A palladium-catalyzed regiospecific synthesis of N-aryl benzimidazoles

Article abstract of DOI:10.1002/anie.200702542

(Chemical Equation Presented) Highly tolerated: A catalytic method employing [Pd₂(dba)₃] and XPhos or RuPhos permits the efficient synthesis of N-aryl benzimidazoles in regioisomerically pure form starting from ortho-halo-anilides (see scheme), and tolerates a wide range of functional groups, dba = trans,trans-dibenzylideneacetone.

Full text of DOI:10.1002/anie.200702542

Angewandte
Chemie
DOI: 10.1002/anie.200702542
Heterocycle Synthesis
A Palladium-Catalyzed Regiospecific Synthesis of N-Aryl
Benzimidazoles**
Nan Zheng, Kevin W. Anderson, Xiaohua Huang, Hanh Nho Nguyen, and
Stephen L. Buchwald*
Benzimidazoles are a class of privileged core structures that
are found in a broad spectrum of biologically active com-
pounds such as nonpeptide luteinizing hormone-releasing
hormone (LHRH) antagonist,[1] lymphocyte specific kinase
(Lck) inhibitor,[2] N-methyl-d-aspartate (NMDA) antago-
nist,[3] neuropeptide Y Y1 receptor antagonist,[4] nonpeptide
thrombin inhibitor,[5] 5-lipoxygenase inhibitor,[6] factor Xa
(FXa) inhibitor,[7] and poly(ADP-ribose)polymerase (PRAP)
inhibitor.[8] Benzimidazoles have also been widely used in
fungicides, herbicides, and other veterinary application.[9] In
addition, they have been frequently used as the backbone in
dyes[10] and high-temperature polymers.[11] Not surprisingly,
numerous efforts have been devoted to the development of
methods for the preparation of benzimidazoles.[12]
steric hindrance. The presence of the C-2 substituent (R ¼
6
H)
on the benzimidazoles or the use of o-substituted aryl halides
further reduces the efficiency of these methods. To our
knowledge, no examples of the arylation of C-2-substituted
benzimidazoles with o-substituted aryl halides have been
reported. A further problem is depicted in Scheme 1. The
Scheme 1. N-Arylation of benzimdazoles at N-1.
Despite these efforts, the preparation of N-substituted
benzimidazoles in regioisomerically pure form remains a
challenging issue. One of the most common methods for the
synthesis of benzimidazoles involves the condensation of a
suitably substituted 1,2-diaminoarene with a carboxylic acid
or an equivalent.[12] ortho-Nitroaniline can also be used in the
place of the 1,2-diaminoarene under reducing conditions.[13]
However, the preparation of N-1-substituted benzimidazoles
using these methods depends on the availability of the
requisite 1,2-diaminoarene or ortho-nitroaniline, which are
oftentimes difficult to prepare.[14] Benzimidazoles unsubsti-
tuted at N-1 such as 1 are more accessible. However, the N-
arylation of these compounds is often not straightforward.
Several issues contribute to this problem. In particular, the N-
arylation of benzimidazoles with electron-rich aryl halides
often requires both forcing conditions and/or the use of aryl
iodides.[15] Additionally, these reactions are very sensitive to
introduction of a substituent on the benzimidazole ring (such
as the C-7 methyl group of 1) renders the N-1 and N-3 atoms
inequivalent. The steric environment of the N-1 and N-3
atoms generally dictates the regioselectivity for the N-
arylation; the less hindered nitrogen atom is preferentially
arylated. For example, while the N-arylation of 1 should
provide 3, no arylation protocol exists for the conversion of 1
to 4.
During the course of our work on developing improved
methods for palladium-catalyzed carbon–nitrogen bond-
forming processes, we examined the amination of ortho-
bromoacetanilide 5 [Eq. (1)]. In contrast to what we had
observed with the reactions of the para and meta isomers of
5,[16] the amination product 7 was not observed. Instead,
benzimidazole 8 was isolated in excellent yield, presumably
formed by the in situ dehydration of 7. This unexpected
finding led us to ask whether we could extend this reaction
into a general and convergent method to prepare N-arylated
benzimidazoles in regioisomerically pure form. By choosing a
suitably substituted o-haloanilide, we envisioned that the Pd-
catalyzed amination protocol shown in Equation (1) could be
used to prepare either regioisomer (for example, 3 and 4).
