Microwave-assisted synthesis of fused piperazine-benzimidazoles via a facile, one-pot procedure

Article abstract of DOI:10.1016/j.tetlet.2015.06.035

Two series of compounds containing fused piperazine-benzimidazole scaffolds have been synthesized using an Ugi/deprotection/cyclization strategy (UDC) followed by an intermolecular nucleophilic substitution reaction. This new strategy allows for the facile synthesis of compounds in a one-pot reaction giving fused piperazine-benzimidazoles in good yields. This synthetic strategy can be readily applied to the construction of a diverse range of compounds for high throughput screening in medicinal chemistry.

Full text of DOI:10.1016/j.tetlet.2015.06.035

Accepted Manuscript
Microwave-assisted synthesis of fused piperazine-benzimidazoles via a facile,
one-pot procedure
Gui-Ting Song, Shi-Qiang Li, Zhi-Wei Yang, Jian-Hui Yuan, Ming-Shu Wang,
Jin Zhu, Zhong-Zhu Chen, Zhi-Gang Xu
PII:
S0040-4039(15)01028-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.035
TETL 46427
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
6 May 2015
9 June 2015
11 June 2015
Please cite this article as: Song, G-T., Li, S-Q., Yang, Z-W., Yuan, J-H., Wang, M-S., Zhu, J., Chen, Z-Z., Xu, Z-
G., Microwave-assisted synthesis of fused piperazine-benzimidazoles via a facile, one-pot procedure, Tetrahedron
Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.035
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Graphical Abstract
Microwave-assisted synthesis of fused
piperazine-benzimidazoles via a facile, one-
pot procedure
Leave this area blank for abstract info.
Gui-Ting Song, Shi-Qiang Li, Zhi-Wei Yang, Jian-Hui Yuan, Ming-Shu Wang, Jin Zhu, Zhong-Zhu
Chen ∗ and Zhi-Gang Xu *

1
Tetrahedron Letters
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Microwave-assisted synthesis of fused piperazine-benzimidazoles via a facile, one-pot
procedure
Gui-Ting Song,a, b Shi-Qiang Li,c Zhi-Wei Yang,c Jian-Hui Yuan,c Ming-Shu Wang,c Jin Zhu,a Zhong-Zhu
Chen*, c and Zhi-Gang Xu∗, c
a Key Laboratory for Asymmetric Synthesis and Chiral Technology of Sichuan Province Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences,
Chengdu, China 610041
b University of Chinese Academy of Sciences, Beijing, China 100049
c Chongqing Key Laboratory of Environmental Materials and Remediation Technologies, Drug Discovery Center of Innovation, Chongqing University of Arts
and Sciences. 319 Honghe Ave., Yongchuan, Chongqing, 402160, P.R. China
ARTICLE INFO
ABSTRACT
Two series of compounds containing fused piperazine-benzimidazole scaffolds have been
synthesized using an Ugi/deprotection/cyclization strategy (UDC) followed by an intermolecular
nucleophilic substitution reaction. This new strategy allows for the facile synthesis of
compounds in a one-pot reaction giving fused piperazine-benzimidazoles in good yields. This
synthetic strategy can be readily applied to the construction of a diverse range of compounds for
high throughput screening in medicinal chemistry.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2013 Elsevier Ltd. All rights reserved.
fused piperazine-benzimidazole
microwave irradiation
UDC strategy
nucleophilic substitution reaction
one-pot procedure
We have previously reported the synthesis of fused
piperazine-benzimidazole scaffolds via an
NHBoc
N
NHBoc
Ugi/deprotection/cyclization (UDC) strategy, using amino acids
as the starting materials.1 Another novel protocol for the
synthesis of these heterocyclic motifs is the use of a four-
component condensation (4CC) Ugi–Smiles reaction, followed
by a three-step cascade involving an acid-catalyzed cyclization,
intramolecular reductive cyclization and oxidation.2 The Ghandi
group have also reported an Ugi 3CC reaction to afford fused
piperazine-benzimidazoles using a bifunctional formyl-acid as
the starting material.3 However, all the above methods involve
starting materials which are not commercially available.
Recently, we reported the use of an intramolecular nucleophilic
substitution reaction on Ugi and Aldol reaction products, to
provide access to compounds containing a new ring system via
the formation of a C–N bond.4 The nucleophilic substitution
reaction used a UDC strategy to provide fused benzimidazole-
quinoxalinones in good yields.5 Ding et al. have also reported the
preparation of β-lactams using a tandem Ugi 4CC/SN cyclization
reaction using bromoacetic acid as one of the Ugi reaction
NH2
O
N
NH
MeOH, r.t
O
1
2
Br
O
CHO
Br
OH
3
Path B
?
Path A
10% TFA/DCE
HN
N
N
N
O
base
Br
N
O
N
5
4
starting materials.6 The bromoacetyl group involved in the
nucleophilic substitution reaction has also been used by other
groups to facilitate the ring closure.7 Based on this, we envisaged
that bromoacetic acid could be used in the Ugi reaction for the
synthesis of fused piperazine-benzimidazole scaffolds.
———
Scheme 1. Synthetic routes to fused piperazine-benzimidazole 5.
The nucleophilic substitution reaction is usually the last step in
the ring-closing process, as the reacting partners are stable to the
∗ Corresponding author. Tel.: +86-023 6116 2837; fax: +86-023 6116 2836; e-mail: 18883138277@163.com; xuzhigangyours@yahoo.com

