U.S. patent application number 14/290855 was filed with the patent office on 2015-12-03 for method of preparing z-alkene-containing insect pheromones.
This patent application is currently assigned to Suterra, LLC. The applicant listed for this patent is Suterra, LLC. Invention is credited to Eric A. Bercot, Brian M. Stoltz.
Application Number | 20150344392 14/290855 |
Document ID | / |
Family ID | 54363376 |
Filed Date | 2015-12-03 |
United States Patent
Application |
20150344392 |
Kind Code |
A1 |
Bercot; Eric A. ; et
al. |
December 3, 2015 |
METHOD OF PREPARING Z-ALKENE-CONTAINING INSECT PHEROMONES
Abstract
Insect pheromones and pheromone precursors, containing one or
more Z-alkenyl groups, are prepared by treating an alkyne with a
copper complex, reducing agent, and proton donor in an organic
solvent. The pheromones and pheromone precursors are prepared with
high stereoselectivity and substantially no over reduction.
Inventors: |
Bercot; Eric A.; (Bend,
OR) ; Stoltz; Brian M.; (San Marino, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Suterra, LLC |
Los Angeles |
CA |
US |
|
|
Assignee: |
Suterra, LLC
Los Angeles
CA
|
Family ID: |
54363376 |
Appl. No.: |
14/290855 |
Filed: |
May 29, 2014 |
Current U.S.
Class: |
568/467 ;
568/448 |
Current CPC
Class: |
C07C 41/48 20130101;
C07C 41/54 20130101; Y02P 20/582 20151101; C07C 47/21 20130101;
C07C 43/303 20130101; C07C 45/00 20130101; C07C 41/48 20130101 |
International
Class: |
C07C 47/21 20060101
C07C047/21; C07C 41/54 20060101 C07C041/54; C07C 45/00 20060101
C07C045/00 |
Claims
1. A method of making an insect pheromone or pheromone precursor,
having one or more Z-alkenyl groups therein, comprising: treating
an alkyne of formula IA, IB, IC, or ID with a copper(I)-nitrogen
heterocyclic carbene complex ("copper(I)-NHC"), which facilitates
semireduction of the alkyne to a Z-alkene, a reducing agent
containing at least one silicon-hydrogen bond, and a proton donor,
thereby forming the insect pheromone or pheromone precursor having
one or more Z-alkenyl groups; wherein IA is
H.sub.3C--(CH.sub.2).sub.a--C.ident.C--(CH.sub.2).sub.b-Q, IB is
H.sub.3C--(CH.sub.2).sub.cC.ident.C--(CH.sub.2).sub.d--C.ident.C--(CH.sub-
.2).sub.e-Q, IC is
H.sub.3C--(CH.sub.2).sub.f--C.ident.C--C.ident.C--(CH.sub.2).sub.g-Q,
and ID is H.sub.3C-A-C.ident.C-E-Q; where functional group Q is an
aldehyde, acetate, acyclic O,O'-acetal (--CH(OR')(OR''), where R'
and R'' are, independently, C1 to C6 alkyl or cyclic alkyl), cyclic
O,O'-acetal (--CHO(CH.sub.2).sub.xO-- where x=2, 3, or 4),
hydroxyl, protected hydroxyl, formate, or halide (Cl, Br) group,
and coefficients a-g are selected such that the alkyne has from 7
to 20 carbon atoms; and wherein in formula IA, a is 0 to 16, b is 1
to 7, and 4.ltoreq.a+b.ltoreq.17, provided that in the case where Q
is Cl or Br, (a,b).noteq.(1,8); in formula IB, c is 0 to 13, d is 1
to 14, e is 1 to 14, and 2.ltoreq.c+d+e.ltoreq.15; in formula IC, f
is 0 to 14, g is 1 to 15, and 2.ltoreq.f+g.ltoreq.15; and in
formula ID, groups A and E are, independently, C1 to C10 alkylenyl
or alkenyl, provided that at least one of A and E is an alkenyl
group and the alkyne has from 7 to 20 carbon atoms.
2. The method recited in claim 1, wherein the Copper(I)-NHC has a
formula II: L-Cu--X (II) where L is a nitrogen-heterocyclic carbene
("NHC") ligand and X is OCOR.sup.5, OR.sup.5, Cl, Br, I, or F,
where R.sup.5 is aryl or C1 to C5 alkyl.
3. The method recited in claim 2, wherein the NHC ligand is
selected from the group consisting of imidazol-2-ylidenes,
imidazolidinylidenes, and 1,2,4-triazolyidenes.
4. The method recited in claim 2, wherein the NHC ligand has a
formula (1) ##STR00026## where R.sup.1 and R.sup.2 are,
independently, alkyl or aryl, and R.sup.3 and R.sup.4 are,
independently, hydrogen, alkyl (C1 to C10), or aryl, or together
R.sup.3 and R.sup.4 form a cycloalkenyl or aryl optionally
substituted with one or more groups consisting of alkyl (C1 to
C10), alkoxy (C1 to C10), and aryl.
