 9.1
Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H), 5.60 (h, J = 6.8 Hz, 1H), 4.81
(p, J = 9.5 Hz, 1H), 2.49-2.42 (m, 2H), 2.42-2.28 (m, 5H), 1.33 (d,
J = 6.5 Hz, 3H) P15 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.48 (d, J = 7.3 Hz,
1H), 8.35 (d, J = 7.2 Hz, 1660 cm.sup.-1
C.sub.24H.sub.22Br.sub.2F.sub.6N.sub.2O.sub.2, 1H), 7.89 (t, J =
1.8 Hz, 1H), 645.0006; Found, 7.82 (d, J = 1.8 Hz, 2H), 7.45 (d, J
= 1.7 Hz, 645.0004 1H), 7.41-7.37 (m, 1H), 7.29 (d, J = 7.9 Hz,
1H), 6.82 (dd, J = 15.7, 9.1 Hz, 1H), 6.72 (d, J = 15.6 Hz, 1H),
5.61 (h, J = 6.7 Hz, 1H), 4.79 (p, J = 9.5 Hz, 1H), 2.56-2.28 (m,
7H), 1.33 (d, J = 6.5 Hz, 3H) P16 HRMS-ESI [M + H].sup.+ .sup.1H
NMR (400 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.47
(d, J = 7.3 Hz, 1H), 8.34 (d, J = 7.2 Hz, 1660 cm.sup.-1
C.sub.24H.sub.21BrCl.sub.2F.sub.6N.sub.2O.sub.2, 1H), 7.85 (s, 2H),
632.0118; Found, 7.50-7.42 (m, 1H), 7.40 (dd, J = 7.9, 1.7 Hz,
635.0128 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.83 (dd, J = 15.7, 8.9 Hz,
1H), 6.72 (d, J = 15.7 Hz, 1H), 5.60 (h, J = 6.8 Hz, 1H), 4.82 (p,
J = 9.4 Hz, 1H), 2.61-2.22 (m, 7H), 1.33 (d, J = 6.5 Hz, 3H) P22
HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
IR (thin film) calcd for 8.59 (d, J = 7.5 Hz, 1H), 8.56 (d, J = 7.3
Hz, 1671 cm.sup.-1 C.sub.23H.sub.20Cl.sub.3F.sub.6N.sub.2O.sub.2,
1H), 7.89 (s, 2H), 7.45 (d, J = 1.8 Hz, 577.0463; Found, 1H), 7.40
(dd, J = 8.0, 1.7 Hz, 577.0470 1H), 7.29 (d, J = 7.9 Hz, 1H), 6.84
(dd, J = 15.7, 9.1 Hz, 1H), 6.73 (d, J = 15.7 Hz, 1H), 5.60 (h, J =
6.8 Hz, 1H), 4.83 (p, J = 9.4 Hz, 1H), 3.26 (q, J = 11.3 Hz, 2H),
2.33 (s, 3H), 1.35 (d, J = 6.5 Hz, 3H) P24 HRMS-ESI [M + H].sup.+
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd
for 8.84 (dd, J = 7.6, 1.6 Hz, 1H), 8.63 (d, J = 7.6 Hz, 1675
cm.sup.-1 C.sub.22H.sub.17BrCl.sub.3F.sub.6N.sub.2O.sub.2, 1H),
7.89 (s, 2H), 7.63 (d, 640.9414; Found, J = 8.2 Hz, 1H), 7.58-7.50
(m, 2H), 640.9414 6.90 (dd, J = 15.7, 9.1 Hz, 1H), 6.76 (d, J =
15.7 Hz, 1H), 5.64 (h, J = 6.8 Hz, 1H), 4.84 (p, J = 9.3 Hz, 1H),
3.29 (q, J = 11.3 Hz, 2H), 1.38 (d, J = 6.5 Hz, 3H) P25 HRMS-ESI [M
+ H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin
film) calcd for 8.47 (d, J = 7.3 Hz, 1H), 8.34 (d, J = 7.2 Hz, 1656
cm.sup.-1 C.sub.24H.sub.21Cl.sub.3F.sub.6N.sub.2O.sub.2, 1H), 7.89
(s, 2H), 7.45 (d, J = 1.7 Hz, 589.0646; Found, 1H), 7.43-7.37 (m,
1H), 589.0657 7.29 (d, J = 7.8 Hz, 1H), 6.84 (dd, J = 15.7, 9.1 Hz,
