1,5-benzothiazepine ring system

Two different quino-1,5-benzothiazepine ring systems have been exploited using a similar general synthetic route. 

The 1,5-benzothiazepine ring system has seen various applications as pharmaceutical scaffold [85] and thus a number of synthetic approaches have been reported mostly involving condensation of 2-aminothiophenol with a, 3-imsaturated carbonyl compoimds, co-bromoacetophenone, or chalcones xmder some kind of acidic or basic catalysis. Recently, an efficient one-step IL-mediated green protocol for the regioselective synthesis of stereoisomeric 2-aryl-3-hydroxy-l,5-benzothiazepines-4-ones (Scheme 25) from the reaction of 2-aminothiophenol with glycidates has been reported [86]. The cis-isomer 124 was formed as the major product in 76-90% yield in [bbim]Br and 82-95% yield in [bbim]PF6. 

Syntheses of a series of pyrrolo-benzazepine acetic acids 381 have been reported (Scheme 77 (1994MI385)). They include acylation of the core heterocycle with ethoxy oxalyl chloride in the first step to afford ketoesters 380. This sequence can also be successfully applied to a pyrrolo-benzothiazepine ring system. 

A gallium(III) triflate-catalyzed [4 + 3] cydoaddition of 1,3-diarylpropanones and OPD has been developed for the synthesis of 2,4-disubstituted-3H-benzo[b][l,4]diazepines using ethanol as a green solvent at room temperature. The product was collected by filtration and the catalyst was directly used for the next cycle. The process was repeated 10 times and the catalyst was found to maintain consistent activity [104,105]. Several approaches to benzodiazepinone and benzothiazepine ring systems xmder solvent-free conditions and using other greener techniques such as MW, US or solid acid catalysis, organocatalysis, and so on are also known [106,107]. 

The pharmacological activity of the 1,5-benzothiazepine derivative diltiazem has given further impetus for synthetic routes to this ring system. A traditional preparation of the intermediate 62 by the reaction sequence shown in Scheme 12 has been subject to microwave studies, when the final product was obtained as a mixture of isomers <96TL6413>. Under optimised conditions irradiation in toluene at 390 watts for 20 minutes gave mainly the cis-isomer as the main product (cis/trans 9 1) in 75% yield. However, reaction at 490 watts in the presence of acetic acid resulted in a reversal of this ratio and a yield of 84%. The... 

Pyrimido[4,5-fc][l,5]benzothiazepines (119) were prepared by reaction of 2-aminothiophenol (5) with 4-chloro-5-acylpyrimidines (118) in almost theoretical yields (Scheme 36) (73CB3524). The UV, IR, and NMR spectra of this ring system are described. 

To date, only the fusion of the thiazole ring to the 1,5-benzothiazepine system involving the d face of the seven-membered ring has been reported. 

A number of papers have been published on the chemistry and biological activity of 1,5-benzothiazepines containing an additional bicyclic system fused to different positions of the seven-membered ring. Tetracyclic indolo-, benzofuro-, pyrazolopyrido-, quino-, benzopyrano-, benzothio-pyrano-, quinazolino-, and quinoxalino-l,5-benzothiazepines are known. 

A further application of 1,3-dipolar additions to the synthesis of seven-membered rings is cycloaddition to the C=N double bond of 1,5-benzothiazepines. In an extension of their investigations into the cyclofunctionalisation of heterocyclic imine systems, Chimirri et al. have demonstrated that the cycloaddition of benzonitriloxide to 1,5-benzothiazepines affords 3a,4-dihydro-l-phenyl-5//-... 

Amongst the benz-fused systems, the question of aromaticity in 1,2-benzothiazepine 1,1-dioxides has been addressed by Abramovitch and co-workers. The benzothiazepines are very stable chemically, but the chemical shifts for the H-4 protons in (25b) and (25c) (5 7.1 and d 7.2, respectively), and for the H-5 protons in (25a) and (25c) (d 6.2 and d 6.3), together with the relatively large size of the A 5 coupling constant (12.7 Hz in (25c)), indicates that the seven-membered ring is not aromatic, favoring structure (25) over (26) (Equation (1))) <83CC520>. 

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