2
other transformations involved in the process, such as the UDC
strategy, Aldol and Diels-Alder reactions.4,8 As we have
previously reported, a benzimidazole scaffold is generated when
2-(N-Boc-amino)-phenyl-isocyanide 1 is used as a starting
material in the Ugi reaction.9 This particular strategy is a facile
method for the construction of benzimidazoles. Furthermore, the
use of the UDC strategy immediately prior to an intramolecular
nucleophilic substitution reaction provides access to compounds
containing a fused benzimidazole scaffold.10 Herein, we describe
our most recent work towards the development of a novel
strategy for the construction of two new chemical scaffolds via a
UDC strategy involving the formation of a new C–N bond.
Ugi product 3 using 10% TFA/DCE with the same optimized
microwave conditions.
Bromoacetic acid 2 was treated with a mixture of aniline,
benzaldehyde and isonitrile 1 in methanol to afford the Ugi
product 3 in 77% yield (Scheme 1). Compound 3 was then
treated with 10% TFA/DCE in a microwave reactor at 100 °C for
10 min to afford compound 4 in 86% yield. We then proceeded
to investigate and optimize the nucleophilic substitution reaction
required for the synthesis of piperazine-benzimidazole 5 (Table
1). We drew on some of our previous research,4, 5 and evaluated
the use of inorganic bases (Table 1, entries 1–4) and the impact
of various organic bases (entries 5–10) on the reaction, and found
that the use of DIPA gave the highest isolated yield of 5 (87%,
92% from HPLC) (Table 1, entry 9).
CF3
N
N
N
N
N
N
Table 1
Optimization of the synthesis of fused piperazine-benzimidazole 7.
O
O
a
b
10a (87%a, 60%b)
10b
(82% , 56% )
Entry
Conditions Eq Temp.
Time
Yield 4 and 5
.
2
2
(°C)
MW 160
MW 150
(min)
10
30
1
Na2CO3
K2CO3
Cs2CO3
Cs2CO3
TEA
-
-
-
-
-
-
-
-
42%a
54%a
76%a
72%a
31%a
52%a
62%a
77%a
2
N
N
3
2
2
5
5
5
5
5
5
MW 150
MW 160
MW 150
MW 150
MW 160
MW 160
MW 160
MW 160
30
20
20
30
20
10
20
30
20
20
10
10
N
N
N
N
4
5
O
O
6
DIPEA
DIPEA
DIPA
10d (88%a, 70%b)
a
b
10c
(89% , 63% )
O
7
8
9
DIPA
- 92%a, 87%b
-
85%a
72%,c 16%a
0% , c 85%a
0% , c 72%a
0% , c 38%a
N
10
11b
12b
13b
14b
DIPA
N
N
N
10% TFA/DCE MW 120
10% TFA/DCE MW 140
10% TFA/DCE MW 150
5% HCl/AcOH MW 100
N
N
O
O
O
10f (58%b)
10e (66%b)
O
aYield (%) for compound 5 based on peak area of the product by HPLC
analysis at 214 nm.
bDirect process from compound 3 to 5.
cYield (%) for compound 4 based on peak area of the product by HPLC
analysis at 214 nm.
N
N
N
The NMR results are consistent with the proposed structure
and are provided in the supplementary data. When the UDC
strategy was carried out to afford compound 4, a small peak
indicating the presence of compound 5 was found in the HPLC
trace. As such, it seemed possible that compound 5 could be
obtained directly from compound 3 in a single step through
pathway B. Lower reaction temperatures and shorter reaction
times were examined (Table 1, entries 11–14). The optimization
of the reaction conditions showed that 10% TFA/DCE at 140 °C
for 20 min were the most suitable (entry 12). The resulting
compound is the same as that produced using pathway A by
NMR analysis, and an 85% yield, as determined by HPLC, is
more than adequate for a one-pot procedure. Compound 5 was
obtained in 61% isolated yield after reaction of the unpurified
O
10g (67%b)
Scheme 2. Synthetic route for the synthesis of fused piperazine-
benzimidazole 10.
a Isolated yield (%) from the nucleophilic substitution reaction via pathway A.
bIsolated yield (%) from the one-pot procedure via pathway B.
With the optimized conditions in hand, we proceeded to
evaluate the scope of this strategy by synthesizing a series of
piperazine-benzimidazoles (10a–d), which were isolated in good
yields (82–89%, Scheme 2). In addition, the two-step, one-pot
procedure via pathway B was examined and used to synthesize
compounds 10a–g with yields ranging from 56–70%. Readily
available amines and aldehydes can be used in this method to
provide Ugi products 8 in good yield. This product can be used

