Syntheses of [1,2,4]triazolo[1,5-: A] benzazoles enabled by the transition-metal-free oxidative N-N bond formation

Article abstract of DOI:10.1039/c6cc01976e

A transition-metal-free oxidative N-N bond formation strategy was developed to generate various structurally interesting [1,2,4]triazolo[1,5-a]benzazoles efficiently. The mechanism of the key oxidative N-N bond formation was investigated by using an intramolecular competition reaction. Notably, the first single crystal structure was also obtained to confirm the structure of 2-aryl[1,2,4]triazolo[1,5-a]benzimidazole.

Full text of DOI:10.1039/c6cc01976e

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DOI: 10.1039/C6CC01976E
A transition-metal-free NCS oxidized N-N bond formation strategy was developed to
generate various structurally interesting [1,2,4]triazolo[1,5-a]benzazoles efficiently.
the first single crystal structure was also obtained to confirm the structure of
2-aryl[1,2,4]triazolo[1,5-a]benzimidazole.

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DOI: 10.1039/C6CC01976E
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Syntheses of [1,2,4]triazolo[1,5-a]benzazoles Enabled by the Tran-
sition-Metal-Free Oxidative N-N Bond Formation
Erchang Shang,ab Junzhi Zhang,a Jinyi Bai,a Zhan Wang,a Xiang Li,c Bing Zhu,c and Xiaoguang Lei*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A transition-metal-free NCS oxidative N-N bond formation strategy heterocycles in chemical biology and drug discovery. Therefore,
was developed to generate various structurally interesting an efficient way to synthesize the title compounds is urgently
[1,2,4]triazolo[1,5-a]benzazoles efficiently. The mechanism of the needed.
key oxidative N-N bond formation was investigated by using an
intramolecular competition reaction. Notably, the first single
crystal structure was also obtained to confirm the structure of 2-
aryl[1,2,4]triazolo[1,5-a]benzimidazole.
The nitrogen-nitrogen (N-N) bond is widely appeared in natural
products and biological active nitrogen-rich heterocycles
(Figure 1).1 For example, penipanoid A, isolated from the marine
sediment-derived fungus Penicillium paneum SD-44, shows
significant cytotoxic activity against the SMMC-7721 cell line.2
Many N-N bond containing drugs, such as anti-inflammatory
drug Celebrex and antihyperglycemic Januvia are among the top
selling medicines.3 Therefore, study of structurally novel and
Figure 1 Examples of N-N bond containing biological active
heterocycles.
biologically active N-N bond containing heterocycles has drawn
significant attention from both academia and pharmaceutical
industry. [1,2,4]Triazolo[1,5-a]benzimidazole is an interesting
type of N-N bond containing heterocycle which shows
promising biological activities, such as antifungal, anti-
inflammatory and analgesic,4 as well as anti-histamine effects.5
Although three methods have been reported for the synthesis
of this type of structure, they all suffered either long synthetic
routes or harsh reaction conditions and only a hand of
substrates were prepared (Scheme 1).6 The lack of efficient
synthetic methodology hindered the application of this type of
In general, hydrazine has been widely used as a synthon to
introduce N-N bond in heterocyclic molecules.7 However, this
method has a lot of limitations including synthetic efficiency and
substrate scope. Direct N-N bond forming reactions are
therefore highly desired, especially in the late stage synthesis of
complex and functionalized molecules. However, this
transformation proves to be challenging and only a handful of
methods have been reported in the literature.8~10 Herein, we
report a mild and efficient N-chlorosuccinimide (NCS) oxidative
N-N bond formation strategy and its broad application in the
preparation of various [1,2,4]triazolo[1,5-a]benzimidazoles as
well as benzothiazole and benzoxazole analogues with excellent
yields and substrate scope. [1,2,4]Triazolo[1,5-a]benzothiazole
and [1,2,4]triazolo[1,5-a]benzoxazole are also interesting
heterocycles and their syntheses were rarely reported.11
Moreover, we also reveal the reaction mechanism for the key
oxidative N-N bond formation and unambiguously determine
the structure of the nitrogen-rich polyheterocyclic 2-
a.Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department of
Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and
Functional Biomolecules Center, and Peking-Tsinghua Center for Life Sciences,
Peking University, Beijing 100871, China. E-mail: xglei@pku.edu.cn
b.National Institute of Biological Sciences (NIBS), Beijing 102206, China.
c. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese
Academy of Sciences, Beijing 100101, China.
