Unexpected regiospecific reduction of the double bond by NaBH4 in 2-(1-methyl/1H-benzimidazole-2-yl)-3-aryl-acrylonitrile

Article abstract of DOI:10.1080/00397910701397177

Condensation of (1H-benzimidazole-2-yl)-acetonitrile 1 with aromatic aldehydes in 5% NaOH solution gave the corresponding 2-(1H-benzimidazole-2-yl)- 3-aryl-acrylonitrile 2, which on treatment with NaBH4 in ethanol unexpectedly gave 2-(1H-benzimidazole-2-yl)-3-aryl-propionitrile 3 by the regiospecific reduction of the double bond. Shaking a solution of 2 with H2/Pd-C in methanol also gave 3. Reaction of 2 with DMS gave the corresponding N-methylated analogue 5, which also with NaBH4 gave 6, once again by the regiospecific reduction of the double bond as in the case of 1-demethylated analogue (i.e., 2). Copyright Taylor & Francis Group, LLC.

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Unexpected Regiospecific Reduction
of the Double Bond by NaBH4 in
2‐(1‐Methyl/1H‐benzimidazole‐2‐yl)‐3‐aryl‐acrylo
P. K. Dubey a & P. V. V. Prasada Reddy a
a Department of Chemistry, College of Engineering, J N T University,
Hyderabad, AP, India
Version of record first published: 03 Jul 2007.
To cite this article: P. K. Dubey & P. V. V. Prasada Reddy (2007): Unexpected Regiospecific Reduction of the
Double Bond by NaBH4 in 2‐(1‐Methyl/1H‐benzimidazole‐2‐yl)‐3‐aryl‐acrylonitrile, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:13, 2259-2266
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Synthetic Communicationsw, 37: 2259–2266, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701397177
Unexpected Regiospecific Reduction of the
Double Bond by NaBH4 in 2-(1-Methyl/1H-
benzimidazole-2-yl)-3-aryl-acrylonitrile
P. K. Dubey and P. V. V. Prasada Reddy
Department of Chemistry, College of Engineering, J N T University,
Hyderabad, AP, India
Abstract: Condensation of (1H-benzimidazole-2-yl)-acetonitrile 1 with aromatic
aldehydes in 5% NaOH solution gave the corresponding 2-(1H-benzimidazole-2-yl)-
3-aryl-acrylonitrile 2, which on treatment with NaBH4 in ethanol unexpectedly gave
2-(1H-benzimidazole-2-yl)-3-aryl-propionitrile 3 by the regiospecific reduction of
the double bond. Shaking a solution of 2 with H2/Pd-C in methanol also gave 3.
Reaction of 2 with DMS gave the corresponding N-methylated analogue 5, which
also with NaBH4 gave 6, once again by the regiospecific reduction of the double
bond as in the case of 1-demethylated analogue (i.e., 2).
Keywords: 2-cyanomethyl benzimidazoles, aromatic aldehydes, NaBH4, regiospecific
reduction, H2/Pd-C, alkylations
Benzimidazole-containing structures have been well documented to exhibit a
wide range of biological and pharmalogical properties.[1–4] In continuation of
our earlier work on the synthesis of new benzimidazole derivatives with
potential biological activity,[5] o-phenylenediamine was condensed with
ethyl cyanoacetate under refluxing conditions, giving (1H-benzimidazole-2-
yl)-acetonitrile[6] 1. The latter, on treatment with p-methylbenzaldehyde in
5% NaOH solution at room temperature for 2 h, resulted in the formation of
2-(1H-benzimidazole-2-yl)-3-p-methylphenyl-acrylonitrile 2a in 86% yield.
Received in India November 15, 2006
Address correspondence to P. K. Dubey, Department of Chemistry, College of
Engineering, J N T University, Kukatpally, Hyderabad, AP 500 072, India. E-mail:
pvvpr@rediffmail.com
2259