3
for the subsequent deprotection and cyclization reactions, without
the need for purification, to afford compounds 9. This strategy
therefore provides rapid access to benzimidazole-containing
compounds. It was envisaged that the UDC strategy could also be
used in conjunction with another ring-closing strategy involving
the reaction of an amine with the carbonyl of a carboxamide
group, and that this strategy would provide better facial
selectivity as a one-pot procedure for the modification of the
structure.10 Furthermore, this UDC strategy would avoid the
formation of by-products resulting from the reaction of the
bromoacetyl group. The synthetic route resulting from this design
process is shown in Scheme 3
The amine that we had used for the previous optimization
experiments was replaced with N-Boc-protected-
phenylenediamine 11 in methanol, to provide Ugi products 12.
The solvent was removed to give a residue, which was subjected
to microwave irradiation in 10% TFA/DCE to facilitate the
removal of the Boc-protecting group and afford 13. In Scheme 3,
the arrows on intermediate 13 show the cyclization direction to
afford intermediate 14, which was converted to 15 without being
isolated. When the microwave conditions were adjusted to 120
°C with a reaction time of 10 min, compounds 15a–f were
formed in good yields (52–67%, Scheme 3). The temperature
used was lower than that used for the previous scaffold (Scheme
1), possibly because the benzimidazole group had an effect on
the nucleophilic substitution reaction. The high yields achieved
in this particular case effectively demonstrate that this strategy
could be applied to the synthesis of a diverse range of piperazine-
benzimidazole scaffolds.11
NHBoc
O
R2
R3
R3
NH2
H
N
1
2
Br
MeOH, r.t.
N
NHBoc
O
BocHN
11
7
12
In conclusion, we have developed a facile microwave-assisted
process for the synthesis of two fused piperazine-benzimidazole
scaffolds using a one-pot procedure.12 This process involved a
UDC strategy followed by an intermolecular nucleophilic
substitution reaction to give the desired products in high yields.
This facile procedure can be readily used to synthesize a diverse
range of compounds for high throughput screening in medicinal
chemistry.
R3
R3
O
R2
NH2
H
Br
N
N
10% TFA/DCE
H2N
O
MW 120oC,
20 min
13
R3
R3
Acknowledgements
NH
R2
R3
R3
The authors thank the Scientific Research Foundation of
Chongqing University of Arts and Sciences (Grant No.
R2013XY01 and R2013XY02), the Chongqing Science and
Technology Commission (Grant No. CSTC2013JCYJA50028),
SRF for ROCS, and SEM for funding this research. We thank Ms.
H.Z. Liu for obtaining LC/MS and NMR data.
N
N
R2
N
N
R3
R3
N
N
N
Br
R3 = H, or CH3
15
14
O
References and notes
1. Xu, Z.; Moliner, F. D.; Cappelli, A. P.; Muhammed, A.; Hulme, C.
Synlett., 2014, 25, 225-228.
2. Kaïm L. E.; Grimaud, L.; Purumandla, S. R. J. Org. Chem., 2011, 76,
4728-4733.
3. Ghandi, M.; Zarezadeh, N.; Taheri, A. Tetrahedron, 2010, 66, 8231-
8237
N
N
N
N
N
N
N
N
15a (54%a)
15b (63%a)
4. (a) Xu, Z.; Moliner, F. D.; Cappelli, A. P.; Hulme, C. Angew. Chem.
Int. Ed. 2012, 51, 8037 -8040. (b) Xu, Z.; Moliner, F. D.; Cappelli, A.
P.; Hulme, C. Org. Lett., 2013, 15, 2738–2741.
Cl
5. Chen, Z.; Zhang, J.; Tang, D.; Xu, Z. Tetrahedron Lett. 2014, 55,
2742-2744.
6. Zeng, X.; Wang, H.; Yan, Y.; Wu, L.; Ding, M. Tetrahedron, 2014,
70, 3647-3652.
N
N
7. (a) Lenman, M. M.; Inghamb, S. L.; Gani, D. Chem. Commun., 1996,
85-87. (b) Liu, J.; Brahimi, F.; Uri Saragovi, H.; Burgess, K. J. Med.
Chem., 2010, 53, 5044–5048. (c) Han, W.; Wu, J.; Dai, W. Synlett.,
2014, 25, 2019-2024. (d) Siman, P.; Karthikeyan, S. V.; Brik, A. Org.
Lett., 2012, 14, 1520-1523. (e) Lin, D. W.; Masuda, T.; Brskup, M. B.;
Nelson, J. D.; Baran, P. S. J. Org. Chem., 2011, 76, 1013-1030.
8. (a) Ilyin, A.; Kysil, V.; Krasavin, M.; Kurashvili, I. and Ivachtchenko,
A. V. J. Org. Chem. 2006, 71, 9544-9547. (b) Oikawa, M.; Ikoma, M.
and Sasaki, M. Tetrahedron Lett. 2005, 46, 415-418.
9. Xu, Z.; Ayaz, M.; Cappelli, A. P.; Hulme, C. ACS comb. Chem. 2012,
14, 460-464.
N
N
N
N
N
N
15c (52%a)
15d (64%a)
Cl
O
Cl
N
N
10. (a) Zhang, W. and Tempest, P. Tetrahedron Lett. 2004, 45, 6757-
6760. (b) Nixey, T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002,
43, 1637.
11. (a) Christensen, M. K.; Erichsen, K. D.; Trojel-Hansen, C.; Tjørnelund,
J.; Nielsen, S. J.; Frydenvang, K.; Johansen, T. N.; Nielsen, B.;
Sehested, M.; Jensen, P. B.; Ikaunieks, M.; Zaichenko, A.; Loza, E.;
Kalvinsh, I.; Björkling, F. J. Med. Chem. 2010, 53, 7140-7145. (b)
Marsden, S. P.; Watson, E. L.; Raw, S. A. Org. Lett. 2008, 10, 2905-
2908.
N
N
N
N
N
N
15e (61%a)
15f (67%a)
.aIsolated yield (%) from the one-pot UDC strategy.
Scheme 3. Synthetic route for the preparation of fused piperazine-
benzimidazoles 15a–f.
12. General procedures for compounds 10 and 15.

