Iridium(III)-Catalyzed One-Pot Access to 1,2-Disubstituted Benzimidazoles Starting from Imidamides and Sulfonyl Azides

Article abstract of DOI:10.1021/acs.orglett.7b02028

A novel Ir-catalyzed annulation of imidamides with sulfonyl azides has been developed. 1,2-Disubstituted benzimidazoles could be easily obtained in up to 99% yield for more than 40 examples. The products further streamline the synthesis of molecules that are important building blocks for organic synthesis and drug discovery. This strategy features high regioselectivity, efficiency, good tolerance of functional groups, and mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.7b02028

Letter
pubs.acs.org/OrgLett
Iridium(III)-Catalyzed One-Pot Access to 1,2-Disubstituted
Benzimidazoles Starting from Imidamides and Sulfonyl Azides
Linhua Xu, Lianhui Wang, Yadong Feng, Yudong Li, Lei Yang, and Xiuling Cui*
Engineering Research Center of Molecular Medicine of Ministry of Education, Key Laboratory of Fujian Molecular Medicine, Key
Laboratory of Xiamen Marine and Gene Drugs, School of Biomedical Sciences, Huaqiao University, Xiamen 361021, P. R. China
S
* Supporting Information
ABSTRACT: A novel Ir-catalyzed annulation of imidamides with sulfonyl azides has been developed. 1,2-Disubstituted
benzimidazoles could be easily obtained in up to 99% yield for more than 40 examples. The products further streamline the
synthesis of molecules that are important building blocks for organic synthesis and drug discovery. This strategy features high
regioselectivity, efficiency, good tolerance of functional groups, and mild reaction conditions.
Scheme 1. Transition-Metal-Catalyzed C−H Amination
ransition-metal-catalyzed C−N bond formation has been
Using Organic Azides
T
one of the major research topics in organic synthesis
because of the ubiquity of C−N bonds in natural products,
synthetic intermediates, pharmaceuticals, and functional
materials.1 Ullmann and Goldberg have developed Cu-
mediated C−N cross-coupling of aryl halides with amines,
which has been proven as a powerful pathway to build C−N
bonds.2 Palladium-catalyzed amination with the help of a
suitable ligand as developed independently by Buchwald and
Hartwig is an alternative procedure.3 Recently, significant
advances in direct C−H amination/amidation reactions have
been achieved. However, harsh conditions or/and stoichio-
metric external oxidants are required for most procedures.4 To
avoid the external oxidants, preactivated amino precursors have
been employed as reagents;5 this requires an additional step to
prepare the amine reagent, and stoichiometric byproducts are
still unavoidable. Organic azide has been developed as an
elegant amino source and internal oxidant by N−N2 bond
cleavage to effectively solve these limitations.6 Chang,
Ackermann, Jiao, and our group have extensively studied Rh-,
Ru-, and Ir-catalyzed directed amination/amidation reactions
under mild reaction conditions with various chelating groups
(path A, Scheme 1),6 such as amide,7 N-phenylamide,7
ketoxime,8 hydrazine,9 ketone,10 carboxylic acid,11 aldehyde,12
nitrone,13 N-oxide,14 and other heterocycles, including
pyridine,15 pyrazol,15a imidazole,16 oxazole,9 pyrrolidinone,9
and carbamate9. However, most of these directing groups were
not easily removed or modified. This shortcoming can be
attenuated if the chelating groups can be converted into the
desired functional groups in the final products. Following this
strategy, construction of azacycles using organic azide as the
nitrogen source has received attention.17 Glorius’ group
recently developed a novel synthesis of 1,3-substituted
indazoles from easily available arylimidates and sulfonyl azides
via Rh(III)/Cu-catalyzed C−H activation/cyclization (path B,
Scheme 1).17a Subsequently, the Jiao group reported the
Rh(III)/Cu-catalyzed C−H annulation of arylimidates and
benzyl azides to synthesize quinazolines (path C, Scheme 1).17b
Benzimidazole is a valuable heterocyclic scaffold and displays
various biological activities. In particular, 1,2-disubstituted
benzimidazoles widely exist in natural products and pharma-
ceuticals.18Herein we report a convenient, efficient, and
straightforward approach to synthesize 1,2-disubstituted
Received: July 4, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzimidazoles via Ir(III)-catalyzed C−H activation of N-
phenylbenzimidamides with organic azides (path D, Scheme 1).
