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Nontoxic, Inexpensive, Ammonium Chloride-Mediated (In Water) Synthesis of Some Novel 1,5-benzothiazepine Derivatives and Their Antimicrobial Activity.

Byline: Demet Coskun and Sevda Kirbag

Summary:

In the present study, a new, nontoxic, easy and inexpensive method for the synthesis of 1,5-benzothiazepine derivatives was described and a mechanism for this reactions was proposed. Ammonium chloride which is inexpensive and readily available reagent catalyzes the thia-michael addition reaction of thiols in water efficiently. 1,5-benzothiazepines derivatives were synthesized by the condensation reactions of o-aminothiophenol (o-ATP) with chalcone derivatives by using saturated solution of NH4Cl in water. The products were characterized by the elemental analysis, NMR and FT-IR techniques. Synthesized compounds were tested for antimicrobial activity against. Staphylococcus aureus ATCC 6538, Escherichia coli ATCC 25922, Bacillus subtilis IMG22 and Candida albicans ATCC 10231. Among the synthesized compounds 2b was found to be most active derivative against Escherichia coli ATCC 25922 and Candida albicans ATCC 10231. The other compounds didn't exhibit any activity against the other test microorganisms.

Keywords: Benzofuran, 1,5-Benzothiazephines, o-Aminothiophenol, Catalysis, Ammonium chloride, antimicrobial activity.

Introduction

Benzofuran derivatives are an interesting class of heterocyclic compounds. Many of benzofuran derivatives find application such as of antioxidants, brightening agents, fluorescent sensor [1] and in other fields of chemistry [2]. Benzofuran derivatives form part of a large of natural products. Several of this benzofurans are bergapten, nodakenetin xanthotoxin and khellin.

1,5-Benzothiazepines are important heterocyclic ring systems because of their biological and pharmacological properties [3]. Many of benzothiazepino derivatives have been used as anti- convulsants [4], anti-depressive [5-6], hypnotic agents [7], anti-cancer agents [8], anti-hypertensives [9], anti-bacterials [10], anti-fungals [11] and anti- HIV agents [12]. This broad effective of biological and pharmocological activities of derivatives bearing the 1,5-benzothiazepine moiety has encouraged in developing new synthetic methods for their synthesis.

A general method to synthesize of 1,5- benzothiazepines is via reactions of o- aminothiophenol with a,AY-unsaturated carbonyl compounds (chalcones), ketones or AY-haloketones. Catalysts such as BF3.Et2O, Al2O3/P2O5, NaBH4, PPA/SiO2, AcOH/MW, MgO/POCl3 have been used to increase the reaction efficiency [13]. However, the process of expensive and toxic metal catalysts not only limits the use of those methods, but also reduces to be an important concern under the aspects of green chemistry. Some of the processes also have other disadvantages such as stringent, or dry reaction conditions, high reaction temperature and low yields. Therefore, the discovery of a new and inexpensive for thia-michael addition reaction under natural and mild conditions is of considirable importance [14].

Nowadays, considareble attention has been centered upon the greening chemistry in the research [15]. Chemists has worked to develop new strategy to avoid the use of auxiliary substance (e.g. solvents, separation agents, etc.), prevent waste, and minimize of chemical accidents (e.g. explosion, fire, etc.) [16].

In this work, 1,5-benzothiazepines have been synthesized of reactions of variety chalcones derivatives with o-aminothiophenol in the presence of ammonium chloride. The reaction starts by the 1,4-Michael addition of the SH on the -C=C- double band after than the condensation of the NH2 on the carbonyl carbon follows(Scheme-1).

Experimental

General Experimental Methods

Method A:

0,001 moles of chalcone compound was added to reaction mixture. Than 1 ml saturated ammonium chloride solution and o-aminothiophenol (0,001 moles, 0,11 ml) was added to mixture. After a while a melting was observed and the reaction mixture was continued for 3 hours in room temperature. At the end of reaction the mixture became solid and was filtered. It was washed with water and was dried. The obtained solid was crystallized in ethanol-acetone-DMF (2:1:1) mixture. Yield was % 65-75.

Method B

o-aminothiophenol (0,001 moles, 0,11 ml) was added to a solution of chalcone (0,001 moles) in dry dioxane (3 ml). BF3.Et2O was added dropwise to reaction mixture while it was stirred. The reaction mixture was stirred for 5 hours at room temperature. The resultant solid was filtered and washed with water and was dried. Crude product was crystallized in ethanol-acetone-DMF (2:1:1) mixture. Yield was % 60-70.

