Nitrobenzenes with carbanions

Arylsulfonylindazoles, novel S-HTe receptor antagonists, have been synthesized via the VNS reactions of para-substituted nitrobenzenes with carbanion of chloromethyl aryl sulfones followed by hydrogenation of the nitro group (Scheme 102). Further reaction of ortAo-aminobenzyl sulfones with sodium nitrite-acetic acid gave the desired 5-substituted indazoles of potential biological activity [237, 238]. 

Products of VNS are generated in the form of carbanions and are isolated upon protonation. Instead of protonation, they can be introduced directly in subsequent reactions with electrophilic partners such as alkylating agents [64a] or aldehydes [64b]. For instance, the VNS in nitrobenzene with carbanion of 2-dichloromethyloxazoline produces nitrobenzylic a-chlorocarbanion that enters the Darzens reaction with aromatic aldehydes to give oxiranes (Scheme 11.40) [64b] whereas the reaction with carbanion of r-butyl dichloroacetate followed by Michael addition gives f-butyl nitroarylcyclopropane carboxylates [64c]. 

Nucleophilic substitution of nitrobenzene with some carbanions was described in Chapter IV. 

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. 

VNS is also of general character in respect to electron-deficient arenes. Nitrobenzene, the model representative of these arenes, can enter into VNS with any carbanion presented earlier. The reaction of nitrobenzene with secondary carbanions such as chloromethyl aryl sulfones or aryloxyacetoni-triles can proceed at positions ortho and para the orientation is controlled by the conditions. At low temperature and excess of strong base (kinetic control), ortho substitution dominates, whereas thermodynamic control favors para substitution (Scheme 11.23) [42]. The reaction proceeds mainly in the ortho position also when carried out in r-BuOK/THF system due to specific solvation effect [38]. StericaUy demanding tertiary carbanions, RcH, react preferentially in para positions. 

All secondary anions react at C-3 of 2-nitrothiophene tertiary carbanions give mixtures of 3- and 5-substituted 2-nitrothiophenes, but still the major substitution occurs at C-3 [168]. It is instructive to compare with nitrobenzenes tertiary carbanions replace only para-hydrogens from nitrobenzenes. Moreover, nitrobenzene is not as reactive under the conditions suitable for the substitution on a thiophene ring f-BuOK as the base in THF [168]. 

In contrast to the facile condensation of o-nitrotoluene with diethyl oxalate, other a-alky] nitrobenzenes are sluggish to react with diethyl oxalate or fail to react at all. It has been suggested that this is due both to steric and electronic factors effected by the alky] group, which destabilizes the methylene group in regard to formation of the carbanion. ... 

Carbanions of ct-chloroalkyl phenyl sulfones react with nitrobenzenes to effect tlirect nucleophilic replacement of hydrogens located on o and para to the nitro group fEq. 9.24. A very important feature is that VNS of hydrogen usually proceeds faster than conventional SnAt of halogen located In equally activated positions fEq. 9.25. The rule that VNS of... 

The ONSH reaction of the carbanion of 2-phenylpropionitrile (45 c) with nitrobenzene in liquid ammonia at -70 °C involves rate-limiting Carom—H bond breaking, as evidenced by the 9.8 times faster rate than for reaction of the analogous substitution of deuterium in 4-<7-nitrobenzene and perdeuterionitrobenzene. Reactions of the carbanion derived from (45c) with 4-chloro-3-trifluoromethylnitrobenzene and 4-chloronitrobenzene in toluene under phase transfer catalysis has also been studied." ... 

Isoxazole rings were annelated onto 5-nitroquinoline and isoquinoline-based o-nitrobenzyl-p-tolylsulfones by treatment with potassium phenoxide, which acted as both base and reductant (Equation (42)) <95H(40)187>. In the cases of quinolines as starting materials, product benzisoxazoles (75) both with and without phenoxy substitution were obtained, but in the case of an isoquinoline starting material no phenoxy-substituted product was generated. The reaction is thought to proceed via a nitrosobenzylsulfone carbanion intermediate, and can be applied to nitronaphthalenes but not to less active nitrobenzenes. 

Draw resonance contributors for the carbanion that would be formed if meta-chloro-nitrobenzene could react with hydroxide ion. Why doesn t it react ... 

Cyclopropylphosphine oxides (140) react with the sodium salts of amides, presumably via cyclopropane ring-opening and intramolecular olefination, to give dihydropyrrole derivatives in moderate to good yield. Vicarious nucleophilic substitution reactions of a variety of substituted nitrobenzene derivatives with the carbanion of chloromethyldiphenylphosphine oxide to give o-(141) and p-(142)-nitrobenzyldiphenylphosphine oxides have been investigated. ... 

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. 

A serious limitation of VNS is connected with its mechanism, namely, conversion of intermediate ct adducts into the VNS products via bimolecular base-induced p-elimination. To cause the reaction, it is therefore necessary that these adducts be produced in a reasonable concentration. Indeed, low nucleophilic carbanions, such as dimethyl chloromalonate, do not react with moderately electrophilic nitrobenzene because of unfavorable equilibrium of the addition step, but react nicely with more electrophilic nitrothiazoles (Scheme 8) [34]. 

Equilibrium of the addition of nucleophiles to nitroarenes is a function of many factors, such as their nucleophilicity, electron deficiency of arenes, and their ability to stabilize adducts, as well as the reaction conditions. Thus, all these parameters are responsible for the feasibility of ONSH with nucleophiles sensitive to oxidation. Of substantial importance is temperature, since, due to the entropy factor, the equilibrium is shifted toward the adducts at a low temperature. For instance, addition of highly nucleophilic carbanion of 2-phenylpropionitrile to moderately active m-chloro nitrobenzene at —70°C in liquid ammonia or DMF/THF proceeds to completion, selectively in the para-position. Further oxidation of the formed adducts with... 

Nitrobenzene has been involved in a regioselective nucleophilic aromatic substitution with a phosphorus-stabilized carbanion. The anion, generated from CH3CH2P(0)Ph2 by butyllithium, attacked nitrobenzene in the para position (Scheme 35). ... 

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