5. The method recited in claim 2, wherein the NHC ligand has a
formula (2) ##STR00027## where R.sup.1 and R.sup.2 are,
independently, alkyl (C1 to C10) or aryl, and R.sup.3 and R.sup.4
are, independently, hydrogen, alkyl (C1 to C10), or aryl, or
together R.sup.3 and R.sup.4 form a cycloalkyl or aryl optionally
substituted with one or more groups consisting of alkyl (C1 to
C10), alkoxy (C1 to C10), and aryl.
6. The method recited in claim 2, wherein the NHC ligand has a
formula (3) ##STR00028## where R.sup.1 and R.sup.2 are,
independently, alkyl (C1 to C10) or aryl, and R.sup.3 is hydrogen,
methyl or aryl, or together R.sup.2 and R.sup.3 form a cycloalkyl
optionally substituted with one or more groups consisting of alkyl
(C1 to C10), alkoxy (C1 to C10), and aryl.
7. The method recited in claim 1, wherein the copper(I)-NHC
comprises IPrCuCl.
8. The method recited in claim 1, wherein the copper(I)-NHC
comprises IMesCuCl.
9. The method recited in claim 1, wherein the copper(I)-NHC
comprises IPrCuOtBu.
10. The method recited in claim 1, wherein the copper(I)-NHC
comprises IMesCuOtBu.
11. The method recited in claim 1, wherein the copper(I)-NHC
comprises IPrCuOtAm.
12. The method recited in claim 1, wherein the copper(I)-NHC
comprises IMesCuOtAm.
13. The method recited in claim 1, wherein the insect pheromone or
pheromone precursor is formed with >80% selectivity.
14. The method recited in claim 1, wherein the insect pheromone or
pheromone precursor is formed with >90% selectivity.
15. The method recited in claim 1, wherein the insect pheromone or
pheromone precursor is formed with >99% selectivity.
16. The method recited in claim 1, wherein the reducing agent
containing at least one silicon-hydrogen bond is selected from the
group consisting of Et.sub.3SiH, (EtO).sub.3SiH, and
polymethylhydrosiloxane.
17. The method recited in claim 1, wherein the proton donor
comprises an alcohol.
18. The method recited in claim 17, wherein the alcohol is selected
from the group consisting of methanol, ethanol, isopropanol,
n-butanol, isobutanol, sec-butanol, tert-butanol, tert-amyl
alcohol, and mixtures thereof.
19. The method recited in claim 17, wherein the alcohol comprises
tert-butanol.
20. The method recited in claim 1, wherein the alkyne is selected
from the group consisting of
H.sub.3C--CH.sub.2--CC--(CH.sub.2).sub.8--OAc,
H.sub.3C--(CH.sub.2).sub.2--CC--(CH.sub.2).sub.7--OAc,
H.sub.3C--(CH.sub.2).sub.3-4--CC--(CH.sub.2).sub.9-11--OR,
H.sub.3C--(CH.dbd.CH)--(CH.sub.2)--CC--(CH.sub.2).sub.8--OAc,
H.sub.3C--(CH.sub.2)--CC--(CH.sub.2)--CC--(CH.sub.2).sub.3--(CH.dbd.CH)---
(CH.sub.2).sub.2--OAc,
H.sub.3C--(CH.sub.2).sub.3--CC--(CH.sub.2).sub.8.about.(CH.dbd.CH)--(CH.s-
ub.2).sub.2--OAc,
HC.sub.3--(CH.sub.2).sub.3).about.(CH.dbd.CH)--(CH.sub.2).sub.2--CC--(CH.-
sub.2).sub.6--OAc,
CH.sub.3--CH.sub.2--CC--CC--(CH.sub.2).sub.9--CH(OEt)OEt,
CH.sub.3--CH.sub.2--CC--(CH.dbd.CH)--(CH.sub.2).sub.6--OAc, and
mixtures thereof, where R is a protecting group.
21. The method recited in claim 1, wherein the alkyne is treated
with the copper(I)-NHC, reducing agent, and proton donor in the
presence of a tertiary butoxide.
22. The method recited in claim 1, wherein the step of treating the
alkyne comprises forming a reaction mixture comprising the alkyne,
copper complex, reducing agent, and proton donor.
23. The method recited in claim 22, wherein the reaction mixture
further comprises a tertiary alkoxide.
24. The method recited in claim 22, wherein the step of treating
the alkyne further comprises bringing the reaction mixture to a
temperature of -50.degree. C. to +100.degree. C.
25. The method recited in claim 24, wherein the reaction mixture is
brought to a temperature of +15.degree. C. to +50.degree. C.
