The synthesis of biologically active 1
H
-1,4-diazepines
4a-d
and 3
H
-1,5-benzodiazepines
5a-d
in good yields, from the heterocyclization reaction of 2-(4-methylthio benzenesulfonyl)-1,3-dimethyl/1-methyl-3-phenyl/1,3-diphenyl/1-methyl-3-ethoxy propane-1,3-dione
3a-d
with ethylenediamine (EDA) and
o
-phenylenediamine (
o
-PDA), respectively, in the presence of silica sulfuric acid (SSA) is described. The novel β-diketones/β-ketoesters
3a-d
were synthesized by the condensation reaction of 4-methylthiobenzenesulfonyl chloride
1
with various β-diketones/β-ketoesters
2a-d
. All structures of the newly synthesized compounds were elucidated by elemental analysis and spectral studies. The compounds
4a-d
and
5a-d
have been screened for antimicrobial, antifungal and anthelmintic activity.
INTRODUCTION
Heterocyclic compounds have recently attracted attention as an important class of organic chemistry in the field of drugs and pharmaceuticals.
1
A large number of heterocyclic compounds derived from β-diketones have been reported as active entities.
2
β-Diketones are important precursors for the synthesis of pharmacologically active heterocyclic compounds as 1,4-diazepines and 1,5-benzodiazepines. These compounds are widely used as anticonvulsant,
3
anti-HIV,
4
CNS activity,
5
anti-ulcer,
6
antiproliferative,
7
antitumor agents,
8
antianxiety,
9
and HDM2 antagonists.
10
These were also inhibitor of the bacterial enoyl-ACP reductase, FabI,
11
antidepressive
12
as well as anti-inflammatory agents.
13
Other than their biological importance, benzodiazepines derivatives are also commercially used as dyes for acrylic fibers.
14
There are various methods for the synthesis of diazepines and benzodiazepines by the condensation of
o
-phenylenediamines with α,β-unsaturated carbonyl compounds, β-haloketones, or ketones in the presence of acid.
15
A variety of reagents, such as BF
3
-etherate, NaBH
4
, polyphosphoric acid, or SiO
2
, MgO/POCl
3
, Yb(OTf)
3
, Sc(OTf)
3
, Al
2
O
3
/P
2
O
5
, (bromodimethyl) sulfonium bromide or under microwave irradiation are utilized for condensation reactions.
16
However, these methods are associated with several drawbacks such as harsh reaction conditions, complex and tedious experimental procedures and low yields. In recent years the use of organic-inorganic hybrid immobilized solid support reagents have received great interest. Such reagents not only simplify the purification process but also provide help in preventing the release of reaction residues into the environment.
17
Furthermore, from the synthetic point of view, these reagents significantly reduce reaction time and make the workup easier. Recently, silica and sulfuric acid in dichloromethane have been reported for the oxathioacetalyzation of carbonyl compounds.
18
The efficiency of silica sulfuric acid (SSA), under operationally simple conditions, has prompted us to explore the possibility of using this reagent for the synthesis of 1
H
-1,4-diazepine and 3
H
-1,5-benzodiazepines from the reaction of β-diketones/β-ketoesters with ethylenediamine (EDA) and
o
-phenylenediamine (
o
-PDA), respectively.
In continuation of our ongoing research program to develop new reagents and synthetic procedure for the synthesis of novel heterocyclic compounds,
19
-
21
we report here a new convenient method for the synthesis of 2-(4-methylthiobenzenesulfonyl) containing 1
H
-1,4-diazepines and 3
H
-1,5-benzodiazepines due to their importance in medicinal chemistry. To achieve this target, we had synthesized β-diketones/β-ketoesters
3a-d
which were condensed with EDA and
o
-PDA in the presence of SSA, to obtain the corresponding substituted 1
H
-1,4-diazepines
4a-d
and 3
H
-1,5-benzodiazepines
5a-d
, respectively, in high yields.
RESULTS AND DISCUSSION
Thioanisole was sulfonated with chlorosulfonic acid, to obtain 4-(methylthio)benzenesulfonyl chloride
1
. This compound
1
, on condensation with various β-diketones/β-ketoesters
2a-d
in the presence of sodium methoxide yielded corresponding substituted β-diketones/β-ketoesters
3a-d
(
1
). All newly synthesized compounds were characterized by elemental analysis and spectral studies (experimental section). When compounds
3a-d
were treated with ethylenediamine in the presence of SSA underwent dehydrative annulation to afford novel substituted 1
H
-1,4-diazepines
4a-d
. Further
3a-d
were treated with
o
-phenylenediamine on similar reaction conditions, to obtain 3
H
-1,5-benzodiazepines
5a-d
(
2
). SSA was prepared by reported method.
