Copper-Mediated Diamination of Arylboronic Acids for the Synthesis of 2-Aryl Benzimidazoles Using Trimethylsilyl Azide as the Amino Sources with Aldehydes

Article abstract of DOI:10.1002/adsc.202000385

A direct and versatile copper-mediated three-component reaction of arylboronic acids, trimethylsilyl azide and aldehydes for the synthesis of benzimidazoles is reported. The reaction is well tolerated by a wide range of substituted aromatic aldehydes and aromatic boronic acids to produce the corresponding benzimidazoles in moderate to high yields. Mechanism investigations demonstrated that copper-promoted Chan-Evans-Lam coupling, C?H amination, and oxidative cycloaddition are involved in the tandem processes. (Figure presented.).

Full text of DOI:10.1002/adsc.202000385

Title: Copper-mediated Diamination of Arylboronic Acids for The
Synthesis of 2-Aryl Benzimidazoles Using Trimethylsilyl Azide As
Amino Sources with Aldehydes
Authors: Zeqiang Xie, Fengtao Zhou, and Ke Ding
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000385
Link to VoR: https://doi.org/10.1002/adsc.202000385

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper-Mediated Diamination of Arylboronic Acids for the
Synthesis of 2-Aryl Benzimidazoles Using Trimethylsilyl Azide
as the Amino Sources with Aldehydes
Zeqiang Xie, Fengtao Zhou, Ke Ding*
International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of
Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development,
School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, P. R. of China
E-mail: dingke@jnu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
functionalized organoazides catalyzed by a Lewis
component reaction of arylboronic acids, trimethylsilyl acid.[7] Jiao and Li reported sequential C(sp2)-H
Abstract. A direct and versatile copper-mediated three-
azide and aldehydes for the synthesis of benzimidazoles is
reported. The reaction is well tolerated by a wide range of
substituted aromatic aldehydes and aromatic boronic acids
to produce the corresponding benzimidazoles in moderate
to high yields. Mechanism investigations demonstrated that
azidation/amination using organic or inorganic azides
followed by intramolecular C-N or N-N bond
formation to produce N-heterocycles (Scheme 1, c).[8a,
b] Zhu also described the preparation of tri-substituted
imidazoles and imidazo[1,5-a]pyridines via azidation
of the alpha C(sp3)-H bond of ketones and benzylic
C(sp3)-H amination, respectively.[9]
copper-promoted
Chan-Evans-Lam
coupling,
C-H
amination, and oxidative cycloaddition are involved in the
tandem processes.
Keywords: copper-mediated; three-component;
benzimidazoles; Chan-Evans-Lam coupling; C-H
amination
Organoboronic compounds are a class of useful
building blocks that can be conveniently transformed
into C-C, C-N, C-O and C-S bonds by employing
Suzuki-Miyaura or Chan-Evans-Lam Couplings
(Scheme 1, a),[1,2] and are widely applied to the
synthesis of a variety of bioactive molecules.[3]
Further extensions and modifications were also
conducted to broaden the application of
organoboronic
compounds.[4,5]
For
instance,
difunctionalization of arylboronic compounds has
been reported by installation of directing groups to
facilitate subsequent inter- or intramolecular C-C or
C-N formation with multiple steps.[4] Organoboronic
compounds could also be multifunctionalized by
oxidization to phenols followed by electrophilic
substitution in
regioselectivity control is a major issue.[5] However,
the direct one-pot difunctionalization of
organoboronic compounds is rarely reported.
Scheme 1. Application of arylboronic acids.
a
one-pot procedure, but
Inspired by the C-H amination involving azides, we
envisioned that tandem Chan-Evan-Lam coupling/C-
H amination using trimethylsilyl azide (TMSN3)
could be a new strategy to achieve difunctionalization
of arylboronic acid and produce benzimidazoles
which exist in many natural products and synthetic
Recently, C-H amination/amidation using azides
has been widely utilized as a new approach for the
construction of heterocycles.[6] Driver et al reported
that
N-heterocycles
C-H
were
synthesized
by
of
intramolecular
amination/amidation
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
molecules with broad biological activities (Scheme 1, concentration of the reactants favored the
c).[10-12]
transformation, and a yield of 55% was obtained
The investigation was initiated by reacting p- when less solvent was utilized (0.5 mL, entry 11).
tolylboronic acid 1a with p-tolualdehyde 2a in the Encouragingly, the addition of TMSN3 (3+2 equiv)
presence of TMSN3 under conditions reported and boronic acid (2+1 equiv) in two portions
previously.[9] We were delighted to find that 2-aryl significantly improved the yield to 80% (entry 12).
benzimidazole derivative 3a could be isolated with The transformation yield was improved to 90% when
17% yield (entry 1, Table 1). Control experiments 1.2 equiv of Cu(TFA)2·xH2O was applied (entry 13).
suggested that the copper salt was essential to this
three-component reaction and that PivOH also played
an important role in the transformation (entries 2 and
3).