26. (canceled)
27. A method of making an insect pheromone or pheromone precursor,
having one or more Z-alkenyl groups therein, comprising: treating
an alkyne of formula IB, IC, or ID with a copper(I)-nitrogen
heterocyclic carbene complex ("copper(I)-NHC"), which facilitates
semireduction of the alkyne to a Z-alkene, a reducing agent
containing at least one silicon-hydrogen bond, and a proton donor,
thereby forming the insect pheromone or pheromone precursor having
one or more Z-alkenyl groups; wherein IB is
H.sub.3C--(CH.sub.2).sub.c--C.ident.C--(CH.sub.2).sub.d--CC--(CH.sub.2).s-
ub.e-Q, IC is
H.sub.3C--(CH.sub.2).sub.f--C.ident.C--C.ident.C--(CH.sub.2).sub.g-Q,
and ID is H.sub.3C-A-CC-E-Q; where functional group Q is an
aldehyde, acetate, acyclic O,O'-acetal (--CH(OR')(OR''), where R'
and R'' are, independently, C1 to C6 alkyl or cyclic alkyl), cyclic
O,O'-acetal (--CHO(CH.sub.2).sub.xO-- where x=2, 3, or 4),
hydroxyl, protected hydroxyl, formate, ester, or halide (Cl, Br)
group, and coefficients a-g are selected such that the alkyne has
from 7 to 20 carbon atoms; and wherein in formula IB, c is 0 to 13,
d is 1 to 14, e is 1 to 14, and 2.ltoreq.c+d+e.ltoreq.15; in
formula IC, f is 0 to 14, g is 1 to 15, and 2.ltoreq.f+g.ltoreq.15;
and in formula ID, groups A and E are, independently, C1 to C10
alkylenyl or alkenyl, provided that at least one of A and E is an
alkenyl group and the alkyne has from 7 to 20 carbon atoms.
28. The method of claim 27, wherein the Copper(I)-NHC has a formula
II: L-Cu--X (II) where L is a nitrogen-heterocyclic carbene ("NHC")
ligand and X is OCOR.sup.5, OR.sup.5, Cl, Br, I, or F, where
R.sup.5 is aryl or C1 to C5 alkyl.
29. The method of claim 28, wherein the NHC ligand is selected from
the group consisting of imidazol-2-ylidenes, imidazolidinylidenes,
and 1,2,4-triazolyidenes.
30. The method of claim 28, wherein the NHC ligand has a formula
(1) ##STR00029## where R.sup.1 and R.sup.2 are, independently,
alkyl or aryl, and R.sup.3 and R.sup.4 are, independently,
hydrogen, alkyl (C1 to C10), or aryl, or together R.sup.3 and
R.sup.4 form a cycloalkenyl or aryl optionally substituted with one
or more groups consisting of alkyl (C1 to C10), alkoxy (C1 to C10),
and aryl.
31. The method of claim 28, wherein the NHC ligand has a formula
(2) ##STR00030## where R.sup.1 and R.sup.2 are, independently,
alkyl (C1 to C10) or aryl, and R.sup.3 and R.sup.4 are,
independently, hydrogen, alkyl (C1 to C10), or aryl, or together
R.sup.3 and R.sup.4 form a cycloalkyl or aryl optionally
substituted with one or more groups consisting of alkyl (C1 to
C10), alkoxy (C1 to C10), and aryl.
32. The method recited in claim 28, wherein the NHC ligand has a
formula (3) ##STR00031## where R.sup.1 and R.sup.2 are,
independently, alkyl (C1 to C10) or aryl, and R.sup.3 is hydrogen,
methyl or aryl, or together R.sup.2 and R.sup.3 form a cycloalkyl
optionally substituted with one or more groups consisting of alkyl
(C1 to C10), alkoxy (C1 to C10), and aryl.
33. The method of claim 27, wherein the copper(I)-NHC comprises
IPrCuCl.
34. The method of claim 27, wherein the copper(I)-NHC comprises
IMesCuCl.
35. The method of claim 27, wherein the copper(I)-NHC comprises
IPrCuOtBu.
36. The method of claim 27, wherein the copper(I)-NHC comprises
IMesCuOtBu.
37. The method of claim 27, wherein the copper(I)-NHC comprises
IPrCuOtAm.
38. The method of claim 27, wherein the copper(I)-NHC comprises
IMesCuOtAm.
39. The method of claim 27, wherein the insect pheromone or
pheromone precursor is formed with >80% selectivity.
40. The method of claim 27, wherein the insect pheromone or
pheromone precursor is formed with >90% selectivity.
41. The method of claim 27, wherein the insect pheromone or
pheromone precursor is formed with >99% selectivity.
42. The method of claim 27, wherein the reducing agent containing
at least one silicon-hydrogen bond is selected from the group
consisting of Et.sub.3SiH, (EtO).sub.3SiH, and
polymethylhydrosiloxane.
43. The method of claim 27, wherein the proton donor comprises an
alcohol.
44. The method of claim 43, wherein the alcohol is selected from
the group consisting of methanol, ethanol, isopropanol, n-butanol,
isobutanol, sec-butanol, tert-butanol, tert-amyl alcohol, and
mixtures thereof.
45. The method of claim 43, wherein the alcohol comprises
tert-butanol.