This study commenced with the reaction of N-phenyl-
benzimidamide (1a) with TsN3 (2a) catalyzed by [Cp*IrCl2]2
(Table 1). The desired benzimidazole 3aa was obtained in 32%
optimized reaction conditions were identified as follows:
[Cp*IrCl2]2 (4 mol %), AgNTf2 (16 mol %), and phenylacetic
acid (1 equiv) in DCE at 80 °C for 12 h under air.
With the optimized reaction conditions in hand, we next
explored the generality and scope of the reaction of N-
phenylbenzimidamides with 2a (Scheme 2). To our delight,
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Ir(III)-Catalyzed Synthesis of N-Tosyl
a b
,
Benzimidazoles from N-Phenylbenzimidamides
yield
b
entry
catalyst
salt
acid (equiv)
solvent
(%)
1
2
3
4
5
6
7
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
AgNTf2
−
DCE
32
45
61
26
28
54
35
AgNTf2 HOAc (0.5)
AgNTf2 HOAc (1.0)
AgNTf2 HOAc (1.0)
AgNTf2 HOAc (1.0)
AgNTf2 PivOH (1.0)
DCE
DCE
dioxane
toluene
DCE
AgNTf2 benzoic acid
(1.0)
DCE
8
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
−
AgNTf2 phenylacetic acid DCE
(1.0)
80
c
9
AgNTf2 phenylacetic acid DCE
(1.0)
97
c
10
AgSbF6 phenylacetic acid DCE
(1.0)
87
c
11
AgOAc
phenylacetic acid DCE
(1.0)
54
c
12
NaOAc phenylacetic acid DCE
(1.0)
45
d
13
AgNTf2 phenylacetic acid DCE
(1.0)
62
a
Reaction conditions: 1 (0.2 mmol), 2a (1.5 equiv), [Cp*IrCl2]2 (4
c
14
AgNTf2 phenylacetic acid DCE
(1.0)
N.R.
N.R.
N.R.
18
mol %), AgNTf2 (16 mol %), phenylacetic acid (1 equiv), DCE (2
mL), 80 °C, 12 h, under air. Isolated yields are shown.
b
c
15
[Cp*RhCl2]2
[Cp*CoCl2]2
AgNTf2 phenylacetic acid DCE
(1.0)
various N-phenylbenzimidamides containing electron-donating
or electron-withdrawing groups or halogens worked well under
the optimized reaction conditions, leading to the functionalized
benzimidazoles. A methyl substituent at the ortho position of
the benzene ring (3ba) led to a lower yield than for the m- and
p-methyl-substituted N-phenylbenzimidamides (3ga, 3la),
perhaps because of steric hindrance. A broad range of
functional groups were also tolerated at the para position.
The desired products were obtained in good to excellent yields
(3la−ta). For instance, N-phenylbenzimidamides bearing
fluoro (3ma), chloro (3na), bromo (3oa), iodo (3pa), methoxy
(3qa), trifluoromethyl (3ra), isopropyl (3sa), and cyano (3ta)
groups reacted smoothly with 2a. These results indicated that
the electronic properties of the N-phenylbenzimidamide had no
apparent effect on the reaction. Meta-substituted N-phenyl-
benzimidamides gave the desired products in moderate to
excellent yields with high regioselectivity, where C−H
functionalization occurred at the less hindered site (3ga−ka).
