Oxidative Synthesis of Benzimidazoles, Quinoxalines, and Benzoxazoles from Primary Amines by ortho-Quinone Catalysis

Article abstract of DOI:10.1021/acs.orglett.7b02786

The bioinspired ortho-quinone catalysts have been applied to heterocycles synthesis. Without any metal cocatalysts, a sole ortho-quinone catalyst enables the oxidative synthesis of benzimidazoles, quinoxalines and benzoxazoles from primary amines in high yields under mild conditions with oxygen as the terminal oxidant.

Full text of DOI:10.1021/acs.orglett.7b02786

Letter
pubs.acs.org/OrgLett
Oxidative Synthesis of Benzimidazoles, Quinoxalines, and
Benzoxazoles from Primary Amines by ortho‑Quinone Catalysis
†,‡
†,‡
†,‡
,†,‡
Ruipu Zhang, Yan Qin, Long Zhang, and Sanzhong Luo*
†Key Laboratory for Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190,
China
‡
University of Chinese Academy of Sciences, Beijing 100049, China
*
S Supporting Information
ABSTRACT: The bioinspired ortho-quinone catalysts have been applied to heterocycles synthesis. Without any metal
cocatalysts, a sole ortho-quinone catalyst enables the oxidative synthesis of benzimidazoles, quinoxalines and benzoxazoles from
primary amines in high yields under mild conditions with oxygen as the terminal oxidant.
n vivo, the metabolism process from amines to aldehydes
requires the involvement of amine oxidases. Quinoproteins
secondary amines with quinone catalysts such as the TPQ
analogue, 4-tert-butyl-2-hydroxybenzoquinone (TBHBQ), or
1,10-phenanthroline-5,6-dione (PHD), respectively. Spectro-
scopic identification and characterization of the hemiaminal
intermediate supported the addition−elimination pathway in
1
I
are an important class of amine oxidases that contain quinones
2
as cofactors. Since Klinman’s pioneering disclosure of quinone
3
cofactors in 1990, biomimic copper amine oxidase has drawn
9
,10
the attention of organic chemists. Recently, several groups have
been developing quinone-based catalysts for the aerobic
the PHD-mediated reaction.
We have recently developed a
11
simple ortho-quinone catalyst that is able to promote the
aerobic oxidation of α-branched primary benzylic amines and
cyclic secondary amines without any metal cocatalyst.
Mechanism studies demonstrated that the transamination
pathway, plausible only for linear primary amines in nature,
would also work for the oxidation of α-branched primary
amines with this biomimic catalyst. Although different kinds of
amine oxidation with quinone-based catalysts have been
realized, the harness of in situ generated imine intermediates
for cascade transformation remains largely unexplored.
Recently, Largeron and co-workers employed the in situ
generated imine intermediates to react with N-alkyl-o-amino-
anilines in the presence of copper co-catalyst, affording 1,2-
4
oxidation of primary and secondary amines (Scheme 1). For
example, Largeron et al. developed a class of o-iminoquinone
catalysts to promote the dehydrogenative coupling of linear
5
,6
7
primary amines. Kobayashi used a cooperative catalytic
system of 4-tert-butylcatechol and Pt/Ir nanocluster to oxidize
secondary amines in moderate to good yields. Stahl and co-
8
workers reported the aerobic oxidation of primary amines and
Scheme 1. Biomimetic Quinone-Based Catalysis
6
,12
disubstituted benzimidazoles.
However, the reaction is
limited to the production of benzimidazoles. On the basis of
our developed ortho-quinone catalysis, we herein present an
organocatalytic synthesis of heterocycles under aerobic
conditions. The current protocol provides convenient accesses
to benzimidazoles, quinoxalines, and benzoxazoles from
13
primary amines without any metal cocatalysts, significantly
expanding the domain of quinone catalysis.
Received: September 6, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
,
b
From the outset of this work, we chose the oxidative
coupling of benzylamine and o-aminoaniline as the model
substrates to synthesize benzimidazole. 4-Methoxy-5-tert-butyl-
o-quinone (o-Q1) was first examined as a catalyst in acetonitrile
at 40 °C. The reaction afforded only a trace amount of the
desired benzimidazole after 24 h (Table 1, entry 2), and homo/
Scheme 2. Substrate Scopes for Benzimidazoles Synthesis
a
Table 1. Optimization of Benzimidazole Synthesis
b
entry
deviation from above
yield (%)
1
2
3
4
5
6
7
8
9
none
93
no TsOH at 40 °C
40 °C instead of 60 °C
o-Q2 instead of o-Q1
o-Q3 instead of o-Q1
o-Q4 instead of o-Q1
o-Q5 instead of o-Q1
no O2
trace
87
90
a
General conditions: 1 (0.22 mmol), 2 (0.20 mmol), o-Q1 (10 mol
), TsOH (10 mol %) and CH CN (1.0 mL) with O balloon at 60
84
%
3
2
89
b
c
d
°
C for 24 h. Isolated yield. 36 h. Gram scale: 1 (5 mmol), 2 (5
62
5
mmol), o-Q1 (10 mol %), TsOH (10 mol %), and CH CN (3.0 mL)
with O balloon at 60 °C for 30 h.
