Facile One-Pot Synthesis of Benzimidazole and Quinoxalin-2(1 H)-one Scaffolds via Two-Component Coupling Reaction, Deprotection, and Intermolecular Cyclization

Article abstract of DOI:10.1055/s-0034-1379016

Two scaffolds, namely benzimidazole and quinoxalin-2(1H)-one, were synthesized by treating 2-(N-Boc-amino)phenylisocyanide (Boc: tert-butoxycarbonyl) with carboxylic acids and glyoxylic acids, respectively. The target compounds were generated directly aft

Full text of DOI:10.1055/s-0034-1379016

2518▌
LETTER
letter
Facile One-Pot Synthesis of Benzimidazole and Quinoxalin-2(1H)-one
Scaffolds via Two-Component Coupling Reaction, Deprotection, and Inter-
molecular Cyclization
One-Pot Synthesis of Benzimidazole and Quinoxalin-2(1H)-one
Zhong-Zhu Chen, Ying Tang, Lei Zuo, Dian-Yong Tang, Jin Zhang,* Zhi-Gang Xu*
Chongqing Key Laboratory of Environmental Materials and Remediation Technologies, Drug Discovery Center of Innovation, Chongqing Uni-
versity of Arts and Sciences, 319 Honghe Avenue, Yongchuan, Chongqing 402160, P. R. of China
Fax +86(23)61162837; E-mail: xuzhigangyours@yahoo.com; E-mail: hxxzj2282@163.com
Received: 02.07.2014; Accepted after revision: 02.08.2014
NHBoc
Abstract: Two scaffolds, namely benzimidazole and quinoxalin-
2(1H)-one, were synthesized by treating 2-(N-Boc-amino)phenyl-
N
F
O
isocyanide (Boc: tert-butoxycarbonyl) with carboxylic acids and
glyoxylic acids, respectively. The target compounds were generated
directly after two-component coupling, deprotection, and intermo-
lecular cyclization.
–
+
NHBoc
1
N
F
F
F
O
O
Key words: benzimidazole, quinoxaline-2(1H)-one, two-compo-
nent coupling, one-pot synthesis, intermolecular cyclization
3
OH
F
2
O
In our previous work, we reported the synthesis of ben-
zimidazoles and quinoxalines using the isonitrile 2-(N-
Boc-amino)phenyl isocyanide (Boc: tert-butoxycarbon-
yl), in a one-pot Ugi–deprotection–cyclization (UDC)
strategy.1 The use of this isonitrile has significant poten-
tial in the synthesis of new scaffolds for biologically ac-
tive amide or peptide synthesis. Recently, Danishefsky’s
group reported two-component coupling (2CC) reactions
of carboxylic acids and isonitriles under suitable thermol-
ytic conditions.2 They also proposed a possible mecha-
nism for formation of a formimidate carboxylate mixed
anhydride (FCMA) as an intermediate.3 Many novel am-
ides have been designed, synthesized, and reported based
on their research.4 Here, we report the facile one-pot syn-
thesis of two scaffolds, namely benzimidazole and quin-
oxalin-2(1H)-one, via reactions of N-Boc-aminophenyl
isocyanide with carboxylic acids and glyoxylic acids, re-
spectively.
N
F
N
4
Scheme 1 Synthetic route of benzimidazole compound 4
Table 1 Optimization of the Reaction Conditions to Obtain Com-
pound 4
Entry Solvent
MW temp (°C) Time (min) Yield (%)a
1
2
DMF
150
160
140
100
140
140
150
160
170
120
120
10
20
10
20
10
20
20
10
10
20
20
63
1,4-dioxane
THF
56
3
46
4
MeOH
EtOH
18
5
51
The 2CC reactions of acids and isonitriles usually occur at
high temperatures, although some have been achieved at
110 °C.2b The Boc group in 2-(N-Boc-amino)phenyliso-
cyanide is labile at high temperatures in numerous sol-
vents.1 We therefore designed a synthetic route that uses
high temperatures generated by microwave irradiation
and suitable solvents for removing the Boc group, as
shown in Scheme 1. Treatment of 2-(N-Boc-ami-
no)phenylisocyanide (1) with carboxylic acid 2 gave the
target benzimidazole compound 4 in high yield via the N-
