U.S. patent application number 16/936725 was filed with the patent office on 2021-10-14 for syntheses of n-heterocyclic carbenes and intermediates therefor.
This patent application is currently assigned to UMICORE AG & CO. KG. The applicant listed for this patent is UMICORE AG & CO. KG. Invention is credited to Sebastien Meiries, Steven P. Nolan.
Application Number | 20210317088 16/936725 |
Document ID | / |
Family ID | 1000005866205 |
Filed Date | 2021-10-14 |
United States Patent
Application |
20210317088 |
Kind Code |
A9 |
Nolan; Steven P. ; et
al. |
October 14, 2021 |
SYNTHESES OF N-HETEROCYCLIC CARBENES AND INTERMEDIATES THEREFOR
Abstract
A method of preparing a 2,6 disubstituted anilines includes,
reacting a 2-amino isophthalic acid diester with sufficient
Grignard reagent R.sub.2CH.sub.2MgX to form the corresponding diol
product, dehydrating the diol product to the corresponding
dialkene; and hydrogenating the diol product to form the
corresponding aniline. The 2,6 disubstituted anilines can be used
to produce N-Heterocyclic Carbenes (NHCs). The NHCs can find
application in various fields such as organic synthesis, catalysis
and macromolecular chemistry. Palladium catalysts containing the
NHCs are also described.
Inventors: |
Nolan; Steven P.; (St
Andrews, GB) ; Meiries; Sebastien; (St Andrews,
GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
UMICORE AG & CO. KG |
Hanau-Wolfgang |
|
DE |
|
|
Assignee: |
UMICORE AG & CO. KG
Hanau-Wolfgang
DE
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20200354323 A1 |
November 12, 2020 |
|
|
Family ID: |
1000005866205 |
Appl. No.: |
16/936725 |
Filed: |
July 23, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
15852367 |
Dec 22, 2017 |
10759763 |
|
|
16936725 |
|
|
|
|
14759595 |
Jul 7, 2015 |
9890125 |
|
|
PCT/GB2014/050021 |
Jan 6, 2014 |
|
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|
15852367 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 15/006 20130101;
B01J 31/2278 20130101; C07C 211/46 20130101; C07D 295/037 20130101;
C07C 213/00 20130101; C07C 211/45 20130101; C07C 215/68 20130101;
C07C 209/68 20130101; C07C 209/70 20130101; C07D 295/096 20130101;
C07D 233/58 20130101; C07C 251/16 20130101; C07C 211/47 20130101;
C07D 233/60 20130101 |
International
Class: |
C07D 233/58 20060101
C07D233/58; C07C 215/68 20060101 C07C215/68; C07F 15/00 20060101
C07F015/00; C07D 295/096 20060101 C07D295/096; C07D 295/037
20060101 C07D295/037; C07C 209/70 20060101 C07C209/70; C07C 211/47
20060101 C07C211/47; C07C 213/00 20060101 C07C213/00; C07C 211/45
20060101 C07C211/45; C07D 233/60 20060101 C07D233/60; C07C 209/68
20060101 C07C209/68; C07C 211/46 20060101 C07C211/46; C07C 251/16
20060101 C07C251/16 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 8, 2013 |
GB |
1300270.4 |
Claims
1-13. (canceled)
14. A method of preparing an N-heterocyclic carbene, the method
comprising: reacting an aniline of general formula I: ##STR00077##
wherein each group R.sup.2 is the same; and is selected from H,
methyl, ethyl, n-propyl and ##STR00078## wherein either R.sup.3 is
H and R.sup.4 is an alkyl that may be substituted; or each of
R.sup.3, R.sup.4 are an independently selected alkyl that may be
substituted; and each group Z.sub.1, Z.sub.2 and Z.sub.3 is
independently selected from the group consisting of --H, --I,
--CF.sub.3, --OR.sup.5--R.sup.6 and --NR.sup.7.sub.2, wherein each
group R.sup.5, R.sup.6 or R.sup.7 is independently selected from
the group consisting of alkyl that may be unsaturated, substituted
alkyl that may be unsaturated, aryl, substituted aryl, aralkyl and
substituted aralkyl; with glyoxal to form a diimine of general
formula II: ##STR00079## cyclizing the diimine of structure II with
paraformaldehyde to form an imidazolium salt of structure III:
##STR00080## wherein X.sup.- is an anion; and reacting the
imidazolium salt of structure III with a base to form the
N-heterocyclic carbene.
15. The method of claim 14 wherein the groups Z.sub.1, Z.sub.2 and
Z.sub.3 are H.
16. The method of claim 14 wherein the groups Z.sub.1 and Z.sub.3
are H and the group Z.sub.2 is selected from methyl, methoxy and
--NMe.sub.2.
17-23. (canceled)
24. A method of preparing an N-Heterocyclic Carbene, the method
comprising: reacting an aniline of general formula XV: ##STR00081##
wherein each group R.sup.2 is the same and is selected from H,
methyl, ethyl, n-propyl and ##STR00082## wherein either R.sup.3 is
H and R.sup.4 is alkyl that may be substituted, or each of R.sup.3,
R.sup.4 are an independently selected alkyl that may be
substituted; and wherein the groups Z.sub.1, Z.sub.2, and Z.sub.3
are H or a substituent independently selected from the group
consisting of: --I, --CF.sub.3, --OR.sup.6, --R.sup.6 and
--NR.sup.7.sub.2; wherein each group R.sup.5, R.sup.6 or R.sup.7 is
independently selected from the group consisting of: alkyl that may
be unsaturated, substituted alkyl that may be unsaturated, aryl,
substituted aryl, aralkyl and substituted aralkyl, with glyoxal to
form a diimine of general formula XVI: ##STR00083## cyclizing the
diimine of structure XVI with paraformaldehyde, to form an
imidazolium salt of structure XVII: ##STR00084## wherein X.sup.- is
an anion; and reacting the imidazolium salt of structure XVI with a
base to form the corresponding N-Heterocyclic Carbene.
25-30. (canceled)
31. The method of claim 24, wherein the aniline alkene double bond
stereochemistry of general formula XV is as in formula XV(E2):
##STR00085##
32. The method of claim 24, wherein the groups Z.sub.1, Z.sub.2 and
Z.sub.3 are H.
33. The method of claim 31, wherein the groups Z.sub.1, Z.sub.2 and
Z.sub.3 are H.
34. The method of claim 14, wherein X.sup.- is an anion of
halogen.
35. The method of claim 14, wherein X.sup.- is an anion of
chloride, bromide, or iodine.
36. The method of claim 24, wherein X.sup.- is an anion of
halogen.
37. The method of claim 24, wherein X.sup.- is an anion of
chloride, bromide, or iodine.
38. The method of claim 24, wherein R.sup.2 is selected from H,
methyl, ethyl and n-propyl.
39. The method of claim 31, wherein R.sup.2 is selected from H,
methyl, ethyl and n-propyl.
40. The method of claim 32, wherein R.sup.2 is selected from H,
methyl, ethyl and n-propyl.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation application of U.S.
patent application Ser. No. 15/852,367, filed Dec. 22, 2017, which
is a continuation application of U.S. patent application Ser. No.
14/759,595, filed Jul. 7, 2015, now U.S. Pat. No. 9,890,125, which
was filed under the provisions of 35 U.S.C. .sctn. 371 and claims
the benefit of International Patent Application No.
PCT/GB2014/050021, filed on Jan. 6, 2014, which claims the benefit
of Patent Application No. 1300270.4, filed in Great Britain on Jan.
8, 2013; the contents of which are incorporated herein by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to the synthesis of
N-heterocyclic carbenes, including the synthesis of 1,3 substituted
anilines as intermediates that are prepared via novel diol
intermediates.
BACKGROUND TO THE INVENTION
[0003] N-Heterocyclic carbenes (NHCs) are considered as an
important class of compounds which have found application in
various fields such as organic synthesis, catalysis and
macromolecular chemistry. In the field of catalysis, NHC ligands
are often compared with phosphine-based ligands which still remain
more commonly used. However, unlike their phosphine analogues,
metal-NHC complexes are now recognized for their unique properties
and their higher air and moisture stability, particularly in the
case of palladium and ruthenium-NHC catalysis.
[0004] The importance of NHC ligands in catalysis is related to
their .sigma.-donating properties as well as their steric hindrance
which has strong effects on both oxidative additions and reductive
eliminations in metal-catalyzed organometallic cross-couplings.
Spectacular reactivity has been attributed to a "flexible steric
bulk" in which the ligands can adjust towards incoming substrates,
while enabling the stabilization of low-valent active
intermediates.
[0005] As an example, the bulky IPr NHC ligand (A, below) reported
by Nolan (Ref 1) exhibits excellent properties in catalysis.
However the rigidity of the IPr ligand can be envisaged as a
significant limitation and the design of new NHC ligands possessing
flexible bulk appears as a major challenge.
##STR00001##
DESCRIPTION OF THE INVENTION
[0006] According to a first aspect the present invention provides a
method of preparing N-heterocyclic carbenes (NHCs), the method
comprising reacting an aniline of general formula I:
##STR00002##
wherein each group R.sup.2 is the same; and is selected from H,
methyl, ethyl, n-propyl and
##STR00003##
wherein either; [0007] R.sup.3 is H and R.sup.4 is an alkyl, for
example C2 to C10 alkyl or even C2 to C5 alkyl; or [0008] each of
R.sup.3, R.sup.4 are an independently selected alkyl, for example
C1 to C10 alkyl or even C1 to C5 alkyl; and [0009] each group
Z.sub.1, Z.sub.2 and Z.sub.3 is independently selected from --H,
--I, --CF.sub.3, --OR.sup.5, --R.sup.6 and --NR.sup.7.sub.2; [0010]
wherein each group R.sup.5, R.sup.6 or R.sup.7 is independently
selected from the group consisting of: alkyl that may be
unsaturated, substituted alkyl that may be unsaturated, aryl,
substituted aryl, aralkyl and substituted aralkyl, for example C1
to C10 alkyl or even C2 to C5 alkyl; [0011] with glyoxal to form a
diimine of general formula II;
##STR00004##
[0011] cyclising the diimine of structure II, to form an
imidazolium salt of structure III;
##STR00005##
wherein X.sup.- is an anion for example halogen, such as chloride,
bromide or iodide; and reacting the imidazolium salt of structure
III with a base to form the NHC.
[0012] Where groups R.sup.3 or R.sup.4 are alkyl they are typically
straight-chain alkyl and unsubstituted, but they may be any one or
more of branched, cyclic, unsaturated and substituted, as discussed
hereafter. Preferably R.sup.3 is H and R.sup.4 is straight chain
saturated unsubstituted alkyl.
[0013] The groups Z.sub.1, Z.sub.2 and Z.sub.3 may preferably be H.
However the properties of the NHC may be adjusted by introducing
different groups Z into the anilines I.
[0014] Where adjustment of the properties of the NHC by substituent
Z is desired then, for example, the groups Z.sub.1, and Z.sub.3 may
preferably and conveniently be H and the Z.sub.2 substituent (i.e.
the substituent para to the aniline --NH.sub.2 function) may be
different e.g. one of --I, --CF.sub.3, --OR.sup.5 and
--R.sup.6.
[0015] Methyl and methoxy (-Me and --OMe) substituents are typical
examples of --R.sup.6 and --OR.sup.5 for the groups Z. Other groups
Z may include --NMe.sub.2 or --NR.sup.7.sub.2; wherein R.sup.7 may
be alkyl aryl, or aralkyl, for example C1 to C10 alkyl or even C1
to C5 alkyl.
[0016] The reaction of anilines of structure I with glyoxal may be
carried out using a glyoxal in water solution, for example a 40%
glyoxal in water solution.
[0017] The cyclisation of the diimine II to imidazolium salt of
structure III may be carried out by using paraformaldehyde as the
source of carbon to complete the imidazolinium ring structure. For
example by reaction of the diimine II with paraformaldehyde in a
suitable solvent system using a protic acid or another source of
X.sup.- such as anhydrous HCl, or trimethylsilyl chloride (TMSCl)
which provides the source of group X.sup.- (chloride in these
examples). Zinc chloride may be used to assist the reaction with
either HCl or TMSCl.
[0018] Ether type solvents such as THF and/or dioxane may be
employed. For example the procedure may be adding a solution of
anhydrous HCl in dioxane to the diimine II and paraformaldehyde in
THF. Other solvents may be used, for example ethyl acetate (EtOAc)
can be used effectively when TMSCl is the chloride source. Elevated
temperatures for example from 50.degree. C. to 100.degree. C. may
be employed e.g. about 70.degree. C. (say .+-.5.degree. C.) for a
THF/dioxane solvent system is convenient.
[0019] The imidazolinium salts of structure III may then be
converted to N-heterocyclic carbenes of structure IV:
##STR00006##
by use of base to remove HX in the known manner. Typically sodium
hydride (NaH) in a suitable solvent such as tetrahydrofuran (THF)
may be employed, together with a catalytic amount of potassium
t-butoxide (KO.sup.tBu).
[0020] The NHCs of formula IV may be described as ITent
N-heterocyclic carbenes (Tent stands for "tentacular" where the
groups ortho to the nitrogen on the benzene rings form tentacle
like bulky groups). Previously described examples are
IPr:-(N,N'-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) and
IPent:-(N,N'-bis[2,6-(dipentan-3-yl)phenyl]imidazol-2-ylidene)
NHCs. The abbreviation after the I in the ITent nomenclature refers
to the alkyl groups on the benzene rings (Pr denoting isopropyl,
Pent denoting pent-3-yl, Hept denoting hept-4-yl, and Non denoting
non-5-yl etc). A convenient nomenclature for the corresponding
imidazolium salts of formula III, where X is chloride, is for
example IP.HCl for the precursor to IPr.