4
A solution of aldehyde (0.50 mmol) and amine (0.50 mmol) in
MeOH (1 mL) was stirred at room temperature for 10 min in a 5 mL
microwave vial. Then, bromoacetic acid (0.50 mmol) and isonitrile
(0.50 mmol) were added separately. The mixture was stirred at room
temperature overnight. The reaction was monitored by TLC and the
solvent was removed under a stream of nitrogen. The residue was
dissolved in 10% TFA/DCE (3 mL) and heated under microwave
irradiation at 140°C for 20 min (compound 15 was 120 °C for 10 min).
After cooling to room temperature, the solvent was removed under
reduced pressure and then diluted with EtOAc (15 mL) and washed
with sat. Na2CO3 and brine. The organic layer was dried over MgSO4
and concentrated. The residue was purified by silica gel column
chromatography using a gradient of ethyl acetate/hexane (20–100%) to
afford the desired piperazine-benzimidazole products 10 and 15.
Compound 15a, yield 54%. 1H NMR (400 MHz, CDCl3) δ 7.81 (t, J =
9.0 Hz, 2H), 7.52 (d, J = 7.5 Hz, 1H), 7.44–7.29 (m, 3H), 7.21 (dd, J =
15.4, 5.6 Hz, 4H), 6.91–6.78 (m, 3H), 5.73 (q, J = 16.8 Hz, 2H), 3.73
(s, 3H). 13C NMR (100 MHz, CDCl3) δ 160.1, 147.8, 144.2, 143.6,
143.5, 133.7, 133.4, 129.0, 127.7, 123.5, 123.4, 120.3, 119.9, 114.8,
110.8, 109.3, 57.0, 55.3, 42.0. LC/MS calculated for C23H19N4O
[M+H]+, 367; found 367.