Molecular iodine catalyzed highly rapid synthesis of 1,5-benzodiazepine derivatives under mild conditions

Article abstract of DOI:10.1081/SCC-120030695

Rapid reaction of o-phenylenediamines with both cyclic and acyclic ketones in the presence of catalytic amount of iodine afforded 1,5-benzodiazepine derivatives in excellent yields at room temperature.

Full text of DOI:10.1081/SCC-120030695

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Molecular Iodine Catalyzed Highly Rapid Synthesis
of 1,5‐Benzodiazepine Derivatives Under Mild
Conditions
a
a
a
B. P. Bandgar , Sampada V. Bettigeri & Neeta S. Joshi
a
Organic Chemistry Research Laboratory, School of Chemical Sciences, Swami Ramanand
Teerth Marathwada University, Vishnupuri, Nanded, 431606, India
Version of record first published: 21 Aug 2006.
To cite this article: B. P. Bandgar , Sampada V. Bettigeri & Neeta S. Joshi (2004): Molecular Iodine Catalyzed Highly Rapid
Synthesis of 1,5‐Benzodiazepine Derivatives Under Mild Conditions, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 34:8, 1447-1453
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w
SYNTHETIC COMMUNICATIONS
Vol. 34, No. 8, pp. 1447–1453, 2004
Molecular Iodine Catalyzed Highly Rapid
Synthesis of 1,5-Benzodiazepine Derivatives
Under Mild Conditions
*
B. P. Bandgar, Sampada V. Bettigeri, and Neeta S. Joshi
Organic Chemistry Research Laboratory, School of Chemical Sciences,
Swami Ramanand Teerth Marathwada University, Vishnupuri,
Nanded, India
ABSTRACT
Rapid reaction of o-phenylenediamines with both cyclic and acyclic
ketones in the presence of catalytic amount of iodine afforded 1,5-benzo-
diazepine derivatives in excellent yields at room temperature.
Key Words: 1,5-Benzodiazepine; Molecular iodine; o-Phenylenediamine;
Catalyst.
Benzodiazepines are very important class of heterocyclic bioactive com-
[
1,2]
pounds.
Most of the members of this family have wide applications in
*
Correspondence: B. P. Bandgar, Organic Chemistry Research Laboratory, School of
Chemical Sciences, Swami Ramanand Teerth Marathwada University, Vishnupuri,
Nanded 431606, India; Fax: 0091-2462-229245; E-mail: bandgar_bp@yahoo.com.
1
447
DOI: 10.1081/SCC-120030695
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

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1
448
Bandgar, Bettigeri, and Joshi
medicinal chemistry such as tranquilizing, anticonvulsant, antianxiety, and
hypnotic agents. In addition, 1,5-benzodiazepines are used as starting materials
[
3,4]
[4]
for the preparation of fused ring compounds such as triazolo-,
[
oxazino-, or
Benzodiazepine derivatives also find commercial
4,5]
furano-benzodiazepine.
use as dyes for acrylic fibers and as anti-inflammatory agents.
[
6]
[7]
Despite their importance from a pharmaceutical, industrial, and synthetic
point of view, comparatively few methods for their preparation are reported in
[
8–11]
the literature,
[
a great number of which have appeared only very
These include condensation reactions of o-phenylenediamines
12–16]
recently.
with a-b-unsaturated carbonyl compounds, b-haloketones or ketones in
[8]
[9]
[
10]
[11]
[12]
the presence of BF -etherate,
3
NaBH4,
[14]
Yb(OTf)3,
polyphosphoric acid,
[15]
[
12]
[13]
[16]
SiO2,
MgO and POCl3,
Al O /P O ,
2
AcOH
Many of these pro-
3
17]
2 5
[
under microwave (MW) irradiation and ionic liquid.
cesses suffer from one or other limitations such as drastic reaction conditions,
expensive reagents and low to moderate yields, relatively long reaction times,
and the occurrence of several side reactions. Almost all of them make use of an
acid catalyst giving rise to tedious work-up procedures.
In recent years, molecular iodine has received considerable attention as an
inexpensive and readily available catalyst for effecting various organic trans-
[
18]
formations.
We now report here the synthesis of 1,5-benzodiazepine
derivatives by condensation of o-phenylenediamine with both cyclic and
acyclic ketones using molecular iodine in CH CN as an efficient catalyst
3
under mild condition (258C) in a very short time (Sch. 1).
The results are summarized in Table 1. The syntheses were carried out
simply by mixing o-phenylenediamine (1 mmol) with the ketone (2 mmol)
in the presence of a catalytic amount (10%) of iodine in CH CN, whereupon
3
Scheme 1.