[0021] Typically the NHC will be generated in the presence of a
metal containing precursor to a desired NHC containing compound.
Typically the NHC containing compound is a metal complex, usually
for use as a catalyst or a catalyst precursor.
[0022] Typical preparations can include the exchange of a ligand on
a metal compound with the NHC. In such cases the ligand can act as
the base that generates the NHC.
[0023] For example Pd(acac).sub.2 where acac is the
acetonylacetonato ligand, can be reacted with an imidazolium salt
of structure III to provide NHCs of structure IV above to form
complexes of the form Pd(acac)(ITent)Cl. The reaction may be
carried out in a suitable solvent, such as an ether, for example
1,4-dioxane. Typically the reaction is carried out at elevated
temperature, for example at the boiling temperature of the
solvent.
[0024] The reaction can be expressed as;
Pd(acac).sub.2+ITentHCl.fwdarw.[Pd(acac)(ITent)Cl]+acacH
[0025] Exemplary complexes include those where ITent is one of, for
example, Pent, IHept, INon i.e. the N-heterocyclic carbenes IV
corresponding to the imidazolium salts IIIa, IIIb and IIIc of
scheme 2, below. For further example the complexes may include
methoxy substituents in the para position i.e. Z.sub.2 is --OMe and
Z.sub.1 and Z.sub.3 are H in NHC ligands of structure IV in these
complexes. Such complexes may conveniently be expressed as
Pd(acac)(ITent-OMe)Cl where --OMe refers to both Z.sub.2 groups
being methoxy substituents.
[0026] Exemplary complexes that can find use as catalysts include
complexes shown below:
##STR00007##
[0027] These complexes with methoxy substituted NHCs can find use
in Buchwald-Hartwig arylamination reactions even with substrates
generally considered disfavoured for the transformation. For
example coupling of electron rich aryl halides with electron
deficient anilines such as methoxy substituted aryl halides and
fluoro substituted anilines. Exemplary results are described in
detail hereafter.
[0028] For further example gold complexes of the form Au (ITent)Cl
where ITent is for example one of Pent, IHept, INon may be prepared
from similar exchange reactions such as:
Au(DMS)Cl+ITent---.fwdarw.Au(ITent)Cl where DMS is dimethylsulfide;
or
Au(THT)Cl+ITent---.fwdarw.Au(ITent)Cl where THT is
tetrahydrothiophene.
[0029] Thus the inventive methods described herein include the
preparation of an NHC and metal containing complex. Typically the
metal and NHC containing complex can find use as a catalyst or
catalyst precursor.
[0030] The method comprises generating an NHC by the methods
described herein and complexing the NHC to a metal to provide a
metal and NHC containing complex.
[0031] Typically the NHC coordinates to the metal.
[0032] Typical metals include Pd, Pt, Ru, Cu, Ag, Rh Ir and Au.
Generally the complex will have ligands other than an NHC as for
existing NHC containing complexes.
[0033] More generally the method produces complexes of the form
M(NHC)L.sub.n where M is a metal; NHC is an N-heterocyclic carbene
as described herein; L is a ligand; and n is the number of ligands
L. The number (n) of ligands L depends on the nature of each L, the
metal M and its oxidation state; as will be understood by the
skilled person. Each L may be the same or different and
coordinating or non-coordinating. Typically n will be from 1 to 6.
Exemplary ligands L can include halogen, and those containing at
least one of P, N, O and S, where the atom P, N, O or S coordinates
to the metal. Non-coordinating ligands are typically anions such as
halide. Other ligands may include an unsaturated carbon-carbon bond
such as C.dbd.C or C.dbd.C that coordinates to the metal (e.g.
cinnamyl).
[0034] Only a few anilines of structure I have been reported
previously. The precursor to IPr, the aniline of structure V below
where the groups R.sup.2 and the Z groups are all H, is
commercially available.
##STR00008##
[0035] The conversion of aniline V to IPr, via the corresponding
imidazolinium salt. is described in U.S. Pat. No. 7,109,348
(Nolan).
[0036] The aniline of structure VI below, where the groups R.sup.2
are methyl and the Z groups are all H, is also known.
##STR00009##
[0037] Prior art methods of manufacture of aniline VI has been
described by Steele (Ref 2) and involves the use of a relatively
complex "superbase"
system--n-BuLi/LiK(OCH.sub.2CH.sub.2NMe.sub.2)/Mg(OCH.sub.2CH.sub.2OEt).s-
ub.2 to add ethylene gas to 1,3 dimethylaniline. The purification
of the product also requires fractional distillation.
[0038] Although the tentacular NHC "IPent"--formula IX;
##STR00010##
where groups R.sup.2 in formula IV are methyl and the Z groups are
all H, has been previously reported, no information regarding the
synthetic route was provided. (Ref 3).
##STR00011##
wherein the groups R.sup.2 in formula I are ethyl and n-propyl
respectively constitute further aspects of the invention, as do
their corresponding diimines II, imidazolium salts III and
N-heterocyclic carbenes IV.
[0039] The present invention provides convenient and general
methods for the manufacture of anilines of formula I, thus allowing
the convenient preparation of NHC's of formula IV. The NHCs can be
used, for example to prepare metal NHC complexes for use in e.g.
catalysis.
[0040] The present invention provides a method of preparing a 2,6
disubstituted aniline, the method comprising: [0041] reacting a
2-amino isophthalic acid diester with sufficient Grignard reagent
R.sup.2CH.sub.2MgX to form the corresponding diol product from
reaction at the diester functions; [0042] wherein R.sup.2 is
selected from H, methyl, ethyl, n-propyl and
[0042] ##STR00012## wherein either; [0043] R.sup.3 is H and R.sup.4
is an alkyl, for example C2 to C10 alkyl or even C2 to C5 alkyl; or
[0044] each of R.sup.3, R.sup.4 are an independently selected
alkyl, for example C1 to C10 alkyl or even C1 to C5 alkyl; and X is
halogen (chloride, bromide or iodide); [0045] dehydrating the diol
product to the corresponding dialkene; and hydrogenating the
dialkene product to form the corresponding aniline.
[0046] Conveniently the 2-amino isophthalic acid diester employed
has H in the meta and para (with respect to amino) positions of the
benzene ring.
[0047] Thus the present invention provides a method of preparing an
aniline of general formula I:
##STR00013##
wherein each group R.sup.2 is the same and is selected from H,
methyl, ethyl, n-propyl and
##STR00014##
wherein either; [0048] R.sup.3 is H and R.sup.4 is an alkyl, for
example C2 to C10 alkyl or even C2 to C5 alkyl; or [0049] each of
R.sup.3, R.sup.4 are an independently selected alkyl, for example
C1 to C10 alkyl or even C1 to C5 alkyl; and [0050] each group
Z.sub.1, Z.sub.2 and Z.sub.3 is independently selected from the
group consisting of --H, --I, --CF.sub.3, --OR.sup.5--R.sup.6 and
--NR.sup.7.sub.2, wherein each group R.sup.5, R.sup.6 or R.sup.7 is
independently selected from the group consisting of: alkyl that may
be unsaturated, substituted alkyl that may be unsaturated, aryl,
substituted aryl, aralkyl and substituted aralkyl.
[0051] Each group R.sup.5, R.sup.6 or R.sup.7 may be for example C1
to C10 alkyl or even C1 to C5 alkyl.
[0052] If substitution is required to provide one or more groups Z
in general formula I that is not H, then substitution of one or
more H by group Z may be achieved after an aniline with H in all
three meta and para positions has been made.
[0053] For example via electrophilic aromatic substitution carried
out in the known manner (and followed if necessary by modification
or replacement of the substituent(s) first added) to produce the
group Z. For example, a para Z substituent (Z.sub.2) may be
introduced via halogenation, nitration or Friedel-Crafts alkylation
or acylation procedures on the aniline followed by subsequent
modifications as required, providing the desired group Z.sub.2.
[0054] Alternatively a 2-amino isophthalic acid diester already
substituted with one or more groups Z may be employed in the
method.
[0055] With either alternative an initially introduced group Z may
be modified at any convenient stage in the synthetic route to the
NHC. For example on the intermediates diimines of formula II or
imidazolium salts of formula III discussed above.
[0056] As an example, anilines of general formula I where all three
Z substituents are H may be readily converted to the corresponding
anilines where the para group Z.sub.2 is iodine by halogenation in
the known manner for iodides; for example, by reaction with iodine
in the presence of a base (e.g. aqueous sodium carbonate and iodine
reacting with the aniline, which may be in a solvent such as
cyclohexane). The reaction may be carried out at ambient or
elevated temperature.
[0057] Subsequent conversion of the iodo function to methoxy
(--OMe); or other alkoxy substituents; can be conveniently carried
out after the iodo containing aniline has been converted to the
corresponding diimine of formula II as discussed hereafter and with
reference to particular embodiments. For example by reaction with
methanol (or other alcohol) in the presence of base and a copper
salt (e.g., a caesium carbonate, phenanthroline and copper iodide
system at elevated temperature in a sealed vessel such as a sealed
tube). For example with methanol as solvent at between 80 and
160.degree. C. or even at between 100 and 140.degree. C. or at
about 120.degree. C.
[0058] If desired poly-iodo anilines (where more than one of
substituents Z is iodine) may be converted to the corresponding
diimines of formula II and then the same approach used to convert
the iodo functions to methoxy or other alkoxy.
[0059] The p-methoxy diimines of formula II may be readily
converted to the p-methoxy anilines of formula I by reaction with
acid; for example hydrochloric acid. Reaction may be carried out
for example in aqueous hydrochloric acid (e.g. 37%) in the presence
of a suitable solvent such as THF at ambient or elevated
temperature (e.g. at about 100 C). Thus the diimine function can
act as a protecting group in a procedure to prepare substituted
anilines of formula I with, for example, methoxy or other alkoxy
substituents at one or more of the positions Z.
[0060] The ester functions of the 2-amino isophthalic acid diester
may have any substituent attached to the ether linkage of the
carboxylate function to form the two ester functions.
[0061] Formula X below shows substituents forming the ester
functions (shown as R.sup.1) on a 2-amino isophthalic acid diester
where all groups Z are H:
##STR00015##
[0062] Typically and conveniently groups R.sup.1 will be the same,
but they could be different. R.sup.1 may be an alkyl group. Other
alternatives include benzyl or substituted benzyl. Alkyl groups
R.sup.1 may be conveniently C1 to C15 alkyl, C1 to C10 alkyl or
even C1 to C5 alkyl. Alkyl groups R.sup.1 may be linear or branched
and may be substituted.
[0063] Thus the present invention provides a method of preparing
anilines of general formula I, the method comprising: [0064]
reacting an aniline of formula X;
[0064] ##STR00016## [0065] wherein each group R.sup.1 is
independently selected from the group alkyl, for example C1 to C15
alkyl, C1 to C10 alkyl or even C1 to C5 alkyl, and benzyl or
substituted benzyl with a Grignard reagent of the form
R.sup.2CH.sub.2MgX, wherein each group R.sup.2 has the same meaning
as before and X is a halogen selected from I, Cl and Br, to form a
diol of formula XI;
[0065] ##STR00017## [0066] dehydrating the diol of formula XI to
form a dialkene; and [0067] hydrogenation of the dialkene to form
an aniline of general formula I.
[0068] Where one or more of the groups Z in an aniline of general
formula I is not to be H, the method further comprises carrying out
one or more substitution reactions on the initial aniline formed to
provide the required group or groups Z.
[0069] Alternatively the method may be carried out with one or more
groups Z (where at least one Z is not H) already in place, i.e.
carrying out the procedure starting with a diester of general
formula Xa:
##STR00018## [0070] wherein the groups R.sup.1, Z.sub.1, Z.sub.2
and Z.sub.3 have the same meaning as before and at least one of the
groups Z is not H.
[0071] The dehydration of the diols in the method, for example of
the diols of general formula XI, to form a corresponding dialkene
may be carried out by the use of any suitable dehydrating agent,
for example by use of concentrated sulphuric acid, typically in a
suitable solvent such as THF or toluene. Typically a variable
mixture of E and Z isomers is formed, which can readily be
hydrogenated to the desired aniline.
[0072] Hydrogenation of the dialkene products may be carried out by
use of H.sub.2, for example H.sub.2 in the presence of a suitable
catalyst, such as palladium on carbon (Pd/C).
[0073] The diol intermediates such as XI or more generally of
formula XIa:
##STR00019##
where the substituents R.sup.2 and Z.sub.1, Z.sub.2, and Z.sub.3
have the same meaning as before; allow convenient preparation of
the anilines I and hence of N-heterocyclic carbenes IV via the
diimines II and imidazolium salts III constitute a further aspect
of the present invention.
[0074] The present invention also provides a convenient synthesis
of diester anilines of formula X or of formula Xa (esters of
2-aminoisophthalic acid), the method starting from the commercially
available 2-nitro-m-xylene XII. For example the method comprises:
[0075] the bis-oxidation of 2-nitro-m-xylene XII to
2-nitroisophthalic acid XIII; [0076] the conversion of
2-nitroisophthalic acid XIII to its corresponding diester XIV
(typically the dimethyl ester where R.sup.1 is methyl); and the
reduction of the nitro diester XIV to the diester aniline X. Where
a diester of formula Xa is desired a substituted 2-nitro-m-xylene
may be employed or one of the other intermediates in the synthetic
route may be substitute.
[0077] Attempts to introduce groups R.sup.2 via a Grignard reaction
on the nitro-substituted diesters XIV were unsuccessful. It is
therefore convenient to reduce the nitro function to amine before
esterification, to provide compounds of formula X.
[0078] The method is illustrated in Scheme 1, below, showing the
convenient procedure to the diester anilines X and continuing
through to the preparation of anilines of formula I. In these
examples each group Z is H.
