Alternate method for the synthesis of N-alkyl/aralkyl-2-(α-hydroxy alkyl/aralkyl)benzimidazoles via regiospecific acetylation

Article abstract of DOI:10.1080/00397910701265556

Acetylation of 1H-2-(α-hydroxyalkyl/aryl)benzimidazoles 2 with Ac2O results in the regiospecific formation of O-acetoxy derivative 3, which on alkylation with alkylating agents in nonaqueous media under phase-transfer catalytic conditions affords N-alkyl

Full text of DOI:10.1080/00397910701265556

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Alternate Method for the Synthesis
of N‐Alkyl/aralkyl‐2‐(α‐hydroxy Alkyl/
aralkyl)benzimidazoles via Regiospecific
Acetylation
P. K. Dubey a , P.V.V. Prasada Reddy a & K. Srinivas a
a Deptartment of Chemistry, College of Engineering, J. N. T. University,
Hyderabad, A. P., India
Published online: 22 May 2007.
To cite this article: P. K. Dubey , P.V.V. Prasada Reddy & K. Srinivas (2007) Alternate Method for the Synthesis
of N‐Alkyl/aralkyl‐2‐(α‐hydroxy Alkyl/aralkyl)benzimidazoles via Regiospecific Acetylation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:10,
1675-1681, DOI: 10.1080/00397910701265556
To link to this article: http://dx.doi.org/10.1080/00397910701265556
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Synthetic Communicationsw, 37: 1675–1681, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701265556
Alternate Method for the Synthesis of
N-Alkyl/aralkyl-2-(a-hydroxy Alkyl/
aralkyl)benzimidazoles via Regiospecific
Acetylation
P. K. Dubey, P. V. V. Prasada Reddy, and K. Srinivas
Deptartment of Chemistry, College of Engineering, J. N. T. University,
Kukatpally, Hyderabad, India
Abstract: Acetylation of 1H-2-(a-hydroxyalkyl/aryl)benzimidazoles 2 with Ac2O
results in the regiospecific formation of O-acetoxy derivative 3, which on alkylation
with alkylating agents in nonaqueous media under phase-transfer catalytic conditions
affords N-alkyl derivatives 4. The latter, on hydrolysis in an aqueous basic medium,
results in the title compounds 5 in good yields in high purity. Alternatively, 5 can
also be obtained by reduction of 1-substituted-2-acetyl/benzoylbenzimidazoles 8
using NaBH4.
Keywords: alkylation, 2-a-hydroxybenzimidazoles, hydrolysis, 2-keto benzimida-
zoles, NaBH4, regiospecific acetylation
Substituted benzimidazole derivatives exhibit[1] have been shown a wide
range of biological properties. They also have commercial application in
veterinary medicine as anthelmintic agents and in such diverse human thera-
peutic areas as anti-ulcerous, antihypertensive, antiviral, antifungal, antican-
cerous, and antihistaminic agents. They also find application as molecular
probes,[2] to name just a few of their uses.
In continuation of our earlier work[3–5] on synthesis of new benzimidazole
derivatives with potential biological activity, we have been interested in the
Received June 29, 2006
Address correspondence to P. K. Dubey, Deptartment of Chemistry, College of
Engineering, J. N. T. University, Kukatpally, Hyderabad, A. P. 500 072, India.
E-mail: pvvpr@rediffmail.com
1675

