A facile synthesis of 3,4-dihydro-2-pyronyl-1,5-benzodiazepine derivatives

Article abstract of DOI:10.1081/SCC-120006030

The reaction of o-phenylenediamine with 3-cinnamoyl-4-hydroxy-6-methyl-2-pyrones (3a-i, chalcone analogs of dehydroactic acid) in ethanol-acetic acid provides a facile method for the synthesis of 3,4-dihydro-2-pyronyl-1,5-benzodiazepine derivatives (2a-i).

Full text of DOI:10.1081/SCC-120006030

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A FACILE SYNTHESIS OF 3,4-DIHYDRO- 2-PYRONYL-1,5-
BENZODIAZEPINE DERIVATIVES
Om Prakash a , Ajay Kumar a , Anil Sadana a & Shiv P. Singh a
a Chemistry Department, Kurukshetra University, Kurukshetra, Haryana, 136 119, India
Version of record first published: 20 Aug 2006.
To cite this article: Om Prakash, Ajay Kumar, Anil Sadana & Shiv P. Singh (2002): A FACILE SYNTHESIS OF 3,4-DIHYDRO- 2-
PYRONYL-1,5-BENZODIAZEPINE DERIVATIVES, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 32:17, 2663-2667
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SYNTHETIC COMMUNICATIONS
Vol. 32, No. 17, pp. 2663–2667, 2002
A FACILE SYNTHESIS OF 3,4-DIHYDRO-
2-PYRONYL-1,5-BENZODIAZEPINE
DERIVATIVES
*
Om Prakash, Ajay Kumar, Anil Sadana,
and Shiv P. Singh
Chemistry Department, Kurukshetra University,
Kurukshetra, Haryana, 136 119, India
ABSTRACT
The reaction of o-phenylenediamine with 3-cinnamoyl-4-
hydroxy-6-methyl-2-pyrones (3a–i, chalcone analogs of dehy-
droactic acid) in ethanol-acetic acid provides a facile method
for the synthesis of 3,4-dihydro-2-pyronyl-1,5-benzodiazepine
derivatives (2a–i).
The importance of 1,5-benzodiazepines and their derivatives as ther-
apeutic agents with widespread biological activity is well established.[1]
Fodili et al.[2] have recently reported the synthesis of a few 3,4-dihydro-2-
pyronyl-1,5-benzodiazepines (2) by the reaction of dehydroacetic acid
(DHA) and o-phenylenediamine (OPD), followed by treatment of the result-
ing ketimine 1 with aromatic aldehydes in the presence of a catalytic amount
*Corresponding author. E-mail: chem@granth.kuk.ernet.in or search@vidya.kuk.
ernet.in
2663
DOI: 10.1081/SCC-120006030
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2664
PRAKASH ET AL.
of trifluoroacetic acid (Scheme A). As part of our ongoing studies on the
reactions and synthetic applications of DHA and its derivatives,[3] we report
herein an alternate and facile method for the synthesis of 2 by the reaction of
OPD with 3-cinnamoyl-4-hydroxy-6-methyl-2-pyrones (3, chalcone analogs
of DHA).
The chalcones analogs of DHA (3a–i), prepared according to the lit-
erature procedure[4] by the condensation of DHA with various aldehydes,
were treated with one equivalent of OPD in ethanol-acetic acid. The reac-
tion afforded the desired 1,5-benzodiazepine derivatives 2a–i in high yields
(Scheme 1). The results of this reaction along with the data of the products
are summarized in Table 1.
Scheme A.
Scheme 1.

