Synthesis of benzimidazoles from amino acids with solvent-free melting method

Article abstract of DOI:10.14233/ajchem.2014.16438

By using low cost and readily available amino acids as the synthetic blocks, a series of 2-Aminomethyl-benzimidazole are synthesized with solvent-free melting method. While the condensation of aspartic acid (or asparagine) with o-diaminobenzene gives the

Full text of DOI:10.14233/ajchem.2014.16438

Asian Journal of Chemistry; Vol. 26, No. 3 (2014), 926-932
http://dx.doi.org/10.14233/ajchem.2014.16438
Synthesis of Benzimidazoles from Amino Acids with Solvent-free Melting Method
1,*
2
2
2
1
3
REN-HONG CHEN , JIN-FENG XIONG , PAI PENG , GUANG-ZHEN MO , XING-SAN TANG , ZHAO-YANG WANG2,* and XIU-FANG WANG
1Guangdong Food and Drug Vocational College, LongDong North Road, TianHe Restrict, Guangzhou 510520, P.R. China
2School of Chemistry and Environment, South China Normal University; Key Laboratory of Theoretical Chemistry of Environment, Ministry
of Education, Guangzhou 510006, P.R. China
3College of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. China
*Corresponding authors: Tel/Fax: +86 20 83965220; E-mail: chenrenhong306@163.com, wangzy@scnu.edu.cn; x_f_wang@163.com
Received: 27 September 2013;
Accepted: 18 November 2013;
Published online: 30 January 2014;
AJC-14670
By using low cost and readily available amino acids as the synthetic blocks, a series of 2-aminomethyl-benzimidazole are synthesized
with solvent-free melting method. While the condensation of aspartic acid (or asparagine) with o-diaminobenzene gives the fluorescent
bisbenzimidazole product without amino group via the further deamination reaction in the melting reaction system. The condensation
reactions between most amino acids and o-diaminobenzenes exhibits higher yields of 58 to 86 % (mostly over 66 %), shorter reaction time
(5 h) than that previously reported and better tolerance for different functional groups in amino acids. The structures of twenty benzimidazoles
with multifunctional groups, including thirteen new compounds, are systematically characterized with FTIR, 1H NMR, 13C NMR, MS and
elemental analysis. These investigations are beneficial to the further researches on their applications in biochemistry, coordination chemistry
and organic synthesis intermediates.
Keywords: Benzimidazole, Synthesis, Amino acid, Solvent-free melting method, Condensation.
reaction time can be greatly shortened to about 20 h21, but
more organic solvents are consumed.
Thus, in view of green chemistry, it is necessary to synthe-
INTRODUCTION
Due to many different biological activities, such as anti-
tumor, antiviral, antifungal, antiinflammatory, antibacterial,
size these 2-amino-methyl-benzimidazoles by an economical
antiprotozoal, antihypertensive, anti-HIV, etc., benzimidazoles
play an important role in medicinal chemistry and bioche-
mistry1-7. At the same time, many simple benzimidazoles are
key intermediates in organic synthesis. Therefore, more and
and environmental way for future applications. Herein, we
investigate the reaction of the more amino acids 1 and o-diamino-
benzene (or its derivatives) 2 via a solvent-free melting method
and a series of benzimidazoles 3a-3t (Scheme-I). Especially
more interests have been aroused to the synthesis of benzimida-
zole and its derivatives recently4-11
thirteen new compounds are systematically characterized
1
13
by m.p., FTIR, UV, H NMR, C NMR, MS and elemental
analysis.
.
As a kind of natural biological resource with physiological
activities, inexpensive amino acids are extensively used in
organic synthesis12-16. Especially, when they are applied to
synthesize benzimidazoles, the products with amino group are
excellent ligands in coordination chemistry and asymmetric
synthesis17-21. Thus, the study on the preparation of benzimida-
zoles with multifunctional groups using amino acids as starting
materials is urgent21.
EXPERIMENTAL
All the melting points were determined on an X-5 digital
melting points apparatus and were uncorrected. Infrared spec-
tra were recorded on a Bruker Vector 33 FT-IR instrument by
liquid film method in the absorption range of 4000-400 cm-1.
1H and 13C NMR spectra were obtained in DMSO-d6 on a
Varian DRX-400 MHz spectrometer and tetramethylsilane
(TMS) was used as an internal standard. UV absorption peaks
were measured by Shimazu UV-2550 ultraviolet absorption
detector with dichloromethane as a solvent. Optical rotations
were determined with anAutopol IV polarimeter in CH3CH2OH
in a 10 cm cell. Elemental analysis was performed on a Perkin
However, there are only limited amino acids utilized in
the literature17,21-24. For all known benzimidazoles directly
prepared from amino acids via one-step condensation, the
synthetic approach is solution reflux method with lower yields
and longer reaction time. Usually, the reflux time in HCl
solution is over 70 h (even 6-7 days)17,21,22. When using the
solvent with the higher boiling point, such as glycol, the

Vol. 26, No. 3 (2014)
Synthesis of Benzimidazoles from Amino Acids with Solvent-free Melting Method 927
Elmer Series II 2400 elemental analyzer. The mass spectra
(MS) were recorded on Thermo LCQ DECA XP MAX mass
spectrometer. All reagents and solvents were commercially
available and used as received.
