One-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines via cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with alkynes and p-tolylsulfonyl azide

Article abstract of DOI:10.1055/s-0029-1217515

A one-pot synthesis of functionalized benzimidazoles and 1H-pyrimidines via the cascade reactions of o-aminoanilines or naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl azide is reported. The protocol is efficient and general. Georg Thiem

Full text of DOI:10.1055/s-0029-1217515

LETTER
2023
One-Pot Synthesis of Functionalized Benzimidazoles and 1H-Pyrimidines via
Cascade Reactions of o-Aminoanilines or Naphthalene-1,8-diamine with
Alkynes and p-Tolylsulfonyl Azide
F
unctiona
i
lized
B
n
S
1
H
-Pyrimidin
h
es e,a Zheng Jiang,a Yanguang Wang*a,b
a
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
b
Received 24 March 2009
as amines, alcohols or water. The reactions involve a
copper-catalyzed azide-alkyne cycloaddtion (CuAAC)
and the generation of a ketenimine intermediate. On the
basis of these works, we investigated the copper(I) iodide
catalyzed reaction of phenyl acetylene (1a) with p-tolyl-
sulfonyl azide (2) and o-aminoaniline (3a), in the pres-
ence of triethylamine. As we expected (Scheme 1), the
reaction proceeded smoothly via a ketenimine intermedi-
ate and afforded N-(2-aminophenyl)-2-phenyl-N¢-tosyl-
acetimid amide (4a) with excellent chemoselectivity and
good yield (86%). When treated with 2% H2SO4 under re-
flux conditions, the latter compound 4a was successfully
converted into 2-benzyl-1H-benzimidazole (5a) in excel-
lent yield (93%) by intramolecular nucleophilic addition
and subsequent elimination.
Abstract: A one-pot synthesis of functionalized benzimidazoles
and 1H-pyrimidines via the cascade reactions of o-aminoanilines or
naphthalene-1,8-diamine with terminal alkynes and p-tolylsulfonyl
azide is reported. The protocol is efficient and general.
Key words: benzimidazole, 1H-pyrimidine, o-aminoanilines,
naphthalene-1,8-diamine, alkynes
Substituted benzimidazoles are an important class of het-
erocyclic compounds due to their wide application as
drugs with biological and pharmaceutical impact,1 and
their use as molecular precursors for the development of
ligands,2 dyes3 and polymers.4 Consequently, the synthe-
sis of substituted benzimidazoles has become a focus of
synthetic organic chemistry. The traditional synthesis of
benzimidazoles involves the reaction between o-amino-
aniline derivatives and carboxylic acids or equivalents
(nitriles, imidates, or orthoesters) under harsh dehydrating
reaction conditions.5 Substituted o-nitroanilines can be
used in place of o-aminoaniline derivatives under reduc-
ing conditions.6 Another general method involves a two-
step procedure that includes the oxidative cyclo-dehydro-
genation of aniline Schiff’s bases, which are often gener-
ated in situ from the condensation of o-aminoanilines and
aldehydes.7 Transition-metal catalyzed approaches to
benzimidazoles have also been developed. For example,
copper8 and palladium-catalyzed8a,9 coupling of o-halo-
acetoanilides with amines can form N-aryl benzimida-
zoles. More recently, Yamamoto et al.10 reported the
synthesis of benzimidazoles by using a-chloroaldoxime,
o-methanesulfonates and anilines. Despite this advance,
there is still a great need to develop convenient, versatile
and diversity-oriented catalytic systems that can accom-
modate attractive features such as easily accessible start-
ing materials and mild reaction conditions. Herein, we
report a novel and efficient one-pot synthesis of benzimi-
dazoles via the cascade reaction of o-aminoaniline deriv-
atives, terminal alkynes and p-tolylsulfonyl azide.
CuI, Et3N
Ph
Ph
MeCN
N
+
TsN3
r.t., N2, 6 h
Ts
2
1a
H2N
H2N
3a
TsN
TsHN
Ph
Ph
NH
NH
NH2
NH2
4a 86%
MeOH
2% H2SO4
reflux, 4 h
H
N
N
NHTs
Bn
Bn
– TsNH2
N
H
N
H
5a 93%
Previously, we11 and other groups12 developed the copper-
catalyzed three-component reaction of sulfonyl azides
with terminal alkynes and a number of nucleophiles, such
Scheme 1 Synthesis of benzimidazole 5a
On the basis of this result, we investigated the possibility
of developing a one-pot synthesis of 5a from phenyl acet-
ylene (1a), p-tolylsulfonyl azide (2) and aminoaniline 3a,
without isolating the intermediates. As shown in
Scheme 2, we obtained 5a in 81% yield. Using the estab-
SYNLETT 2009, No. 12, pp 2023–2027
x
x
.x
x
.2
0
0
9
Advanced online publication: 25.06.2009
DOI: 10.1055/s-0029-1217515; Art ID: W04109ST
© Georg Thieme Verlag Stuttgart · New York

