1.5- Benzothiazepine 1,1-dioxide

The 1,2-benzothiazepine 1,1-dioxides 126 were prepared in fair yields (e.g. 126, R = H, Ar = p-ClC6H4, 52%) by a Heck coupling on the precursors 125, which were obtained in turn from an aza Baylis-Hillman reaction involving the appropriate sulfonamide, aldehyde, and methyl acrylate reactants <06TL8591>. 

The cyclic sulfonamide (377) can be prepared by heating 5-aminopentanesulfonyl chloride. 4-Chloro-2-benzoylbenzenesulfonyl chloride reacts with acetamidine to give the o-benzoyl-N-phenylsulfonylamidine which can be cyclized with base to give the fully unsaturated 1,2-benzothiazepine 1,1-dioxide (378 R = R1 = H). Alkyl-substituted amidines give the 3-imino derivatives (66USP3377357). 

Very little further work has been reported in this area. Heating of the 1,2-benzothiazepine 1,1-dioxides 12 in an aqueous sulfuric acid solution gave ketone 13 in good yield (Equation 1) <1996T3339>. 

A-Tosylsulfimines, e.g., 250, are converted into 1,2-benzothiazepines 252 by triethylamine (Scheme 142). In the absence of base the intermediate 251 can be isolated <1981J(P1)1037>. 1,2-Benzothiazepine 1,1-dioxides 254 are prepared by ring expansion of the 1,2-benzoisothiazole derivatives 253 upon treatment with 1-diethylamino-l-propyne (Scheme 143) <1996T3339, CHEC-III(13.07.4.2)241>. 

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>. 

The 1,2-benzothiazepine 1,1-dioxide (59) can be made by intramolecular Friedel-Crafts cycliz-ation of the sulfamoyl chloride (58), with aluminum chloride as the catalyst (Equation (9))... 

The 3,2-benzothiazepine 3,3-dioxide (385) has been prepared in high yield from (384) by intramolecular sulfonyl-amidomethylation (76CC470). 

The 4,5-dihydro-3,2-benzothiazepine (380) has been prepared by the thermally induced ring expansion of 1-azidoisothiochroman (74LA734). The product reacted with acetyl chloride and then with alcohols to give the l-alkoxy-2-acyl derivatives, and was oxidized to the 3,3-dioxide. 

Benzoisothiazole dioxides undergo [2+2] cycloaddition with 1-diethylaminopropyne followed by ring expansion to give 3-diethylamino-l,2-benzothiazepine 1,1-dioxides (378 R1 = Me, R = Et) (76H(5)95). JV-Tosylsulfimines, e.g. (386), are converted into 1,2-benzothiazepines (388) in high yield when treated with triethylamine in benzene under reflux. In the absence of base the intermediate (387) can be isolated (80JCS(Pl)2830, 81JCS(P1)1037). 

As with 1,4-oxazepines the Schmidt reaction of cyclic ketones and the Beckmann rearrangement of their oximes can be applied to the synthesis of monocyclic 1,4-thiazepines, 1,4- and 1,5-benzothiazepines and their 1-oxides and 1,1-dioxides (75CJC276). 

The 2,3-benzoxazepin-l-one system (436) is prepared by the reaction of benzonitrile oxide with the benzopyranone (435) (80JCS(P1)846). The tetrahydro-3,2-benzothiazepine 3,3-dioxide (438) was prepared from (437) by intramolecular sulfonamidomethylation (76CC470). 

Ethers of the 1,2-benzisothiazole 1,1-dioxides (35 R = Et, Me3Si) have been shown to form 1,2-benzothiazepines 12 (R = Et, Mc Si) when treated with 1-diethylamino-l-propyne 37 <1996T3339>. These ethers 12 may be hydrolyzed to the ketone 13 (see also Section 13.07.2.1), which in the solid state is in equilibrium with the enol 12 (R = H) on the basis of infrared (IR) evidence (Scheme 3). In solution (CDCI3), only the keto form 13 was detectable by H nuclear magnetic resonance (NMR). 

Some pyrrolo[2,l-Vilsmeier-Haack formylation and successive base-catalyzed intramolecular cyclization (Scheme 6) (72FES1003 73FES494 80FES279). 

By the reaction of 4-amino-2,3-dihydro-l,5-benzothiazepine (79) with triethyl orthoacetate at 150°C followed by treatment with ammonia at room temperature, an acetamidine intermediate was obtained which, by oxidative cyclization with sodium hypochlorite, was converted to 4,5-dihydrol[ 1,2,4]triazolo[5, -d [ 1,5]benzothiazepine 6,6-dioxide (98) (Scheme 29) (92M1023). 

The cycloaddition of l-methoxy-3-trimethylsilyoxy-1,3-butadiene with 3-methyl-1,2-benziso-thiazole 1,1-dioxide (107) (R = Me) affords the pyridone (108) <84H(22)67l>. An improved synthesis of 1,2-benzisothiazole 1,1-dioxide has led to the preparation of the benzothiazepine (109) (R = H) by cycloaddition of the ynamine followed by ring expansion <83CC520>. Addition of yV,7V-diaikylprop-l-ynamines to 3-substituted 1,2-benzisothiazole 1,1-dioxide (107) (R = SMe, SPh, SePh) gives mainly the imine-vinylamine (110) with only small amounts of the benzothiazepine (109) <85CC845>. 

There are also ring transformations of monocyclic and benzisothiazolium salts by ring extension to 1,3-thiazines, quinolines, 1,4-benzothiazepines and 1,2,3-thiadiazine 1,1-dioxides. 

Ring-closing metathesis methodology has been applied to the synthesis of the 1,5-benzothiazepine 1,1-dioxide 152 from 151 in moderate yield using Grubbs catalyst 153 <04TL9171>. 

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