2260
P. K. Dubey and P. V. V. P. Reddy
Treatment of 2a with NaBH4 in 95% ethanol at room temperature
unexpectedly gave 2-(1H-benzimidazole-2-yl)-3-p-methylphenyl-propionitrile
3a, by the reduction of the double bond. NaBH4 is a frequently used hydride
in reduction processes. It is known to reduce polar carbonyl groups such as
aldehydes, ketones,[7] and esters.[8] It is also known to selectively reduce
carbonyl groups in a,b-unsaturated ketones[9] and nitriles under certain con-
ditions.[10] Thus, the reduction of a carbon–carbon double bond by NaBH4
as in the present case appears to be highly unusual. Compared 3a was also
formed when 2a was shaken with H2 over Pd-C in methanol at room tempera-
ture (Scheme 1).
Treatment of 2a with dimethyl sulphate in CH3CN, using triethylbenzy-
lammonium chloride (TEBAC) as a phase-transfer catalyst (PTC) and
K2CO3 as a base at room temperature for 2 h, resulted in the formation of
N-methylated product [i.e., 2-(1-methyl-1H-benzimidazole-2-yl)-3-p-methyl-
phenyl-acrylonitrile 5a]. It could also be prepared by direct condensation of
(1-methyl-1H-benzimidazole-2-yl)-acetonitrile 4a with p-methylbenzalde-
hyde in methanol under basic conditions, which in turn could also be
prepared by alkylation of 1 with DMS in CH3CN as a solvent under PTC con-
ditions. Literature reports[11] indicate preparation of 4a from N-methyl-o-phe-
nylenediamine by refluxation with ethyl cyanoacetate.
When 3a was subjected to methylation with DMS, in the presence of K2CO3
as a base and triethylbenzyl ammonium chloride (TEBAC) as PTC, 2-(1-methyl-
1H-benzimidazole-2-yl)-3-p-methylphenyl-propionitrile 6a was formed. Alter-
natively, 6a could also be obtained by treatment of 5a with NaBH4 in ethanol
or with H2/Pd-C in methanol by the saturation of double bond.
When the reaction of 2-styrylbenzimidaole[12] 7 (R55H or CH3)
(Scheme 2) with NaBH4 in 95% ethanol under the same conditions as before
was attempted, it led to the recovery of the starting material. However,
shaking a solution of 7 with H2 gas over Pd-C at room temperature gave the
corresponding reduced product 8 involving saturation of the double bond.
Scheme 1.

Regiospecific Reduction of the Double Bond by NaBH4
2261
Scheme 2.
Based on these findings, it may be inferred that C55C is reduced regio
specifically, when it is in conjugatation with an electron-withdrawing group
such as nitrile, because of increase in polarization of the double bond.
This method involving saturation of the double bond of 2a, leading to the
formation of 3a, is very advantageous from the synthetic point of view
because preparation of 3a by C-benzylation of 1a with benzyl chloride will
lead to the formation of the N-benzyl derivative in the first instance and
further benzylation will yield N,N1-dibenzylated compound as shown by
our other studies.[13]
EXPERIMENTAL
General
Melting points are uncorrected and were determined in open capillary tubes in
sulphuric acid bath. Thin-layer chromatography (TLC) was performed on
silica gel G, and spotting was done using iodine or UV light. IR spectra
1
were recorded with a Jasco FT-IR 5300, H NMR on a Varian 200-MHz
instrument, and mass spectra on an Agilent LC-MS instrument giving only
Mþ.values using Q þ 1 mode.
Preparation of 2 (General Procedure)
To a solution of 1 (1.57 g, 10 mmol) in 5% NaOH (20 mL), aromatic aldehyde
(11 mmol) was added, and the mixture was stirred at rt for 2–3 h. The progress
of the reaction was monitored on TLC for the disappearance of 1. At the end of
this period, the reaction mixture was poured into ice-cold water and neutral-
ized with AcOH. The separated product was filtered, washed with water,
and dried to obtain 2. The crude product thus obtained was purified by recrys-
tallization from hot methanol to get pure 2 (Tables 1 and 2).
Similarly, condensation of 4 with aromatic aldehydes in aq. methanolic
NaOH solution yielded crude 5 as products, which were purified by recrystal-
lization to obtain pure 5.