1676
P. K. Dubey, P. V. V. P. Reddy, and K. Srinivas
synthesis of N-alkyl/aralkyl-2-sub-(a-hydroxyalkyl/aralkyl)benzimidazoles.
The results of our studies in this direction are presented in this communication.
o-Phenylenediamine 1, on condensation with (+) lactic acid in 4N HCl
(i.e., Phillips condition), gave the previously reported[6] 1H-2-(a-hydro-
xyethyl)benzimidazole (2a, i.e., 2, R ¼ CH3). Acetylation of 2a with acetic
anhydride gave an acetyl derivative of 3a, which could probably be one of
the two regiospecific products (i.e., the N-acetyl or O-acetyl derivative of
1
2a) based on its mass spectrum and H NMR spectrum. Treatment of this
product with dimethyl sulphate, in the presence of a base, gave a monomethy-
lated derivative 3a, which could once again be one of the two probable regioi-
somers (i.e., N-methylated derivative or O-methylated derivative) based on
the starting intermediate being O-acetylated or N-acetylated compound.
However, hydrolysis of 3a with aq. alkali gave N-methyl-2-(a-hydroxyethyl)-
benzimidazole 5a1, an authentic sample of which was also obtained by direct
condensation of N-methyl-o-phenylenediamine 6a (i.e., 6, R1 ¼ CH3) with
(+) lactic acid under the Phillips condition using the literature procedure.[7]
Based on these results, the structure of the regioisomer 2a was unambiguously
assigned as the O-acetyl derivative of 1H-2-(a-hydroxyethyl)benzimidazole.
Thus, reaction of 3awith diethyl sulphate and PhCH2Cl gavethecorrespond-
ing N-ethyl/benzyl derivatives, which on aq. alkaline hydrolysis yielded the res-
pective N-ethyl/benzyl-2-(a-hydroxyethyl)benzimidazoles.[8] This sequence of
reactions has been advantageous in preparing N-substituted-2-(a-hydroxyethyl)-
benzimidazoles. The reactions of 3a have also been carried out with 3b (i.e.,
R ¼ Ph) (Scheme 1) and similar results were obtained. The compound 3b
itself was prepared from 1 and mandelic acid using the literature[9] procedure.
Furthermore, it was found that 5a1 could also be obtained by the reduction of
Scheme 1.

N-Alkyl/aralkyl-2-(a-hydroxy Alkyl/aralkyl)benzimidazoles
1677
N-methyl-2-acetylbenzimidazole 8a1, which in turn was prepared by literature
methods,[10,11] with NaBH4, thereby establishing in an unambiguous manner
the regiospecificity of acetylation of 2a. All these reactions appear to be very
general and have been extended to other derivatives of 8a1.
Condensation of 1 with glycolic acid in 4N HCl gave the previously
reported[5] 2-hydroxymethylbenzimidazole 2c. Acetylation of 2c with acetic
anhydride unexpectedly gave a diacetyl derivative of 2c, as found from its
spectral data. This latter product was assigned N-acetoxy-2-(acetoxymethyl)-
benzimidazole 2d, corresponding to simultaneous N- and O-acetylation of 2c.
Further, it was hydrolyzed by hot water, forming a monoacetyl derivative,
which may be an N-acetyl or O-acetyl compound. Regiospecific studies
were carried out for this compound similar to the previously mentioned
sequence of reactions (i.e., alkylation followed by hydrolysis of 4c). The
resultant product 5c (obtained by hydrolysis of diacetyl compound 2d)
could also be obtained by direct condensation of glycolic acid with 6 under
Phillips conditions, which was confirmed by spectral and analytical data.
From these studies, the product 3c was found to be the O-acetyl derivative
(Scheme 2).
The advantages of this protocol are regioselective acetylation, followed
by alkylation studies in nonaqueous media under phase-transfer catalytic con-
ditions to get the title compounds in good yields.
Alternatively, title compounds could also be prepared by reduction of
1-substituted-2-acetyl/benzoylbenzimidazole using NaBH4 in excellent yields.
EXPERIMENTAL
Melting points are uncorrected and were determined in open capillary tubes in
a sulphuric acid bath. Thin-layer chromatography (TLC) was performed on
silica-gel G, and spotting was done using iodine or ultraviolet (UV) light.
IR spectra were recorded with a Perkin-Elmer 1000 instrument in KBr
1
phase. H NMR was recorded on a Varian 200-MHz instrument, and mass
Scheme 2.

