Development of a Stepwise Reductive Deoxygenation Process by Ru‐Catalysed Homogeneous Ketone Reduction and Pd‐Catalysed Hydrogenolysis in the Presence of Cu Salts

Abstract

A stepwise catalytic reduction of ketone 1 to alcohol 2 and subsequently to aryl(imidazo[1,2‐b]pyridazinyl)methane 3 is described, which provides synthetically useful chemoselectivity at acceptably low catalyst loadings. Undesired reactive sites include an aryl chloride, heteroarylchloride and benzylic amine group. The presence of these functional groups presents a significant challenge to chemoselectivity for both reduction steps. For selective CO reduction of highly functionalised 1, high chemoselectivity was observed at low catalyst loading by using Wills’ tethered Ru transfer‐hydrogenation catalyst 13. The selective hydrogenolysis of 2 was then accomplished under acidic hydrogenation conditions by using a Pd/C catalyst in the presence of Cu salts. This procedure has been demonstrated on a multi‐gram scale, which makes this approach a viable method to use a combination of homogeneous and heterogeneous catalysis.

Photoredox Catalysis in a Complex Pharmaceutical Setting: Toward the Preparation of JAK2 Inhibitor LY2784544

“…The next step in the synthesis of LY2784544 after 2 is the carbonyl reduction giving 27 , a transformation that required significant investigation. 33 The formation of the key benzylic morpholine unit from 26 would therefore offer the attractive prospect of eliminating the carbonyl reduction sequence. Additionally the reactivity of 26 , albeit moderate, suggested the intriguing possibility of extending this reaction to less activated heterocycles.…”

“…Furthermore, while no reaction was observed on the parent heterocyclic core 28 without substitution at the C-3 position, the benzylic imidazopyridiazine 26 gave a low isolated 14% yield of the exo product 27 . The next step in the synthesis of LY2784544 after 2 is the carbonyl reduction giving 27 , a transformation that required significant investigation . The formation of the key benzylic morpholine unit from 26 would therefore offer the attractive prospect of eliminating the carbonyl reduction sequence.…”

The Development of Phosphine‐Free "Tethered" Ruthenium(II) Catalysts for the Asymmetric Reduction of Ketones and Imines

“…However, a successful route was developed by Eli Lilly in collaboration with Johnson Matthey using an achiral tethered catalyst derivative22 in the first step to form intermediate alcohol 37 . This was followed by a carefully optimized hydrogenolysis in the second step (Figure ) 58. As little as 0.01 mol% of the achiral catalyst was required in the first reduction; ammonium formate was conveniently used as the reducing agent.…”

Hydrogen

“…58 Selected examples include high-yielding multigram global debenzylation of a fully protected procyanidin species (eq 24); 59 and multikilo 1 Stepwise reductive deoxygenation of a benzylic ketone has been achieved using a Ru-catalyzed transfer hydrogenation to give the alcohol, followed by Pd-catalyzed alcohol hydrogenolysis to furnish the methylene species, which was an intermediate to an experimental JAK-2 inhibitor (eq 26). 65 An interesting related application is shown below (eq 27), in which the reduction of a benzyl alcohol results in selective deuteration of the resulting toluic acid derivative. 66 Amine functions are often protected using benzyloxycarbonyl (Cbz or Z) groups and these can be readily cleaved by transition metal-catalyzed (usually Pd) hydrogenolysis, leading to cleavage of the C-O bond of the benzylic species, revealing a carbamic acid that spontaneously decomposes releasing the amine.…”