Enamine hydrogenation

The first example of this type of transformation was reported in 1974 [76]. Three catalysts were investigated, namely [Co2(CO)8], [Co(CO)g/PBu ], and [Rh6(CO)i6]. The [Co OJg/PBu ] catalyst showed activity for reductive animation using ammonia and aromatic amines. The [Rh6(CO)16] catalyst could be used for reductive animation using the more basic aliphatic amines that were found to poison the cobalt catalyst. This early report pointed out that the successful reductive animation of iso-butanal (Me2CCHO) with piperidine involves selective enamine hydrogenation, that reductive animation of cyclohexanone with isopropylamine probably involves imine hydrogenation, and that reductive amination of benzaldehyde with piperidine would presumably involve the reduction of a carbinolamine. 

Despite the remarkable enantioselectivities observed with the Ti-ebthi catalyst for the imine and enamine hydrogenation, we consider its technical potential rather low. The ligand is difficult to prepare, the activation of the catalyst precursor is tricky, for the moment the catalytic activity is far too low for preparative purposes, and last - but not least - its tolerance for other functional groups is low. 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

Table 6.14 Asymmetric enamine hydrogenation using [L"lr(COD)] [BArr] catalysts.

Hydrogenation of olefins, enols, or enamines with chiral tVilkinson type catalysts, e.g., Noyort hydrogenation. Hydroboration of olefins with chiral boranes. Sharpless epoxi-dation of allylic alcohols. 

The direct connection of rings A and D at C l cannot be achieved by enamine or sul> fide couplings. This reaction has been carried out in almost quantitative yield by electrocyclic reactions of A/D Secocorrinoid metal complexes and constitutes a magnificent application of the Woodward-Hoffmann rules. First an antarafacial hydrogen shift from C-19 to C-1 is induced by light (sigmatropic 18-electron rearrangement), and second, a conrotatory thermally allowed cyclization of the mesoionic 16 rc-electron intermediate occurs. Only the A -trans-isomer is formed (A. Eschenmoser, 1974 A. Pfaltz, 1977). 

Two synthetic bridged nitrogen heterocycles are also prepared on a commercial scale. The pentazocine synthesis consists of a reductive alkylation of a pyridinium ring, a remarkable and puzzling addition to the most hindered position, hydrogenation of an enamine, and acid-catalyzed substitution of a phenol derivative. The synthesis is an application of the reactivity rules discussed in the alkaloid section. The same applies for clidinium bromide. 

This genera] scheme could be used to explain hydrogen exchange in the 5-position, providing a new alternative for the reaction (466). This leads us also to ask whether some reactions described as typically electrophilic cannot also be rationalized by a preliminary hydration of the C2=N bond. The nitration reaction of 2-dialkylaminothiazoles could occur, for example, on the enamine-like intermediate (229) (Scheme 141). This scheme would explain why alkyl groups on the exocyclic nitrogen may drastically change the reaction pathway (see Section rV.l.A). Kinetic studies and careful analysis of by-products would enable a check of this hypothesis. 

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. 

Synthesis of the title compound is representative of a number of syntheses of nonaromatic nitrogen heterocycles via Pd(Ill-catalyzed amination of olefins. These tosylated enamines are not readily available by standard synthetic methods, and show potential for further functionalization of the heterocycle. The saturated amine can be synthesized from the title compound by hydrogenation of the double bond followed by photolytic deprotection. ... 

Systems usually fluonnated by electropositive fluorine reagents include acti-vated alkenes (enol ethers, enol acetates, silyl enol ethers, and enamines), activated aromatic systems, certain slightly activated carbon-hydrogen bonds, and selected organometallics. 

Johnson and Whitehead have further shown that the reductive elimination of the pyrrolidine group from the pyrrolidine enamine of 2,4-dimethyl-cyclohexanone (16), which involved treating it with a mixture of lithium aluminum hydride and aluminum chloride (9), gave the trans isomer of 3,5-dimethyl-/l -cyclohexene (17) which on subsequent hydrogenation on a platinum catalyst led to the // onr-3,5-dimethylcyclohexane (18). 

The presence of 1,3-diaxial interaction between the C-2 alkyl group and the C-4 axial hydrogen atom is reflected in the rate of enamine formation of 2-substituted cyclohexanone. It has been shown by Hunig and Salzwedel (20) that even under forcing conditions, the yield of pyrrolidine and morpholine enamines of 2-methylcyclohexanone does not exceed 58%, whereas the C-2 unsubstituted ketones underwent enamine formation under rather milder conditions in better than 80 % yield. 

Malhotra et al. (5pyrrolidine enamine of 3-methyl-cyclohexanone, prepared under equilibrating conditions, is a 3 7 mixture of A and A isomers (67 and 68) on the basis of NMR spectral data. The preponderance of the A isomer in the mixture was attributed to strain between the equatorial methyl group and the vinylic hydrogen atom... 

Interestingly the pyrrolidine enamine of 3-t-butylcyclohexanone (41) consists of a 3 2 mixture of A and A isomers (79 and 80). The preference for the A isomer in this case is due to the relief of two of the four skew butane interactions, which are present in the isomer. The A isomer, owever, contains two additional interactions, i.e., one modified skew utane interaction 0.4 kcal/mole (42) and one interaction between c C-2 vinylic hydrogen atom and the ethyl portion of the t-butyl group hich is pointed toward it. 

Information regarding the position of the substituents can be obtained from the mass spectra of the enamines of cyclic ketones. For instance in the case of the morpholine enamine of 3-methylcyclohexanone, which is shown to be a 2 1 mixture of/ and isomers by NMR spectroscopy, the fragmentation of the radical ion from the /) isomer results in the loss of a methyl radical from the C-3 position. The d isomer gives a complicated spectrum due to the loss of the hydrogen radical. 

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