Synthesis of benzimidazoles via iridium-catalyzed acceptorless dehydrogenative coupling

Article abstract of DOI:10.1039/c5ob00904a

Iridium-catalyzed acceptorless dehydrogenative coupling of tertiary amines and arylamines has been developed. A number of benzimidazoles were prepared in good yields. An iridium-mediated C-H activation mechanism is suggested. This finding represents a novel strategy for the synthesis of benzimidazoles.

Full text of DOI:10.1039/c5ob00904a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Yan, X. Sun, L.
Ye, X. Lv, Y. Hu, Y. Chen and X. Zhang, Org. Biomol. Chem., 2015, DOI: 10.1039/C5OB00904A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/obc

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 1 of 4
View Article Online
DOI: 10.1039/C5OB00904A
Organic & Biomolecular Chemistry
COMMUNICATION
Synthesis of Benzimidazoles via Iridium‐catalyzed Acceptorless
Dehydrogenative Coupling
Received 00th January 20xx,
Accepted 00th January 20xx
Xiang Sun, Xiao‐Hui Lv, Lin‐Miao Ye, Yu Hu, Yan‐Yan Chen, Xue‐Jing Zhang and Ming Yan*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Iridium‐catalyzed acceptorless dehydrogenative coupling of
tertiary amines and arylamines has been developed. A number of
benzimidazoles were prepared in good yields. An iridium‐
mediated C‐H activation mechanism is suggested. This finding
represents a novel stragety for the synthesis of benzimidazoles.
Benzimidazole derivatives possess a wide variety of biological
activities1, including anti‐bacterial, antivirus, anticancer, antifungal,
antiulcer, and antihypertensive. Many benzimidazole drugs went to
the market such as Albendazole, Omeprazole, Tiabendazole,
Mizolastine and Telmisartan (Figure 1). A number of synthetic
methods of benzimidazoles have been developed.2‐3 The general
methods include the condensation of 1,2‐phenylenediamine with
aldehydes, carboxylic acids or their derivatives (nitriles, orthoesters),
the transition metal‐catalyzed C−N coupling of N‐(2‐haloaryl)
amidines, and the intramolecular oxidative C−N couplings of
arylamidine. In 2014, Long and co‐workers reported an attractive
synthesis of benzimidazoles from N‐benzyl/alkyl‐1,2‐phenylenedi‐
amines via the TEMPO−air promoted oxidative C‐N coupling.3d In
recent years, cross dehydrogenative coupling (CDC) has emerged as
a new strategy for the construction of C−N bonds.4‐5 Generally, CDC
reactions require the presence of stoichiometric amount of
oxidants or hydrogen acceptors. Acceptorless CDC reactions, which
are completed with the release of hydrogen gas, have proven to be
more challenge. So far, only few successful examples were
reported.6 Recently we developed two iridium‐catalyzed
acceptorless CDC reactions of tertiary amines with ketones and
amides.7 The C‐C and C‐N double bonds could be generated
Figure 1 Marketed drugs with benzimidazole scafford.
Table 1 Optimization of reaction conditionsa
Yield b
(%)
62
82
57
41
55
‐
Entry
Catalyst
[Cp*IrCl2]2
[Ir(cod)Cl]2
[Ir(coe)2Cl]2
[Ir(cod)OMe]2
Ir(cod)acacc
IrCl3
1
2
3
4
5
6
7
8
9
respectively. As
a continuous effort, herein we report an
acceptorless CDC reaction of tertiary amines and arylamines. The
reaction provided a series of benzimidazoles in good yields under
mild reaction conditions.
[Cp*RhCl2]2
‐
9
33
d
PtCl2
e
[Ir(cod)Cl]2
a Conditions: 1a (0.2 mmol), catalyst (5 mol% metal), trifluoroethanol (2 mL),
b
1
Institute of Drug Synthesis and Pharmaceutical Process, School of Pharmaceutical
Sciences, Sun Yat‐sen University, Guangzhou 510006, China.