4-(1-benzofuran-2-yl)-2-(thiophen-2-yl)-2,3-dihydro- 1,5-benzothiazepine (2a)

Equation

m.p.161 oC. FTIR (KBr, cm-1) : 1604 (C=N), ; 1H-NMR (400 MHz, CDCl3), ppm: 7.68- 6.94 (m, 12H, aromatic), 5.35 (dd, J=13.00 and 5.20 Hz, 1H, 12-H), 3.50 (dd, J= 11.80 and 5.20 Hz, 1H,12-H), 3.00 (dd, J=13,00 and 11.8 Hz, 1H, 6-H), 13C-NMR (400 MHz, DMSO-d6) ppm : 160.19 (11- C), 155.78 (19-C), 153.49, 152.06, 148.05, 135.83, 130.91, 128.21, 127.72, 127.18, 126.07, 125.52, 124.60, 124.20, 123.11, 122.08, 112.55, 112.31, 55.89 (6-C), 38.45 (12-C), Anal. Calc. for 2a; % C, 69.78; H, 4.18; N, 3.87; S, 17.74; Observed: C, 69.81; H, 4.22; N, 3.84; S, 17.73

4-(1-benzofuran-2-yl)-2-(furan-2-yl)-2,3-dihydro-1,5- benzothiazepine (2b)

Equation

m.p.158 oC. FTIR (KBr, cm-1) : 1600 (C=N), ; 1H-NMR (400 MHz, CDCl3), ppm: 7.69- 6.22 (m, 12H, aromatic), 5.15 (dd, J=11.80 and 5.20 Hz, 1H, 3-H), 3.40 (dd, J= 13.20 and 5.20 Hz, 1H,3- H), 3.10 (t, J=11.60 Hz, 1H, 2-H), Anal. Calc. for 2b; % C, 73.02; H, 4.38; N, 4.06; S, 9.28; Observed: C, 73.06; H, 4.40; N, 4.03; S, 9.26

3-[4-(1-benzofuran-2-yl)-2,3-dihydro-1,5- benzothiazepin-2-yl]phenol (2c)

Equation

m.p.249 oC. FTIR (KBr, cm-1) : 1589 (C=N), ; 1H-NMR (400 MHz, DMSO-d6), ppm: 9,40 (s, 1H, 27-H), 7.85 (s, 1H, 22H), 7.75-6.65 (m, 12H, aromatic), 5.15 (dd, J=12.20 and 5.00 Hz, 1H, 3-H), 3.35 (dd, J= 12.60 and 5.00 Hz, 1H, 3-H), 2.85 (t, J=12,80 Hz, 1H, 2-H), 13C-NMR (400 MHz, DMSO- d6) ppm : 160.58 (4-C), 157.90 (14-C), 155.77 (20- C), 153.57, 145.79, 135.44, 130.55, 130.01, 127.66, 126.19, 125.80, 124.18, 123.10, 122.98, 117.18, 115.07, 113.42 (13-C), 112.31 (15-C), 60.43 (2-C),37.60 (3-C), HMBC (400 MHz) ppm: 27-H (14-C, 15-C, 13-C), 13-H (14-C, 12-C), 2-H (12-C), 3-H (4- C), 22-H (21-C, 18-C, 20-C), 26-H (21-C, 25-C, 20- C), 23-H (20-C, 24-C), 11-H (6-C), 9-H (10-C), Anal. Calc. for 2c; % C, 74.37; H, 4. 61; N, 3.77; S, 8.63; Observed: C, 74.40; H, 4.65; N, 3.76; S, 8.66

4-(1-benzofuran-2-yl)-2-(3-fluorophenyl)-2,3- dihydro-1,5-benzothiazepine (2d)

Equation

147 oC. FTIR (KBr, cm-1) : 1609 (C=N), ; 1H-NMR (400 MHz, CDCl3), ppm: 7.67- 6.98 (m, 13H, aromatic), 5.05 (dd, J=12.00 and 4.80 Hz, 1H, 3-H), 3.30 (dd, J= 13.00 and 5.00 Hz, 1H, 3- H), 3.02 (t, J=12,60 Hz, 1H, 2-H), Anal. Calc. for 2d; % C, 73.97; H, 4.32; N, 3.75; S, 8.59; Observed: C 73.99; H, 4.29; N, 3.79; S, 8.63