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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aryl[1,2,4]triazolo[1,5-a]benzimidazole
crystallographic analysis.
through
X-ray Table 1 Optimization of the reaction conditionsa
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DOI: 10.1039/C6CC01976E
entry oxidant
base
solvent temp (oC) Yield (%)b
1
2
PIDA
-
-
MeOH
MeOH
rt
rt
19
32
o-OMePIDA
3
4
5
6
7
8d
9
I2
n-BuLi THF
-78~rt
NR
FeCl3
CuCl2
NBS
NCS
NCS
NCS
n-BuLi THF/DMF -78~rt
NR
n-BuLi THF
KOtBu THF
KOtBu THF
-78~rt
-78
decomposed
66
-78
100 (99)c
KOtBu
THF
-78
52
16
NaOtBu THF
-78
Scheme 1 Strategies for the syntheses of [1,2,4]triazolo[1,5-
a]benzimidazoles.
aGeneral condition: 2a (0.1 mmol), oxidant (0.12 mmol), base
b
1
(0.4 mmol), solvent (2 mL). Determined by H NMR analysis
using 1,3,5-trimethoxybenzene as an internal standard.
cIsolated yield. d0.3 mmol KOtBu was used in this case. NR = no
reaction.
The
synthesis
of
title
compound
2-phenyl-4H-
from N-(1H-
[1,2,4]triazolo[1,5-a]benzimidazole
1a
benzo[d]imidazole-2-yl)benzimidamide 2a was used for the
condition screening (Table1). Starting materials were smoothly
prepared through the addition of 2-aminobenzimidazole to
benzonitrile using tin (IV) tetrachloride as a Lewis acid (see
Supporting Information for details). We started the
investigation of N-N bond formation by screening the known
inorganic oxidants widely used in organic synthesis, such as
sodium periodate, potassium hexacyanoferrate(III), ammonium
ceric nitrate, manganese dioxide, and lead(IV) acetate.
Unfortunately, all of these oxidants failed to form the desired
N-N bond in an efficient manner. The organic oxidant,
(diacetoxyiodo)benzene (PIDA) afforded the desired product in
only 19% NMR yield (Table1, entry 1). However, further
optimization based on PIDA, such as the change of solvents and
the structural modification of PIDA by adding electron donor
group on ortho or para position of PIDA,12 had not led to the
significantly improved yields (Table 1, entries 1~2) (see
Supporting Information for a full list of the conditions screening).
Then, we shifted attention to the oxidative coupling conditions
that have been widely used in the C-C/N bond formation.13
Initially, the treatment of substrate 2a with iodine, ferric
trichloride, or copper (II) chloride using n-butyllithium as a base
failed to generate the cyclization product (Table 1, entries 3~5).
To our delight, when N-bromosuccinimide (NBS) was used as an
oxidant and potassium tert-butoxide as a base we observed a
promising result (Table 1, entry 6). Further optimization by
changing NBS to N-chlorosuccinimide (NCS) led to the excellent
yield (Table 1, entry 7). We also examined the condition with
less equivalent of base (Table 1, entry 8), sodium tert-butoxide
(Table 1, entry 9), and found 4 equiv. of potassium tert-butoxide
could provide the optimal result.