Table 1. Optimization of Reaction Conditions.a
yield
(%)
17
n.d.
11
<5
entry
Copper (equiv)
Solvent (mL)
1
2
3b
4
5
6
7
8
Cu(TFA)2·xH2O (1.0)
-
Cu(TFA)2·xH2O (1.0)
Cu(OAc)2 (1.0)
DCB (2)
DCB (2)
DCB (2)
DCB (2)
DCB (2)
toluene (2)
DMF (2)
DCE (2)
DCB (2)
DCB (2)
DCB (0.5)
DCB (0.5)
DCB (0.5)
CuCl2 (1.0)
<5
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (0.2)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.0)
Cu(TFA)2·xH2O (1.2)
trace
trace
trace
<5
40
55
Scheme 2. Scope of Aldehydes. Reaction conditions: 1a
(0.4 mmol), 2 (1.0 equiv, 0.2 mmol), Cu(TFA)2xH2O (1.2
equiv), PivOH (1.0 equiv), TMSN3 (3.0 equiv), DCB (0.5
mL), stirred at 110 °C under Ar. After 6 h, a mixture of 1a
(1.0 equiv)+TMSN3 (2.0 equiv) in DCB (0.2 mL) was
further added, and the reaction time was prolonged to 18 h
in total; Isolated yields shown.
9c
10d
11d,
12d,e
80
90
13d,e
a
Reaction conditions: 1a (0.2 mmol), 2a (1.0 equiv, 0.2
mmol), copper salt, PivOH (0.2 mmol), TMSN3 (3.0
After identifying the optimal reaction conditions,
we examined the scope of aldehydes applicable to this
three-component reaction (Scheme 2). Benzaldehydes
bearing electron-donating groups, e.g., 4-Me or 4-
OMe, at the para-position proceeded smoothly with
1a to give the corresponding products in 90% and
68% yields, respectively (3a, 3c). Benzaldehydes
bearing electron-withdrawing groups such as NO2 and
CO2Me at the meta-position also performed well to
afford the corresponding products in good yields (3g,
3h). The above results demonstrated that the
electronic density of the aromatic aldehydes had little
impact on the product formation. Further
investigation showed that meta-methyl and ortho-
methyl substituted benzaldehydes resulted in
decreased yields (3f, 3e), suggesting that the reaction
was sensitive to steric hindrance of the substituents at
the ortho-position of aldehydes. Notably, natural
isovanillin containing hydroxy group and oxidatively
b
equiv), solvent, stirred at 110 °C under Ar for 18 h.
C
d
Withour PivOH. Under O2 atmosphere, 1a (2.0 equiv,
e
0.4 mmol), 2a (0.2 mmol). Addition of TMSN3 (3.0
equiv) at the beginning of the reaction, and additional 1a
(1.0 equiv) + TMSN3 (2.0 equiv) in DCB (0.2 mL) was
added after 6 h. DCB = o-dichlorobenzene, PivOH =
pivalic acid, TFA = trifluoroacetate.
Investigation of the copper species showed that
utilization of other copper salts such as Cu(OAc)2,
and CuCl2, caused significantly decreased yields
(entries 4-5). In addition, DCB (o-dichlorobenzene)
was an optimal solvent compared to all of the organic
solvents investigated, including toluene, DMF, and
DCE (entries 6-8). Notably, when the reaction was
conducted in air or O2 with a catalytic amount of
Cu(TFA)2·xH2O (0.2 equiv), only trace amounts of
desired product 3a were obtained (entry 9). The
results also showed that p-tolylboronic acid 1a could
be consumed easily to cause a low yield of the
product. The yield of 3a could be improved to 40%
when the amount of 1a was double (entry 10).