1678
P. K. Dubey, P. V. V. P. Reddy, and K. Srinivas
spectra were recorded on Agilent LC-MS instrument giving only Mþ. values
using Q þ 1 mode.
Typical Procedure for 3
To a solution of 2 (10 mmol), acetic anhydride (11 mmol) was added, and
the mixture was heated at 125–1308C under reflux for 2 h. At the end of this
period, the reaction mixture was cooled to rt and poured into ice-cold water.
The separated product was filtered, washed with water, and dried to obtain 3.
The crude 3 obtained was recrystallized from hot benzene to yield pure 3.
When 2c (10 mmol) was treated with acetic anhydride (22 mmol), it
resulted in the formation of diacetyl derivative, which was hydrolyzed with
water to give the monoacetyl derivative.
Typical Procedure for 4
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 3 (10 mmol) in CH3CN (10 mL) was added, followed by alkylating
agent (12 mmol). The progress of the reaction was monitored on TLC for the
disappearance of 3. On completion of reaction (ꢀ4 h), the mixture was
filtered, and insoluble material was washed with CH3CN (2 ꢀ 5 mL). The
CH3CN filterate was evaporated to dryness. The residue was treated with
CHCl3 (30 mL) and washed with water (3 ꢀ 30 mL), and the CHCl3 layer
was evaporated to dryness to obtain the product. The crude product was
recrystallized from hot benzene to obtain pure 4.
Typical Procedure for 5
A mixture of 4 (10 mmol) and aq. NaOH (20%, 10 mL) in MeOH
(10 mmol) was stirred at rt for 30 min. The progress of the reaction was
monitored on TLC for disappearance of 4. On completion of the reaction,
the mixture was poured into ice-cold water and neutralized with acetic acid.
The mixture was extracted with ethyl acetate (2 ꢀ 10 mL). The organic
layer was dried over anh. Na2SO4 and then evaporated to dryness, yielding
a crude product. The crude product was recrystallized from ethyl acetate to
obtain pure 5.
Typical Procedure for Reduction of 8
NaBH4 (0.37 g, 10 mmol) was added to MeOH (10 mL) under cooling con-
ditions (5–108C) and stirred for 5 min. To this, a solution of 7 (10 mmol)

N-Alkyl/aralkyl-2-(a-hydroxy Alkyl/aralkyl)benzimidazoles
1679
taken in MeOH under cooling conditions was added over a period of 10 min.
Then, the reaction mixture was brought to rt and stirred for 2 h. On completion
of reaction, as confirmed by TLC, the excess solvent was removed by distilla-
tion. The residual reaction mixture was poured into ice-cold water under
vigorous stirring. The separated product was filtered, washed with ice-cold
water, and dried to obtain 5.
Data
3a: R ¼ CH3, R1 ¼ H; yield ¼ 82%; mp 150–1528C; IR (KBr): 2935,
1
1745 cm21; H NMR (DMSO-d6, 200 MHz): d 1.87 (d, 3H, -CH-CH3 ),
ꢁ
2.13 (s, 3H, -O-CO-CH3), 6.11 (q, 1H, -CHꢁ-CH3), 7.27–7.8 (m, 4H, aryl
protons), 9.92 (bs, 1H, D2O exchangeable, -NH); Mþ þ 1:205.
3b: R ¼ C6H5, R1 ¼ H; yield ¼ 80%; mp 170–1728C; IR (KBr): 3025,
1
1741 cm21; H NMR (DMSO-d6, 200 MHz): d 2.19 (s, 3H, -O-CO-CH3),
6.89 (s, 1H, -CH-), 7.14–7.58 (m, 9H, aryl protons), 12.5 (bs, 1H, D2O
exchangeable, -NH); Mþ þ 1:267.
3c: R ¼ R1 ¼ H; yield ¼76%; mp 164 – 1668C; IR (KBr): 2895, 1736 cm21
;
1H NMR (DMSO-d6, 200 MHz): d 2.15 (s, 3H, -O-CO-CH3), 5.39 (s, 2H,
-CH2-), 7.26–7.80 (m, 4H, aryl protons), 10.10 (bs, 1H, D2O exchangeable,
-NH).; Mþ þ 1:191.
1
4a1: R ¼ R1 ¼ CH3; yield ¼ 82%; mp 70–728C; IR (KBr): 1738 cm21; H
ꢁ
NMR (CDCl3, 200 MHz): d 1.8 (d, 3H, -CH-CH3 ), 2.1 (s, 3H, -O-CO-
CH3), 3.8 (s, 3H, -NCH3), 6.15 (q, 1H, -CHꢁ-CH3), 7.2–7.7 (m, 4H, aryl
protons). Mþ þ 1:219
4a2: R ¼ CH3, R1 ¼ C2H5; yield ¼ 68%; mp 150–1528C; IR (KBr):
1
1742 cm21; H NMR (CDCl3, 200 MHz): d 1.45 (t, 3H, -CH2-CH3 ), 1.8
ꢁ
ꢁ
(d, 3H, ꢁ-CH-CH3 ), 2.1 (s, 3H, -O-CO-CH3), 4.25 (doublet of quartet, 2H,
-N-CH2 -CH3), 6.15 (q, 1H, -CHꢁ-CH3), 7.15–7.7 (complex m, 4H, aryl
proton; Mþ þ 1:233.
4a3: R ¼ CH3, R1 ¼ CH2-C6H5; yield ¼ 72%; mp 78–808C; IR (KBr):
1
1739 cm21; H NMR (CDCl3, 200 MHz): d 1.75 (d, 3H, -CH-CH3 ), 1.8
ꢁ
(s, 3H, -O-CO-CH3), 5.45 (q, 2H, -CH2 -Ph), 6.15 (q, 1H, -CHꢁ-CH3), 6.9–
ꢁ
7.9 (m, 9H, aryl protons); Mþ þ1:295.
4b1: R ¼ C6H5, R1 ¼ CH3; yield ¼ 73%; mp 48–508C; IR (KBr):
1
1745 cm21; H NMR (CDCl3, 200 MHz): d 2.2 (s, 3H, -O-CO-CH3), 3.65
(s, 3H, -NCH3), 7.1 (s, 1H, -CH-), 7.2–7.8 (m, 9H, aryl protons); Mþ þ 1:281.
4b2: R ¼ C6H5, R1 ¼ C2H5; yield ¼ 69%; mp 118–1208C; IR (KBr):
1
1734 cm21; H NMR (CDCl3, 200 MHz): d 1.23 (t, 3H, -CH2-CH3 ), 2.2
ꢁ