3
2
no o-Q1
no reaction
14
10
no TsOH
33
products. Optimizations in terms of solvents and reaction
time did not lead to any improvement on the yield of
quinoxaline. Delightfully, increasing the loading of acid additive
to 20 mol % led to a quantitative conversion to the quinoxaline
a
b
General conditions: 1 (0.20 mmol), 2 (0.20 mmol). Isolated yield.
heteroimines were the major products. Significant improve-
ments were achieved by adding Brønsted acid cocatalyst,
presumably to activate the in situ generated imine for
subsequent transformation (Table 1, entries 3 and 10). Other
ortho-quinone catalysts have also been examined, showing
inferior activities (Table 1, entries 4−7). Conducting the
reaction at slight higher temperature (60 °C) further increased
the yield up to 93% (Table 1, entry 1 vs 3).
(
96% yield, Scheme 3). In the absence of o-Q1, no desired
product was detected, highlighting the critical role of quinone
catalysis in this case.
a
Scheme 3. Quinoxaline Synthesis
Under the optimized conditions, the scope of this catalytic
system was examined with a range of benzylamines and o-
aminoanilines (Scheme 2). Alkyl groups and halogen groups at
the para position of benzylamines worked well and afforded the
products in moderate to good yields regardless of the electronic
character of the substituents (3a−i). m-Tolylmethanamine (3j)
showed better reactivity than o-tolylmethanamine (3k).
Heterocyclic amines such as furfurylamine and 2-thiophene-
methylamine could also give the corresponding benzimidazoles
a
General conditions: 1 (0.22 mmol), 4 (0.20 mmol). Yield determined
1
by H NMR using 1,3,5-trimethoxybenzene as internal standard.
(
3m,n) in moderate yields. Substituted at phenyl ring of o-
aminoanilines (3o−r) did not have significant effects on the
yields. N-substituted o-aminoanilines (3t−w) that were more
reactive than o-aminoanilines exhibited better results. Non-
activated aliphatic amines such as cyclopropylmethanamine
The scope of quinoxaline synthesis was next investigated
(Scheme 4). 2-Phenethylamines bearing an electron-with-
drawing or an electron-donating group were proven to be
suitable substrates, affording products in good yields (5a−h). In
cases where the productivity was low, we isolated a phenazine
side product 5′ resulted from the condensation of o-
aminoanilines and ortho-quinone catalyst. By increasing the
loading of 2-phenethylamine, the formation of 5′ can be largely
inhibited, and the reaction led to a better yield of quinoxaline.
The reactions of monosubstituted o-aminoanilines resulted in a
mixture of two possible regioisomers in good yields (5m−o),
albeit with nearly 1:1 regioselectivities. Most regioisomers could
be readily separated by column chromatography. Unfortu-
nately, the use of aliphatic amines other than 2-phenethylamine
led to complicated reaction mixtures.
(3u) and cyclohexylmethanamine (3v) also worked well to
afford 1,2-disubstituted benzimidazoles. The lower yield might
be caused by the instability of the in situ generated alkylimine
intermediates, which easily isomerized to the enamine
tautomers. A gram-scale reaction also proceeded well with
slightly lower yield.
When 2-phenethylamine was employed as substrate, the
reaction gave an unexpected quinoxaline as the major product
(
62%) along with the expected benzimidazole as a minor
product. Quinoxalines are widely used as building blocks in
medicinal chemistry and constitute the framework of natural
B
DOI: 10.1021/acs.orglett.7b02786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 4. Substrate Scopes for Quinoxaline Synthesis
Table 2. Substrate Scopes for Benzoxazole Synthesis
entry
R6
4-H
R7
product
yield (%)
1
2
3
4
5
6
7
8
9
H
7a
7b
7c
7d
7e
7f
89
78
83
81
87
91
93
81
75
70
70
69
67
4-OMe
4-Me
4-tBu
4-Cl
4-Br
4-CF3
2-Me
2,4-Cl
H
H
H
H
H
H
H
7g
7h
7i
H
H
1
1
0
1
4-Me
5-Me
4-Cl
4-Br
7j
H
7k
7l
a
12
H
General conditions: 1 (0.20 mmol), 4 (0.20 mmol), o-Q1 (10 mol
), TsOH (20 mol %) and CH CN (1.0 mL) with O balloon at 60
1
3
H
7m
%
3
2
a
°
C for 36 h; isolated yield; regioselectivity ratio and regioisomer
General conditions: 2 (0.30 mmol), 6 (0.20 mmol), o-Q1 (20 mol
%), Na HPO (10 mol %), and PhCl (0.2 mL) with an O balloon at
1
13
b
c
determined by H NMR or C NMR. 4 (0.30 mmol). 4 (0.30
mmol), 24 h. 4 (0.30 mmol), o-Q1 (20 mol %), 24 h.