The steric effect of a 2-substituted benzene ring had no
significant influence on the reactivity (3aaa vs 3aac). 2-
Diphenylacetimidamide also worked well, affording the
corresponding product 3aaf in 99% yield. N-Naphthylbenzimi-
damide was a suitable substrate, giving the corresponding
benzimidazole 3aag in 26% yield through selective reaction at
the 2-position rather than the 8-position.
c
16
AgNTf2 phenylacetic acid DCE
(1.0)
c
17
[Ru(p-cymene) AgNTf2 phenylacetic acid DCE
Cl2]2 (1.0)
a
Reaction conditions: 1a (0.20 mmol), 2a (1.5 equiv), [Cp*IrCl2]2
(2.5 mol %), salt (10 mol %), acid, solvent (2 mL), 80 °C, 12 h, under
b
c
air. Isolated yields. N.R. = no reaction. [Cp*IrCl2]2 (4 mol %), salt
(16 mol %). [Cp*IrCl2]2 (4 mol %), 70 °C.
d
yield (entry 1). Addition of HOAc (0.5 equiv) resulted in a
higher yield of 45% (entry 2), which encouraged us to further
increase the amount of HOAc. Product 3aa was isolated in 61%
yield when the amount of HOAc was increased to 1 equiv
(entry 3). Subsequently, screening of solvents revealed that 1,2-
DCE was optimal (entries 4−5). We then examined various
acids. Phenylacetic acid was the most efficient (entries 6−8).
To our delight, benzimidazole 3aa was isolated in 97% yield
when the loading of [Cp*IrCl2]2 was increased to 4 mol %
(entry 9). Among various salts tested, AgNTf2 gave the best
yield (entries 9−12). Temperature also has a great impact on
this reaction, as 1a showed low reactivity at 70 °C (entry 13).
Control experiments revealed that no reaction occurred when
the [Cp*IrCl2]2 catalyst was omitted, which revealed the metal
catalyst to be essential for this transformation (entry 14).
Meanwhile, no desired conversion was observed using
[Cp*RhCl2]2 or [Cp*CoCl2]2 as a catalyst (entries 15 and
16). A trace amount of 3aa was detected when [Ru(p-
cymene)Cl2]2 was used as the catalyst (entry 17). Finally, the
Next, we investigated the scope of sulfonyl azides 2 in the
sulfamidation of 1a under the optimized conditions (Scheme
3). It was found that a broad range of functional groups could
B
DOI: 10.1021/acs.orglett.7b02028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Ir(III)-Catalyzed Synthesis of N-Sulfonyl
Benzimidazoles with Sulfonyl Azides
Scheme 4. Mechanism Studies
a b
,
a
Reaction conditions: 1a (0.2 mmol), 2 (1.5 equiv), [Cp*IrCl2]2 (4
mol %), AgNTf2 (16 mol %), phenylacetic acid (1 equiv), DCE (2
mL), 80 °C, 12 h, under air. Isolated yields are shown.
b
Scheme 5. Plausible Mechanism
be tolerated. The arenesulfonyl azide with an o-methyl group
(3ac) exhibited slightly decreased reactivity, presumably due to
steric hindrance. Aromatic rings substituted with halogens
worked well, providing the desired products in excellent yields
(3ah and 3ai). Moderate yields were obtained with 4-
trifluoromethylbenzenesulfonyl azide and 4-nitrobenzenesul-
fonyl azide (3ak and 3al). In addition, alkylsulfonyl azides
worked well (3am and 3an). No target products were obtained
when aryl azides, benzyl azide, TMSN3, and benzoyl azides
were used as the substrates under the standard conditions.
Compared with methods in the literature,19 the current reaction
provides easier, more straightforward, and more step-
economical access to various 1,2-disubstituted benzimidazole
derivatives with important biological and pharmacological
activities.18
To shed light on the reaction mechanism of this cyclization
process, a series of experiments were performed. To further
probe the C−H activation process, the kinetic isotope effect
was determined by running two parallel reactions using 1a and
1a-D5 under the standard reaction conditions and terminating
them after 3 h. A kH/kD value of 1.3 was obtained on the basis
of the product yields of 3aa and 3aa-Dn, indicating that C−H
bond cleavage is likely not involved in the turnover-limiting
step (Scheme 4a). To our surprise, H/D exchange of 1a-D5 at
the ortho position (the 4-position of the benzimidazole) was
observed (with 26% H) according to the 1H NMR spectra (see
the Supporting Information), suggesting reversible C−H
activation. Furthermore, a radical trapping experiment was
carried out using TEMPO as the radical trap under the
standard reaction conditions (Scheme 4b). The reaction was
not obviously inhibited, suggesting that a radical process could
be ruled out. In addition, no desired product was attained when
N-methyl-N-phenylbenzimidamide (3a) was used as a substrate
(Scheme 4c), which indicated the requirement of a free N−H
group in the benzimidamide. Moreover, a control reaction
between 1a and TsCl did not deliver the target product
(Scheme 4d), which proved that the nitrogen attached to Ts in
3aa is from 2a rather than 1a.
