Substitution, electrophilic with nitrites

Electrophilic substitution of the ring hydrogen atom in 1,3,4-oxadiazoles is uncommon. In contrast, several reactions of electrophiles with C-linked substituents of 1,3,4-oxadiazole have been reported. 2,5-Diaryl-l,3,4-oxadiazoles are bromi-nated and nitrated on aryl substituents. Oxidation of 2,5-ditolyl-l,3,4-oxadiazole afforded the corresponding dialdehydes or dicarboxylic acids. 2-Methyl-5-phenyl-l,3,4-oxadiazole treated with butyllithium and then with isoamyl nitrite yielded the oxime of 5-phenyl-l,3,4-oxadiazol-2-carbaldehyde. 2-Chloromethyl-5-phenyl-l,3,4-oxadiazole under the action of sulfur and methyl iodide followed by amines affords the respective thioamides. 2-Chloromethyl-5-methyl-l,3,4-oxadia-zole and triethyl phosphite gave a product, which underwent a Wittig reation with aromatic aldehydes to form alkenes. Alkyl l,3,4-oxadiazole-2-carboxylates undergo typical reactions with ammonia, amines, and hydrazines to afford amides or hydrazides. It has been shown that 5-amino-l,3,4-oxadiazole-2-carboxylic acids and their esters decarboxylate. 

Nitration of benzo[6]furan may be achieved with nitric acid in acetic acid and affords the 2-nitro compound, although nitrogen dioxide in benzene is reported to give the 3-nitro compound. 2-Phenylbenzo[6]furan with nitric acid in acetic acid yields the 3- and 6-nitro compounds. Treatment of 2-bromobenzo[6]furan with nitric acid and sodium nitrite yields 2-nitrobenzo[6]furan. The only electrophilic substitution reported with a benzo[c]furan is nitration of 1,3-diphenylbenzo[c ]furan with sodium nitrate and sulfuric acid, and this occurs on a phenyl group. 

Azides are formed by the reaction of lithio derivatives with />-toliicncsulfonyl azide, and these in turn can be converted into the corresponding amino compounds by a variety of reductive procedures. Nitro compounds are available by a novel reversal of the general pattern of reaction with electrophiles. This approach requires the initial conversion of the lithio compound into an iodonium salt followed by reaction with nitrite ion. This is illustrated by the preparation of 3-nitrothiophene (Scheme 145). Other nucleophiles, such as thiocyanate ion which yields the 3-thiocyanate, can be employed. The preparative significance of these reactions is again that products not accessible by electrophilic substitution can be obtained. 

Phenylenediamine is readily converted by HN02 into 1,2,3-benzotriazole 438 and by SOCl2 into 2,1,3-benzothia-diazole 439. Best synthetic methods for the preparation of 1,2,3-benzotriazoles are summarized in the related section of CHEC-III most important procedures are based on the reactions of substituted 0-pheny-lenediamines with nitrous acid or nitrites as illustrated by Scheme 227 <2006JME4762>. Likewise, the annulated thiadiazoles are commonly synthesized by the reaction of sulfur electrophiles with appropriate 1,2-diamines (e.g., Scheme 228) <1999JA10281, 2004BML5045, CHEC-III(5.09.9.2)550>. 

Ambident anions are mesomeric, nucleophilic anions which have at least two reactive centers with a substantial fraction of the negative charge distributed over these cen-ters ) ). Such ambident anions are capable of forming two types of products in nucleophilic substitution reactions with electrophilic reactants . Examples of this kind of anion are the enolates of 1,3-dicarbonyl compounds, phenolate, cyanide, thiocyanide, and nitrite ions, the anions of nitro compounds, oximes, amides, the anions of heterocyclic aromatic compounds e.g. pyrrole, hydroxypyridines, hydroxypyrimidines) and others cf. Fig. 5-17. 

The vast literature on applications of PTC in substitution reactions is mainly restricted to nucleophilic substitution reactions with an anionic reagent. However, recently the use of PTC in electrophilic reactions, like diazotization andazocou-pling C-and N-nitrosation, C-alkylation, acid hydrolysis of esters, chloromethylation, nitrite-initiated nitrations, and so on have been reported(Velichko et al., 1992 Kachurin et al., 1995). Alkylbenzene sulfonates and lipophilic sodium tetrakis[3,5-bis(trifluoromethyl)phenylboranate are typical electrophilic PT catalysts. Lipophilic dipolar molecules of the betaine type and zwitterionic compounds also function well as PT agents for both nucleophilic as well as electrophilic reactions. 

A mechanistically different type of nitrosation was discovered by Keefer and Roller (1973), namely a nitrosation of secondary aliphatic amines with nitrite anions in alkaline solution, catalyzed by aldehydes. Although it is unlikely to be applicable to diazotization, i. e., to primary amines, it will be mentioned here because it is a good example of the fact that, in chemistry, particularly in organic chemistry, for a certain type of reaction, e. g., nitroso-de-protonation (which includes substitution of protons bonded to C, N, O, S, etc., atoms), practically all methods follow the same basic pattern (in the case of nitrosation substitution by an electrophilic nitrosating reagent). The Keefer-Roller nitrosation is apparently different if one looks at the stoichiometric equation (4-8). A careful kinetic investigation (Casado et al., 1981b, 1984 a) on the concentration and pH dependence of this reaction revealed that the nitrite anion and free amine base enter the substitution process and that formaldehyde is a true catalyst, as it is not required in equimolar amounts. 

A-Oxides, just as in the pyridine series, show a remarkable duality of effect - they encourage both electrophilic substitutions and nucleophilic displacements. The sequence below shows pyridazine A-oxide undergoing first, electrophilic nitration, then, the product, nucleophilic displacement, with nitrite as leaving group. 