4-(1-benzofuran-2-yl)-2-(2-fluorophenyl)-2,3- dihydro-1,5-benzothiazepine (2e)

Equation

m.p.173 oC. FTIR (KBr, cm-1) : 1606 (C=N), ; 1H-NMR (400 MHz, Acetone-d6), ppm: 7.79-7.02 (m, 13H, aromatic), 5.51 (dd, J=12.60 and 5.00 Hz, 1H, 3-H), 3.45 (dd, J= 13.50 and 5.00 Hz, 1H, 3-H), 3.10 (t, J=12,80 Hz, 1H, 2-H), 13C-NMR (400 MHz, DMSO-d6) ppm : 160.43 (4-C), 155.80 (20-C), 153.47, 151.92, 135.48, 130.72, 130.06, 128.20, 127.93, 127.74, 126.19, 125.90, 125.11, 124.21, 123.17, 122.52, 116.24, 116.02, 112.02, 53.62 (2-C), 35.23 (3-C), Anal. Calc. for 2d; % C, 73.97; H, 4.32; N, 3.75; S, 8.59; Observed: C, 73.96; H, 4.35; N, 3.76; S, 8.61

3-[(2-aminophenyl)sulfanyl]-1-(1-benzofuran-2-yl)- 3-[4-(dimethylamino) phenyl]propan-1-one (4)

Equation

0,001 moles (0,291 g) of chalcone compound 3 was added to reaction mixture. Than 1 aminothiophenol (0,001 moles, 0,11 ml) was added to mixture. After a while a melting was observed and the reaction mixture was continued for 3 hours in room temperature. At the end of reaction the mixture became solid and was filtered. It was washed with water and was dried. The obtained solid was washed with hot ethanol. Yield was % 67.

m.p.185 oC. FTIR (KBr, cm-1 ) : 3460-3300 (NH2), 1673 (C=O); 1H-NMR (400 MHz, CDCl3), ppm: 7.69-6.58 (m, 13H, aromatic), 4.73 (t, J=7,60 Hz, 1H, 13-H), 4.3 (NH2, broad), 3.60 (dd, J= 16.80 and 7,60 Hz, 1H, 12-H), 3.53 (dd, J=16,80 and 7,60 Hz, 1H, 12-H), 2.9 (s, 6H, 29-30-H), C-NMR (400 MHz, CDCl3) ppm : 188.47 (10-C), 155.64 (5-C), 152.46 (24-C), 149.45 (16-C), 137.70, 130.55, 128.47, 128.32, 127.03, 123.92, 123.34, 118.06, 116.22, 114.86, 113.09, 112.49, 46.89 (13-C), 44.72 (12-C), 40.99 (29,30-C), Anal. Calc. for 2e; % C, 72.09; H, 5.81; N, 6.73; S, 7.70; Observed: C, 72.13; H, 5.80; N, 6.77; S, 7.68

Evaluation of Biological Action

The antimicrobial tests were carried out by the disc diffusion method. Bacterial cultures were obtained in MuellerHinton broth (Difco) for all the bacterial strains after 24 h of incubation at 37 0.1 C. The yeasts were propagated in Sabouraud dextrose broth (Difco) after incubation for 24 h at 25 0.1 C. Test compounds were dissolved in DMSO.

The suspension containing 106 per/mL of bacteria, 104 per/mL inoculated into Mueller Hinton Agar (Difco). The discs (6 mm) were then impregnated with compounds ( 100 g/disc ) and then placed on the inoculated agar. Petri dishes were waited at 4C for 2 h. Then, the inoculated plates were incubated at 370.1C for 24 h for bacterial strains and also 250.1C for 72 h for yeast and. At the end of the incubation period, the inhibition zones were measured.

Results and Discussion

Ammonium chloride, which is not expensive and easily available, has been used as efficient catalyst in organic synthesis [17]. The results obtained by thia-michael addition reaction with saturated solution of NH4Cl in water is shown in scheme 1.

The 1,5-benzothiazephines was synthesized by from the reaction of benzofuran substituted chalcone derivatives (1 a-e) and aminothiophenol with saturated NH4Cl solution. This reaction was also carried out in the presence of BF3 .Et2O as a catalyst. It was observed that the efficiency of the reaction was slightyl decrease when BF3.Et2O was used as catalyst. Product of nucleophilic addition to AY-carbon is obtained instead of 1,5-benzothiazepine from the reaction of number 3 chalcone compound and o- aminothiophenol in NH4Cl medium.