2262
P. K. Dubey and P. V. V. P. Reddy
Preparation of 3/6 (General Procedure) (using NaBH4)
To a solution of NaBH4 (0.37 g, 10 mmol) in 95% ethanol (50 mL), 2/5
(10 mmol) was added at 10–158C. Slowly the reaction mixture was
brought to rt and stirred for 2–2.5 h. The progress of the reaction was
monitored on TLC for the disappearance of starting material (i.e., 2/5).
On completion of reaction, the mixture was subjected to evaporation on a
hot-water bath to half of its volume, then poured into ice-water and neutral-
ized with AcOH. The separated product was filtered, washed with water, and
dried. The crude products were recrystallized from hot ethyl acetate to get
pure 3/6.
Alkylation (General Procedure)
To a solution of TEBAC (0.2 g) in CH3CN (20 mL), K2CO3 (1.4 g, 10 mmol)
was added, and the mixture was stirred at rt. To this mixture, under stirring, a
solution of 1/2/3 (10 mmol) in CHCl3 (10 mL) was added followed by the
alkylating agent (11 mmol). The progress of the reaction was monitored on
TLC for the disappearance of 1/2/3. On completion of the reaction (ꢀ3–
4 h), the mixture was filtered, and insoluble material washed with CH3CN
Table 1. Characterization data of 2, 4 and 5a
Time
(min)
Yield
(%)b
Entry
Substrate
Ar-CHO
Reagent Product
a
b
c
d
e
1
1
1
1
1
-C6H4-CH3-p
-C6H5
NaOH
NaOH
NaOH
NaOH
NaOH
2a
2b
2c
2d
2e
120
110
140
130
140
86
72
70
71
72
-C6H4-OCH3-p
-C6H3-N(CH3)2-p
-C6H3-(OCH3)-m-
(OCH3)-p
—
f
1
4
DMS
NaOH
DMS
4
5a
190
125
180
120
180
140
190
135
185
140
76
72
75
73
72
72
70
70
72
73
g
-C6H4-CH3-p
—
-C6H5
2a
4
h
i
NaOH
DMS
5b
5c
5d
5e
2b
4
—
-C6H4-OCH3-p
—
NaOH
DMS
2c
4
j
-C6H3-N(CH3)2-p-
—
NaOH
DMS
NaOH
2d
4
k
-C6H3-(OCH3)-m-
(OCH3)-p
—
2e
DMS
190
70
1
aAll products are characterized by IR, H NMR and mass spectroscopy.
bIsolated yields after purification.

Regiospecific Reduction of the Double Bond by NaBH4
2263
(2 ꢀ 5 mL). The CH3CN filterate was evaporated, and the residue was treated
with a chloroform layer (2 ꢀ 15 mL), washed with water (2 ꢀ 15 mL), and
evaporated to dryness, giving 6 as a crude residual product. The latter was
then recrystallized from a suitable solvent, giving pure 4/5/6.
Spectral and Analytical Data of Compounds
Compound 3a: Mp 208–108C. IR (KBr): 3084, 2254 cm21 1H NMR
;
(200 MHz, CDCl3 þ DMSO-d6): d 2.24 (s, 3H, -CH3), 3.33 (m, 2H, -CH2-),
4.85 (t, 1H, -CH-), 7.08–7.60 (m, 8H, Ar-H), 12.70 (s, 1H, -NH). M/z
(Mþ þ 1): 262. Anal. calcd. for (C17H15N3) requires C, 78.13; H, 5.79;
_
found C, 78.10; H, 5.75%.
Table 2. Characterisation data of 3 and 6a
Time
(min)
Yield
(%)b
Entry
a
Substrate
Reagent
Product
2a
NaBH4
H2/Pd-C
NaBH4
H2/Pd-C
NaBH4
H2/Pd-C
NaBH4
H2/Pd-C
NaBH4
H2/Pd-C
NaBH4
H2/Pd-C
DMS
3a
120
115
120
130
120
125
80
71
79
70
75
69
76
70
74
68
82
72
75
78
70
74
80
70
72
79
68
70
78
69
70
b
c
d
e
f
2b
2c
2d
2e
5a
3b
3c
3d
3e
6a
3a
5b
180
120
180
g
h
i
NaBH4
H2/Pd-C
DMS
6b
6c
6d
6e
3b
5c
NaBH4
H2/Pd-C
DMS
140
3c
5d
190
135
NaBH4
H2/Pd-C
DMs
3d
5e
185
140
j
NaBH4
H2/Pd-C
DMS
3e
190
1
aAll products are characterized by IR, H NMR, and mass spectroscopy.
bIsolated yields after purification.

