Diastereoselective Reformatsky Reaction Mediated by Dichlorocyclopentadienyltitanium(III)

The Reformatsky reaction, first reported in 1887, has long been recognized as a fundamental method for carbon-carbon bond construction due to its mild conditions and functional group tolerance. Over the past few decades, this transformation has undergone a notable revival, with modern catalytic variants addressing limitations of stoichiometric protocols and expanding its role in complex molecule synthesis. Yet, despite its versatility, achieving stereoselective control remains a longstanding challenge. Herein we report the use of dichlorocyclopentadienyltitanium(III) (CpTiCl₂), generated in situ from CpTiCl₃ and manganese, as an efficient catalyst for Reformatsky-type couplings of aldehydes with α-haloesters and α-iodonitriles. Under mild conditions, CpTiCl₂ promotes the formation of β-hydroxy esters in high yields and with significant diastereoselective preference for the <i>syn</i> isomer (up to 100:0 <i>syn:anti</i>). This behavior contrasts sharply with the poor or <i>anti</i>-selective outcomes previously observed with titanocene(III) chloride (Cp₂TiCl). Mechanistic analysis suggests that the unique steric and electronic environment of CpTiCl₂-characterized by enhanced Lewis acidity and increased coordination vacancies-favors a Zimmerman-Traxler-type transition state that enforces <i>syn</i> stereocontrol. The methodology tolerates a wide variety of substrates, including aliphatic and aromatic aldehydes as well as α-iodonitriles, extending the scope of titanium-mediated Reformatsky chemistry. These findings establish CpTiCl₂ as a sustainable, selective, and robust organotitanium catalyst for stereoselective carbon-carbon bond formation, providing a promising alternative to the Nugent reagent and paving the way for new applications in complex molecule synthesis.