Synthesis, Spectral Studies and Biological Activity of Some 1, 5-Benzodiazepine Derivatives

 

Chandak B.G.1*, Sarpate R.V.1 , Chatterjee N.R.2 and Baheti K.G.2

1Siddhant College of Pharmacy, Sudumbare, Pune. 2Department of Pharmaceutical Chemistry, Pad Dr. D.Y. P. College of Pharmacy, Akurdi, Pune-411044

*Corresponding Author E-mail: badri_chandak30@yahoo.co.in

 

ABSTRACT:

An efficient method for green synthesis of some 2, 3-dihydro 1H-1, 5-benzodiazepine derivatives has been developed by simple cyclocondensation reaction of o-phenylendiamine with aromatic, cyclic and acyclic ketones as well as 1, 3-β dicarbonyl compounds in presence of catalytic amount of silica gel under ultrasound irradiation. The title compounds have been characterized by physico-chemical methods and screened for anti-microbial activity in order to evaluate for the effectivity against Crofloxin and Ciclopiroxoamine as standard.

 

KEYWORDS: 1, 5-benzodiazepines, o-phenylenediamine, ketones, 1, 3-β dicarbonyl compounds, silica gel, ultrasound irradiation, anti-microbial.

 

INTRODUCTION:

Benzodiazepines and their polycyclic derivatives are important classes of bio-active compounds Benzodiazepines are an important class of compounds finding application as anti-inflammatory, anti-anxiety, anticonvulsant, hypnotic agents1 and also employed as valuable synthons for the preparation of many fused heterocyclic ring system2. The introduction of diazepam as a tranquilizer in 1971 by Sternbach followed by many other psychotropic agents sharing 1, 4-benzodiazepine skeleton afforded a great impetus to synthetic studies of the isomeric 1, 5-benzodiazepine ring system. Some members of this class of compound have demonstrated an array of pharmacological properties e.g. CNS depressent, antiproliferative agent, arginine vasopressin antagonists. Furthermore 1, 5-benzodiazepines are valuable synthons for the preparation of other fused ring systems such as triazolo3a, oxazino3b, furano3c or oxadiazolo-benzodiazepines3d.

 

The easy accessibility of 1,5-benzodiazepine derivatives via cycloaddition  reaction of o-phenylenediamine with α, β-unsaturated carbonyl compounds4, β-haloketone5, acyclic and cyclic ketones in presence of various catalysts viz:

 

CdCl26, [(L)proline]2Zn7, molecular iodine8, BF3-etherate9, NaBH410, polyphosphoric acid-SiO211, MgO/POCl312, Yb (OTf)313, sulfated zirconia14, Al2O3/P2O515, AcOH under microwave irradiation16 ,Sc (OTf)317, polymer (PVP) supported ferric chloride18, CeCl3-NaI-SiO219, ionic liquid medium20 and NBS21 are well documented. However majority of these reactions suffer from one or other drawbacks such as expensive reagent, low to moderate yield, longer or drastic reaction condition leading to side reactions, tedious work-up procedure for product isolation and environmental pollution.

 

In recent days great emphasis has been provided upon adopting greener methodologies in most chemical reactions; primarily due to their eco-friendly nature. Hence the importance of ultrasound accelerated organic reactions has drawn attention of medicinal chemists because of their many fold advantages over the traditional methods22.

 

Hence it was considered worthwhile to carry out a simple expeditious synthesis of 2, 3-dihydro-1H-1, 5-benzodiazepine derivatives because of their variety of pharmacological activity and industrial applications.  In continuation of our work on green organic synthesis of pharmacologically active heterocyclic compounds23, we report herein solvent free synthesis of some 1,5-benzodiazepine derivatives by cyclocondensation of o-phenylendiamine with ketones as well as 1, 3-β-dicarbonyl compounds under eco-friendly condition using silica gel as a catalyst (Scheme-I) and preliminary evaluation of their anti-anxiety or anti-depressant action .

