Nitrilium salts formation

Little attention seems to have been paid to this type of reaction involving intramolecular nitrilium salt formation. Typical experimental conditions of the Ritter reaction have always been employed in the few instances which have been studied. The reaction does not appear to be widely applicable and at least three exceptions have been recorded in the literature.75-77... 

In some instances the attack of the arene on the nitrilium salt occurs at the ipso carbon rather than the ortho carbon. For example, the Bischler-Napieralski cyclization of phenethyl amide 10 affords a 2 1 mixture of regioisomeric products 11 and 12. The formation of 12 presumably results from attack of the ipso aromatic carbon on the nitrilium salt 13 followed by rearrangement of the spirocyclic carbocation 14 to afford 15, which upon loss of a proton vields product 12. ... 

Dealkylation of related salt 145b, which is stable up to — 20 °C, led to the formation of a nitrilium salt 146. The latter was transformed to amide 147 upon hydrolysis (see Equation 42) <1995HAC559>. 

In the case of the most reactive compounds, substitution at the carbon atom of diselenonium and ditelluronium dications is also a possible pathway. For example, formation of diselenide 117 from selenoxide 115 was explained by demethylation of intermediate dication 116 with trifluoroacetate anion.126 Dealkylation of salt 118, which is stable up to —20°C, leads to formation of nitrilium salt 119. The latter is transformed to amide 120 upon hydrolysis.64 Dealkylation of intermediate diselenonium dication 122 was suggested as the key step in the oxidative synthesis of 1,2,4-diselenazolidines 123 from eight-membered heterocycles 121 (Scheme 46).127... 

Whereas the value of this reaction lies in the forging of the N—A bond, the importance of the C—X bond formation cannot be overlooked since it is often intrinsically necessary in heterocycle formation. It is with reactions of type (2) that this chapter deals. The only previous review article pertaining to this subject is that of E. N. Zil berman4 which does not deal with heterocyclic syntheses specifically. Recent advances justify a new review of the latter area. Principally, the use of three types of reactions are discussed (a) the Ritter reaction (b) reactions involving nitrilium salts and (c) a, j-dinitrile cyclizations. All appear to be variations of the above theme. 

Again, since mixtures of 2-oxazolines are obtained from nitriles and unsymmetrical epoxides,15 it does not seem likely in this case that a purely carbonium ion mechanism is involved, for this would require the formation of primary carbonium ions. An alternate possibility is that the nitrile nucleophilically attacks the oxonium salt (27) of the epoxide to give the nitrilium salts 28 and 29, which then cyclize, thus ... 

We should also mention that Ziegler et al.72 have described the formation of l,3-oxazine-4-ones (91) by reactions taking place between benzylmalonyl chloride and several nitriles. They interpret the process as taking place via an IV-acyl-nitrilium salt (90). 

A similar procedure, taking advantage of the nitrilium salt reactivity for the —OH grouping, permits the synthesis of several 5-oxo-pyrano[3,4-e]-l,3-oxazine derivatives (93) which Davis and Elvidge73 have recently described and in the formation of which an intermediate iV-acyl-nitrilium salt (92) has also been postulated. 

C—C—O+N—C. a-Hydroxy ketones react with monosubstituted cyanamides under the influence of sodium hydroxide to yield derivatives of 2-aminooxazole (equation 125) (76S591). Oxazoles are obtained by the action of nitriles on a-diazo carbonyl compounds in the presence of Lewis acids, such as aluminum chloride or boron trifluoride, and the reaction is thought to involve the intermediacy of nitrilium salts (equation 126). Nitrilium salts are also the effective agents in the formation of oxazoles from a-chloro ketones and nitriles in the presence of tin(IV) chloride (equation 127). 

Nitrilium salts (40 equation 10) can be prepared from nitriles and triethyloxonium fluoroborate. Early workers concluded that the nitrilium salts could be reduced to amines but that the reduction could not be stopped at the aldehyde (aldimine) stage.Later, it was demonstrated that reduction of the nitrilium salts with NaBH4 was rapid and did give the corresponding amine, but with triethylsilane yields of 60-90% of both aliphatic and aromatic aldehydes were obtained. Triethylsilane is a mild reagent which reduces carbocations but neutral compounds are generally not reduced and so overreduction is not a problem with this reagent. Formation of the nitrilium salts with triethyloxonium fluoroborate is slow but can be speeded up by the use of iron(III) chloride (Scheme 19). There were some notable exceptions to aldehyde formation with some aromatic nitriles. 

The addition of alcohols to nitrilium salts gives rise to formation of alkoxymethyleneiminium salts, which react with bases to yield imido esters (231 Scheme 33). - By deprotonation of carboxylic acid amides ambident anions are formed, which can be alkylated in the presence of silver ions to give imido esters, e.g. (232). " Secondary amides react with trifluoroacetic acid anhydride or trifluorosulfonic acid anhydride to give mixed anhydrides of imidic acids (233). ... 

Dehydrohalogenation of amide chlorides affords a-chloroenamines, which undergo cycloaddition with IV-diphenylmethylaldimines to furnish azetidinium salts (303 equation 161). From these salts the diphe-nylmethyl group can be removed by hydrogenation, subsequent deprotonation yields 2-amino-1-aze-tines. The addition of primary or secondary amines to nitrilium salts gives rise to formation of amidinium salts and amidines respectively, e.g. (304 equation 162). In a similar reaction from copper(I) imidazolide, r-butyl bromide and nitriles amidines (305 equation 163) were prepared. ... 

The formation of a nitrilium salt facilitates the formation of this ring from a bromomethyl-sulphonamide and a nitrile. 

For the polar 2 1 adduct the term nitrilium salt is often used. Hantzsch in 1931 postulated the formation of nitrilium salts, but it was not until later that iminium halides were detected and isolated ( 87,208 ... 

Iminium halides are intermediates in the hydrolysis of nitriles and in a variety of chemical reactions. For example, in the Ritter reaction addition of a nitrile or hydrogen cyanide to a carbonium ion occurs, leading to the intermediate formation of a nitrilium salt. Nitrilium salt intermediates have also been postulated in the Schmidt reaction and in the Beckmann rearrangement, provided the latter was performed in concentrated sulfuric acid. However, since we are predominantly concerned with imidoyl halides, these reactions are not discussed in this monograph. 

It is believed that this reaction proceeds via initial formation of hydrochloric salts of imidoyl chloride when POCI3, PCI5, or SOCI2 is used as a reagent, followed by the formation of imidoyl chloride by the loss of hydrogen chloride, which is in equilibrium with nitrilium salt. Then the 3,4-dihydroisoquinoline is formed via the ring closure of nitrilium salt, as indicated in the direct formation of such dihydroisoquinoline via alkylation of nitrile with phenylethyl halide in the presence of a Lewis acid. An exemplary mechanism of the Bischler-Napieralski reaction is illustrated here. 

A nitrilium ion E or an imidate derivative G is formed as an intermediate. Their hydrolysis leads either to the formation of amide H or, in the case of nitrihum ion E, to nitrile F by fragmentation and formal loss of a carbocation. Under particular conditions nitrilium salts E derived from special substrates can be isolated [356]. 

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