22
- Antimicrobial, antifungal and anthelmintic activities of compounds 4a-d and 5a-d
The newly synthesized diazepines
4a-d
and benzodiazepines
5a-d
were evaluated for the antibacterial activity against
Staphylococcus aureus
,
Klebsiella pneumoniae
and antifungal activity against
Aspergillus niger
,
Candia albicans
by the cup-plate method.
23
Ciprofloxin and ciclopiroxolamine were used as standards for comparison of antibacterial and antifungal activities, respectively. The results indicate that these compounds were active against all the four organisms. The anthelmintic activity was carried out on earth worms
Pherituma posthuma
, by a technique as described by Bagavant
et al
. with slight modification.
24
Piperazine citrate was used as standard drug. The values of antimicrobial and anthelmintic activity are terms of mean ± SEM of results done in triplicate, reported in
1
. The compounds
4a-c
and
5a-c
exhibited antimicrobial as well as antifungal activities, but
4d
and
5d
showed significant anthelmintic activity due to presence of more electronnegative groups.
From these results it is apparent that attempts to introduce functionality methyl/phenyl at position 5 and 7 resulted in significantly increased antibacterial and antifungal activities due to its electron donating character but steric hindrance also played a major important role. The diazepine-5-one and benzodiazepine-2-one showed more anthelmintic activity than others due to more electronegativity of oxygen. This result implies that the presence of electron withdrawing groups at position 5 in diazepines and position 2 of benzodiazepines can increase anthelmintic activity.
Antimicrobial, antifungal and anthelmintic activities of compounds4a-dand5a-d
aValues are in terms of Mean±SEM of results done in triplicate.
CONCLUSION
In conclusion, this new method for the synthesis of 1
H
-1,4-diazepines and 3
H
-1,5-benzodiazepines using silica sulfuric acid (SSA) offers significant improvement over existing method. Also, this simple and reproducible method affords various 1
H
-1,4-diazepines and 3
H
-1,5-benzodiazepines with short reaction times, high yields and without the formation of undesirable by products. Among the synthesized compounds evaluated (
4a-d
and
5a-d
), compound
4a-c
,
5a-c
exhibited antimicrobial as well as antifungal activities in comparison the standard drug but compounds
4d
and
5d
showed significant anthelmintic activity. More extensive study is needed to confirm the preliminary results and mode of action studies are required to be able to optimize the ffectiveness of this series of compounds
4a-d
and
5a-d
.
EXPERIMENTAL
- Instrumentation
All the melting points were determined in open capillary tubes and are uncorrected. The purity of the newly synthesized compounds was checked by TLC on aluminium oxide 60 F
254
plates (Merck) and spots were visualized by exposing the dry plates in iodine vapor. The IR spectra were recorded on a Nicolet-Magna-FT-IR-550 spectrometer in using KBr pellets.
1
H NMR and
13
C NMR spectra were run on model DRX 300 at 300.13 MHz and 75 MHz, respectively, in CDCl
3
and mass spectra on a LCMS instrument. The elemental analysis (C, H, N) of compounds was performed on Carlo Erba-1108 element analyzer. Their results were found to be in good agreement with the calculated values.
- General procedure for the preparation of 2-[(4-methylthio)benzenesulfonyl]-1,3-dimethyl/1-methyl-3-phenyl/1,3-diphenyl/1-methyl-3-ethoxypropane-1,3-dione (3a-d)
Sodium methoxide (0.54 g, 10.0 mmol) and β-diketones (10.0 mmol) were placed in a dried round bottom flask and stirred for 1 h on a magnetic stirrer at 50 ℃, after which a creamy mass was obtained. The 4-(methylthio)benzenesulfonyl chloride
1
(2.22 g, 10.0 mmol) was taken in dry toluene and added drop by drop in above said reaction mass. The reaction mixture was refluxed for 7 h at 100 ℃ with stirring. The progress of the reaction was monitored by TLC. After completion of the reaction, the mixture was cooled and toluene was removed under reduced pressure. The reaction mixture was extracted using chloroform and washed with water. The chloroform layer was dried using anhydrous sodium sulfate and distilled to yield the solid compound. The product was purified by column chromatography over silica gel using pet ether: ethyl acetate (1:2) as an eluent. It was purified by recrystallization from absolute ethanol. Purity of the compound was checked by TLC on aluminum oxide 60 F
254
plates (Merck) in a 7:2:1 (benzene:ethanol:ammonia) upper layer using as a mobile phase. The yield and spectral data were reported in experimental section.