SCHEME-I

 

MATERIAL AND METHODS:

General procedure for the preparation of 1, 5-benzodiazepines.  Acetophenone (2c) (2.6ml, 22mmole), o-phenylendiamine (1.08g, 10mmole) and silica gel (0.3gm) was taken in a 100ml iodine flask, mixed well by gentle shaking and then stoppered. The contents of the flask were then irradiated in a sonicator bath maintaining for 25-30min at room temperature. After completion of the reaction (TLC) [EtOAc: pet. ether: CHCl3], chloroform (15ml) was added in the reaction mixture and filtered to remove silica gel; which was washed twice with chloroform (3-4ml). The combined organic layer was washed with water (4-5ml) and then dried over anhydrous Na2SO4. The dried organic layer was then concentrated under vacuo to get a thick dark liquid; which on trituration with hexane gave the crude product 3c (6.35g; 20.1 mmole) melting around 138-148°C. A portion of this compound was recrystallized from methanol to get the pure product 3c melting at 150-152°C; whose m.m.p remained undepressed in admixture with an authentic sample. All compounds (3a-i) reported herein were prepared by this procedure and were characterized by comparison of their m.p. and spectral data [IR, 1HNMR and mass] as well as m.m.p. with their respective authentic sample prepared by conventional procedure as reported in literature.

 

ANTI-MICROBIAL ACTIVITY:

The new synthesis 1, 5-benzodiazepine compounds have been screened for antibacterial activity against Staphylococcus aurens and Klebsiella pneumoniae as well as antifungal activity against Aspergillus niger and Candida albicans by cup-plate method28,29. Ceprofloxin and Ciclopiroxoamine were used as standards for comparison of antibacterial and antifungal activity, respectively. The results indicate that these compounds were active against the entire four organisms. Compound 3a-h was tested and results of antimicrobial activity were recorded in Table II. The compound 3c-3e exhibited higher antimicrobial and antifungal activity then the standard drug.

 

SPECTRAL STUDIES:

All commercially available compounds were used without further purification. The reactions were followed and checked by TLC (silica gel G60) for completion using EtOAc: pet. ether: CHCl3 (4:1:1) and the spots were examined by either I2 vapor or under UV lamp; whereas the identity and purity of the final products were checked against the authentic sample using EtOAc: pet. ether (1:9) and their Rf-value has been reported. The IR spectra of the products were recorded on a 300 MHz shimadzu FTIR-8400S spectrophotometer using KBr pellets. ­1H NMR spectra were recorded in CDCl3 on a 300 MHz Shimadzu FT-NMR (δ in ppm) relative to TMS as internal standard and mass spectra were recorded on a SSQ7000 mass spectrometer at 70eV.

 

2,2,4-trimethyl-2,3-dihydro-1H-1,5-benzodiazepine (3a): Yellow crystals; m.p.136-38°C7; Rf=0.76, IR (KBr): 3343,1657, 1610 cm-1; 1HNMR (CDCl3):δ 1.35 (s, 6H), 2.20 (s,2H), 2.35(s, 3H), 2.95 (br s,1H,NH), 6.65-7.3(m, 4H); MS: m/z 188(M+).

 

2, 4-diethyl-2-methyl-2, 3-dihydro-1H-1, 5-benzodiazepine (3b): Yellow solid; m.p.  138-40oC 8, Rf=0.71, IR(KBr); 3350,1648,1615 cm-1 ; 1H NMR (CDCl3) δ 0.99 (t,3H)), 1.25(t, 3H), 1.70(q, 2H), 2.15(m, 2H), 2.35(3H), 2.69(q, 2H), 3.25(br s, NH, 1H) 6.65-7.35  (m, 4H); MS: m/z 217(M+).

 

2-methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-benzodiazepine (3c):Yellow solid; m.p. 150-52°C7; Rf= 0.69, IR (KBr): 3343,3010,1635,1510 cm-1; 1HNMR (CDCl3):δ 1.65 (s, 3H), 3.15 (d,2H), 4.1(br s, NH) 6.8-7.55(14H, Ar-H), MS: m/z 312(M+).

 

2,4-bis(4-chlorophenyl)-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3d): Yellow crystals; m.p. 160-63oC 9; Rf= 0.71, IR (KBr): 3343, 2950, 1624, 1518 cm-1; 1HNMR (CDCl3):δ 1.65 (s, 3H), 2.90 (s,2H), 3.95(br s, NH) 6.85-7.45(m, 12H, Ar-H) MS: m/z 381(M+).

Table 1. Silica gel catalyzed cyclocondensation of o-phenylendiamine with acyclic, cyclic and aromatic ketones and 1,3-β-dicarbonyl compound.

