Dithiocarbamate and CuO promoted one-pot synthesis of 2-(N-substituted)-aminobenzimidazoles and related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2007.12.022

A rapid and efficient one-pot method for the synthesis of 2-(N-substituted)-aminobenzimidazoles is described. The reaction is promoted by dithiocarbamate and catalytic CuO. This procedure is general and can be applied to synthesize many potential drug can

Full text of DOI:10.1016/j.tetlet.2007.12.022

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Tetrahedron Letters 49 (2008) 992–995
Dithiocarbamate and CuO promoted one-pot synthesis of
2-(N-substituted)-aminobenzimidazoles and related heterocycles q
Parthasarathi Das *, C. Kiran Kumar, K. Naresh Kumar, Md. Innus, Javed Iqbal,
Nanduri Srinivas
Discovery Research, Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad, 500 049 AP, India
Received 13 July 2007; revised 26 November 2007; accepted 5 December 2007
Available online 8 December 2007
Abstract
A rapid and efficient one-pot method for the synthesis of 2-(N-substituted)-aminobenzimidazoles is described. The reaction is pro-
moted by dithiocarbamate and catalytic CuO. This procedure is general and can be applied to synthesize many potential drug candidates.
Ó 2007 Elsevier Ltd. All rights reserved.
2-(N-Substituted)-aminobenzimidazoles are widely used
structural motifs in medicinal chemistry as well as in drug
discovery and can be found in a number of biologically
active molecules.1 Several compounds from this class have
been used as anticancer,1d antihistamine1e and antiviral
agents.2 Some examples of pharmaceutical interest are
shown below (Fig. 1).
great value for drug discovery. Several synthetic methodol-
ogies have been reported in the literature for the synthesis
of 2-aminobenzimidazoles. Most involve formation of thio-
ureas using isothiocyanates followed by cyclodesulfuri-
zation using desulfurizing agents such as mercury(II)
oxide,3 mercury(II) chloride,4 copper(I) chloride,5 methyl
iodide,6 tosyl chloride,7 dicyclohexylcarbodiimide (DCC)8
and PS-carbodiimide9 (Fig. 2).
Most of the above reagents are either expensive or
highly toxic in nature and commonly require cumbersome
work-up and purification procedures. Apart from these
toxic agents, the synthesis of isothiocyanates requires the
use of highly toxic thiophosgene. Moreover, disadvantages
with isothiocyanates are that they are unstable if stored for
long periods.
Therefore, an efficient practical method for the synthesis
of a diverse collection of aminobenzimidazoles would be of
R
N
O
N
N
O
NH
O
N
NH
We were particularly interested in the synthesis of 2-
aminobenzimidazoles via a method suitable for large scale
preparations as well as not requiring toxic starting materi-
als and reagents.
N
H
Mebendazole
anticancer
F
Norastemizole : R = H
Astemizole : R = CH2CH2
OCH3
antiallergic, antihistamine
NH2
H
H
H
N
desulfurizing
agents
N
N
Fig. 1.
R1
R1
NH
R2
S
N
R2
q
DRL Publication No. 663.
Corresponding author. Tel.: +91 40 2304 5439; fax: +91 40 2304 5438.
*
Fig. 2.
E-mail address: parthasarathi@drreddys.com (P. Das).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.022

P. Das et al. / Tetrahedron Letters 49 (2008) 992–995
993
Table 2
Herein, we report a highly efficient copper(II) oxide
Cyclization of diamines with various dithiocarbamates
mediated one-pot synthesis of 2-aminobenzimidazoles
using various substituted diamines and substituted dithio-
carbamates. Unlike isothiocyanates, dithiocarbamates are
highly stable and easy to handle. They are easy to synthe-
size in large quantities using readily available substituted
anilines.10 The initial experiments were performed with
commercially available o-phenylenediamines and methyl-
N-aryldithiocarbamate using CuO (0.2 equiv)11 and
K2CO3 in DMF at 60 °C for 1–2 h. The desired 2-amino-
benzimidazole was isolated in good yield.12 We also inves-
tigated this methodology with respect to different diamines
and dithiocarbamates (Table 1). Several functionalized 2-
aminobenzimidazoles were synthesized from structurally
diverse diamines. The reaction gave good yields with both
electron-withdrawing groups (entries 11 and 14) and elec-
tron-donating groups (entry 6).