1680
P. K. Dubey, P. V. V. P. Reddy, and K. Srinivas
ꢁ
(s, 3H, -O-CO-CH3), 4.2 (doublet of quartet, 2H, -N-CH2 -CH3), 7.1 (s, 1H,-
CH), 7.2–7.8 (m, 9H, aryl protons); Mþþ1:295.
4b3: R ¼ C6H5, R1 ¼ CH2- C6H5; yield ¼ 74%; mp 98–1008C; IR (KBr):
1
1735 cm21; H NMR (CDCl3, 200 MHz): d 1.95 (s, 3H, -O-CO-CH3), 5.35
(dd, 2H, -CH2-), 7.0 (s, 1H, -CH-), 7.1–7.75 (m, 14H, aryl protons);
Mþ þ 1:357.
4c1: R ¼ H, R1 ¼ CH3; yield ¼ 75%; mp 60–628C; IR (KBr): 1747 cm21; 1H
NMR (CDCl3, 200 MHz): d 1.92 (s, 3H, -O-CO-CH3), 3.58 (s, 3H, -NCH3),
5.36 (s, 2H, -CH2-), 7.15–7.8 (m, 4H, aryl protons); Mþ þ 1:205.
4c2: R ¼ H; R1 ¼ CH2-C6H5; yield ¼ 69%; mp 78–808C; IR (KBr):
1
1751 cm21; H NMR (CDCl3, 200 MHz): d 1.9 (s, 3H, -O-CO-CH3), 5.35
(s, 2H, -CH2-), 5.44 (s, 2H, -CH2), 7.0–7.8 (m, 9H, aryl protons); Mþ þ 1:281.
5a1: R ¼ R1 ¼ CH3; yield ¼ 80/71% (aq. NaOH/NaBH4); mp 80–828C; IR
1
(KBr): 3145 cm21; H NMR (CDCl3, 200 MHz): d 1.70 (d, 3H, -CH-CH3 ),
ꢁ
3.9 (s, 3H, -NH3) 5.1 (q, 1H, -CHꢁ-CH3), 5.45 (bs, 1H, D2O exchangeable,
-OH), 7.1–7.7 (m, 4H, aryl protons); Mþ þ 1:177.
5a2: R ¼ CH3, R1 ¼ C2H5; yield ¼ 75/69% (aq. NaOH/NaBH4); mp
102–1048C; IR (KBr): 3128 cm21
;
1H NMR (CDCl3, 200 MHz): d 1.4
ꢁ
ꢁ
ꢁ
(t, 3H, -N-CH2-CH3 ), 1.6 (d, 3H, -CH-CH3 ), 4.25 (q, 2H, -N-CH2 -CH3),
5.02 (q, 1H, -CHꢁ-CH3), 7.1-7.6 (m, 4H, aryl protons), 5.4 (bs, 1H, D2O
exchangeable, -OH); Mþ þ 1:191.
5a3: R ¼ CH3, R1 ¼ CH2-C6H5; yield ¼ 78/68% (aq. NaOH/NaBH4); mp
1
124–1268C; IR (KBr): 3192 cm21; H NMR (CDCl3, 200 MHz): d 1.65
ꢁ
(d, 3H, -CH-CH3 ), 5.1 (doublet of quartet 1H, -CHꢁ-CH3), 5.4 (d, 1H, D2O
exchangeable, -OH), 5.65 (s, 2H, -NCH2Ph), 7.1–7.8 (m, 9H, aryl protons);
Mþ þ 1:253.
5b1: R ¼ C6H5, R1 ¼ CH3; yield ¼ 78/70% (aq. NaOH/NaBH4); mp
1
158–1608C; IR (KBr): 3062 cm21; H NMR (CDCl3, 200 MHz): d 3.45
(s, 3H, -NCH3), 5.4 (bs, 1H, D2O exchangeable, -OH), 6.10 (s, 1H, -CH-),
7.1–7.8 (m, 9H, aryl protons); Mþ þ 1:239.
5b2: R ¼ C6H5, R1 ¼ C2H5; yield ¼ 76/69% (aq. NaOH/NaBH4); mp
1
162–1648C; IR (KBr): 3058 cm21; H NMR (CDCl3, 200 MHz): d (t, 3H,
ꢁ
ꢁ
-CH2- CH3 ), 4.0 (doublet of quartet, -CH2 -CH3), 5.1 (bs, 1H, D2O
exchangeable, -OH), 6.0 (s, 1H, -CH-), 7.1–7.8 (m, 9H, aryl protons);
Mþþ1:253.
5b3: R ¼ C6H5, R1 ¼ CH2-C6H5; yield ¼ 78/69% (aq. NaOH/NaBH4); mp
1
162–1648C; IR (KBr): 3058 cm21; H NMR (CDCl3, 200 MHz): d 5.38

