Efficient one-pot synthesis of 2-substituted benzimidazoles from triacyloxyborane intermediates

Article abstract of DOI:10.1055/s-0031-1290129

An efficient one-pot synthesis of 2-substituted benzim?idazoles via triacyloxyborane intermediates is reported. The mild protocol is efficient and tolerant of acid-labile functional groups. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0031-1290129

LETTER
247
Efficient One-Pot Synthesis of 2-Substituted Benzimidazoles from
Triacyloxyborane Intermediates
S
ynthesis of 2-Substitut
e
ed Benzimi
n
dazoles ge Cui,* Robert B. Kargbo, Zohreh Sajjadi-Hashemi, Feryan Ahmed, Jolicia F. Gauuan
Department of Medicinal Chemistry, AMRI, 26 Corporate Circle, Albany, NY 12212-5098, USA
Fax +1(518)5122079; E-mail: wenge.cui@amriglobal.com
Received 11 October 2011
Acyloxyboranes have been used as reactive intermediates
to acylate amines to furnish amides for more than forty
years.14 Recently, Huang et al. developed an efficient syn-
thesis of amides and esters using triacyloxyboranes as in-
termediates (Scheme 1).14d The triacyloxyboranes were
generated by reacting carboxylic acids with borane–THF
or borane–methyl sulfide and effectively react with vari-
ous nucleophiles including alkylamines, arylamines,
hydrazides, alcohols, and phenols.
Abstract: An efficient one-pot synthesis of 2-substituted benzim-
idazoles via triacyloxyborane intermediates is reported. The mild
protocol is efficient and tolerant of acid-labile functional groups.
Key words: benzimidazoles, borane–THF, carboxylic acids, tri-
acyloxyboranes, diacyloxyboric acids, benzoxazoles
The benzimidazole motif can be found in a number of nat-
ural products (represented prominently by vitamin B12)
and biological and therapeutic active agents.1 It has been
commonly exploited in many therapeutic areas, such as
antiulcers,1 anticoagulants,2 antihypertensives,3 antivi-
rals,4 antifungals,4 anticancers,5 and antihistaminics.6
Marketed drugs containing benzimidazoles are Nexium,
Prevacid, Protonix, Vetmedin, Candesartan, and Telmi-
sartan. Benzimidazoles also have been frequently used as
the backbone in dyes7 and high-temperature polymers.8
BH3•THF
(0.35 equiv)
O
O
B
R
OH
R
O
toluene
r.t., 1 h
3
R1R2NH
or R3OH
O
O
R1
R3
or
R
N
R2
R
O
reflux
There is an extensive body of literature documenting the
syntheses of bezimidazoles.9 The most popular ap-
proaches generally involve the condensation–dehydration
of o-aryl diamines with carboxylic acids or their equiva-
lents (esters, nitriles, imidates, etc.),10 or the condensation
of o-aryl diamines with aldehydes under oxidative condi-
tions. The use of carboxylic acids or equivalents is usually
performed under strongly acidic or harsh dehydrating
conditions at elevated temperatures.9 The aldehyde ap-
proach involves an oxidative step for conversion to the
corresponding benzimidazole through a benzimidazoline
intermediate, which often requires heating in nitroben-
zene or DMF at elevated temperatures, as well as the use
of metal ions, iodine, organic oxidants, or inorganic
sulfites under heating.11 Condensation of anilines with a-
chloroaldoxime o-methanesulfonates can also provide
benzimidazoles.12 In addition, transition-metal catalyzed
approaches have been developed more recently to synthe-
size benzimidazoles from anilines or o-haloanilines.13 De-
spite these advances, many of the processes require harsh
reaction conditions and conditions which are incompati-
ble with acid-labile functional groups. Herein, we report a
novel protocol for the rapid synthesis of a variety of sub-
stituted benzimidazoles under mild reaction conditions
using triacyloxyborane intermediates.
Scheme 1 Synthesis of amides and esters
On the basis of this work, we envisioned an application to-
ward the synthesis of substituted benzimidazoles. We hy-
pothesized that a key triacyloxyborane intermediate could
undergo condensation with an aryldiamine to afford an
amide, followed by intramolecular nucleophilic addition
and subsequent elimination to yield a benzimidazole
(Scheme 2).
We started our exploration of the benzimidazole synthesis
by treating glacial acetic acid in toluene with one third
equivalent of borane in THF at ambient temperature. The
resulting triacyloxyborane was heated at reflux with 1.0
equivalent of benzene-1,2-diamine. After 12 hours, 2-me-
thylbenzimidazole was formed in only 32% yield while
60% of benzene-1,2-diamine remained unreacted. It was
thought that benzene-1,2-diamine could only be acylated
by the more reactive triacyloxyborane; the less active
mono- or diacyloxyboric acid resulting from the triacyl-
oxyborane was unreactive toward benzene-1,2-diamine
under these conditions. By reducing the reaction stoichi-
ometry, from 1.0 equivalent to 0.33 equivalents of ben-
zenediamine, we found that benzimidazole was formed
cleanly and in excellent yield (88%); no benzene-1,2-di-
amine was observed after the reaction was complete
(Table 1, entry 1). With the initial success of the reaction,
we set out to determine the variability and scope of the
one-pot procedure. Using the standard conditions,17 we
selected six different substituted benzenediamines and a
SYNLETT 2012, 23, 247–250
x
x.
x
x.
2
0
1
1
Advanced online publication: 03.01.2012
DOI: 10.1055/s-0031-1290129; Art ID: S54111ST
© Georg Thieme Verlag Stuttgart · New York

