Nitroarenes with nucleophiles

Arenes, on complexation with Cr, Fe, Mn, and so forth, acquire strongly electrophilic character such complexes in reactions with nucleophiles behave as electrophilic nitroarenes.71 Synthesis of aromatic nitriles via the temporary complexation of nitroarenes to the cationic cyclopentadienyliron moiety, cyanide addition, and oxidative demetalation with DDQ has been reported (Eq. 9.43).72... 

Some useful elaboration of the initially introduced nucleophiles has also been reported.113 Thus, for-mylation of nitro aromatic rings was achieved via VNS reaction of the nitroarene with the anions of tris-phenylthiomethane114 and chloroform,115 followed by hydrolysis, as in the example of Scheme 12. 

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... 

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... 

Oxidative nucleophilic substitution of the hydrogen in nitroarenes with the carbanion of isopropyl phenylacetate using lb gives corresponding isopropyl hydroxyaryl(phenyl)acetates, which is not the case with Bu4N Mn04 or 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidants <2005T11952>. 

Most nitroarenes or nitroheteroarenes are reduced in a stepwise manner, forming nitroso (-(- 2 e ), hydroxyamino (-K 4 e ) or amino (+ 6 e ) derivatives through disproportionation reactions. Amine formation can be viewed as a detoxifying/excretion route, but the reduction intermediates are potentially cytotoxic because they can react with nucleophiles such as protein thiol groups and DNA bases. 

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 ... 

There are two major variants of ONSH with nucleophiles sensitive to oxidation (a) addition is an irreversible process and (b) equilibrium of the reversible addition is shifted in favor of the adducts. Nucleophilic organometallic compounds, alkyllithium and alkyl-magnesium reagents, are active enough to add irreversibly to nitroarenes in positions occupied by hydrogen to form the adducts [72]. Due to irreversibility of the addition, the SNAr reaction on treatment of ortho- and para-halonitrobenzenes with these C-nucleophiles is not observed. Further oxidation of the formed adducts with a variety of oxidants, preferably KMn04, affords products of oxidative nucleophilic alkylation. This reaction appears to be an important method for direct incorporation of alkyl substituents into aromatic rings (Scheme 14) [72, 73]. 

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 adducts of nitroarenes with various nucleophiles can be oxidized with a few oxidants, and oxygen is probably the most common oxidant, although it has a limited application. It oxidizes adducts resulted from the addition of OH anion to nitroarenes to produce nitrophenols and also adducts of secondary and primary carbanions. Some observations and experiments lead to conclusion that for oxidation by oxygen the anionic adducts should first be deprotonated, so in fact, dianions are oxidized [78]. Oxidation of such adducts with oxygen appears to proceed via an electron transfer. On the other hand, oxidation of the adducts of nitroarenes with ammonia, the Grignard reagents, various carbanions, or diphenylphosphine by action of KMn04 appears to proceed via direct abstraction of the... 

Table 3 Yields of products obtained by electrochemical oxidation of a -complexes of nitroarenes with various nucleophiles...

The reaction of nitroarenes with an excess of nucleophile (RNH2) (without a base) begins with the formation of a zwitterionic complex at the first step. In the presence of nucleophile (RNH2) and base the o-complexes are formed directly. The ratio of or o -complexes depends on the nature of substituents. The complexes, as the key intermediates, can eliminate two electrons and a proton to give rise to the products, while the o -complexes, by loss of an electron and X, can be transformed into the Sn product. The Sn products are formed through selective electrochemical oxidation (lower oxidation potential of the intermediates) or from the compounds. An excess of amine present in the reaction mixture is not oxidized because the oxidation potentials for primary amines are about 1.50 V. The oxidation potential peaks for o-complexes are lower in all cases. Finally, a comparison of chemical [42, 43] and electrochemical oxidation reactions shows that the electro-oxidation is a more convenient process in those cases when the oxidation peak potentials for o -complexes are more positive than 0.6 V. 

Scheme 13 Vicarious and oxidative nucleophilic substitutions of hydrogen in nitroarenes with phosphorous-containing reagents...

Table 6 shows experimental values of Dc nu bond dissociation energies for various nucleophiles [95-97]. In accordance with the data of thermodynamic calculations, the complexes of nitroarenes with the OH, OR, SR nucleophiles have to undergo the SN -type process, since their bond dissociatimi energies are lower than 95 kcal mol ... 

The high effectiveness of PTC conditions for nucleophilic substitution of halogen in nitroarenes with organic anions, particularly carbanions, is apparently because these ionic nucleophiles are in the organic phase in low concentration and in form of loose ion pairs with TAA cations thus in the organic phase eventual competing processes are suppressed. 