N-Alkyl/aralkyl-2-(a-hydroxy Alkyl/aralkyl)benzimidazoles
1681
(dd, 2H, -N-CH2Ph), 6.2 (s, 1H, -CH-), 6.45 (bs, 1H, D2O exchangeable, -OH),
6.8–7.7 (m, 14H, aryl protons); Mþ þ 1:315.
5c1: R ¼ H, R1 ¼ CH3; yield ¼ 76% (aq. NaOH); mp 96–988C; IR (KBr):
1
3065 cm21; H NMR (CDCl3, 200 MHz): d 1.28 (s, 2H, -CH2-), 3.8 (s, 3H,
-NCH3), 4.88 (s, 1H, D2O exchangeable, -OH), 7.2–7.7 (m, 4H, aryl
protons); Mþ þ 1:163.
5c2: R ¼ H, R1 ¼ CH2-C6H5; yield ¼ 75% (aq. NaOH); mp 180–1828C;
1
IR (KBr): 3145 cm21; H NMR (CDCl3, 200 MHz): d 4.72 (d, 2H, -CH2 -
ꢁ
OH), 5.55 (s, 2H, -CH2Ph), 5.72 (improperly resolved triplet, 1H, D2O
exchangeable, -OH), 7.10–7.64 (m, 9H, aryl); Mþ þ 1:239.
ACKNOWLEDGMENT
The authors are highly indebted to the University Grants Commission,
Government of India, New Delhi, for financial support.
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