7028
J. Yuan et al. / Tetrahedron 69 (2013) 7026e7030
Then the scopes and limitations of this protocol were in-
3. Conclusions
vestigated starting from o-phenylenediamine bearing 4-nitro-, 3-
nitro- and itself, reacted with phenyl aldehydes (Table 4) using
the optimized reaction condition.
A novel strategy of benzimidazole synthesis using sodium per-
borate (SPB) as oxidant was developed. Mild reaction conditions,
convenient synthesis and workup, excellent substrate tolerance
were the highlights of this procedure. In addition, low cost and
ready availability of reagents, an environmentally benign procedure
and good chemoselectivity made this methodology a useful con-
tribution to the existing procedures available for the synthesis of
2-phenylbenzimidazoles.
Table 4
The reactions between substituted o-phenylenediamine and phenyl aldehydesa
4. Experimental section
Entry
R1
R2
Yield (%)b
Compound
1
2
3
4
5
6
7
8
4-Nitro
4-Nitro
4-Nitro
4-Nitro
4-Nitro
4-Nitro
4-Nitro
H
4-Nitro
2-Nitro
3-Nitro
4-Methoxy
3-Methoxy
3,4-Dimethoxy
2-Hydroxy
4-Nitro
2-Nitro
3-Nitro
2-Hydroxy
2,6-Dimethyl
4-Dimethylamino
3,4-Dimethoxy
90
92
90
93
90
92
92
95
96
95
98
99
95
95
1b
1c
1d
1e
1f
1g
1h
2a
2b
2c
3a
3b
3c
3d
4.1. General experimental details
All chemical reagents and solvent were commercial
products without further purification. Thin-layer chromatog-
raphy (TLC) was performed on silica gel plates. Column
chromatography was performed using silica gel (Hailang,
Qingdao) 200e300 mesh. 1H and 13C NMR spectra were
9
H
H
recorded employing
a Bruker AV-400 spectrometer with
10
11
12
13
14
3-Nitro
3-Nitro
3-Nitro
3-Nitro
chemical shifts expressed in parts per million (in DMSO-d6,
Me4Si as internal standard). Electrospray ionization (ESI) mass
spectrometry was performed in a HP 1100 LC-MS spectrome-
try. Melting points were determined by an X-6 micro-melting
point apparatus and were uncorrected.
a
All reactions were carried out with 1.0 equiv of two substrates and 1.1 equiv of
SPB in H2O/HOAc¼1:2 (v/v, 3 mL) at 50 ꢀC for 0.5 h.
b
Isolated yields. Characterized by 1H NMR, ESI-MS.
4.2. General procedure for the synthesis of 2-
phenylbenzimidazoles
Compared the results of compounds 1b with 2a, 1c with 2b, and
1d with 2c, it seems that the yield was reduced slightly by the in-
troduction of strong electron withdrawing 4-nitro group, which
decreases the nucleophilicity of o-phenylenediamine. From 1b to
1h, the substituents on aldehyde moiety had little influence on the
reaction either electron withdrawing groups or electron donating
groups. Comparing 1e to 1h with 3a to 3d, m-nitro- on o-phenyl-
enediamine had higher yield than that of p-nitro. For 1h and 3a, this
method could tolerate easily oxidized groups like hydroxyl. The
influences of steric hindrance of the substrates were also consid-
ered, 3b was tested and the results were still satisfied. As can be
seen, this procedure had great substrate tolerance as the yields
were all greater than 90%.
The oxidative capacity of SPB is due to the generation of H2O2
with the proceeding of reaction.28 It was speculated that when
diamine interacted with aldehyde, forming the Schiff bases, the
generated hydrogen peroxide finished the oxidation of cyclic in-
termediates (Scheme 2).20b,c The advantages of SPB natural prop-
erties, such as easy soluble in water, mild reaction condition, non-
hazardous, and extremely cheap, made this method match green
chemistry requirements. In this work, it makes this reaction ex-
cellent chemoselectivity and broad substrate tolerances.
4.2.1. Exemplified with 2-(4-chlorophenyl)-6-nitro-1H-benzimid-
azole (compound 1a). The 4-nitro-1,2-phenylenediamine (50.0 mg,
0.30 mmol), p-chlorobenzaldehyde (45.9 mg, 0.30 mmol), and SPB
(55.3 mg, 0.33 mmol) were added to a solution of H2O/HOAc¼1:2
(v/v, 3 mL) at 50 ꢀC for 0.5 h (Table 3). The progress of the reaction
was monitored by TLC (eluent: 2/1, v/v, n-hexane/ethyl acetate).
After completion of the reaction, the solution was poured into
a beaker containing 20 mL of water. Many solid precipitated. It was
filtered, washed with water (10 mLꢁ2), and then purified by quick
column chromatography (eluent: 4/1, v/v, n-hexane/ethyl acetate).
Yellow solid; yield: 83.1 mg, 93%; mp 304.7e304.9 ꢀC. 1H NMR
(400 MHz, DMSO-d6)
d
7.67 (d, J¼8.0 Hz, 2H), 7.75 (d, J¼8.8 Hz,
2H), 8.12 (d, J¼8.8 Hz, 1H), 8.20 (d, J¼8.0 Hz, 1H), 8.45 (s, 1H);
HRMS (ESI): calcd for C13H9ClN3O2 [MþH]þ 274.0383, found
274.0378.
4.2.2. 2-(4-Nitrophenyl)-6-nitro-1H-benzimidazole (Table 4, com-
pound 1b). Yellow solid; yield: 83.5 mg, 90%; mp 289.2e289.9 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d 7.77 (s, 1H), 8.15 (s, 1H), 8.41e8.45
(m, 4H), 8.59 (s, 1H), 13.92 (s, 1H); HRMS (ESI): calcd for C13H7N4O4
[MꢂH]ꢂ 283.0467, found 283.0467.
4.2.3. 2-(2-Nitrophenyl)-6-nitro-1H-benzimidazole (Table 4, com-
pound 1c). Yellow solid; yield: 85.4 mg, 92%; mp 219.9e220.6 ꢀC.
1H NMR (400 MHz, DMSO-d6)
d 7.81e7.84 (m, 2H), 7.92e7.96 (m,
1H), 8.02 (dd, J1¼7.6 Hz, J2¼1.6 Hz, 1H), 8.13 (dd, J1¼8.0 Hz,
J2¼2.4 Hz, 1H), 8.18 (dd, J1¼8.8 Hz, J2¼1.2 Hz, 1H), 8.54 (s, 1H), 13.77
(s, 1H); HRMS (ESI): calcd for C13H7N4O4 [MꢂH]ꢂ 283.0467, found
283.0463.
4.2.4. 2-(3-Nitrophenyl)-6-nitro-1H-benzimidazole (Table 4, com-
pound 1d). Yellow solid; yield: 83.5 mg, 90%; mp 282.7e283.0 ꢀC.
1H NMR (400 MHz, DMSO-d6)
J¼8.0 Hz, 1H), 8.17 (s, 1H), 8.40 (dd, J1¼8.0 Hz, J2¼1.6 Hz, 1H),
8.52e8.56 (m, 1H), 8.63 (d, J¼8.0 Hz, 1H), 9.03 (d, J¼1.6 Hz, 1H),
d
7.81 (d, J¼8.0 Hz, 1H), 7.90 (t,
Scheme 2. A possible pathway for the synthesis of 2-phenylbenzimidazoles.