With the optimal condition in hand, we further investigated
the substrate scope and generality of this efficient N-N bond
formation. As shown in Table 2, the scope of this cyclization with
respect to different substituents at 2-position and the left
benzene ring of 1,2,4-triazolo [1,5-a] benzimidazole were
initially explored. Firstly, the substrates with various substituted
phenyl groups at 2-position were subjected to the optimal
reaction condition. We found that all of these tested substrates
led to good or excellent yields (Table 2, 1a-1i). Both electron-
donating groups, such as dimethylamino (Table 2, 1b), as well
as electron-withdrawing groups, such as chloro (Table 2, 1d and
1i) and nitro (Table 2, 1e), at the para-position or meta-position
provided the cyclization products in excellent yields. Comparing
to the excellent yields achieved on the substrates with meta-
and para- substitutions, substrates with ortho-substituted
phenyls led to a slightly lower yields (Table 2, 1f and 1g),
presumably due to the steric effect of ortho-substitution. And
we also found that both electron-donating and withdrawing
group at ortho-substitution showed similar yields. Therefore,
electronic effect played limited influence for this
transformation. Secondly, we further evaluated the heterocycle
containing substrates. Without exception, all of these tested
substrates showed high yields (Table 2, 1j-1m). Thirdly, aliphatic
substituents were also tested and the moderate to excellent
yields were obtained (Table 2, 1n-1p). 2-Benzyl substrates
(Table 2, 1o and 1p) showed moderate yield because of the
undesired chlorination on the benzylic position. Finally, the
scope of the substituent at the left benzene ring was also
explored. As shown in Table 2, 6,7-dimethyl-2-phenyl-4H-
2 | J. Name., 2012, 00, 1-3
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[1,2,4]-triazolo[1,5-a]benzimidazole 1q was obtained with shown in Table 3, most substrates provided moderate to good
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excellent yield under the optimized condition.
yields. And we also found that the subDstOraI:t1e0s.10w3i9t/hC6eClCec0t1r9o76nE-
donating groups at the left side benzene ring provided higher
yields (Table 3, 4b and 4c) than the substrates with electron-
withdrawing groups at the same position (Table 3, 4d-4g).
Table 2 The substrate scopea b
Table 3 The generality of the reactiona
aGeneral condition:
3
(0.1 mmol), KtOBu (0.3 mmol), NCS (0.15
mmol), THF (4 mL), -78 oC to 60 oC.
In order to gain insight into the reaction mechanism of the
interesting oxidative N-N bond formation and cyclization, we
designed the substrate
5 to investigate the intramolecular
competition reaction under the optimized condition (Scheme 2).
As expected, two different products with exactly the same
molecular weight were formed (Scheme 2,
the instabilities of compound and , the free NH and OH were
protected with tert-butyloxycarbonyl (Boc) and the resulting
compounds and 10 were isolated and characterized
successfully (Scheme 2). These results confirmed the formation
of chloride intermediate . Therefore, we proposed the
mechanism as shown in Scheme 2: under the basic condition,
the nitrogen atom of imine was chlorinated by NCS to
generate the chloride intermediate , which was then attacked
by another nitrogen atom (path a) or the hydroxyl group (path
b) under basic condition to obtain benzimidazole and
benzoisoxazole respectively.
7 and 8). Considering
aGeneral condition:
2
(0.1 mmol), KtOBu (0.4 mmol), NCS (0.12
7
8
mmol), THF (4 mL), -78 oC. bIsolated yield.
9
The generality of the reaction to generate benzothiazole and
benzoxazole were then evaluated (Table 3). However, 2-
phenyl[1,2,4]triazolo[1,5-a]benzothiazoles
phenyl[1,2,4]triazolo[1,5-a]benzoxazoles did not provide the
cyclization products under the previously developed reaction
condition. We observed chlorinated intermediate which could
be further cyclized when the system was heated to 60 oC.