2
4
2
d
100 °C for 36 h; isolated yield.
Benzoxazole is an important class of heterocycles that
function as key skeletons for natural products and pharma-
Scheme 6. Proposed Mechanism for (A) Benzimidazole,
Benzoxazole, and (B) Quinoxaline Formation
1
5
16
ceuticals. Previous methodologies usually require transition-
metal catalysts, harsh conditions, stoichiometric chemical
oxidants, or the assistance of strong acids. Therefore, we
decided to challenge benzoxazole synthesis through the
oxidative coupling of benzylamine and o-aminophenol. As a
starting point, we employed the standard conditions which
were used for quinoxaline synthesis. However, only imines were
isolated after 24 h. Significant improvements were achieved by
increasing the reaction temperature to 100 °C (Scheme 5).
a
Scheme 5. Benzoxazole Synthesis
a
General conditions: 2 (0.30 mmol), 6 (0.20 mmol); isolated yield.
Using base as additive could further improve the reaction
outcome. High reaction concentration also led to a better
result. The reactions with substituted benzylamines worked
well (Table 2). Benzylamines bearing either an electron-rich
(7a−d) or an electron poor (7e−g and 7i) substituent could be
generally tolerated to produce the benzoxazoles in good yields.
Alkyl (7j and 7k) and halogen group (7l and 7m) substituted o-
aminophenols have also been examined, giving the desired
benoxazoles in good yields.
would facilitate the cyclization step via iminium ion activation.
On the other hand, the presence of base in the cases with
aminophenols would facilitate the cyclization via phenoxide
anion generation. As for the unexpected quinoxaline, the
product is formed through the tautomerization of imine 10 to
enamine 11, which upon further oxidation, cyclization (Int),
and aromatization leads to quinoxaline (Scheme 6B).
In summary, a simple ortho-quinone catalyst was shown to
effectively promote oxidative synthesis of heterocycles such as
benzimidazoles, benzoxazoles, and quinoxalines from primary
A transamination mechanism can be proposed on the basis of
the known quinone mediated primary amine oxidation
6
process. The formation of cross-coupling imine (8) via a
transamination pathway is the initial step. Then, the o-amino
group or free hydroxyl group would add to the imine, affording
the saturated cyclic intermediate (9), which is further oxidized
to unsaturated heterocycles in the presence of oxygen and
quinone catalyst (Scheme 6A). The use of acid co-catalyst
C
DOI: 10.1021/acs.orglett.7b02786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
amines. The current protocol provides a convenient approach
to access these medicinally interesting heterocycles under
metal-free and mild reaction conditions.
(9) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136, 506.
(
10) Wendlandt, A. E.; Stahl, S. S. J. Am. Chem. Soc. 2014, 136,
1910.
11) Qin, Y.; Zhang, L.; Lv, J.; Luo, S.; Cheng, J.-P. Org. Lett. 2015,
7, 1469.
12) For heterocycles with o-quinone as intermediates, see: Esguerra,
1
(
1
ASSOCIATED CONTENT
Supporting Information
■
(
*
S
K. V. N.; Xu, W.; Lumb, J.-P. Chem. 2017, 2, 533.
(13) For another example of benzimidazoles synthesis without metal
co-catalyst, see: Largeron, M.; Fleury, M.-B. Chem. - Eur. J. 2017, 23,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02786.
6
(
763.
14) For selected examples, see: (a) Seitz, L. E.; Suling, W. J.;
Experimental procedures, detailed characterization data
Reynolds, R. C. J. Med. Chem. 2002, 45, 5604. (b) Kim, Y. B.; Kim, Y.
H.; Park, J. Y.; Kim, S. K. Bioorg. Med. Chem. Lett. 2004, 14, 541.
(c) Yang, Y.; Ni, F.; Shu, W.-M.; Wu, A.-X. Chem. - Eur. J. 2014, 20,
1
13
of substrates, catalysts and products, and H and
C
NMR spectra (PDF)
1
(
1776.