2-[(4-Methylthio)benzenesulfonyl]-1,3-dimethylpropane-1,3-dione (3a).
2.23 g (78%), mp 145 ℃; Anal. Calcd. C
12
H
14
O
4
S
2
: C, 50.33; H, 4.93; S, 22.39. Found: C, 50.35; H, 4.90; S, 22.40. IR (KBr): 3025 (Ar-H), 2915 (C-H), 1700 (C=O), 1290, 1415 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 1.58 (s, 6H, CH
3
), 2.46 (s, 3H, S-CH
3
), 6.07 (s, 1H, -CH=), 7.40 (dd,
J
= 7.46 , 6.89 Hz, 2H, Ar-H), 7.55 (dd,
J
= 7.45, 6.89 Hz, 2H, Ar-H);
13
C NMR (CDCl
3
): δ 18.9, 19.3, 106.2, 127.6, 129.0, 136.9, 198.4; MS (
m/z
): 287 (M+H
+
).
2-[(4-Methylthio)benzenesulfonyl]-1-methyl-3-phenylpropane-1,3-dione (3b).
2.56 g (74%), mp 145 ℃; Anal. Calcd. C
15
H
16
O
4
S
2
: C, 58.60; H, 4.63; S, 18.41. Found: C, 58.57; H, 4.62; S, 18.40. IR (KBr): 3030 (Ar-H), 2919 (C-H), 1715 (C=O), 1295, 1410 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 1.58 (s, 3H, CH
3
), 2.45 (s, 3H, S-CH
3
), 6.08 (s, 1H, -CH=), 7.40-7.86 (m, 10H, Ar-H);
13
C NMR (CDCl
3
): δ 18.9, 19.2, 101.2, 125.7, 127.6, 128.4, 128.6, 129.0, 132.9, 136.9, 137.5, 198.4; MS (
m/z
): 349 (M+H
+
).
2-[(4-methylthio)benzenesulfonyl]-1,3-diphenylpropane-1,3-dione (3c).
3.54 g (82%), mp 155 ℃; Anal. Calcd. C
22
H
18
O
4
S
2
: C, 64.37; H, 4.42; S, 15.62. Found: C, 64.35; H, 4.40; S, 15.63. IR (KBr): 3020 (Ar-H), 2915 (C-H), 1710 (C=O), 1300, 1420 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 2.46 (s, 3H, S-CH
3
), 6.10 (s, 1H, -CH=), 7.65-7.80 (m, 14H, Ar-H);
13
C NMR (CDCl
3
): δ 19.8, 101.2, 125.7, 127.6, 128.4, 128.6, 129.0, 132.9, 136.9, 137.5, 198.4; MS (
m/z
): 411 (M+H
+
).
2-[(4-Methylthio)benzenesulfonyl]-1-methyl-3-ethoxypropane-1,3-dione (3d).
2.42 g (73%), mp 105 ℃; Anal. Calcd. C
13
H
16
O
5
S
2
: C, 49.35; H, 5.10; S, 20.27. Found: C, 49.36; H, 5.13; S, 20.25. IR (KBr): 3030 (Ar-H), 2915(C-H), 1720 (C=O), 1297, 1415 (S-CH
3
), 1350, 1145 (-SO
2
), 1210, 1240 (C-O-C) cm
-1
;
1
H NMR (CDCl
3
): δ 1.30 (t,
J
= 7.25 Hz, 3H, CH
3
CH
2
-), 2.08 (s, 3H, CH
3
), 4.12 (q,
J
= 7.26 Hz, 2H, O-CH
2
CH
3
), 2.45 (s, 3H, S-CH
3
), 6.15 (s, 1H, -CH=), 7.40 (dd, 2H,
J
= 7.46 , 6.89 Hz, Ar-H), 7.55 (dd,
J
= 7.25, 7.09 Hz, 2H, Ar-H);
13
C NMR (CDCl
3
): δ 14.7, 18.9, 19.3, 59.5, 106.2, 127.6, 129.0, 136.9, 198.4; MS (
m/z
): 317 (M+H
+
).
