Study On The Synthesis Of 1,3-Benzothiazepines By Hypervalent Iodine Reagents

Benzothiazepines motifs and its derivatives are an extensively existed class of heteroatomic compounds in nature,which exhibit versatile bioactivities,such as anticancer,antiviral,and antipsychotic activities.The representative compound Diltiazem is a marketed drug for angina pectoris and hypertension.Quetiapine,a drug for the treatment of schizophrenia,also contains the benzothiazepine scaffold.Despite this remarkable progress in the construction of 1,4-and 1,5-benzothiazepines,the1,3-benzothiazepine motif was almost undeveloped.Therefore,developing a general and efficient approach for the synthesis of 1,3-benzothiazepines would be highly desirable.Hypervalent iodine reagent is a important kind of organic reagent in organic synthesis and has good reaction activity.Hypervalent iodine reagents exhibit diverse reactivity and find widespread use in organic synthesis.Under suitable conditions they may be utilized as less toxic and safer replacements for metal oxidants.Among them,iodobenzene diacetate and phenyliodine bis-?trifluoroacetate?and Koser's reagent are the most frequently used compounds in intramolecular dehydrogenative cross-coupling reactions,involving C-N,C-O,and C-S bond formations.Because of its unique chemical properties,the hypervalent iodine reagent has attracted the attention of the chemical workers in recent years,and has been widely studied by the organic chemical workers.ThisarticleusesN-phenethylthioamideandsubstituted[Hydroxy?tosyloxy?iodo]benzene as substrate,report herein an efficient protocol for the synthesis of 1,3-benzothiazepines through a hypervalent iodine mediated intramolecular C-S bond coupling reaction.Through a series of experiments,the optimal conditions were obtained as the use of hexafluoroisopropanol?HFIP?as a solvent was crucial,the ratio of N-phenethyl thioamide and substituted[Hydroxy?tosyloxy?iodo]benzene was 1:1,catalyst-free and the transformation can becompletedwithin1minatroomtemperature.When4-methoxyphenethylthioamides?R¹=4-OMe?were used as the starting materials,a new type of thiazaspiro[5.5]undecanones were afforded in moderate to good yields,whereas the expected benzothiazepines were not observed.Twenty-seven different substituted1,3-benzothiazepinesandfivedifferentsubstituted thiazaspiro[5.5]undecanones were synthesized.The effects of substituents on the raction has also been studied systematically which proved that the reaction features a broad substrate scope.A scaled-up experiment was performed under the optimized conditions and a one-pot reaction was carried out smoothly using phenylethyl isothiocyanate and diphenylphosphine oxide.The typical radical trapping experiments showed a plausible mechanism:The reaction undergoes a cyclization of the Friedel-Crafts reaction mode,which is a carbocation process.The structures of all new compounds have been characterized by ¹H NMR,¹³C NMR and HRMS,and the structures of target compounds have been confirmed by the X-ray single crystal diffraction analysis of compound 3a.