2024
J. She et al.
LETTER
1. CuI, Et3N
MeCN
r.t., N2, 6 h
lished procedure, we examined a variety of terminal
alkynes 1 and o-aminoanilines 2; the results are summa-
rized in Table 1. In all cases, the one-pot protocol afforded
the corresponding benzimidazoles 5 in moderate to good
yields (49–86%). The protocol was effective for both aro-
matic (Table 1, entries 1–6 and 13–17) and aliphatic ter-
minal alkynes (Table 1, entries 7–12). The trimethylsilyl-
protected acetylene gave the deprotected product 5l
(Table 1, entry 12). The electron-deficient o-aminoa-
nilines (Table 1, entry 14) gave lower yields in compari-
son with the electron-rich o-aminoanilines (Table 1, entry
13). It is noteworthy that the protocol also worked well
when using N-methyl o-aminoanilines as substrates to af-
ford N-methyl benzimidazoles (Table 1, entries 15–17).
NH2
NH2
N
+
TsN3
+
Bn
2. H2SO4
reflux, 4 h
N
H
Ph
1a
2
3a
5a, 81%
Scheme 2 One-pot synthesis of benzimidazoles 5
1.TsN3, CuI
NH2
NH
N
R
Et3N, MeCN
+
2. H+
R
NH2
1
6
7a R = 3-ClC6H4, 74%
7b R = 4-ClC6H4, 61%
7c R = n-Bu, 30%
To extend the substrate scope, the reaction was carried out
using naphthalene-1,8-diamine (6), alkynes 1 and p-tolyl- Scheme 3 One-pot synthesis of 1H-pyrimidines 7a–c
sulfonyl azide (Scheme 3). In this case, however, 1H-
pyrimidines 7a–c were obtained in 30–74% yields.
Table 1 Synthesis of Benzimidazoles from o-Aminoaniline Derivatives, Terminal Alkynes and p-Tolylsufonyl Azidea
Entry
Aniline
Alkyne
Product
Yield (%)b
81
N
NH2
NH2
Bn
1
N
H
(5a)
N
NH2
NH2
N
H
2
62
MeO
OMe
Bu-t
(5b)
N
NH2
NH2
N
H
3
4
86
71
t-Bu
(5c)
(5d)
N
Cl
NH2
NH2
N
H
Cl
N
NH2
NH2
N
H
Cl
5
78
Cl
(5e)
N
NH2
NH2
N
H
6
7
84
77
Cl
Cl
(5f)
N
NH2
NH2
(CH2)4Me
Me(CH2)3
N
H
(5g)
Synlett 2009, No. 12, 2023–2027 © Thieme Stuttgart · New York