Nucleophilic Substitutions. 7V,7V-Dimethyldithiocarbamoyl-acetonitrile (1) serves as an active methylene compound, because its carbanion is stabilized by sulfur and cyano groups. It can be alkylated stepwise in aqueous sodium hydroxide under phase transfer catalysis (eq 1). The anion undergoes nucleophilic aromatic substitution to give nitroarenes, with elimination of the dithiocarbamate group (eq 2). Nucleophilic addition of (1) to phenyl isothiocyanate also occurs readily. ... 

The reactions of nitroarenes with anionic nucleophiles in liquid ammonia have been reviewed. This report includes the reactions of alkali metal phenolates, and it is... 

Substrates 4 have a fluorine and a hydrogen atom located in similarly activated positions of the same nitroarene molecule. The reaction of substrates 4 with nucleophiles would result in the substitution of either the hydrogen or the fluorine atom, leading to a mixture of SNAr (6) and VNS (7) products (Scheme 36.5). In consequence, compounds 4 are ideal to evaluate the effect of base concentrations on the VNS mechanism. As the SwAr mechanism is not influenced by base concentration (a reasonable assumption in most of the cases), the study of the VNS/ SNAr product ratio gives information about the effect of the base on the VNS reaction rate. 

The foregoing examples show that the nucleophilic attack to nitroarenes at theorr/io-posidcn followed by cyclizadon is a generid method for the synthesis of various heterocycles. When nucleophiles have an electrophilic center, heterocyclic compounds are obtained in one step. Ono and coworkers have used the anion dedved from ethyl isocyanoacetate as the reacdve anion for the preparadon of heterocyclic compounds. The carbanion reacts with various nitroarenes to give isoindoles or pyriirddines depending on the stnicture of nitroarenes fEqs. 9.56 and9.57. The synthesis of pyrroles is discussed in detail in Chapter 10. 

The reaction with nitrite proceeds smoothly and with relatively high yields of the corresponding nitroarene (see Sec. 10.6). Obviously a major part of the driving force of this reaction is the formation of a stable, i. e., an energetically favorable, radical, nitrogen dioxide. With the hydroxide ion — a much stronger nucleophile than the nitrite ion — the reaction is expected to produce very unstable radicals, the hydroxy radical OH and the oxygen radical anion O, from the diazohydroxide (Ar - N2 — OH) and the diazoate (Ar-N20 ) respectively. Consequently, dediazoniation in alkaline aqueous solution does not follow the simple Scheme 8-41 with Yn = OH, but instead involves diazoanhydrides (Ar — N2 —O —N2 —Ar) as intermediates (see Sec. 8.8). 

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>. 

Control of the regioselectivity of VNS is important. It is governed by three major factors the structure of the nitroarene the nature of the nucleophile, and the reaction conditions, especially solvent and base. The different effect of methoxy and hydroxy groups is interesting the reaction of l-methoxy-2,4-dinitrobenzene with chloromethyl phenyl sulfone proceeds in... 

Because the nucleophiles can be introduced at the ortho-position of the nitro group, various heterocycles can be prepared via VNS and related reactions. Indoles and related compounds are prepared via the VNS reaction and subsequent cyclization. The VNS reaction of nitroarenes followed by cyclization with Et3N-Me3SiCl gives 1-hydroxyindoles (Eq. 9.53).86 Cyclization is also catalyzed on treatment with bases, in which nitroso intermediates are postulated. 

As discussed in Chapter 9, various nucleophiles can be introduced at the ortho position of nitroarenes via the VNS process. This provides a useful strategy for the synthesis of indoles. One of the most attractive and general methods of indoles and indolinones would be the reductive cyclization of a-nitroaryl carbonyl compounds (Eq. 10.54). The VNS and related reactions afford a-nitroaryl carbonyl compounds by a simple procedure. For example, alkylation of 4-fluoronitrobenzene with a lactone silyl enol ether followed by reductive cyclization leads to tryptophols (Eq. 10.55).73... 

The vicarious nucleophilic substimtion of carbo- and hetero-cyclic nitroarene hydrogen by a hydroxyl group, on reaction with silylhydroperoxide anions, has been shown to proceed via nucleophilic addition of ROO followed by base induced elimination of ROH by an ii2-type mechanism the required orientation of the hydroxylation can be controlled by the conditions selected. ... 

Acceptor-substituted haloarenes have been successfully used to O-arylate phenols by aromatic nucleophilic substitution (Table 7.14). The most common arylating agents are 2-fluoro-l-nitroarenes, 2-halopyridines, 2-halopyrimidines, and 2-halotriazines. When sufficiently reactive haloarenes are used, the reaction proceeds smoothly with either the arylating agent or the phenol linked to the support. The thallium(III) nitrate catalyzed arylation of phenols with aryl iodides has been used for macrocycli-zations on solid phase [184], Burgess and co-workers have developed a solid-phase synthesis of 3-turri mimetics based on ring-closure by aromatic nucleophilic substitution (Entry 4, Table 7.14 see also Table 10.5). Phenols, alkylamines, and thiols have been successfully used as nucleophiles for this type of macrocyclization [185],... 

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