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Synthesis of 1,5-Benzodiazepine Derivatives
Table 1. catalyzed synthesis of 1,5-benzodiazepines.
Time Yield
1449
I
2
a,b
Entry
Substrate
Ketone
Benzodiazepines
(min)
(%)
a
5
99
96
98
b
c
10
10
d
e
10
10
97
98
f
10
98
g
02
99
(continued)

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Bandgar, Bettigeri, and Joshi
Table 1. Continued.
a,b
Time Yield
Entry
h
Substrate
Ketone
Benzodiazepines
(min)
(%)
99
02
a
Yields of pure isolated products.
b
1
Products were characterized by IR, H NMR, C NMR, elemental analysis, and by
13
comparison with authentic samples.
the benzodiazepine derivatives were obtained in almost quantitative yield. It is
highly rapid method as compared to literature reported methods for the
synthesis of benzodiazepines. It was ascertained that a minimum 10% of the
catalyst, I is required to achieve optimum conversion. No reaction was
2
observed when o-phenylenediamine was treated with acetone under similar
conditions in the absence of a catalyst. When the amount of catalyst used
was less than 10%, yields of benzodiazepine derivatives were decreased due
to incomplete conversion of substrates and any excess of catalyst beyond this
proportion (.10%) did not show any further increase in conversion and yield.
In conclusion, we have developed a new and efficient method for the
regioselective synthesis of 1,5-benzodiazepines in excellent isolated yields
at room temperature in short reaction times. The easy work-up procedure,
mild reaction conditions, neutral, inexpensive, and readily available catalyst
makes the method amenable for scale-up operations.
GENERAL PROCEDURE
A mixture of o-phenylenediamine or 4-methyl o-phenylenediamine
1 mmol), methylketone or cyclohexanone (2 mmol), and iodine (0.1 mmol)
(
in acetonitrile (10 mL) was stirred at room temperature. After completion of
the reactions (TLC), the solvent was removed under reduced pressure and
the crude product obtained was further purified by column chromatography
(
pet. ether : ethyl acetate ¼ 9 : 1).
2
1
3
a. M.p. ¼ 828C, IR (KBr): 1597 (Ar), 1637 (C 55 N), 3289 (NH) cm
;
1
H NMR (300 MHz, CDCl ): d 1.35 (s, 6H, 2 Â CH ), 2.25 (s, 2H, –CH ),
3
3
2
2.33 (s, 3H, CH ), 3.45 (brs, 1H, NH), 6.60–7.25 (m, 4H). Anal. calcd for
C H N (188.26): C, 76.56%; H, 8.56%; N, 14.87%; Found: C, 76.77%,
3
1
2 16 2
H, 4.48%; N, 14.80%.

