Silica Sulfuric Acid as a Mild and Efficient Reagent for the Synthesis of 1,4-Diazepine and 1,5-Benzodiazepine Derivatives

Silica Sulfuric Acid를 이용한 효율적인 1,4-diazepine and 1,5-benzodiazepine 유도체의 합성

Abstract

The synthesis of biologically active 1H-1,4-diazepines 4a-d and 3H-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 ${\beta}$-diketones/${\beta}$-ketoesters 3a-d were synthesized by the condensation reaction of 4-methylthiobenzenesulfonyl chloride 1 with various ${\beta}$-diketones/${\beta}$-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.

Silica sulfuric acid (SSA)를 이용하여 ethylenediamine (EDA)과 o-phenylenediamine (o-PDA)을 2-(4-methylthio benzenesulfonyl)-1,3-dimethyl/1-methyl-3-phenyl/1,3-diphenyl/1-methyl-3-ethoxypropane-1,3-dione 3a-d과의 헤테로고리화 반응을 통하여 좋은 생리활성을 나타내는 1H-1,4-diazepines 4a-d과 3H-1,5-benzodiazepines 5a-d을 좋은 수율로 합성하였다. 이 반응에서 ${\beta}$-diketones/${\beta}$-ketoesters 3a-d는 4-methylthiobenzenesulfonyl chloride 1과 다양한 ${\beta}$-diketones/${\beta}$-ketoesters 2a-d과의 축합반응으로 합성하였으며, 합성한 4a-d와 5a-d 화합물들에 대해서 fantimicrobial, antifungal 및 anthelmintic 활성을 측정하였다.

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 antidepressive12 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 BF3-etherate, NaBH4, polyphosphoric acid, or SiO2, MgO/POCl3, Yb(OTf)3, Sc(OTf)3, Al2O3/P2O5, (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 1H-1,4-diazepine and 3H-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 1H-1,4-diazepines and 3H-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 1H-1,4-diazepines 4a-d and 3H-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 (Scheme 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 1H-1,4-diazepines 4a-d. Further 3a-d were treated with o-phenylenediamine on similar reaction conditions, to obtain 3H-1,5-benzodiazepines 5a-d (Scheme 2). SSA was prepared by reported method.22

Scheme 1.

Scheme 2.

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 Table 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.

Table 1.aValues are in terms of Mean±SEM of results done in triplicate.

 

CONCLUSION

In conclusion, this new method for the synthesis of 1H-1,4-diazepines and 3H-1,5-benzodiazepines using silica sulfuric acid (SSA) offers significant improvement over existing method. Also, this simple and reproducible method affords various 1H-1,4-diazepines and 3H-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 F254 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. 1H NMR and 13C NMR spectra were run on model DRX 300 at 300.13 MHz and 75 MHz, respectively, in CDCl3 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 F254 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. C12H14O4S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 1.58 (s, 6H, CH3), 2.46 (s, 3H, S-CH3), 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); 13C NMR (CDCl3): 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. C15H16O4S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 1.58 (s, 3H, CH3), 2.45 (s, 3H, S-CH3), 6.08 (s, 1H, -CH=), 7.40-7.86 (m, 10H, Ar-H); 13C NMR (CDCl3): 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. C22H18O4S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 2.46 (s, 3H, S-CH3), 6.10 (s, 1H, -CH=), 7.65-7.80 (m, 14H, Ar-H); 13C NMR (CDCl3): 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. C13H16O5S2: 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-CH3), 1350, 1145 (-SO2), 1210, 1240 (C-O-C) cm-1; 1H NMR (CDCl3): δ 1.30 (t, J = 7.25 Hz, 3H, CH3CH2-), 2.08 (s, 3H, CH3), 4.12 (q, J = 7.26 Hz, 2H, O-CH2CH3), 2.45 (s, 3H, S-CH3), 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); 13C NMR (CDCl3): 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. C14H18N2O2S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 2.07 (s, 6H, CH3), 2.46 (s, 3H, S-CH3), 3.10 (t, J = 6.98 Hz, 4H, N-CH2-CH2-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); 13C NMR (CDCl3): 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. C19H20N2O2S2: 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-CH3), 1350, 1145 (-SO2) cm-1; 1H NMR (CDCl3): δ 2.10 (s, 3H, CH3), 2.50 (s, 3H, S-CH3), 3.10 (t, J = 6.90 Hz, 4H, N-CH2-CH2-N), 6.10 (s, 1H, -CH=), 7.45-7.88 (m, 10H, Ar-H); 13C NMR (CDCl3): 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. C24H22N2O2S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 2.45 (s, 3H, S-CH3), 3.15 (t, J = 7.05 Hz, 4H, N-CH2-CH2-N), 6.09 (s, 1H, -CH=), 7.65-7.80 (m, 14H, Ar-H); 13C NMR (CDCl3): 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. C13H16N2O3S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 1.83 (s, 3H, CH3), 2.48 (s, 3H, CH3), 2.46 (s, 3H, S-CH3), 2.95-3.10 (m, 4H, N-CH2-CH2-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); 13C NMR (CDCl3): 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. C14H18N2O2S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 1.60 (s, 6H, CH3), 2.45 (s, 3H, S-CH3), 6.07 (s, 1H, -CH=), 7.65-7.80 (m, 8H, Ar-H); 13C NMR (CDCl3): 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. C23H20N2O2S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 1.70 (s, 3H, CH3), 2.47 (s, 3H, S-CH3), 6.10 (s, 1H, -CH=), 7.65-7.80 (m, 13H, Ar-H); 13C NMR (CDCl3): 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. C28H22N2O2S2: 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-CH3), 1345, 1140 (-SO2) cm-1; 1H NMR (CDCl3): δ 2.46 (s, 3H, S-CH3), 6.09 (s, 1H, -CH=), 7.65-7.80 (m, 18H, Ar-H); 13C NMR (CDCl3): 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 C17H16N2O3S2: 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-CH3), 1350, 1145 (-SO2) cm-1; 1H NMR(CDCl3): δ 1.75 (s, 3H, CH3), 2.50 (s, 3H, S-CH3), 3.95 (s, 1H, -CH=), 7.65-7.80 (m, 8H, Ar-H), 8.30 (br s, 1H, NH); 13C NMR (CDCl3): 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+).