1H), 6.73 (d, J = 15.7 Hz, 1H), 5.60 (h, J = 6.7 Hz, 1H), 4.83 (p,
J = 9.4 Hz, 1H), 2.56-2.28 (m, 7H), 1.33 (d, J = 6.5 Hz, 3H) P27
HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
IR (thin film) calcd for 8.70 (dd, J = 7.2, 1.9 Hz, 1H), 8.37 (d, J
= 7.6 Hz, 1666 cm.sup.-1
C.sub.23H.sub.19BrCl.sub.3F.sub.6N.sub.2O.sub.2, 1H), 7.89 (s, 2H),
7.62 (d, 654.9571; Found, J = 8.3 Hz, 1H), 7.55 (t, J = 1.9 Hz,
654.9582 1H), 7.52 (ddd, J = 8.0, 5.3, 2.2 Hz, 1H), 6.89 (ddd, J =
15.8, 9.1, 1.8 Hz, 1H), 6.75 (d, J = 15.6 Hz, 1H), 5.62 (h, J = 6.7
Hz, 1H), 4.83 (p, J = 9.5 Hz, 1H), 2.56-2.43 (m, 2H), 2.42-2.29 (m,
2H), 1.35 (d, J = 6.5 Hz, 3H) P30 ESIMS 657 Mixture of
diastereomers: .sup.1H NMR Mixture of ([M - H].sup.-) (400 MHz,
CDCl.sub.3) .delta. 7.67-7.63 (m, diastereomers: 1H), 7.59-7.51 (m,
1H), (Major) .sup.19F 7.46-7.40 (m, 3H), 7.18-7.04 (m, 2H), NMR
(376 MHz, 6.61 (d, J = 15.9 Hz, 1H), 6.42 (dd, J = 16.0,
CDCl.sub.3) .delta. 7.9 Hz, 1H), 5.40 (hept, J = 7.0 Hz, -59.09,
-64.97, 1H), 4.12 (p, J = 8.6 Hz, 1H), -68.59; 2.71-2.45 (m, 2H),
2.20-1.97 (m, (Minor) 19F 1H), 1.71-1.61 (m, 3H), NMR (376 MHz,
1.24-1.19 (m, 3H) CDCl.sub.3) .delta. -59.11, -64.96,
-68.60 P33 ESIMS 657 .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.64
(d, J = 1.7 Hz, .sup.19F NMR (376 MHz, ([M - H].sup.-) 1H), 7.55
(dd, J = 8.0, 1.7 Hz, CDCl.sub.3) .delta. 1H), 7.45-7.40 (m, 3H),
-59.12, -68.60, 7.30 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 7.5 Hz,
-74.48 1H), 6.61 (d, J = 15.9 Hz, 1H), 6.42 (dd, J = 15.9, 7.9 Hz,
1H), 5.46 (h, J = 7.0 Hz, 1H), 4.20-4.03 (m, 1H), 1.66 (d, J = 6.7
Hz, 3H), 1.38 (s, 6H) P36 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.92-8.86 (m,
1H), 8.64-8.56 (m, 1H), 1671 cm.sup.-1
C.sub.23H.sub.19Cl.sub.3F.sub.6N.sub.2O.sub.3S, 7.99 (s, 1H), 7.91
(d, J = 16.8 Hz, 625.0132; Found, 3H), 7.50-7.45 (m, 1H), 7.06 (dd,
J = 15.7, 625.0136 9.1 Hz, 1H), 6.87 (d, J = 15.7 Hz, 1H),
5.65-5.56 (m, 1H), 4.86 (p, J = 9.4 Hz, 1H), 3.74-3.59 (m, 2H),
2.65-2.61 (m, 3H), 1.39-1.31 (m, 3H) P43 HRMS-ESI [M + H].sup.+
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd
for 8.93 (d, J = 7.5 Hz, 1H), 8.72 (d, J = 7.4 Hz, 1677 cm.sup.-1
C.sub.23H.sub.19Cl.sub.3F.sub.6N.sub.2O.sub.4S, 1H), 8.03-7.96 (m,
1H), 641.0082; Found, 7.91 (d, J = 14.8 Hz, 3H), 7.47 (d, J = 7.9
Hz, 641.0089 1H), 7.06 (dd, J = 15.8, 9.1 Hz, 1H), 6.87 (d, J =
