Nitroarenes, reactions with carbanions

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. 

The carbanion of 2,3-dimethylthiazolidine-4-one reacted with nitroarenes to give either a ting opened product (50) via a VNS (vicarious nucleophilic substitution) reaction or a product resulting from oxidative nucleophilic substitution of hydrogen (51). Ring opening VNS reactions with 5-membered 5-heterocycles are limited to those heterocycles which show some conformational flexibility <96TL983>. 

There has been a short review of the oxidative nucleophilic substitution of hydrogen in nitroarenes in which recent results with carbon, nitrogen, and oxygen nucleophiles are summarized and the preferred oxidants are discussed.11 The oxidative substitution of nitroarenes with carbanions of isopropyl phenylacetate in liquid ammonia-KMn04 initially yields products (4) which may suffer hydroxylation at the o -position, and dimeric and trimeric products may be formed by couplings of nitrobenzylic radicals formed during the reaction.12... 

In a so-called vicarious nucleophilic substitution of hydrogen,75 2,3-diphenylpyrido[2,3-6]-pyrazine is alkylated in the 8-position by [(chloromethyl)sulfonyl]benzene. This reaction proceeds by addition of the carbanion to the electron-deficient ring position of a nitroarene or electrophilic heteroaromatic system, followed by base-induced -elimination of the corresponding hydrogen halide.76,77 As with quinoxalines and naphthyridines, the reaction with pyrido[2,3-6]pyrazines also affords products bisannulated at the pyrazine or the pyridine moiety, depending on the kind of 2/3-substitution (cf. Section 7.2.3.1.2.2.2.). 

The VNS in nitroarenes with carbanions is presented in general in Scheme 7, thus, discussion of the scope and limitations of this reaction should clarify what kind of carbanions (nature of Y, L, and R) and nitroarenes (kind of Z) can enter the reaction. 

Diarylmethylation of nitroarenes can be performed efficiently via VNS, using carbanions of benzhydryl aryl sulfides [92]. Similarly, the VNS reaction of 4-ethoxy-3-nitropyridine with carbanion of 9-chlorofluorene results in incorporation of the... 

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. 

Direct methods are based on the reactions of nitroarenes or nitroheteroarenes with carbanions affording the intermediate o adducts that, under the reaction conditions, are converted into nitrosoarenes according to the intramolecular redox stoichiometry. The nitrosoarenes are known to be rather active electrophilic partners and are able to enter in situ further reactions to produce quinolines as the ultimate products. 

The ONSH in nitroarenes with carbanions carried out at low temperature and KMnO in liquid ammonia or DDQ and DMD in THF/DMF is a general process. For instance, this reaction has found valuable application for introduction of nitroaryl and hydroxyaryl substituents into molecules of a-amino acids. Thus, carbanions of esters of protected amino acids upon addition to nitroarenes form o -adducts that are oxidized by KMnO in liquid ammonia or DDQ in THF/ DMF. The subsequent hydrolysis produces a-nitroaryl a-amino acids (Scheme 11.7) [15]. 

Similarly to ONSH reaction in nitroarenes with carbanions proceeds ONSH with diphenylphos-phine anion. At low temperature in liquid ammonia, this anion adds to p-fluoronitrobenzene at the ortho position subsequent oxidation of the produced a -adduct with KMnO gives... 

AllyUc carbanions, under conditions that promote conversion of the o -adducts into nitrosoarenes, react with nitroarenes to form a variety of heterocychc systems. For instance, carbanion of aUyl tolyl sulfone in the reaction with 2-nitrothiophene forms substituted pyridothiophene (Scheme 11.14) [29]. 

The Barton Zard condensation is one more important and marvelous SnH heterocyclization leading to pyrrole ring annulation to nitroalkenes, nitroarenes or nitrohetarenes on being treated with alkyl isocyanoacetates in the presence of a base (85CC1098, 90T7587). The reaction starts with nucleophilic attack of alkyl isocyanoacetate carbanion 160 ortho to the NCT group of substrate 161. The... 

Nucleophilic substitution of halogen atoms in highly electrophilic arenes (most often nitroarenes) by carbanions proceeds efficiently under PTC conditions. However, the catalytic process operates only with methynic carbanions, when the products do not possess an acidic hydrogen atom. In the case of methylenic carbanions, introduction of nitroaryl substituents gives products that are much stronger C-H acids thus, they are immediately converted into nitrobenzylic carbanions which, associated with the lipophilic TAA cations of the catalyst, stay in the organic phase. The low nucleophilic activity of these carbanions prevents their further reactions. In this situation the catalytic process is arrested. 

When analyzing plausible mechanisms of the VNS reactions of nitroarenes with a-chlorocarbanions, one should clarify a few key questions how to proceed the addition and subsequent conversion of adducts and how other substituents may affect both of these steps - rate and orientation of the addition, rate of the elimination, etc. It is well known that nitroarenes are active electron acceptors, whereas carbanions are good electron donors thus, these reactants can enter a single-electron transfer (SET) to form anion radicals of nitroarenes and radicals from carbanions [21, 22]. Further coupling of these electrophilic radicals with nucleophilic anion-radical species could give adducts. This SET pathway, alternative to the direct addition, is often favored by authors and the concept is sometimes abused, see [23] and rebuttal [24]. Nevertheless, numerous observations contradict participation of the SET mechanism in the VNS reactions ... 

