Rhodium-Catalyzed Asymmetric Hydroformylation of Vinyl Ethers as a Key Step in the Synthesis of Chiral Fine Chemicals

Abstract

The rhodium-catalyzed asymmetric hydroformylation (AHF) of vinyl ethers provides a powerful synthetic step to yield chiral aldehydes as products or intermediates for industrially relevant fine chemicals. Out of the 40 chiral ligands tested, the phosphine-phosphorodiamidite (S,S,RP,S)-BettiPhos L7 and the phosphine-phosphoramidite ligand L6 performed best in this transformation, combining high activity, regio- and enantioselectivity. Branched 2-aryloxypropionaldehydes (16 examples) were obtained with b/l-ratios ranging from 3.1:1 to exclusive branched products, and with enantioselectivities between 79 and 94% ee. Interestingly, for these substrates, the selective decomposition of the linear aldehydes to the respective arenols and acrolein via β-hydride elimination was observed. Branched 2-alkyloxypropionaldehydes (3 examples) were obtained with fair b/l-ratios (1.7:1–2.6:1) and good to high enantioselectivities (85–95% ee). The utility of this transformation was demonstrated by synthesizing the commercial herbicide (R)-Mecoprop on a gram scale in 69% yield and 91% ee via hydroformylation of 4-chloro-2-methyl-1-(vinyloxy)benzene, followed by oxidation. The catalytic system could also be used under slightly modified reaction conditions for reductive asymmetric hydroformylation to produce in one-pot chiral 2-aryloxypropanols. The synthetic potential was further explored by applying the tandem asymmetric hydrohydrazonemethylation (AHHM) followed by reduction, yielding γ-chiral N′-substituted acetohydrazides as shown for 6 examples. Hydrogenolysis of the crude product mixtures results in the corresponding chiral primary amines, as demonstrated in the synthesis of 2-phenoxypropanamine from (vinyloxy)benzene with an overall yield of 74% and 94% ee on a gram scale. Moreover, another tandem reaction—specifically, the asymmetric hydrosulfiniminomethylation (AHSM)—enables access to halogen-containing chiral primary amines, as demonstrated by the synthesis of 2-(4-chlorophenoxy)propanamine in an overall yield of 53% and >99% ee.