248
W. Cui et al.
LETTER
Table 1 Synthesis of Benzimidazoles from Benzene-1,2-diamine
O
BH3•THF
(0.35 equiv)
Derivatives and Carboxylic Acids17
O
B
R1
OH
R1
O
N
1. BH3•THF(0.35 equiv), toluene
toluene
r.t., 1 h
3
R1CO2H
R1
NH2
I
R2
N
H
NH2
NH2
2.
(0.33 equiv), reflux
O
R1
R2
R2
NH2
R1
O
O
B
(0.3 equiv)
reflux
Entry
1
R1
R2
H
Yield (%)a
8810e
O
OH
II
H3C
O
H
N
I and II
(cat.)
H
N
R1
R1
R2
6915a
R2
2
3
H
H
OH
N
H
NH2
8115b
N
S
R2
R1
N
H
4
5
H
H
5015c
Scheme 2 Synthesis of benzimidazoles from benzene-1,2-diamines
F3C
O2N
and acids
7311c
variety of aliphatic or aromatic acids. As shown in
Table 1, this method can be applied to numerous sub-
strates, and the benzimidazole products were obtained in
moderate to excellent yields.
6
7
8
H
H
H
7815d
8215d
6015e
Among our 16 examples, electron-donating (methyl and
methoxy) and weak electron-withdrawing (chloro and
bromo) functional groups on the o-phenylenediamines
have little impact on the reaction yields. However, a
strong electron-withdrawing nitro group on the o-phe-
nylenediamine led to a very low conversion under the
standard conditions and only 15% isolated yield even with
extended reaction time (Table 1, entry 15). Both aliphatic
carboxylic acids and aromatic carboxylic acids were able
to afford benzimidazoles in excellent yields. Aromatic
carboxylic acids with electron-donating and electron-
withdrawing functional groups on the phenyl ring gave
similar reaction yields (Table 1, entries 4–7 and 9–11). In
a very recent paper describing the synthesis of benzimida-
zoles via boric acid catalysis,16c aromatic carboxylic acids
were found much less reactive than aliphatic carboxylic
acids and required more than three days in refluxing tolu-
ene or xylene with the azeotropic removal of water for
complete conversion. In comparison, the protocol we re-
ported here requires much shorter reaction time for aro-
matic carboxylic acids to furnish benzimidazoles and no
azeotropic removal of water ist needed. It is noteworthy
that the acid-sensitive Boc group in entries 12 and 13
(Table 1) survived under the standard reaction conditions
and afforded their corresponding benzimidazoles in 74%
and 56% yield, respectively. Furthermore, cinnamic acid,
a Michael acceptor, was converted to benzimidazole in
60% yield without affecting the styrene at the b-position
of the acid (Table 1, entry 8).
O2N
MeO
9
Me
8711d
Cl
10
11
Me
Me
8511c
H3C
8117
MeO2C
BocHN
12
13
Me
Cl
7417
5617
BocN
S
14
15
Br
9517
NO2
15b,17
Cl
Synlett 2012, 23, 247–250
© Thieme Stuttgart · New York

