Synthesis of novel heterocyclic compounds containing 1,5-benzodiazepine

Article abstract of DOI:10.14233/ajchem.2015.18011

The purpose of this work is the development of a synthetic pathway that allows access to heterocyclic compounds containing the 1,5-benzodiazepines. The dehydroacetic acid has been widely studied as a starting material for the synthesis of natural products that exhibit interesting pharmacological properties. In the present work, we describe an easy and cost effective access way to new products 1,5-benzodiazepines involving a pyranic residue. All synthesized products were subjected to IR, 1H NMR and mass spectra studies.

Full text of DOI:10.14233/ajchem.2015.18011

Asian Journal of Chemistry; Vol. 27, No. 6 (2015), 2175-2177
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18011
Synthesis of Novel Heterocyclic Compounds Containing 1,5-Benzodiazepine
1,2
1,2
3
4
B.E. MISSAOUI1,2,*, M.R. OUAHRANI , Y. KOUADRI , F. CHEBROUK and N. GHERRAF
1Laboratoire de Chimie Organique, Université KASDI Merbah, Ouargla, Algéria
2Laboratoire VPRS Université KASDI Merbah, Ouargla, Algéria
3Centre de Recherche Scientifique et Technique en Analyses Physico-chimiques (CRAPC), BP 248, Alger 16004, Algéria
4Laboratoire des Ressources Naturelles et Aménagement des milieux Sensibles, Université Larbi ben M'hidi, Oum Elbouaghi, Algeria
*Corresponding author: Fax: +213 32 424213; Tel: +213 559103485; E-mail: hadadberini@yahoo.com
Received: 15 May 2014;
Accepted: 7 October 2014;
Published online: 17 March 2015;
AJC-16987
The purpose of this work is the development of a synthetic pathway that allows access to heterocyclic compounds containing the 1,5-
benzodiazepines. The dehydroacetic acid has been widely studied as a starting material for the synthesis of natural products that exhibit
interesting pharmacological properties. In the present work, we describe an easy and cost effective access way to new products 1,5-
benzodiazepines involving a pyranic residue. All synthesized products were subjected to IR, 1H NMR and mass spectra studies.
Keywords: Dehydroacetic acid, 1,5-Benzodiazepine.
azepines whose basic cores are known for their pharmaco-
logical effects. Moreover, 1,5-benzodiazepine type compounds
are particularly active on the central nervous system9 and anticon-
vulsants10, antiinflammatory, analgesics11 and antibacterial12.
The present work is focused on the use of dehydroacetic
acid and its derivatives in heterocyclic synthesis. We report in
this paper the synthesis of new molecules susceptible to present
valuable pharmacological properties namely 1.5-benzodiazepine.
The synthesis approach we adopted involves, in one hand,
the opening of pyranic ring by binucleophiles reagents such
as 2-amino-3-benzyloxypyridine and on the other hand, the
action of hydrazine hydrate on pyridopyrimidine. Finally we
obtain pyrano-1,5-benzodiazepine (10) by the condensation
reaction of o-phenylenediamines substituted on the cyna-
moyles from the dehydroacetic acid.
INTRODUCTION
Benzodiazepines, from the pharmacological standpoint,
are very interesting molecules. Numerous studies have
demonstrated anxiolytic effect on the human nervous system.
They are used in the therapeutic field1 and have important
biological activities, particularly the 1,4- and 1,5-benzodi-
azepines2. Benzodiazepines are also used as anticonvulsant
agents3, anti-inflammatory and analgesic4, antidepressive of
the central nervous system5 and antibacterial6. For instance,
Valium (diazepam) is marketed as a sedative and noveril
(dibenzepin) as an antidepressive. The strategy of using benzo-
diazepines essentially depends on the knowledge of their
pharmacokinetics that can take advantage of their "qualities"
but also to avoid some of their "side effects". In addition, benzo-
diazepines are the most powerful anticonvulsant substances
known so far: they are able of antagonize, common amongst
animal, convulsions induced by a wide variety of chemical
substances e.g., isoniazid, picrotoxin, strychnine, pentetrazole.
On the other hand, they are less effective in protecting seizures
due to electric shock7.
EXPERIMENTAL
1H NMR spectra were performed on spectrometer Bruker
AC 200 MHz and 300 MHz. Chemical shifts are given in ppm
13
relative to TMS (internal reference). The C NMR spectra
were made in J modulated on a spectrometer Bruker AC 200
and 300 MHz. Infrared spectra were recorded on a Perkin
Elmer 225 network spectrophotometer, compounds being in
solid suspension in Nujol. The results are given in cm-1. Mass
spectra were performed on a Nermag R10-10C spectrometer
with the ionization mode by electronic impact to 70 EV and/
or by chemical ionization by NH3. Melting points were taken
on using a Köfler bench.
Synthesis of 1,5-benzodiazepines structures were made
from different lactones, such as tetronic acid, 4-hydroxy
coumarin, demidone and dehydroacetic acid8. It therefore
seemed interesting to carry on further research by investigating
the reactivity of the dehydroacetic acid and its derivatives
which are susceptible to serve as starting material for the
synthesis of other heterocyclic compounds such as benzodi-

