Reductions of Imines Using Zirconocene Chloride Hydride

Abstract

Herein, we describe the fast, chemoselective, and clean reduction of imines with zirconocene chloride hydride. The reaction works well on aromatic and enolizable aliphatic aldimines, as well as ketimines. A range of N-protecting groups and various functional groups were tolerated in the imine struc-

Stereoselective Amine Synthesis Mediated by a Zirconocene Hydride to Accelerate a Drug Discovery Program

“…Seeking a more practical solution, we took inspiration from an example using Zirconocene chloride hydride (Schwartz's reagent, initially reported by Wailes and Weigold) 19 reported by scientists at Sepracor Inc. (now Sunovion Pharmaceuticals Inc.) in a provisional patent application demonstrating a highly diastereoselective reduction of an alkyl sulfinyl ketimine at −20 °C in tetrahydrofuran. 20 Additionally, a report by S ̌ebesta and co-workers demonstrat- ing the reduction of sulfonyl imines using Schwartz's reagent in dichloromethane at room temperature provided additional support that this reactivity could be possible. 21 Gratifyingly, we found that the use of this highly oxophilic zirconium hydride (1.1 equiv) in the noncoordinating solvent dichloromethane provided a 77% isolated yield of our desired sulfinamide diastereomer 8 in >20:1 selectivity after just 1 hour at room temperature under an ambient atmosphere.…”

Are Organozirconium Reagents Applicable in Current Organic Synthesis?

“…While working on this project, the reducing properties of the Schwartz reagent (1) towards imines 77 were disclosed. 100 The employment of alkenylzirconium compounds 5 in 1,2-additions to C=X bonds has been widely studied, however, in the majority of cases, stoichiometric or catalytic transmetalation to other organometallics took place. As the alkenylzirconium species 5 were unreactive themselves, the hydrozirconation reaction was only employed to generate the organometallic reagent from alkynes that would not be otherwise accessible.…”

Deciphering the Unconventional Reduction of C═N Bonds by Old Yellow Enzymes Using QM/MM

“…The reduction of CX double bonds (with X = N or O) represents a fundamental and widely used transformation in synthetic chemistry and biocatalysis. − It provides an indispensable route to a broad range of complex organic compounds and, therefore, has wide-ranging applications in the synthesis of pharmaceuticals and agrochemicals, in environmental remediation and beyond. − Conventionally, the reduction of CX bonds proceeds through the transfer of a hydride ion to the less electronegative carbon atom, followed by a proton transfer to the more electronegative heteroatom X. This fundamental mechanistic understanding has played a significant role in shaping many synthetic and biocatalytic methods. − However, ene-reductases from the Old Yellow Enzyme (OYE) family offer a distinct perspective on this conventional understanding. Widely used for the asymmetric reduction of electronically activated CC double bonds, e.g., in α, β-unsaturated ketones, ,− these enzymes have also recently been demonstrated to catalyze the reduction of α-oximo β-ketoesters to the respective α-amino compounds via α-imine intermediates (as shown in Scheme for the conversion of ethyl-( Z )-2-(hydroxyimino)-3-oxopentanoate 1 ). , This OYE-catalyzed transformation is assumed to involve two “ping-pong” cycles. ,, The first phase involves the conversion of 1 to the respective α-imine intermediate 2 via hydride transfer and a dehydration reaction (Scheme a).…”