Rhodium-Catalyzed Asymmetric Hydrohydrazonemethylation of Styrenes: Access to Chiral Hydrazones, Hydrazides, Hydrazines and Amines

The catalytic asymmetric hydroformylation of styrenes was combined with condensation of the resulting aldehydes with acetohydrazide as nucleophile leading to gamma-chiral N'-substituted acetohydrazones. This cascade reaction is called hydrohydrazonemethylation (HHM) in analogy to similar hydroformylation/condensation sequences. The catalyst was formed in situ from the commercially available chiral phosphine-ligand (R,R)-Ph-BPE and [Rh(acac)(CO)(2)] and used at a loading of 0.2 mol%. The stable condensation products are not prone to tautomerization providing versatile chiral intermediates. Their one-pot reduction with DMAB/TsOH resulted in the corresponding gamma-chiral N'-substituted acetohydrazides (14 examples) with yields ranging from 73% to 91% and enantioselectivities from 77% to 97% ee. Deprotection of the acetohydrazides led to the corresponding beta-chiral hydrazines. Reduction and hydrogenolysis of the hydrazones over Raney-Ni yielded the corresponding beta-chiral primary amines with 95% ee. Diastereoselective functionalization of the C=N bond of the hydrazones is a further synthetic option, as demonstrated by allylation with (allyl)SiCl3.

Automated summary

The catalytic asymmetric hydroformylation of styrenes was combined with condensation of the resulting aldehydes with acetohydrazide as nucleophile, producing gamma-chiral N'-substituted acetohydrazones. This cascade reaction, called hydrohydrazonemethylation (HHM), was achieved using a commercially available chiral phosphine-ligand and [Rh(acac)(CO)(2)] as catalysts. The stable condensation products provided versatile chiral intermediates, which can be further reduced to obtain gamma-chiral N'-substituted acetohydrazides and beta-chiral hydrazines.