Additionally, the results further showed that a higher
labile
2,
3-dihydrobenzo[b][1,4]dioxine-6-
carbaldehyde were also tolerated in the reaction (3i,
3j). We further tested other aromatic aldehydes such
as 2-naphthaldehyde (3k) and heterocyclic aromatic
aldehydes such as 5-chlorothiophene-2-carbaldehyde
2
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
(3l) and thiophene-3-carbaldehyde (3m). The results
showed that they were also compatible in the reaction,
leading to the corresponding products with 48-66%
yields. Unfortunately, aliphatic aldehydes failed to
deliver the corresponding products in this reaction.
intermediates in the reaction of p-tolylboronic acid
without benzaldehydes under standard conditions.
Encouragingly, p-toluidine 5 and 2-azidoaniline 6
were isolated although the yields were relatively low
(eq. 1, Scheme 4). Additionally, intermediate 5 could
be transformed to the final product with p-
tolualdehyde in 38% yield, which demonstrated a
higher yield than that with p-tolylboronic acid as the
substrate under the same conditions (Table 1, entry 1)
due to avoiding the yield loss caused by the Chan-
Evans-Lam process during the reaction. In addition,
intermediate 6 also delivered the benzimidazoles in
36% yield, suggesting that the aniline and 2-
azidoaniline could be the key intermediates for this
reaction (eq. 2, 3, Scheme 4). An intermolecular
kinetic isotope labeling experiment was further
performed to study the C-H azidation process. When
the mixture of 1c and 1c-d5 was subjected to the
reaction conditions, a 1:1 mixture of 3c and 3c-d4 was
1
obtained in 3 h according to H-NMR detection,
Scheme 3. Scope of Arylboronic Acids. Reaction
conditions: 1a (0.4 mmol), 2 (1.0 equiv, 0.2 mmol),
Cu(TFA)2xH2O (1.2 equiv), PivOH (1.0 equiv), TMSN3
(3.0 equiv), DCB (0.5 mL), stirred at 110 °C under Ar.
Addition the mixture of 1a (1.0 equiv)+TMSN3 (2.0 equiv)
in DCB (0.2 mL) occurred after 6 h, and the reaction
continued for a total of 18 h; Isolated yields are shown.
The reactions of p-tolualdehyde 2a with diverse
substituted arylboronic acids were also investigated
(Scheme 3). Phenylboronic acid bearing para-Me, i-
Pr, Ph, OMe or Cl reacted smoothly with 2a to furnish
the corresponding benzimidazoles in 39-90% yields
(3a, 4a-e). The steric hindrance of substituents at the
ortho-position of the phenylboronic acid slightly
decreased the yields (4f-i). In addition, 3-tolylboronic
acid delivered a mixture of products with a total yield
of 86% (para/ortho ratio = 1.4:1) (4j). Unfortunately,
the phenylboronic acids with an electron-withdrawing
substituted group only furnished trace amounts of
products (4l, 4m), while that an electron-donating
group proceeded well with a 64% yield (4k).
although it showed a low yield due to the absence of
an additional amount of TMSN3 compared to the
standard condition with shorter reaction time, which
also proved that the C-H activation process might not
be the rate-determining step in the reaction (Scheme
5).
Scheme 5. Isotope Labeling Experiment.
Scheme 6. Proposed Mechanism.
As a result, a plausible mechanism was proposed
(Scheme 6). Phenylboronic acid 1c initially
underwent Chan-Evans-Lam coupling reaction with
TMSN3 to give aniline A. Intermediate imine B was
then produced via condensation with aldehyde.
Complex C could be consequently formed by
chelation of the imine nitrogen with Cu(III) derived
from the disproportionated reaction of Cu(II).
Subsequently, the azido anion derived from HOPiv
and TMSN3 replaced the ligand of C to form
intermediate D. A single electron transfer (SET) from
the aryl ring to the metal center D yielded
Scheme 4. Probable Intermediate Verification.
To gain insight into the mechanism of this
diamination process, we tried to detect the probable
3
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
Organic Synthesis Medicine and Materials (Ed., D. G.
Hall, ), Wiley-VCH, New York, 2011.
intermediate E which was followed by the formation
of F via transfer of the azido anion to the aryl ring
with the release of protons through SET process.[8d]
Copper-assisted transformation of azide into amine
gave intermediate G.[13] Finally, oxidative cyclization
by Cu(II) occurred to give the desired product.[14]
In summary, an efficient and novel method for the
synthesis of benzimidazole starting from arylboronic
acid and aldehydes using TMSN3 as an amino source
was developed. Two nitrogen atoms derived from
TMSN3 were formally inserted into the heterocyclic
products by the formation of multiple C-N bonds. In
this process, tandem Chan-Evans-Lam coupling and
C-H amination of boronic acid followed by oxidative
cyclo-condensation with aldehydes was proposed to
be a possible mechanistic pathway.