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1,5-BENZODIAZEPINE DERIVATIVES
2665
Table 1. Benzodiazepines 2a–i, Prepared According to Scheme 1
M.P. (ꢀC)
(Literature M.P.)[2]
Yield
(%)a
Molecular
Formula
Benzodiazepines
b
b
b
b
b
b
2a
2b
2c
2d
2e
2f
2g
2h
2i
218–220 (226)
228–230 (240)
229–230 (230)
238–240 (238)
239–240 (238–240)
226–228 (240)
224–225
78
79
86
86
82
85
86
76
80
c
c
C23H23N3O3
C21H17N3O5
C19H16N2O3Sc
152–154
183–184
aYields of isolated products w.r.t. the quantity of chalcone analog 3.
bSpectral properties (IR, 1H NMR and MS) were in full agreement with those reported
previously. The spectral data for the new products (2g–i) are given: 2g, IR (nujol)
1
(n cmꢀ1) 3326, 1704, 1655. H NMR (CDCl3): d 2.87 (dd, 1H, J ¼ 11.2 Hz, 10.8 Hz,
CH2), 4.36 (dd, 1H, J ¼ 11.2 Hz, 2.9 Hz, CH2), 5.19 (dd, 1H, J ¼ 10.8 Hz, 2.9 Hz,
p-NMe2C6H4CH), 3.99 (s, 1H, NH), 2.15 (s, 3H, CH3), 5.76 (s, 1H, CH¼C),
6.69–7.72 (m, 8H, arom), 15.49 (s, 1H, OH), 2.94 (s, 6H, NMe2); 2h, IR (nujol)
1
(n cmꢀ1) 3399, 1705, 1644. H NMR (CDCl3): d 3.39 (dd, 1H, J ¼ 12.8 Hz, 9.7 Hz,
CH2), 4.05 (dd, 1H, J ¼ 12.8 Hz, 3.2 Hz, CH2), 5.44 (dd, 1H, J ¼ 9.7 Hz, 3.2 Hz,
p-NO2C6H4CH), 3.88 (s, 1H, NH), 2.14 (s, 3H, CH3), 5.75 (s, 1H, CH¼C),
6.69–8.19 (m, 8H, arom), 15.48 (s, 1H, OH); 2i, IR (nujol) (n cmꢀ1) 3309, 1694,
1
1656. H NMR (CDCl3): d 2.98 (dd, 1H, J ¼ 12.2 Hz, 10.7 Hz, CH2), 4.37 (dd, 1H,
J ¼ 12.2 Hz, 3.7 Hz, CH2), 5.61 (dd, 1H, J ¼ 10.7 Hz, 3.7 Hz, 2-thineyl CH), 3.99 (s, 1H,
NH), 2.16 (s, 3H, CH3), 5.77 (s, 1H, CH¼C), 6.88–7.2 (m, 7H, arom), 15.45
(s, 1H, OH).
cElemental analyses (C, H, N, S) were satisfactory.
The noteworthy features, which account for the significance of the new
route for the synthesis of 2a–i, are:
(a) The method involving simple experimentation is quite general as
various substituted DHA chalcone analogs (2a–i) are smoothly
converted to the corresponding 1,5-benzodiazepines 2a–i.
(b) The p-nitrophenyl derivative 2h, which could not be synthesized
by the method used by Fodili et al.,[2] is easily accessible through
the present approach.
(c) Three new 1,5-benzodiazepines 2g, 2h and 2i (2-thienyl analog)
are also available.
(d) The quantity of aldehydes employed in the present procedure is
one equivalent with respect to the quantity of DHA and OPD as

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2666
PRAKASH ET AL.
compared to 1.5–3.0 equivalents of the aldehydes used in the
reported procedure.[2]
(e) The other electrophilic sites (indicated as a–c) present in the struc-
ture of 3 remain unaffected.[5]
EXPERIMENTAL
Melting points were determined in open capillaries and are uncor-
1
rected. H NMR spectra were recorded on Brucker 300 MHz instrument
using TMS as an internal standard. Chalcone analogous 3a–i were prepared
according to literature procedure.[4]
Conversion of Substituted 3-Cinnamoyl-4-hydroxy-6-methyl-2-pyrones
(3a–i) to 3,4-Dihydro-2-pyronyl-1,5-benzodiazepine Derivatives (2a–i)
General procedure: To a solution of 3 (1 mmol) in ethanol (20 mL) was
added a few drops of piperidine and o-phenylenediammine (1 mmol,
108 mg). The mixture was heated under reflux for 3–4 h and then added
1 mL of AcOH. The refluxing was continued for another 3–4 h. About
half of the solvent was distilled off and the resulting mixtures was allowed
to stand at room temperature overnight. The crystalline solid product 2 thus
separated was filtered, washed with 2–3 mL of cold aq. ethanol (50 : 50 by
v/v) and dried (Table 1).
ACKNOWLEDGMENT
We are grateful to the UGC, New Delhi for financial assistance.
REFERENCES
1. Katritzky, A.R.; Abonia, R.; Yang, B.; Qi, M.; Insuasty, B. Synthesis
1998, 1487 and references therein.

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1,5-BENZODIAZEPINE DERIVATIVES
2667
2. Fodili, M.; Amari, M.; Kolli, B.; Robert, A.; Floc’h, M.B.; Grel, P.L.
Synthesis 1999, 811.
3. (a) Singh, S.P.; Prakash, O.; Vaid, R.K. Indian J. Chem. 1984, 23B, 191;
(b) Singh, S.P.; Tarar, L.S.; Kumar, D. Synth. Commun. 1993, 23, 1855;
(c) Singh, S.P.; Tarar, L.S.; Kumar, D. Indian J. Heterocycl. Chem.
1993, 3, 5.
4. Wiley, R.H.; Jarboe, C.H.; Elert, H.G. J. Am. Chem. Soc. 1955, 77, 5102.
5. Chrgui, D.; Hamdi, M.; Baboulene, M.; Speziale, V.; Lattes, A.
J. Heterocycl. Chem. 1986, 23, 1721.
Received in the Netherlands September 13, 2001

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