46. The method of claim 27, wherein the alkyne is selected from the
group consisting of H.sub.3C--CH.sub.2--CC--(CH2).sub.8--OAc,
H.sub.3C--(CH.sub.2).sub.2--CC--(CH.sub.2).sub.7--OAc,
H.sub.3C--(CH.sub.2).sub.3-4--CC--(CH.sub.2).sub.9-11--OR,
H.sub.3C--(CH.dbd.CH)--(CH.sub.2)--CC--(CH.sub.2).sub.8--OAc,
H.sub.3C--(CH.sub.2)--CC--(CH.sub.2)--CC--(CH.sub.2).sub.3--(CH.dbd.CH)---
(CH.sub.2).sub.2--OAc,
H.sub.3C--(CH.sub.2).sub.3--CC--(CH.sub.2).sub.8.about.(CH.dbd.CH)--(CH.s-
ub.2).sub.2--OAc,
HC.sub.3--(CH.sub.2).sub.3).about.(CH.dbd.CH)--(CH.sub.2).sub.2--CC--(CH.-
sub.2).sub.6--OAc,
CH.sub.3--CH.sub.2--CC--CC--(CH.sub.2).sub.9--CH(OEt)OEt,
CH.sub.3--CH.sub.2--CC--(CH.dbd.CH)--(CH.sub.2).sub.6--OAc, and
mixtures thereof, where R is a protecting group.
47. The method of claim 27, wherein the alkyne is treated with the
copper(I)-NHC, reducing agent, and proton donor in the presence of
a tertiary butoxide.
48. The method of claim 27, wherein the step of treating the alkyne
comprises forming a reaction mixture comprising the alkyne, copper
complex, reducing agent, and proton donor.
49. The method of claim 48, wherein the reaction mixture further
comprises a tertiary alkoxide.
50. The method of claim 48, wherein the step of treating the alkyne
further comprises bringing the reaction mixture to a temperature of
-50.degree. C. to +100.degree. C.
51. The method of claim 50, wherein the reaction mixture is brought
to a temperature of +15.degree. C. to +50.degree. C.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates to insect pheromones and their
synthesis, particularly methods of synthesizing Z-alkenyl insect
pheromones.
[0003] 2. Description of the Related Art
[0004] Insects use sex pheromones as a form of chemical
communication to attract members of the opposite sex in order to
engage in reproduction. Increasingly, synthetic insect sex
pheromones are used as eco-friendly alternatives to conventional
pesticides. They have been used in attract-and-kill, mating
disruption, mass trapping, and insect monitoring approaches to pest
control, and offer a number of advantages over conventional
pesticides: they only affect the targeted species, they are
typically not environmentally persistent, and the target insect
does not develop resistance to the treatment.
[0005] The sex pheromones produced by female moths (Lepidoptera)
are complex mixtures of straight chain acetates, alcohols, and
aldehydes, typically 10-18 carbons in length, with one-three double
bonds. It has been stated that this class of pheromones, Type I,
according to Ando's classification scheme (Ando T. et al.,
"Lepidopteran sex pheromones," Top Curr Chem 239: 51-96, 2004)
accounts for roughly 75% of the known pheromones. Another class of
pheromones, Type II (15%), comprises polyunsaturated hydrocarbons
and epoxy derivatives with long, straight chains (C17-C23).
[0006] One example of a Type I insect sex pheromone is
(Z,Z)-11,13-hexadecadienal (HDAL). HDAL has been identified as the
primary component of the sex pheromones of the navel orangeworm
(Amyelois tranitella)--a significant crop pest--and the meal moth
(Pyralis farinalis)--which infests grains and other dry foodstuffs.
A method of synthesizing HDAL in seven or more steps was described
as early as 1980 (Sonnett, P. E. and R. R. Heath, "Stereospecific
synthesis of (Z,Z)-11,13-hexadienal, a female sex pheromone of the
navel orangeworm, Amyelosis transitella, (Lepidoptera:Pyralidae)"
Journal of Chemical Ecology, 6,221-228, 1980). U.S. Pat. Nos.
4,198,533 and 4,228,093 describe similar seven or more reaction
step methods. An improved synthesis of HDAL is described in U.S.
Pat. No. 8,115,035.
[0007] A traditional route to accessing Z-alkenes is
semi-hydrogenation of alkynes, using hydrogen gas and a
Lindlar-type catalyst. Lindlar-type catalysts typically consists of
palladium metal deposited on calcium carbonate or barium sulfate,
with a "catalyst poison," such as lead acetate or lead oxide, added
to deactivate some of the palladium active sites. Homogeneous
catalysts can also be used. Traditional semi-hydrogenation has
certain benefits, including low-cost reagents, reusable catalysts,
high selectivity for Z isomers, clean (efficient) reactions, and a
proven track record in the petroleum and fine chemicals industries.
Unfortunately, the method also suffers from a number of drawbacks:
Hydrogenation processes using heterogeneous catalysts can be
challenging to scale; catalyst cost and availability are
problematic; specialized equipment is required; the scope of viable
substrates is limited; and the use of lead additives poses
environmental problems.
