Iminium salts, from nitriles

RCOOH — RCHO. The iminium salt (1) formed on reaction of a carboxylic acid with the Vilsmeier reagent (formed from DMF and oxalyl chloride) is reduced by lithium tri-/-butoxyaluminum hydride (1 equiv.) to an aldehyde. The chemo-selectivity is noteworthy ester, nitrile, keto, and halide groups are not affected.3... 

Another field of research is concerned with the one-pot synthesis of this system from readily available starting materials. In Scheme 12, reaction of phenyl azide and malononitrile in the presence of sodium ethoxide leads, via the intermediate triazole (139), to the self-condensation product (140), itself a triazolopyrimidine. In the presence of other nitriles the preferred formation of the more useful compounds (141) occurs in low to moderate yields with small amounts of dimer <87JHC997>. Direct synthesis of the 5,7-dione derivatives (143) (60-90%) is achieved by the reaction of the readily available aminopyrimidinedione (142) with an azide iminium salt in dichloromethane at moderately high dilution <87JHC1493>. 

From alkylmercaptomethyleneiminium salts various types of amidinium salts have been synthesized. Ammonia, primary and secondary amines, hydrazines and IV-unsubstituted and N-monosubstituted hydrazones were the reaction partners. Side reactions can include the dealkylation of the iminium salt by the amine. If A, A(-unsubstituted salts (141 equation 85) are treated with amines, the desired exchange reaction can be accompanied by nitrile formation. 

Aromatic and aliphatic aldehydes in the presence of dialkylamines and an equivalent of acid such as hydrochloric, perchloric or p-toluenesulfonic acid give iminium salts, which add cyanide ion to form a-(dialkylamino)nitriles. An alternative preparation involves the reaction of the aldehyde with dialkylamines in the presence of acetone-cyanohydrin, a-(A, -dialkylamino)isobutyronitiiles, diethyl phosphorocyanidate or TMS-CN. Another route to a-aminonitrile starts with an aldehyde, the salt of an amine and KCN in organic solvents under solid-liquid two-phase conditions by combined use of alumina and ultrasound. Chiral a-aminonitriles were prepared by Strecker-type reactions, cyano-silylation of Schiffs bases, amination of a-siloxynitriles or from an A -cyanomethyl-l,3-oxazolidine synthon. Reaction of tertiary amines with CIO2 in the presence of 5.1 mol equiv. of aqueous NaCN as an external nucleophile affords a-aminonitrile. °... 

The stereoselective total synthesis of ( )-lepadiformine was accomplished in the laboratory of S.M. Weinreb. The introduction of the hexyl chain in a stereoselective fashion was achieved by a Grignard reaction to an iminium salt during the last steps of the synthetic sequence. The iminium salt was generated in situ from an a-amino nitrile with boron trifluoride etherate, and the addition of hexylmagnesium bromide gave a 3 1 mixture of alkylated products favoring the desired stereoisomer. Removal of the benzyl group completed the total synthesis. 

Reduction of iminium salts. 1,3-Diamines can be elaborated via reduction of the monoiminium species which arise from condensation of enamines with aldiminium salts. The subsequent reduction is carried out with NaBH, in methanol. Oximes of a-aminocycloalkanones undergo fragmentation and reduction, furnishing co-amino nitriles. A route to substituted ureas involves reductive alkylation, condensation with aldehydes in the presence of MejSiCl followed by treatment with NaBH. The borohydride reduction of P-amino-a,P-unsaturated esters in the presence of isobutanoic acid may also proceed via iminium species. 

Figure 7.2 illustrates the phosphorus pentoxide-mediated dehydration of a primary amide to a nitrile, using the transformation of nicotine amide (A) into nicotine nitrile (B) as an example. The reaction of phosphorus pentoxide at the carboxyl oxygen furnishes the partially ring-opened iminium ion E (simplified as F) via the polycyclic iminium ion C. E is deprotonated to give the mixed anhydride G from imidic acid and phosphoric acid. Imidic acids are characterized by the functional group R-C(=NH)-OH. This anhydride is transformed into the nitrile B by an El elimination via the intermediate nitrilium salt D. Nitrilium salts are iV-pro-tonated or V-alkylated nitriles. 

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