C. S. Radatz et al. / Tetrahedron Letters 52 (2011) 4132–4136
4135
Table 4
containing electron donating (EDG) (Table 3, entries 2–3 and 6) and
electron withdrawing groups (EWG) (Table 3, entries 4 and 5) at the
benzene ring could be obtained in good yields. Excellent yield
of condensation was achieved using furan-2-carbaldehyde 4g
(Table 3, entry 7). Finally, when we employed the naturally occur-
ring aldehyde 4h, the corresponding benzimidazole derived from
(R)-citronellal 5h was synthesized in 91% after 6 h (Table 3, entry 8).
After extending the scope of synthesis of benzimidazoles, we
check the recyclability of glycerol in this reaction (Table 4). After
completion of condensation, the reaction mixture was extracted
with hexane/ethyl acetate (95:5) and the glycerol phase was dried
and reused. It could then be reused for further catalytic reactions
and the yields of benzimidazole 5a after four recycles were almost
the same without loss of solvent activity.
In order to investigate if glycerol could be used as a selective
solvent, we carried out a competitive condensation reaction using
o-phenylenediamine 1 (1.0 mmol) and an equimolar mixture of
acetophenone 2a (2.0 mmol) and benzaldehyde 4a (2.0 mmol).
After 12 h of reaction, only o-phenylenediamine 1 and benzalde-
hyde 4a were totally consumed, and the product derived from
o-phenylenediamine and benzaldehyde was formed exclusively
and isolated in 90% yield (Scheme 2). The resulting acetophenone
2a was recovered quantitatively.
Reuse of glycerol in the synthesis of benzimidazole 5aa
N
N
NH2
NH2
glycerol
90 C, air
Ph
Ph
O
+
°
Ph
H
1
4a
5a
Run
Reaction time (h)
Yield 5ac (%)
1
1.0
1.0
1.0
1.5
1.5
91
91
90
89
85
2b
3b
4b
5b
a
Reaction is performed using o-phenylenediamine 1a (1.0 mmol), acetophenone
2a (2.0 mmol) in glycerol (3 mL) at 90 °C.
b
Recovered glycerol was used.
Yields are given for isolated products.
c
NH2
H
N
N
N
O
O
Ph
NH2
1
Ph
Ph
+
+
Ph
Ph
H
In conclusion, we have presented here a simple, efficient, and
catalyst-free methodology for the synthesis of benzodiazepines
and benzimidazoles in good yields by the condensation of o-phen-
ylenediamine with several ketones and aldehydes, respectively,
using glycerol as solvent. Glycerol can be directly reused without
previous purification for further condensation reactions.
glycerol
N
3a
Ph
2a
4a
5a
90%
90 °C, air
Scheme 2. Competitive condensation reaction in glycerol.
obtained (Table 1, entry 5). When we performed the reaction using
other alcoholic solvents such as ethanol, no product 3a was ob-
tained (Table 1, entry 6). In an optimized reaction,18 o-phenylene-
diamine 1 (1.0 mmol) was dissolved in glycerol (3 mL) and reacted
with acetophenone 2a (2.0 mmol) at 90 °C during 4 h, yielding ben-
zodiazepine 3a in 96% yield (Table 1, entry 4).
Acknowledgments
The authors are grateful to FAPERGS (FAPERGS/PRONEX 10/
0005-1 and 10/0027-4), CAPES, FINEP and CNPq for the financial
support.
After reaction optimization, a study regarding the reuse of glyc-
erol was performed. After the total consumption of reagents, the
reaction mixture was diluted and extracted with a mixture of hex-
ane/ethyl acetate 95:5 (3 Â 3 mL). The upper phase was dried and
the solvent evaporated. The inferior, glycerol phase, was dried under
vacuum and directly reused.19 Glycerol maintained its good level of
efficiency even after being reused four times. The product 3a was ob-
tained in 96%, 96%, 96%, 91%, and 89% yields after successive cycles.
To demonstrate the generality of this method, we prepared a
series of benzodiazepines 3a–h using aryl, alkyl, and cyclic ketones
(Table 2). In most cases, the reactions proceeded smoothly to give
benzodiazepines 3a–h in satisfactory yields. Symmetrical alkylke-
tones 2b and 2c were suitable substrates for the reaction, and
the respective products were obtained in satisfactory yields (Table
2, entries 2 and 3). Using unsymmetrical ketones, such as butan-2-
one 2d, pentan-2-one 2e and 4-methylbutan-2-one 2f as
substrates, corresponding products 3d–f were formed in good
yields (Table 2, entries 4–6). It is interesting to note that the ring
closure in these examples was selective from one side of the car-
bon chain giving a single product. Cyclic ketones 2g and 2h reacted
to give the desired benzodiazepines 3g and 3h in excellent yields
(Table 2, entries 7 and 8).
References and notes
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To extend the scope of our methodology, the possibility of the
synthesis of benzimidazoles using glycerol as solvent was investi-
gated. Thus, o-phenylenediamine 1 (1.0 mmol) was dissolved in
glycerol (3 mL) and reacted with benzaldehyde 4a (2.0 mmol) at
90 °C, and to our satisfaction benzimidazole 5a was obtained in
91% isolated product yield (Table 3, entry 1). In view of this result,
a variety of aryl aldehydes were condensed to corresponding
benzimidazoles in good yields (Table 3, entries2–6). Benzimidazoles
9. For the synthesis of benzimidazoles see: (a) Perumal, S.; Mariappan, S.;
Selvaraj, S. ARKIVOC 2004, viii, 46; (b) Trivedi, R.; De, S. K.; Gibbs, R. A. J. Mol.
Catal. A: Chem. 2006, 245, 8; (c) Oskooie, H. A.; Heravi, M. M.; Sadnia, A.;