LETTER
Functionalized Benzimidazoles and 1H-Pyrimidines
2025
Table 1 Synthesis of Benzimidazoles from o-Aminoaniline Derivatives, Terminal Alkynes and p-Tolylsufonyl Azidea (continued)
Entry
8
Aniline
Alkyne
Product
Yield (%)b
75
N
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
NH2
(CH2)5Me
Me(CH2)4
N
H
(5h)
(5i)
(5j)
(5k)
(5l)
N
(CH2)6Me
(CH2)7Me
(CH2)8Me
Me
9
10
11
12
71
74
66
54
Me(CH2)5
Me(CH2)6
Me(CH2)7
N
H
N
N
H
N
N
H
N
TMS
N
H
N
NH2
N
H
13
85
NH2
Cl
Cl
(5m)
Cl
N
Cl
Cl
NH2
N
Cl
14
15
16
49
72
76
H
NH2
Cl
Cl
(5n)
N
Cl
NH2
N
Me
Cl
NHMe
(5o)
N
NH2
N
Cl
Me
NHMe
Cl
(5p)
(5q)
N
NH2
N
17
79
Me
NHMe
Cl
Cl
a Reaction conditions: (i) o-aminoaniline (2 mmol), phenyl acetylene (2.1 mmol), p-tolylsulfonyl azide (2.2 mmol), CuI (0.2 mmol), Et3N
(2 mmol), MeCN (10 mL), N2, r.t., 6 h; (ii) concd. H2SO4 (0.4 mL), reflux, 4 h.
b Isolated yield starting from o-aminoanilines.
Synlett 2009, No. 12, 2023–2027 © Thieme Stuttgart · New York

2026
J. She et al.
LETTER
(6) (a) VanVlier, D. S.; Gillespiean, P.; Scicinski, J.
In conclusion, we have developed a general, efficient,
one-pot synthesis of functionalized benzimidazoles from
terminal alkynes, o-aminoanilines, and p-tolylsulfonyl
azide.13 When using naphthalene-1,8-diamine as sub-
strate, the reaction gave 1H-pyrimidines. Since the start-
ing materials are either commercially available or readily
prepared, our protocol will be useful in organic synthesis.
Tetrahedron Lett. 2005, 46, 6741. (b) Hornberger, K. R.;
Adjabeng, G. M.; Dickson, H. D.; Davis-Ward, R. G.
Tetrahedron Lett. 2006, 47, 5359. (c) Wu, Z.; Rea, P.;
Wickham, G. Tetrahedron Lett. 2000, 41, 9871. (d) Yang,
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47.
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Yang, L. Tetrahedron Lett. 2005, 46, 4315. (c) Gogoi, P.;
Konwar, D. Tetrahedron Lett. 2006, 47, 79.
(d) Harapanhalli, R. S.; McLaughlin, L. W.; Howell, R. W.;
Rao, D. V.; Adelstein, S. J.; Kassis, A. I. J. Med. Chem.
1996, 39, 4804.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
(8) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(b) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org.
Chem. 2008, 73, 7841. (c) Zou, B.; Yuan, Q.; Ma, D.
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Acknowledgment
We thank the National Natural Science Foundation of China (No.
20672093) for financial support of this research.
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(13) General Procedure for the Synthesis of Benzimidazoles
and Pyrimidines
To a solution of p-tolylsulfonyl azide (2.2 mmol), terminal
alkyne (2.1 mmol), diamine (o-aminoaniline or naphthalene-
1,8-diamine; 2 mmol), and CuI (0.2 mmol) in MeCN (10
mL), was added dropwise Et3N (2 mmol). The reaction was
stirred at r.t. under N2 for 6 h, then concd. H2SO4 (98%,
0.4 mL) was added to the reaction mixture. The resulting
solution was heated under reflux for 4 h. After cooling to r.t.,
the solution was poured into H2O (20 mL), and neutralized
with K2CO3. MeCN was removed in vacuum, and the
resulting solution was extracted with EtOAc (3 × 5 mL). The
organic layer was combined, dried over anhydrous sodium
sulfate, and the solvent was removed under vacuum. The
residue was purified by column chromatography on silica
gel (petroleum ether–EtOAc, 2:1→1:2).
2-Benzyl-1H-benzo[d]imidazole (5a): White solid; mp 187–
188 °C; 1H NMR (400 MHz, DMSO-d6): d = 4.18 (2 H, s),
7.11–7.13 (2 H, m), 7.20–7.24 (1 H, m), 7.29–7.35 (4 H, m),
7.48 (2 H, br s), 12.32 (1 H, br s); 13C NMR (100 MHz,
DMSO-d6): d = 35.4, 121.7, 126.9, 128.9, 129.1, 138.1,
153.9; IR (KBr): 3432, 3083, 3050, 3025, 2837, 2738, 2687,
2637, 1624, 1588, 1536, 1493, 1457, 1447, 1427, 1323,
Synlett 2009, No. 12, 2023–2027 © Thieme Stuttgart · New York

