Isothiazoles lithiation

Isothiazoles lithiate preferentially at the 5 position, and this enables various functions to be introduced at this position. The preparation of an isothiazole Grignard reagent and its reactions are reported (see Section 3.05.7.8). 

Most isothiazoles are lithiated at the 5-position by the action of butyllithium or other organolithium compounds, provided that this position is vacant (65AHC(4)107, 72AHC(14)l, 77SST(4)339). 3-Methyl-4-nitroisothiazole, however, is inert (65AHC(4)107). 2,1-... 

Isothiazole itself is best prepared by the reaction between propynal, ammonia and sodium thiosulfate (see Section 4.17.9.3). A wide range of substituted mononuclear isothiazoles can be obtained by oxidative cyclization of y-iminothiols and related compounds (see Section 4.17.9.1.1). Substituents at the 3-position need to be in place before cyclization, but 4-substituents are readily introduced by electrophilic reagents (see Section 4.17.6.3), and 5-substituents via lithiation (see Section 4.17.6.4). 

Halogenoisothiazoles and isothiazoles unsubstituted in the 5-position lithiate readily at —70° with i-butyllithium. These lithium derivatives react normally to give a variety of substituted isothiazoles as indicated in Scheme I (yields shown on arrows). This... 

In a manner analogous to that seen with N-substituted pyrazoles (Section II,D), isothiazole undergoes lithiation at the 5-position, adjacent to the 5p -heteroatom, and reaction with electrophiles then leads to a variety of 5-substituted derivatives (Scheme 74) [64JCS446 72AHC(14)1 84JMC1245]. 

Syntheses and reactions of lithiated isothiazoles and thiazoles were reviewed. [95H533] Phenylisothiazoles and phenylthiazoles are known to undergo a variety of phototranspositions upon irradiation in benzene solvent. These reactions were reinvestigated. [94JA2292]... 

On treatment with mercuric acetate in aqueous acetic acid at 100°, isothiazole gives a 48% yield of a dimercuriacetate, which with bromine affords 4,5-dibromoisothiazole. Unlike lithiation, a nitro group does not interfere, and mercuriation provides a convenient route to 5-bromo-4-nitroisothiazole (Scheme 30).106... 

Cleavage of isothiazoles during lithiation was discussed in Section III,B, and a related example is provided by the fission of the isothiazole ring of an isothiazolo[5,4-6][l,4]benzothiazine during alkylation with sodium hydride and alkyl halide.123... 

Lithiation at C-5 in isothiazoles occurs rapidly with the formation of relatively stable metallated derivatives whereas lithiation at C-3 gives rise to N—S cleavage and nitrile formation. Hence cleavage reactions by base of isothiazoles fused to azines are predictable, especially since the acidity of H-3 is increased in the fused systems. Such cleavage reactions are shown for the quinoline-fused isothiazole (124) (75JCS(P1)2271, 78JHC1527). 

The first reported regioselective lithiation of the 5-position of 3-(benzyloxy)isothiazole (1) using LDA in diethyl ether has been described. Subsequent quench with a variety of electrophiles gave the desired products 2 in 54-68% yield. Only benzolyation proved to be unsuccessful, resulting in a complex reaction mixture <02JOC2375>. 

O-Lithiation of TV-/er/-butyIbenzenesulfonamide (4) followed by reaction with a variety of ketones gave carbinol derivatives 5. Subsequent cyclisation using TMSCl-Nal-MeCN afforded 3,3-disubstituted and spiro-2,3-dihydrobenzo[. 

Direct lithiation of 3-(Boc-amino)-5-methylisoxazole and 5-(Boc-amino)-3-methylisoxazole gives N/C-dianions which react with a variety of electrophiles to afford 4-substituted aminoisoxazoles in good yields <1996TL3339>. Metallation of 3-substituted isothiazoles <2002JOC2375, 2004JOC1401> and isoselenazoles proceeds satisfactorily at the 5-positions. 

Isothiazoles react at the a to the sulfur atom at higher T, fragmentation results. The ease of substitution of isothiazoles enables lithiation even of the 4-iodo deriva-tive ... 

The reactions of 5-lithiated isothiazoles and of 5-lithiated-l-substituted pyrazoles allow the introduction of substituents at that position by reaction with a range of electrophiles three examples are shown... 

Synthesis and reactions of lithiated monocyclic azoles containing two or more hetero-atoms. Part 1 Isoxazoles , Iddon, B., Heterocycles, 1994, 37, 1263 Part III Pyrazoles , Grimmett, M. R. and Iddon, B., ibid., 1994, 37, 2087 Part V Isothiazoles and thiazoles , Iddon, B., ibid., 995,41, 533. Heinisch, G., Holzer, W. and Pock, S., J. Chem. Soc., Perkin Trans. 1, 1990, 1829. 

Oxazoles, imidazoles and thiazoles are lithiated in the 2-position, and pyrazoles and isothiazoles in the 5-position. With isoxazoles, w-butyllithium causes ring-opening. 

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