A Metal‐Free Transfer Hydrogenation: Organocatalytic Conjugate Reduction of α,β‐Unsaturated Aldehydes (2004)

Impressive tolerance is displayed in the efficient and chemoselective organocatalytic transfer hydrogenation of α,β-unsaturated aldehydes in the presence of a Hantzsch dihydropyridine and a catalytic amount of dibenzylammonium trifluoroacetate (see scheme). Various sensitive functional groups such as the nitro, cyano, alkenyl, and benzyloxy groups survive these reaction conditions. Hydrogenations of double-bond-containing compounds such as carbonyls, imines, and olefins are crucial for living organisms as well as for the industrial production of chemicals. While chemical hydrogenations require metal catalysts or the use of stoichiometric amounts of metal hydrides, nature typically relies on organic cofactors such as nicotinamide adenine dinucleotide (NADH) in combination with metalloenzymes. Metal-free catalytic hydrogenations of olefins have been unknown both in nature and in chemical synthesis.1 Herein we disclose a highly efficient and remarkably chemoselective but completely metal-free catalytic transfer hydrogenation of α,β-unsaturated aldehydes. The hydrogenation of α,β-unsaturated carbonyl compounds is a useful but challenging transformation. As both 1,2- and conjugate reductions readily occur, low selectivity for either of the two pathways is common. Catalytic hydrogenations of α,β-unsaturated aldehydes are possible, but the chemoselectivity is often low, and additional functional groups that are sensitive to hydrogenation conditions such as the benzyloxy, nitro, and nitrile groups are usually not tolerated.2 Alternative conjugate reductions have been realized with various substrate classes,3 but a mild, general, highly chemoselective, and catalytic variant that is applicable to α,β-unsaturated aldehydes has not been described. Reported conjugate reductions of aldehydes are either noncatalytic and require stoichiometric amounts of an (organo)metallic hydride source,4 require elevated temperatures,5 or show only modest selectivity.6 Clearly, a mild, catalytic, and highly chemoselective variant is highly desirable. Recently iminium catalysis emerged as a powerful method for the asymmetric catalysis of cycloadditions and conjugate additions to enals and enones.7 We reasoned that this catalysis strategy might be applicable to the conjugate reduction of α,β-unsaturated carbonyl compounds if a suitable hydride donor could be identified.8 Such a process would constitute the first metal-free catalytic transfer hydrogenation. Entry Catalyst 2 Yield [%] 1 1 2 a 94 2 1 2 b 65 3 1 2 c 81 4 1 2 d 92 5 1 2 e 90 6 1 2 f 35 Entry Substrate Product Yield [%][a] 1 1 1 94 2 1 1 96 3 1 1 93 4 1 1 81[b] 5 1 1 92 6 1 1 92 7 1 1 92[c] 8 1 1 90 9 1 1 94 10 1 1 90[b,c] 11 1 1 86[b,c] 12 1 1 92 In terms of the mechanism we assume the reaction to proceed by the iminium catalysis cycle illustrated in Scheme 1. Accordingly, after an initial reversible formation of iminium ion 5 (which effectively lowers the LUMO energy of the substrate), conjugate hydride and proton transfer from dihydropyridine 1 follows. This step generates pyridine 7 along with iminium ion 6. Hydrolysis then releases saturated aldehyde product 4 and regenerates catalyst 2 a. We suggest the hydride transfer to proceed via transition state A. Proposed mechanism of iminium catalysis. In summary, we have developed the first metal-free catalytic transfer hydrogenation. This novel iminium catalytic conjugate reduction of α,β-unsaturated aldehydes is highly efficient and chemoselective. It requires low catalyst loadings and tolerates various functional groups that are sensitive to the conditions of standard hydrogenations and alternative conjugate reductions. Current work in our laboratory focuses on a) expanding the scope of the reaction even further to include other substrate classes such as ketones and α-substituted α,β-unsaturated aldehydes, b) improving the overall atom economy, potentially by regeneration of the cofactor in situ,12 c) including the reaction in tandem sequences utilizing the presumed enamine intermediate,13 and d) developing an efficient catalytic asymmetric variant. First results will be reported shortly. General procedure for the transfer hydrogenation reaction: Synthesis of aldehyde 4 a: To a solution of o-nitrocinnamaldehyde (3 a, 88.6 mg, 0.5 mmol) and catalyst 2 a (7.8 mg, 0.025 mmol, 5 mol %) in dry THF (2 mL) was added dihydropyridine 1 (140 mg, 0.55 mmol, 1.1 equiv). The reaction mixture was stirred at room temperature for 5 h under argon, after which the solvent was removed and the residue was chromatographed on silica gel (30 % diethyl ether/n-hexane) to give 84 mg (94 %) of 4 a as an oil. All aldehydes 3 and 4 are commercially available or have been described previously, and their analytical data match literature values.