The procedure could also be applied to other diamine
moieties, providing quinazolines and purine-like products
in good yields (Table 2).
In connection with a drug discovery program, we
recently required an efficient synthetic protocol into the
new class of trisubstituted purines known as Aurora-A
Kinase inhibitors.13 To synthesize this class of compound
we applied this methodology (Scheme 1). Thus, condensa-
Entry Reactant
Product
Time Yielda
(h)
(%)
N
N
NH2
NH2
1
2
1
92
N
N
H
H
O
NH2
NH2
1
2
2
1
85
82
80
80
N
H
N
H
O
Cl
N
N
NH2
NH2
3
4
N
H
N
H
O
O
NH2
NH2
N
H
N
H
H
NH2
N
N
N
5
N
H
N
NH2
N
N
a
Isolated yields. All the compounds were characterized by IR, 1H
NMR, 13C NMR spectroscopy and mass spectrometry.
R1
R2
NH2
NH
R3
S
N
+
N
N
H
S
N
H
Table 1
Synthesis of 2-aminobenzimidazoles from various diamines and dithio-
carbamates
1
2
R3
a
R1
R2
NH2
NH2
R3
R4
R1
S
+
R2
N
N
N
S
N
NH
H
N
H
N
K2CO3 (2 eq) , CuO (0.2 eq)
60 oC , DMF, 1-2 h
R3
3 - 7
Scheme 1. Reagents and conditions: (a) CuO, K2CO3, DMF, 60 °C, 2 h.
R4
H
N
R1
R2
Table 3
Trisubstituted purines
NH
N
Compound
R1
R2
H
R3
Cl
Yielda (%)
75
Entry
R1
R2
R3
R4
Time (h)
Yielda (%)
O
1
2
3
4
5
6
7
8
9
CH3
CH3
CH3
OCH3
OCH3
OCH3
F
F
F
Cl
Cl
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
H
H
H
H
Cl
OCH3
H
Cl
OCH3
H
Cl
OCH3
H
Cl
H
H
OCH3
H
H
OCH3
H
H
OCH3
H
H
0.5
1
78
70
76
80
75
82
72
70
76
70
69
70
75
75
78
3
N
0.5
0.5
0.5
0.5
1
1.5
0.5
1.5
1.5
1
O
4
H
H
Cl
Cl
77
74
N
N
5
6
10
11
12
13
14
15
a
N
O
Cl
OCH3
H
Cl
OCH3
H
H
H
H
NHCOPh
75
73
NO2
NO2
NO2
1.5
1.5
1
N
O
O
7
OCH3
OCH3
NH
Isolated yields. All the compounds were characterized by IR, 1H
NMR, 13C NMR spectroscopy and mass spectrometry.
N
a
Isolated yield.

994
P. Das et al. / Tetrahedron Letters 49 (2008) 992–995
tion of 2,4,5-trisubstituted pyrimidines 114 with dithiocarb-
amates 2 in the presence of CuO (0.2 equiv) and K2CO3 in
DMF at 60 °C for 2 h furnished the desired substituted
purines 3–7 (Table 3) in good yields.15
In conclusion, we have developed an efficient and prac-
tical procedure for the synthesis of a wide variety of 2-(N-
substituted)-aminobenzimidazoles using a catalytic amount
of CuO and nontoxic dithiocarbamate. This procedure can
be scaled-up and can be applied to synthesize many poten-
tial drug candidates.