[0079] A one-pot version of the dehydration-hydrogenation sequence
of steps v and vi may be carried out but lower product purity may
be obtained. The illustrated 6-step synthetic route allows for the
preparation of multigram quantities of anilines I with minimal
purification procedures being required.
[0080] The bis-oxidation of 2-nitro-m-xylene XII to
2-nitroisophthalic acid XIII may be carried out by an Etard type
reaction, conveniently employing alkaline potassium permanganate as
the oxidising reagent in this case (e.g. with sodium hydroxide
employed as the base).
[0081] The esterification to form diesters XIV can be carried out
with a selected alcohol R.sup.1OH in the usual way, for example to
form the dimethyl diester by using methanol and acid catalyst such
as sulphuric acid. Other esterification procedures, known to the
skilled person, may be employed.
[0082] The reduction of nitro diesters XIV to diester anilines X
may be carried out by hydrogen in the presence of a suitable
catalyst such as palladium on carbon.
##STR00020##
[0083] It will be appreciated that one or more of the meta and para
substituent hydrogens on the benzene ring in the structures of
Scheme 1 may be substituted by one of the alternative groups Z
described herein, at a convenient point in the synthetic route.
[0084] The exemplary reagents and reaction conditions provided
above with Scheme 1 are discussed in more detail under the heading
"Description of Some Preferred Embodiments and Experimental
Results", below.
[0085] Having prepared the anilines I by the convenient route
exemplified in Scheme 1, they can then be used to prepare the
imidazolium salts III as illustrated below in Scheme 2, where
X.sup.- is chloride in these examples. If desired substituents Z
(where one or more group Z is not H) as discussed above, especially
Z.sub.2 (para) substituents, may be introduced first. The
imidazolium salts III can then be used to prepare NHCs by the
action of base as discussed above. Thus the route exemplified in
schemes 1 and 2 provides an effective synthesis of NHCs of formula
IV (and their precursors) from the commercially available
2-nitro-m-xylene XII.
##STR00021##
[0086] As an alternative to the use of anilines of general formula
I
##STR00022##
to prepare useful NHCs in accordance with the invention, the
intermediate dialkene products prepared by the dehydration of the
diol intermediates of formula XI may be employed. These dehydrated
products are of general formula XV:
##STR00023##
where the groups R.sup.2 and Z (Z.sub.1, Z.sub.2, Z.sub.3) have the
same meanings as before. The stereochemistry about both the double
bonds can vary as suggested by the wavy bond lines to H and
R.sup.2. As discussed above typically mixtures of Z and E isomers
are formed on dehydration of the diols XI (except where R.sup.2 is
H). If desired these isomers may be isolated e.g. by chromatography
or recrystallisation techniques. Alternatively a mixture may be
used. It will be understood that unless the context dictates
otherwise structure XV means one or more of the isomers possible by
varying the stereochemistry about the double bonds.
[0087] Typically the procedure produces a preponderance of the
isomer where both double bonds have the E conformation as in
formula XV(E2) below.
##STR00024##
[0088] The compounds of general formula XV (or XV(E2)) may be
converted to diimines and imidazolium salts and hence to NHCs and
catalysts containing the corresponding NHCs by the same procedures
as described for anilines of general formula I (Scheme 2). This is
illustrated in Scheme 3 for a compound XVa where the groups Z are
H. The same route may be employed for compounds of general formula
XV(E2).
##STR00025##
[0089] Thus the present invention provides a method of manufacture
of anilines of general formula XV, the method comprising reacting a
2-amino isophthalic acid diester with sufficient Grignard reagent
R.sup.2CH.sub.2MgX, [0090] wherein R.sup.2 has the same meaning as
before and X is halogen (chloride, bromide or iodide), [0091] to
form the corresponding diol product from reaction at the diester
functions; and [0092] dehydrating the diol product to the
corresponding dialkene of formula XV.
[0093] Where groups Z other than H are desired then they may be
introduced after forming an aniline of general formula XVa (Scheme
3). This can be done in the same manner as described above when
forming anilines of formula I with one or more Z groups that are
not H. Alternatively the 2-amino isophthalic acid diester may have
the desired Z group or groups already present. As discussed above
with respect to the anilines of formula I groups Z may be modified
at any convenient point in the synthetic route to the corresponding
NHCs.
[0094] Thus the present invention provides a method of preparing
N-heterocyclic carbenes (NHCs), the method comprising:
[0095] reacting an aniline of general formula XV as described above
with glyoxal to form a diimine of general formula XVI;
##STR00026## [0096] cyclising the diimine of structure XVI, to form
an imidazolium salt of structure XVII;
##STR00027##
[0096] wherein X.sup.- is an anion for example halogen, such as
chloride, bromide or iodide; and [0097] reacting the imidazolium
salt of structure XVI with a base to form the corresponding
NHC.
[0098] Typically the NHC will be generated in the presence of a
metal containing precursor to a desired NHC containing compound,
usually intended for use as a catalyst or a catalyst precursor.
[0099] Typical preparations can include the exchange of a ligand on
a metal compound with the NHC. The same procedures described above
for the preparation of NHCs of structure IV may be used to prepare
NHCs of structure XVIII or XVIII(E2) below; and the corresponding
metal containing complexes M(NHC)L.sub.n:
##STR00028##
[0100] As a yet further alternative the methods described herein
may be used to form N-heterocyclic carbenes wherein the ring
containing the two nitrogen atoms is saturated i.e. a structure
according to one of the following:
##STR00029##
where the substituents R.sup.2 and Z have the same meanings as
before. These NHCs may be used to make corresponding metal
containing complexes M(NHC)L.sub.n.
[0101] To provide these structures the methods described above may
include the reduction of the corresponding intermediate
diazabutadiene compound; for example of formula II:
##STR00030##
to the corresponding diamine; for example of formula XIX:
##STR00031##
[0102] This may be accomplished by reduction using a suitable
reducing agent such as dibal (diisobutylaluminium hydride) in a
suitable solvent, such as THF or toluene. The reduction may also be
carried out using lithium aluminium hydride in a suitable solvent
such as ethers (e.g. dioxane, THF, or mixtures thereof). The
diamine can then be cyclised to the corresponding
dihydroimidazolinium salt using a suitable one carbon source (e.g.
triethylorthoformate) in the present of an acid HX. For example
hydrochloric acid, which may be supplied in a solvent such as an
ether, for example dioxane.
[0103] An exemplary synthesis is shown below for the production of
the SIPr--OMe dihydroimidazolinium salt (SIPr--OMe.HCl) The
nomenclature "S" indicating that the imidazolinium ring has been
saturated by the reduction step and the term --OMe indicating a
methoxy substituent at the para (Z.sub.2) position of both phenyl
rings.
##STR00032##
[0104] The resulting dihydroimidazolinium salts, for example of
formula XX or XXa;
##STR00033##
can then be converted to the corresponding NHC as described above
for the imidazolium salts, such as those of formula III or formula
XVII. The introduction and (if desired) subsequent modification of
groups Z (where Z is not H) may be carried out at convenient points
in the described synthetic route.
[0105] Throughout the description of the present invention groups R
(R.sup.1, R.sup.2 etc) are defined as alkyl, aryl or benzyl. Except
where otherwise specified, or the context dictates to the contrary,
by alkyl is meant herein a hydrocarbyl radical, which may be
straight-chain, cyclic, branched or unsaturated (typically
straight-chain and saturated). Typically alkyl groups comprise from
1 to 25 carbon atoms, more usually 1 to 10 carbon atoms, more
usually still 1 to 6 carbon atoms, it being of course understood
that the lower limit to the number of carbon atoms in cycloalkyl
and cycloalkylene groups is 3.
[0106] Where an alkyl group is unsaturated (i.e. is an alkenyl or
alkynyl group) it may have one or more sites of unsaturation,
constituted by carbon-carbon double bonds or carbon-carbon triple
bonds. The presence of a carbon-carbon double bond provides an
alkenyl group; the presence of a carbon-carbon triple bond provides
an alkynyl group. Typically, alkenyl and alkynyl groups comprise
from 2 to 25 carbon atoms, more usually 2 to 10 carbon atoms, more
usually still 2 to 5 carbon atoms. Examples of alkenyl groups
include vinyl, styryl and acrylate; an example of an alkynyl group
is propargyl. For the avoidance of any doubt, a hydrocarbyl radical
comprising both a carbon-carbon double bond and a carbon-carbon
triple bond may be regarded as both an alkenyl and an alkynyl
group.
[0107] Except where otherwise specified or the context dictates
otherwise, groups R may be substituted, for example once, twice, or
three times, e.g. once, i.e. formally replacing one or more
hydrogen atoms of the group. Examples of such substituents are
hydroxy, amino, halo, aryl, (including heteroaryl), nitro, alkoxy,
alkylthio, cyano, sulfhydryl, acyl and formyl. Where an alkyl group
is substituted by an aryl group, this is sometimes referred to as
an aralkyl group (e.g. benzyl or substituted benzyl). Typically,
aralkyl groups comprise a C.sub.1-6 alkyl group substituted by an
optionally substituted aryl group.
[0108] Except where otherwise specified or the context dictates
otherwise, by aryl is meant herein a radical formed formally by
abstraction of a hydrogen atom from an aromatic compound. Aryl
groups are typically monocyclic groups, for example phenyl,
although bicyclic aryl groups, such as naphthyl, and tricyclic aryl
groups, such as phenanthrene and anthracene, are also embraced by
the term aryl. As known to those skilled in the art, heteroaromatic
moieties are a subset of aromatic moieties that comprise one or
more heteroatoms, typically O, N or S, in place of one or more
carbon atoms and optionally any hydrogen atoms attached thereto.
Consequentially, it will be understood that heteroaryl groups are a
subset of aryl groups. Illustrative heteroaromatic moieties include
pyridine, furan, pyrrole and pyrimidine. Further examples of
heteroaromatic rings include pyridazine (in which two nitrogen
atoms are adjacent in an aromatic 6-membered ring); pyrazine (in
which two nitrogens are 1,4-disposed in a 6-membered aromatic
ring); pyrimidine (in which two nitrogen atoms are 1,3-disposed in
a 6-membered aromatic ring); or 1,3,5-triazine (in which three
nitrogen atoms are 1,3,5-disposed in a 6-membered aromatic
ring).
[0109] Aryl groups may be substituted one or more times with
substituents selected from, for example, the group consisting of
hydroxy, amino, halo, alkyl, aryl, (including heteroaryl), nitro,
alkoxy, alkylthio, cyano, sulfhydryl, acyl and formyl.
DESCRIPTION OF SOME PREFERRED EMBODIMENTS AND EXPERIMENTAL
RESULTS
[0110] All reagents, reactants and solvents were used as purchased.
Anhydrous tetrahydrofuran was collected from a solvent purification
system. Flash column chromatography was performed on silica gel 60
.ANG. pore diameter and 40-63 .mu.m particles size. .sup.1H and
.sup.13C Nuclear Magnetic Resonance (NMR) spectra were recorded on
a Bruker-400 MHz or 300 MHz spectrometer at ambient temperature in
CDCl3 without TMSCl as internal standard. NMR peaks were assigned
by using COSY and HSQC experiments. Elemental analyses were
performed at London Metropolitan University 166-220 Holloway Road,
London, N7 8DB. High resolution mass spectrometry was performed by
the EPSRC National Mass Spectrometry Service Centre (NMSSC), Grove
Building Extn., Swansea University, Singleton Park, Swansea, SA2
8PP, UK.
2-Nitroisophthalic Acid XIII
[0111] KMnO.sub.4 (643 g, 4.07 mol, 4.0 eq) was added to solution
of NaOH (135 g, 3.38 mol, 3.3 eq) in tap water (4080 mL) at room
temperature. 2-Nitro-m-xylene XII (153 g, 1.01 mol, 1.0 eq) was
added and the resulting solution was allowed to stir vigorously
under strong reflux. The purple colour slowly disappeared as the
KMnO.sub.4 was reduced and the reaction was continued overnight (12
h). The suspension was cooled to room temperature before being
filtered through a sintered funnel. The resulting yellow filtrate
was carefully acidified below pH 2 with concentrated sulphuric acid
(98%, 200 mL). The white solid formed was collected by filtration
and washed with dichloromethane to recover the pure unreacted
starting material (31.9 g) after evaporation. The crude white cake
was washed with ethyl acetate and filtered. The insoluble white
solid was discarded and the resulting filtrate was dried over
anhydrous magnesium sulphate. Evaporation of the solvents in vaccuo
provided the pure diacid XIII as a white powder (112 g, 52%) and
was taken on crude to the next step. (CAS 21161-11-5)
Dimethyl 2-Nitroisophthalate XIV (where R.sup.1 is Methyl)
[0112] The diacid XIII (136 g, 0.64 mol, 1.0 eq) was diluted in
regular methanol (1200 mL) and the resulting solution was carefully
treated with concentrated sulphuric acid (98%, 122 mL, 2.24 mol,
3.5 eq). The mixture was allowed to stir overnight under strong
reflux and stirring. A large quantity of white solid formed and the
condenser was removed to allow half of the methanol to evaporate.