7.06-7.16 (2H, m, Ar-H), 7.44-7.51 (2H, m, Ar-H), 7.52 (1H,
s, Ar-H); ESI-MS m/z (%): 228 ([M + H]+, 100 %).
(S)-2-(1H-imidazol-5-yl)-1-(6-methyl-1H-benzo[d]-
imidazol-2-yl)ethanamine (Product 3f): Yellowish solid,
Typical procedure for the synthesis of compounds 3a-
3t: A flame-dried 50 mL flask was charged with 4 mmol amino
acid 1 and 5 mmol o-diaminobenzene 2, 17.5 % equiv. SnCl2.
Then, the reactants were heated to 170 ºC and the reaction
was carried out for 5 h. Once the reaction was finished, the
mixture was dissolved with alcohol. The pH value of the
resulted solution was adjusted to 9-10 with KOH solution to
give the crude product, which was purified by flash chroma-
tography on silica gel to afford the samples 3a-3t for analysis.
(1H-benzo[d]imidazol-2-yl)methanamine (Product
3a): Yellowish solid, yield 83 % (38 %17); m.p. 139.6-140.4
ºC; 1H NMR (400 MHz, DMSO-d6-TMS) δ: 1.29 (2H, s, NH2),
3.96 (2H, s, CH2), 7.13-7.20 (2H, m, Ar-H), 7.51-7.56 (2H,
m, Ar-H), 12.11 (1H, b, NH) [the corresponding lit. data17: 1H
NMR (300 MHz, D2O) δ: 3.78 (2H, s, CH2), 7.38-7.06 (4H,
m, Ar-H)]; ESI-MS m/z (%): 148 ([M + H]+, 100).
yield 74 %; m.p. 141.5-143.5 ºC; [α]20 = -30.2º (c 0.039,
D
CH3CH2OH); UV-visible (CH3CH2OH) λmax: 280 nm; 1H NMR
(400 MHz, DMSO-d6-TMS) δ: 1.73-2.22 (2H, m, NH2), 2.40
(3H, s, CH3), 3.34-3.47 (2H, m, CH2), 4.85 (1H, t, J = 8.0 Hz,
CH), 6.92 (1H, s, Ar-H), 7.03 (1H, d, J = 8.0 Hz, Ar-H), 7.35
(2H, s, Ar-H), 7.45 (1H, d, J = 8.0 Hz, Ar-H), 7.64-7.83 (1H,
m, NH), 7.92 (1H, s, Ar-H), 8.35 (1H, b, NH); 13C NMR (100
MHz, DMSO-TMS) δ: 21.67, 30.38, 49.19, 114.92, 116.52,
124.04, 131.86, 135.42, 135.55, 136.46, 137.17, 150.68,
150.71; IR (CHCl3) ν: 3126, 2969, 1625, 1564, 1488, 1446,
1245, 878, 806; ESI-MS m/z (%): 240 ([M-H]-, 100); Anal.
calcd. for C13H15N5: C 64.71, H 6.27, N 29.02, Found: C 64.65,
H 6.36, N 28.93.
(S)-1-(1H-benzo[d]imidazol-2-yl)-2-(1H-indol-3-yl)-
ethanamine (Product 3g): Yellowish solid, yield 58 % (the
last step yield is 55 % when by multi-step condensation24);
1
(6-Methyl-1H-benzo[d]imidazol-2-yl)methanamine
(Product 3b): White solid, yield 84 %; m.p. 114.1-115.4 ºC;
UV-visible (CH3CH2OH) λmax: 280 nm; 1H NMR (400 MHz,
DMSO-d6-TMS) δ: 1.91-2.02 (2H, m, NH2), 2.35 (3H, s,
CH3), 3.82 (2H, s, CH2), 6.90 (1H, d, J = 4.0 Hz, Ar-H), 7.22
(1H, s, Ar-H), 7.31 (1H, d, J = 4.0 Hz, Ar-H), 12.10 (1H, b,
NH); 13C NMR (100 MHz, DMSO-TMS) δ: 21.67, 47.27,
114.57, 115.08, 123.17, 130.82, 137.62, 138.93, 155.10; IR
(CHCl3) ν: 3148, 3048, 2919, 1628, 1561, 1485, 1449, 1278,
862, 803; ESI-MS m/z (%): 162 ([M + H]+, 100);Anal. calcd.
for C9H11N3: C 67.06, H 6.88, N 26.07, Found: C 67.21, H
7.01, N 25.99.
m.p. 119.5-121.2 ºC; H NMR (400 MHz, DMSO-d6-TMS)
δ: 1.84-2.14 (2H, m, NH2), 2.97-3.17 (2H, m, CH2), 4.34 (1H,
t, J = 8.0 Hz, CH), 6.92-6.96 (1H, m, Ar-H), 7.02-7.07 (2H,
m, Ar-H), 7.10-7.15 (2H, m, Ar-H), 7.32 (1H, d, J = 8.0 Hz,
Ar-H), 7.45-7.59 (3H, m, Ar-H), 10.78-10.91 (1H, m, NH),
12.26 (1H, b, NH); ESI-MS m/z (%): 277 ([M + H]+, 100).
