Microwave enhanced solution synthesis of 1,4-benzodiazepin-5-ones

Article abstract of DOI:10.1016/S0040-4039(01)00155-1

Some 2-methyl-1,4-benzodiazepin-5-ones have been synthesized by the application of microwave irradiation. Conventional heating and microwave irradiation of the reactions were compared. Synthesis by microwave irradiation gave the desired compounds in better yields than those obtained by conventional heating. The overall times for the syntheses were considerably reduced.

Full text of DOI:10.1016/S0040-4039(01)00155-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2397–2400
Microwave enhanced solution synthesis of
1,4-benzodiazepin-5-ones
Vincenzo Santagada,* Elisa Perissutti, Ferdinando Fiorino, Beniamino Vivenzio and
Giuseppe Caliendo
Dipartimento di Chimica Farmaceutica e Tossicologica, Universita` di Napoli ꢀFederico IIꢁ Via D. Montesano, 49,
80131 Naples, Italy
Received 10 November 2000; revised 15 January 2001; accepted 25 January 2001
Abstract—Some 2-methyl-1,4-benzodiazepin-5-ones have been synthesized by the application of microwave irradiation. Conven-
tional heating and microwave irradiation of the reactions were compared. Synthesis by microwave irradiation gave the desired
compounds in better yields than those obtained by conventional heating. The overall times for the syntheses were considerably
reduced. © 2001 Elsevier Science Ltd. All rights reserved.
Heterocyclic compounds hold a special place among
pharmaceutically important natural and synthetic mate-
rials. The remarkable ability of heterocyclic nuclei to
serve both as biomimetics and active pharmacophores
has largely been contributed to their unique value as
traditional key elements of numerous drugs. Hetero-
cyclic derivatives such as morphine alkaloids, b-lactam
antibiotics, and benzodiazepines are just a few familiar
examples from various pharmaceuticals featuring a het-
erocyclic component.1
The application of microwave energy to organic com-
pounds for conducting synthetic reactions at highly
accelerated rates is an emerging technique. In recent
years, microwaves have become popular among syn-
thetic organic chemists both to improve classical
organic reactions,7–13 shortening reaction times and/or
improving yields, as well as to promote new reactions.
Moreover, often when carrying out a reaction in a
microwave oven the use of a solvent can sometimes be
avoided, which is important in order to make the
synthesis more environmentally friendly (‘green chem-
istry’). These observations led us to investigate the
possibility of improving the methods used for the syn-
thesis of the 1,4-benzodiazepin-5-one scaffold.
The benzodiazepine nucleus is a well-studied traditional
pharmacophoric scaffold that has emerged as a core
structural unit of various sedative-hypnotic, muscle
relaxant, anxiolytic, antistaminic, and anticonvulsant
agents. Therefore diversely substituted benzodiazepine
nuclei can serve as synthons for developing new drugs.
This paper describes a facile synthesis of 2-methyl-1,4-
benzodiazepin-5-one,14 based on an intramolecular
azide cycloaddition, by application of microwave
energy in the presence of solvents. Conventional heat-
ing (oil bath) and microwave irradiation of the reac-
tions are compared.
A number are 1,4-benzodiazepin-5-ones, e.g. the antibi-
otic Neothramicin, the antidepressant Flumazenil, and
the antistaminic Clobenzepam.2–6 The literature on this
subject, although very copious, is mainly constituted by
patents. This fact led us to carry out studies to improve
the synthesis of this scaffold bearing in mind new
synthetic methodologies.
The synthetic procedure, summarized in Scheme 1, was
performed using a microwave oven (ETHOS 1600,
Milestone) especially designed for organic synthesis.
The experimental conditions used in our work were
similar to those used by conventional heating, with the
same concentration of starting material and volume of
solvent. The parameters of power, time and tempera-
ture used for the irradiation were as reported in Tables
1 and 2.
Keywords: 2-methyl-1,4-benzodiazepin-5-ones; microwave irradiation
in solution; medium ring heterocycles.
* Corresponding author. Tel.: 0039-81-678648; fax: 0039-81-678648;
e-mail: santagad@unina.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00155-1