12. A typical experimental procedure: To a suspension of 4-methyl-
benzene-1,2-diamine (0.1 g, 0.819 mmol) (Table 1, entry 1) and
methylphenylcarbamodithioate (0.165 g, 0.901 mmol) (entry 1) in
2 ml of DMF were added CuO (0.013 g, 0.163 mmol) and K2CO3
(0.226 g, 1.63 mmol). The resulting mixture was heated to 60 °C and
kept at this temperature for 30 min. The reaction mixture was then
cooled to room temperature and filtered through Celite and washed
with ethyl acetate (100 ml). The combined filtrate was washed with
brine and water. The organic layer was dried over Na2SO4 and
concentrated in vacuo and the resulting mixture chromatographed on
silica gel (hexane–acetone, 90:10) to yield 5-methyl-N-phenyl-1H-
benzo[d]imidazol-2-amine (0.137 g, 78% yield) as a light yellow solid:
mp 164–165 °C; 1H NMR (DMSO-d6, 400 MHz) d 10.74 (s, 1H) 9.28
(d, J = 13.2 Hz, 1H) 7.73 (d, J = 8 Hz, 2H) 7.31–7.27 (m, 2H) 7.21–
6.77 (m, 4H) 2.35 (s, 3H); 13C NMR (50 MHz, DMSO-d6) d 150.46,
141.04, 140.43, 132.95, 130.59, 128.78, 121.23, 120.43, 116.99, 116.34,
115.54, 21.32; MS (ESI) 224 (M+H+); HPLC = 99.56%.
Acknowledgements
We thank Dr. Reddy’s Laboratories Ltd for financial
support and encouragement. Help from the analytical
department in recording spectral data is appreciated.
13. (a) Carmena, M.; Earnshaw, W. C. Nat. Mol. Cell. Biol. 2003, 4, 842;
(b) Matthews, N.; Visintin, C.; Hartzoulakis, B.; Jarvis, A.; Selwood,
D. L. Expert Rev. Anticancer Ther. 2006, 6, 109–120; (c) Marumoto,
T.; Zhang, D.; Saya, H. Nat. Rev. Cancer 2005, 5, 42–50; (d) Lee, E.
C. Y.; Frolov, A.; Li, R.; Ayala, G.; Greenberg, N. M. Cancer Res.
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References and notes
14. Compound 1 was synthesized from commercially available 5-nitro-
uracil. Das, P.; Kirankumar, C.; Iqbal, J., unpublished results.
15. Experimental procedure and spectral data for compound 3: To a
suspension of 1 (0.1 g, 0.333 mmol) and methyl 4-chlorophenylcar-
bamodithioate 2 (0.079 g, 0.364 mmol) in 2 ml of DMF were added
CuO (0.005 g, 0.066 mmol) and K2CO3 (0.092 g, 0.666 mmol). The
resulting mixture was heated to 60 °C and kept at this temperature for
2 h. The reaction mixture was then cooled to room temperature and
filtered through Celite and washed with ethyl acetate (100 ml). The
combined filtrate was washed with brine and water. The organic layer
was dried over Na2SO4 and concentrated in vacuo and the resulting
mixture chromatographed on silica gel (DCM/MeOH, 97:3) to yield
compound 3 (0.108 g, 75% yield). The physical data of the synthesized
compounds are reported below.
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Compound 3. Yellow solid; mp 215–217 °C; IR (KBr, cmÀ1) 2959,
2924, 1672, 1610, 1565, 1494, 1453, 1411; 1H NMR (DMSO-d6,
400 MHz) d 9.67 (s, 2H), 8.42 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.44–
7.42 (m, 2H), 7.24–7.17 (m, 3H), 3.78–3.71 (m, 4H), 3.69 (s, 3H), 3.14–
3.12 (m, 4H); 13C NMR (DMSO-d6, 50 MHz) d 154.77, 153.01,
151.43, 149.63, 142.23, 142.16, 139.07, 128.70, 128.42, 126.95, 125.09,
119.79, 109.45, 107.81, 104.95, 66.14, 48.74, 27.60; MS (ESI) 436
(M+H+); HRMS calcd for C22H23N7OCl [M+H+] 436.1653, found:
436.1645.