E‐mail: yanming@mail.sysu.edu.cn; Fax/Tel: + 86‐20‐39943049
† Electronic Supplementary Information (ESI) available: 1H and 13C NMR spectra.
See DOI: 10.1039/x0xx00000x
argon atmosphere, 80 °C, 72 h. The yields were determined by H NMR
using dimethyl terephthalate as the internal standard. c 10 mol% catalyst
d
was used. 5Å Molecular sieves was added. e Hexafluoroisopropanol was
used instead of trifluoroethanol.
This journal is © The Royal Society of Chemistry 20xx
Organic & Biomolecular Chemistry., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 4
COMMUNICATION
Organic & Biomolecular Chemistry
Table 2 Dehydrogenative coupling of substrates 1a‐1pa,b
View Article Online
a,b
Table 3 Dehydrogenative coupling of substrates 3DaO‐3I:i10.1039/C5OB00904A
N
N
N
N
N
N
2k trace
2l 83%
2j 77%
a Conditions: 3a‐3i (0.2 mmol), [Ir(cod)Cl]2 (0.01 mmol), trifluoroethanol
(2.0 mL), argon atmosphere, 80 °C, 72 h. b Isolated yields.
N
N
N
N
N
N
2m 85%
2n 87%
2o 74%
solvents (such as DMF, AcOH, toluene, CHCl3, etc.). Lower yield was
obtained in hexafluoroisopropanol (Table 1, entry 9). The emitted
gas from the reaction of 1a catalyzed by [Ir(cod)Cl]2 was collected
via the water‐repulsion method. GC‐TCD analysis of the gas
components confirmed the existence of hydrogen gas. The result
approves an acceptorless dehydrogenative process.
N
N
N
N
2pa 45%
2pb 36%
The substrate scope of this reaction was explored and the
results are summarized in Table 2. The reaction of 2‐
methylpiperidine, pyrrolidine and azepane derivatives (1b‐1d)
provided the products (2b‐2d) in good yields. However, 2‐
morpholinoaniline (1e) and 2‐(4‐methylpiperazin‐1‐yl)aniline (1f)
are unreactive. The lower electronic density of these nitrogen
heterocycles may inhibit the reaction. The anilines with 2‐
tetrahydroisoquinolinyl (1g‐1h), 2‐thieno[3,2‐c]piperidinyl (1i) and
2‐(isoindolin‐2‐yl) (1j) are suitable substrates. Good yields were
generally obtained. N,N‐Dimethylamino aniline (1k) is unreactive,
however the reaction of N,N‐diethylamino, N,N‐dipropylamino, and
N,N‐dibenzylamino anilines (1l‐1n) provided benzimidazole
products in good yields. Again, the results demonstrate that the
reaction is highly sensitive to the electronic density of α‐carbon of
tertiary amine. N‐Isopropyl‐N‐benzyl‐amino aniline (1o) gave 2o as
the major product, but N‐ethyl‐N‐benzyl‐amino aniline (1p) gave a
mixture of benzimidazoles 2pa and 2pb. The steric hindrance seems
to exert significant effect on the regioselectivity of the reaction.
The effect of the substitution at the phenyl ring of aniline was
investigated and the results are summarized in Table 3. The
a Conditions: 1a‐1p (0.2 mmol), [Ir(cod)Cl]2 (0.01 mmol), trifluoroethanol
(2.0 mL), argon atmosphere, 80 °C, 72 h. b Isolated yields.
We chose 2‐(piperidin‐1‐yl)aniline 1a as the model substrate. A
number of iridium catalysts were examined and the results are
summarized
in
Table
1.
[Cp*IrCl2]2
(Cp*
=
pentamethylcyclopentadienyl) gave
a
moderated yield of
benzimidazole 2a (Table 1, entry 1). [Ir(cod)Cl]2 (cod = 1,5‐
cyclooctadiene) afforded 2a in a better yield (Table 1, entry 2).