formylamide intermediate 3. The results of reaction opti-
mization using various solvents, temperatures, and reac-
tion durations are shown in Table 1.
6
DCE
78
7
DCE
89, 85b
80
8
DCE
9
DMSO
acetone
EtOAc
77
10
11
19
23
a The yield (%) was based on the integration area of HPLC peaks de-
tected at 214 nm.
b Isolated yield (%) after column chromatography.
The data in Table 1 show that dimethylformamide (DMF)
and dimethyl sulfoxide (DMSO) gave good yields; even
acetone gave a yield of 19%. 1,2-Dichloroethane (DCE)
was the best solvent choice, taking purification into con-
SYNLETT 210014, 2517, 2518–2520
Advanced online publication: 26.08.2014
DOI: 10.1055/s-0034-1379016; Art ID: st-2014-w0558-l
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
One-Pot Synthesis of Benzimidazole and Quinoxalin-2(1H)-one
2519
sideration, because it can be easily removed under re- duced by modification of the benzimidazole scaffold by
duced pressure. Compound 4 was obtained in 85% yield changing the carboxylic acid.
using column chromatography.
Previous reports have shown that glyoxylic acids are good
Based on experiments5 and the calculation-supported building blocks for constructing bioactive scaffolds using
mechanism proposed by Danishefsky’s group,6 a possible the UDC strategy.1b,10 Replacement of the carboxylic ac-
mechanism for the reaction between isonitrile 1 and a car- ids by glyoxylic acids in the 2CC reaction provides new
boxylic acid 2 is shown in Scheme 2. FCMA 5 is formed, scaffolds. The reaction of glyoxylic acids 10 with isoni-
followed by a 1,3 O→N acyl transfer to give 3. The fol- triles is shown in Scheme 4. The microwave irradiation
lowing deprotection reaction removes the Boc group to time was shortened to ten minutes, because long reaction
form 6; the subsequent cyclization gives benzimidazole 4 times at high temperatures gave low yields. Under these
at high temperature.7
conditions, the intermediate FCMA 11 was obtained, fol-
lowed by Boc removal from compound 12 to give N-
formylamide 13. The addition of trifluoroacetic acid pro-
moted the formation of a Schiff base, leading to ring clo-
sure. The unstable amide bond was broken under acidic
conditions and formed quinoxalin-2(1H)-one 1417 in good
yields, that is, 72–83%.15 The use of glyoxylic acids
broadens the scope of the 2CC reaction, enabling the cre-
ation of diverse platforms of interest in medicinal chemis-
try.
F
O
BocHN
+
1
2
3
O
N
••
F
5 (FCMA)
F
O
F
4
N
NH2
O
R1
R1
1 R1 = H
9 R1 = Me
NHBoc
N
R1
R1
Scheme 2 Proposed mechanism of 2CC reaction between isonitrile
and carboxylic acid
R2
+
–
DCE
O
O
MW 150 °C, 10 min
A series of benzimidazoles 8 were synthesized using the
one-pot conditions, as shown in Scheme 3. The structures
of compounds 8b and 8d matched those reported in the lit-
erature;7,8 the reactions gave good yields (78–83%), for
both alkyl and aromatic carboxylic acids.9 Various struc-
tures of interest in medicinal chemistry can be easily pro-
O
BocHN
N
O
11 (FCMA)
O
OH
10
R1
R1
R1
R1
O
N
O
O
N
NHBoc
O
NH2
O
NHBoc
O
O
R1
R2
R2
DCE
N
N
N
+
12
13
–
MW 150 °C, 20 min
1
H
N
R1
O
O
TFA–DCE (10%)
8a–e
R1
OH
R1
N
R2
MW 100 °C, 10 min
7
14a–f
O
H
H
N
H
N
O
N
N
O
N
N
N
O
O
O
N
O
N
N
N
14a 82%11
14b 83%12
14c 72%13
8a 80%
8b 78%7
H
N
N
O
O
N
O
O
O
H
H
N
N
O
O
N
N
N
N
O
O
S
N
N
N
N
CN
8c 83%
8d 81%8
8e 79%
14d 72%14
14e 81%15
14f 80%16
Scheme 3 The detailed structures and yields of benzimidazole com-
pounds 8
Scheme 4 The synthetic route, detailed structures, and yields of the
Synlett 2014, 25, 2518–2520
© Georg Thieme Verlag Stuttgart · New York

