Synthesis of 1,4-Thiazepines

Abstract

An efficient, general, and unprecedented methodology for the synthesis of 2-methylene-2,3-dihydro-1,4-thiazepines from N-propargylic β-enaminones is described. Initially, N-propargylic β-enaminones were thionated with Lawesson's reagent in good to high yields, and then the resulting N-propargylic β-enaminothiones were subjected to electrophilic cyclization. When treated with zinc chloride in refluxing chloroform, N-propargylic β-enaminothiones underwent electrophilic cyclization to yield 2-methylene-2,3-dihydro-1,4-thiazepines in good to high yields. A general trend was observed for all N-propargylic β-enaminothiones, and the cyclization proceeded with high efficiency and large functional group tolerance. This process is also applicable to the cyclization of internal alkyne-tethered N-propargylic β-enaminothiones. This operationally simple and facile method may represent a very rapid entry to a library of functionalized 1,4-thiazepines in the area of pharmaceuticals.

Recent advances in the synthetic chemistry of 1,5‐benzothiazepines: A minireview

“…The scope of synthetic methodology was explored and the mechanistic investigations were performed to get insight into the regio-and stereoselective outcome of the synthesis (Scheme 4, entry 2). [33] Fukata et al developed a facile and highly efficient enantioselective net [4 + 3] cycloaddition approach for the synthesis of optically active 1,5-benzothiazepinones (20). The reaction between α,β-unsaturated substrate (18), and o-aminothiophenol (1) in the presence of chiral benzotetramisole (19) as a catalyst, generated acylammonium intermediate.…”

“…[7,8] The 1,5-benzothiazepine nucleus is present in numerous drugs used for the treatment of different disorders and has been widely acclaimed as eminent cardiotherapeutic and psycho-therapeutic scaffold. [9] They were reported to possess a broad range of biological activities such as Ca 2+ channel blockers and vasodilators, antiviral, CNS acting agents, anti-platelet aggregation, anti-HIV, antimicrobial, antifungal, angiotensin-converting enzyme (ACE) inhibitors, anticancer, histone deacetylase 6 (HDAC6) inhibitors, V2 arginine vasopressin receptor antagonism, HIV-1 reverse transcriptase inhibition, and bradykinin agonist activity [6,[10][11][12][13][14][15][16][17][18][19][20] and also present in the core structure of various commercially available drugs such as diltiazem, clentiazem, thiazesim, quetiapine hemifumarate, and clothiapine as shown in Figure 2.…”

Diversity of Lawesson's Reagent: Advances and Scope

“…Though some reports consisting of multistep reactions did not solely depend on LR for the construction of heterocyclic framework but still LR played therein crucial role for the synthesis of attractive scaffolds. These included the synthesis of NIR dye, HN7‐S ( 102 ) and library of functionalized 1,4‐thiazepines ( 105 ) in the area of pharmaceuticals, and bicyclic seven‐and eight membered ring systems containing sulfur bridge ( 108 ) (Scheme ).…”

Design and diversity-oriented synthesis of benzo- and pyrido-annulated medium-sized N,S-heterocycles via thio-Michael and Friedel-Crafts approaches

“…Interestingly, an overview of general aspects about the structure, application and synthetic efforts for the generation of various fused 1,2-, 1,3-, 1,4-thiazepine frameworks have been disclosed. [4][5][6][7][8][9] In comparison with the regioisomeric thiazepines, a survey shows there are a limited number of published protocols accessing the thiazocines 10 and higher medium-sized N,S-heterocyclic systems.…”