[Ir(coe)2Cl]2 (coe = cyclooctene), [Ir(cod)OMe]2 and Ir(cod)acac gave
inferior yields (Table 1, entries 3‐5). IrCl3 is completely inefficient,
probably due to its poor solubility in trifluoroethanol (Table 1, entry
6). [Cp*RhCl2]2 did not show any catalytic activity (Table 1, entry 7).
PtCl2 in combination with 5Å molecular sieves provided 2a in 9%
yield (Table 1, entry 8).6a A series of nitrogen ligands were screened
to improve the yield, however detrimental effect was observed.8
The use of trifluoroethanol as the reaction solvent is important. The
reaction did not occur in usual organic
2 | Organic & Biomolecular Chemistry., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 3 of 4
Organic & Biomolecular Chemistry
Please do not adjust margins
Organic & Biomolecular Chemistry
COMMUNICATION
reaction of 3‐, 4‐, 5‐ and 6‐methyl derivatives (3a‐3d) afforded the
benzimidazole products in good yields. The steric hindrance of the
methyl group had a slight impact on the reaction. 4‐Methoxyl and
4‐hydroxyl substituted substrates (3e‐3f) gave the products in good
Buschauer, Eur. J. Med. Chem., 2011, 46, 4419; (b) T. W. Moore,
K. Sana, D. Yan, S. A. Krumm, P. Thepchatri, J. P. Snyder, J.
View Article Online
DOI: 10.1039/C5OB00904A
Marengo, R. F. Arrendale, A. J. Prussia, M. G. Natchus, D. C.
Liotta, R. K. Plemper and A. M. Sun, ACS Med. Chem. Lett.,
2013, 4, 762; (c) S. N. Lin and L. H. Yang, Tetrahedron Lett.,
2005, 46, 4315; (d) A. R. Porcari, R. V. Devivar, L. S. Kucera, J. C.
Drach and L. B. Townsend, J. Med. Chem., 1998, 41, 1252; (e) B.
Fang, C. H. Zhou and X. C. Rao, Eur. J. Med. Chem., 2010, 45,
4388.
2
3
For the reviews of benzimidazole synthesis, see: (a) P. N.
Preston, Chem. Rev., 1974, 74, 279; (b) L. B. Townsend and G. R.
Revankar, Chem. Rev., 1970, 70, 389; (c) K. M. Dawood and B. F.
Abdel‐Wahabb, Arkivoc, 2010, I, 333; (d) A. Chawla, R. Kaur
and A. Goyal, J. Chem. Pharm. Res., 2011, 3, 925; (e) S. S. Panda,
R. Malik and S. C. Jain, Curr. Org. Chem., 2012, 16, 1905.
For the selected recent examples of benzimidazole synthesis,
see: (a) B. Das, H. Holla and Y. Srinivas, Tetrahedron Lett., 2007,
48, 61; (b) J. B. Huang, Y. M. He, Y. Wang and Q. Zhu, Chem.
Eur. J., 2012, 18, 13964; (c) F. Wang, M. Tran‐Dubé, S. Scales, S.
Johnson, I. McAlpine and S. Ninkovic, Tetrahedron Lett., 2013,
54, 4054; (d) D. Xue and Y. Q. Long, J. Org. Chem., 2014, 79,
4727.
Scheme 1 Proposed Reaction Mechanism
4
5
For the reviews of CDC reactions, see: (a) C. J. Li, Acc. Chem.
Res., 2009, 42, 335; (b) W. J. Yoo and C. J. Li, Top. Curr. Chem.,
2010, 292, 281; (c) C. J. Scheuermann, Chem. Asia. J., 2010, 5,
436; (d) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111,
1215‐1292; (e) M. L. Louillat and F. W. Patureau, Chem. Soc.
Rev., 2014, 43, 901.
yields. Lower yield was obtained for the 4‐bromo substituted
substrate 3g. The introduction of electron‐withdrawing
trifluoromethyl groups led to
a poor yield. Pyridin‐2‐amine
For the selected recent examples of the formation of C‐N bonds
via CDC, see: (a) H. L. Jiang, A. J. Lin, C. J. Zhu and Y. X. Cheng,
Chem. Commun., 2013, 49, 819; (b) R. A. Leal, D. R. Beaudry, S.
