Isothiazoles ring synthesis

The isothiazole ring was used as a template in Woodward s brilliant total synthesis of colchicine (237 Scheme 42) (72AHC(l4)l). 

Aminoisothiazoles are readily available by direct ring synthesis (see Section I,B), and most of those described in the literature have been prepared in this way. However, those methods do not lead to 3-chloroisothiazoles, and 5-amino-3-chloro-4-cyanoisothiazole was prepared in excellent yield from 3,5-dichloro-4-cyanoisothiazole and ammonia.8,51 5-Aminoisothiazole itself has been prepared by Curtius degradation of isothiazole-5-carboxylic acid (Scheme 31),115 although a triketotriazine has also been obtained under Curtius conditions.116... 

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... 

Acetyl- and 5-formylisothiazoles are readily available from 5-lithioisothiazoles.71,102 However, 3-methyl-4-nitroisothiazole does not form a lithium derivative,72 and 4-formyl-3-methyl-4-nitro-isothiazole was prepared by reduction of the appropriate acid chloride with lithium tri-Lbutoxyaluminum hydride.140 A 5-formyl-4-hydroxy-isothiazole has been prepared by direct ring synthesis [Eq. (12)].29... 

A variety of strategies have been developed for the synthesis of the isothiazole ring system, and the route selected will depend on the substituents required and the availability of starting materials. The most useful and general method remains the formation of the S—N bond by oxidative cycli-zation of a suitable S—C—C—C—N unit because such compounds are readily available. Depending on the choice of starting material the route is applicable to the synthesis of isothiazoles, isothiazolin-... 

Isothiazolium salts " are often prepared by ring synthesis involving oxidative nitrogen-to-sulfur bond formation, however these quaternary salts can be prepared in the normal way from an isothiazole with a reactive electrophile. They are cleanly cleaved by reducing agents, for example sodium borohydride, producing P-enamino-thioketones. ... 

Isothiazoles Fused to other Nitrogen-containing Heterocycles.—In view of the ease with which, in the laboratory at least, an isothiazole ring may be fused to biological nitrogen heterocycles, it is, perhaps, surprising that no naturally occurring isothiazole has yet been found. Typical recent work includes the efficient synthesis of isothiazolo[3,4-d]pyrimidines (114 X = NHR or SMe), of isothiazolo[4,5-i>l-... 

There are two series of benzisothiazoles, derived from benz[c]iso-thiazole (2) and benz[d]isothiazole (3), and both, if the benzene ring were suitable weakened, could doubtless be oxidized to isothiazole-dicarboxylic acids. In their first synthesis Adams and Slack... 

Although not presented specifically as a potential synthesis of mononuclear derivatives, the ready conversion of cyanocarbon sulfides (19) into condensed ring isothiazoles (20) is of interest and may provide new approaches to simpler isothiazoles. ... 

If ammonium thiocyanate is used, the ammonium ion can itself provide a nitrogen atom for heterocyclic ring construction. Such nitrogen and sulfur transfer is the basis of an elegant synthesis of isothiazoles (15) from 3-chloropropenals (16).18... 

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>. 

Following publication of the first synthesis of a mononuclear isothiazole in 1956, this ring system has attracted considerable interest. The aim of the present review is to present a coherent survey of the... 

Isothiazoles are reductively desulfurized by Raney nickel, and this method has been used to confirm structures.3,51 In his remarkable synthesis of colchicine, Woodward employed the isothiazole nucleus as a template on which the various rings were constructed, and finally removed the sulfur with Raney nickel to leave a nitrogen function in the correct position [Eq. (22)].e7,68... 

Fused ring systems can be prepared either from an azine precursor or from an isoxazole or isothiazole precursor. In the sections on synthesis of these compounds the former method is grouped under Azine approach , the latter under Azole approach . 

Judging from these early results, it appears that the reaction of 1,2-dithiolium salts with ammonia offers an elegant synthesis of certain substituted isothiazoles that are difficult to obtain by other methods.98 The reaction of the unsubstituted 1,2-dithiolium salt with NH8, however, does not yield the parent isothiazole system. Moreover, in the case of the 3(5)-methyl salts, the abstraction of a methyl proton activated by the positive charge of the ring successfully competes with this reaction (Section II,B,4).14a... 

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