Electrophilic substitution isothiazole

A multiply bonded nitrogen atom deactivates carbon atoms a or y to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (110) and (111). Pyrazoles (110 Z = NH), isoxazoles (110 Z = 0), isothiazoles (110 Z = S), imidazoles (111 Z = NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (111 Z = S) do indeed undergo electrophilic substitution as expected. Little is known of the electrophilic substitution reactions of oxazoles (111 Z = O) and compounds containing three or more heteroatoms in one ring. Deactivation of the 4-position in 1,3-dihetero compounds (111) is less effective because of considerable double bond fixation (cf. Sections 4.01.3.2.1 and 4.02.3.1.7), and if the 5-position of imidazoles or thiazoles is blocked, substitution can occur in the 4-position (112). 

The substitution properties of isothiazole are in broad agreement with the electron distribution pattern. Thus, electrophilic substitution occurs predominantly in the 4-position, if this is free, and metalation in the 5-position. The ring appears to be stable to acid, alkali, and mild oxidation and forms a chloroplatinate and an unstable merouriohloride. ... 

Side-chain reactions are able to give accurate quantitative values for the electrophilic reactivities of the free bases, but there have as yet been far fewer such studies than of the conventional electrophilic substitutions already discussed. Reactions can be carried out in solution or in the gas phase. Solution work has been due to Noyce and co-workers using the solvolysis of either 1-arylethyl chlorides, 2-arylprop-2-yl chlorides, or the corresponding p-nitrobenzoates. Results for thiazole, isothiazole, and N-methylimidazole (in terms of cr+ values) are given in Scheme 7.12 (73JOC3316, 73JOC3762 75JOC3381). These demonstrate a number of points. 

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. 

Five-membered rings with two or more heteroatoms are usually good at electrophilic substitution as one of the heteroatoms must be either O or S or a pyrrole-like nitrogen atom any of which supply lone pair electrons. Pyrazole 12, imidazole 13, oxazole 17, thiazole 18, isoxazole 19 and isothiazole 20 are examples. Multiple substitution can be a problem but is less so than for pyrrole because there are fewer carbon atoms available and the pyridine-like nitrogen atoms deactivate the ring. 

Isothiazole is aromatic. The NMR spectra confirm a largely undisturbed delocalization of the tt-electrons. In consequence, the aromaticity of isothiazole is greater than that of isoxazole, just as the aromaticity of thiophene is greater than that of furan. From the calculated r-electron densities, it follows by analogy to isoxazole (see p 138) that electrophilic substitution should occur at the 4-position, while nucleophiles should attack the 3-position. The most important reactions of isothiazoles can be summarized as follows ... 

Electrophilic substitutions, e.g. halogenation, nitration and sulfonation, take place regioselectively at the 4-position. The pyridine-like N-atom again impairs electrophilic substitution. For this reason, isothiazole reacts more slowly than thiophene, but faster than benzene. 

Both 1,2- and 2,1-benzisothiazoles react with electrophiles to give 5- and 7-substituted products (see Section 4.02.3.2). The isothiazole ring has little effect on the normal characteristics of the benzene ring. C-Linked substituents react almost wholly normally, the isothiazole ring having little effect except that phenyl substituents are deactivated (see Section 4.17.2.1). There are, however, considerable differences in the ease of decarboxylation of the carboxylic acids, the 4-isomer being the most stable (see Section 4.02.3.3). 

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). 

The 4-position of isothiazole is attacked by electrophilic reagents, and many simple derivatives are thus readily available by direct substitution followed, if necessary, by suitable transformation of the group introduced. For example, bromination of 3-methylisothiazole... 

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]. 

A multiply bonded nitrogen atom deactivates carbon atoms a or t to it toward electrophilic attack thus initial substitution in 1,2- and 1,3-dihetero compounds should be as shown in structures (136) and (137). Pyrazoles (136 Z=NH), isoxazoles (136 Z = 0), isothiazoles (136 Z=S), imidazoles (137 Z=NH, tautomerism can make the 4- and 5-positions equivalent) and thiazoles (137 Z=S) do indeed... 

Abstract Synthesis methods of various C- and /V-nitroderivativcs of five-membered azoles - pyrazoles, imidazoles, 1,2,3-triazoles, 1,2,4-triazoles, oxazoles, oxadiazoles, isoxazoles, thiazoles, thiadiazoles, isothiazoles, selenazoles and tetrazoles - are summarized and critically discussed. The special attention focuses on the nitration reaction of azoles with nitric acid or sulfuric-nitric acid mixture, one of the main synthetic routes to nitroazoles. The nitration reactions with such nitrating agents as acetylnitrate, nitric acid/trifluoroacetic anhydride, nitrogen dioxide, nitrogen tetrox-ide, nitronium tetrafluoroborate, V-nitropicolinium tetrafluoroborate are reported. General information on the theory of electrophilic nitration of aromatic compounds is included in the chapter covering synthetic methods. The kinetics and mechanisms of nitration of five-membered azoles are considered. The nitroazole preparation from different cyclic systems or from aminoazoles or based on heterocyclization is the subject of wide speculation. The particular section is devoted to the chemistry of extraordinary class of nitroazoles - polynitroazoles. Vicarious nucleophilic substitution (VNS) reaction in nitroazoles is reviewed in detail. 

Few examples of functionalization on the benzene ring of benzisothiazole have been reported (see Section 4.05.7.2). Studies on the reactivity of unsaturated chains in cycloaddition reactions have been reported (see Section 4.05.7.3). The high reactivity of 4-vinylisothiazolin-3-one A-oxides in Diels-Alder cycloadditions, both as diene and dienophile, is illustrated by their tendency to dimerize. 5-Vinylisothiazole A,A-dioxides react at the vinyl function with different 1,3-dipoles. Isothiazolo-3-sulfolenes 265 give an o-quinodimethane which can be trapped with a dienophile. Different isothiazole derivatives substituted with a carbon chain functionalized with heteroatoms have been prepared as ligands for the formation of complexes. 3-Oxocamphorsulfonimide reacts with the anion of alkynes and several studies on the reactivity of the products with electrophiles are reported. 

A different synthetic pathway, which is useful for the preparation of 4-cyano-isothiazoles 28-31 substituted at C-3 with different heteroatoms (Hal, S, 0), is exploited by Methods E (Scheme 8). These procedures start from dicyanomalonate 26 and different electrophiles giving the key intermediates 27a-d, subsequently cyclised to the isothiazole-4-carbonitriles 28-31. A number of modifications of these procedures are known and are very useful for obtaining different starting materials for the preparation of isothiazole derivatives of biological interest [1,2,4]. 

Electrophilic sulfonation of isoxazole is of no preparative value the substitution of only the phenyl-substituent of 5-phenylisoxazole with chlorosulfonic acid makes the same point. Both isothiazole and pyrazole can be satisfactorily sulfonated at C-4. 

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... 

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