K. Alzghari and R. Sarpong, Org. Lett., 2012, 14, 5350; (c) S. J.
Lou, D. Q. Xu, D. F. Shen, Y. F. Wang, Y. K. Liu and Z. Y. Xu,
Chem. Commun., 2012, 48, 11993; (d) A. M. Martínez, N.
Rodríguez, R. G. Arrayás and J. C. Carretero, Chem. Commun.,
2014, 50, 2801; (e) F. Jafarpour, N. Jalalimanesh, M. Teimouri
and M. Shamsianpour, Chem. Commun.,2015, 51, 225.
(a) X. Z. Shu, Y. F. Yang, X. F. Xia, K. G. Ji, X. Y. Liu and Y. M.
Liang, Org. Biomol. Chem., 2010, 8, 4077; (b) N. Ortega, C.
Richter and F. Glorius, Org. Lett., 2013, 15, 1776; (c) D. Srimani,
Y. Ben‐David and D. Milstein, Chem. Commun., 2013, 49, 6632;
(d) K. Taniguchi, S. Itagaki, K. Yamaguchi and N. Mizuno, Angew.
Chem. Int. Ed., 2013, 52, 8420; (e) D. Talwar, A. Gonzalez‐de‐
Castro, H. Y. Li and J. L. Xiao, Angew. Chem. Int. Ed., 2015, 54,
5223.
(a) S. Z. Nie, X. Sun, W. T. Wei, X. J. Zhang, M. Yan and J. L. Xiao,
Org. Lett., 2013, 15, 2394; (b) X. Sun, Y. Hu, S. Z. Nie, Y. Y. Yan,
X. J. Zhang and M. Yan, Adv. Synth. Catal., 2013, 355, 2179.
For the screening of nitrogen ligands, see the Supporting
Information.
The dihydro‐benzimidazole intermediate C was prepared
according to the literature method (R. Garner, G. V. Garner,
and H. Suschitzky, J. Chem. Soc. (C) Org., 1970, 825). The
transformation of C to 2a was observed under the reaction
conditions.
derivative (3i) is applicable and the expected product 4i was
obtained in a good yield.
A tentative reaction mechanism is proposed (Scheme 1). The
C‐H insertion assisted by the coordination of the amino group with
Ir(I) catalyst generates the intermediate A. After the release of one
molecule of hydrogen gas, the Ir(III) intermediate B is formed. The
reductive elimination leads to the dihydro‐benzimidazole C. The Ir‐
catalyzed hydride transfer provides iminium intermediate D. After
the release of second molecule of hydrogen gas, benzimidazole 2a
is obtained.9
In summary, we have developed an acceptorless
dehydrogenative coupling of tertiary amines and arylamines. A
number of benzimidazoles were prepared in good yields. An
iridium‐mediated C‐H activation mechanism is suggested. The
reaction provides a new strategy for the synthesis of benzimidazole
derivatives from 2‐(N,N‐dialkylamino)‐anilines.
6
7
Acknowledgements
8
9
We thank the National Natural Science Foundation of China (Nos.
21202208, 21172270, 21472248), Guangdong Engineering Research
Center of Chiral Drugs for the financial support of this study.
Notes and references
1
For the biological activities of benzimidazole, see: (a) S. Braun,
A. Botzki, S. Salmen, C. Textor, G. Bernhardt, S. Dove and A.
This journal is © The Royal Society of Chemistry 20xx
Organic & Biomolecular Chemistry., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 4
View Article Online
DOI: 10.1039/C5OB00904A
Organic & Biomolecular Chemistry
COMMUNICATION
This journal is © The Royal Society of Chemistry 20xx
Organic & Biomolecular Chemistry., 2013, 00, 1‐3 | 4
Please do not adjust margins