Therefore, we applied this modified condition to conduct the
cyclization of benzothiazole and benzoxazole analogues. As
6
and
2-
5
6
7
8
Scheme 2 Proposed mechanism of the NCS mediated N-N bond formation
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2
3
C. S. Li, C. Y. An, X. M. Li, S. S. Gao, C. M. Cui, H. F. Sun, B. G.
Finally, we sought to elucidate the structure of
[1,2,4]triazolo[1,5-a]benzimidazole. In principle, there are three
different possible tautomers for [1,2,4]triazolo[1,5-
a]benzimidazole (Figure 2). Kuz’menko and co-workers studied
the tautomerism of the title compounds, and found that the 4H-
tautomer is the overwhelmingly major existence based on
spectroscopies studies and quantum-mechanical calculations.14
However, no crystal structures were obtained yet for this kind
of nitrogen-rich polyheterocycles.15 Fortunately, after many
View Article Online
Wang, J. Nat. Prod. 2011, 74, 1331.
DOI: 10.1039/C6CC01976E
PMLiVE, Top 50 pharmaceutical products by global sales,
http://www.pmlive.com/top_pharma_list/Top_50_pharmac
eutical_products_by_global_sales.
B. G. Mohamed, A. M. Abdel-alim, M. A. Hussein, Acta
Pharm. 2006, 56, 31.
A. A. Spasov, M. V. Chernikov, V. A. Anisimova, T. A.
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(a) I. H. Richard, R. D. Allan, J. Org. Chem. 1973, 38, 3084; (b)
P. J. Rao, K. K. Reddy, Syn. Comm. 1988, 18, 1995; (c) B. S.
Reddy, T. Sambaiah, K. K. Reddy, Indian J. Chem. Section B:
Org. Chem. Including Med. Chem. 1992, 31, 191.
For a review of N-N bond containing heterocycles syntheses
employing a hydrazine derivative, see: S. Tšupova, U.
Mäeorg, Heterocycles, 2014, 88, 129.
4
5
6
attempts, we obtained the single crystal structures of 1f and 1q
.
As shown in Figure 2, comparing the four key C-N bonds in the
structure 1q, the bond lengths of N1-C2 (1.336 Å) and N3-C3a
(1.326 Å) correspond to a C=N double bond. The X-ray structure
of 1f shows similar data as 1q (See Supporting Information).
Accordingly we were able to make a conclusion for the first time
that 2-aryl[1,2,4]triazolo[1,5-a]benzimidazoles exist mostly in
the 4H tautomeric form in crystalline state, which is consistent
with the result from Kuz’menko’s solution state study.
7
8
For recent examples on transition-metal mediated N-N bond
formation, see: (a) S. Ueda, H. Nagasawa, J. Am. Chem. Soc.
2009, 131, 15080; (b) B. J. Stokes, C. V. Vogel, L. K. Urnezis,
M. Pan, T. G. Driver, Org. Lett. 2010, 12, 2884; (c) J. J.
Neumann, M. Suri, F. Glorius, Angew. Chem. Int. Ed, 2010
,
49, 7790; (d) J. Hu, Y. Cheng, Y. Yang, Y. Rao, Chem. Commun.
2011, 47, 10133; (e) D. Yu, M. Suri, F. Glorius, J. Am. Chem.
Soc. 2013, 135, 8802; (f) Z. Chen, Q. Yan, Z. Liu, Y. Xu, Y.
Zhang, Angew. Chem. Int. Ed. 2013, 52, 13324; (g) X. Meng,
C. Yu, P. Zhao, RSC Adv. 2014, 4, 8612; (h) S. H. Kwark, K.
Kim, H. Yoo, Y. Gong, Synthesis, 2015, 47, 3874.
9
For examples on transition-metal free N-N bond formation,
see: (a) V. J. Grenda, R. E. Jones, G. Gal, M. Sletzinger, J. Org.
Chem. 1965, 30, 259; (b) K. T. POTTS, H. R. Burton, J.
