Synthesis of Dibenzothiazepine Analogues by One-Pot S-Arylation
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Heterocycl. Commun. 2018; 24(4): 219–230 Yasutaka Shimotori*, Masayuki Hoshi, Mari Murata, Narihito Ogawa, Tetsuo Miyakoshi and Taisei Kanamoto Synthesis of dibenzothiazepine analogues by one-pot S-arylation and intramolecular cyclization of diaryl sulfides and evaluation of antibacterial properties https://doi.org/10.1515/hc-2018-0099 as antibacterial agents, and ritonavir [21, 22] used as an Received June 18, 2018; accepted June 19, 2018; previously published anti-HIV therapeutic agent are well-known sulfur-con- online July 12, 2018 taining cyclic compounds. In addition, benzothiazepines exhibit antimicrobial [23–25], antiviral [26], cytostatic [27], Abstract: Dibenzothiazepine analogues containing anticonvulsant [28, 29] and antipsychotic activities [30]. lactam, amidine and imine moieties were prepared Previously, we have reported synthesis of sulfides from from 2-aminophenyl disulfides via one-pot S-arylation. aryl disulfides [31, 32] by cleavage of an S-S bond of aryl The S-arylation involved cleavage of an S-S bond of disulfides using ammonium thioglycolate, followed by disulfides and S Ar reaction in aqueous ammonia solu- N S-arylation and alkylation in one-pot treatment. In this tion of L-cysteine to afford diaryl sulfides. Dibenzothi- study, the S-S bond cleavage of 2-aminophenyl disulfides azepine analogues having lactam and amidine moieties was carried out using L-cysteine instead of thioglycolic were obtained by cyclization of the corresponding diaryl acid. Diaryl sulfides were synthesized by a one-pot S Ar sulfides under acidic conditions. One-pot S-arylation of N reaction using nitroarenes. Various dibenzothiazepine 2-bromo-5-nitrobenzaldehyde gave dibenzothiazepine analogues were synthesized by cyclization of the cor- analogues with an imine moiety in one step through intra- responding diaryl sulfides. Furthermore, antibacterial molecular cyclization. Compounds with antibacterial activities of the synthesized compounds against Staphylo- activities against Staphylococcus aureus and Escherichia coccus aureus and Escherichia coli were investigated. coli were obtained. Keywords: antibacterial activity; aryl disulfide; diaryl sulfide; dibenzothiazepine; L-cysteine; one-pot; S-aryla- tion; SNAr reaction; sulfur-containing heterocycle. Results and discussion Diltiazem and its derivatives, benzothiazepines having Introduction a lactam moiety, are used as antiarrhythmic drugs [33]. Benzothiazepines with an amidine moiety exhibit Heterocyclic compounds exhibit various biological activi- anti psychotic activity [34]. Based on these facts, we ties including antibacterial [1–5], antitumor [6–9], anti- considered synthesizing various dibenzothiazepine ana- inflammatory [10–14] and antiviral properties [15–19]. logues (Scheme 1). Dibenzothiazepines with lactam could Important bioactive compounds are sulfur-containing be obtained by intramolecular cyclization of the corre- heterocycles. Penicillin and cephalosporin C [20] used sponding diaryl sulfides substituted with a methyl ester. Similarly, those with imine could be obtained from the corresponding diaryl sulfides substituted with a formyl *Corresponding author: Yasutaka Shimotori, School of Regional group. Furthermore, those with amidine could be obtained Innovation and Social Design Engineering, Kitami Institute of by the Pinner reaction at amino and cyano groups. Diaryl Technology, 165 Koen-cho, Kitami, Hokkaido 090-8507, Japan, sulfides are readily available by one-pot S-arylation of e-mail: [email protected] Masayuki Hoshi: School of Regional Innovation and Social Design disulfides with disubstituted nitroarenes [31, 32]. Engineering, Kitami Institute of Technology, 165 Koen-cho, Kitami, The effect of a leaving group on the SNAr reaction in Hokkaido 090-8507, Japan 2-aminophenyl disulfide and various nitroarenes was Mari Murata, Narihito Ogawa and Tetsuo Miyakoshi: Department investigated. The nitro group, which is a strong electron of Applied Chemistry, School of Science and Technology, Meiji withdrawing group for anion stabilization, is required to University, 1-1-1 Higashi-mita, Tama-ku, Kawasaki 214-8571, Japan Taisei Kanamoto: Faculty of Pharmaceutical Sciences, Showa decrease the electron density at the benzene ring [35–39]. Pharmaceutical University, 3-3165 Higashi-Tamagawagakuen, Various leaving groups of nitroarene were investigated. Machida 194-8543, Japan The S-S bond of bis(2-aminophenyl) disulfide was cleaved 220 Y. Shimotori et al.: Synthesis and evaluation of antibacterial properties of dibenzothiazepines S S S NO2 NO2 NO2 R R R N N N H O NH2 Lactam type Amidine type Imine type R′ H2N R′ S R X S + S R R NH NO NO 2 2 NH2 2 R′ = CO2Me, CN, CHO Scheme 1 Retrosynthetic analysis of three types of dibenzothiazepine analogues. in aqueous