Herein, we report our efforts towards this goal, resulting in a
catalytic method that allows the preparation of a variety of N-
aryl benzimidazoles in regioisomerically pure form.[17]
[*] Dr. N. Zheng, Dr. K. W. Anderson, Dr. X. Huang, Dr. H. N. Nguyen,
Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
Fax: (+1)617-253-3297
E-mail: sbuchwal@mit.edu
[**] We thank the National Institutes of Health (GM 58160) and the
National Cancer Institute (Cancer Training Grant CA09112) for
support of this work. N.Z. acknowledges the National Institutes of
Health for a postdoctoral fellowship (F32-GM074407). We are
grateful to Merck, Amgen, and Boehringer Ingelheim for unre-
stricted support. The Varian 300 and 500 MHz instruments used in
this study were purchased with funding from the National Science
Foundation (CHE 9808061 and DBI 9729592). We thank Dr. Takashi
Ikawa for developing a protocol for the conversion of 24 into 25.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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The coupling of 2-bromoacetanilide 5 and p-toluidine 6
be accommodated at the ortho, meta, or para positions of the
aniline moiety. Examples of the R’ group included methyl,
methoxy, chloride, and isopropyl groups. Of note is that this
method is effective for the preparation of N-aryl benzimida-
zoles in which the C-2’ position can be substituted with
substituents as large as iPr. Moreover, the method is
amenable to the preparation of compounds containing
substituents at both the C-2 position of the benzimidazole
and the C-2’ position of the N-1 aryl group. While the former
can sometimes be accessed with difficulty, to our knowledge,
the latter have never been prepared by direct N-arylation
processes. However, with sterically more hindered anilines
such as ortho, ortho’-disubstituted anilines, the amination
process was too slow to be preparatively useful. In some
instances, either the position or electronic nature of the Y
group (the substituent of aryl halide 10 or 11) affected the
carbon–nitrogen coupling. For example, when Y was a strong
electron-withdrawing group (e.g., cyanide) and para to the
amide, hydrolysis of the amide group necessitated the use of
an increased quantity of the catalyst. In addition, if the
substituent, Y, was strongly electron-donating (e.g., methoxy)
and para to the bromide, the rate of the amination reaction
was too slow to be synthetically useful. Otherwise, the
efficiency of the reaction was independent of the electronic
character and/or the position of the Y group. We were also
able to extend this method to heteroaromatic halides as
coupling partners. In this way, 5-azabenzimidazole 13r and 7-
azabenzimidazole 13s were efficiently prepared. Aryl bro-
mides and aryl chlorides were both suitable substrates for the
process. In most cases, XPhos and RuPhos could be used
interchangeably. However, when hindered aryl halides (e.g.,
14a) were used in the coupling, RuPhos gave far superior
results.
was studied as a model system for optimizing the formation of
N-aryl benzimidazoles. Screening experiments revealed
tBuOH and K3PO4 to be the optimal combination of solvent
and base. Using these conditions, we examined the efficiency
of a series of ligands (Table 1). One common side reaction was
Table 1: Screening of phosphine ligands for palladium-catalyzed amina-
tion of ortho-haloanilides.
L
% conv. (5)[a,b]
Yield of 8 [%][a,b]
L1 (XPhos)
L2 (tBuXPhos)
L3 (JohnPhos)
L4 (DavePhos)
L5 (RuPhos)
L6 (rac-Binap)
L7
89
38
41
46
100
26
86
13
14
6
100
0
42
32
21
0
L8
L9
29
0
[a] GC results using dodecane as an internal standard. [b] Average of two
runs.
Having established the substrate scope for this method,
we turned our attention to the preparation of pairs of N-aryl
benzimidazole regioisomers, each in isomerically pure form.
Indeed, three pairs of isomeric aryl bromides were success-
fully coupled with three different aromatic amines to provide
benzimidazoles in regioisomerically pure form (Table 3).
Using the optimized conditions (RuPhos), aryl bromides
14a and 14b were converted in a straightforward manner to
benzimidazoles 15a and 15b. However, some further opti-
mization was needed for the synthesis of the other two pairs of
benzimidazoles due to the electronic effects of the Y groups
(see above). While the coupling reaction of aryl bromide 16a
and p-anisidine 21 proceeded as expected under the standard
conditions, the corresponding reaction of aryl bromide 16b
was significantly slower. Increasing the quantity of catalyst
(2 mol% [Pd2(dba)3]and 16 mol% RuPhos) allowed the
reaction to go to completion in 18 h and provided benzimi-
dazole 17b in 90% yield. Similarly, increasing the catalyst
loading was required in the coupling of aryl bromide 18a and
aniline 22 to overcome the competitive hydrolysis of 18a to
23. The coupling of aryl bromide 18b and aniline 22 was
conducted at a lower temperature (1008C) to maximize the
yield of benzimidazole 19b.
the reduction of 2-bromoacetanilide 5 to acetanilide 9.