(S)-2-(1H-indol-3-yl)-1-(6-methyl-1H-benzo[d]-
imidazol-2-yl)ethanamine (Product 3h): Yellowish solid,
yield 59 %; m.p. 124.6-126.3 ºC; [α]20 = -16.9º (c 0.036,
D
CH3CH2OH); UV-visible (CH3CH2OH) λmax: 221 nm; 1H NMR
(400 MHz, DMSO-d6-TMS) α: 1.51 (2H, s, NH2), 2.23 (3H,
s, CH3), 2.52-2.56 (1H, m, Ha in CH2), 2.86-2.91 (1H, m, Hb
in CH2), 4.09-4.19 (1H, m, CH), 6.75-6.81 (2H, m, Ar-H),
6.84-6.91 (2H, m, Ar-H), 7.11-7.23 (3H, m, Ar-H), 7.37 (1H,
d, J = 8.0 Hz, Ar-H), 10.62-10.74 (1H, m, NH), 12.07 (1H, b,
NH); 13C NMR (100 MHz, DMSO-TMS) δ: 21.75, 27.53,
55.17, 109.68, 110.67, 111.85, 112.13, 118.72, 118.86, 121.31,
124.13, 124.80, 127.69, 130.71, 136.54, 136.79, 138.51,
171.94; IR (CHCl3) ν: 3392, 3029, 2969, 1666, 1586, 1457,
1232, 845, 806; ESI-MS m/z (%): 289 ([M-H]-, 100); Anal.
calcd. for C18H18N4: C 74.46, H 6.25, N 19.30, Found: C 74.39,
H 6.29, N 19.28.
(5,6-Dimethyl-1H-benzo[d]imidazol-2-yl)methanamine
(Product 3c): White solid, yield 86 %; m.p. 135.1-136.9 ºC;
UV-visible (CH3CH2OH) λmax: 283 nm; 1H NMR (400 MHz,
DMSO-d6-TMS) δ: 1.62 (2H, s, NH2), 2.25 (6H, s, 2CH3),
3.82 (2H, s, CH2), 7.21 (2H, s, Ar-H), 12.24 (1H, b, NH); 13C
NMR (100 MHz, DMSO-TMS) δ: 20.42, 36.82, 104.99,
130.95, 147.50, 166.58; IR (CHCl3) ν: 3339, 3048, 2964, 1608,
1502, 1463, 1441, 1211, 848; ESI-MS m/z (%): 176 ([M +
H]+, 100);Anal. calcd. for C10H13N3: C 57.09, H 7.48, N 23.98,
Found: C 57.10, H 7.35, N 23.89.
(6-Chloro-1H-benzo[d]imidazol-2-yl)methanamine
(Product 3d): Yellowish solid, yield 66 %; m.p. 160.9-162.9
(S)-1-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-(1H-
indol-3-yl)ethanamine (Product 3i): Yellow solid, yield 64
%; m.p. 121.5-123.3 ºC; [α]20D = -19.6º (c 0.036, CH3CH2OH);
UV-visible (CH3CH2OH) λmax: 228 nm; 1H NMR (400 MHz,
DMSO-d6- TMS) δ: 1.68 (2H, s, NH2), 2.51 (6H, s, 2CH3),
2.81-2.98 (2H, m, CH2), 4.14-4.32 (1H, m, CH), 6.97 (1H, d,
J = 8.0 Hz, Ar-H), 7.04-7.10 (2H, m, Ar-H), 7.21 (2H, s, Ar-
H), 7.34 (1H, d, J = 8.0 Hz, Ar-H), 7.56 (1H, d, J = 8.0 Hz, Ar-
H), 10.98 (2H, s, 2NH); 13C NMR (100 MHz, DMSO-TMS)
δ: 19.06, 37.83, 52.51, 110.45, 111.97, 115.71, 117.06, 118.24,
121.33, 124.31, 127.23, 131.73, 133.00, 138.96, 177.43; IR
(CHCl3) ν: 3307, 3025, 2924, 2852, 1666, 1592, 1515, 1422,
1214, 867; ESI-MS m/z (%): 305 ([M + H]+, 100); Anal. calcd.
for C19H20N4Br2: C 74.97, H 6.62, N 18.41, Found: C 74.89, H
6.69, N 18.50.
1
ºC; UV-visible (CH3CH2OH) λmax: 282 nm; H NMR (400
MHz, DMSO-d6-TMS) δ: 1.67-2.03 (2H, m, NH2), 3.90 (2H,
s, CH2), 7.13 (1H, d, J = 8.0 Hz, Ar-H), 7.48 (1H, d, J = 8.0
Hz, Ar-H), 7.52 (1H, s, Ar-H), 12.26 (1H, b, NH); 13C NMR
(100 MHz, DMSO-TMS) δ: 37.59, 113.26, 114.65, 122.16,
133.49, 144.13, 153.69, 166.99; IR (CHCl3) ν: 3188, 3059,
2969, 2928, 1561, 1446, 1270, 851, 803, 744; ESI-MS m/z
(%): 180 ([M-H]–, 100); Anal. calcd. for C8H8N3Cl: C 52.90,
H 4.44, N 23.14, Found: C 52.79, H 4.47, N 23.28.
