Reduction of imines and enamines

Hydrogen telluride, sodium hydrogen telluride as well as phenyltelluroP afford the reduction of imines to secondary amines. 

In the reduction of imines and enamines with hydrogen telluride and sodium hydrogen telluride, hydrolysis leading to primary amines and carbonyl compounds is frequently competitive with the reduction. This undesired side reaction is minimized by the addition of triethylamine, in the case of hydrogen telluride.  

Control of the pH to within the 6-7 range has been shown to be important in the reduction of imines with sodium hydrogen telluride. At a higher pH (10-11) no reduction occurs.  

A valuable application of the above-described reduction is the one-step reductive alkylation of amines with carbonyl compounds.  

Good yields of secondary amines are achieved using both the methods in the reactions of aromatic and aliphatic aldehydes as well as of diaUcyl ketones and cycloalkanones with aliphatic and alicyclic amines (and ammonia). Anilines give low yields, but when 2 equiv is used in the sodium hydrogen telluride method, the yields are improved. In the reaction of ammonia with aldehydes, symmetrical secondary amines are obtained, whereas glu-taraldehyde and amines lead to N-substituted piperidines. 

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Reductions of imines and enamines with metal hydrides including boron, silicon, tin, and tellurium have been reviewed. ... 

A very interesting FLP catalyst design was recently disclosed by Repo, Rieger and co-workers [38], Coined the ansa-aminoborane [39] FLP catalyst, it is based on the use of amines instead of phosphines as the Lewis basic component (Scheme 6.19). This catalyst is also active in 10 mol% quantities for the reduction of imines and enamines. The X-ray structure of the ansa-catalyst is illustrated below (Fig. 6.6). 

The spiro compound 206 was prepared in five steps from (S)-l-naphthyl-ethylamine and was composed of a mixture of imine and enamine tautomers. Reduction of the imine function by sodium borohydride occurred on the less hindered si face, leading to the diamine with the R configuration of the newly formed stereo center, then the N-benzyl substituent was removed by hydrogenolysis to give 207 with good overall yield [98] (Scheme 30). 

TiCl4 also effectively promotes formation of imines and enamines from carbonyl compounds (Scheme 31). The combination of imine formation using TiCl4 and reduction leads to reductive alkylation of an amine moiety.113,114... 

The catalysts are Tim hydrides which are generated in situ by reduction of enantio-merically pure L TiCl2 with butyllithium and PhSiH3 they are also highly effective in the asymmetric hydrogenation of imines and enamines.20 The lutetium ansa-metallocene complex (22-XVII) catalyzes the deuteration of 1-pentene (63% e.e.)21 Related samarium compounds hydrogenate imines.22... 

Chirally pure benzylic amines have been used extensively as chiral auxiliaries in drug diseovety. Their reactivity towards ketones means they can readily be used for the formation of imines and enamines which can undergo subsequent asymmetrie reductions. 

Abstract Aldehydes obtained from olefins under hydroformylation conditions can be converted to more complex reaction products in one-pot reaction sequences. These involve heterofunctionalization of aldehydes to form acetals, aminals, imines and enamines, including reduction products of the latter in an overall hydroaminomethylation. Furthermore, numerous conversions of oxo aldehydes with additional C.C-bond formation are conceivable such as aldol reactions, allylations, carbonyl olefinations, ene reactions and electrophilic aromatic substitutions, including Fischer indole syntheses. 

Imines and enamines under hydroformylation conditions can also be reduced to give saturated amines. With or without additional reduction, these conversions can be used in synthesis of various types of heterocycles. 

In all of these reactions, a nucleophile adds to a positively polarized carbonyl carbon to form a tetrahedral intermediate. There are three possible fates for the tetrahedral intermediate (1) The intermediate can be protonated, as occurs in Grignard reactions, reductions, and cyanohydrin formation. (2) The intermediate can lose water (or OH), as happens in imine and enamine formation. (3) The intermediate can lose a leaving group, as occurs in most reactions of carboxylic acid derivatives. 

List and coworkers developed an excellent approach to synthesize p branched amines in optically active forms by combining the enamine and reductive amination processes (Scheme 3.45) [96]. The reductive amination of unsymmetrically a,a disubstituted aldehydes and aniline derivatives proceeded through a tautomerization between imine and enamine forms. Dynamic kinetic resolution occurred under the... 

The first hypothesis of an in-situ reduction of acetonitrile and propionitrile in the presence of 1 to 4 and 5 suggested that one might be able to use this approach as a new synthetic route to this class of heterocyclics. Hexahydropyrimidines are conventionally prepared by condensation of aldehydes or ketones with 1,3-diamines (4). Water is a by-product in these reactions and must be removed either to favor the imine or enamine equilibrium or for product purification. Generally, the condensation is acid or base catalyzed and run in solvents (6). In some cases... 

Aldehydes and ketones react with primary amines to form imines and with secondary amines to form enamines. The mechanisms are the same, except for the site from which a proton is lost in the last step of the reaction. Imine and enamine formation are reversible imines and enamines are hydrolyzed under acidic conditions back to the carbonyl compound and amine. A pH-rate profile is a plot of the observed rate constant as a function of the pH of the reaction mixture. Hydroxide ion and heat differentiate the Wolff-Kishner reduction from ordinary hydrazone formation. 

The ability to reduce compounds under acidic conditions is ideal for the reduction of enamines. Protonation of nitrogen gives an iminium salt in acidic media that is then reduced with cyanoborohydride to an amine.Imines can be reduced in acidic media in the presence of many other functional groups, as shown by Cook s reduction of imine 165 to give 166 in 79% yield in a synthesis of substituted tetrahydro-P-carbolines. 2 This reagent is excellent for the reduction of iminium salts at neutral pH as well,l 3 and it is also useful for the reductive alkylation of amines. Dimethylamino derivatives such as 168 can be prepared from the amine (167 in this case) by treatment with formaldehyde and cyanoborohydride, even in the presence... 

Reduction of Enamines. The reduction of enamines with NaBHsCN under acidic conditions proceeds via an iminium ion, similar to that seen in the reduction of imines. Examples, such as the reduction of an enamine-fulvene to the corresponding amine target (eq 45) and the reduction of the enamino-butenolide to the expected lactone (eq 46), are abundant in the current literature. 

Reductive amination the imines and enamines formed from the reaction of aldehydes and ketones with ammonia and primary and secondary amines are reduced to primary, secondary, and tertiary amines (Section 17.10). 

This strategy has been extended by Maikov and Kocovsky to the reduction of imines/enamines derived from a-substituted P-keto nitriles and P-keto esters (Scheme 15.27, 131-134, H) [97dj. In this case, the fast enamine-imine... 

After great success in the reduction of imines, quinolines, and pyridines. Rueping et al. designed a chiral phosphoric acid-catalyzed cascade reaction, in which enamines and enones are heated with Hantzsch ester la and (R)-6, then a Michael addition, cyclization, isomerization and hydride transfer reaction take place successively to afford chiral tetrahydropyridine 59 and azadecaUnone 60 products in excellent enantioselectiYities (Scheme 32.11) [33]. Remarkably,... 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

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