2176 Missaoui et al.
Asian J. Chem.
Synthesis of cynamoyles (9): 1.68 g (10-2) Dehydroacetic
acid, 1.19 g (10-2) of N,N-dimethylformamide-dimethylacetal
(DMF-DMA) in 40 mL of dichloromethane in the presence
of a catalytic amount of acetic acid is heated under reflux for
24 h. After evaporation of the solvent, the oil obtained preci-
pitates in ethanol to afford compound 9a with a yield of 75 %
and m.p. = 170-172 °C.
Synthesis of pyrano-1,5-benzodiazepines (10): To an
ethanolic solution of 30 mL containing 2.23 g (0.01 mol) of
compound 9a, we add 1.08 g (0.01 mol) of o-phenylenedi-
amine in the presence of a catalytic amount of triethylamine.
The reaction mixture was heated under reflux with magnetic
stirring for 6 h. Benzodiazepine (10a) precipitates by cooling
in the form of a very dark purple solid with a yield of 48 %
and m.p. = 238-241 °C.
X
OH
N
O
H3C
CH3
H
NH
H
OH
O
O
N
H2N
H2N
EtOH, NEt3
eflux
+
r
H
X
H3C
O
H3C
O
10
9a
X
= H, CH3 , Cl , NO2
Scheme-II: Formation of 1,5-benzodiazepines by the action of o-phenylene-
diamine on cynamoyles (9); (10a: X = H, 10b: X = CH3, 10C:
X = Cl, 10d: X = NO2)
13C NMR spectrum shows the cyclization of cynamoyles
(9) in pyrano-1,5-benzodiazepines (10) by the disappearance
of the signals due to the carbons of the dime-thylamino group
and the presence of two peaks at about 129 and 130 ppm corres-
ponding to carbons in position 2,5.
The obtained result from the reaction of cynamoyles (9)
with the o-phenylenediamine allows proposing a mechanism
explaining the formation of 10 (Scheme-III).
RESULTS AND DISCUSSION
As a first step, the condensation of N,N-dimethylform-
amide-dimethylacetal (DMF-DMA) on dehydroacetic acid (1)
under reflux in dichloromethane in the presence of a catalytic
amount of acetic acid, leads to the isolation of the cynamoyles
9a (Scheme-I).
X
CH3
H3C
O
OH
N
..
H2N
..
OH
O
H N
2
H
NH
-NH(CH3)2
EtOH, NEt3
+
H C
CH
R
OH
O
3
3
H3C
O
9a
OH
O
N
O
H2N
CH
3
H3C
O
A
CH3COOH
O
+
(CH3)2NCR(OMe)2
CH2Cl2, reflux
H C
O
O
3
H C
O
O
3
1
-H2O
9a: R= H
9b: R= CH3
X
Scheme-I:Formation of cynamoyles (9) by condensation N,N-dimethyl-
formamide dimethylacetal (DMF-DMA) on dehydroacetic
acid (1)
OH
N
O
NH
Characteristics of 9a: 1H NMR (CDCl3, 200 MHz): 2.11
(s, 3H, CH3), 2.99 (s, 3H, CH3), 3.17 (s, 3H, CH3), 5.72 (s, 1H,
CH=C), 6.59 (d, 1H, J = 8.20, CH=CHa), 7,99 (d, 1H, J =
H3C
O
10
Scheme-III: Formation of product 10 by initial attack of an amino group
of the o-phenylenediamine of the carbon in position 13
13
8,20, CHb=CH), 14,28 (s, 1H, OH). C NMR (CDCl3, 200
MHz): 184(C2), 104(C3), 164(C4), 92(C5), 162(C6), 186(C8),
20(C11), 105(C12), 156(C13), 38(C15), 46(C17). S.M (IE,
70 ev): M = 223.
Characteristics of 9b: This derivative is obtained under
