Nitroarenes chloromethyl substituents

We have described a two-step method for introduction of chloromethyl substituents into nitroarenes. This approach consists in the VNS of hydrogen with fert-butyl dichloroacetate anion [58] followed by one-pot hydrolysis and decarboxylation [101], This approach has been used for the synthesis of (chloromethyl) nitroimidazole, a precursor of (nitroheteroaryl)methyl mustard, which was tested as hypoxia-selective cytotoxins (Scheme 27) [102],... 

The effect of substituents on the rate of addition of carbanions to nitroarenes and the rate of p-elimination of HL from the o adducts have also been studied [8, 30, 31]. The former effect is an important parameter, because it is, in fact, a measure of influence of substituents on electrophilic activity of nitroaromatic rings. The effect of substituents on rate of the S Ar reactions of o- and p-halonitrobenzenes has been thoroughly studied [2, 32]. However, since the S Ar of halogen is a secondary process, the obtained data cannot be used as a real measure of electrophilicity of halonitroarenes. We have determined the effects of substituents and the ring structure on the rate of the VNS reactimi of nitroarenes with the carbanion of chloromethyl phenyl sulfone by using competitive experiments under the conditions, which assure a fast p-eUmination of HL from the o adducts [30, 31]. The values of VNS rates obtained under such conditions proved to correlate with those of the addition step. Selected values of the relative rate constants in relation to nitrobenzene as the standard are shown in Fig. 1. 

The VNS is the reaction of choice for incorporation of a-sulfonylalkyl substituents into nitroarenes and their heteroanalogues. Particularly accessible and useful are nitroarylmethyl phenyl sulfones and their heteroanalogues that are efficiently produced in the VNS reactions of carbanions of chloromethyl aryl sulfones with a great variety of nitroarenes and nitroheteroarenes. Nitro derivatives of heterocycles, such as pyrrole [54,55], furan [54], thiophene [54], imidazole [106, 112, 113], pyrazole [114], pyridine [57], indole [115], indazole [116, 117], benzimidazole [118], benzotriazole [119], benzofuroxan [120], quinoline [121], and porphyrins [122, 123], have been shown to enter this reaction. 

Since VNS can proceed under kinetic control, namely, initially formed a -adducts can be converted into the products faster than they dissociate, the reaction can serve as a proper tool for determination of electrophilic activities of nitroarenes. Effects of substituents on rates of S Ar was subject of thorough studies [43] however, the results, although useful in practice of synthesis, cannot be considered as a reliable measure of electrophilic activities of nitroarenes because S Ar of halogens is a slow secondary process preceded by a reversible formation of the o -adducts. On the other hand, the rate of VNS reaction under kinetic control reflects the rates of the initial nucleophilic addition of carbanions to nitroaromatic rings, thus can be used as measure of electrophilic activities of these compounds. Particularly convenient and reliable way to determine such effects is the competitive experiments in which two nitroarenes compete for the VNS reaction with carbanion of chloromethyl phenyl sulfone under conditions that assure faster (1-elimination of HCl from the o -adducts than their dissociation [42]. Relative rate constants of the addition of this carbanion to some nitroarenes in relation to nitrobenzene are given in Scheme 11.24. 

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