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. 

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... 

The effect of temperature on the addition equilibrium can, for instance, be observed in the reaction of the carbanion of diethyl benzylphosphonate with 4-fluoronitrobenzene. At low temperature the addition proceeds exclusively at the position 2, and oxidation of the produced adduct affords the product of ONSH. On the other hand, at room or a higher temperature the S Ar of fluorine in the position 4 takes place [76]. Similarly, when the reaction of nitroarenes with the anion of diphenylphosphine is carried out at low temperature in liquid ammonia in the presence of KMn04 diphenyl(nitroaryl)phosphine oxides are formed, as illustrated by the ONSH in 4-fluoronitrobenzene (Scheme 16) [77]. 

There are numerous examples of construction of condensed pyridines (and also quinolines and acridines) via cascade reactions, involving conversion of the adducts of benzylic or allylic carbanions to nitroarenes followed by their intramolecular cyclization to form the pyridine ring. Thus, the reaction between 4-chloronitrobenzene and phenylacetonitrile, which is known to produce in protic media the corresponding 2,1-benzisoxazole via conversion of the intermediate adduct into nitrosoarene and its further condensation reaction [80], can proceed in aprotic media along another way. The same o adduct formed in tetrahydrofuran, when treated with trialkylchlorosilanes or pivaloyl chloride, undergoes cycUzatiOTi into acridine derivative (Scheme 85) [208]. 

The 2,1 -benzisoxazole (anthranil) ring system is of interest as a key intermediate for the synthesis of other heterocycles. 2,1-Benzisoxazoles can be derived from the direct multistep domino reaction of some carbanions with nitroarenes or by conversion of the products of nucleophilic substitution of hydrogen in nitroarenes. As early as in 1960, Davis and Pizzini reported that the reaction of 4-chloronitrobenzene with phenylacetonitrile in the presence of potassium hydroxide in protic media affords 3-phenyl-5-chloro-2,l-benzisoxazole in high yield [80] (Scheme 17). 

Use of oxygen, the most common oxidant, for oxidation of the a"-adducts is limited to the adducts of primaiy and secondary carbanions. Since the oxidation of these a"-adducts by oxygen proceeds efficiently only in the presence of an excess of base, we suppose that the dianions produced via further deprotonation of the a"-adducts are oxidized by oxygen [17]. This process is illustrated by direct ONSH in nitroarenes with enolates of ketones that proceeds selectively para to the nitro group [18, 19]. On the other hand, reaction of such enolates with m-nitroanilines—an efficient synthesis of nitroindoles proceeds mostly ortho to the amino and nitro groups [18]. Both of these reactions proceed in the presence of atmospheric oxygen and do not require another oxidant (Scheme 11.9). 

On the other hand, when o -adducts of arylacetonitrile carbanions to para-substituted nitroarenes are converted into substituted nitrosoarenes in aprotic media via silylation in the presence of trialkylamines, the produced o-nitrosoaryl acetonitriles can undergo further hetero-cyclization on alternative pathway to produce substituted acridines [28]. Reactions of arylacetonitriles with nitroarenes unsubstituted in the para position under identical protic conditions result in the formation of p-nitrosoaryl arylacetonitriles that can be isolated in the tautomeric form of p-arylcyanomethylene quinone oximes (Scheme 11.13) [27b]. 

On the basis of the previously presented results and discussion, we can conclude that the VNS proceeds via direct addition of a-halocarhanions to nitroarenes. The produced o"-adducts react with base according to base-induced P-ehmination of HL pathway to form products in the form of nitrobenzyUc carbanions. Depending on the nature of the reaction partners and the reaction conditions—particularly strength and concentration of the base and temperature— the reaction can be controlled kinetically or thermodynamically. At low temperature in the presence of an excess of strong base, the elimination proceeds faster than dissociation of the a -adducts thus, the reaction proceeds under kinetic control. On the other hand, when the reaction is carried out at higher temperature in the presence of a weak base at low concentration, the dissociation of the o -adducts is faster than P-ehmination thus, the addition is really a reversible process, and the reaction proceeds under thermodynamic control. 

On the other hand, the VNS reaction of chloroform with nitroarenes carried out in the presence of t-BuOK that gives dichloromethyl nitroarenes [65] proceeds via addition of trichloromethyl carbanions to electrophihc aromatic rings of nitroarenes and formation of anionic intermediates [65]. One can therefore consider VNS as an umpolimg of the Friedel-Crafts reaction. It is also a process complementary to the Friedel-Crafts reaction, because it proceeds with nitroarenes that usually do not enter the Friedel-Crafts reaction (Scheme 11.41). 

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