[0008] In an effort to determine whether traditional
semihydrogenation of diynes could be a viable route to
(Z,Z)-1,3-dienes found in many insect pheromones, the present
applicant undertook a detailed study of catalysts and conditions
for the following reaction:
##STR00001##
[0009] The applicant screened 22 catalysts and 22 solvents under a
variety of reaction conditions, including different hydrogen
pressures, different reaction times, different catalyst poisons,
and several different hydrogen sources. A total of ca. 180 data
points were collected over the course of more than 100 different
reactions. The best result achieved was 60% conversion (alkyne to
alkene), 52% desired product (the ZZ isomer). From this, the
applicant discerned that traditional semihydrogenation of alkynes
is not a commercially viable route to this particular Z, Z-alkenyl
insect pheromone backbone.
[0010] An alternate approach to semireduction of alkynes is
described in Lalic, G., et al., "Monophasic Catalytic System for
the Selective Semireduction of Alkynes," Organic Letters, Vol. 15,
No. 5, 1112-1115, 2013. The approach uses a copper catalyst (e.g.,
ICyCuOtBu, IPrCuOtBu, IMesCuOtBu, etc.), a silane, and an alcohol
to semi-reduce an alkyne to a Z-alkene with high stereoselectivity.
The reference provides little or no guidance for the semireduction
of long-chain (>C12) alkynes, mixed alkyne-alkene compounds
(other than 1,3-terminal enynes), or alkynes bearing specific
functional groups of interest in the manufacture of insect
pheromones. Lalic et al. do not describe a method for making insect
pheromones or pheromone precursors by this semireduction
protocol.
SUMMARY OF THE INVENTION
[0011] The present invention provides a more efficient method of
making an insect pheromone or pheromone precursor having a
Z-alkenyl group, and compounds prepared by the method. In general,
the method entails the steps of providing a C7-C20 alkyne having a
terminal hydroxyl, protected hydroxyl, aldehyde, protected aldehyde
(as the corresponding acetal), formate, ester, or halide (Cl, Br)
group, and then treating the alkyne with a proton donor and a
reducing agent containing at least one silicon-hydrogen bond, in
the presence of a copper complex that facilitates the semireduction
of an alkyne to a Z-alkene, thereby forming an insect pheromone or
pheromone precursor having one or more Z-alkenyl groups, with high
stereoselectivity.
DETAILED DESCRIPTION
[0012] According to a first aspect of the invention, a method is
provided for making an insect pheromone or pheromone precursor by
selectively semi-reducing an alkyne to a Z-alkene, the method
comprising the steps of (1) providing a C7-C20 alkyne having a
terminal hydroxyl, protected hydroxyl, aldehyde, protected aldehyde
(as the corresponding acetal), formate, ester, or halide (Cl, Br)
group; and (2) treating the C7-C20 alkyne with a proton donor in
the presence of a copper(I)-nitrogen heterocyclic carbene complex
("copper(I)-NHC"), which facilitates the semireduction of the
alkyne to a Z-alkene, thereby converting the C7-C20 alkyne to a
C7-C20 Z-alkene having a terminal hydroxyl, protected hydroxyl,
aldehyde, protected aldehyde (as the corresponding acetal),
formate, ester, or halide (Cl, Br) group. Advantageously, the
alkyne is converted to an insect pheromone or pheromone precursor
with high stereoselectivity. In a second aspect, the invention
provides C7-C20 insect pheromones or pheromone precursors having
one or more Z-alkenyl groups therein, prepared by the
aforementioned method.
[0013] In a preferred embodiment, the starting alkyne has any of
four distinct formulas, IA-ID:
H.sub.3C--(CH.sub.2).sub.a--C.ident.C--(CH.sub.2).sub.b-Q (an
internal alkyne) IA:
H.sub.3C--(CH.sub.2).sub.c--C.ident.C--(CH.sub.2).sub.d--C.ident.C--(CH.-
sub.2).sub.e-Q (an internal diyne) IB:
H.sub.3C--(CH.sub.2).sub.f--C.ident.C--C.ident.C--(CH.sub.2).sub.g-Q
(a conjugated diyne) IC:
H.sub.3C-A-C.ident.C-E-Q (an internal alkyne with alkenyl
functionality), ID:
where functional group Q is an aldehyde, acetate, acyclic
O,O'-acetal (--CH(OR')(OR''), where R' and R'' are, independently,
C1 to C6 alkyl or cyclic alkyl, e.g., methyl, ethyl, propyl, butyl,
cyclohexyl, etc.), cyclic O,O'-acetal (--CHO(CH.sub.2).sub.xO--
where x=2, 3, or 4), hydroxyl, protected hydroxyl, formate, ester,
or halide (Cl, Br) group. Coefficients a-g are selected such that
the alkyne has from 7 to 20 carbon atoms, with additional
caveats:
[0014] In formula IA, a is 0 to 16, b is 1 to 7, and
4.ltoreq.a+b.ltoreq.17, provided that in the case where Q is Cl or
Br, then (a,b).noteq.(1,8). An important subclass of IA is alkynes
where a is 1, 2, 3, or 4.
