Isothiazoles amides

In most other reactions the azolecarboxylic acids and their derivatives behave as expected (cf. Scheme 52) (37CB2309), although some acid chlorides can be obtained only as hydrochlorides. Thus imidazolecarboxylic acids show the normal reactions they can be converted into hydrazides, acid halides, amides and esters, and reduced by lithium aluminum hydride to alcohols (70AHC(12)103). Again, thiazole- and isothiazole-carboxylic acid derivatives show the normal range of reactions. 

Simple isothiazole-4-carboxylic acids have been made from the corresponding nitriles, which are available in turn from the halogeno derivatives, or directly by the olefin route.5-Aminoiso-thiazole-4-esters and -nitriles are readily obtained by the thioamide route. The 4-acids behave normally and form acid chlorides, esters, amides, and hydrazides. In contrast to the 5-series... 

Isothiazole-3-carboxylic acid and its 4-bromo derivative have been obtained by oxidation of the corresponding aldehydes with silver oxide. They form acid chlorides, esters, and amides. The amides may be dehydrated to give the corresponding nitriles. ... 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

The standard means for preparing oxicams 285, initially developed by Lombardino, is through the base-promoted rearrangement reaction of isothiazole dioxides 286, which in turn are prepared from saccharin derivatives such as 287 (Scheme 40) <1981AHC(28)73>. The oxicam core can be further derivatized by N-alkylation of oxicam 285 and amidation of the C-3 ester functionality of 288 to form the common drug scaffold 289. 

Isothiazole-3-carboxylic acids are conveniently prepared by oxidation of 3-methylisothiazoles with chromium trioxide in sulfuric acid.112 Permanganate oxidation is less satisfactory, although 3-bromomethylisothiazole has been oxidized to the acid in 47% yield.113 The amides, prepared via the acid chlorides and ammonia, may be dehydrated to the 3-nitriles by phosphorus oxychloride.71... 

Many isothiazole-4-carboxylic acids, esters, amides, and nitriles have been prepared by direct ring synthesis (see Section I), but another widely employed route is the sequence bromo compound, nitrile, amide, or acid (Scheme 37) 70- s-95.107... 

In a two-step process, pyrido[3,2-e]thiazines (621) have been converted into isothiazolo[5,4-h]pyridin-3-ones (Scheme 79). In the first step, the salts (621) are hydrolyzed by treatment with 1 N HC1 at room temperature for 12 h to give the amides (622). Subsequent oxidation with SOCl2 <85JHC1353> effects closure of the isothiazole ring to give the products (623) in good yield. 

True 3-imino-2,3-dihydrobenz[d]isothiazole-l,1-dioxides (82) are capable of existence provided they bear an alkyl or aryl substituent in 2-position as in saccharin anils (23). The free imino compound (82a R = Me, R =H) is obtained from isomerization of o-cyano-V-methyl-phenylsulfonamide in the presence of methylamine,256 or more generally preparation of 82 may start from o-cyanophenylsulfonyl chloride together with an excess of amine.3, 256 A straightforward approach uses cyclization of an o-sulfamylbenzamide monosubstituted at each amide function, like o-(iV-phenylsulfamyl)benzanilide (83)257 with phosphorus pentoxide, phosphorus pentachloride, or preferably phosphorus oxychloride.135,257 Similarly, 2-chlorocarbonylbenzene sulfonyl chloride... 

Phenyl-l,3,4-oxathiazol-2-one (370), prepared from primary amides and tri-chloromethanesulfenyl chloride, undergoes a ready thermal elimination of carbon dioxide with the formation of the nitrile sulfide ylide (371). This can be trapped by a wide variety of unsaturated dipolarophiles, and with an alkyne provides a ready route to isothiazoles (372) (see Chapter 4.17). Applications to 1,2,4-thiadiazole synthesis are described in Chapter 4.25. Thermolysis of l,3,4-oxadiazolin-5-ones (500 C/10 mmHg) results in the loss of CO2 and generation of the corresponding nitrilimine (78JOC2037). 

Isothiazole-A-carboxylates are obtained starting from amides by first forming the oxathlazolone by means of ClCOSCl. Condensation with methyl acetylene dicarboxylate followed by hydrolysis and decarboxylation completes the sequence. ... 

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