Compound
Ketone  (2)
Yield (%) a
Product b  (3)
M.P. (°C)

a

 

89

 

126-28

b

 

78

 

138-40

c

 

92

 

156-58

d

 

75

 

136-38

e

 

87

 

142-45

f

 

92

 

138-40

g

 

85

 

133-35

h

 

82

 

 

142-44

i

 

 

 

80

 

 

 

184-86

 

a Pure solid product as isolated.

bAll the products are known, characterized by their m.p. and spectral (IR 1HNMR and MS) analysis and compared with the authentic samples.

Table II ­­­­– Anti microbial activity of compounds 3a-h.

Compounds

Antibacterial activity zone of inhibition (in mm)

Antifungal activity zone of inhibition (in mm)

A. aurens

K. pneumoniae

A. niger

C. albicans

Control (vehicle)

24

26

22

24

1, 5-BDZ- 3a

12

12

10

10

1, 5-BDZ- 3b

13

12

11

12

1,5-BDZ-3c

22

23

19

22

1,5-BDZ-3d

24

24

21

23

1, 5-BDZ- 3e

23

23

21

22

1, 5-BDZ- 3f

15

16

14

15

1,5-BDZ-3g

16

17

15

16

1,5-BDZ-3h

12

12

11

11

 

2,4-bis(4-methylphenyl)-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3e): Yellow crystals; m.p. 142-45°C 10; Rf= 0.74, IR (KBr): 3253, 1654, 1528 cm-1; 1HNMR (CDCl3):δ 1.65 (s, 3H), 2.1(s, 9H, 3xAr-CH3), 2.70 (s,1H), 3.05 (d,1H), 3.60(br s, 1H, NH)7.1-7.5(m, 11H, Ar-H); MS: m/z 378(M+).

 

10-Spirocyclohexane-2,3,4,10,11,11a-hexahydro 1H-dibenzo [b,e] [1,4]diazepine (3f) : Yellow crystals; m.p. 138-40°C 9, Rf=.072, IR(KBr); 3290, 2980, 1645,           1525 cm-1; 1H NMR (CDCl3) δ 1.96-2.75 (m, 16H),2.80-2.90 (m,3H), 3.80(br s, NH, 1H) 7.0-7.35  (m, 4H); MS: m/z 268(M+)

 

10-Spirocyclopentane-1,2,3,9,10,10a-hexahydro benzo[b] cyclopenta[e] [1,4]diazepine (3g) : Yellow solid; m.p. 138-40oC 8, Rf= 0.73, IR(KBr); 3335,1665,1605 cm-1 ; 1H NMR (CDCl3) δ 1.30-190(m, 12H), 2.30-2.60 (m,3H) 4.45(br s, NH, 1H) 6.65-7.35  (m, 4H); MS: m/z 240(M+).

 

4-methyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one (3h) : Yellow crystals; m.p. 142-44oC24  Rf = 0.72  IR(KBr); 3300, 3010,1675,1605 CM-1 ; 1H NMR (CDCl3) δ 10.50 (s, 1H,NH), 7.5-7.0 (m,4H arom.), 3.30 (s, 2H, CH2), 2.40 (s, 3H, CH3); MS: m/z 180(M+).

 

2,4-dimethyl-3H-1,5-benzodiazepine (3i) :yellowish crystals; m.p. 184-86°C25, Rf = 0.74  IR(KBr); 3010,1675,1605 CM-1 ; 1H NMR (CDCl3) δ 7.5-7.0 (m,4H arom.), 3.30 (s, 2H, CH2), 2.40 (s, 3H, CH3); MS: m/z 183(M+).

 

RESULTS AND DISCUSSION:

An expeditious solvent free synthesis of 2,3-dihydro-1H-1,5-benzodiazepine derivatives has been carried out by reacting o-phenylenediamine with a variety of acyclic (2a and b), aromatic (2c-e), cyclic (2f and g) ketones and 1,3-dicarbonyl compounds (2h and i) in presence of a catalytic amount (<10%) of silica gel under ultrasonic cavitation affording very good to excellent yield within 25-30 min as shown in Scheme-I and the results are summarized in Table I.

 

ACKNOWLEDGEMENT:

The author sincerely thanks Prin. A. D. Deshpande for providing all facilities for the said work as well as for his valuable advice and constant encouragement during this work. Our sincere thanks are also due to pharmacology

 

section of our Institute for all help in carrying out pharmacological screening of the compounds.

 

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Received on 04.07.2009       Modified on 25.02.2010

Accepted on 28.03.2010      © RJPT All right reserved

Research J. Pharm. and Tech.3 (3): July-Sept. 2010; Page 938-941