[0015] In formula IB, c is 0 to 13, d is 1 to 14, e is 1 to 14, and
2.ltoreq.c+d+e.ltoreq.15.
[0016] In formula IC, f is 0 to 14, g is 1 to 15, and 2 f+g 15.
[0017] In formula ID, groups A and E are, independently, C.sub.1 to
C.sub.10 alkylenyl (e.g., --CH.sub.2--, --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2--, etc.) or alkenyl (e.g.,
--CH.dbd.CH--, --CH.sub.2(CH.dbd.CH)--,
--CH.sub.2CH.sub.2(CH.dbd.CH)--, --CH.sub.2(CH.dbd.CH)CH.sub.2--,
etc.) groups, provided that at least one of A and E is an alkenyl
group and the compound as a whole has from 7 to 20 carbon
atoms.
[0018] Nonlimiting examples of protecting groups useful in the
practice of the invention include tert-butyl (tBu), acetyl (Ac),
silyl (SiR.sub.3, where each R is, independently, phenyl or C1 to
C6 alkyl or cyclic alkyl, e.g., methyl, ethyl, propyl, isopropyl,
butyl, tert-butyl), pivaloyl (Piv), and acetal (tetrahydropyranyl
(THP), dialkyl acetal (--CH.sub.2OCH(OR')(OR''), where R' and R''
are, independently, C1 to C6 alkyl or cyclic alkyl, e.g., methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, cyclohexyl,
etc.).
[0019] The starting alkyne is selected so that the product alkene
is an insect pheromone or pheromone precursor, i.e., a chemical
intermediate structurally related to a desired pheromone. In some
cases, the pheromone precursor differs from the actual pheromone
only by the presence of a protective group]. Table 1 lists several
examples of alkynes useful in the practice of the invention, the
target Z-alkene products, and the pheromone-producing insect
species.
TABLE-US-00001 TABLE 1 Representative examples of alkyne reactants,
target Z-alkene products, and pheromone-producing species.
Pheromone Product Producing Entry Starting Alkyne Product
(Z)-alkene description species 1 ##STR00002## ##STR00003##
pheromone component Eupoecilia ambiguella 2 ##STR00004##
##STR00005## pheromone component Grapholita molesta 3 ##STR00006##
##STR00007## chemical intermediate Platyptilia carduidactyla and/or
Chilo suppressalis 4 ##STR00008## ##STR00009## pheromone component
Plodia interpunctella 5 ##STR00010## ##STR00011## pheromone
component Tuta absoluta 6 ##STR00012## ##STR00013## chemical
intermediate Paranthrene robiniae 7 ##STR00014## ##STR00015##
pheromone component Pectinophora gossypiella 8 ##STR00016##
##STR00017## chemical intermediate Amyelois transitella 9
##STR00018## ##STR00019## pheromone component Lobesia botrana
[0020] The copper complex plays an essential role in producing a
Z-alkene with high stereoselectivity and little to no
over-reduction. In concert with the reducing agent and the proton
donor (and, optionally, an alkoxide; see the discussion below), it
facilitates Z-selective semireduction of the alkyne. Without being
bound by theory, it is believed that the copper complex is either a
catalyst, a catalyst precursor, or a promoter for the semireduction
reaction.
[0021] In one embodiment, the copper complex is a copper(I)
N-heterocyclic carbene represented by Formula II: L-Cu--X (II),
where L is a nitrogen-heterocyclic carbene (NHC) and X is
OCOR.sup.5, OR.sup.5, Cl, Br, I, or F, where R.sup.5 is aryl or C1
to C5 alkyl. Presently preferred NHCs are 5-membered heterocycles
containing two or three nitrogen atoms, including:
(1) Imidazol-2-Ylidene-Based Carbenes Having the Formula (1)
##STR00020##
[0022] where R.sup.1 and R.sup.2 are, independently, alkyl
(including isopropyl, tert-butyl, cyclohexyl, n-butyl, adamantyl,
benzyl, and alpha-methyl benzyl) or aryl (including
2,4,6-trimethylphenyl (mesityl) and 2,6-diisopropylphenyl), and
R.sup.3 and R.sup.4 are, independently, hydrogen, alkyl (C1 to
C10), or aryl, or together R.sup.3 and R.sup.4 form a cycloalkenyl
or aryl optionally substituted with one or more groups consisting
of alkyl (C1 to C10), alkoxy (C1 to C10), and aryl;
(2) Imidazolidinylidene-Based Carbenes Having the Formula (2)
##STR00021##
[0023] where R.sup.1 and R.sup.2 are, independently, alkyl (C1 to
C10, including isopropyl, tert-butyl, cyclohexyl, n-butyl,
adamantyl, benzyl, and alpha-methyl benzyl) or aryl (including
2,4,6-trimethylphenyl (mesityl) and 2,6-diisopropylphenyl), and
R.sup.3 and R.sup.4 are, independently, hydrogen, alkyl (C1 to
C10), or aryl, or together R.sup.3 and R.sup.4 form a cycloalkyl or
aryl optionally substituted with one or more groups consisting of
alkyl (C1 to C10), alkoxy (C1 to C10), and aryl; and
(3) 1,2,4-Triazol-3-Ylidene-Based Carbenes Having the Formula
(3)
##STR00022##
[0024] where R.sup.1 and R.sup.2 are, independently, alkyl (C1 to
C10, including isopropyl, tert-butyl, cyclohexyl, n-butyl,
adamantyl, benzyl, and alpha-methyl benzyl) or aryl (including
2,4,6-trimethylphenyl (mesityl) and 2,6-diisopropylphenyl), and
R.sup.3 is hydrogen, methyl or aryl, or together R.sup.2 and
R.sup.3 form a cycloalkyl optionally substituted with one or more
groups consisting of alkyl (C1 to C10), alkoxy (C1 to C10), and
aryl.
