2,1-Benzisothiazole ethylation

There are many related examples which are now known as the general Dimroth rearrangement. For example, 3-ethylamino-l,2-benzisothiazole (419) is in equilibrium in aqueous solution with the 2-ethyl-3-imino isomer (420) <72AHCf 14)43). Dimroth rearrangements are known in the 1,2,4-thiadiazole series (421- 422), and in the 1,3,4-thiadiazole series as products of reactions of halogeno-l,3,4-thiadiazoles see Section 4.02.3.9.1 <68AHC(9)165). For a similar example in the 1,2,3,4-thiatriazole series, see Section 4.02.3.1.9. 

A few isothiazoles, 2,1-benzisothiazoles and monocyclic sultams have been prepared by methods involving formation of the 4,5-bond. Thus, condensation of a-cyanooximes (179) with ethyl mercaptoacetate or related compounds gives a compound (180) which cyclizes... 

CN 5-[2-[4-(l,2-Benzisothiazol-3-yl)-l-piperazinyl]ethyl]-6-chloro-l,3-dihydro-2//-indol-2-one hydrochloride hydrate... 

C20H2SO3 302-97-6) see Finasteride 3-oxo-4-aza-5a-androstane-17p-carboxylic acid (C ijH2i)N03 103335-55-3) see Finasteride 3-oxo-l,2-benzisothiazole-2(3/7)"ac t c acid ethyl ester 1,1-dioxide... 

The 1,4- and 1,5-benzothiazepines (382) and (384) have been prepared by the photochemical reactions of the benzisothiazole (381) and the benzothiazole (383), respectively, with ethyl vinyl ether (81TL529, 81TL2081). 

A clean and dry 20-gallon reactor was charged with 17.4 gallons of deionized water and 4.44 L of concentrated hydrochloric acid, to give a 0.77 M solution. To the solution was added 4.44 kg of the anhydrous 5-(2-(4-(l,2-benzisothiazol-yl)-l-piperazinyl)-ethyl)-6-chloro-l,3-dihydro-2H-indol-2-one free base. The slurry was warmed to 65°C and held for 18 hours. The slurry was cooled to room temperature. The product was filtered and washed with 2x5-gallon portions of deionized water, and then air dried at 50°C for 30 hours. The dried product contained 4.4% water and the x-ray diffraction method confirmed that the desired product was obtained. 

A reaction of rather less general application, but one which produces valuable intermediates, is the treatment of dithiosalicylamide and its A-substituted derivatives with phosphorus pentachloride. Thus, A.A-diethyldithiosalicylamide (20) yields 3-chloro-2-ethyl-l,2-benz-isothiazolium chloride (21).14-16 This salt (21) is a versatile compound for example, heating it with diethylamine gives 3-diethylamino-l,2-benzisothiazole (22)16, treatment with base yields 2-ethyl-l,2-benzisothiazolinone (23), and reaction with ammonia, followed by hydrochloric acid, affords 3-ethylamino-l,2-benzisothiazole (24).14 This final reaction involves an interesting rearrangement which will be discussed in more detail in Sections II, C, 2 and II, C, 3. 

Linear thieno[c J]benzothiadiazoles dimerize by linking at the carbocyclic peri positions <75ACR139>. While most [c] fused heterocycles add dienophiles across the heterocyclic ring, the thieno[l,2-c 4,5-c ]benzisothiazole (21) added ethyl azodicarboxylate across the benzenoid ring <86CB3158>. 

Oxidation of 3-piperazin-l-yl-l,2-benzisothiazole (54) (w = 0) with nitric acid or MCPBA at low temperatures gives the 1-oxide (54) (n = 1), while MCPBA at room temperature, oxone and sodium periodate afford the 1,1-dioxide (54) (n = 2) <91JMC3316>. The oxidation of 2-[(S)-l-phenyl-ethyl]isothiazolin-3-one (55) with MCPBA yields a mixture of the diastereomer 1-oxides (56) and... 

X = S) to DMAD to yield dimethyl 5-phenylisothiazole-3,4-dicarboxylate is much slower than the corresponding oxathiazolone (282) (X = O) <89JCS(Pl)2489>. The thermal decomposition of ethyl 2-azido-3-(3-azido-2-thienyl)propenoate (283) results in the formation of ethyl 5-cyano-isothiazole-3-carboxylate (284) together with the thienopyridazine (285) <84JCS(P1)915>. The addition of benzyne to 3,4-dimethyl-1,2,5-thiadiazole (286) gives 3-methyl-1,2-benzisothiazole <82CC299>. 

Chloro-2-ethyl-l,2-benzisothiazolium chloride 109b reacted with Ar-mono- and IV,IV-dialkylanilines 356 to give 3-phenyl 1,2-benzisothiazolium salts 357, which were converted by thermal treatment to isothiazole 358 and with hydrochloric acid to salts 359 in 70-80% yield (79CB3286, Scheme 119). The isothiazole 358 can be oxidized to 2-phenyl 1,2-benzisothiazole 1,1-dioxides. 

Nucleophilic displacement of the chlorine atom of 3-chloro-1,2-benzisothiazole has proved to be a popular procedure. Boeshagen and Geiger34 have continued their earlier work on nitrogen nucleophiles, and now include carbon, oxygen, and sulfur nucleophiles.35 In some cases, rearrangements occur, as in the formation of 3-amino-2-acylbenzo[6]thiophenes (20) from reaction of 21 with methyl ketones. Similar results are obtained from the reaction of other carbon nucleophiles, and it has been suggested that attack may be either at the 3-carbon or the sulfur atom.36 The reaction of 3-chloro-1,2-benzisothiazole (8) with the anion of ethyl cyanoacetate, for example,... 

Benzaldehyde, 100, 105, 154, 175, 336 Benzamide, 320 Benzene, 134, 154, 198, 286 Benzenesulfenyl chloride, 182 Benzenesulfinic acid sodium salt, 18 Benzenesulfonamide, 18 Benzenesulfonyl azide, 17—18 Benzenesulfonyl bromide, 18 Benzenesulfonyl chloride, 17 N-Benzenesulfonylformimidic acid ethyl ester, 18-19 Benzenethiol, 182 Benzhydrol, 238 Benzil, 312 Benzimidazole, 126 2,1-Benzisothiazole, 290 Benzobicyclo[2.2.2]octadiene, 46 Benzocyclobutadiene, 227 Benzohydroquinones, 60 Benzoic acid, 175... 

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