The suspension was cooled down to room temperature and was diluted
with water (1200 mL) to precipitate more solid. The solid was
isolated by filtration and washed with water (1200 mL) before being
dissolved in dichloromethane. The solution was dried over anhydrous
magnesium sulphate and the solvents were evaporated to give the
pure diester 3 (130 g, 84%) as a white powder. (CAS 57052-99-0)
Dimethyl 2-aminoisophthalate X (where R.sup.1 is Methyl)
[0113] A stream of hydrogen was bubbled through a solution of
nitroarene XIV (130 g, 544 mmol, 1.0 eq) and Pd/C (10%, dry, 7.95
g, 6.31 mmol, 1.2 mol %) in regular ethyl acetate (1450 mL) at room
temperature. Completion was obtained within 20 h as indicated by
TLC analysis. However the reaction time greatly varied depending on
the scale and conditions used. The mixture was filtered through a
sintered funnel and Pd/C was recovered and successfully reused in
other hydrogenations. In the case where wet Pd/C was used, the
filtrate was first dried over anhydrous sodium sulphate. The
solvents were removed under vacuum to give the desired aniline X
(where R.sup.1 is methyl) (113 g, 99%) in excellent purity and as a
smelly off-white powder. (CAS 57053-02-3)
General Procedure for Grignard Reaction
[0114] A solution of alkylmagnesium bromide was prepared under
strictly anhydrous conditions from commercially available magnesium
and alkylbromide as followed. A suspension of fresh magnesium (9
eq) in anhydrous THF was treated with the slow addition of a
premade solution of alkylbromide (8 eq) in anhydrous THF over 1 h
in maintaining the temperature below 40 C. After 2 h at room
temperature, the suspension was cooled down to 0.degree. C. and a
solution of diester (1 eq) in THF was cannulated at 0.degree. C.
The reaction was allowed to warm up to room temperature and was
stirred until completion as indicated by TLC analysis (<1 h).
The reaction was then cooled down to 0 C and carefully quenched
with sat. NH.sub.4Cl solution and diluted in Et.sub.2O. The organic
layer was washed with sat. NH.sub.4Cl solution then dried over
anhydrous magnesium sulphate and concentrated under vacuum. The
resulting crude oil was generally obtained in excellent purity and
no further purification was required.
2,6-Di(3-hydroxypentan-3-yl)aniline XIa (R.sup.2=Me)
[0115] A solution of ethylmagnesium bromide was prepared under
strictly anhydrous conditions from commercially available magnesium
and ethylbromide. A suspension of fresh magnesium (105 g, 4.33 mol,
9.0 eq) in anhydrous THF (1700 mL) was treated with the slow
addition of a premade solution of ethylbromide (285 mL, 3.82 mol,
8.0 eq) in anhydrous THF (1700 mL) over 1 h in maintaining the
temperature below 40.degree. C. After 2 h at room temperature, the
suspension was cooled down to 0.degree. C., causing the formation
of a precipitate, and the diester X (where R.sup.1 is methyl) (100
g, 0.48 mol, 1.0 eq) was carefully added portionwise over 5 min at
0.degree. C. The reaction was allowed to warm up to room
temperature and was stirred until completion as indicated by TLC
analysis (<1 h). The reaction was then cooled down to 0.degree.
C. and carefully quenched with sat. NH.sub.4Cl solution (500 mL).
The mixture was diluted in Et.sub.2O (1700 mL) and washed with sat.
NH.sub.4Cl solution (2.times.500 mL). The organic layer was then
dried over anhydrous magnesium sulphate and concentrated under
vacuum. The resulting crude oil was then filtered thru a pad of
silica and flushed with Et.sub.2O to get a more accurate yield.
Evaporation of the solvent provided the crude diol XIa (116 g, 91%)
as a yellow/greenish oil in excellent purity. No further
purification was required for the next steps.
[0116] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (12H, app t,
J=7.4 Hz, 4.times.CH.sub.3), 1.92 (4H, m, 4.times.CH), 2.05 (4H, m,
4.times.CH), 4.26 (2H, vbs, NH.sub.2), 6.57 (1H, t, J=7.7 Hz,
H.sup.p-Ar), 6.92 (2H, d, J=7.7 Hz, H.sup.m-Ar).
[0117] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 8.3
(4.times.CH.sub.3), 30.8 (4.times.CH.sub.2), 79.9
(2.times.C.sub.IV--OH), 115.4 (CH.sup.p-Ar), 126.8
(2.times.CH.sup.m-Ar), 128.2 (2.times.CH.sup.o-Ar), 146.7
(C.sub.IV.sup.Ar--NH.sub.2).
[0118] HRMS (NSI+): found m/z [M+H]+ 266.2115, calcd for
C.sub.16H.sub.28NO.sub.2 266.2115.
2,6-Di(4-hydroxyheptan-4-yl)aniline XIb (R.sup.2=Et)
[0119] A suspension of fresh magnesium (20.9 g, 0.86 mol, 8.6 eq)
in anhydrous THF (300 mL) was treated with the slow addition of a
premade solution of n-propylbromide (69.5 mL, 0.77 mol, 7.7 eq) in
anhydrous THF (300 mL) over 20 min in maintaining the temperature
below 40.degree. C. After 1.5 h at room temperature, the suspension
was cooled down to 0.degree. C., causing the formation of a
precipitate, and a premade solution of diester X (where R.sup.1 is
methyl) (20.0 g, 0.10 mol, 1.0 eq) in dry THF (300 mL) was
cannulated at 0.degree. C. The reaction was allowed to warm up to
room temperature and was stirred for 2 h. The reaction was then
cooled down to 0.degree. C. and carefully quenched with sat.
NH.sub.4Cl solution (300 mL). The mixture was diluted in Et.sub.2O
(400 mL) and washed with sat. NH.sub.4Cl solution (2.times.200 mL).
The organic layer was then dried over anhydrous magnesium sulphate
and concentrated under vacuum. The resulting brown crude solid
(30.9 g) (Pure by .sup.1H NMR) was then further purified by
successive recrystallisation from pentane to give the pure diol XIb
(26.6 g, 86%) as a white crystalline solid.
[0120] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.90 (12H, app t,
J=7.3 Hz, 4.times.CH.sub.3), 1.08-1.23 (4H, m, 4.times.CH),
1.26-1.41 (4H, m, 4.times.CH), 1.78-1.88 (4H, td, J=12.5, 4.5 Hz,
4.times.CH), 1.95-2.05 (4H, td, J=12.5, 4.5 Hz, 4.times.CH), 4.24
(3H, vbs, NH.sub.2+2.times.OH), 6.54 (1H, t, J=7.7 Hz, H.sup.p-Ar),
6.89 (2H, d, J=7.7 Hz, H.sup.m-Ar).
[0121] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 14.5
(4.times.CH.sub.3), 17.2 (4.times.CH.sub.2), 41.2
(4.times.CH.sub.2), 79.4 (2.times.C.sub.IV--OH), 115.1
(CH.sup.p-Ar), 126.5 (2.times.CH.sup.m-Ar), 128.7
(2.times.CH.sup.o-Ar), 146.7 (C.sub.IV.sup.Ar--NH.sub.2).
[0122] HRMS (NSI+): found m/z [M+H]+ 322.2745, calcd for
C.sub.20H.sub.36O.sub.2N 322.2741.
2,6-Di(5-hydroxynonan-5-yl)aniline XIc (R.sup.2=n-Pr)
[0123] A solution of n-butylmagnesium bromide was prepared under
strictly anhydrous conditions from commercially available magnesium
and n-butylbromide as followed. A suspension of fresh magnesium
(16.0 g, 0.66 mol, 9.4 eq) in anhydrous THF (200 mL) was treated
with the slow addition of a premade solution of n-butylbromide
(58.0 mL, 0.54 mol, 7.7 eq) in anhydrous THF (200 mL) over 1 h in
maintaining the temperature below 40.degree. C. After 2 h at room
temperature, the suspension was cooled down to 0.degree. C.,
causing the formation of a precipitate, and a solution of diester X
(where R.sup.1 is methyl) (14.0 g, 0.07 mol, 1.0 eq) in dry THF
(200 mL) was cannulated at 0.degree. C. The reaction was allowed to
warm up to room temperature and was stirred until completion as
indicated by TLC analysis (<1 h). The reaction was then cooled
down to 0.degree. C. and carefully quenched with sat. NH.sub.4Cl
solution (200 mL). The mixture was diluted in Et.sub.2O (250 mL)
and washed with sat. NH.sub.4Cl solution (2.times.150 mL). The
organic layer was then dried over anhydrous magnesium sulphate and
concentrated under vacuum. The resulting brownish crude solid (pure
by .sup.1H NMR) was then recrystallized from hot pentane to give
the pure diol XIc (24.4 g, 97%) as an off-white crystalline
solid.
[0124] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (12H, app t,
J=7.2 Hz, 4.times.CH.sub.3), 1.14 (4H, m, 4.times.CH), 1.32 (12H,
m, 12.times.CH), 1.87 (4H, m, 4.times.CH), 2.03 (4H, m,
4.times.CH), 2.24 (2H, partially hidden vbs, 2.times.OH), 5.98 (2H,
vbs, NH.sub.2), 6.56 (1H, t, J=7.9 Hz, H.sup.p-Ar), 6.91 (2H, d,
J=7.9 Hz, H.sup.m-Ar).
[0125] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 14.0
(4.times.CH.sub.3), 23.1 (4.times.CH.sub.2), 26.1
(4.times.CH.sub.2), 38.1 (4.times.CH.sub.2), 79.3
(2.times.C.sub.IV--OH), 115.0 (CH.sup.p-Ar), 126.5
(2.times.CH.sup.m-Ar), 128.4 (2.times.CH.sup.o-Ar), 146.7
(C.sub.IV.sup.Ar--NH.sub.2).
[0126] HRMS (NSI+): found m/z [M+H]+ 378.3369, calcd for
C.sub.24H.sub.44NO.sub.2 378.3367.
General Procedure for Diol Dehydration and Dialkene
Hydrogenation
[0127] A solution of diol (1.0 eq) in regular THF was treated with
the careful addition of conc. sulphuric acid (98%, 10 eq) and
stirred at 100.degree. C. in an open vessel. After 1-2 h at
100.degree. C. most of the THF evaporated and completion was
observed by TLC analysis of a worked up crude sample. The reaction
was cooled down to room temperature and was carefully poured into a
separating funnel containing a saturated aqueous solution of sodium
hydroxide. The basic mixture was then extracted with diethyl ether
and the combined extracts were dried over anhydrous magnesium
sulphate. Filtration followed by concentration of the organic
extracts under vacuum gave the crude dialkene as a brownish viscous
oil. The crude dialkene was obtained in excellent purity as a
variable mixture of (E)- and (Z)-double bond isomers and was used
without any further purification in the next step.
[0128] Pd/C (10 mol %) was added to a solution of crude dialkene
(1.0 eq) in regular ethanol. The reaction was then purged under
vacuum then nitrogen and was finally placed under positive pressure
of hydrogen. The mixture was allowed to reflux until completion as
indicated by .sup.1H NMR. The reaction time required to reach
completion varied (6 to 48 h) depending on the substrate, the scale
and the conditions used. The mixture was filtered through a
sintered funnel and the recovered Pd/C was efficiently reused for
larger scale reactions. The yellow filtrate was concentrated under
vacuum to afford the desired aniline as a light yellow to brown
oil. Excellent purity was obtained and the crude oil was generally
used without any further purification. However filtration through a
pad of silica and flushing with pentane/Et.sub.2O can be used to
get rid of coloured impurities and traces of Pd/C.
2,6-Di(pentan-3-yl)aniline Ia (R.sup.2=Me)
[0129] A solution of diol (2.72 g, 10.2 mmol, 1.0 eq) in regular
THF (100 mL) was treated with the careful addition of conc.
sulphuric acid (98%, 5.50 mL, 101 mmol, 9.9 eq) and stirred at
100.degree. C. in an open vessel. After 2 h at 100 C most of the
THF evaporated and completion was observed by TLC analysis of a
worked up crude sample. The reaction was cooled down to room
temperature and was carefully poured into a separating funnel
containing a saturated aqueous solution of sodium hydroxide (12
mL). The basic mixture was then extracted with diethyl ether
(3.times.100 mL) and the combined extracts were dried over
anhydrous magnesium sulphate. Filtration followed by concentration
of the organic extracts under vacuum gave the crude dialkene (2.31
g, 98%) as a brownish viscous oil in excellent purity.
[0130] Pd/C (10%, 59.6% wet, 1.84 g, 1.03 mmol, 10 mol %) was added
to a solution of crude dialkene (2.31 g, .about.10.2 mmol, 1.0 eq)
in regular ethanol (50 mL). The mixture was allowed to reflux under
a positive pressure of hydrogen until completion (48 h) and was
filtered through a sintered funnel. The yellow filtrate was
concentrated under vacuum to afford the desired aniline Ia (2.00 g,
84% over 2 steps) as a light yellow to brown oil in excellent
purity. (KS19) On larger scale (>80 g) the aniline was purified
by distillation under reduced pressure as described in the
literature. Distillation afforded the pure aniline Ia as a slightly
yellowish oil (7 mbar, bp 140.degree. C.). However slight
decomposition was observed during distillation and prolonged
storage at room temperature. The data obtained are in full
agreement with those from the literature.
[0131] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (12H,
2.times.t, J=2.times.7.5 Hz, 4.times.CH.sub.3), 1.65 (4H, m,
2.times.CH.sub.2), 1.75 (4H, m, 2.times.CH.sub.2), 2.53 (2H, m,
2.times.CH), 3.62 (23H, vbs, NH.sub.2), 6.82 (1H, t, J=7.4 Hz,
H.sup.p-Ar), 6.95 (2H, d, J=7.4 Hz, H.sup.m-Ar).
[0132] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 12.0
(4.times.CH.sub.3), 28.0 (4.times.CH.sub.2), 42.3 (2.times.CH),
118.4 (CH.sup.p-Ar), 123.8 (2.times.CH.sup.m-Ar), 129.9
(2.times.C.sub.IV.sup.o-Ar), 142.5
(2.times.N--C.sub.IV.sup.Ar).