(S)-1-(1H-benzo[d]imidazol-2-yl)-2-(1H-imidazol-5-
yl)ethanamine (Product 3e): Yellowish solid, yield 70 % (the
last step yield is 70 % when by multi-step condensation24);
1
m.p. 163.2-165.2 ºC (163-165 °C24); H NMR (400 MHz,
DMSO-d6- TMS) δ: 1.60-2.04 (2H, m, NH2), 2.85-3.18 (2H,
m, CH2), 4.29 (1H, t, J = 8.0 Hz, CH), 6.72 (1H, s, Ar-H),
(S)-1-(1H-benzo[d]imidazol-2-yl)-2-phenylethanamine
(Product 3j): Yellowish solid, yield 63 % (the last step yield

928 Chen et al.
Asian J. Chem.
is 70 % when by multi-step condensation24); m.p. 163.7-165.4
three-step total yield is 45 %23); m.p. 104.2-105.9 ºC; 1H NMR
(400 MHz, DMSO-d6-TMS) δ: 1.62-1.65 (2H, m, CH2), 1.72-
1.76 (1H, m, Ha in CH2), 1.88-2.01 (1H, m, Hb in CH2), 2.06-
2.15 (1H, m, NH), 2.37 (3H, s, CH3), 2.85-3.01 (2H, m, CH2),
4.29 (1H, t, J = 8.0 Hz, CH), 6.91 (1H, d, J = 8.0 Hz, Ar-H),
7.24 (1H, s, Ar-H), 7.33 (1H, d, J = 8.0 Hz, Ar-H), 12.14 (1H,
b, NH) (the data are similar to the reported23); ESI-MS m/z
(%): 202 ([M + H]+, 100).
1
ºC (164-166 °C24); H NMR (400 MHz, DMSO-d6-TMS) δ:
1.92-2.01 (2H, m, NH2), 2.98-3.05 (2H, m, CH2), 4.19 (1H, t,
J = 8.0 Hz, CH), 6.61-6.70 (1H, m, Ar-H), 7.09-7.14 (2H, m,
Ar-H), 7.16-7.24 (4H, m, Ar-H), 7.58-7.76 (2H, m, Ar-H),
8.49 (1H, s, NH); ESI-MS m/z (%): 238 ([M + H]+, 100).
(S)-1-(6-methyl-1H-benzo[d]imidazol-2-yl)-2-phenyl-
ethanamine (Product 3k): Yellowish solid, yield 66 %; m.p.
153.3-155.3 ºC; [α]20 = -20.8º (c 0.031, CH3CH2OH); UV-
1-(6-methyl-1H-benzo[d]imidazol-2-yl)ethanamine
(Product 3p): Yellowish solid, yield 72 %; m.p. 85.6-87.3 ºC;
[δ]20D = -20.5º (c 0.031, CH3CH2OH); UV-visible (CH3CH2OH)
D
1
visible (CH3CH2OH) λmax: 280 nm; H NMR (400 MHz,
DMSO-d6-TMS) δ: 1.84-2.08 (2H, m, NH2), 2.38 (3H, s, CH3-
6), 2.91-2.97 (1H, m, Ha in CH2), 3.21-3.25 (1H, m, Hb in
CH2), 4.19-4.25 (1H, m, CH), 6.93 (1H, d, J = 4.0 Hz, Ar-H),
7.11-7.19 (3H, m, Ar-H), 7.21-7.29 (3H, m, Ar-H), 7.31-7.39
(1H, m, Ar-H), 12.17 (1H, b, NH); 13C NMR (100 MHz,
DMSO-TMS) δ: 23.77, 30.45, 55.87, 100.59, 104.98, 126.97,
128.67, 130.29, 132.00, 137.00, 145.33, 163.23, 166.62; IR
(CHCl3) ν: 3160, 3025, 2924, 1583, 1491, 1448, 1225, 875,
803; ESI-MS m/z (%): 252 ([M + H]+, 100); Anal. calcd. for
C16H17N3: C 76.46, H 6.82, N 16.72, Found: C 76.37, H 6.78,
N 16.84.
1
λmax: 280 nm; H NMR (400 MHz, DMSO-d6-TMS) δ: 1.43
(3H, d, J = 8.0 Hz, CH3), 1.49-1.99 (2H, m, NH2), 2.28 (3H, s,
CH3), 4.16-4.24 (1H, m, CH), 7.25-7.34 (3H, m, Ar-H), 8.65
13
(1H, b, NH); C NMR (100 MHz, DMSO-TMS) δ: 20.41,
23.23, 46.12, 115.27, 115.31, 129.85, 130.14, 137.44, 155.40,
158.93; IR (CHCl3) ν: 3183, 3044, 2970, 1672, 1585, 1534,
1448, 1268, 851, 803; ESI-MS m/z (%): 176 ([M + H]+, 100);
Anal. calcd. for C10H13N3: C 68.54, H 7.48, N 23.98, Found: C
68.45, H 7.43, N 24.07.