LETTER
Synthesis of 2-Substituted Benzimidazoles
249
Table 1 Synthesis of Benzimidazoles from Benzene-1,2-diamine
In summary, we described a mild one-pot protocol for the
synthesis of 2-substituted benzimidazoles using triacyl-
oxyboranes generated from carboxylic acids and borane–
THF requiring no azeotropic removal of water. We also
successfully showcased the extension of this methodolo-
gy toward the synthesis of a benzoxazole. The reaction
conditions are mild and are fully compatible with acid-
labile functional groups. Studies aimed at generating an
extended scope of benzoxazoles are ongoing.
Derivatives and Carboxylic Acids17 (continued)
N
1. BH3•THF(0.35 equiv), toluene
R1CO2H
R1
NH2
R2
N
H
2.
(0.33 equiv), reflux
R2
NH2
Entry
16
R1
R2
Yield (%)a
7217
OMe
Acknowledgment
Cl
We thank AMRI for independent research funding.
a Isolated yield based on benzene-1,2-diamine precursors. All com-
pounds produced satisfactory HPLC, 1H NMR, and MS data.
b Isolated yield after refluxing for 36 h.
References and Notes
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The reaction is thought to undergo a stepwise process in-
volving the formation of an N-acylphenylenediamine in-
termediate, which is the rate-limiting step, followed by
cyclization and dehydration to yield the desired benzim-
idazoles (Scheme 2). It is known that the cyclization–
dehydration of the N-monoacyl intermediates to benzimi-
dazoles could occur upon heating, even in the absence of
a catalyst,16b and could be greatly accelerated as well by
acid/base catalysis.16 The diacyloxyboric acid side prod-
uct (II, Scheme 2) and the triacyloxyborane itself (I,
Scheme 2) as mild Lewis acids might help to catalyze the
dehydrating step. Potential N,N¢-diacylphenylenediamine
intermediates were not observed, suggesting that either
the N-acylphenylenediamine intermediates (less nucleo-
philic than o-phenylenediamine) do not further react with
the triacyloxyboranes, or the subsequent cyclization–
dehydration was much faster as compared to the acylation
step.
To extend the substrate scope, the reaction was carried out
using 2-aminophenol and p-chlorobenzoic acid
(Scheme 3). In this case, however, the initial protocol
failed to yield the desired benzoxazole product. We were
pleased to find that switching the solvent from toluene to
xylenes in order to increase the reaction temperature to
140 °C in the second step gave a very good yield of the
benzoxazole (83%).
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CO2H
1. BH3•THF (0.35 equiv)
xylene, r.t., 1 h
O
N
Cl
NH2
2.
Cl
OH
(0.33 equiv)
reflux, 12 h
Comprehensive Heterocyclic Chemistry, Vol. 5; Katritzky,
A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1984,
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83%
Scheme 3 Synthesis of benzoxazole using xylenes as solvent
© Thieme Stuttgart · New York
Synlett 2012, 23, 247–250