[4] a) A. Khan, R. Karim, H. Dhimane, S. Alam,
ChemistrySelect, 2019, 4, 6598; (b) Q. Li, S.-Y.
Zhang, G. He, Z. Ai, W. A. Nack, G. Chen, Org. Lett.
2014, 16, 1764; (c) J. Li, S. Benard, L. Neuville, J.
Zhu, Org. Lett. 2012, 14, 5980.
[5] a) G. K. S. Prakash, S. Chacko, C. Panja, T. E.
Thomas, L. Gurung, G. Rasul, T. Mathew, G. A. Olah,
Adv. Synth. Catal. 2009, 351, 1567; b) Q. Zhang, K. R.
Badu, Z. Huang, J. Song, X. Bi, Synthesis, 2018, 50,
2891.
[6] For a review on C-H amination/amidation using
azides see: a) Y. Park, Y. Kim, S. Chang, Chem. Rev.
2017, 117, 9247; b) K. Shin, H. Kim, S. Chang, Acc.
Chem. Res. 2015, 48, 1040. c) J. Peng, M. Chen, Z.
Xie, S. Luo, Q. Zhu, Org. Chem. Front. 2014, 1, 777;
d) J. Peng, Z. Xie, S. Luo, Q. Zhu, Org. Lett. 2014, 16,
4702; e) R. R. Donthiri, V. Pappula, N. N. K. Reddy,
D. Bairagi, S. J. Adimurthy, J. Org. Chem. 2014, 79,
11277; f) Y. M. Badiei, A. Dinescu, X. Dai, R. M.
Palomino, F. W. Heinemann, T. R. Cundari, T.
Warren, Angew. Chem. Int. Ed. 2008, 47, 9961;
Angew. Chem. 2008, 120, 10109.
Experimental Section
General procedure for the synthesis of 2-
arylbenzimidazoles
Arylboronic acid (0.4 mmol) and Cu(TFA)2•xH2O (0.24
mmol) were added to a Schlenk tube. Then, the tube was
vacuumed and refilled with argon for 3 times. A solution of
aldehyde (0.2 mmol), pivalic acid (0.2 mmol), TMSN3 (0.6
mmol), and o-dichlorobenzene (0.5 mL) was added
via a syringe. The reaction mixture was stirred at 110 °C,
followed by the addition of a solution of TMSN3 (0.4
mmol) and arylboronic acid (0.2 mmol) in 0.2 mL of o-
dichlorobenzene via a syringe after 6 h. The reaction was
stirred for another 12 h at this temperature. After cooling,
saturated aqueous NaCl (10 mL), NH4OH (1 mL) and
EtOAc (10 mL) were added to the reaction mixture. The
aqueous phase was further extracted with EtOAc (2 × 10
mL). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography to provide the desired
product.
[7] a) M. Shen, T. G. Driver, Org. Lett. 2008, 10, 3367; b)
T. G. Driver, Org. Biomol. Chem. 2010, 8, 3831; c) B.
J. Stokes, T. G. Driver, Eur. J. Org. Chem. 2011,
4071; d) H. Dong, R. T. Latka, T. G. Driver, Org. Lett.
2011, 13, 2726; e) A. L. Pumphrey, H. Dong, T. G.
Driver, Angew. Chem. Int. Ed. 2012, 51, 5920; Angew.
Chem. 2012, 124, 6022; f) Q. Nguyen, K. Sun, T. G.
Driver, J. Am. Chem. Soc. 2012, 134, 7262; g) Q.
Nguyen, T. Nguyen, T. G. Driver, J. Am. Chem. Soc.
2013, 135, 620.
[8] a) Q. Z. Zheng, P. Feng, Y. F. Liang, N. Jiao, Org.
Lett. 2013, 15, 4262; b) F. Xie, Z. S. Qi, X. W. Li,
Angew. Chem. Int. Ed. 2013, 52, 11862; Angew. Chem.
2013, 125, 12078; c) N. Khatun, A. Modi, W. Ali, B.
K. Patel, J. Org. Chem. 2015, 80, 9662; d) C. Tang, N.
Jiao, J. Am. Chem. Soc. 2012, 134, 18924; e) Y. Peng,
W. Wan, G. Ma, W. Gao, H. Jiang, S. Zhu, J. Hao,
Chem. Commun. 2014, 50, 5733; f) D. Mahesh, P.
Sadhu, T. Punniyamurthy, J. Org. Chem. 2015, 80,
1644; g) D. Mahesh, V. Satheesh, S. V. Kumar, T.
