Formic acid reaction with enamines

A number of products in which one of the naphthalene rings has been reduced have interesting pharmacological properties. Reaction of tetralone 30 with dimethylamine under TiCl catalysis produces the corresponding enamine (31). Reaction with formic acid at room temperature effects reduction of the... 

The reduction of the morpholine enamine from camphor by the reaction with formic acid was discussed in Chapter 5. In the example below, this reaction was applied to the reduction of the corresponding pyrrolidine enamine. The reaction was conducted without any solvent present, i.e. by adding formic acid dropwise to the hot enamine, and afforded an almost quantitative conversion to the corresponding bornyl pyrrolidine. However, the reaction was not stereoselective and a mixture of endo and exo isomers was formed. The proportions were endo isomer (85 %), exo isomer (15 %). This was regarded as a promising result. 

H. Reaction with Formic and Trichloroacetic Acids Enamines derived from aldehydes have been treated with formic acid under the conditions of the Leuckart-Wallach reaction 141) to give saturated tertiary amines 142). The enamine (98) reacts vigorously with formic acid at room temperature to give N-isobutyl morpholine (204). 

Enamines are also reduced with formic acid (247). Distillation of 1,2-dimethyl-.d -pyrroline formate (156) affords 1,2-dimethylpyrrolidine (248). The reaction is usually carried out by heating of the enamine salt with... 

Enamines are also reduced with formic acid, e.g. under the conditions of the Wallach-Leuckart reaction. The first reduction reported was the observation of LukeS308 that the cleavage of l,l-dimethyl-2-methylenepyrrolidinium formate (91) by dry distillation is accompanied by reduction with the formation of 1,2-dimethylpyrrolidine... 

Enamines can be reduced to the corresponding saturated amines by treatment with formic acid. A very simple experimental procedure can be used in which formic acid is added to the neat enamine at such a rate that foaming due to evolution of carbon dioxide can be kept under control. The reduction of the morpholine enamine from camphor was studied in a two-level factorial design in order to determine whether or not an excess of formic acid should be used and at which temperature the reaction should be run. 

Further, enamines can be formylated by treatment with formic acid and acetic anhydride467 or with dimethylformamide and carbonyl chloride, the latter process being analogous to the Vilsmeier reaction and sometimes giving very good yields.471... 

Another interesting fact to be noted is that the bicyclic enamine (87) and its pyrrolidine analogue failed to undergo reduction with 98% formic acid, whereas the pyrrolidine enamine of 2-bicyclo[2.2.1]hepten-5-carboxalde-hyde (94), which exists largely in the transoid form (49), was readily reduced to (95). However, the saturated amine-substituted norbornane can be obtained directly from norbornanone under the more vigorous conditions of the Leuckart reaction (49a). 

The reaction has been applied to more complex enamines 13) and to dienamines 19). The reduction may be rationalized by initial protonation at the enamine carbon and subsequent decarboxylation of formate ion and addition of the hydride ion to the iminium cation. This mechanism has been given support by the reaction of the enamine (205) with deuterated formic acid 143) to give the corresponding amines. The formation of 206 on reaction with DCOOH clearly indicates that protonation at the enamine carbon is the initial step. 

The use of formic acid for reduction of enamines is so characteristic that this reaction can be used for detection of the enamine group.128,129 Even enamines that are resistant to catalytic hydrogenation with Raney nickel or palladium can be reduced smoothly by formic acid.130... 

A Leimbruger-Batcho-type amino-enamine intermediate is likely to be involved on reduction of the base-catalysed condensation product of an ortho-nitro araldehydes with nitromethane. Reduction, traditionally with metal/acid combinations, but now with reagents such as palladium/carbon with ammonium formate and formic acid, iron with acetic acid and silica gel, or titanium(III) chloride, gives the indole. The arylacetaldehyde precursors can also be generated by Heck reactions on vinylidene carbonate. ... 

Imidazoles.—Formation. Several new syntheses of imidazoles from isocyanides have been reported these include the formation of 1-alkyl-imidazoles (396) by the action of primary amines on 2-isocyano-2-tosylstyrene, PhCH=C-(NOTos, the cyclization of the enamine Me2NCH=C(NC)C02Me to compound (397) in the presence of methyl iodide,and the preparation of the ethers or thioethers (398) from isocyano-cyanides R CH(NC)CN by their reaction with alcohols or thiols R XH, respectively.Aromatic aldehydes are converted into 2-aryl-4,5-dichloroimidazoles (399) by the combined action of cyanogen and hydrochloric acid. 5-Acetyl-4-methylimidazole (400) results when form-amido-acetylacetone, AC2CHNHCHO, is heated with formamide and formic acid. Exhaustive chlorination of tetramethyldithio-oxamide leads to the tri-chloro-imidazolium cation (401). ... 

Alkylation via enamine 18 and successive alkaline hydrolysis furnished 2-oxo-cyclohexylacelic acid derivative 19. Refluxing keto acid with benzylamine in orf/io-xylene and then in 87 % formic acid yielded unsaturated lactame 20. Catalytic hydrogenation of the C=C bond afforded trans,cis 21 as the sole stereoisomeric product. In the last steps, reduction of lactame by a complex hydride, hydrogenolytic debenzylation and the Pictet-Spengler reaction gave ( )-a-lycorane TM 9.4 in a moderate overall yield. 

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