Tetrahedron Letters 52 (2011) 4132–4136

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Tetrahedron Letters
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Catalyst-free synthesis of benzodiazepines and benzimidazoles

using glycerol as recyclable solvent
Catia S. Radatz, Rodrigo B. Silva, Gelson Perin, Eder J. Lenardão, Raquel G. Jacob ⇑, Diego Alves ⇑
LASOL, IQG, Universidade Federal de Pelotas, UFPel, PO Box 354, 96010-900 Pelotas, RS, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: We described herein the use of glycerol as solvent in the catalyst-free synthesis of benzodiazepines and
Received 15 March 2011 benzimidazoles. This simple and efficient method furnishes the corresponding 1-H-1,5-benzodiazepines
Revised 25 May 2011 and 1,2-disubstituted benzimidazoles in good yields by the condensation of o-phenylenediamine with
Accepted 27 May 2011
several ketones and aldehydes, respectively. In addition, glycerol can be easily re-utilized for further con-
Available online 23 June 2011
densation reactions up to four times without lost of activity.
Ó 2011 Elsevier Ltd. Open access under the Elsevier OA license.
Keywords:
Glycerol
Benzodiazepines
Benzimidazoles

Benzodiazepines and benzimidazoles represent a significant using green solvents, such as, water and ionic liquids has been
class of biologically active nitrogen compounds and exhibit a num- described.10
ber of important biological properties,1,2 such as anticonvulsant, In organic synthesis, the choice of the solvent is a crucial step in
antianxiety, antiinflammatory, analgesic, hypnotic, antidepressive, a chemical reaction. The development of green methodologies
antihistaminic, anti-ulcerative, antiallergic, and antipyretic. Their from renewable resources has gained much interest recently be-
syntheses have received much attention in the field of medicinal cause of the extensive uses of solvents in almost all of the chemical
and pharmaceutical chemistry.1,2 For example, the use of 1-H- industries, and of the predicted disappearance of fossil oil.11 The
1,5-benzodiazepines has been extended to various diseases, such wanted characteristics for a green solvent include no flammability,
as cancer, viral infection, and cardiovascular disorders.3 Benzimid- high availability, obtaining from renewable sources, and biode-
azole derivatives are effective against the human cytomegalovirus gradability.12 With the increase in biodiesel production world-
(HCMV)4 and are also efficient selective neuropeptide Y Y1 recep- wide, the market saturation of glycerol, a side product of biodiesel
tor antagonists.5 In addition, the derivatives of benzodiazepines are production, is inevitable.13 The use of glycerol14 and their eutet-
used as dyes for acrylic fibers in photography6 and benzimidazoles ics15 as a sustainable solvent for green chemistry were recently re-
derivatives, because their great electron mobility, have been devel- lated. Heck and Suzuki cross-couplings, ring closing metathesis of
oped as layer materials for electron transport.7 diolefins, multicomponent reactions, asymmetrical reduction, and
Benzodiazepines and benzimidazoles are principally synthe- cycloisomerization of (Z)-enynols into furans, are some examples
sized by the condensation of o-phenylenediamine with ketones8 of the use of glycerol as solvent in organic reactions.14
and aldehydes,9 respectively, in the presence of conventional or The peculiar physical and chemical properties of glycerol, such
Lewis acid catalysts. In these procedures, many reagents have been as polarity, low toxicity, biodegradability, high boiling point, and
used, however, a number of these processes have some limitations, ready availability from renewable feed stocks16 prompted us to ex-
such as long reaction times, tedious work-up procedures and gener- tend its use as a green solvent in organic synthesis. According to
ation of by-products. Therefore, the search for a better reaction sys- our interest in the green protocols in organic chemistry,9f,17 we de-
tem for the synthesis of benzodiazepines and benzimidazoles in scribe here the use of glycerol as green solvent in the catalyst-free
terms of mild reaction conditions, economic viability, and selectiv- synthesis of benzodiazepines and benzimidazoles by the conden-
ity continues to attract the interest of synthetic organic chemists. In sation of o-phenylenediamine with several ketones and aldehydes
this context, synthesis of benzodiazepines and benzimidazoles (Scheme 1).
Initially, we reacted o-phenylenediamine 1 (1.0 mmol) with an
⇑ Corresponding authors. excess of acetophenone 2a (2.5 mmol) using glycerol as solvent at
E-mail addresses: [Link]@[Link] (R.G. Jacob), [Link]@ufpel.
different temperatures to optimize the reaction conditions to
[Link] (D. Alves). access benzodiazepine 3a (Table 1). When the reaction was

0040-4039 Ó 2011 Elsevier Ltd. Open access under the Elsevier OA license.
doi:10.1016/[Link].2011.05.142
 C. S. Radatz et al. / Tetrahedron Letters 52 (2011) 4132–4136 4133

O O
R1 R1 N
H R NH2 R H
N 2a-h 4a-h R
R
N
R1 glycerol glycerol
NH2 R
N o 5a-h
R 90 C, air 1 90 °C, air
3a-h
R = Aryl, alkyl
R 1 = Alkyl

Scheme 1. General scheme of reaction.

