Formic acid enamines

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 cyclic thioketone, 3-oxotctrahydrothiophene (11), gives a mixture of enamines (12,13) when caused to react with a secondary amine such as piperidine or pyrrolidine (31). The enamine mixture can be reduced to the 3-aminotetrahydrothiophene using formic acid or oxidized to the 3-amino-thiophene using diisopentylsulfide. 

Anhydrides have also been employed (31). The mixed anhydride of acetic and formic acid reacts with the enamine (113) to give a 50% yield of 2-hydroxymethylene cyclohexanone (119). 

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). 

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 reduction of the double bond of an enamine is normally carried out either by catalytic hydrogenation (MS) or by reduction with formic acid (see Section V.H) or sodium borohydride 146,147), both of which involve initial protonation to form the iminium ion followed by hydride addition. Lithium aluminum hydride reduces iminium salts (see Chapter 5), but it does not react with free enamines except when unusual enamines are involved 148). 

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... 

Dihydro- and 1,4-dihydro derivatives are formed as intermediates in the reduction of quaternary pyridine salts and their homologues with sodium borohydride or formic acid. A proton is added to the present enamine grouping and the formed immonium salts are reduced to the l-methyl-l,2,5,6-tetrahydropyridine derivatives (157) and to completely saturated compounds (158) (254) (Scheme 14). 

Greater stereoselectivity for the formation of equatorial amines has been found in the reduction of enamines with formic acid or formamides (553-559). The selective formation of 3-a-amino-5- -steroids by this method and of 3- 3-amino-5- 3-steroids by catalytic reduction (5<50) of the corresponding enamines is of interest. 

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... 

Vinylamines (enamines) are reduced by alane, mono- and dichloroalane to saturated amines, and hydrogenolyzed to amines and alkenes [710]. Reduction is favored by dichloroalane while hydrogenolysis is favored by alane. Alane, chloroalane and dichloroalane gave the following results with -N-pyrrolidinylcyclohexene V-pyrrolidinylcyclohexane in 13, 15 and 22% yield, and pyrrolidine and cyclohexene in 80, 75 and 75% yields, respectively [710]. Saturated amines were also obtained by treatment of enamines with sodium borohydride [711], with sodium cyanoborohydride [103, 712] (Procedure 22, p. 210) and by heating for 1-2 hours at 50-70° with 87% or 9S% formic acid (yields 37-89%) [320]. 

The nature of aromatic enamines has no substantial effect on the pathway thus, pyrrolo[2,3-d]pyrimidines 265-267 were synthesized in comparable yields under the same conditions using thenoine 213 with fused aminopyrimidines (06MI2). Also new pyrrolo[2,3-d]pyridazines were prepared by the condensation of thenoine 213 with substituted 5-aminopyr-idazines 268 in formic acid followed by alkylation. Spectroscopic studies of 269 and 270 (Scheme 74) were reported. 

For a review of the reduction of enamines and indoles with NaBH, and a carboxylic acid, see Gribble Nutaitis Org. Prep. Proced. Int. 1985, 17, 317-384. Enamines can also be reduced by formic acid sec Nilsson Carlson Acta Chem. Scand. Sect. B 1985, 39, 187. 

An alternative synthesis of ( )-a- and ( )--y-lycoranes (57 and 93) commenced with the 2-oxocyclohexyl acetic acid derivative 114 obtained by the alkylation of the enamine derived from 113 (Scheme 10) (116). Refluxing the oxime of 114 with zinc dust in glacial acetic acid afforded a mixture of the lactams 115, 116, and 117 in an approximate ratio of 4 6 3. The structure of 115 was verified by catalytic hydrogenation to give the lactam 118, which had previously been converted to ( )-a-lycorane (57). When the lactam 116 was subjected to sequential catalytic hydrogenation, hydride reduction, and Pictet-Spengler cyclization, ( )-y-lycorane (93) was obtained. A more efficient route to ( )-a-lycorane (57) involved refluxing the ketone 114 first with benzylamine in xylene and then with 87% formic acid to furnish the unsaturated lactam 119. 

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... 

Reduction of both the free bases and their quaternary salts proceeds by similar mechanisms. In pyridine and its quaternary salts, a hydride ion, or its equivalent, attacks a position of a low electron density, i.e. the 2- or 4-position. The mechanism of the reduction of quaternary salts of pyridine and its homologs (LukeS and Ferles414) has been elucidated using deuterated formic acid.415 The hydride ion attack in position 2 is followed by addition of a proton to the enamine grouping with the formation of A 3-piperideines (124). If the reduction commences with attack in the 4-position, a saturated base (125) is the final product. In agreement, a-picoline methobromide yields 1,2-dimethyl-... 

A similar photolytic cyclization has been achieved, with concomitant oxidation, of the iV-formyl-enamine (85) in the presence of hydrogen iodide to produce (86), no evidence being found of non-oxidative cyclization. The enamine with the (Z)-configuration is obtained directly from the 3,4-dihydroisoquinoline by the action of formic acid and acetic anhydride.95... 

The number of incorporated D atoms and their positions led to the conclusion that the proton of formic acid attacks the enamine / -carbon by a reversible process (which would explain incorporation of more than 1 D per molecule). Then the hydride derived from the formate becomes attached to the iminium carbon to give the saturated amine. 

Alkylcyclohexanone enamines were reduced by formic acid with a high degree of stereoselectivity, giving a. ca 9 cis/trans ratio of the resulting amines202 (Scheme 135). 

A great variety of tertiary enamines derived from aliphatic ketones, aryl alkyl ketones and functionalized ketones were reduced by formic acid, most of them in good yields, even in the presence of other functional groups, such as carbonyl, cyano and other carbon-carbon double bonds205 (Scheme 137). 

Enamines of steroids formed in situ by condensation of the corresponding ketones with secondary amines, followed by treatment with formic acid, gave the 3/ -saturated amine derivatives as the main products206. 

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. 

From the model it is seen that the best yield if found when xt is at its low level (—1) which corresponds to a stoichiometric amount of formic acid and that an excess is detrimental to the yield (the coefficient is negative). The temperature x2 is the most important factor and should be at its upper level. The experimental conditions established for this very simple procedure could be applied as a method for the reduction of a number of enamines [17]. 

The observation that enamines may be reduced by NBH in acetic acid/ THF ° and sodium cyanoborohydride coupled with the tendency for indoles to protonate at the 3-position enabled Gribble and co-workers to reduce indoles to indolines (201,205) in high yield. //-Alkyl indoles (204) were also reduced, as was 3-methylindole. The use of formic acid favored the formation of l-methyl-3-[2-(2-dimethylaminophenyl)ethyl]indoline (207) via an intermeuiate 3,2 dimer (206). ... 

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