2,6-Di(heptan-4-yl)aniline Ib (R.sup.2=Et)
[0133] A solution of diol (25.9 g, 80.6 mmol, 1.0 eq) in regular
THF (200 mL) was treated with the careful addition of conc.
sulphuric acid (98%, 43.0 mL, 790 mmol, 9.8 eq) and stirred at
100.degree. C. in an open vessel. After 2 h at 100.degree. C. most
of the THF evaporated and completion was observed by TLC analysis
of a worked up crude sample. The reaction was cooled down to room
temperature and was carefully poured into a separating funnel
containing a saturated aqueous solution of sodium hydroxide (90
mL). The basic mixture was then extracted with diethyl ether
(3.times.500 mL) and the combined extracts were dried over
anhydrous magnesium sulphate. Filtration followed by concentration
of the organic extracts under vacuum gave the crude dialkene (22.7
g, 99%) as a viscous light yellow oil in excellent purity.
[0134] Pd/C (.about.10%, recycled, 30.0 g, .about.28.2 mmol,
.about.35 mol %) was added to a solution of crude dialkene (22.7 g,
.about.80.6 mmol, 1.0 eq) in regular ethanol (600 mL). The mixture
was allowed to reflux under a positive pressure of hydrogen until
completion (3.5 h) and was filtered through a sintered funnel. The
yellow filtrate was concentrated under vacuum to afford the desired
aniline Ib (21.1 g, 91% over 2 steps) as a light yellow oil in
excellent purity.
[0135] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.87 (12H, app t,
J=7.3 Hz, 4.times.CH.sub.3), 1.21-1.31 (8H, m, 4.times.CH.sub.2),
1.52-1.68 (8H, m, 4.times.CH.sub.2), 2.66 (2H, m, 2.times.CH), 3.66
(2H, vbs, NH.sub.2), 6.77 (1H, t, J=7.5 Hz, H.sup.p-Ar), 6.92 (2H,
d, J=7.5 Hz, H.sup.m-Ar).
[0136] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3, SEM233) .delta.
14.5 (4.times.CH.sub.3), 17.2 (4.times.CH.sub.2), 41.2
(4.times.CH.sub.2), 79.4 (2.times.C.sub.IV--OH), 115.1
(CH.sup.p-Ar), 126.5 (2.times.CH.sup.m-Ar), 128.7
(2.times.CH.sup.o-Ar), 146.7 (C.sub.IV.sup.Ar--NH.sub.2).
[0137] HRMS (NSI+): found m/z [M+H]+ 290.2847, calcd for
C.sub.20H.sub.36N 290.2842.
2,6-Di(nonan-5-yl)aniline Ic (R.sup.2=n-Pr)
[0138] A solution of diol (10.1 g, 26.7 mmol, 1.0 eq) in regular
THF (230 mL) was treated with the careful addition of conc.
sulphuric acid (98%, 14.3 mL, 263 mmol, 9.9 eq) and stirred at
100.degree. C. in an open vessel. After 1 h at 100.degree. C. most
of the THF evaporated and completion was observed by TLC analysis
of a worked up crude sample. The reaction was cooled down to room
temperature and was carefully poured into a separating funnel
containing a saturated aqueous solution of sodium hydroxide (42
mL). The basic mixture was then extracted with diethyl ether
(3.times.250 mL) and the combined extracts were dried over
anhydrous magnesium sulphate. Filtration followed by concentration
of the organic extracts under vacuum gave the crude dialkene (10.2
g) as a yellowish clear viscous oil in excellent purity.
[0139] Pd/C (10% dry, 3.21 g, 3.02 mmol, 11 mol %) was added to a
solution of crude dialkene (10.2 g, .about.26.7 mmol, 1.0 eq) in
regular ethanol (150 mL). The mixture was allowed to reflux under a
positive pressure of hydrogen until completion (19 h) and was
filtered through a sintered funnel. The yellow filtrate was
concentrated under vacuum to afford the desired aniline Ic (8.05 g,
87% over 2 steps) as a clear yellow to orange oil in excellent
purity.
[0140] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (12H, app t,
J=7.0 Hz, 4.times.CH.sub.3), 1.28 (16H, m, 8.times.CH.sub.2), 1.65
(8H, m, 4.times.CH.sub.2), 2.65 (2H, m or bs, 2.times.CH), 3.65
(2H, bs, NH.sub.2), 6.80 (1H, m, H.sup.p-Ar), 6.95 (2H, d, J=7.2
Hz, H.sup.m-Ar). .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3)
.delta. 14.0 (4.times.CH.sub.3), 23.0 (4.times.CH.sub.2), 29.8
(4.times.CH.sub.2), 35.7 (4.times.CH.sub.2), 39.0 (2.times.CH),
118.4 (CH.sup.p-Ar), 123.7 (2.times.CH.sup.m-Ar), 130.6
(2.times.CH.sup.o-Ar), 142.1 (C.sub.IV.sup.Ar--NH.sub.2).
[0141] HRMS (NSI+): found m/z [M+H]+ 346.3474, calcd for
C.sub.24H.sub.44N 378.346.3468.
[0142] General Procedure for Diimine Preparation: A stirred
solution of aniline (2.0 eq) in regular methanol was treated with
glyoxal (40% in H.sub.2O, 1.2 eq) followed by catalytic amount of
formic acid (0.3 eq) at room temperature. The desired diimine
started to precipitate from the reaction media and stirring was
continued until completion as indicated by .sup.1H NMR analysis.
The pure diimine was successfully obtained by either
recrystallization of the crude from methanol or ethanol or by
filtration through a pad of silica.
[0143] The spontaneous crystallisation of the diimine at the end of
the reaction can be increased by ceasing the stirring after 15 min,
and leaving the reaction mixture overnight or placing the reaction
mixture in the freezer. The reaction can also be done in ethanol
but spontaneous crystallisation of the diimine at the end of the
reaction was not as efficient as in methanol. Residual diimine
obtained by concentration of the filtrate can also be purified
successfully by filtration through silica gel and flushing
(eluting) with pentane.
N,N'-Bis[2,6-di(pentan-3-yl)phenyl]diazabutadiene IIa
(R.sup.2=Me)
[0144] A stirred solution of IPent aniline (Ia)(18.3 g, 78.6 mmol,
2.0 eq) in regular methanol (230 mL) was treated with glyoxal (40%
in H.sub.2O, 5.40 mL, 49.1 mmol, 1.3 eq) followed by catalytic
amount of formic acid (460 .mu.L, 12.2 mmol, 0.3 eq) at room
temperature. The desired diimine started to precipitate from the
reaction media and stirring was continued until completion (3 h).
The solid was isolated by filtration and the filtrate was
concentrated under vacuum. The resulting brownish solid was
recrystallized from methanol. Both solids were combined and dried
under high vacuum to afford the pure desired diimine IIa as a
bright and shiny yellow crystalline powder (16.0 g, 83%).
[0145] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.82 (24H, t,
J=7.3 Hz, 8.times.CH.sub.3), 1.59 (8H, m, 4.times.CH.sub.2), 1.68
(8H, m, 4.times.CH.sub.2), 2.52 (4H, m, 4.times.CH), 7.08-7.10 (4H,
m, 4.times.H.sup.m-Ar), 7.14-7.18 (2H, m, 2.times.H.sup.p-Ar), 8.04
(2H, s, 2.times.HC.dbd.N).
[0146] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 12.2
(8.times.CH.sub.3), 28.9 (8.times.CH.sub.2), 42.5 (4.times.CH),
123.9 (4.times.CH.sup.m-Ar), 124.8 (2.times.CH.sup.p-Ar), 133.8
(4.times.C.sub.IV.sup.o-Ar), 150.9 (2.times.N--C.sub.IV.sup.Ar),
163.9 (2.times.HC.dbd.N).
[0147] HRMS (NSI+): found m/z [M+H]+ 489.4199, calcd for
C.sub.34H.sub.53N.sub.2 489.4203.
N,N'-Bis [2,6-di(heptan-4-yl)phenyl]diazabutadiene IIb
(R.sup.2=Et)
[0148] A stirred solution of IHept aniline (Ib)(20.6 g, 71.2 mmol,
2.0 eq) in regular methanol (210 mL) was treated with glyoxal (40%
in H.sub.2O, 4.88 mL, 44.4 mmol, 1.2 eq) followed by catalytic
amount of formic acid (420 .mu.L, mmol, 0.3 eq) at room
temperature. The desired diimine started to precipitate from the
reaction media and stirring was continued until completion (5 h).
The solid was isolated by filtration and the filtrate was
concentrated under vacuum. The resulting brownish solid was
filtered through a plug of silica and flushed with pentane. After
concentration, both solids were combined and dried under high
vacuum to afford the pure desired diimine IIb as a bright and shiny
yellow crystalline powder (19.1 g, 89%).
[0149] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.88 (24H, app t,
J=7.4 Hz, 8.times.CH.sub.3), 1.24 (16H, m, 8.times.CH.sub.2), 1.59
(16H, m, 8.times.CH.sub.2), 2.74 (4H, m, 4.times.CH), 7.12-7.19
(6H, m, H.sup.Ar), 8.05 (2H, s, 2.times.CH.dbd.N).
[0150] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 14.3
(4.times.CH.sub.3), 20.8 (4.times.CH.sub.2), 38.4 (4.times.CH),
39.1 (4.times.CH.sub.2), 123.8 (CH.sup.p-Ar), 124.8
(2.times.CH.sup.m-Ar), 134.3 (2.times.CH.sup.o-Ar), 150.6
(C.sub.IV.sup.Ar--NH.sub.2), 163.8 (CH.dbd.N).
[0151] HRMS (APCI+): found m/z [M+H]+ 601.5453, calcd for
C.sub.42H.sub.69N.sub.2 601.5455.
N,N'-Bis [2,6-di(nonan-5-yl)phenyl]diazabutadiene IIc
(R.sup.2=n-Pr)
[0152] A stirred solution of INon aniline (Ic) (1.43 g, 4.14 mmol,
2.0 eq) in regular methanol (12 mL) was treated with glyoxal (40%
in H.sub.2O, 284 .mu.L, 2.48 mmol, 1.2 eq) followed by catalytic
amount of formic acid (24 .mu.L, mmol, 0.3 eq) at room temperature.
The desired diimine started to precipitate from the reaction media
and stirring was continued until completion (4 h). The methanol was
evaporated under vacuum and the residue was diluted in pentane (12
mL) then dried over anhydrous sodium sulfate. The filtrate was
passed through a short pad of silica and flushed with pentane. The
pentane was evaporated under vacuum and the remaining yellow solid
was recrystallized from ethanol. The pure desired diimine IIc was
obtained as a bright and shiny yellow crystalline powder (1.02 g,
69%).
[0153] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.85 (24H, app t,
J=7.2 Hz, 4.times.CH.sub.3), 1.13-1.33 (32H, m, 16.times.CH.sub.2),
1.53-1.66 (16H, m, 8.times.CH.sub.2), 2.68 (4H, m, 4.times.CH),
7.11 (4H, d, J=6.8 Hz, H.sup.m-Ar), 7.16 (2H, t, J=6.8 Hz,
H.sup.m-Ar), 8.00 (2H, s, 2.times.CH.dbd.N).
[0154] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 14.0
(8.times.CH.sub.3), 22.9 (8.times.CH.sub.2), 29.9
(8.times.CH.sub.2), 36.6 (8.times.CH.sub.2), 38.9 (4.times.CH),
123.8 (2.times.CH.sup.p-Ar), 124.8 (4.times.CH.sup.m-Ar), 134.4
(4.times.CH''r), 150.7 (2.times.C.sub.IV.sup.Ar--NH.sub.2), 163.6
(2.times.CH.dbd.N).
[0155] HRMS (APCI+): found m/z [M+H]+ 713.6711, calcd for
C.sub.50H.sub.85N.sub.2 713.6707.
General Procedure for Imidazolium Chloride Preparation
[0156] A solution of diimine (1.0 eq) in regular THF was treated
with anhydrous zinc chloride (1.0 eq) at 70.degree. C. and stirred
for 5 min. para-formaldehyde (1.1 eq) was subsequently added
followed by the dropwise addition of anhydrous HCl (4.0 M in
dioxane, 1.5 eq). The reaction was stirred for 3 h at 70.degree. C.
and concentrated down under vacuum. The residue was dissolved in
ethyl acetate and was washed with water and brine. The combined
aqueous phases were extracted with ethyl acetate and the organic
phases were combined and dried over anhydrous magnesium sulphate.
The solvent was partially evaporated under vacuum until the
formation of a solid and the resulting suspension was diluted with
pentane and placed in the freezer for 20 min. The solid was
isolated by filtration and washed with pentane to afford the pure
desired imidazolium chloride as an off-white crystalline
powder.
[0157] In general it was found that crystallization of the crude
imidazolinium salts is improved by work up procedures such as that
described above, including extraction into ethyl acetate and/or
brine washes after reaction.
1,3-Bis[2,6-di(pentan-3-yl)phenyl]imidazolium chloride IIIa
(R.sup.2=Me, IPent.HCl)
[0158] A solution of IPent diimine IIa (3.00 g, 6.14 mmol, 1.0 eq)
in regular tetrahydrofuran (240 mL) was treated with anhydrous zinc
chloride (837 mg, 6.14 mmol, 1.0 eq) at 70.degree. C. and stirred
for 5 min. p-formaldehyde (193 mg, 6.43 mmol, 1.1 eq) was
subsequently added followed by the dropwise addition of anhydrous
HCl (4.0 M in dioxane, 2.3 mL, 9.1 mmol, 1.5 eq). The reaction was
stirred for 3 h at 70.degree. C. and concentrated down under
vacuum. The residue was dissolved in ethyl acetate (200 mL) and was
washed with water (3.times.200 mL) and brine (200 mL). The combined
aqueous phases were extracted with ethyl acetate (200 mL) and the
organic phases were combined and dried over anhydrous magnesium
sulphate. The solvent was partially evaporated under vacuum until
the apparition of a solid and the resulting suspension was diluted
with pentane and placed in the freezer for 20 min. The solid was
isolated by filtration and washed with pentane to afford the pure
desired imidazolium chloride IIIa as an off-white crystalline
powder (2.36 g, 71%).