through anion exchange. Coordination of 1a to the catalyst and
subsequent cyclometalation generates iridacyclic intermediate
A′. Coordination of TsN3 followed by elimination of nitrogen
gives iridium carbene species C′. The Ir−Ar bond is proposed
to undergo migratory insertion into the carbene unit to
generate intermediate D′. The Ir−N(TsN3) bond then
undergoes migratory insertion into the CN bond to afford
amide species E′. The product 3aa is eventually formed from E′
by elimination of the active Ir(III) catalyst and one molecule of
NH3 from E′ upon protonolysis and intramolecular proto-
nolysis, which was proven by the reaction shown in Scheme 4c.
In conclusion, we have developed an efficient synthetic route
to access 1,2-disubstituted benzimidazoles via Ir(III)-catalyzed
C−H activation/annulation of readily available N-phenyl-
benzimidamides by coupling with sulfonyl azides. Good
functional group tolerance, high atom efficiency, and moderate
to high yields under relatively mild conditions make this
protocol useful in preparing various substituted benzimidazole
According to these observations and literature prece-
dents,20,21 a plausible reaction mechanism is given in Scheme
5. First, the active catalyst, [Cp*Ir(NTf2)]2, is generated
C
DOI: 10.1021/acs.orglett.7b02028
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
4497−4503. (c) Lanke, V.; Prabhu, K. R. Chem. Commun. 2017, 53,
5117. (d) Zhang, Y.; Wu, B.; Shi, Z. Chem. - Eur. J. 2016, 22, 17808.
(13) Pi, C.; Cui, X.; Wu, Y. J. Org. Chem. 2015, 80, 7333.
(14) Hwang, H.; Kim, J.; Jeong, J.; Chang, S. J. Am. Chem. Soc. 2014,
136, 10770.
(15) (a) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.;
Chang, S. J. Am. Chem. Soc. 2012, 134, 9110. (b) Ali, M. A.; Yao, X.; Li,
G.; Lu, H. Org. Lett. 2016, 18, 1386.
(16) Thirunavukkarasu, V. S.; Raghuvanshi, K.; Ackermann, L. Org.
Lett. 2013, 15, 3286.
(17) (a) Yu, D.; Suri, M.; Glorius, F. J. Am. Chem. Soc. 2013, 135,
8802. (b) Wang, X.; Jiao, N. Org. Lett. 2016, 18, 2150. (c) Wan, J.;
Cao, S.; Liu, Y. Org. Lett. 2016, 18, 6034.
derivatives. Further mechanistic studies and other novel
transformations of imidamides are underway in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02028.
General procedures, relevant NMR spectra, and catalytic
experiments (PDF)
(18) (a) Zhu, Z.; Lippa, B.; Drach, J. C.; Townsend, L. B. J. Med.
Chem. 2000, 43, 2430. (b) Gupta, S. K.; Pancholi, S. S.; Gupta, M. K.;
Agrawal, D.; Khinchi, M. P. J. Pharm. Sci. Res. 2010, 4, 228. (c) Elleder,
D.; Baiga, T. J.; Russell, R. L.; Naughton, J. A.; Hughes, S. H.; Noel, J.
P.; Young, J. A. T. Virol. J. 2012, 9, 305. (d) Kadri, H.; Matthews, C. S.;
Bradshaw, T. D.; Stevens, M. F. G.; Westwell, A. D. J. Enzyme Inhib.