2520
Z.-Z. Chen et al.
LETTER
(9) General Procedures for Compounds 4 and 8
In conclusion, two scaffolds, namely benzimidazole and
quinoxalin-2(1H)-one, were obtained via a facile one-pot,
three-step procedure. The use of carboxylic and glyoxylic
acids broadened the scope of the 2CC method and signifi-
cantly extended the range of biologically active amides or
peptides that could be synthesized. The deprotection and
intermolecular cyclization steps may have applications in
other reactions for designing druglike compounds in me-
dicinal chemistry.
A solution of 2-(N-Boc-amino)phenylisocyanide (0.50
mmol) and carboxylic acid (0.50 mmol) in DCE (2 mL) was
subjected to microwave irradiation at 150 °C for 20 min.
After the microwave vial was cooled to r.t., the solvent was
removed, and the product was purified by silica gel column
chromatography using a gradient of EtOAc–hexane (10–
100%) to afford the relative benzimidazole products.
Compound 4: 85% yield. 1H NMR (400 MHz, CDCl3): δ =
8.28 (s, 1 H), 8.05–7.96 (m, 1 H), 7.88–7.77 (m, 1 H), 7.67–
7.57 (m, 1 H), 7.49–7.46 (m, 2 H), 7.19–7.09 (m, 2 H). 13
C
NMR (100 MHz, CDCl3): δ = 160.8, 158.2, 144.2, 142.1,
134.0, 131.4, 126.3, 125.9, 120.8, 115.5, 112.6, 112.4.
HRMS: m/z calcd for C14H8F2N2O [M + H]+: 258.0605;
found: 258.0603.
Acknowledgment
The authors thank the Scientific Research Foundation of Chongqing
University of Arts and Sciences (R2013XY01, R2013XY02,
R2013CJ03), the Chongqing Science & Technology Commission,
(Grant No. CSTC2013JCYJA50028) for funding this research. We
would also like to thank one of the reviewers for providing insight-
ful comments to our manuscript.
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at
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10.1055/s-00000083.SunpfgIpi
o
o
nr
i
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(17) General Procedure for the Synthesis of Compound 14
A solution of 2-(N-Boc-amino)phenylisocyanide (0.50
mmol) and carboxylic acid (0.50 mmol) in DCE (2 mL) was
subjected to microwave irradiation at 150 °C for 10 min.
After the microwave vial was cooled to r.t., TFA (0.20 mL)
was added to the mixture and treated in microwave again at
100 °C for 10 min. Then, the solvent was removed, and the
residue was diluted with EtOAc (15 mL) and washed with
sat. Na2CO3 (15 mL) and brine (10 mL). The organic layer
was dried over MgSO4 and concentrated. The residue was
purified by silica gel column chromatography using a
gradient of EtOAc–hexane (10–80%) to afford the relative
benzimidazole products.
Compound 14a: yield 82%. 1H NMR (400 MHz, DMSO-d6):
δ = 12.59 (s, 1 H), 8.40–8.21 (m, 2 H), 7.85 (dd, J = 8.0, 1.4
Hz, 1 H), 7.63–7.44 (m, 4 H), 7.41–7.27 (m, 2 H). 13C NMR
(100 MHz, DMSO-d6): δ = 155.0, 154.6, 136.1, 132.5,
130.8, 130.6, 129.7, 129.2, 128.3, 123.8, 115.5. HRMS: m/z
calcd for C14H10N2O [M + H]+: 222.0793; found: 222.0796.
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Synlett 2014, 25, 2518–2520
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