ammonia solution of L-cysteine. Subsequently, The use of 1,2-dinitrobenzene and 1,4-dinitrobenzene one-pot S-arylation was performed between thiolate anion gave the corresponding diaryl sulfides with 99% yields, and various nitroarenes (Scheme 2). In the case of using and no S-arylation was observed using 1,3-dinitroben- an arylating agent with a bromo group at ortho- or para- zene. Among halogeno groups at the para-position, the position of the nitro group, S-arylation progressed with presence of the fluoro group gave rise to the highest 99% 48% and 69% yields, respectively. By contrast, S-arylation yield, and the use of iodophenyl gave rise to a low yield of was not observed using 1-bromo-3-nitrobenzene. When 36%. This analysis largely agrees with the order of degree the thiolate nucleophile attacks the ipso position contain- of electronegativity. As the electronegativity increases, ing a bromo substituent, σ-complex is formed as an inter- the positive charge at the ipso-position increases, which mediate. The bromo group at the ortho- or para-position enhances electrophilicity. On the other hand, the yields stabilizes the σ-complex by a resonance effect, and no res- are higher when using an arylating agent with a sterically onance effect is possible at the meta-position. The same smaller leaving group. Apparently, the addition of thiolate feature may be operative in the case of dinitrobenzenes. anion at the ipso-position is a rate-controlling step. Methyl [2-(2-aminophenyl)sulfanyl]-5-nitrobenzoates 2 are precursors to dibenzothiazepine analogues having a lactam moiety. These compounds were prepared by 1) DMF, 50°C, under N2 H2N 2) L-cysteine/H 2O one-pot S-arylation of 2-aminophenyl disulfides with S S NH3 aq., pH 9, 1 min S 2 NO2 methyl 2-bromo-5-nitrobenzoate (Scheme 3). All diaryl NO2 3) X , 10 min NH2 sulfides 2 were obtained in a quantitative yield. With NH2 1a–c 1-bromo-4-nitrobenzene used as an arylating agent, the conversion was not 100% after 10 min and the yield of X NO NO2 X NO2 2 2-aminophenyl 4-nitrophenyl sulfide (1c) was 69%. By a: b: c: contrast, when using methyl 2-bromo-5-nitrobenzoate, X all diaryl sulfides 2 were quantitatively obtained after X = Br, F, Cl, I, NO 2 10 min regardless of the substituents. In nitroarenes with a methyl ester group at the ortho-position to the leaving Scheme 2 SNAr reaction of 2-aminophenyl disulfide and nitroarenes. group, the ester group acts as an electron withdrawing R3 1) DMF, 50°C 2 under N2 H2N R 2) L-cysteine/H 2O CO2Me 1 1 1 R S NH3 aq., pH 9, 1 min R S p-TsOH · H2O R S S R1 NO2 2 solvent 2 MeO2C NO2 2 2 R NH2 3) R NH2 NO2 ∆, 24 h R N 3 3 3 H O R Br R R 10 min 2a–i 3a–i a: R1 = R2 = R3 = H d: R1 = R2 = Me; R3 = H g: R1 = R3 = H; R2 = F b: R1 = Me; R2 = R3 = H e: R1 = OMe; R2 = R3 = H h: R1 = Cl; R2 = R3 = H c: R1 = R2 = H; R3 = Me f: R1 = F; R2 = R3 = H i: R1 = R2 = H; R3 = Cl Scheme 3 Synthesis of lactam-containing dibenzothiazepines 3. Y. Shimotori et al.: Synthesis and evaluation of antibacterial properties of dibenzothiazepines 221 group, which decreases the electron density at the carbon chloride in ethanol and the mixture was heated under atom at the ipso-position of the halogen. This feature facil- reflux for 24 h. Various concentrations of hydrogen chloride itates the nucleophilic attack of thiolate anion, increasing were investigated. In the presence of 5, 10, 20 and 30 wt% the yields of diaryl sulfides 2. of hydrogen chloride in ethanol, 2-nitrodibenzo[b,f][1,4] Lactam dibenzothiazepine analogues 3 were obtained thiazepin-11-amine (5a) was obtained in the respective by intramolecular cyclization of the corresponding diaryl yields of 28, 26, 38 and 61%. As can be seen, the yields sulfides 2 (Scheme 3). The cyclization was carried out in the increased with increasing concentration of HCl. Accord- presence of p-TsOH · H2O as an acid catalyst under reflux ingly, synthesis of other products 5b–i from 2-aminophe- for 24 h. With 0.2 and 0.4 equivalents of p-TsOH · H2O, the nyl-2-cyano-4-nitrophenyl sulfides 4 was conducted using cyclization of methyl [2-(2-aminophenyl)sulfanyl]-5-ni- 30 wt% hydrogen chloride ethanolic solution. Dibenzo- trobenzoate (2a) in o-xylene yielded 2-nitrodibenzo[b,f][1,4] thiazepines 5b–i were obtained regardless of the nature thiazepin-11(10H)-one (3a) in the respective yields of 40% of substituents R1, R2 and R3. When diaryl sulfides 4f with and 95%. When the reaction was conducted under reflux R1 = F and 4h with R1 = Cl were used, the yields of 5f and with 0.4 equivalent of p-TsOH · H2O in toluene instead of 5h were improved by at least 10% as compared with the o-xylene, the yield of 3a dropped to 15%. It can be suggested yield of 5a. On the other hand, the yields of dibenzothiaz- that the reaction requires 0.4 equivalent of acid and should epines 5b–e having methyl or methoxy groups decreased be conducted at least at 140°C.