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V. Santagada et al. / Tetrahedron Letters 42 (2001) 2397–2400
Scheme 1. Reagents: (i) DMF, reflux 1 h, mv; (ii) 1N HCl, NaNO2, AcOH, 30 min; (iii) NaN3, Et2O, 40 min; (iv) DMF, mv.
Table 1. Conventional heating versus microwave irradiation for intermediates 2-amino-5-X-N-alkyl-N-(2-propenyl)benzamide
(3a–f)a
Compd.
R
X
Conventional heatingb
Microwave irradiation
Yieldc (%)
65
Time (min)
180
Temp. (°C)
Yieldc (%)
91
Time (min)
Power (W)
Temp. (°C)
3a
3b
3c
3d
3e
3f
Me
H
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
5
50
5
5
50
5
5
50
5
5
50
5
5
50
5
5
50
5
150
250
300
150
250
300
150
250
300
150
250
300
150
250
300
150
250
300
80
110
110
80
120
110
80
110
110
80
120
110
80
Allyl
Me
H
20
69
60
180
180
180
180
180
50
97
85
92
60
Cl
Cl
Allyl
Me
Br 65
Br 45
120
110
80
120
110
Allyl
a All the reactions were performed three times and the reaction time and yields given are the average values.
b Oil bath.
c With respect to the starting amount of anhydride.
The general procedure is as follows: the 5-X-isatoic
anhydride (1) (2.0 mmol) was dissolved in DMF (10 ml)
and was introduced into the reaction vessel followed by
the allylamine (2) (4.5 mmol). The desired parameters
(microwave power, temperature and time) were set as
reported in Table 1. After irradiation, the solution was

V. Santagada et al. / Tetrahedron Letters 42 (2001) 2397–2400
2399
Table 2. Conventional heating versus microwave irradiation for final compounds (5a–f)a
Compd.
R
X
Conventional heatingb
Microwave irradiation
Yieldc (%)
40
Time (min)
60
Temp. (°C)
Yieldc (%)
69
Time (min)
Power (W)
Temp. (°C)
5a
5b
5c
5d
5e
5f
Me
H
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
5
50
5
5
50
5
5
50
5
5
50
5
5
50
5
5
50
5
150
250
300
150
250
300
150
250
300
150
250
300
150
250
300
150
250
300
80
110
110
80
120
110
80
110
110
80
120
110
80
Allyl
Me
H
45
38
34
60
60
60
60
60
61
55
58
60
60
Cl
Cl
Allyl
Me
Br 30
Br 27
120
110
80
120
110
Allyl
a All the reactions were performed three times and the reaction time and yields given are the average values.
b Oil bath.
c With respect to the starting amount of amine.
treated as follows. The pH of the solution was adjusted
to pH 9 with 5% NaOH and extracted with Et2O. The
organic layer was dried and evaporated under reduced
pressure to give compounds 3a–f.
solutions gave the desired compounds 5a–f in better
yields and cleaner reactions to those obtained by con-
ventional heating. The overall times for the syntheses
were considerably reduced.
The results obtained with the various reagents are
summarized in Table 1.
In conclusion, we have described a rapid synthesis of
the 2-methyl-1,4-benzodiazepin-5-ones using a micro-
wave oven and provided further example of the utility
of microwave irradiation in organic synthesis in the
presence of solvents.
In the second step, intermediates 3a–f (6.3 mmol) were
subjected to diazotization (NaNO2 12.6 mmol/1N HCl
30 ml and CH3COOH 65 ml at 0°C) and subsequent
nucleophilic substitution by sodium azide (37.8 mmol).
Since the species (4) so-formed were rather unstable, we
preferred to use them as crude materials without full
characterization. The intermediates (4) were cyclized
either by refluxing in DMF or by subjecting to a second
exposure to microwave irradiation. After evaporation
of the solvent, the crude products were purified by
chromatography on silica gel (diethyl ether/EtOH,
9.5:0.5 v/v). The final compounds (5a–f) listed in
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