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Synthesis of 1,5-Benzodiazepine Derivatives
1451
3
b. M.p. ¼ 1198C, IR (KBr): 1605 (Ar), 1665 (C 55 N), 32,689
2
1
1
(
NH) cm
;
H NMR (300 MHz, CDCl ): d 0.94 (d, 6H, J ¼ 7.8 Hz,
3
CH(CH ) ), 1.15 (s, 3H, CH ), 1.42 (d, 6H, J ¼ 7.2 Hz, N 55 C–CH(CH ) ),
3
2
3
3 2
1
.85 (m, 1H, CH(CH ) ), 2.1 (m, 1H, CH(CH ) ), 2.52 (d, 1H, J ¼ 16.0 Hz,
3
2
3 2
a
b
CH ), 2.60 (d, 1H, J ¼ 16 Hz, CH ), 3.65 (brs, 1H, NH), 6.75–7.40 (m, 4H,
2 2
1
3
Ar-H); C NMR (75 MHz, CDCl ): d 14.7, 16.5, 23.5, 29.4, 36.3, 40.5,
3
113.8, 118.7, 123.0, 127.5, 132.81, 137.0, 164.5. Anal. calcd for C H N:
C, 78.64%; H, 9.90%; N, 11.46%; Found: C, 78.51%; H, 9.81%; N, 11.54%.
16 24
2
1 1
3
c. M.p. ¼ 1218C, IR (KBr): 1651 (C 55 N), 3270 (NH) cm , H NMR
a
2
(
300 MHz, CDCl ): d 1.82 (s, 3H, CH ), 3.01 (d, 1H, J ¼ 13.2 Hz, CH ),
3
3
b
2
3
.18 (d, 1H, J ¼ 13.2 Hz, CH ), 3.50 (brs, 1H, NH), 6.75–6.85 (m, 14H,
Ar-H). Anal. calcd for C H N (312.40): C, 84.58%; H, 6.45%; N, 8.96%;
2
2 20 2
Found: C, 84.38%, H; 6.38%; N, 8.90%.
d. M.p. ¼ 91–928C, IR (KBr): 1660 (C 55 N), 3280 (NH) cm ; H
NMR (300 MHz, CDCl ): d 1.80 (s, 3H, CH ), 2.41 (s, 3H, Ar-CH ), 3.02
21
1
3
3
3
3
a
2
b
2
(d, 1H, J ¼ 13.0 Hz, CH ), 3.15 (d, 1H, J ¼ 13.0 Hz, CH ), 3.50 (brs, 1H,
NH), 6.70–7.50 (m, 13H, Ar-H); C NMR (75 MHz, CDCl ): d 21.0, 28.5,
1
3
3
4
1
6.0, 51.0, 113.5, 124.0, 125.5, 126.0, 127.0, 128.1, 128.4, 128.6, 128.8,
29.0, 131.0, 131.5, 135.0, 137.0, 165.5. Anal. calcd for C H N (326.42):
2
3 22 2
C, 84.63%; H, 6.79%; N, 8.58%; Found: C, 84.75%; H, 6.68%; N, 8.65%.
2
1
3
e. M.p. ¼ 1438C; IR (KBr): 1600 (Ar), 1645 (C 55 N), 3265 (NH) cm
;
1
H NMR (300 MHz, CDCl ): d 2.1 (s, 9H, 3 Â Ar-CH ), 3.05 (d, 1H,
3
3
a
b
2
J ¼ 13.5 Hz, CH ), 3.17 (d, 1H, 13.5 Hz, CH ), 3.60 (brs, 1H, NH), 7.1–7.5
2
1
3
(
m, 11H, Ar-H); C NMR (75 MHz, CDCl ): d 21.2, 24.5, 28.2, 29.1, 46.2,
3
5
1
2.7, 114.7, 122.3, 126.2, 127.1, 128.5, 132.7, 133.0, 133.7, 135.5, 136.1,
64.7. Anal. calcd for C H N (338.44): C, 85.18%; H, 6.55%; N, 8.27%.
2
4 22 2
Found: C, 85.12%, H, 6.50%; N, 8.19%.
f. M.p. ¼ 1328C; IR (KBr): 1610 (Ar), 1670 (C 55 N), 3250 (NH) cm
H NMR (300 MHz, CDCl ): d 1.75 (s, 3H, CH ), 2.41 (s, 3H, Ar-CH ), 2.95
2
1
3
;
1
3
3
3
a
b
(d, 1H, CH ), 3.1 (d, 1H, CH ), 3.60 (brs, 1H, NH), 7.2–7.6 (m, 9H, Ar-H).
2 2
Anal. calcd for C H N Cl (450.19): C, 58.77%; H, 3.58%; N, 6.22%; Cl,
2
2
16
2
4
3
1.50%; Found: C, 58.56%; H, 3.62%; N, 6.98%; Cl, 31.41%.
21 1
3
g. M.p. ¼ 948C; IR (KBr): 1655 (C 55 N), 3260 (NH) cm ; H NMR
(300 MHz, CDCl ): d 1.90–2.65 (m, 16H, 8 Â CH ), 2.90–3.25 (m, 3H,
3
2
13
N 55 C–CH and N 55 C–CH ), 4.80 (brs, 1H, NH), 7.2–7.6 (m, 4H, Ar-H);
C
NMR (75MHz, CDCl ): d 20.8, 23.8, 26.3, 27.7, 33.2, 34.8, 43.7, 47.6, 113.1,
2
3
123.5, 127.3, 128.5, 132.4, 134.1, 165.2. Anal. calcd for C H N (268.39):
C, 80.56%; H, 9.01%; N, 10.43%; Found: C, 80.66%; H, 9.11%; N, 10.55%.
18 24 2
2
1 1
3
h. M.p. ¼ 1388C; IR (KBr): 1665 (C 55 NH), 3260 (NH) cm ; H NMR
(
(
(
300 MHz, CDCl ): d 2.1–2.75 (m, 19H, 8 Â CH and Ar-CH ), 2.90–3.30
3
2
3
m, 3H, N 55 C–CH and N 55 C–CH )), 4.95 (brs, 1H, NH), 7.00–7.50
2
1
m, 3H, Ar-H); C NMR (75 MHz, CDCl ): d 20.2, 21.0, 23.7, 26.7, 27.5,
3
3

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Bandgar, Bettigeri, and Joshi
33.0, 35.0, 43.8, 47.5, 113.5, 123.5, 127.5, 128.5, 132.7, 134.0, 164.5. Anal.
calcd for C H N : C, 80.80%; H, 9.28%; N, 9.92%; Found: C, 80.88%;
H, 9.19%; N, 9.85%.
1
9 26 2
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Received in India November 15, 2003

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