[0025] NHCs and copper(I)-NHC complexes are readily prepared in a
number of ways, as described in the literature. The following
schemes are representative:
##STR00023##
[0026] Copper(I)-NHC complexes containing an NHC other than an
imidazolyidene are prepared in a similar manner, starting with the
appropriate NHC. In some cases, a particular ligand X can be
introduced by an exchange reaction, for example, the reaction of
L-Cu-Cl with sodium tert-butoxide:
L-Cu--Cl+Na.sup.+[O-t-Bu].sup.-.fwdarw.L-Cu-O-t-Bu+NaCl.
[0027] Preferred copper(I)-NHCs are sterically hindered; the NHC
ligands contain two or more bulky organic groups attached to the
heterocycle, most preferably at the ring positions flanking the
carbene (--C:--) carbon. Nonlimiting examples of such bulky groups
include 2,6-diisopropylphenyl and 2,4,6-trimethylphenyl. A specific
example of a sterically hindered copper(I)-NHC is
chloro[1,3-bis(2,6-di-isopropylphenyl)imidazole-2-ylidene]copper
(I) ("IPrCuCl"):
##STR00024##
, commercially available from Sigma-Aldrich (cat. No. 696307).
Another sterically hindered copper(I)-NHC is the mesitylene analog,
chloro[1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene]copper (I)
("IMesCuCl"). Closely related are the tert-butoxide analogs,
IPrCuOtBu and IMesCuOtBu, and tert-amyloxide analogs, IPrCuOtAm and
IMesCuOtAm, in which the chloro group has been replaced by a
tertiary-butoxide or tertiary-amyloxide group. They can be prepared
by treating one equivalent of IPrCuCl or IMesCuCl with one
equivalent of M-OtBu or M-OtAm (where M is lithium, sodium, or
potassium) in a suitable organic solvent, preferably
tetrahydrofuran (THF), 2-methyl-THF, t-butanol, or t-amyl alcohol,
at a temperature of from -20 to +60.degree. C.
[0028] The preparation of IPrCuCl, IMesCuCl, and other Cu(I)-NHCs
is described in Cisnetti, F., et al., "Simplified Preparation of
Copper (I) NHCs using Aqueous Ammonia," Organometallics 2013, 32,
4279-4283, which is incorporated by reference herein in its
entirety. See also Son, U.S., et al., "Cu.sub.2O: A Versatile
Reagent for Base-Free Direct Synthesis of NHC-Copper Complexes and
Decoration of 3D-MOF with Coordinatively Unsaturated NHC-Copper
Species," Organometallics 2010, 29, 1518-1521 (preparation of
IPrCuX where X=Cl, Br, I) and Sadighi, J. P., "Synthesis,
Structure, and Alkyne Reactivity of a Dimeric (Carbene)copper(I)
Hydride," Organometallics 2004, 23, 3369-3371 (in-situ preparation
of IPrCuOtBu), both references being incorporated by reference
herein in their entirety.
[0029] In addition to the alkyne starting material and the copper
complex, the reaction mixture includes a reducing agent containing
at least one Si--H bond, and a proton donor. In the reducing agent,
the silicon atom(s) is less electronegative than the adjacent
hydrogen atom(s), and the "silane" serves as a radical H-donor or
hydride donor. Nonlimiting examples of such compounds include
trialkylsilicon hydrides, such as triethylsilane (Et.sub.3SiH) and
diethylmethylsilane (Et.sub.2MeSiH); arylakylsilicon hydrides, such
as phenyldimethylsilane (PhMe.sub.2SiH); triarylsilicon hydrides,
such as triphenylsilane (Ph.sub.3SiH); arylchloro- and
alkylarylchlorosilicon hydrides, such as methylphenylchlorosilane
(PhMeClSiH) and diphenylchlorosilane (Ph.sub.2SiHCl); trialkoxy-
and trisiloxysilicon hydrides, such as triethoxysilane
((EtO).sub.3SiH) and tris(trimethylsiloxy)silane ((TMSO).sub.3SiH);
and related oligomers and polymers, such as polymethylhydrosiloxane
(PMHS).