Punniyamurthy, Org. Lett. 2017, 19, 6554.
Acknowledgements
We are grateful for the financial support of the China
Postdoctoral Science Foundation Grant (2018M643360),
National Natural Science Foundation of China (21572230,
81425021, 81673285 and 81820108029) and Guangdong
Province (2015A030312014).
References
[1] N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett.
1979, 20, 3437;
[9] a) Z. Xie, J. Peng, Q. Zhu, Org. Chem. Front. 2016, 3,
82; b) Z. Xie, J. Deng, Z. Qiu, J. Li, Q. Zhu, Chem.
Commun. 2016, 52, 6467.
[2] a) D. M. T. Chan, K. L. Monaco, R.-P. Wang, M. P.
Winter, Tetrahedron Lett. 1998, 39, 2933; b) D. A.
Evans, J. L. Katz, T. R. West, Tetrahedron Lett. 1998,
39, 2937; c) P. Y. S. Lam, C. G. Clark, S. Saubern, J.
Adams, M. P. Winters, D. M. T. Chan, A. Combs,
Tetrahedron Lett. 1998, 39, 2941. d) M. J. West, J. W.
B. Fyfe, J. C. Vantourout, A. J. B. Watson, Chem. Rev.
2019, 119, 12491.
[10] For a review, see: a) D. A. Horton, G. T. Bourne, M. L.
Smythe, Chem. Rev. 2003, 103, 893; For some
selected examples in recent years, see b) R. B. Baudy,
H. Fletcher III, J. P. Yardley, M. M. Zaleska, D. R.
Bramlett, R. P. Tasse, D. M. Kowal, A. H. Katz, J. A.
Moyer, M. Abou-Gharbia, J. Med. Chem. 2001, 44,
1516; c) M. Kataoka, M. Tatsuta, K. Yasoshima, T.
Yura, K. Urbahns, A. Kiba, N. Yamamoto, J. B.
Gupta, K. Hashimoto, Bioorg. Med. Chem. Lett. 2005,
15, 805; d) K. K.-C. Liu, S. M. Sakya, C. J. O.
[3] a) Contemporary Boron Chemistry (Eds., M. G.
Davidson, A. K. Hughes, T. B. Marder, K. Wade),
Royal Society of Chemistry, Cambridge, 2000; b)
Boronic Acids: Preparation and Applications in
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
Donnell, A. C. Flick, J. Li, Bioorg. Med. Chem. 2011,
21, 1136.
[11] a) D. Yang, D. Fokas, J. Li, L. Yu, C. M. Baldino,
Synthesis, 2005, 47; b) W. J. Ebenezer, M. G.
Hutchings, K. Jones, D. A. Lambert, I. Watt,
Tetrahedron Lett. 2007, 48, 1641; c) C. Zhu, Y. Wei,
ChemSusChem. 2011, 4, 9513.
[12] a) B. Zou, Q. Yuan, D. Ma, Angew. Chem. Int. Ed.
2007, 46, 2598; Angew. Chem. 2007, 119, 2652; b) N.
Zheng, K. W. Anderson, X. Huang, H. N. Nguyen, S.
L. Buchwald, Angew. Chem. Int. Ed. 2007, 46, 7509;
Angew. Chem. 2007, 119, 7653; c) G. Brasche, S. L.
Buchwald, Angew. Chem. Int. Ed. 2008, 47, 1932;
Angew. Chem. 2008, 120, 1958; d) Q. Xiao, W.-H.
Wang, G. Liu, F.-K. Meng, J.-H. Chen, Z. Yang, Z.-J.
Shi, Chem. Eur. J. 2009, 15, 7292; e) J. Huang, Y. He,
Y. Wang, Q. Zhu. Chem. Eur. J. 2012, 18, 13964.
[13] T. Ramana, T. Punniyamurthy, Chem. Eur. J. 2012, 18,
13279.
[14] M. M. Guru, M. A. Ali, T. Punniyamurthy, J. Org.
Chem. 2011, 76, 5295.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202000385
Advanced Synthesis & Catalysis
UPDATE
Copper-Mediated Diamination of Arylboronic
Acids for the Synthesis of 2-Aryl Benzimidazoles
Using Trimethylsilyl Azide as the Amino Sources
with Aldehydes
Adv. Synth. Catal. Year, Volume, Page – Page
Zeqiang Xie, Fengtao Zhou, Ke Ding*
6
This article is protected by copyright. All rights reserved.