- General procedure for the preparation of 1H-1,4-diazepine 4a-d and 3H-1,5-benzodiazepine 5a-d derivatives
An equimolar ratio of β-diketones/β-ketoesters (10 mmol)
3a-d
, and EDA/
o
-PDA (10.0 mmol) in ethyl acetate (50 mL) in the presence of silica sulfuric acid (10.0 mmol) was stirred 50 ℃ for 2 h. The progress of reaction was monitored by TLC using 7:2:1 (benzene:ethanol:ammonia) upper layer as mobile phase. Upon completion of reaction, the mixture was extracted with ethyl acetate (2 × 25 mL) and the solvent was removed. The crude product was washed with dry ether and recrystallized from pet ether:ethyl acetate (1:1). The product was purified by column chromatography over silica gel using pet ether:ethylacetate (40: 60) as an eluent.
6-[(4-Methylthio)benzenesulfonyl]-5,7-dimethyl-2,3-dihydro-1H-1,4-diazepine (4a).
2.35 g (76%), mp 160 ℃; Anal. Calcd. C
14
H
18
N
2
O
2
S
2
: C, 54.17; H, 5.84; N, 9.02. Found: C, 54.15; H, 5.85; N, 9.03. IR (KBr): 3050 (Ar-H), 2895(C-H), 1580 (C=N), 1290, 1415 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 2.07 (s, 6H, CH
3
), 2.46 (s, 3H, S-CH
3
), 3.10 (t,
J
= 6.98 Hz, 4H, N-CH
2
-CH
2
-N), 6.05 (s, 1H, -CH=), 7.43 (dd,
J
= 7.46, 6.89 Hz, 2H, Ar-H), 7.59 (dd,
J
= 7.46 , 6.89 Hz, 2H, Ar-H);
13
C NMR (CDCl
3
): δ 12.7, 18.9, 48.5, 70.3, 114.5, 125.7, 127.6, 127.9, 128.4, 134.3, 140.5, 164.7; MS (
m/z
): 311 (M+H
+
).
6-[(4-Methylthio)benzenesulfonyl]-5-methyl-7-phenyl-2,3-dihydro-1H-1,4-diazepine (4b).
2.39 g (69%), mp 145 ℃; Anal. Calcd. C
19
H
20
N
2
O
2
S
2
: C, 61.26; H, 5.41; N, 7.52. Found: C, 61.28; H, 5.40; N, 7.50. IR (KBr): 3030 (Ar-H), 2919 (C-H), 1580 (C=N), 1295, 1410 (S-CH
3
), 1350, 1145 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 2.10 (s, 3H, CH
3
), 2.50 (s, 3H, S-CH
3
), 3.10 (t,
J
= 6.90 Hz, 4H, N-CH
2
-CH
2
-N), 6.10 (s, 1H, -CH=), 7.45-7.88 (m, 10H, Ar-H);
13
C NMR (CDCl
3
): δ 15.3, 18.9, 47.9, 48.5, 70.3, 114.5, 125.7, 126.5, 127.6, 127.9, 128.7, 130.7, 135.3, 140.9, 164.8; MS (
m/z
): 378 (M+H
+
).
6-[(4-Methylthio)benzenesulfonyl]-5,7-diphenyl-2,3-dihydro-1H-1,4-diazepine (4c).
5.36 g (83%), mp 175 ℃; Anal. Calcd. C
24
H
22
N
2
O
2
S
2
: C, 66.35; H, 5.10; N, 6.45. Found: C, 66.33; H, 5.08; N, 6.47. IR (KBr): 3030 (Ar-H), 2920 (C-H), 1585 (C=N), 1295, 1410 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 2.45 (s, 3H, S-CH
3
), 3.15 (t,
J
= 7.05 Hz, 4H, N-CH
2
-CH
2
-N), 6.09 (s, 1H, -CH=), 7.65-7.80 (m, 14H, Ar-H);
13
C NMR (CDCl
3
): δ 18.9, 47.9, 72.3, 114.5, 125.7-137.9, 164.7; MS (
m/z
): 435 (M+H
+
).
6-[(4-Methylthio)benzenesulfonyl]-7-methyl-2,3,4,6-tetrahydro-1H-1,4-diazepine-5-one (4d).
2.46 g (78%), mp 140 ℃; Anal. Calcd. C
13
H
16
N
2
O
3
S
2
: C, 49.98; H, 5.16; N, 8.97. Found: C, 50.00; H, 5.15; N, 8.95. IR (KBr): 3350 (N-H), 3030 (Ar-H), 2915 (C-H), 1740 (C=O), 1630 (C=N), 1295, 1410 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 1.83 (s, 3H, CH
3
), 2.48 (s, 3H, CH
3
), 2.46 (s, 3H,
S
-CH
3
), 2.95-3.10 (m, 4H, N-CH
2
-CH
2
-N), 4.09 (s, 1H, -CH=), 7.45 (dd,
J
= 7.46, 6.89 Hz, 2H, Ar-H), 7.60 (dd,
J
= 7.46, 6.89 Hz, 2H, Ar-H), 8.30 (br s, 1H, NH);
13
C NMR (CDCl
3
): δ 13.7, 18.9, 43.8, 50.9, 64.9, 126.7, 127.6, 134.5, 140.6, 164.6, 170.8; MS (
m/z
): 313 (M+H
+
).