2264
P. K. Dubey and P. V. V. P. Reddy
1H NMR
Compound 3b: Mp 208–108C. IR (KBr): 3057, 2252 cm21
.
(200 MHz CDCl3 þ DMSO-d6): d 3.35 (m, 2H, -CH2-), 4.90 (t, 1H, -CH-),
7.12–7.63 (m, 9H, Ar-H), 12.70 (s, 1H, D2O exchangeable -NH). M/z
(Mþ þ 1): 248. Anal. calcd. for (C16H13N3) requires C, 77.71; H, 5.30;
_
found C, 77.68; H, 5.28%.
Compound 3c: Mp 208–108C. IR (KBr): 3081, 2242 cm21 1H NMR
.
(200 MHz CDCl3 þ DMSO-d6): d. 3.33 (m, 2H, -CH2-), 3.70 (s, 3H,
-OCH3), 4.83 (t, 1H, -CH-), 6.8–7.6 (m, 8H, Ar-H), 12.69 (s, 1H, D2O
exchangeable -NH). M/z (Mþ þ 1): 278. Anal. calcd. for (C17H15N3O)
_
requires C, 73.63; H, 5.45; found C, 73.61; H, 5.41%.
Compound 3d: Mp 206–088C. IR (KBr): 3081, 2245 cm21 1H NMR
.
(200 MHz CDCl3 þ DMSO-d6): d 2.83 [s, 6H, -N (CH3)2], 3.29 (m, 2H,
-CH2-), 4.76 (t, 1H, -CH-), 6.6–7.6 (m, 8H, Ar-H), 12.68 (s, 1H, D2O
exchangeable -NH). M/z (Mþ þ 1): 291. Anal. calcd. for (C18H18N4)
_
requires C, 74.46; H, 6.25; found C, 74.42; H, 6.24%.
Compound 3e: Mp 186–888C. IR (KBr): 3075, 2238 cm21 1H NMR
.
(200 MHz CDCl3 þ DMSO-d6): d 3.33 (m, 2H, -CH2-), 3.59 (s, 3H,
-OCH3), 3.69 (s, 3H, -OCH3), 4.85 (t, 1H, -CH-), 6.78–7.62 (m, 7H, Ar-H),
12.68 (s, 1H, D2O exchangeable -NH). M/z (Mþ þ 1): 308. Anal. calcd. for
_
(C18H17N3O2) requires C, 70.34; H, 5.58; found 70.32; H, 5.56%.
1
Compound 5a: Mp 110–1128C. IR (KBr): 2225 cm21. H NMR (200 MHz
CDCl3): d 3.10 (s, 3H, -CH3), 4.05 (s, 3H, -NCH3), 6.70–8.0 (m, 8H, Ar-H),
8.10 (s, 1H, 55CH-, vinylic proton). M/z (Mþ þ 1): 274. Anal. calcd. for
_
(C18H15N3) requires C, 79.10; H, 5.53; found C, 79.09; H, 5.52%.
1
Compound 5b: Mp 122–1248C. IR (KBr): 2224 cm21. H NMR (200 MHz
CDCl3): d 4.07 (s, 3H, -NCH3), 7.28–8.45 (m, 9H, Ar-H), 8.24 (s, 1H,
55CH-, vinylic proton). M/z (Mþ þ 1): 260. Anal. calcd. for (C17H13N3)
requires C, 78.74; H, 5.05; found C, 78.71; H, 5.01%.
1
Compound 5c: Mp 138–1408C. IR (KBr): 2214 cm21. H NMR (200 MHz
CDCl3): d 3.90 (s, 3H, -OCH3), 4.03 (s, 3H, -NCH3), 7.0–8.02 (m, 8H, Ar-
H), 8.12 (s, 1H, 55CH-, vinylic proton). M/z (Mþ þ 1): 290. Anal. calcd.
for (C18H15N3O) requires C, 74.72; H, 5.23; found C, 74.70; H, 5.20%.
1
Compound 5d: Mp 166–1688C. IR (KBr): 2228 cm21. H NMR (200 MHz
CDCl3): d 3.10 [s, 6H, -(NCH3)2], 4.04 (s, 3H, -NCH3), 6.70–7.95 (m, 8H,
Ar-H), 8.18 (s, 1H, 55CH-, vinylic proton). M/z (Mþ þ 1): 303. Anal.
calcd. for (C19H18N4) requires C, 75.47; H, 6.00; found C, 75.45, H, 5.98%.
1
Compound 5e: Mp 156–1588C. IR (KBr): 2225 cm21. H NMR (200 MHz
CDCl3): d 3.95 (s, 6H, -3,4-(OCH3)2), 4.05 (s, 3H, -NCH3), 6.9–7.85

