Amines to enamines

Reductive amination ol aldehydes or ketones by cyanoborohydride (or tnacetoxyborohydride) anion Selective reduction of carbonyls to alcohol, oximes to N alkylhydroxylarmnes, enamines to amines... 

Sodium cyanoborohydride reduces enamines to amines. Diborane reduces nitriles to amines but the nitro group remains unaffected. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Two-step 1,4 cycloaddition of enamines, such as was observed with methyl vinyl ketone, is not possible with acrylate or maleate esters. This is due to the fact that, following the initial simple substitution, no side-chain carbanion is available for nueleophilic attack on the a carbon of the iminium ion. Likewise two-step 1,3 eycloaddition, such as that found when alicyclic enamines were treated with acrolein, is impossible with acrylate or maleate esters because transfer of the amine moiety from the original enamine to the side chain to form a new enamine just prior to the final cyclization step is not possible. That is, the reaction between a seeondary amine and an ester does not produce an enamine. 

The stereochemical course of reduction of imonium salts by Grignard reagents was found to depend on the structure of the reagent 714). Hydro-boration of enamines and oxidation with hydrogen peroxide led to amino-alcohols (7/5). While aluminum hydrogen dichloride reacted with enamines to yield mostly saturated amines and some olefins on hydrolysis, aluminum hydride gave predominantly the unsaturated products 716). 

Rearrangement of an enamine to a Sehiff s base through N- to C-alkyl migration was reported 729). These authors also found that enamines, rather than aminals, were formed from butyraldehyde and seeondary amines (730). Chloramines and aeetylenes reacted to give chloroenamine intermediates, which hydrolyzed on work-up of the reactions (731). 

The generation of a library of 2-aminoquinoline derivatives has been described by Wilson and colleagues (Scheme 6.240) [423]. The process involved microwave irradiation of the secondary amine and aldehyde components to form an enamine (1,2-dichloroethane, 180 °C, 3 min) and subsequent addition of the resulting crude enamine to a 2-azidobenzophenone derivative (0.8 equivalents) and further micro-wave heating for 7 min at the same temperature. 

Enamines are reduced to amines in good yields with Et3SiH/TFA.529 533 This reagent combination causes a variety of indoles to undergo stereoselective cis... 

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 Pechmann and Knoevenagel reactions have been widely used to synthesise coumarins and developments in both have been reported. Activated phenols react rapidly with ethyl acetoacetate, propenoic acid and propynoic acid under microwave irradiation using cation-exchange resins as catalyst <99SL608>. Similarly, salicylaldehydes are converted into coumarin-3-carboxylic acids when the reaction with malonic acid is catalysed by the montmorillonite KSF <99JOC1033>. In both cases the use of a solid catalyst has environmentally friendly benefits. Methyl 3-(3-coumarinyl)propenoate 44, prepared from dimethyl glutaconate and salicylaldehyde, is a stable electron deficient diene which reacts with enamines to form benzo[c]coumarins. An inverse electron demand Diels-Alder reaction is followed by elimination of a secondary amine and aromatisation (Scheme 26) <99SL477>. 

Prior to the beginning of our work on sitagliptin, there had been some reports in the literature of catalytic asymmetric hydrogenation of enamines to access chiral secondary amines [19]. The synthesis of P-amino acids had also been established by catalytic asymmetric hydrogenation of enamides [20]. All these reports relied on N-acylenamines as substrates, since it was believed that the N-acyl group was required in order to achieve good reactivity and selectivity [21]. 

C(R)=NR group with a nitrilium salt RCssNR .222 The acylation of the enamine can take place by the same mechanism as alkylation, but another mechanism is also possible, if the acyl halide has an a hydrogen and if a tertiary amine is present, as it often is (it is added to neutralize the HX given off). In this mechanism, the acyl halide is dehydrohalogenated by the tertiary amine, producing a ketene (7-14) which adds to the enamine to give a cyclobutanone (5-49). This compound can be cleaved in the solution to form the same acylated imine salt (27) that would form by the more direct mechanism, or it can be isolated (in the case of enamines derived from aldehydes), or it may cleave in other ways.223... 

Secondary amino compounds of the type R2N—H add to aldehyde and ketone carbonyl groups in an acid-catalyzed reaction in much the same way as do RNH2 compounds—with one important difference. The product contains the structural unit C=C—N rather than C—C—N and because there is a carbon-carbon double bond, such a substance is called an enamine (alkene + amine). An example is ... 

Reductive amination. Conversion of ketones or aldehydes to amines is usually accomplished by reduction of the carbonyl compound with sodium cyanoborohydride in the presence of an amine (Borch reduction, 4, 448-449). However, yields are generally poor in reactions of hindered or acid-sensitive ketones, aromatic amines, or trifluoromethyl ketones. Yields can be improved markedly by treatment of the ketone and amine first with TiCl4 or Ti(0-i -Pr)42 in CH2C12 or benzene to form the imine or enamine and then with NaCNBH3 in CH3OH to effect reduction. Note that primary amines can be obtained by use of hexamethyldisilazane as a substitute for ammonia (last example). 

Secondary amines react with ketones that contain an H atom in the a-position through an addition and subsequent El elimination to form enamines (Figure 9.29). In order for enamines to be formed at all in the way indicated, one must add an acid catalyst. In order for them to be formed completely, the released water must be removed (e.g. azeotropically). The method of choice for preparing enamines is therefore to heat a solution of the carbonyl compound, the amine, and a catalytic amount of toluenesulfonic acid in cyclohexane to reflux in an apparatus connected to a Dean-Stark trap. Did someone say Le Chateher ... 

Palladium, by far the most effective of platinum metals for isomerization, is also the most effective in this reaction. The isomerization involves not only tautomerization of an enamine to an imine, but additionally, isomerization of double bonds remote from the amine into a vinylic position. Platinum, ruthenium, and rhodium afford mixtures of less cyclo-hexanols and more dimethylcyclohexylamines (17). 

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