3-[(4-Methylthio)benzenesulfonyl]-2,4-dimethyl-3H-1,5-benzodiazepine (5a).
2.49 g (70%), mp 165 ℃; Anal. Calcd. C
14
H
18
N
2
O
2
S
2
: C, 60.31; H, 5.06; N, 7.81. Found: C, 60.30; H, 5.07; N, 7.80. IR (KBr): 3050 (Ar-H), 2895 (C-H), 1580 (C=N), 1290, 1415 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 1.60 (s, 6H, CH
3
), 2.45 (s, 3H, S-CH
3
), 6.07 (s, 1H, -CH=), 7.65-7.80 (m, 8H, Ar-H);
13
C NMR (CDCl
3
): δ 12.7, 18.9, 70.3, 114.5, 123.7, 127.9, 128.4, 134.3, 140.6, 142.5, 164.7; MS (
m/z
): 358 (M+H
+
).
3-[(4-Methylthio)benzenesulfonyl]-2-methyl-4-phenyl-3H-1,5-benzodiazepine (5b).
2.64 g (63%), mp 185 ℃; Anal. Calcd. C
23
H
20
N
2
O
2
S
2
: C, 65.69; H, 4.79; N, 6.66. Found: C, 65.70; H, 4.80; N, 6.65. IR (KBr): 3030 (Ar-H), 2919 (C-H), 1583 (C=N), 1295, 1413 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 1.70 (s, 3H, CH
3
), 2.47 (s, 3H,
S
-CH
3
), 6.10 (s, 1H, -CH=), 7.65-7.80 (m, 13H, Ar-H);
13
C NMR (CDCl
3
): δ 15.3, 18.7, 70.8, 114.6, 125.7, 126.5, 127.6, 127.9, 128.4, 130.7, 133.8, 140.5, 142.7, 164.9; MS (
m/z
): 421(M+H
+
).
3-[(4-Methylthio)benzenesulfonyl]-2,4-diphenyl-3H-1,5-benzodiazepine (5c).
3.47 g (72%), mp 175 ℃; Anal. Calcd. C
28
H
22
N
2
O
2
S
2
: C, 69.68; H, 4.59; N, 5.80. Found: C, 69.67; H, 4.60; N, 5.83. IR (KBr): 3035 (Ar-H), 2915 (C-H), 1585 (C=N), 1295, 1410 (S-CH
3
), 1345, 1140 (-SO
2
) cm
-1
;
1
H NMR (CDCl
3
): δ 2.46 (s, 3H, S-CH
3
), 6.09 (s, 1H, -CH=), 7.65-7.80 (m, 18H, Ar-H);
13
C NMR (CDCl
3
): δ 18.9, 72.3, 114.5, 125.7, 126.9, 128.3, 129.4, 130.5, 134.5, 142.4, 145.5, 146.9, 164.7; MS (
m/z
): 483 (M+H
+
).
3-[(4-Methylthio)benzenesulfonyl]-1,3-dihydro-4-methyl-3H-1,5-benzodiazepine-2-one (5d).
2.30 g (68%), mp 170 ℃; Anal. Calcd for C
17
H
16
N
2
O
3
S
2
: C, 56.65; H, 4.47; N, 7.77. Found: C, 56.63; H, 4.45; N, 7.80. IR (KBr): 3420 (N-H), 3025 (Ar-H), 2920 (C-H), 1745 (C=O), 1625 (C=N), 1300, 1415 (S-CH
3
), 1350, 1145 (-SO
2
) cm
-1
;
1
H NMR(CDCl
3
): δ 1.75 (s, 3H, CH
3
), 2.50 (s, 3H, S-CH
3
), 3.95 (s, 1H, -CH=), 7.65-7.80 (m, 8H, Ar-H), 8.30 (br s, 1H, NH);
13
C NMR (CDCl
3
): δ 13.7, 18.9, 64.9, 121.7, 125.4, 126.6, 127.6, 134.3, 134.7, 140.9, 164.6, 168.2; MS (
m/z
): 361 (M+H
+
).
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1984
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