̈
15) For selected examples, see: (a) Endo, Y.; Backvall, J.-E. Chem. -
AUTHOR INFORMATION
Corresponding Author
■
Eur. J. 2012, 18, 13609. (b) Viirre, R. D.; Evindar, G.; Batey, R. A. J.
Org. Chem. 2008, 73, 3452. (c) Shih, Y.; Ke, C.; Pan, C.; Huang, Y.
RSC Adv. 2013, 3, 7330.
*
E-mail: luosz@iccas.ac.cn.
(
16) For a recent review about benzoxazole synthesis, see:
ORCID
Rajasekhar, S.; Maiti, B.; Chanda, K. Synlett 2017, 28, 521.
Sanzhong Luo: 0000-0001-8714-4047
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (21390400
and 21521002) and the Chinese Academy of Sciences for
financial support (QYZDJ-SSW-SLH023). S.L. is supported by
the National Program of Top-notch Young Professionals.
REFERENCES
■
(
1) Boobis, A.; Watelet, J. B.; Whomsley, R.; Benedetti, M. S.;
Demoly, P.; Tipton, K. Drug Metab. Rev. 2009, 41, 486.
(
2) For selected reviews about quinoproteins, see: (a) Mure, M. Acc.
Chem. Res. 2004, 37, 131. (b) Klinman, J. P.; Bonnot, F. Chem. Rev.
2
2
014, 114, 4343. (c) Mure, M.; Mills, S. A.; Klinman, J. P. Biochemistry
002, 41, 9269. (d) Rinaldi, A. C.; Rescigno, A.; Rinaldi, A.; Sanjust, E.
Bioorg. Chem. 1999, 27, 253.
(
3) For related reports and mechanism studies, see: (a) Janes, S. M.;
Mu, D.; Wemmer, D.; Smith, A. J.; Kaur, S.; Maltby, D.; Burlingame,
A. L.; Klinman, J. P. Science 1990, 248, 981. (b) Janes, S. M.; Palcic, M.
M.; Scaman, C. H.; Smith, A. J.; Brown, D. E.; Dooley, D. M.; Mure,
M.; Klinman, J. P. Biochemistry 1992, 31, 12147. (c) Hartmann, C.;
Brzovic, P.; Klinman, J. P. Biochemistry 1993, 32, 2234. (d) Mure, M.;
Klinman, J. P. J. Am. Chem. Soc. 1993, 115, 7117. (e) Mure, M.;
Klinman, J. P. J. Am. Chem. Soc. 1995, 117, 8698. (f) Mure, M.;
Klinman, J. P. J. Am. Chem. Soc. 1995, 117, 8707. (g) Plastino, J.;
Green, E. L.; Sanders-Loehr, J.; Klinman, J. P. Biochemistry 1999, 38,
8204. (h) Schwartz, B.; Olgin, A. K.; Klinman, J. P. Biochemistry 2001,
40, 2954. (i) Mure, M.; Wang, S. X.; Klinman, J. P. J. Am. Chem. Soc.
2003, 125, 6113.
(
4) For reviews, see: (a) Wendlandt, A. E.; Stahl, S. S. Angew. Chem.,
Int. Ed. 2015, 54, 14638. (b) Largeron, M. Eur. J. Org. Chem. 2013,
013, 5225. (c) Largeron, M. Org. Biomol. Chem. 2017, 15, 4722.
5) For selected examples, see: (a) Largeron, M.; Fleury, M.-B. J. Org.
2
(
Chem. 2000, 65, 8874. (b) Largeron, M.; Neudorffer, A.; Fleury, M.-B.
Angew. Chem., Int. Ed. 2003, 42, 1026. (c) Largeron, M.; Chiaroni, A.;
Fleury, M.-B. Chem. - Eur. J. 2008, 14, 996. (d) Largeron, M.; Fleury,
M.-B. Org. Lett. 2009, 11, 883. (e) Largeron, M.; Fleury, M.-B. Angew.
Chem., Int. Ed. 2012, 51, 5409. (f) Largeron, M.; Fleury, M.-B. Science
2
013, 339, 43.
6) (a) Nguyen, K. M. H.; Largeron, M. Chem. - Eur. J. 2015, 21,
2606. (b) Nguyen, K. M. H.; Largeron, M. Eur. J. Org. Chem. 2016,
016, 1025.
7) Yuan, H.; Yoo, W.-J.; Miyamura, H.; Kobayashi, S. J. Am. Chem.
Soc. 2012, 134, 13970.
8) Wendlandt, A. E.; Stahl, S. S. Org. Lett. 2012, 14, 2850.
(
1
2
(
(
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DOI: 10.1021/acs.orglett.7b02786
Org. Lett. XXXX, XXX, XXX−XXX