Med. Chem. 2008, 23, 641.
(19) (a) Jin, H.; Xu, X.; Gao, J.; Zhong, J.; Wang, Y. Adv. Synth. Catal.
2010, 352, 347. (b) Alla, S. K.; Kumar, R. K.; Sadhu, P.;
Punniyamurthy, T. Org. Lett. 2013, 15, 1334. (c) Fu, S.; Jiang, H.;
Deng, Y.; Zeng, W. Adv. Synth. Catal. 2011, 353, 2795.
(20) (a) Qi, Z.; Yu, S.; Li, X. Org. Lett. 2016, 18, 700. (b) Li, Y.; Qi,
Z.; Wang, H.; Yang, X.; Li, X. Angew. Chem. 2016, 128, 12056.
(21) (a) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040.
(b) Kim, H.; Shin, K.; Chang, S. J. Am. Chem. Soc. 2014, 136, 5904.
(c) Ryu, J.; Kwak, J.; Shin, K.; Lee, D.; Chang, S. J. Am. Chem. Soc.
2013, 135, 12861.
AUTHOR INFORMATION
■
Corresponding Author
*cuixl@hqu.edu.cn
ORCID
Xiuling Cui: 0000-0001-5759-766X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (21572072 and 21602064), Xiamen
Southern Oceanographic Center (15PYY052SF01), and the
Science and Technology Bureau of Xiamen City
(3502Z20150054).
REFERENCES
■
(1) (a) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284.
(b) Candeias, N. R.; Branco, L. C.; Gois, P. M. P.; Afonso, C. A. M.;
Trindade, A. F. Chem. Rev. 2009, 109, 2703.
(2) Related reviews: (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36,
2382. (b) Goldberg, I. Ber. Dtsch. Chem. Ges. 1906, 39, 1691.
(c) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(3) Related reviews: (a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534.
(b) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
(c) Bariwal, J.; Van der Eycken, E. Chem. Soc. Rev. 2013, 42, 9283.
(4) Examples of direct C−N coupling reactions: (a) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (b) Wencel
Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40,
4740. (c) Xie, F.; Qi, Z. S.; Li, X. W. Angew. Chem., Int. Ed. 2013, 52,
11862. (d) Huang, X.; Bergsten, T. M.; Groves, J. T. J. Am. Chem. Soc.
2015, 137, 5300. (e) Tang, C.; Jiao, N. J. Am. Chem. Soc. 2012, 134,
18924.
(5) Examples of C−N bond formation with preactivated amino
sources: (a) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc.
2010, 132, 12862. (b) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J.
Am. Chem. Soc. 2010, 132, 6900. (c) Yoo, E. J.; Ma, S.; Mei, T.-S.;
Chan, K. S. L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7652. (d) Sun,
K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133,
1694.
(6) Related reviews: (a) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017,
117, 9247. (b) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48,
1040.
(7) Kim, J.; Kim, J.; Chang, S. Chem. - Eur. J. 2013, 19, 7328.
(8) Kang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. J. Am. Chem. Soc.
2014, 136, 4141.
(9) Lee, D.; Kim, Y.; Chang, S. J. Org. Chem. 2013, 78, 11102.
(10) (a) Zheng, Q.; Liang, Y.; Qin, C.; Jiao, N. Chem. Commun. 2013,
49, 5654. (b) Shin, K.; Chang, S. J. Org. Chem. 2014, 79, 12197.
(11) (a) Lee, D.; Chang, S. Chem. - Eur. J. 2015, 21, 5364. (b) Wei,
M.; Wang, L.; Li, Y.; Cui, X. Chin. Chem. Lett. 2015, 26, 1336.
(12) (a) Li, Y.; Feng, Y.; Xu, L.; Wang, L.; Cui, X. Org. Lett. 2016, 18,
4924. (b) Mu, D.; Wang, X.; Chen, G.; He, G. J. Org. Chem. 2017, 82,
D
DOI: 10.1021/acs.orglett.7b02028
Org. Lett. XXXX, XXX, XXX−XXX