Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes

Abstract

The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.Cross-coupling reactions have revolutionized the landscape of carbon-carbon bond construction, with extensive application in the synthesis of natural products, pharmaceuticals, agrochemicals, and functionalized polymers. 1 Coupling of Grignard or organolithium reagents with carbonyl compounds remains among the most frequently used synthetic reactions (Figure 1A), 2 although limitations exist due to the instability, basicity, and lack of functional group compatibility of the requisite highly nucleophilic reagents. Barbier-type reactions 3 and Nozaki-Hiyama-Kishi (NHK) 4 couplings are attractive as they avoid the handling of air-and moisture-sensitive organometallic reagents, and have been employed in many complex settings, 5 although the reaction scope is often limited in cases where sp 3 alkyl fragments are added to aliphatic enolizable aldehydes.An attractive approach to deliver organohalide feedstocks to carbonyl compounds that obviates the need for preformed organometallic reagents are transition-metal-catalyzed reductive coupling reactions. 6 To date, the coupling of aldehydes with organohalides using a stoichiometric reducing agent can be catalyzed by Cr, 7 Rh, 8 Co, 9 and Ni, 10 but current systems are often restricted to aryl, allylic or propargylic halides and aromatic aldehydes. The catalytic transformation of aliphatic aldehydes with less-activated sp 3 counterparts remains a synthetic challenge. 7c-e,11 Aliphatic aldehydes often exhibit attenuated reactivity, and competing enolization reactions lead to side product formation. 10d Additionally, compared with sp 2 -hybridized halides, unactivated alkyl halides are less suitable coupling partners due to lower reactivity and undesirable side pathways such as homocoupling or competing b-H eliminations of reactive intermediates. 12 The wide availability of alkyl carboxylic acids makes this substrate class an attractive coupling partner for processes of this type. 13 In recent studies, Baran, Weix, and others have extensively explored the utility of redox-active esters (RAEs), as a carboxylic acid-derived radical precursors in a variety of carbon-carbon and carbon-heteroatom bon...

Deoxygenative Cross-Coupling of C(aryl)–O and C(amide)═O Electrophiles Enabled by Chromium Catalysis Using Bipyridine Ligand

“…In the reaction with 2a , Mg and TMSCl, the oxo-electrophile coupling motif 3a can be formed. As shown in Scheme b, by the reaction with Mg and TMSCl, the silachromate of (dmbpy)Cr(Naph)(TMS) IN2 was detected . Upon reaction with amide, the addition of silachromate to carbonyl occurred to afford alkylated Cr intermediate IN3 , which was detected by HRMS analysis, as well as the related silyloxy compound IN4 , formed by reductive elimination during the oxo-electrophile coupling between C–O and CO bonds (Scheme b).…”

α-Branched amines through radical coupling with 2-azaallyl anions, redox active esters and alkenes

“…Before initiating our investigation, reaction conditions used in 2-azaallyl coupling reactions, 19,42 alkene functionalization reactions 75,76 and reductive activation of RAEs 60,77–82 were studied. Based on these works, Ni(COD) 2 was selected as the metal source, 33 DIPEA as base, 31,59,69,83 THF/DMF as solvent (4 : 1, based on literature precedence 50,51,84 ).…”

Recent Progress on Transition-Metal-Mediated Reductive C(sp3)–O Bond Radical Addition and Coupling Reactions

“…Montgomery has illustrated a Ni-catalyzed coupling of aldehydes with alkyl NHP-esters, alkyl tosylates and epoxides (Scheme 25). 55 The latter two electrophiles may involve alkyl halides generated from in situ halide exchange and epoxide ring opening due to the presence of excess NaI. Under reductive conditions, an α-silyloxy alkyl-Ni II intermediate is possibly generated that can be reduced to an alkyl-Ni I species.…”