[0159] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.78 (12H, t,
J=7.4 Hz, 4.times.CH.sub.3), 0.86 (12H, t, J=7.4 Hz,
4.times.CH.sub.3), 1.68 (16H, m, 8.times.CH.sub.2), 1.96 (4H, m,
4.times.CH), 7.29 (4H, d, J=7.9 Hz, 4.times.H.sup.m-Ar), 7.61 (2H,
t, J=7.9 Hz, 2.times.H.sup.p-Ar), 8.32 (2H, app d, J=1.7 Hz,
2.times.HC.dbd.N), 8.87 (1H, bs, N--CH--N).
[0160] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 11.9
(4.times.CH.sub.3), 12.1 (4.times.CH.sub.3), 28.0
(4.times.CH.sub.2), 28.7 (4.times.CH.sub.2), 43.1 (4.times.CH),
125.0 (4.times.CH.sup.m-Ar), 127.5 (2.times.HC.dbd.N), 131.8
(2.times.CH.sup.p-Ar), 132.1 (4.times.C.sub.IV.sup.o-Ar) or 135.9
(N--CH--N), 142.0 (2.times.Anal. Calcd for
C.sub.35H.sub.53ClN.sub.2: C, 78.24; H, 9.94; N, 5.21; Found: C,
78.13; H, 10.03; N, 5.19.
1,3-Bis [2,6-di(heptan-4-yl)phenyl]imidazolium chloride IIIb
(R.sup.2=Et, IHept.HCl)
[0161] A solution of diimine (19.1 g, 31.8 mmol, 1.0 eq) in regular
tetrahydrofuran (1500 mL) was treated with anhydrous zinc chloride
(4.33 g, 31.8 mmol, 1.0 eq) at 70.degree. C. and stirred for 5 min.
p-formaldehyde (1.00 g, 33.4 mmol, 1.1 eq) was subsequently added
followed by the dropwise addition of anhydrous HCl (4.0 M in
dioxane, 11.8 mL, 47.72 mmol, 1.5 eq). The reaction was stirred for
3 h at 70.degree. C. and concentrated down under vacuum. The
residue was dissolved in ethyl acetate (1000 mL) and was washed
with water (2.times.750 mL) and brine (750 mL). The combined
aqueous phases were extracted with ethyl acetate (200 mL) and the
organic phases were combined and dried over anhydrous magnesium
sulphate. The solvent was partially evaporated under vacuum until
the formation of a solid and the resulting suspension was diluted
with pentane and placed in the freezer for 20 min. The solid was
isolated by filtration and washed with pentane to afford the pure
desired imidazolium chloride IIIb as a white crystalline powder
(9.72 g, 47%).
[0162] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.84 (12H, t,
J=7.2 Hz, 4.times.CH.sub.3), 0.87 (12H, t, J=7.2 Hz,
4.times.CH.sub.3), 0.97-1.14 (12H, m, 4.times.CH+4 CH.sub.2), 1.27
(4H, m, 4.times.CH), 1.49-1.69 (16H, m,
4.times.CH.sub.2+4.times.CH.sub.2), 2.05 (4H, sharp m, 4
CH+impurity), 7.29 (4H, d, J=7.8 Hz, H.sup.m-Ar), 7.60 (2H, t,
J=7.8 Hz, H.sup.p-Ar), 8.20 (1H, s, N--CH--N), 8.41 (2H, s,
2.times.CH.dbd.N).
[0163] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 13.8
(4.times.CH.sub.3), 14.1 (4.times.CH.sub.3), 20.6
(4.times.CH.sub.2), 21.0 (4.times.CH.sub.2), 37.9 (4.times.CH),
39.1 (4.times.CH.sub.2), 40.3 (4.times.CH), 125.0 (CH.sup.m-Ar),
127.7 (2.times.HC.dbd.N), 131.4 (2.times.C.sub.IV.sup.o-Ar), 132.0
(2.times.CH.sup.p-Ar), 134.9 (N--CH--N), 142.5
(N--C.sub.IV.sup.Ar).
[0164] Anal. Calcd for C.sub.43H.sub.69ClN.sub.2: C, 79.52; H,
10.71; N, 4.31; Found: C, 79.39; H, 10.72; N, 4.35.
1,3-Bis [2,6-di(nonan-5-yl)phenyl]imidazolium chloride IIIc
(R.sup.2=n-Pr, INon.HCl)
[0165] A solution of diimine IIc (685 mg, 0.96 mmol, 1.0 eq) in
regular tetrahydrofuran (35 mL) was treated with anhydrous zinc
chloride (131 mg, 0.96 mmol, 1.0 eq) at 70.degree. C. and stirred
for 5 min. p-formaldehyde (30.0 mg, 1.00 mmol, 1.0 eq) was
subsequently added followed by the dropwise addition of anhydrous
HCl (4.0 M in dioxane, 355 .quadrature.L, 1.42 mmol, 1.5 eq). The
reaction was stirred for 3 h at 70.degree. C. and concentrated down
under vacuum. The residue was dissolved in ethyl acetate (30 mL)
and was washed with water (3.times.20 mL) and brine (20 mL). The
combined aqueous phases were extracted with ethyl acetate (10 mL)
and the organic phases were combined and dried over anhydrous
magnesium sulphate. The solvent was completely evaporated under
vacuum and the resulting solid was washed with pentane to afford
the pure desired imidazolium chloride IIIc as a white crystalline
powder (262 mg, 36%).
[0166] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 0.81 (12H, t,
J=7.2 Hz, 4.times.CH.sub.3), 0.88 (12H, t, J=7.2 Hz,
4.times.CH.sub.3), 0.96-1.10 (12H, m, 4.times.CH+4CH.sub.2),
1.18-1.34 (20H, m, 8.times.CH.sub.2+4.times.CH), 1.51-1.77 (16H, m,
4.times.CH.sub.2+4.times.CH.sub.2), 2.06 (4H, m, 4 CH), 7.32 (4H,
d, J=7.8 Hz, H.sup.m-Ar), 7.63 (2H, t, J=7.8 Hz, H.sup.p-Ar), 8.23
(1H, s, N--CH--N), 8.48 (2H, s, 2.times.CH.dbd.N).
[0167] .sup.13C {.sup.1H} NMR (100 MHz, CDCl.sub.3) .delta. 13.8
(4.times.CH.sub.3), 13.9 (4.times.CH.sub.3), 22.6
(4.times.CH.sub.2), 22.9 (8.times.CH.sub.2), 30.0
(4.times.CH.sub.2), 30.1 (4.times.CH.sub.2), 35.5
(4.times.CH.sub.2), 36.8 (4.times.CH.sub.2), 40.6 (4.times.CH),
125.3 (CH.sup.m-Ar), 128.0 (2.times.HC.dbd.N), 131.7
(2.times.C.sub.IV.sup.o-Ar), 132.3 (2.times.CH.sup.p-Ar), 135.0
(N--CH--N), 142.8 (N--C.sub.IV.sup.Ar).
[0168] Anal. Calcd for C.sub.51H.sub.85ClN.sub.2: C, 80.42; H,
11.25; N, 3.68; Found: C, 80.25; H, 11.12; N, 3.77.
Procedure for the Preparation of Imidazolium Chlorides with
Para-Methoxy Substituents
p-Iodo Anilines
##STR00034##
[0170] A solution of the aniline in regular cyclohexane was treated
with a saturated aqueous solution of Na.sub.2CO.sub.3 followed by
solid iodine at room temperature. The reaction was stirred
overnight at room temperature (14 h). The crude solution was
diluted in Et.sub.2O and washed with a saturated aqueous solution
of Na.sub.2S.sub.2O.sub.3. The organic layer was then dried over
anhydrous sodium sulphate and concentrated under vacuum. The
resulting residue was generally obtained in excellent purity and
was either used without further purification or filtered through
silica and flushed with 1% Et.sub.2O in pentane.
Procedure for p-Iododiimine Preparation
##STR00035##
[0172] A solution of p-iodo-aniline (2.0 eq) in MeOH was treated
with formic acid (1 drop) followed by the dropwise addition of
glyoxal (40% in H.sub.2O, 1.2 eq) at 70 C. The solution was stirred
at this temperature for 3 h and the methanol was evaporated under
vacuum and replaced by Et.sub.2O. Reaction overnight at room
temperature may also be used to affect the transformation. The
solution was dried over anhydrous sodium sulphate, filtered and
concentrated in vacuuo. The residue was purified by flash column
chromatography (silica gel, 1-5% Et.sub.2O in pentane) to yield the
pure desired diimine as a bright yellow solid. Purification by
flash column chromatography was preferred on small scale synthesis
to obtain accurate yields. However on larger scale, the pure
desired diimines usually precipitated out of the methanolic
solution and can be easily isolated by filtration.
Procedure for p-Methoxydiimine Preparation
##STR00036##
[0174] A sealed tube was loaded with regular methanol, CuI (0.5
eq), phenanthroline (0.8 eq) and Cs.sub.2CO.sub.3 (4.3 eq) at room
temperature. To this brown mixture was added the starting diiodo
diimine (1.0 eq) and the reaction was stirred overnight at for
example 110 C. The reaction was allowed to cool down to room
temperature and was filtered through cotton wool. The remaining
solid was washed with diethyl ether and the filtrate was
transferred into a separating funnel. The organic layer was washed
with 10% NH.sub.4OH then brine and was then dried over anhydrous
sodium sulphate. Concentration in vacuuo afforded the crude
dimethoxy diimine. Although excellent purity was generally obtained
(.sup.1H NMR), filtration through silica was preferred to remove
colouring agents and traces of copper. The silica was flushed with
pentane and the filtrate was evaporated to yield the pure desired
diimine.
[0175] Anhydrous conditions are not required. Preliminary results
show that completion is actually reached within a few hours.
Conditions were not optimised and quantities of reagents may be
significantly reduced.
[0176] Where the diimine has groups R.sup.2.dbd.H (isopropyl
substituents at the 2 and 6 positions) the expected
p-methoxydiimine was not formed but instead the corresponding
p-methoxyaniline (below) was produced (73% yield, overnight in a
sealed tube reaction at 120 C). The diimine bridge is cleaved in
this example. Bulkier R.sup.2 groups such as methyl, ethyl and
n-propyl produced high yields 100% to 94%) of the methoxydiimines,
with little free aniline (3%) indicating a steric effect.
[0177] The diisopropyl aniline produced can be readily converted to
the corresponding diimine by reacting again with formic acid and
glyoxal (40% in H.sub.2O) in methanol as shown below.
##STR00037##
[0178] More generally if the p-methoxy anilines are desired the
diimine bridge of the p-methoxy diimines can be readily cleaved as
shown below. For example reaction with acid such as hydrochloric
acid in aqueous solvent (e.g. water/THF) at moderate temperature
(e.g. room temperature to 100 C). Reaction may be complete in as
little as 20 to 30 minutes. Thus the diimine function can serve as
a protecting group when anilines of the invention are desired
products.
##STR00038##
Procedure for p-Methoxyimidazolium Chloride Preparation
##STR00039##
[0180] A solution of p-methoxydiimine (1.0 eq) in regular
tetrahydrofuran was treated with anhydrous zinc chloride (1.0 eq)
at 70.degree. C. and stirred for 5 min. p-formaldehyde (1.1 eq) was
subsequently added followed by the dropwise addition of anhydrous
HCl (4.0 M in dioxane, 1.5 eq). The reaction was stirred for at
70.degree. C. and concentrated under vacuum. The residue was
dissolved in ethyl acetate and was washed with water and brine. The
combined aqueous phases were extracted with ethyl acetate and the
organic phases were combined and dried over anhydrous magnesium
sulphate. The solvent was evaporated under vacuum and the resulting
brown solid was triturated with pentane to yield the pure desired
imidazolium chloride as the remaining solid.
[0181] The above procedure was used to prepare the imidazolium
salts: IPr--OMe.HCl IPent-OMe.HCl, IHept-OMe.HCl and INon-OMe.HCl.
(The structures III(OMe) above where groups R.sup.2 are
respectively H, Me, Et, and n-Pr.) These imidazolium salts were
used to prepare NHC containing palladium complexes as described
below.
Procedure for the Preparation of SIPr--OMe.HCl
##STR00040##
[0183] A--The diimine precursor
N,N'-Bis(4-methoxy-2,6-diisopropylphenyl)1,4-diazabutadiene (A) was
made by following a variation of the General Procedure for Diimine
Preparation discussed above. A solution of
4-methoxy-2,6-diisopropylaniline (15.2 g, 73.4 mmol, 2.0 eq) in
MeOH (300 mL) was treated with formic acid (2 drops) followed by
the dropwise addition of glyoxal (40% in H.sub.2O, 6.43 mL, 74.4
mmol, 1.0 eq) at rt. The solution was stirred at this temperature
for 2 h and the methanol was evaporated under vacuum and replaced
by pentane (300 mL). The solution was dried over anhydrous sodium
sulfate, filtered and partially concentrated in vacuuo. Although
good purity was obtained, the residual oil was preferably purified
by flash column chromatography (silica gel, 10% Et.sub.2O in
pentane to yield the pure desired diimine A as an orange solid
(11.5 g, 72%). 1H NMR (400 MHz, CDCl3) .delta. 0.81 (24H, d, J=6.9
Hz, 8.times.CH3), 3.04 (4H, m, 4.times.CH), 3.87 (O--CH3), 6.79
(4H, s, 4.times.Hm-Ar), 8.14 (2H, s, 2.times.HC.dbd.N). 13C NMR
(100 MHz, CDCl3) .delta. 23.3 (8.times.CH3), 28.1 (4.times.CH),
55.1 (2.times.O--CH3), 108.6 (4.times.CHm-Ar), 138.6
(4.times.CIVo-Ar), 141.6 (2.times.N--CIVAr), 157.2
(2.times.O--CIVAr), 163.5 (2.times.HC.dbd.N). HRMS (NSI+): found
m/z [M+H]+ 437.3158, calcd for C28H41O2N2 437.3163.