(S)-1-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-3-
methylbutan-1-amine (Product 3q): Yellowish solid, yield
(S)-1-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-
phenylethanamine (Product 3l): White solid, yield 67 %;
72 %; m.p. 114.5-115.9 ºC; [α]20 = -25.0º (c 0.034,
D
m.p. 155.3-157.1 ºC; [α]20 = -24.4º (c 0.030, CH3CH2OH);
CH3CH2OH); UV-visible (CH3CH2OH) λmax: 280 nm; 1H NMR
(400 MHz, DMSO-d6-TMS) δ: 0.85-0.98 (6H, m, 2CH3-10),
1.54-1.59 (1H, m, CH), 1.97-2.05 (2H, m, CH2), 2.19-2.24
(2H, m, NH2), 2.38 (6H, s, 2CH3), 4.17-4.24 (1H, m, CH),
7.27 (2H, s, Ar-H), 12.06 (1H, b, NH); 13C NMR (100 MHz,
DMSO-TMS) δ: 18.86, 20.94, 21.45, 34.87, 53.20, 118.00,
128.24, 135.46, 167.11; IR (CHCl3) ν: 3361, 2923, 2855, 1663,
1514, 1458, 1216, 803; ESI-MS m/z (%): 232 ([M + H]+, 100);
Anal. calcd. for C14H21N3: C 72.69, H 9.15, N 18.16, Found: C
72.56, H 9.08, N 18.24.
D
UV-visible (CH3CH2OH) λmax: 289 nm; 1H NMR (400 MHz,
DMSO-d6-TMS) δ: 1.24-1.46 (2H, m, NH2), 2.29 (6H, s, 2CH3-
6), 2.83-3.17 (2H, m, CH2), 4.08-4.51 (1H, m, CH), 7.05-7.33
(7H, m, Ar-H), 12.28 (1H, b, NH); 13C NMR (100 MHz,
DMSO-TMS) δ: 20.45, 33.79, 49.74, 118.58, 120.47, 127.00,
128.44, 130.28, 134.91, 157.11, 164.73; IR (CHCl3) ν: 3374,
3030, 2926, 2855, 1594, 1513, 1451, 1225, 801; ESI-MS m/z
(%): 266 ([M + H]+, 100); Anal. calcd. for C17H19N3: C 76.95,
H 7.22, N 15.84, Found: C 76.99, H 7.30, N 15.78.
(S)-1-(1H-benzo[d]imidazol-2-yl)-3-(methylthio)-
propan-1-amine (Product 3m): Yellowish solid, yield 75 %
(the last step yield is 87 % when by multi-step condensation24);
m.p. 71.9-73.7 ºC (72-73 °C24); 1H NMR (400 MHz, DMSO-
d6-TMS) δ: 1.61-1.76 (2H, m, NH2), 1.99-2.13 (5H, m, CH2,
CH3), 2.57 (2H, t, J = 8.0 Hz, CH2), 4.04-4.15 (1H, m, CH),
7.12-7.24 (2H, m, Ar-H), 7.48-7.68 (2H, m,Ar-H), 12.41 (1H,
b, NH-1); ESI-MS m/z (%): 222 ([M + H]+, 100 %).
N-methyl-1-(6-methyl-1H-benzo[d]imidazol-2-yl)-
methanamine (Product 3r): White solid, yield 82 %; m.p.
1
119.5-121.2 ºC; UV-visible (CH3CH2OH) λmax: 280 nm; H
NMR (400 MHz, DMSO-d6-TMS) δ: 1.72 (1H, s, NH), 2.30
(3H, s, CH3), 2.38 (3H, s, CH3), 3.81 (2H, s, CH2), 6.93 (1H,
d, J = 8.0 Hz, Ar-H), 7.26 (1H, s, Ar-H), 7.35 (1H, d, J = 8.0
Hz,Ar-H); 13C NMR (100 MHz, DMSO-TMS) δ: 21.70, 36.24,
49.45, 114.63, 114.82, 122.91, 130.53, 138.66, 139.48, 154.39;
IR (CHCl3) ν: 3194, 3034, 2924, 1663, 1512, 1482, 1446,
1251, 878, 801; ESI-MS m/z (%): 176 ([M + H]+, 100); Anal.
calcd. for C10H13N3: C 68.54, H 7.48, N 23.98, Found: C 68.51,
H 7.55, N 23.83.
(S)-1-(6-methyl-1H-benzo[d]imidazol-2-yl)-3-
(methylthio)propan-1-amine (Product 3n): Yellowish solid,
yield 76 %; m.p. 44.3-45.7 ºC; [α]20 = -30.5º (c 0.026,
D
CH3CH2OH); UV-visible (CH3CH2OH) λmax: 280 nm; 1H NMR
(400 MHz, DMSO-d6-TMS) δ: 1.84-1.95 (2H, m, NH2), 2.00-
2.02 (1H, m, Ha in CH2), 2.04 (3H, s, CH3), 2.08-2.13 (1H, m,
Hb in CH2), 2.39 (3H, s, CH3), 2.55 (2H, t, J = 8.0 Hz, CH2),
4.08 (1H, t, J = 8.0 Hz, CH), 6.93 (1H, d, J = 8.0 Hz, Ar-H),
7.26 (1H, s, Ar-H), 7.36 (1H, d, J = 8.0 Hz, Ar-H), 12.13 (1H,
b, NH); 13C NMR (100 MHz, DMSO-TMS) δ: 14.86, 21.70,
29.03, 32.43, 48.21, 122.27, 112.47, 124.03, 131.83, 136.43,
139.99, 150.78; IR (CHCl3) ν: 3277, 3036, 2963, 2891, 1603,
15273, 1505, 1466, 11586, 873, 800, 644; ESI-MS m/z (%):
236 ([M + H]+, 100); Anal. calcd. for C12H17N3S: C 61.24, H
7.28, N 17.85, Found: C 61.17, H 7.34, N 17.78.