Table 1 Table 2 (continued)

Reaction conditions optimizationa
Entry Ketone Time (h) Product
Yieldb (%)
H
NH2 N Ph O H
O glycerol N
+
air
NH2 Ph
N 4 5.0
Ph 2d
1 2a 3a N

Entry Temperature (°C) Time (h) Yield 3ab (%) 3d (85%)

1 rt 24 20 O H
2 60 9 73 N
3 90 4 97
4c 90 4 96
5 2e 5.0
5d 90 24 — N
6e Reflux 24 —
a
Reactions are performed using of o-phenylenediamine 1a (1.0 mmol), aceto-
phenone 2a (2.5 mmol) in glycerol (3 mL). 3e (84%)
b
Yields are given for isolated product. O
c
Reaction using 2.0 mmol of acetophenone 2a.
d H
Reaction performed without glycerol. N
e
Reaction performed in ethanol.
2f
6 7.0

3f (80%)
O
H
Table 2 N
Synthesis of benzodiazepines 3a–h using glycerol as solventa
7 6.0
Entry Ketone Time (h) Product
Yieldb (%) 2g N
O H 3g (89%)
N
O
H
N
1 4.0 N
8 5.5
2a
2h N

3a (96%) 3h (72%)
O H a
N Reactions are performed using o-phenylenediamine 1a (1.0 mmol), ketones 2a–
h (2.0 mmol) in glycerol (3 mL) at 90 °C.
b
Yields are given for isolated product.
2 2b 8.0
N

3b (45%) performed at room temperature, product 3a was formed in low

O yield (Table 1, entry 1). To our satisfaction, by increasing the tem-
H
N perature, the reaction proceeds smoothly, and at 90 °C benzodiaz-
epine 3a was obtained in 97% (Table 1, entry 3). However, as a
3 2c 4.5 positive result, when the amount of acetophenone 2a was reduced
N from 2.5 to 2.0 mmol, excellent yield of product 3a was still ob-
tained (Table 1, entry 4). It is also important to mention that when
3c (92%) the reaction was performed without glycerol no product was
4134 C. S. Radatz et al. / Tetrahedron Letters 52 (2011) 4132–4136

Table 3
Synthesis of benzimidazoles 5a–h using glycerol as solventa

Entry Aldehyde Time (h) Product

Yieldb (%)

CHO N

N
1 1.0
4a

5a (91%)
CHO N
OMe
N
MeO
2 4.0
4b
OMe

5b (92%)
CHO N

N
3 3.5
4c

5c (94%)
CHO N
Cl
N
Cl
4 1.0
4d
Cl

5d (84%)
CHO N
NO2
N
O2N
5 0.8
4e NO2

5e (88%)
CHO MeO
N
OMe
N
6 4f 4.0

MeO
5f (80%)
O N O
CHO

N
7 0.7 O
4g

5g (93%)