Variable amounts of 9 were observed during these ligand-
screening experiments. The catalysts derived from two
ligands, XPhos[18] (L1) and RuPhos[19] (L5), showed superior
activity in the coupling reaction. With either ligand, a high
yield of 8 was realized.
With a useful catalyst system (1 mol% [Pd2(dba)3](dba =
trans,trans-dibenzylideneacetone), 8 mol% XPhos or RuPhos
(Pd:L = 1:4), and 2.5 equiv K3PO4 in tBuOH) in hand, we set
out to examine the substrate scope of the method for the
preparation of N-aryl benzimidazoles (Table 2). The method
tolerated a wide range of amide substituents (R group)
including methyl, isobutyl, tert-butyl, phenyl, furyl, cyclo-
propyl, and CH2OBn. Avariety of substituents (R’) could also
The preparation of N-aryl benzimidazoles using this
method required the aryl halides bearing an amide group
ortho to a halide. In principle, the requisite starting material
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Table 2: Palladium-catalyzed synthesis of N-aryl benzimidazoles.
13a (R=iBu, X=Br, L1, 89%)
13b (R=tBu, X=Br, L1, 89%)[a]
13c (R=Me, X=Br, L1, 56%)
13d (R=iBu, X=Br, L1, 67%)
13e (R=CH2OBn, X=Br, L5, 82%)
13 f (R’=iPr, X=Br, L1, 85%)
13g (R’=OMe, X=Br, L1, 83%)
13h (R’=Cl, X=Br, L1, 59%)
13i (R=Ph, X=Br, L5, 86%)
13j (R=furyl, X=Br, L5, 86%)
13k (R=cyclopropyl, X=Br, L5, 83%)
13l (Y=Me, X=Br, L1, 91%)
13m (Y=F, X=Br, L1, 68%)
13n (X=Cl, L5, 87%)
13o (X=Br, L5, 74%)
13p (R’=Cl, X=Br, L5, 80%)
13q (R’=NH2, X=Br, L1, 52%)
13r (X=Cl, L5, 88%) 13s (X=Cl, L5, 83%)
[a] 4n HCl iin 1,4-dioxane, 1008C.
could be prepared by performing amidation on an aromatic
compound bearing two ortho-disposed halides. This approach
is illustrated with one example shown in Scheme 2. 1-Bromo-
addition to the methods available for the synthesis of
benzimidazoles, an important class of heterocycles.
Experimental Section
General procedure for Pd-catalyzed synthesis of N-aryl benzi-
midazoles (Table 2 and Table 3): An oven-dried Schlenk tube
containing a Teflon-coated stir bar was charged with [Pd2(dba)3]
(4.6 mg, 0.005 mmol, 2.0 mol% Pd), ligand L1 or L5
(0.04 mmol, 8 mol%), ortho-haloanilides (0.5 mmol), aromatic
amines (0.75 mmol) and K3PO4 (265.3 mg, 1.25 mmol). The
Schlenk tube was capped with a Teflon screw cap and then
evacuated and backfilled with argon (3 cycles). tBuOH
(1.0 mL) was added to the Schlenk tube under a positive flow
of argon (liquid aromatic amines were added to the Schlenk
tube at this point). The Schlenk tube was sealed and put into a
pre-heated oil bath at 1108C. After stirring for 18 h, the reaction
mixture was allowed to cool to room temperature and diluted
with dichloromethane (ca. 4 mL). The diluted mixture was
filtered through Celite with the aid of dichloromethane. The filtrate
was concentrated under vacuum to give a residual that was purified by
flash chromatography on silica gel.
Scheme 2. Synthesis of N-aryl benzimidazoles by sequential amidation/ami-
nation.
2-chlorobenzene 24 was first preferentially coupled with
acetamide using a catalyst system composed of [Pd2(dba)3],
tetramethyl tBuXPhos (L10), and K3PO4 in tBuOH.[20] Sub-
sequently, amide 25 and p-toluidine 6 were combined by using
the method described earlier to produce benzimidazole 8.
In summary, we have developed a catalytic method for the
synthesis of N-aryl benzimidazoles. This method provides a
protocol that enables the synthesis of N-aryl benzimidazoles
in regioisomerically pure form, while displaying good func-
tional group tolerance. We expect it will become a valuable
Received: June 12, 2007
Published online: August 23, 2007
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Communications
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Keywords: amination · heterocycles · N-aryl benzimidazole ·
palladium
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