In IR spectra, most important evidence of formation of 2 a-e products was disappearance of C=O stretching vibration at about 1646-1660 cm-1. Additionally absence of NH2 stretching vibration proved that 1,5-benzothiazepines was formed. One of CH2 protons in thiazepine ring that is near the N and S atom in the ring showed a signal at 5,51-5,05 ppm as a doublet of doublet in 1H-NMR. The other CH2 proton in the ring that are far away from the N and S atoms in the ring was observed signal at 3,45-3,35 ppm as a doublet of doublet. Also CH proton in the thiazepine ring was observed signal at 3,1-2,85 ppm as a doublet of doublet. In addition, absence of NH2 signal in 1H-NMR also supported that 1,5- benzothizepines was formed.

In the FT-IR spectra of compound 4, C=O stretching vibration was observed at 1673 cm-1. Also NH2's stretching vibration at 3450 cm-1 supported the formation of compound 4. SCH proton of compound 4 was observed as a triplet at 4,73 ppm in 1H-NMR. One of the CH2 protons appeared as a doublet of doublet at 3,53 ppm and the other at 3,60 ppm. Furthermore broad peak at 4,5 ppm supports the existence of NH2.

Most important proof in the 13C-NMR is disappearence of signal belonging to C=O carbon at about 180 ppm.

The mechanism of the reaction is most likely to be involve in the intermolecular hydrogen bonding promoted by ammonium chloride (NH4Cl) that activates chalcone towards the nucleophilic attack by amino group of the o-phenelenediamine or sulfur in 2-aminothiophenol to afford the intermediate (A). 1,3-Hydrogen shift occurs to give an isomeric enamine (B) that cyclizes to give the seven- membered ring product. (Scheme 2) [18]

When di-methylamino substitute chalcone is used as chalcone derivative, compound 4 which was product of nucleophilic addition to AY-carbon was obtained. Closure of the ring doesn't occur because di-methylamino group is a strong electron donating. So, it decreases the positivity of the carbon in C=O group. Consequently, N atom in the NH2 group didn't form bond with carbon in C=O group and closure of the ring doesn't occur. Also we can conclude that nucleophilic addition doesn't occur over the NH2 nucleophil but over the SH nucleophil, and compound (4) is produced.

Biological Evaluation

Synthesized novel compounds of benzofuran substituted 1,5-benzothiazepine class, in order to investigate antimicrobial activity. The compounds (2a, 2b, 2c, 2d, 2e, 4) were tested for antimicrobial activity against S. aureus, E. coli, B. subtilis and C. albicans. The test results obtained are listed in Table-2.

For microbe species see experimental ; compound concentrations = 100 g/disk; including disc diameter (6 mm); Streptomycin sulfat 10 g/disk, Nystatin 30 g/disc. The symbol (-) means that the compounds had no activity against the microorganisms.

Table-2: Antimicrobial effect of the compounds.

###Zone of inhibition/mm

###2a###2b###2c 2d###2e###4###Standart

Escherichia coli###-###20###-###-###-###-###13

Bacillus subtilis###-###17###-###-###-###-###18

Staphylococus aureus###-###18###-###-###-###-###17

Candida albicans###-###27###-###-###-###-###18

Among the synthesized compounds only 2b was found to be the most active derivative against S. aureus, E. coli, B. subtilis and C. albicans. Unexpectedly, the other substances tested not showed any activity against the bacteria and the fungi under the test conditions.

To our surprise, 2b, which was the best in that of all 1,5-benzothizepines reported was more effective against C. albicans than reference drug Nystatin.

These results indicate that the furan ring in structure was required for enhancing antimicrobial activity. Additionally, it may be thought that the benzofuran ring substituted to 1,5-Benzothizepine structure contributes to antimicrobial activity of compound 2b. 1,5-Benzothizepine derivatives containing benzofuran moiety and furan ring perhaps can be taken up for the development of suitable antifungal drugs.

Conclusions

The above study shows that ammonium chloride has been found to be an efficient catalyst for the synthesis of 1,5-benzothiazephine derivatives in moderate to good yields in water. The simplycity of this catalytic procedure and its environmentally friendly natur maket his catalytic reaction a potential, environmentally acceptable method for the synthesis 1,5-benzothiazephines.

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