15.7 Hz, 1H), 5.60 (h, J = 6.8 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H),
4.15 (d, J = 14.2 Hz, 1H), 4.06-4.02 (m, 1H), 3.12 (s, 3H), 1.35
(d, J = 6.5 Hz, 3H) P47 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd for 8.77 (d, J =
7.1 Hz, 1H), 8.46 (d, J = 7.4 Hz, 1670 cm.sup.-1
C.sub.24H.sub.21Cl.sub.3F.sub.6N.sub.2O.sub.4S, 1H), 7.98 (d, J =
1.7 Hz, 1H), 655.0238; Found, 7.94-7.86 (m, 3H), 7.47 (d, J = 7.9
Hz, 655.026 1H), 7.05 (dd, J = 15.8, 9.1 Hz, 1H), 6.86 (d, J = 15.7
Hz, 1H), 5.58 (h, J = 6.7 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H),
3.35-3.29 (m, 2H), 2.98 (s, 3H), 2.63-2.52 (m, 2H), 1.33 (d, J =
6.5 Hz, 3H) P49 HRMS-ESI [M + H].sup.+ .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. calcd for 8.80-8.74 (m, 1H), 8.45-8.39 (m,
1H), C.sub.24H.sub.21Cl.sub.3F.sub.6N.sub.2O.sub.3S, 7.99-7.97 (m,
1H), 7.90 (d, J = 22.0 Hz, 639.0289; Found, 3H), 7.47 (d, J = 7.9
Hz, 639.0299 1H), 7.05 (dd, J = 15.7, 9.1 Hz, 1H), 6.87 (d, J =
15.7 Hz, 1H), 5.58 (h, J = 6.7 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H),
3.06-2.97 (m, 1H), 2.81 (ddt, J = 11.3, 7.1, 5.5 Hz, 1H), 2.53 (s,
3H), 2.52-2.51 (m, 2H), 1.33 (d, J = 6.5 Hz, 3H) P53 HRMS-ESI [M +
H].sup.+ .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film)
calcd for 8.74 (d, J = 7.2 Hz, 1H), 8.27 (d, J = 7.5 Hz, 1662
cm.sup.-1 C.sub.24H.sub.21Cl.sub.3F.sub.6N.sub.2O.sub.2S, 1H), 7.98
(d, J = 1.9 Hz, 1H), 623.034; Found 7.92 (s, 2H), 7.89 (d, J = 7.8
Hz, 623.0342 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.05 (dd, J = 15.7, 9.1
Hz, 1H), 6.86 (d, J = 15.7 Hz, 1H), 5.57 (h, J = 6.8 Hz, 1H), 4.86
(p, J = 9.4 Hz, 1H), 2.65 (t, J = 7.0 Hz, 2H), 2.45-2.31 (m, 2H),
2.06 (s, 3H), 1.32 (d, J = 6.5 Hz, 3H) P54 HRMS-ESI [M + H].sup.+
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. IR (thin film) calcd
for 8.81 (d, J = 7.4 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1664 cm.sup.-1
C.sub.23H.sub.19Cl.sub.3F.sub.6N.sub.2O.sub.2S; 1H), 8.01-7.97 (m,
1H), 609.0183; 7.94-7.87 (m, 3H), 7.47 (d, J = 7.9 Hz, Found,
609.0188 1H), 7.05 (dd, J = 15.7, 9.1 Hz, 1H), 6.86 (d, J = 15.7
Hz, 1H), 5.59 (h, J = 6.8 Hz, 1H), 4.86 (p, J = 9.4 Hz, 1H), 3.09
(s, 2H), 2.10 (s, 3H), 1.34 (d, J = 6.5 Hz, 3H).
TABLE-US-00007 TABLE 7 Structure and Preparation Method for FC
Series Compounds Prep. according to No. Structure example: FC1
##STR00298## 30 FC2 ##STR00299## 30
TABLE-US-00008 TABLE 8 Analytical Data for Compounds in Table 7 No.