Bhattacharyya, J. Org. Chem. 1966, 31, 260; (c) A. Correa, I.
Tellitu, E. Dominguez, R. SanMartin, J. Org. Chem. 2006, 71,
3501; (d) Y. Takeda, S. Okumura, S. Minakata, Angew. Chem.
Int. Ed. 2012, 51, 7804; (e) L. E. Evans, M. D. Cheeseman, K.
Jones, Org. Lett. 2012, 14, 3546; (f) Z. J. Cai, X. M. Lu, Y. Zi, C.
Yang, L. J. Shen, J. Li, S. Y. Wang, S. J. Ji, Org. Lett. 2014, 16,
5108; (g) Z. Chen, Q. Yan, Z. Liu, Y. Zhang, Chem. Eur. J. 2014
,
Figure
aryl[1,2,4]triazolo[1,5-a]benzimidazoles and the crystal
structure of 1q
2
Three possible tautomeric forms of 2-
20, 17635; (h) Z. Zheng, S. Ma, L. Tang, D. Zhang-Negrerie, Y.
Du, K. Zhao, J. Org. Chem. 2014, 79, 4687; (i) L. Song, X. Tian,
.
Z. Lv, E. Li, J. Wu, Y. Liu, W. Yu, J. Chang, J. Org. Chem. 2015
80, 7219.
,
In summary, a transition-metal-free NCS mediated oxidative N-
N bond formation has been developed for the efficient
10 For an elegant natural product total synthesis via
electrochemical oxidative N-N bond formation, see: Rosen,
B. R. Rosen, E. W. Werner, A. G. O'Brien, P. S. Baran, J. Am.
Chem. Soc. 2014, 136, 5571.
11 (a) T. Sambaiah, K. K. Reddy, Synthesis, 1990, 422; (b) H.
Wang, L. Chen, OPPI New J. Org. Syn. 1996, 28, 362.
syntheses
of
various
2-phenyl-4H-[1,2,4]triazolo[1,5-
a]benzazoles and analogues. The reaction proves to be highly
functional group tolerant and proceeds under mild conditions,
affording the corresponding products in good to excellent yields
and with broad substrate scope. The reaction mechanism as
well as the exact structure of 2-aryl[1,2,4]triazolo[1,5-
a]benzimidazole have also been elucidated. Further biological
evaluations of these interesting heterocycles are currently
under investigation and will be reported in due course.
12 P. Kazmierczak, L. Skulski, L. Kraszkiewicz, Molecules 2001, 6,
881.
13 For selected examples, see: (a) P. S. Baran, J. M. Richer, J.
Am. Chem. Soc. 2004, 126, 7450; (b) C. L.Martin, L. E.
Overman, J. M. Rohde, J. Am. Chem. Soc. 2008, 130, 7568; (c)
S. P. West, A. Bisai, A. D. Lim, R. R. Narayan, R. Sarpong, J.
Am. Chem. Soc. 2009, 131, 11187; (d) Z. Zuo, W. Xie, D. Ma, J.
Am. Chem. Soc. 2010, 132, 13226.
14 V. V. Kuz'menko, T. A. Kuz'menko, A. F. Pozharskii, V. N.
Doron'kin, N. L. Chikina, S. S. Pozharskaya, Chem. Heterocycl.
Compd. 1989, 168.
15 A. S. Morkovnik, T. A. Kuz’menko, L. N. Divaeva, G. S.
Borodkin, Russ. J. Org. Chem. 2013, 49, 895.
We thank Mr. Jing Zhang for research assistance, and Prof.
Wenxiong Zhang and Prof. Nengdong Wang for X-ray analysis.
Financial support from the National High Technology Project
973 (2015CB856200) and NNSFC (21472010 and 21561142002)
is gratefully acknowledged.
Notes and references
1
L. M. Blair, J. Sperry, J. Nat. Prod. 2013, 76, 794.
4 | J. Name., 2012, 00, 1-3
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