Compound 4. Brown solid; mp 268–270 °C; IR (KBr, cmÀ1) 3255,
1
2961, 2803, 1606, 1553, 1537; H NMR (DMSO-d6, 400 MHz) d 9.41
(s, 1H), 8.95 (s, 1H), 8.3 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.74 (d,
J = 9.2 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H),
3.76–3.73 (m, 4H), 3.65 (s, 3H), 3.17–3.05 (m, 4H); 13C NMR
(DMSO-d6, 50 MHz) d 153.87, 153.46, 150.84, 146.39, 140.84, 140.58,
132.29, 128.11, 127.84, 123.28, 119.91, 119.01, 115.62, 66.12, 49.16,
27.57; MS (ESI) 436 (M+H+); HRMS calcd for C22H23N7OCl
[M+H+] 436.1653, found: 436.1638.
Compound 5. Pink solid; mp 191–193 °C; IR (KBr, cmÀ1) 3259, 3046,
1
2802, 1606, 1557, 1514, 1490; H NMR (DMSO-d6, 400 MHz) d 9.43
(s, 1H), 8.93 (s, 1H), 8.32 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.71 (d,
J = 9.2 Hz, 2H), 7.29 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H),
3.65 (s, 3H), 3.09 (m, 4H), 2.50 (s, 3H), 2.49–2.44 (m, 4H); 13C NMR
(DMSO-d6, 50 MHz) d 153.87, 153.48, 150.89,146.42, 140.80, 140.60,
131.97, 128.12, 127.89, 123.30, 119.97, 119.03, 115.84, 54.65, 48.76,
45.72, 27.57; MS (ESI) 449 (M+H+); HRMS calcd for C23H26N8Cl
[M+H+] 449.1969, found: 449.1953.
Compound 6. Brown solid; mp 319–320 °C; IR (KBr, cmÀ1) 3335,
2927, 2857, 1603, 1568, 1524, 1436, 1409, 1323; 1H NMR (DMSO-d6,
400 MHz) d 10.08 (s, 1H), 9.22 (s, 1H), 8.29 (s, 1H), 8.31 (s, 1H), 7.96
(d, J = 6.8 Hz, 2H), 7.81 (d, J = 9.2 Hz, 2H), 7.74 (d, J = 9.2 Hz, 2H),
11. In this reaction protocol, increasing the amount of catalyst loading up
to 1 equiv did not show noticeable improvement in product conver-
sion whereas a reduced catalyst loading (0.1 equiv) led to a significant
drop in product conversion.

P. Das et al. / Tetrahedron Letters 49 (2008) 992–995
995
7.65 (d, J = 9.2 Hz, 2H), 7.57 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 3.76
(m, 4H), 3.66 (s, 3H), 3.07 (m, 4H); 13C NMR (DMSO-d6, 50 MHz) d
164.98, 154.38, 153.50, 150.62, 146.35, 141.09, 137.73, 135.17, 132.42,
131.89, 131.23, 128.27, 127.49, 120.97, 119.89, 117.79, 115.65, 66.14,
49.20, 27.56; MS (ESI) 521 (M+H+); HRMS calcd for C29H29N8O2
[M+H+] 521.2413, found: 521.2413.
(DMSO-d6, 400 MHz) d 10.07 (s, 1H), 9.03 (d, J = 12.8 Hz, 2H), 8.29
(s, 1H), 7.79 (d, J = 9.2 Hz, 2H), 7.69 (d, J = 8.8 Hz, 2H), 7.55 (d,
J = 8.8 Hz, 2H), 6.89 (d, J = 9.2 Hz, 2H), 3.75 (m, 4H), 3.64 (s, 3H),
3.30 (m, 4H), 1.78 (m, 1H), 0.80 (m, 4H); 13C NMR (DMSO-d6,
50 MHz) d 171.11, 154.87, 153.41, 149.98, 145.29, 141.55, 134.30,
133.65, 126.95, 119.53, 119.16, 118.75, 115.80, 66.18, 49.55, 27.53,
14.38, 6.88; MS (ESI) 485 (M+H+); HRMS calcd for C26H29N8O2
[M+H+] 485.2413, found: 485.2425.
Compound 7. White solid; mp 300–302 °C; IR (KBr, cmÀ1) 3314,
3094, 2962, 2847, 1664, 1613, 1588, 1522, 1437, 1409, 1315; 1H NMR