An efficient approach to chiral ferrocenyl ligands via asymmetric hydrogenation of ferrocenyl ketones

Abstract

Asymmetric hydrogenation is one of the most advanced industrial technologies to access chiral alcohols in consideration of its high S/C ratio, clean in process and slim in the cost of multi-steps of synthesis. In this project, a simple, efficient and highly enantioselective method for the synthesis of enantiomerically pure ferrocenyl alcohols has been developed. We found that (R)-Xylyl-P-PhosRuCl2(R,R)-DPEN was the most efficient precatalyst for the hydrogenation of ferrocenyl ketones to the corresponding ferrocenyl alcohols. The best result of 99.3% ee with full conversion was obtained in the hydrogenation of acetylferrocene. The reaction can be easily upgraded to industrial entry level with S/C ratio of 100,000 and the conversion completed in 48 hours without deterioration of enantioselectivity. Starting from optically pure ferrocenyl alcohols, new ferrocenyl ligands were easily synthesized via three steps and used for screening different asymmetric catalysis. Ru-Complexes of these ferrocenyl ligands and diamine or diphosphine ligands were firstly selected for catalyzing hydrogenation of acetophenone. The diamine-Ru-complexes have better enantioselectivity in comparison with diphosphine-Ru-complexes. The catalysts prepared from ferrocenyl ligands with DPEN gave hydrogenation product with up to 68.7% ee and complete conversion. Matching and mismatching effect were observed. The BINAP-Ru-complexes exhibited high activity regardless of the presence of N-methyl substituent on hydrogenation of acetophenone although preliminary results in enantioselectivity were poor. Presence of non-substituted amine on ferrocenyl ligand significantly reduced the activity in P-Phos-Ru-complexes. Our results showed that N-methyl substituent on the ligand is crucial for the control of product's configuration in the diphosphine Ru-complexes. In addition, our ferrocenyl ligands were also active in asymmetric allylic alkylation and gave products with up to 88.7% ee. The product's configuration and enantioselectivity were controlled by structure of the N-alkyl group and alkyl group on central chirality of ferrocenyl ligand as they determined the conformational structure of the pi-allylpalladium intermediate. The ferrocenyl ligand in the presence of t-butyl amine and phenyl group a-stereogenic center provided the highest enantioselectivity in catalyzed allylic alkylation under optimized reaction condition.