Regiospecific Reduction of the Double Bond by NaBH4
2265
(m, 7H, Ar-H), 8.15 (s, 1H,55CH-, vinylic proton). M/z (Mþ þ 1): 320. Anal.
calcd. for (C19H17N3O2) requires C, 71.46; H, 5.37; found C,71.43; H, 5.36%.
1
Compound 6a: Mp 134–1368C. IR (KBr): 2247 cm21. H NMR (200 MHz
CDCl3): d 2.33 (s, 3H, -CH3), 3.50 (m, 2H, -CH2-), 3.59 (s, 3H, -NCH3),
4.35 (t, 1H, -CH-), 7.12–8.0 (m, 8H, Ar-H). M/z (Mþ þ 1): 276. Anal.
calcd. for (C18H17N3) requires C, 78.52; H, 6.22; found C, 78.49; H, 6.21%.
1
Compound 6b: Mp 142–1448C. IR (KBr): 2245 cm21. H NMR (200 MHz
CDCl3): d 3.55 (m, 2H, -CH2-), 3.58 (s, 3H, -NCH3), 4.36 (t, 1H, -CH-),
7.21–7.82 (m, 9H, Ar-H). M/z (Mþ þ 1): 262. Anal. calcd. for (C17H15N3)
requires C, 78.13; H, 5.79; found C, 78.10; H, 5.76%.
1
Compound 6c: Mp 148–1508C. IR (KBr): 2247 cm21. H NMR (200 MHz
CDCl3): d 3.47 (m, 2H, -CH2-), 3.50 (s, 3H, -NCH3), 3.78 (s, 3H, -OCH3),
4.32 (t, 1H, -CH-), 6.82–7.70 (m, 8H, Ar-H). M/z (Mþ þ 1): 292. Anal.
calcd. for (C18H17N3O) requires C, 74.20; H, 5.88; found C, 74.18; 5.85%.
1
Compound 6d: Mp 120–1228C. IR (KBr): 2244 cm21. H NMR (200 MHz
CDCl3): d 2.9 (s, 6H, -N (CH3)2), 3.42 (m, 2H, -CH2-), 3.50 (s, 3H,
-NCH3), 4.3 (t, 1H, -CH-), 6.6–7.8 (m, 8H). M/z (Mþ þ 1): 305. Anal.
calcd. for (C19H20N4) requires C, 74.97; H, 6.62; found C, 74.96; H, 6.60%.
1
Compound 6e: Mp 128–1308C. IR (KBr): 2246 cm21. H NMR (200 MHz
CDCl3): d 3.5 (s, 3H, -OCH3), 3.6 (s, 3H, -OCH3), 3.8 (m, 2H, -CH2-),
3.82 (s, 3H, -NCH3), 4.3 (t, 1H, -CH-), 6.6–7.8 (m, 8H, Ar-H). M/z
(Mþ þ 1): 322. Anal. calcd. for (C19H19N3O2) requires C, 71.01; H, 5.96;
found C, 70.99; H, 5.98%.
ACKNOWLEDGMENT
The authors are highly indebted to the University Grants Commission (UGC),
Govternment of India, New Delhi, for financial support in the form of a major
research project grant.
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