250
W. Cui et al.
LETTER
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(17) General Procedure for the Formation of Benzimidazoles
To a carboxylic acid (2 mmol) in toluene (10 mL) in an ice-
water bath was added dropwise a solution of borane–THF (1
M, 0.70 mmol) in THF. The mixture was stirred at r.t. for 30
min. Benzene-1,2-diamine (0.66 mmol) was added, and the
mixture was heated at reflux with stirring for 12 h. After
cooling, the mixture was concentrated in vacuo, and the
residue was purified by flash chromatography. The physical
data of the products in Table 1, entries 1–11, 15, and 16 are
consistent with those of reported literatures,10e,11c,d,15 or those
of authentic samples. The new compound characterizations
are provided below.
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tert-Butyl 2-(5-Methyl-1H-benzo[d]imidazol-2-yl)-
ethylcarbamate (Table 1, Entry 12)
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1H NMR (300 MHz, CDCl3): d = 7.43 (d, J = 8.1 Hz, 1 H),
7.32 (s, 1 H), 7.04 (d, J = 8.1 Hz, 1 H), 5.40 (br, 1 H), 3.68–
3.61 (m, 2 H), 3.12–3.18 (m, 2 H), 2.45 (s, 3 H), 1.40 (s, 9
H). 13C NMR (125 MHz, CDCl3): d = 156.7, 152.2, 132.0,
123.7, 114.3, 114.0, 79.9, 38.4, 30.2, 28.4, 21.6. ESI-HRMS:
m/z calcd for C15H21N3O2 + H+: 276.1712; found 2761723.
tert-Butyl 4-[(5-Chloro-1H-benzo[d]imidazol-2-yl)-
methyl]piperidine-1-carboxylate (Table 1, Entry 13)
1H NMR (500 MHz, CD3OD): d = 7.53 (d, J = 1.9 Hz, 1 H),
7.47 (d, J = 8.7 Hz, 1 H), 7.20 (dd, J = 1.5, 8.6 Hz, 1 H), 4.15
(d, J = 13.2 Hz, 2 H), 2.83 (d, J = 7.3 Hz, 2 H), 2.76 (br, 2
H), 2.10–2.02 (m, 1 H), 1.66 (d, J = 12.2 Hz, 2 H), 1.44 (s, 9
H), 1.36–1.28 (m, 2 H). 13C NMR (125 MHz, CD3OD): d =
156.6, 156.5, 140.4, 137.8, 129.0, 123.8, 116.3, 115.4, 81.0,
44.6, 37.0, 36.4, 33.0, 28.7. ESI-HRMS: m/z calcd for
C18H24ClN3O2 + H+: 350.1635; found: 350.1642.
5-Bromo-2-(thiophen-2-ylmethyl)-1H-benzo[d]-
(15) (a) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin Trans.
1 1997, 2319. (b) Nasal, A.; Kaliszan, R.; Kuzmierkiewicz,
W. QSAR 1987, 6, 22. (c) Blacker, A. J.; Farah, M. M.; Hall,
M. I.; Marsden, M. P.; Saidi, O.; Williams, J. M. Org. Lett.
2009, 11, 2039. (d) Moorthy, J. A.; Neogi, I. Tetrahedron
Lett. 2011, 52, 3868. (e) Trivedi, R.; De S, K.; Gibbs, R. A.
J. Mol. Catal. A: Chem. 2006, 245, 8.
imidazole (Table 1, Entry 14)
1H NMR (500 MHz, CD3OD): d = 7.72 (d, J = 1.5 Hz, 1 H),
7.47 (d, J = 8.5 Hz, 1 H), 7.41 (dd, J = 1.5, 8.5 Hz, 1 H), 7.32
(dd, J = 1.5, 5.5 Hz, 1 H), 7.04–7.03 (m, 1 H), 6.99 (dd,
J = 3.5, 5.0 Hz, 1 H), 4.52 (s, 2 H). 13C NMR (125 MHz,
CD3OD): d = 155.8, 141.1, 139.4, 138.4, 128.1, 127.6,
126.6, 126.1, 118.7, 117.0, 116.3, 30.3. ESI-HRMS: m/z
calcd for C12H9BrN2S + H+: 292.9748; found: 292.9768.
Synlett 2012, 23, 247–250
© Thieme Stuttgart · New York

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