4-(2-Amino-2-(6-methyl-1H-benzo[d]imidazol-2-
yl)ethyl)phenol (Product 3s): Yellow solid, yield 65 %; m.p.
168.3-169.9 ºC; [α]20 = -21.1º (c 0.040, CH3CH2OH); UV-
D
1
visible (CH3CH2OH) λmax: 246 nm; H NMR (400 MHz,
DMSO-d6-TMS) δ: 1.70 (2H, b, NH2), 2.41 (3H, s, CH3), 2.88-
3.30 (2H, m, CH2), 3.82-4.22 (1H, m, CH), 6.66 (1H, s, OH),
6.89-7.01 (2H, m, Ar-H), 7.37-7.47 (3H, m, Ar-H), 8.02-8.12
(2H, m, Ar-H), 12.56 (1H, s, NH); 13C NMR (100 MHz,
DMSO-TMS) δ: 21.70, 37.40, 55.25, 114.82, 115.01, 115.27,
121.50, 123.49, 123.53, 126.08, 131.16, 131.49, 142.02,
156.68, 167.49; IR (CHCl3) ν: 3374, 3110, 3022, 2918, 1665,
1610, 1591, 1512, 1484, 1449, 1251, 804; ESI-MS m/z (%):
268 ([M + H]+, 100); Anal. calcd. for C16H17N3O: C 71.89, H
6.41, N 15.72, Found: C 71.72, H 6.36, N 15.85.
(S)-6-methyl-2-(pyrrolidin-2-yl)-1H-benzo[d]imi-
dazole (Product 3o): Yellowish solid, yield 81 % (the last
step yield is 75 % when by multi-step condensation and the

Vol. 26, No. 3 (2014)
Synthesis of Benzimidazoles from Amino Acids with Solvent-free Melting Method 929
1,2-bis(6-methyl-1H-benzo[d]imidazol-2-yl)ethene
(Product 3t): Yellow solid, yield 68 %; m.p. > 300 ºC (m.p. >
300 ºC25,26); 1H NMR (400 MHz, DMSO-d6-TMS) δ: 2.38 (3H,
s, CH3), 2.44 (3H, s, CH3), 6.90-7.03 (2H, m, 2CH), 7.18-7.41
(4H, m, Ar-H), 7.58-7.71 (2H, m, Ar-H), 12.15 (2H, b, 2NH);
13C NMR (100 MHz, DMSO-TMS) δ: 22.18, 104.99, 129.13,
132.39, 133.35, 137.32, 138.63, 141.72, 154.98; ESI-MS m/z
(%): 289 ([M + H]+, 100).
(Entry 14) and the longer time is disadvantageous (Entry 15).
Similarly, the higher temperature is disadvantageous for the
condensation also (Entry 16). Even when the reaction tempe-
rature is 190 ºC, no anticipated product can be obtained for
the carbonization of the reactants (Entry 17).
At the same time, the suitable molar feed ratio of o-diamino-
benzene 2a and glycine 1a is investigated. The results (Entries
18 and 19) further show that, neither more nor less glycine 1a
feed ratio is advantageous for the reaction. Therefore, the appro-
priate synthetic conditions can be summarized as follows: the
molar feed ratio (amino acid/o-diaminobenzene) 4/5, catalyst
0.175 equiv. SnCl2, 170 ºC and 5 h. Under these conditions,
product 3a is obtained by solvent-free melting method with
the best yield of 83 % (Entry 14).
RESULTS AND DISCUSSION
Condition optimization: Directly using amino acids as
starting materials, the benzimidazoles can be synthesized via
one-step21 or multi-step condensation21,23,24. Due to the simpler
process, there are a lot of reports on the one-step solution
condensation in the past years21. In this paper, we investigate
the one-step melting condensation. When choosing glycine
1a and o-diaminobenzene 2a as the model substrates, the
reaction conditions of this condensation under solvent-free
melting state are optimized first (Table-1).
Influences of different substrates: According to the above
optimized conditions, the influences of different substrates,
including amino acids 1 and o-diaminobenzenes 2 are investi-
gated and twenty products are synthesized (Table-2). Among
them, thirteen 2-aminomethylbenzimidazoles are new comp-
ounds with systematical spectra data.
Obviously, when different catalysts, including phospho-
wolframic acid (PWA), polyphosphoric acid (PPA), are screened
(Entries 1-5), only the reaction catalyzed by polyphosphoric
acid or SnCl2 can give the anticipated product and the yield
using SnCl2 is better (Entry 5). However, there is no synergistic
effect between them (Entry 6). Thus, the low cost SnCl2 is
selected as the catalyst in the following experiments. Altering
the loading of SnCl2 (Entries 5, 7-12), the results show that its
best dosage should be 0.175 equiv. (Entry 11).
Obviously, the better yields of some known compounds
indicate that the novel one-step method is more efficient than
the multi-step condensation21,23,24.And compared with the tradi-
tional solution reflux method17,21,22, our solvent-free melting
method also gives higher yields in shorter reaction time. For
example, for 2-amino-methylbenzimidazole 3a, in the litera-
ture17, the reflux reaction time is 72 h and the yield is only
38 %. Herein, the melting reaction time is 5 h and the yield is
83 % (Entry 1).