LETTER
Functionalized Benzimidazoles and 1H-Pyrimidines
2027
1271, 1224, 1196, 1148, 1024, 1013, 1001, 926, 890, 848,
DMSO-d6): d = 40.9, 118.8, 121.8, 127.2, 128.0, 128.8,
129.1, 130.8, 133.5, 135.6, 139.7, 156.0; IR (KBr): 3404,
3047, 2813, 1639, 1609, 1597, 1542, 1479, 1445, 1433,
1416, 1369, 1341, 1300, 1241, 1174, 1094, 1078, 1052,
1032, 991, 866, 824, 786, 770, 759, 709, 682, 632 cm–1; MS
(ESI): m/z = 291.1 [M – H]–; HRMS (ESI): m/z [M + H]+
calcd for C18H14ClN2: 293.0840; found: 293.0842.
2-(4-Chlorobenzyl)-1H-Pyrimidine (7b): Yellow solid; mp
183–185 °C; 1H NMR (400 MHz, DMSO-d6): d = 3.57 (2 H,
s), 6.30–6.53 (2 H, br), 6.98 (2 H, d, J = 8.0 Hz), 7.09 (2 H,
br), 7.38–7.43 (4 H, m), 10.64 (1 H, br s); 13C NMR (125
MHz, DMSO-d6): d = 40.8, 108.4, 119.1, 121.9, 128.7,
129.0, 131.2, 132.2, 135.7, 136.3, 156.6; IR (KBr): 3398,
3047, 2927, 2823, 1918, 1635, 1594, 1535, 1491, 1476,
1442, 1425, 1413, 1373, 1342, 1309, 1291, 1238, 1182,
1165, 1092, 1051, 1030, 1017, 988, 825, 805, 793, 765, 713,
692, 616, 512 cm–1; MS (ESI): m/z = 291 [M – H]–; HRMS
(ESI): m/z [M + H]+ calcd for C18H14ClN2: 293.0840; found:
293.0829.
768, 749, 723, 695, 670, 619, 565 cm–1; MS (ESI): m/z = 209
[M + H]+; HRMS (ESI): m/z [M + H]+ calcd for C14H13N2:
209.1073; found: 209.1073.
2-(4-Methoxybenzyl)-1H-benzo[d]imidazole (5b): Slightly
yellow solid; mp 165–166 °C; 1H NMR (400 MHz, DMSO-
d6): d = 3.71 (3 H, s), 4.10 (2 H, s), 6.88 (2 H, d, J = 8.8 Hz),
7.10–7.13 (2 H, m), 7.25 (2 H, d, J = 8.4 Hz), 7.47 (2 H, br
s), 12.24 (1 H, br s); 13C NMR (125 MHz, DMSO-d6): d =
34.5, 55.4, 114.3, 114.8, 121.5, 129.9, 130.1, 139.2, 154.3,
158.4; IR (KBr): 3436, 2999, 2937, 2901, 2841, 2759, 1611,
1584, 1537, 1512, 1456, 1442, 1412, 1326, 1305, 1271,
1244, 1184, 1105, 1029, 1000, 922, 838, 814, 769, 752, 729,
715, 573, 511 cm–1; MS (ESI): m/z = 239.0 [M + H]+; HRMS
(ESI): m/z [M + H]+ calcd for C15H15N2O: 239.1179; found:
239.1179.
2-(3-Chlorobenzyl)-1H-Pyrimidine (7a): Yellow solid; mp
171–173 °C; 1H NMR (400 MHz, DMSO-d6): d = 3.59 (2 H,
s), 6.34–6.50 (2 H, br), 6.97–7.09 (4 H, m), 7.32–7.39 (3 H,
m), 7.46 (1 H, s), 10.64 (1 H, br s); 13C NMR (125 MHz,
Synlett 2009, No. 12, 2023–2027 © Thieme Stuttgart · New York

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