One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Abstract

Two efficient methods for the preparation of 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoates 1a -1c with thiols in the presence of Et 3 N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2, which underwent spontaneous cyclization at the same temperature by an attack of the S-atom at the prop-2-enoyl moiety in a 1,4-addition manner (Michael addition) to give 2-(2-sulfanyl-4H-3,1-benzothiazin-4-yl)acetates in one pot. The second method involves treatment of 3-(2-isothiocyanatophenyl)prop-2-enoic acid derivatives 1b -1d with Na 2 S leading to the formation of 2-(2-sodiosulfanyl-4H-3,1-benzothiazin-4-yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3. 2-(2-Thioxo-4H-3,1-benzothiazin-4-yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.

New simple synthesis of ring-fused 4-alkyl-4H-3,1-benzothiazine-2-thiones: Direct formation from carbon disulfide and (E)-3-(2-aminoaryl)acrylates or (E)-3-(2-aminoaryl)acrylonitriles

“…The newly developed method tolerates a wide range of substrates in moderate to excellent yields and provides promise for further alkylation or arylation. Moreover, this method is advantageous over previous ones [16–17] for the easy synthesis of reactants.…”

“…Therefore, 4-alkyl-4 H -3,1-benzothiazine-2-thione derivatives are also of potential biological importance. However, only a few practical routes for the synthesis of this class of 4-alkyl-4 H -3,1-benzothiazine-2-thione derivatives have been reported [16–17]. Although Kobayashi and co-workers have reported the synthesis of 2-(2-thioxo-4 H -3,1-benzothiazin-4-yl)acetic acid derivatives by the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoates with sodium sulfide, this method suffers from the tedious synthesis of the substrates prepared in four steps from 2-iodoaniline [16].…”

“…However, only a few practical routes for the synthesis of this class of 4-alkyl-4 H -3,1-benzothiazine-2-thione derivatives have been reported [16–17]. Although Kobayashi and co-workers have reported the synthesis of 2-(2-thioxo-4 H -3,1-benzothiazin-4-yl)acetic acid derivatives by the reaction of 3-(2-isothiocyanatophenyl)prop-2-enoates with sodium sulfide, this method suffers from the tedious synthesis of the substrates prepared in four steps from 2-iodoaniline [16]. Molina et al also described the preparation of 4 H -3,1-benzothiazine-2-thione derivatives by intramolecular heteroconjugate addition of carbodiimides or isothiocyanates bearing one o -substituted α,β-unsaturated carbonyl fragment promoted by the CS 2 /TBAF system [17].…”