Mass (m/z) .sup.1H NMR .sup.19F NMR/IR FC1 HRMS-ESI [M + H].sup.+
Rotomers: .sup.1H NMR (400 MHz, DMSO- Rotomers: .sup.19F calcd for
d.sub.6) .delta. 8.63 (d, J = 7.2 Hz, 1H), NMR (376 MHz,
C.sub.23H.sub.20Cl.sub.3F.sub.6N.sub.2O.sub.2; 8.29 (d, J = 7.1 Hz,
1H), 7.88 (s, 2H), CDCl.sub.3) .delta. 575.0489; Found, 7.82 (d, J
= 8.4 Hz, 2H), 7.63 (d, J = 8.4 Hz, -66.76, -68.68 575.0490 2H),
6.93-6.88 (m, 1H), 6.77 (d, J = 15.7 Hz, 1H), 5.63 (h, J = 6.7 Hz,
1H), 4.82 (h, J = 9.2 Hz, 1H), 2.47-2.39 (m, 1H), 2.39-2.27 (m,
2H), 1.33 (d, J = 6.5 Hz, 3H) FC2 HRMS-ESI [M + H].sup.+ Rotomers:
.sup.1H NMR (400 MHz, CDCl.sub.3) .sup.19F NMR (376 MHz, calcd for
.delta. 8.51 (d, J = 8.1 Hz, 1H), 8.37 (d, J = 7.9 Hz, CDCl.sub.3)
.delta. C.sub.22H.sub.18Cl.sub.3F.sub.6N.sub.2O.sub.2; 1H), 7.76
(d, J = 8.1 Hz, -62.90, -65.78, 561.0333; Found, 2H), 7.37 (d, J =
2.4 Hz, 2H), -68.73 561.0330 7.33-7.28 (m, 2H), 6.64-6.51 (m, 1H),
6.41-6.29 (m, 1H), 6.09 (q, J = 8.3, 7.7 Hz, 1H), 4.17-3.97 (m,
1H), 3.20-3.10 (m, 2H), 1.54 (d, J = 6.5 Hz, 3H)
TABLE-US-00009 BAW & CL Rating Table % Control (or Mortality)
Rating 50-100 A More than 0-Less than 50 B Not Tested C No activity
noticed in this bioassay D
TABLE-US-00010 GPA & YFM Rating Table % Control (or Mortality)
Rating 80-100 A More than 0-Less than 80 B Not Tested C No activity
noticed in this bioassay D
TABLE-US-00011 TABLE ABC Assay Results (F) Insect species No. BAW
CL GPA YFM F1 A A C C F2 A A D A F3 A A C A F4 A A C A F5 A A C A
F6 A A C A F7 A A C A F8 A A C A F9 A A C A F10 A A C A F11 A A C A
F12 A A C A F13 A A C C F14 A A C A F15 A A C A F16 A A C A F17 A A
C A F18 A A C A F19 A A C A F20 A A C A F21 A A C B F22 A A C A F23
A A C A
TABLE-US-00012 TABLE ABCD Assay Results (C) Insect species No. BAW
CL GPA YFM C113 A A D A C115 A D C C C116 A A C A
TABLE-US-00013 TABLE ABCDE Assay Results (P) Insect species No. BAW
CL GPA YFM P1 A A C C P2 A A C A P3 A A C B P4 A A C A P5 A A C A
P6 A A C A P7 A A C A P8 A A C C P9 A A C C P10 A A C A P11 A A C A
P12 A A C A P13 A A C A P14 A A C A P15 A A C C P16 A A C C P22 A A
C C P24 A A C D P25 A A C C P27 A A C B P30 A A C C P33 A A C A P36
A A D C P43 A A C C P47 A A C C P49 A A B C P53 A A C C P54 A A C
C
Data
[0640] Bioassays on BAW and CL were conducted according to the
procedures outlined in Example A: Bioassays on Beet Armyworm
("BAW") and Cabbage Looper ("CL") using the following
concentrations: 5, 0.5, and 0.05 .mu.g/cm.sup.2. The results are
indicated in Table CD1.
TABLE-US-00014 TABLE CD1 ##STR00300## 5 .mu.g/cm.sup.2 0.5
.mu.g/cm.sup.2 0.05 .mu.g/cm.sup.2 No. R10 R14 BAW CL BAW CL BAW CL
FC1.sup..dagger. H CH.sub.2CH.sub.2CF.sub.3 13* 71 0 0 0 0 P25
CH.sub.3 CH.sub.2CH.sub.2CF.sub.3 100 100 100 100 100 100 P27 Br
CH.sub.2CH.sub.2CF.sub.3 7 100 0 7 0 0 F1 CF.sub.3
CH.sub.2CH.sub.2CF.sub.3 100 100 100 100 100 97 FC2 H
CH.sub.2CF.sub.3 0 0 0 0 0 0 P22 CH.sub.3 CH.sub.2CF.sub.3 100 100
100 100 25 63 P24 Br CH.sub.2CF.sub.3 87 100 7 19 0 6 F2 CF.sub.3
CH.sub.2CF.sub.3 100 100 100 100 100 100 .sup..dagger.Compound 30%
pure. *Percent control (or mortallity)
* * * * *