Nucleophilic substitution of hydrogen vicarious

SCHEME 11.17 Vicarious nucleophilic substitution in p-halonitrobenzenes with carbanion of chloromethyl 

For the VNS reaction to proceed satisfactorily, the carbanions should be in the form of loose ion pairs when they form tight ion pairs or aggregates with countercations, the addition does not proceed. The most convenient base-solvent systems are therefore f-BuOK, NaOH, or NaH in dipolar aprotic solvents, such as DMF, DMSO, or their mixtures with THF. An excellent solvent for this reaction is liquid ammonia. According to stoichiometry of the reaction, the base should be used in an excess. In majority of cases, the reaction is carried ont preferably at low temperatures of-20to-70°C [35]. 

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Aromatic nitro compounds undergo nucleophilic aromatic substitutions with various nucleophiles. In 1991 Terrier s book covered (1) SNAr reactions, mechanistic aspects (2) structure and reactivity of anionic o-complexes (3) synthetic aspects of intermolecular SNAr substitutions (4) intramolecular SNAr reactions (5) vicarious nucleophilic substitutions of hydrogen (VNS) (6) nucleophilic aromatic photo-substitutions and (7) radical nucleophilic aromatic substitutions. This chapter describes the recent development in synthetic application of SNAr and especially VNS. The environmentally friendly chemical processes are highly required in modem chemical industry. VNS reaction is an ideal process to introduce functional groups into aromatic rings because hydrogen can be substituted by nucleophiles without the need of metal catalysts. 

In the presence of KOH, /m(benzotriazol-l-yl)methane 729 reacts with nitrobenzenes to produce />-(/fc (bcnzo-triazol-lyl)methyl]nitrobenzenes 730 (Scheme 114) <1996TL347>. This vicarious nucleophilic substitution of hydrogen <1991S103> can be considered as a convenient way to />-nitrobenzaldehydes 731. Meta and para substituted nitrobenzenes do not react with compound 729 under these conditions, probably due to steric reasons, but 1-nitronaphthalene reacts producing a naphthalene analog of derivative 730. 

Scheme 3.8 represents a typical ion-radical mechanism of the so-called vicarious nucleophilic substitution of hydrogen as it was described by the pioneering chemist M kocza (M kocza 1989) in his summarizing review. ESR studies of other heterocyclic systems in conditions of the hydrogen-to-nucleophile vicarious substitution were reported by the research group at the Siberian branch of the Russian Academy of Sciences (Donskaya et al. 2002, Vakul skaya et al. 2005, 2006, Titova et al. 2005). 

The vicarious nucleophilic substitution of hydrogen in nitrothiophenes is of great synthetic potential (87ACR282,91S103). Carbanions bearing leaving groups (L) at the carbanion center can initially add to... 

The theory and practice of vicarious nucleophilic substitution of hydrogen (VNS) were examined in detail mostly by Mqkosza and his co-workers (87ACR282,... 

Selected substituted thiophene derivatives may also react with nucleophiles. Primary and secondary amines react with 2-bromo-3-substituted-5-nitrothiophenes to produce 11 <95T5403>. Vicarious nucleophilic substitution of hydrogen (VNS) works generally for both 2-nitro- and 3-... 

Vicarious nucleophilic substitution of hydrogen in heterocyclic chemistry 91S103 93MI25. 

Deoxygenative v.s vicarious nucleophilic substitution of hydrogen in reactions of 1,2,4-triazine-4-oxides with a-halocarbanions has been described <02EJO1412>. Tandem vicarious nucleophilic substitution of hydrogen/intramolecular Diels-Alder reaction of 1,2,4-triazine (19) into functionalized cycloalkenopyridines 21 has been reported <02CPB463>. 

The nitroazoles are widely used in the reaction of vicarious nucleophilic substitution of hydrogen. Vicarious nucleophilic C-amination is, practically, the single method of direct introduction of the amino group into nitro compounds. Using the vicarious nucleophilic substitution reaction we have successfully carried out the C-amination of some representatives of nitrobenzazoles, nitroazoles, and model compounds thereof and studied the structure of aminated products and the C-amination mechanism [673-678],... 

