3- Methyl-5-phenylisothiazole

On subjection of 3-methyl-5-phenylisothiazole or 3-methyl-5-phenylisoxazole to lithiation conditions, competitive side-chain and C-4 deprotonation is observed, except when lithium j-propyl(cyclohexyl)amide (LICA) is used - this allows exclusive side-chain Uthiation. ... 

C3NS S N — — — Methyl 3-hydroxy-4-phenylisothiazole-5-sulfonate dehydromethionine... 

Sometimes compounds which exist predominantly in the hydroxyl form give products of N-methylation with diazomethane, for example 3-hydroxy-5-phenylisothiazole (63AHCi2)245) of course, the ambident anion (493) is an intermediate. 3-Hydroxypyrazoles, under rather severe conditions, can be converted into 3-chloropyrazoles with POCI3 <66AHQ6)347). 

The action of diazomethane on 3-hydroxyisothiazole gave approximately equal proportions of 0- and iV-methyl products,129 whereas 3-hydroxy-5-phenylisothiazole gave exclusively an A-methyl derivative.18 Nucleophilic reagents lead to ring cleavage,132-134 which will be discussed in a later section (see Section IV). 

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>. 

Thionyl diloride added below 0 to dimethylformamide, the resulting soln. mixed with l-amino-l-phenyl-2-butanone hydrochloride, and heated 1.5-2 hrs. at 60-90° on a water bath after the initial exothermic reaction has ceased 4-hydroxy-5-methyl-3-phenylisothiazole. Y 78%. F. e., also with sulfur monodiloride, s. T. Naito et al., Bull. Chem. Soc. Japan 41, 959, 965 (1968). 

The above, as well as other substitution reactions, both electrophilic and nucleophilic, has been taken advantage of in studies of penicillin analogues, particularly in an exploration of possible synthetic routes to 5-methyl-3-phenylisothiazole-4-carboxylic acid (100) (Scheme 6). 

Amino-4-bromo-3-phenylisothiazole (96), obtained by bromination of (95) or directly from 3-phenyl-3-iminothiopropionamide (94), was deaminated to 3-phenyl-4-bromoisothiazole (97) and converted into the 4-cyano-analogue (98) by the action of cuprous cyanide in boiling picoline. Methylation of 3-phenyl-4-cyanoisothiazole (98) with butyl-lithium and methyl iodide gave low yields of the 5-methyl homologue (101) the alternative route (97) (102) (101) proved to be more advantageous. 

Alkylation and Quaternization.—4-Bromo-5-hydroxy-3-methylisothiazole is O-methylated by diazomethane in contrast, 3-hydroxy-5-phenylisothiazole is N-methylated, and equimolar mixtures of the O- and N-methyl derivatives are produced from 3-hydroxyisothiazoles. N-Methylation also prevails when 3-hydroxy-4,5-diphenylisothiazole is alkylated by dimethyl sulphate. ... 

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