CHO N
8 6.0

4h
5h (91%)
a
Reactions are performed using o-phenylenediamine 1a (1.0 mmol), aldehydes 4a–h (2.0 mmol) in glycerol (3 mL) at 90 °C.
b
Yields are given for isolated product.
 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
Reuse of glycerol in the synthesis of benzimidazole 5aa electron withdrawing groups (EWG) (Table 3, entries 4 and 5) at the
N benzene ring could be obtained in good yields. Excellent yield
NH2 O glycerol Ph of condensation was achieved using furan-2-carbaldehyde 4g
+ N
90 °C, air (Table 3, entry 7). Finally, when we employed the naturally occur-
NH2 Ph H
Ph ring aldehyde 4h, the corresponding benzimidazole derived from
1 4a 5a
(R)-citronellal 5h was synthesized in 91% after 6 h (Table 3, entry 8).
After extending the scope of synthesis of benzimidazoles, we
Run Reaction time (h) Yield 5ac (%) check the recyclability of glycerol in this reaction (Table 4). After
1 1.0 91 completion of condensation, the reaction mixture was extracted
2b 1.0 91 with hexane/ethyl acetate (95:5) and the glycerol phase was dried
3b 1.0 90 and reused. It could then be reused for further catalytic reactions
4b 1.5 89
and the yields of benzimidazole 5a after four recycles were almost
5b 1.5 85
the same without loss of solvent activity.
a
Reaction is performed using o-phenylenediamine 1a (1.0 mmol), acetophenone In order to investigate if glycerol could be used as a selective
2a (2.0 mmol) in glycerol (3 mL) at 90 °C.
b
solvent, we carried out a competitive condensation reaction using
Recovered glycerol was used.
c
Yields are given for isolated products.
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
NH2
o-phenylenediamine and benzaldehyde was formed exclusively
H
O O N N and isolated in 90% yield (Scheme 2). The resulting acetophenone
NH2 Ph
1 Ph 2a was recovered quantitatively.
+ +
Ph Ph H N In conclusion, we have presented here a simple, efficient, and
glycerol N
Ph Ph catalyst-free methodology for the synthesis of benzodiazepines
2a 4a 90 °C, air 3a 5a
90% and benzimidazoles in good yields by the condensation of o-phen-
ylenediamine with several ketones and aldehydes, respectively,
Scheme 2. Competitive condensation reaction in glycerol. using glycerol as solvent. Glycerol can be directly reused without
previous purification for further condensation reactions.
obtained (Table 1, entry 5). When we performed the reaction using
Acknowledgments
other alcoholic solvents such as ethanol, no product 3a was ob-
tained (Table 1, entry 6). In an optimized reaction,18 o-phenylene-
The authors are grateful to FAPERGS (FAPERGS/PRONEX 10/
diamine 1 (1.0 mmol) was dissolved in glycerol (3 mL) and reacted
0005-1 and 10/0027-4), CAPES, FINEP and CNPq for the financial
with acetophenone 2a (2.0 mmol) at 90 °C during 4 h, yielding ben-
support.
zodiazepine 3a in 96% yield (Table 1, entry 4).
After reaction optimization, a study regarding the reuse of glyc-
References and notes
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13. Johnson, D. T.; Taconi, K. A. Environ. Prog. 2007, 26, 338. (dd, 1H, J = 13.0, 4.4), 2.97 (dd, 1H, J = 13.0, 4.4), 1.76 (sd, 3H, J = 4.3). 13C NMR
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(b) Bakhrou, N.; Lamaty, F.; Martinez, J.; Colacino, E. Tetrahedron Lett. 2010, 51, 127.0, 126.3, 125.4, 121.6, 121.4, 73.7, 43.0, 29.8. IR (KBr) (cm 1): 3452, 1633,
3935; (c) Li, M.; Chen, C.; He, F.; Gu, Y. Adv. Synth. Catal. 2010, 352, 519; (d) 1597. MS(EI): m/z (% relative intensity) = 312 (M+, 6), 297 (16), 194 (100), 103
Francos, J.; Cadierno, V. Green Chem. 2010, 12, 1552. (17), 77 (14). 1-Benzyl-2-phenyl-1H-1,3-benzimidazole (5a): White solid: mp
15. Abbott, A. P.; Harris, R. C.; Ryder, K. S.; D’Agostino, C.; Gladden, L. F.; Mantle, M. 132–133 °C. 1H NMR (100 MHz, CDCl3) d (ppm) 7.85–7.89 (m, 1H), 7.68–7.71
D. Green Chem. 2011, 13, 82. (m, 2H), 7.41–7.46 (m, 3H), 7.26–7.31 (m, 4H), 7.18–7.22 (m, 2H), 7.05–7.10
16. Pagliaro, M.; Rossi, M. In The Future of Glycerol: New Usages for a Versatile Raw (m, 2H), 5.42 (s, 2H); 13C NMR (75 MHz, CDCl3) d (ppm) 153.7, 142.7, 136.0,
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17. Recent examples: (a) Thurow, S.; Pereira, V. A.; Martinez, D. M.; Alves, D.; Perin, m/z (% relative intensity) = 284 (M+, 52), 207 (3), 180 (2), 92 (8), 91 (100), 77
G.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2011, 52, 640; (b) Alves, D.; (5), 65 (9).
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Tetrahedron Lett. 2011, 52, 133; (c) Gonçalves, L. C.; Fiss, G. F.; Perin, G.; Alves, was used with o-phenylenediamine 1 (1.0 mmol), appropriated carbonyl
D.; Jacob, R. G.; Lenardão, E. J. Tetrahedron Lett. 2010, 51, 6772; (d) Perin, G.; compound (2.0 mmol), and glycerol (3 mL). After the reaction was complete,
Mello, L. G.; Radatz, C. S.; Savegnago, L.; Alves, D.; Jacob, R. G.; Lenardão, E. J. the reaction mixture was washed with a mixture of hexane/ethyl acetate
Tetrahedron Lett. 2010, 51, 4354; (e) Silveira, C. C.; Mendes, S. R.; Líbero, F. M.; (95:5) (3  3 mL) and the upper organic phases were separated from glycerol.
Lenardão, E. J.; Perin, G. Tetrahedron Lett. 2009, 50, 6060; (f) Lenardão, E. J.; The product was isolated according procedure above. The glycerol was dried
Feijó, J. O.; Thurow, S.; Perin, G.; Jacob, R. G.; Silveira, C. C. Tetrahedron Lett. under vacuum and reused for further reactions without previous purification.