First the mechanism of vicarious nucleophilic substitution of hydrogen in nitroazoles and nitrobenzene has been discussed in terms of an electron transfer [273-277]. Community of the observed effects in vicarious C-amination of nitroazoles allows... 

Carbanions of a-haloalkyl aryl sulfones, sulfonates and sulfonamides react with quinoxalines according to two general pathways vicarious nucleophilic substitution of hydrogen and/or bis-annulation to bis(azirino)quinoxaline derivatives. The charge distribution in the anionic (T-adducts and reaction conditions influence the direction of these reactions. ... 

Reaction of l-methyl-4-nitropyrazole with 1,1,1-trimethylhydrazinium halides in the presence of sodium methoxide or potassium fert-butoxide afforded 5-amino-l-methyl-4-nitropyrazoles <1999CHE1109>. Specifically, the primary radical anions of substrate in the vicarious nucleophilic substitution of hydrogen in 1-methyl-4-nitropyrazole 192 with 1,1,1-trimethylhydrazinium iodide yielded 5-amino-l-methyl-4-nitropyrazole 193, which was studied by electron spin resonance (ESR) (Equation 31) <2005MRC1023>. Reaction of 3,5-dinitropyrazole 194 with trimethylhydrazinium iodide in DMSO afforded 4-amino-3,5-dinitro-l//-pyrazole 195 via another vicarious nucleophilic substitution (Equation 32) <2001JHC1227>. 

Intramolecular substitution of chlorine in 3-[iV-alkanesulfonyl-iV-alkyl)-amino-2-chloropyridines 455 affords pyridosultams 456 (see Section 4.05.6.3.2) <2000EJ01263, 1997TL4667>. The application of intramolecular vicarious nucleophilic substitution of hydrogen in A -oxides and quaternary salts of chloromethansulfonamides 457 (R =0, Me R = R = H) afforded isothiazolo[4,3-/ ]pyridines 458 and 459. Starting from 3-aminoquinoline 457 (R -R = -CH=CH-CH=CH-), the corresponding compounds 458 and 459 were obtained <2001T5009>. 

The ci e-substitution of 1,4-dinitropyrazoles affords 4-nitro-3(5)-substituted pyrazoles including the antibiotics formycin and pyrazofurin <91JCS(P1)1077>. Makosza <89LA545> has illustrated his vicarious nucleophilic substitution of hydrogen by examples of 4-nitropyrazole derivatives. The reduction of 1-nitropyrazole into 1-aminopyrazole was achieved by lithium aluminum hydride... 

Vicarious nucleophilic substitution of hydrogen , Makosza, M. and Winiarski, J., Acc. Chem. Res., 1987, 20, 282 Applications of vicarious nucleophilic substitution in organic synthesis , Makosza, M. and Wojciechowski, K., Liebigs Ann JReceuil, 1997, 1805. 

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.). 

In a so-called vicarious nucleophilic substitution of hydrogen, the carbanion of an arene halomethyl sulfone adds to the electron-deficient ring position of nitroarenes or azaaromatic systems such as quinoxalines and naphthyridines, followed by base-induced /(-elimination of the corresponding hydrogen halide.73... 

M A K 0 S Z A Vicarious nucleophilic substitution Synthesis of afcyl substituted heterocydes by vicarious" nucleophilic substitution of hydrogen in heteroarenes, nitroderivatives of heteroarenes. 

Autoaromatization can also be facilitated by an auxiliary group which is present in a nucleophile (Scheme 44, route c). This approach is commonly known as the vicarious nucleophilic substitution of hydrogen (VNS), and it is illustrated by several examples of the displacement of hydrogen at C-5 of the 1,2,4-triazine ring by action of chloromethyl arylsulfones as C-nucleophiles <1992PJC3, 19%RCB491, 2004CRV2631>. 

An interesting feature of this process is that vicarious nucleophilic substitution of hydrogen usually proceeds faster than conventional nucleophilic substitution of halogen activated by the nitro group. 

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