[0030] The proton donor is typically an alcohol or other compound
capable of donating a hydrogen group (H) to the reaction.
Nonlimiting examples include methanol, ethanol, isopropanol,
n-butanol, isobutanol, sec-butanol, tert-butanol, and tert-amyl
alcohol. One or a combination of proton donors can be used.
[0031] In one embodiment, the reaction mixture also includes a
metal alkoxide, preferably an alkali metal alkoxide, particularly
an alkali metal tertiary-butoxide. Nonlimiting examples include
sodium tert-butoxide, potassium tert-butoxide, sodium
tert-amyloxide, and potassium tert-amyloxide. The alkoxide can
react with the copper complex to form a catalytically active (or
more active) species that facilitates Z-selective semireduction of
the alkyne.
[0032] The method of converting a starting alkyne to a Z-alkenyl
insect pheromone or pheromone precursor is carried out in a
straightforward manner. In one embodiment, the reaction is run as a
batch process by mixing the starting materials (alkyne, copper
complex, reducing agent, proton donor, and alkoxide (if present) in
a suitable solvent (e.g., an organic solvent, such as toluene) or
mixture of solvents, at a temperature of from -50.degree. C. to
+100.degree. C., more preferably +15.degree. C. to +50.degree. C.
In a second embodiment, the process is run semi-batch. The copper
complex is typically treated with one equivalent of metal alkoxide
in a suitable organic solvent, preferably THF or 2-methyl-THF, at a
temperature of -50.degree. C. to +100.degree. C., more preferably
+15.degree. C. to +50.degree. C. The resulting catalyst solution is
added to a mixture of starting alkyne, 1 to 10 equivalents of
reducing agent, and 1 to 10 equivalents of proton donor, preferably
an alcohol, in an organic solvent or mixture of solvents at a
temperature of -50.degree. C. to +100.degree. C., more preferably
+15.degree. C. to +50.degree. C. In a third embodiment, the
reaction is run semi-batch. The copper complex is treated with one
equivalent of metal alkoxide in a suitable organic solvent,
preferably THF or 2-methyl THF, at a temperature of -50.degree. C.
to +100.degree. C., more preferably +15.degree. C. to +50.degree.
C. The resulting catalyst solution is added to a mixture of
starting alkyne, 1 to 10 equivalents of reducing agent, in an
organic solvent or mixture of solvents, at a temperature of
-50.degree. C. to +100.degree. C., more preferably +15.degree. C.
to +50.degree. C. To the resulting mixture are added 1 to 10
equivalents of a proton donor, preferably an alcohol.
EXAMPLES
[0033] The following are Nonlimiting examples of the invention.
Example 1
[0034] Preparation of 16,16-(diethoxy)-(Z,Z)-3,5-hexadecadiene
##STR00025##
[0035] A dry 100 mL round bottom flask equipped with a magnetic
stir bar intered under nitrogen was charged with
chloro[1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]copper (I)
(IPrCuCl) (1.22 g, 2.5 mmol, 0.036 equiv) and solid potassium
tert-butoxide (0.300 g, 2.7 mmol, 0.039 equiv). THF (30 mL) was
then added as a solvent. The resulting catalyst mixture was stirred
at ambient temperature for 25 min. A second dry 500 mL round bottom
flask equipped with a magnetic stir bar under a nitrogen atmosphere
was charged with diyne 1 (21.3 g, 69.5 mmol, 1.0 equiv), toluene
(240 mL), polymethyhydroxysilane (PMHS) (40 mL, 658 mmol, 9.5
equiv) and tert-butanol (35 mL, 366 mmol, 5.27 equiv). The catalyst
solution was added to the reaction mixture via syringe. The
resulting reaction mixture was stirred at ambient temperature for
18 hours. Saturated aqueous ammonium chloride (50 mL) was added to
the reaction mixture and the biphasic mixture was rapidly stirred
for 30 min. The phases were split and the aqueous phase back
extracted with ethyl acetate (1.times.50 mL). The organic extracts
were combined, washed with water (1.times.100 mL), brine
(1.times.50 mL), dried over Na.sub.2SO.sub.4, filtered and the
organic stream assayed for product content by gas chromatography.
The assay indicated that the organic extracts contained 18.61 g
(86% yield) of desired diene 2. The diene bears an acetal group
(--CH(OEt).sub.2) at one end. It can be converted to an aldehyde by
treatment with acid and water to yield the insect pheromone
(Z,Z)-11,13-hexadecadienal (HDAL).
[0036] The preceding disclosure presents various aspects and
embodiments of the invention, including preferred embodiments,
examples, and features. From this disclosure, various modifications
and alternate embodiments of the invention will be apparent to
persons skilled in the art to which the invention pertains. All
such modifications and embodiments are within the scope of the
invention, which is limited only by the appended claims and
equivalents thereof.
* * * * *