Increasing the melting temperature and reaction time, the
yield of 3a is obviously increased (Entry 13). When the melting
temperature is 170 ºC, the suitable reaction time should be 5 h
Furthermore, the product 3a is synthesized from glycine
1a with the least steric hindrance of all amino acids, but its
TABLE-1
CONDITION OPTIMIZATION FOR THE CONDENSATION REACTION OF GLYCINE
1a AND o-DIAMINOBENZENE 2a BY SOLVENT-FREE MELTING METHODa
H
H
N
H
NH2
NH2
NH2
NH2
Condensation
Solvent-free
HOOC
+
N
H
H
2
1a
3a
Entry
1
Catalyst (equiv.)
PWA (0.100)
Temp. (ºC)
Time (h)
Yield (%)
160
160
160
160
160
160
160
160
160
160
160
160
170
170
170
180
190
170
170
3
3
3
3
3
3
3
3
3
3
3
3
4
5
6
5
5
5
5
0
2
Anhydrous CuCl (0.100)
CuCl2 (0.100)
PPA (0.100)
0
3
0
4
40
5
SnCl2 (0.100)
PPA/SnCl2 (0.050/0.050)
SnCl2 (0)
46
6
33
7
0
8
SnCl2 (0.050)
SnCl2 (0.075)
SnCl2 (0.150)
SnCl2 (0.175)
SnCl2 (0.200)
SnCl2 (0.175)
SnCl2 (0.175)
SnCl2 (0.175)
SnCl2 (0.175)
SnCl2 (0.175)
SnCl2 (0.175)
SnCl2 (0.175)
25
9
32
10
11
12
13
14
15
16
17
18b
19c
62
68
53
79
83
76
56
Carbonization
71
53
aUsually using 4 mmol amino acid as starting material, and the molar feed ratio (1a/2a) is 4/5 except for special explanation, bThe molar feed ratio
(1a/2a) is 3/5, cThe molar feed ratio (1a/2a) is 5/5

930 Chen et al.
Asian J. Chem.
TABLE-2
YIELDS OF TARGET COMPOUNDS 3 WITH DIFFERENT STRUCTURES
Entry
1
Amino acids 1
Diamines 2 (m.p., ºC)
Products 3
Yield (%)
83
NH2
HOOC
NH2
H
N
1a
NH2
N
NH2
2a (102-103)
3a
H
N
NH2
NH2
2
3
4
84
86
66
1a
1a
1a
NH2
N
2b (87-89)
3b
H
N
NH2
NH2
NH2
N
2c (127-129)
NH2
3c
H
N
Cl
Cl
NH2
NH2
N
2d (70-74)
3d
H
N
H
NH2
H
NH2
H
N
H
N
HOOC
5
6
70
74
58
59
64
63
66
67
2a
2b
2a
2b
2c
2a
2b
2c
N
N
N
1b
1b
3e
H
N
H
NH2
H
N
N
N
3f
H
N
H
H
NH2
NH2
HOOC
7
N
NH
NH
1c
1c
3g
H
N
H
NH2
8
N
NH
3h
H
N
H
NH2
NH2
NH2
NH2
9
1c
N
NH
3i
H
N
H
NH2
H
HOOC
10
11
12
N
1d
1d
3j
H
N
H
N
3k
H
N
H
1d
N
3l
H
N
H
NH2
H
NH2
HOOC
S
S
13
14
15
75
76
81
2a
2b
2b
N
1e
1e
H
3m
H
N
H
NH2
S
N
3n
H
N
H
N
H
N
H
HOOC
N
1f
3o

Vol. 26, No. 3 (2014)
Synthesis of Benzimidazoles from Amino Acids with Solvent-free Melting Method 931
H
H
H
NH2
NH2
N
HOOC
16
2b
2c
72
72
N
1g
3p
H
N
NH2
H
H
NH2
HOOC
17
18
N
1h
3q
H
N
HN
HN
HOOC
82
65
2b
2b
N
1i
3r
H
NH2
H
NH2
N
HOOC
19
OH
N
H
OH
1j
3s
H
NH2
H
N
H
N
HOOC
O
20a
21a
2b
2b
65
68
CH=CH
N
N
NH2
3t
1k
1l
H
NH2
HOOC
3t
COOH
aMolar feed ratio (amino acid/diamine 2b) is 4/10
yield is the highest when using the same o-diamino-benzenes
2 (Entries 1 vs. 5, 7, 10, 13, or 2 vs. 6, 8, 11, 14-16, 18, 19, or
3 vs. 9, 12, 17). This not only shows that the bigger steric
hindrance from the group R in amino acids (Scheme-I) is dis-
advantageous for the reaction, but also implies that the novel
method will be more effective for other amino acids than the
traditional solution reflux method.
Thus, usually methyl substituted o-diaminobenzenes (2b
and 2c) are selected as the diamine substrates to synthesize
novel 2-aminomethyl-benzimidazoles (3). And more impor-
tantly, they are used as the diamine substrates to investigate
the tolerance of this solvent-free melting condensation method
for different functional groups in amino acids. Table-2 shows
that many functional groups, such as hydroxyl, (methyl)amino,
methylthio, benzyl, heterocyclic ring, are tolerable with the
satisfactory yields (58 to 86 %, mostly over 66 %).