[0184] B--N,N'-Bis-(4-methoxy-2,6-diisopropylphenylamino)ethane
(B). A solution of diimine A (11.5 g, 26.3 mmol, 1.0 equiv) in
anhydrous THF (200 mL) was cooled to -20.degree. C. and treated
with LiAlH.sub.4 (2.4 M in THF, 44.0 mL, 106 mmol, 4.0 equiv). Upon
addition of LiAlH.sub.4, the yellow solution rapidly turned very
dark purple and important bubbling was observed. After 15 min at
-20.degree. C., the colour of the reaction changed back to clear
orange and the reaction was allowed to stir for 45 min at room
temperature. The reaction was then cooled to 0.degree. C., diluted
with diethyl ether (200 mL), and carefully quenched with water (5.0
mL). After stirring for 10 min, a 15% aqueous solution of NaOH (5.0
mL) was added, followed by water (12 mL). The suspension was
allowed to warm to room temperature and was stirred for 15 min
before anhydrous magnesium sulfate was added until a fine solid was
obtained. The solids were discarded by filtration and the filtrate
was concentrated in vaccuo affording a clear orange and very
viscous oil (11.80 g) in excellent purity. However, the oil was
preferably purified by flash column chromatography (silica, 10-20%
diethyl ether in pentane) to provide the pure desired diamine 25 as
an orange viscous oil (11.35 g, 98%). 1H NMR (400 MHz, CDCl3)
.delta. 1.26 (24H, d, J=6.9 Hz, 4.times.CH3), 3.08 (6H, vbs,
2.times.CH2+2.times.NH), 3.40 (4H, m, 4.times.CH), 3.82 (6H, m,
2.times.OCH3), 6.68 (4H, s, 4.times.Hm-Ar). 13C NMR (100 MHz,
CDCl3) .delta. 24.2 (8.times.CH3), 27.9 (4.times.CH), 52.6
(2.times.CH2), 55.2 (2.times.OCH3), 108.9 (4.times.CHm-Ar), 136.4
(2.times.O--CIVp-Ar), 144.6 (4.times.CIVo-Ar), 156.2
(2.times.N--CIVAr). HRMS (NSI+): found m/z [M+H]+ 441.3470, calcd
for C28H45O2N2 441.3476.
[0185] C--1,3-Bis-(4-methoxy-2,4-diisopropylphenyl)imidazolinium
chloride (SIPrOMe.HCl). A solution of diamine B (7.35 g, 16.7 mmol,
1.0 equiv) in triethyl orthoformate (60 mL) was heated to
120.degree. C. and treated with the rapid addition of HCl (4.0 M in
dioxane, 5.0 mL, 1.2 equiv). Upon addition of the HCl, the clear
solution immediately turned into a white suspension and the
stirring was continued for 10 min at 120.degree. C. The reaction
was cooled to room temperature and was diluted with pentane (60
mL). The white solid was isolated by filtration and washed with
pentane (3.times.60 mL). After drying under high vacuum, the
desired imidazolinium chloride C was obtained as a bright white
powder (7.80 g, 96%). 1H NMR (400 MHz, CDCl3) .delta. 1.14 (12H, d,
J=6.9 Hz, 4.times.CH3), 1.25 (12H, d, J=6.9 Hz, 4.times.CH3), 2.84
(4H, m, 4.times.CH), 3.74 (6H, m, 2.times.OCH3), 4.58 (4H, s,
2.times.N--CH2), 6.62 (4H, s, 4.times.Hm-Ar), 8.64 (1H, s,
N.dbd.CH--N). 13C NMR (100 MHz, CDCl3) .delta. 23.3 (4.times.CH3),
25.1 (4.times.CH3), 29.1 (4.times.CH), 55.2 (2.times.OCH3), 109.8
(4.times.CHm-Ar), 121.9 (2.times.CHp-Ar), 147.4 (4.times.CIVo-Ar),
159.4 (N--CH--N), 161.1 (2.times.N--CIVAr). Anal. Calcd for
C29H43ClN2O2: C, 71.51; H, 8.90; N, 5.75; Found: C, 71.40; H, 9.01;
N, 5.85.
Procedure for the Preparation of Palladium Complexes
Synthesis of [Pd(IPent)(acac)Cl]
[0186] In a Schlenk flask equipped with a magnetic stirring bar
were added IPent.HCl (IIIa) (215 mg, 0.4 mmole) and Pd(acac).sub.2
(91 mg, 0.4 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of
nitrogen. The reaction mixture was heated under reflux for 24 h.
After this time, the dioxane was evaporated and the crude product
dissolved in pentane.
[0187] The solution was filtered on a pad of silica covered with
Celite and the product eluted with pentane. After evaporation of
the solvent and drying under high vacuum, the desired complex was
obtained as a yellow powder (183 mg, 82%).
[0188] 1H NMR (300 MHz, CDCl3): .delta.=7.39 (t, J=8 Hz, 2H), 7.20
(d, J=8 Hz, 4H), 7.04 (s, 2H), 5.00 (s, 1H), 2.71 (m, 4H), 2.15 (m,
4H), 1.73 (s, 3H), 1.53 (s, 3H), 1.80-1.38 (m, 12H), 0.96 (t, J=7.3
Hz, 12H), 0.74 (t, J=7.4, 12H). Anal. Calcd for C40H59ClN2O2Pd: C,
64.77; H, 8.02; N, 3.78. Found: C, 64.86, H, 8.15, N, 3.82.
Procedure for the Synthesis of [Pd(IHept)(acac)Cl]
[0189] In a Schlenk flask equipped with a magnetic stirring bar
were added IHept.HCl (IIIb)(260 mg, 0.4 mmole) and Pd(acac)2 (91
mg, 0.30 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of
nitrogen. The reaction mixture was heated under reflux during 24 h.
After this time, the dioxane was evaporated and the crude product
dissolved in Et.sub.2O.
[0190] The solution was filtered on a pad of silica covered with
Celite and the product eluted with Et.sub.2O. After evaporation of
the solvent and drying under high vacuum, the desired complex was
obtained as a yellow powder (219 mg, 87%).
[0191] 1H NMR (300 MHz, CDCl.sub.3): .delta.=7.36 (t, J=7.8 Hz,
2H), 7.21 (d, 7.8 Hz, 4H), 7.02 (s, 2H), 4.98 (s, 1H), 2.82 (m,
4H), 2.17 (m, 4H), 1.77 (s, 3H), 1.40 (s, 3H), 1.73-1.25 (m, 20H),
1.15-1.08 (m, 8H), 0.80 (t, J=7.1 Hz, 24H). 13C NMR (CDCl.sub.3, 75
MHz): 186.36, 184.05, 154.47, 144.77, 136.98, 129.32 125.25, 99.94,
67.51, 39.99, 39.94, 39.74, 39.06, 26.86, 25.99, 21.95, 21.73,
21.22, 15.14. Anal. Calcd for C48H75ClN2O2Pd: C, 67.51; H, 8.85; N,
3.28. Found: C, 67.39; H, 8.77; N, 3.39.
Procedure for the Synthesis of [Pd(INon)(acac)Cl]
[0192] A similar procedure was employed to those discussed above
for the IHept and IPent complexes.
[0193] Anal. Calcd for C56H91ClN2O2Pd: C, 69.61; H, 9.49; N, 2.90.
Found: C, 69.67; H, 9.62, N, 3.01.
Procedure for the Synthesis of [Pd(IPent-OMe)(acac)Cl]
[0194] In a Schlenk flask equipped with a magnetic stirring bar
were added IPentOMe.HCl (223 mg, 0.37 mmole) and Pd(acac)2 (85 mg,
0.28 mmole) in dry 1,4-dioxane (6 mL) under an atmosphere of
nitrogen.
[0195] The reaction mixture was heated under reflux for 24 h. After
this time, the dioxane was evaporated and the crude product
dissolved in pentane. The solution was filtered on a pad of silica
covered with Celite and the product eluted with pentane. After
evaporation of the solvent and drying under high vacuum, the
desired complex was obtained as a yellow powder (152 mg, 68%).
Higher yield can be obtained on heating the reaction mixture for
longer e.g. 82% after using a heating time of 40 h.
[0196] 1H NMR (300 MHz, CDCl3): .delta.=7.01 (s, 2H), 6.73 (s, 4H),
5.04 (s, 1H), 3.86 (s, 6H), 2.66 (m, 4H), 2.11 (m, 4H), 1.78 (s,
3H), 1.61 (s, 3H), 1.75-1.40 (m, 12H), 0.97 (t, J=7.3 Hz, 12H),
0.75 (t, J=7.4 Hz, 12H). 13C NMR (CDCl3, 75 MHz): 186.57, 184.07,
159.89, 155.21, 145.94, 130.63, 125.68, 110.79, 100.17, 55.67,
41.93, 28.93, 27.85, 27.13, 26.42, 12.81, 11.93. Anal. Calcd for
C42H63ClN2O4Pd: C, 62.91; H, 7.92; N, 3.49. Found: C, 62.84; H,
8.03; N, 3.53.
Procedure for the Synthesis of [Pd(IHept-OMe)(acac)Cl]
[0197] In a Schlenk flask equipped with a magnetic stirring bar
were added IHeptOMe.HCl (193 mg, 0.27 mmole) and Pd(acac)2 (62 mg,
0.2 mmole) in dry 1,4-dioxane (5 mL) under an atmosphere of
nitrogen.
[0198] The reaction mixture was heated under reflux for 24 h. After
this time, the dioxane was evaporated and the crude product
dissolved in pentane. The solution was filtered on a pad of silica
covered with Celite and the product eluted with pentane. After
evaporation of the solvent and drying under high vacuum, the
desired complex was obtained as a yellow powder (150 mg, 82%). A
higher yield (87%) was obtained after using a heating time of 40
h.
[0199] 1H NMR (300 MHz, CDCl3): .delta.=6.96 (s, 2H), 6.70 (s, 4H),
4.99 (s, 1H), 3.84 (s, 3H), 2.76 (m, 4H), 2.10 (m, 4H), 1.76 (s,
3H), 1.46 (s, 3H), 1.68-1.04 (m, 20H), 0.79 (t, J=7.1 Hz, 24H). 13C
NMR (CDCl3, 75 MHz): 186.36, 184.02, 178.93, 159.89, 154.88,
146.33, 130.42, 125.44, 110.49, 99.97, 55.68, 40.05, 28.92, 26.89,
26.13, 21.67, 21.17, 15.15. Anal. Calcd for C50H79ClN2O4Pd: C,
65.70; H, 8.71; Cl, N, 3.06. Found: C, 65.64; H, 8.80; N, 3.15.
Procedure for the Synthesis of [Pd(INon-OMe)(acac)Cl]
[0200] In a Schlenk flask equipped with a magnetic stirring bar
were added INonOMe.HCl (221 mg, 0.27 mmole) and Pd(acac)2 (62 mg,
0.2 mmole) in dry 1,4-dioxane (5 mL) under an atmosphere of
nitrogen. The reaction mixture was heated under reflux for 24 h.
After this time, the dioxane was evaporated and the crude product
dissolved in pentane.
[0201] The solution was filtered on a pad of silica covered with
Celite and the product was eluted with pentane. After evaporation
of the solvent and drying under high vacuum, the desired complex
was obtained as a yellow powder (160 mg, 78%).
[0202] 13C NMR (CDCl3, 75 MHz): 186.36, 183.83, 159.88, 154.87,
146.39, 130.45, 125.36, 110.47, 100.11, 59.69, 40.10, 37.45, 36.42,
30.88, 30.22, 27.02, 26.24, 23.94, 23.70, 14.59, 14.48. Anal. Calcd
for C58H95ClN2O4Pd: C, 67.88; H, 9.33; N, 2.73. Found: C, 67.72; H,
9.46; N, 2.88.
Exemplary Reactions of [Pd(IPent-OMe)(acac)Cl],
[Pd(IHept-OMe)(acac)Cl] and [Pd(INon-OMe)(acac)Cl]
Example 1 Amination with 4-fluoroanisole
TABLE-US-00001 ##STR00041## [0203] ##STR00042## ##STR00043## Entry
Catalyst. Solvent Base Conv..sup.b 1 [Pd(IPent-OMe)(acac)Cl]
Toluene KO.sup.tBu 91 2 [Pd(IPent-OMe)(acac)Cl] Toluene KO.sup.tAm
100 3 [Pd(IPent-OMe)(acac)Cl] Toluene LiHMD 85 S 4
[Pd(IPent-OMe)(acac)Cl] 1,4-dioxane KO.sup.tBu 48 5
[Pd(IPent-OMe)(acac)Cl] 1,4-dioxane KO.sup.tAm 35 6
[Pd(IPent-OMe)(acac)Cl] 1,4-dioxane LiHMD 18 S 7
[Pd(IPent-OMe)(acac)Cl] DME KO.sup.tBu 40 8 [Pd(IPent-OMe)(acac)Cl]
DME KO.sup.tAm 37 9 [Pd(IPent-OMe)(acac)Cl] DME LiHMD 21 S 10
[Pd(IPent-OMe)(acac)Cl] DMF KO.sup.tAm 23 11
[Pd(IHept-OMe)(acac)Cl] Toluene KO.sup.tAm 100 12
[Pd(INon-OMe)(acac)Cl] Toluene KO.sup.tAm 100 Reagents and
conditions: 4-chloroanisole (0.5 mmol), 4-fluoroaniline (0.55
mmol), base (0.55 mmol), solvent (1.0 mL), catalyst (0.25 mol %) .