the same operating conditions as the derivative 9a with a yield
of 81 % and m.p. = 193-195 °C. 1H NMR (CDCl3, 200 MHz):
2.11(s, 3H, CH3), 2.98 (s, 3H, CH3), 3,15 (s, 3H, CH3), 3.95
(s, 3H, CH3), 5.75 (s, 1H, CH=C), 8,11 (s, 1H, CHb=CH3),
14,30 (s, 1H, OH). S.M (IE, 70 ev): M = 237
The formation of pyrano-1,5-benzodiazepines (10) can
be explained by an initial attack of an amino group of o-phenyl-
enediamine on carbon at position 13 leading to the intermediate
[A], after the elimination of dimethylamine molecule. The
cyclization of [A] involves the attack of the second nitrogen
of the amino group on the carbonyl in position 8 followed by
the elimination of a water molecule to lead to compounds of
benzodiazepine 10 structure.
Characteristics of 10a: 1H NMR (CDCl3, 200 MHz): 2.15
(s, 3H, CH3), 5.80 (s, 1H, CH=C), 6.05 (dd, 1H, J = 9.7, 1.98, N-
CH=CHa), 6.25 (dd, 1H, J = 9.7, 7.2, N-CHb=CH), 6.75-6.85 (m,
4H, arom), 8,7 (d, 1H, J = 7.2, NH), 14,30 (s, 1H, OH). 13C NMR
(CDCl3, 200 MHz): 185(C2), 107(C3), 165(C4), 94(C5), 152(C6),
174(C8), 139(C10), 140(C11), 129(C13), 130(C14), 123(C15),
128(C16), 127(C17), 124(C18). S.M (IE, 70 ev): M = 268.
Characteristics of 10b: Under the same operating condi-
tions as 10a, we get compound 10b with a yield of 55 %, m.p.
= 244-246 °C. 1H NMR (CDCl3, 200 MHz) : 2.17 (s, 3H, CH3),
2.35 (s, 3H, p-CH3), 5.78 (s, 1H, CH=C), 6.08 (dd, 1H, J =
9.5, 2.0, N-CH=CHa), 6.28 (dd, 1H, J = 9.5, 7.15, N-CHb=CH),
6.73-6.87 (m, 3H, arom), 8,9 (d, 1H, J = 7.15, NH), 14,28 (s,
1H, OH). S.M (IE, 70 ev): M = 268.
1H NMR spectrum of compound 9 shows the disappea-
rance of the signal due to the protons of -CH3 of the acetyl
grouping and the appearance of dimethylamino system. The
aromatic protons signals appear at about 6.59 and 7.99 ppm.
When compound 9 is heated under reflux with o-phenylenedi-
amine in equimolar amounts in ethanol solution in the presence
of triethylamine for 6 h, it affords compound 10 (Scheme-II).
1H NMR spectrum at 300 MHz of derivatives 10 shows
the expected signals for the considered structure. It is noted
that the absence of the signals due to the protons of dimethyl-
amino group, the appearance of a broad peak due to NH proton
in position 1 and the presence of the signals due to protons of
an aromatic system AB at 6.05 and 6.25 ppm.

Vol. 27, No. 6 (2015)
Synthesis of Novel Heterocyclic Compounds Containing 1,5-Benzodiazepine 2177
Characteristics of 10c: Under the same operating condi-
tions as 10a, we get compound 10c with a yield of 51 %, m.p.
= 250-252 °C. H NMR (CDCl3, 200 MHz) : 2.14 (s, 3H,
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Conclusion
The obtained results confirm the interest of dehydroacetic
acid for the synthesis of heterocyclic compound derived from
the 1,5-benzodiazepine.