H
H
1
H
N
1
NH
R
2
R
NH
NH
2
Condensation
Solvent-free
2
HOOC
+
Condensation with subsequent deamination: When
asparagine 1k is used as the substrate, the structure of the
product is different from the usually anticipated (Scheme-I).
Interestingly, a fluorescent bisbenzimidazole 3t is obtained
(Scheme-II). The structure of 3t is confirmed by the test results
of 1H NMR, 13C NMR and MS. Furthermore, there is no optical
rotation nearly and the result is also consistent with the property
of 3t. When changing the molar feed ratio (1k/2b) from 4/5 to
4/10, the increased yield of 3t is 65 % (Table-2, entry 20).
In literatures25,26, the synthetic method of fluorescent
brightening agent (FBA) 3t is the condensation of 2b with
maleic acid (the product is cis-isomer and the yield is 7.9 %)
or 2-hydroxysuccinic acid 4 (the product is trans-isomer and
the yield is 44.3 %). When the latter starting material 4
(Scheme-II) is used, there is a dehydration step26. Therefore,
on the basis of these experimental results and literatures, it
can be seen that during the melting process, the amide group
of asparagine 1k also takes part in the condensation27,28 and
the following reaction is the elimination of ammonia.
2
2
N
R
NH
R
2
R
1a-1l
R
2
1
2
3a-3t
R
R
= H, CH , X
3
(Only for typical
structure)
(Only for typical structure)
= H, CH
3
Scheme-I: Synthetic route of target compounds 3
When the same amino acids 1 are used, the results of diffe-
rent diamines 2 show that, the electron-donating methyl in o-
diaminobenzenes 2 is beneficial to the condensation (Entries
1 vs. 2, 5 vs. 6, 7 vs. 8, 10 vs. 11, 13 vs. 14). And the more
methyl groups, the higher yield (Entries 2 vs. 3, 8 vs. 9, 11 vs.
12). Contrarily, the electron-withdrawing chlorine as the
substituent group in o-diaminobenzenes 2 can decrease the
yield (Entries 1 vs. 2). When 4-bromo-benzene-1,2-diamine
is used as a diamine, the anticipated product is not obtained,
even changing different amino acids 1.
Of course, the results may be related to not only the
electronic effect of different substituents, but also the melting
point (m.p.) of the diamine substrates (Table-2, Entries 1-4).
For the 4-halobenzene-1,2-diamines 2, including 2c and
4-bromobenzene-1,2-diamine (m.p. 62-64 ºC), the lower m.p.
makes them easily escape out of the reaction system at 170
ºC melting state. However, the diamine substrate with the
higher m.p., 4-nitrobenzene-1,2-diamine (m.p. 199-201 ºC),
is also disadvantageous for the reaction and its condensation
with different amino acids 1 can not give the expected
results.
H
N
H
N
Y
COOH
NH2
NH2
Condensation
Heating
2
+
CH=CH
O
Z
N
N
1k
: Y = Z = NH2
Y = OH, Z = NH2
Y = Z = OH
1l
:
3t
2b
4:
Scheme-II: Synthesis of the bisbenzimidazole 3t

932 Chen et al.
Asian J. Chem.
3. B. Narasimhan, D. Sharma and P. Kumar, Med. Chem. Res., 21, 269
(2012).
In order to verify the mechanism, especially the forma-
tion of double band in 3t in the later stage, aspartic acid 1l is
used as an amino acid substrate in the solvent-free melting
condensation (Scheme-II) and the product 3t is still obtained
with the yield of 68 % (Table-2, entry 21). In a word, when
aspartic acid 1l (or asparagine 1k) is reacted with the o-diamino-
benzenes 2, bisbenzimidazole products without amino group
can be obtained via the normal condensation and the subsequent
deamination reaction in the melting reaction system. This may
be a novel route to some FBAs with higher yields.
4. Z.Z. Mao, Z.Y. Wang, X.N. Hou, X.M. Song and Y.F. Luo, Chin. J.
Org. Chem., 28, 542 (2008).
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Conclusion
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135, 118 (2013).
A new route for the synthesis of 2-aminomethyl-benzimi-
dazoles via the utilization of amino acids has been developed.
The direct solvent-free melting method is finished in one step
with shorter reaction time and higher yields than before and
bigger tolerance for amino acid substrates. For the amino acids
with two carboxyl groups (or similar structure), some functional
bisbenzimidazoles also can be formed efficiently. These novel
investigations on the synthesis of serial benzimidazoles with
multi-functional groups afford a basis for their applications in
biochemistry, coordination chemistry and organic synthesis
intermediates.
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ACKNOWLEDGEMENTS
19. S. Guo and H.V. Huynh, Organometallics, 31, 4565 (2012).
20. X.N. Li, H.Y. Zhou, L. Feng, K. Duan and J.X. Wang, Appl. Organomet.
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The authors are grateful to the Nation Natural Science
Foundation of China (50802017), the Natural Science Founda-
tion of Guangdong Province (S2011010001556), Guangzhou
Science and technology plan project (11C56040725) and the
Third Talents Special Funds of Guangdong Higher Education
(Guangdong-Finance-Education [2011]431) for Financial
Support.
21. P. Peng, J.F. Xiong, B. Li, G.Z. Mo, R.H. Chen and Z.Y. Wang, Chin.
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