.sup.bConversion to coupling product based on starting aryl
chloride by GC, average of three runs. DME; dimethoxyethane.
[0204] As can be seen from the above table more polar solvents such
as DME tended to give poorer results whilst the combination of
toluene as solvent and KO.sup.tAm as base can give 100%
conversion.
Example 2
[0205] Amination with 4-fluoroaniline (entry 1, table below) and
3-trifluoromethylaniline (entry 2) at reduced catalyst loading.
[0206] 4-Chloroanisole was reacted with the aniline using palladium
catalysts with ITent or ITent-OMe as NHC ligands.
[0207] The results show that in each case the catalyst with the
ITent-OMe ligand produced higher yields than the corresponding
catalyst without the --OMe ligand. As the gain in activity is
general with all of the ITent-OMe series, these results indicate
the positive effect of the methoxy group. As the methoxy
substituent resides away from the coordination sphere of the metal,
the stronger .sigma.-donor properties of ITent-OMe ligand compared
with ITent ligands could explain the difference in the catalytic
activity observed. This extra .sigma.-donation may offer a greater
stabilization of the Pd.sup.0-NHC complex. [Pd(IHept-OMe)(acac)Cl]
combines the presence of the methoxy group and the optimal length
of alkyl chain for C--N bond formation in these experiments.
TABLE-US-00002 ##STR00044## Entry Product NHC ligand GC conversions
(%).sup.d 1.sup.b ##STR00045## IPent 58 IPent-OMe 70 IHept 82
IHept-OMe 98 INon 76 INon-OMe 86 2.sup.c ##STR00046## IPent 41
IPent-OMe 53 IHept 68 IHept-OMe M INon 64 INon-OMe 76
.sup.aReagents and conditions: ArCl (0.5 mmol), Ar'NH.sub.2 (0.55
mmol), KO.sup.tAm (0.55 mmol), toluene (1.0 mL). b 0.05 mol % Pd
catalyst, 80.degree. C., 3 h; c 0.1 mol % Pd catalyst, 110.degree.
C., 6 h. .sup.dConversion to coupling product based on starting
aryl chloride by GC, average of three runs.
Example 3 Scope of the Buchwald-Hartwig Arylamination with
[Pd(IHept-OMe)(acac)Cl]
TABLE-US-00003 ##STR00047## [0208] Catalyst Entry ArCl Product (%)
Yield 1 ##STR00048## ##STR00049## 0.05 95 2 ##STR00050##
##STR00051## 0.05 91 3 ##STR00052## ##STR00053## 0.05 96 4
##STR00054## ##STR00055## 0.1 92 5 ##STR00056## ##STR00057## 0.1 87
6 ##STR00058## ##STR00059## 0.1 79 7 ##STR00060## ##STR00061## 0.1
74 8 ##STR00062## ##STR00063## 0.2 91 9 ##STR00064## ##STR00065##
0.2 88 10 ##STR00066## ##STR00067## 0.2 90 11 ##STR00068##
##STR00069## 0.2 83 .sup.aReagents and conditions: ArCl (0.5 mmol),
Ar'NH.sub.2 (0.55 mmol), KO.sup.tAm (0.55 mmol),
[Pd(IHept-OMe)(acac)Cl] (x mol %), toluene (1.0 mL), 80.degree. C.,
3 h. .sup.bIsolated yields after chromatography on silica gel,
average of two runs. .sup.c110.degree. C., 6 h.
[0209] The system, shown in the table above, displays excellent
catalytic activity for the coupling of various substrates. Good
yields are obtained with electron-poor anilines and electron-rich
aryl chlorides, which are challenging coupling partners (entries
1-4 and 8-10). The system appears unaffected by the presence of
substituents in the ortho-position of the aryl chlorides: couplings
of 2-chloroanisole and 4-chloroanisole with 4-fluoroaniline gave
very similar results (Entries 1 and 3). Similar results are
observed for the coupling of 2-chloroanisole or 4-chloroanisole
with 3-trifluoromethylaniline (Entries 8 and 9). Moreover, very
good yields were obtained with sterically hindered substrates
(Entries 4, 6 and 11). The increased conformational flexibility of
IHept-OMe may allow it to better accommodate sterically hindered
substrates in the coordination sphere of the metal center. Finally,
various anilines were successfully coupled with deactivated
1,3-dimethoxychlorobenzene (entries 5, 6 and 9) and, for the first
time, with very deactivated 1,3,5-trimethoxychlorobenzene at low
catalyst loading (entry 10), attesting to the high reactivity of
[Pd(IHept-OMe)(acac)Cl].
Example 4
[0210] The efficiency of catalyst, [Pd(IHept-OMe)(acac)Cl] with
more nucleophilic amines was also tested.
[0211] Non-activated aryl chlorides were successfully coupled with
N-methylaniline at low catalyst loadings (as low as 50 ppm of
[Pd(IHept-OMe)(acac)Cl]); remarkable catalyst productivity-turnover
number [TON] up to 18,000 or more, was observed (Entries 2 and 3 in
the table below). These results are comparable with results
obtained with the most efficient Pd/phosphine systems for similar
substrates.
TABLE-US-00004 ##STR00070## [Pd(IHept- OMe) (acac)Cl] Yield Entry
Product (ppm) (%).sup.b TON 1 ##STR00071## 0 (control) 0 2
##STR00072## 50 91 18200 3 ##STR00073## 50 93 18600 4 ##STR00074##
100 84 8400 5 ##STR00075## 200 83 4150 .sup.aReagents and
conditions: ArCl (0.5 mmol), Ar'NH.sub.2 (0.55 mmol), KO.sup.tAm
(0.55 mmol), [Pd(IHept-OMe)(acac)Cl] (x ppm), toluene (1.0 mL),
110.degree. C. .sup.bIsolated yields after chromatography on silica
gel, average of two runs.
Preparation of [Pd(NHC)(cinnamyl)Cl]
General Procedure
[0212] In a glovebox (under a nitrogen atmosphere), in a round
bottom flask equipped with a magnetic stirring bar were added the
NHC.HCl imidazolium salt precursor (2.2 eq) and KO.sup.tBu (2.4 eq)
in THF. In these examples IPent.HCl, IHept.HCl and INon.HCl were
employed.
[0213] The reaction mixture was stirred at room temperature for 3 h
and then [Pd(cinnamyl)(.mu.-Cl)].sub.2 (1 eq) was added. The
reaction mixture was then stirred overnight at room
temperature.
[0214] After this time, outside the glovebox, the THF was
evaporated and the crude product was dissolved in DCM, filtered on
a pad of celite and eluted with DCM. After evaporation of the
solvent, the complex was dissolved in pentane and passed through a
frit (sintered glass filter). The pentane was evaporated and after
drying under high vacuum, the pure complex was obtained.
##STR00076##
Pd(Ipent)(cinnamyl)Cl
[0215] The general procedure starting from 0.425 mmol of
[Pd(cinnamyl)(.mu.-Cl)].sub.2 yielded the complex as a yellow
powder (600 mg, 93%).
[0216] The pentane was evaporated rapidly using a Schlenk line,
yielding the complex as a foam which was crumbled to a powder.
[0217] .sup.1H NMR (400 MHz, C.sub.6D.sub.6): .delta. 7.31-7.26 (m,
2H, H.sub.Ar), 7.19 (t, J=7.7 Hz, 2H, H.sub.Ar), 7.04 (d, J=7.7 Hz,
4H, H.sub.Ar), 7.04-6.93 (m, 3H, H.sub.Ar), 6.63 (s, 2H, H.sub.lm),
5.23 (dt, J=12.8 Hz; J'=9.3 Hz, 1H, H.sub.cin), 4.54 (d, J=12.8 Hz,
1H, H.sub.cin), 2.89-2.50 (m, br, 5H, CH+H.sub.cin), 2.23-2.06 (m,
br, 4H, CH.sub.2), 1.82-1.36 (m, br, 13H, CH.sub.2+H.sub.cin),
1.23-1.03 (m, br, 12H, CH.sub.3), 0.76 (t, J=7.4 Hz, 12H,
CH.sub.3). .sup.13C NMR (100 MHz, CD.sub.2Cl.sub.2): .delta. 182.1
(NCN), 144.5 (br, C.sub.Ar), 138.4 (C.sub.Ar), 138.2 (C.sub.Ar),
129.1 (CH.sub.Ar), 128.5 (CH.sub.Ar), 127.6 (CH.sub.Ar), 126.9
(CH.sub.Ar), 125.3 (br, CH.sub.Ar), 124.9 (CH.sub.Im), 108.5 (Cm),
90.5 (Cm), 46.5 (Cm), 42.1 (CH), 28.3 (CH.sub.2), 27.9 (CH.sub.2),
13.1 (CH.sub.3), 11.5 (br, CH.sub.3). Anal. Calcd. for
C.sub.44H.sub.61ClN.sub.2Pd: C, 69.55; H, 8.09; N, 3.69. Found: C,
69.52; H, 8.03; N, 3.75.
Pd(Ihept)(cinnamyl)Cl
[0218] The general procedure starting from 0.35 mmol of
[Pd(cinnamyl)(.mu.-Cl)].sub.2 yielded the complex as an orange
powder (605 mg, 99%).
[0219] The pentane was evaporated rapidly using a Schlenk line,
yielding the complex as a foam which was crumbled to a powder.
[0220] .sup.1H NMR (400 MHz, C.sub.6D.sub.6): .delta. 7.38-7.34 (m,
2H, H.sub.Ar), 7.23 (t, J=7.9 Hz, 2H, H.sub.Ar), 7.10 (d, J=7.9 Hz,
4H, H.sub.Ar), 7.05-7.00 (m, 2H, H.sub.Ar), 6.98-6.94 (m, 1H,
H.sub.Ar), 6.83 (s, 2H, H.sub.lm), 5.26 (dt, J=12.9 Hz; J'=9.2 Hz,
1H, H.sub.cin), 4.64 (d, J=12.9 Hz, 1H, H.sub.cin), 2.93-2.66 (m,
br, 5H, CH+H.sub.cin), 2.18-2.05 (m, 4H, CH.sub.2), 1.78-1.34 (m,
21H, CH.sub.2+H.sub.cin), 1.25-1.11 (m, 8H, CH.sub.2), 1.11-0.94
(m, 12H, CH.sub.3), 0.82 (t, J=7.2 Hz, 12H, CH.sub.3). .sup.13C NMR
(100 MHz, CD.sub.2Cl.sub.2): .delta. 181.8 (NCN), 145.1 (br,
C.sub.Ar), 138.5 (C.sub.Ar), 137.8 (C.sub.Ar), 129.2 (CH.sub.Ar),
128.5 (CH.sub.Ar), 127.7 (CH.sub.Ar), 126.9 (CH.sub.Ar), 125.2 (br,
CH.sub.Ar), 124.9 (CH.sub.Im), 108.5 (C.sub.cin), 91.1 (C.sub.cin),
46.0 (C.sub.cin), 39.7 (CH), 39.5 (CH.sub.2), 38.4 (CH.sub.2), 22.0
(CH.sub.2), 20.9 (CH.sub.2), 14.9 (CH.sub.3), 14.8 (CH.sub.3).
Anal. Calcd. for C.sub.52H.sub.77ClN.sub.2Pd: C, 71.62; H, 8.90; N,
3.21. Found: C, 71.75; H, 8.84; N, 3.18.
[Pd(INon)(cinnamyl)Cl]
[0221] The general procedure starting from 0.113 mmol of
[Pd(cinnamyl)(.mu.-Cl)].sub.2 yielded the complex as a yellow/green
powder (200 mg, 90%).
[0222] After evaporation of the pentane, the complex remained an
oil. It solidified slowly after a few weeks storage inside a
glovebox (under an N.sub.2 atmosphere).
[0223] .sup.1H NMR (400 MHz, C.sub.6D.sub.6): .delta. 7.40-7.36 (m,
2H, H.sub.Ar), 7.25 (t, J=7.7 Hz, 2H, H.sub.Ar), 7.13 (d, J=7.7 Hz,
4H, H.sub.Ar), 7.06-7.01 (m, 2H, H.sub.Ar), 7.00 (s, 2H, H.sub.lm),
6.98-6.94 (m, 1H, H.sub.Ar), 5.28 (dt, J=12.9 Hz; J'=9.3 Hz, 1H,
H.sub.cin), 4.68 (d, J=12.9 Hz, 1H, H.sub.cin), 2.99-2.71 (m, br,
5H, CH+H.sub.Cin), 2.24-2.10 (m, br, 4H, CH.sub.2), 1.89-1.34 (m,
29H, CH.sub.2+H.sub.Cin), 1.28-1.15 (m, 16H, CH.sub.2), 1.09-0.97
(m, 12H, CH.sub.3), 0.89-0.82 (m, 12H, CH.sub.3). .sup.13C NMR (100
MHz, CD.sub.2Cl.sub.2): .delta. 181.9 (NCN), 145.2 (br, C.sub.Ar),
138.6 (C.sub.Ar), 137.7 (C.sub.Ar), 129.2 (CH.sub.Ar), 128.5
(CH.sub.Ar), 127.7 (CH.sub.Ar), 126.9 (CH.sub.Ar), 125.2 (br,
CH.sub.Ar), 124.9 (CH.sub.Im), 108.7 (C.sub.cin), 91.0 (C.sub.cin),
46.0 (C.sub.cin), 39.8 (CH), 36.9 (CH.sub.2), 35.9 (CH.sub.2), 31.3
(br, CH.sub.2), 29.9 (br, CH.sub.2), 23.9 (CH.sub.2), 23.7
(CH.sub.2), 14.5 (CH.sub.3), 14.2 (CH.sub.3). Anal. Calcd. for
C.sub.60H.sub.93ClN.sub.2Pd: C, 73.22; H, 9.52; N, 2.85. Found: C,
73.40; H, 9.69; N, 2.84.
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