In agreement with the theory of polarized radicals, the presence of substituents on heteroaromatic free radicals can slightly affect their polarity. Both 4- and 5-substituted thiazol-2-yl radicals have been generated in aromatic solvents by thermal decomposition of the diazoamino derivative resulting from the reaction of isoamyl nitrite on the corresponding 2-aminothiazole (250,416-418). Introduction in 5-position of electron-withdrawing substituents slightly enhances the electrophilic character of thiazol-2-yl radicals (Table 1-57). 

The thiazolyl radicals are, in comparison to the phenyl radical, electrophilic as shown by isomer ratios obtained in reaction with different aromatic and heteroaromatic compounds. Sources of thiazolyl radicals are few the corresponding peroxide and 2-thiazolylhydrazine (202, 209, 210) (see Table III-34) are convenient reagents, and it is the reaction of an alky] nitrite (jsoamyl) on the corresponding (2-, 4-, or 5-) amine that is most commonly used to produce thiazolyl radicals (203-206). The yields of substituted thiazole are around 40%. These results are summarized in Tables III-35 and IIT36. 

Electrophilic nitrosation of the carbanion generated from the reaction of an organic base with a strong organic acid, such as a-hydrohexafluoroisobutyronitnle [2], a hydrohexafluoroisobutyric acid or its acid chloride [2], or a hydrotetra fluoroethanesulfonyl fluoride [4], yields the corresponding a-nitroso compound as the major product (equations 2 and 3) The a-hydrohexafluoroisobutyric acid or acid chloride reacts with excess trifluoroacetyl nitrite in dimethylformamide to afford the O substituted oxime [3] (equation 4)... 

The nitrosonium cation can serve effectively either as an oxidant or as an electrophile towards different aromatic substrates. Thus the electron-rich polynuclear arenes suffer electron transfer with NO+BF to afford stable arene cation radicals (Bandlish and Shine, 1977 Musker et al., 1978). Other activated aromatic compounds such as phenols, anilines and indoles undergo nuclear substitution with nitrosonium species that are usually generated in situ from the treatment of nitrites with acid. It is less well known, but nonetheless experimentally established (Hunziker et al., 1971 Brownstein et al., 1984), that NO+ forms intensely coloured charge-transfer complexes with a wide variety of common arenes (30). For example, benzene, toluene,... 

The most common reactions involving nucleophiles and porphyrin systems take place on the metalloporphyrin 77-cation radical (i.e. the one-electron oxidized species) rather than on the metalloporphyrin itself. One-electron oxidation can be accomplished electrochemi-cally (Section 3.07.2.4.6) or by using oxidants such as iodine, bromine, ammoniumyl salts, etc. Once formed, the 77-cation radicals (61) react with a variety of nucleophiles such as nitrite, pyridine, imidazole, cyanide, triphenylphosphine, thiocyanate, acetate, trifluoroace-tate and azide, to give the correspondingly substituted porphyrins (62) after simple acid catalyzed demetallation (79JA5953). The species produced by two-electron oxidations of metalloporphyrins (77-dications) are also potent electrophiles and react with nucleophiles to yield similar products. 

The nitrosonium ion (NO), generated in situ from sodium nitrite in the presence of hydrochloric acid at 0-5 °C, is also a weak electrophile and with tertiary amines, e.g. AyV-dimethylaniline, ring substitution occurs leading to the p-nitroso derivative (Expt 6.62). 

Like its sulfur and selenium analogs, 2,6-diphenyl- 1,4-ditellurofulvene 2 on treatment with amyl nitrite and phenyldiazonium tetrafluoroborate undergoes electrophilic substitution at the terminal methine carbon, giving rise to the corresponding nitroso and phenylazo derivatives (81CC828). 

The conversion of (57) into (60) or (61) starts with the halogen/nitro 8, 2 substitution from (57) to (58) promoted by IRA-402 nitrite, followed by in situ generation of the nitronate (59) under Amberlyst A-21 catalysis, then nucleophilic addition of (59) to the electrophilic substrates. 

Nitroimidazoles are readily made by nitration of imidazole or 1-substituted imidazoles in concentrated sulfuric acid (see Section 7.2.1). It is much more difficult to make 2-nitroimidazoles since direct nitration is seldom observed in the 2-position. Although electrophilic nitrodehalogenation reactions, too, occur mainly at C-4(5) [1], Katritzky has recently selectively nitrodeiodinated 2,4,5-triiodoimidazole to prepare 2,4(5)-dinitro-5(4)-iodo-and 2,4,5-triiiitroimidazoles, albeit in poor yield [2], Other routes to 2-nitroimidazoles include those which react a diazonium fluoroborate with the nitrite ion, and methods which oxidize 2-amino derivatives, themselves often only available by laborious sequences. The most appealing routes to 2-nitroimidazoles are the methods which make the 2-lithio derivative and treat it with a source of nitronium ion (e.g. n-propyl nitrate or N2O4) [3-5] (see Section 7.2.2). 

Mesomeric structures of propionyl nitrite show the O-NO bond with the NO unit having a partially positive charge. Therefore, propionyl nitrite, the mixed anhydride of propionic and nitrous acid formed under the reaction conditions, behaves rather like nitrosyl propionate, i.e. as a polarised covalent source of a nitrosyl cation. Hence, the regioselectivity of this reaction can be understood in terms of the weak electrophilicity of the NO -generating species. Finally, the substituted 2-nitrosophenols were easily oxidised with nitric acid to yield the substituted 2-nitrophenols required as precursors [119]. 

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