Nickel-Catalyzed Addition of Aryl Bromides to Aldehydes To Form Hindered Secondary Alcohols

Abstract

Transition-metal-catalyzed addition of aryl halides across carbonyls remains poorly developed, especially for aliphatic aldehydes and hindered substrate combinations. We report here that simple nickel complexes of bipyridine and PyBox can catalyze the addition of aryl halides to both aromatic and aliphatic aldehydes using zinc metal as the reducing agent. This convenient approach tolerates acidic functional groups that are not compatible with Grignard reactions, yet sterically hindered substrates still couple in high yield (33 examples, 70% average yield). Mechanistic studies show that an arylnickel, and not an arylzinc, adds efficiently to cyclohexanecarboxaldehyde, but only in the presence of a Lewis acid co-catalyst (ZnBr 2 ).

Nickel Catalyzed Intermolecular Carbonyl Addition of Aryl Halide

“…Weix's pioneering work on the reductive arylation of carbonyl compounds proposed that the reaction mechanism involved the 1,2‐migratory insertion of aryl groups into carbonyl groups to either form alkoxy‐Ni II intermediates or directly release the product . To confirm this, we performed several control experiments (Scheme ) by comparing aldehydes bearing electron withdrawing groups ( 1h ) with those bearing electron donating groups ( 1d ) (Equ.…”

“…We tried a NiCl 2 catalyst with a zinc reductant in the presence of HN i Pr 2 , (PhO) 2 PO 2 H, and sodium iodide in n ‐hexane at 95 °C for 7 h, obtaining the desired reductive coupling product but with poor yields (Table , entry 1). Further, we examined diimine‐type ligands, which had been used in a previously developed nickel‐catalyzed reductive coupling reaction (entries 2–9) , , . Combining a nickel salt with a series of diamine‐type ligands produced the corresponding secondary alcohol 3aa , particularly with normal bipyridyl and 4‐dimethylamino bipyridyl ligands, gives higher yields (entries 4 and 7).…”

“…In the reductive coupling chemistry field, there have been a few reports of a surprising process for the intermolecular addition of aryl halides to aldehydes via transition‐metal catalysis , . Although several methods have been proposed for the reductive arylation of carbonyls based on pioneering work, the idea of nickel‐catalyzed reductive arylation of aldehydes remains underdeveloped …”

Electrochemical Arylation of Aldehydes, Ketones, and Alcohols: from Cathodic Reduction to Convergent Paired Electrolysis

“…Reductive arylation of aldehydes or ketones has emerged as an alternative approach to access secondary or tertiary alcohols with transition-metal catalysis or photocatalysis strategies. [3][4][5] Fori nstance,n ickel and rhodium-catalyzed reductive coupling reaction of aldehydes with aryl halides have been reported by Weix and Krische,r espectively [4b,c] (Scheme 1b). With regards to photocatalytic reactions,X ia and Wu developed independently ar eductive arylation of aldehydes and ketones using iridium catalysts (Scheme 1c).…”

Nickel-Catalyzed Reductive Coupling of Unactivated Alkyl Bromides and Aliphatic Aldehydes

“…[4][5][6] Net reductive couplings using organohalide feedstocks have been developed using stoichiometric reductants to achieve catalytic activity, obviating the need for pre-generation of the organometallic nucleophile. [7][8][9][10][11][12][13] Among the most common systems are Rh 7 , Ni 8,11,14,15 and Cr [16][17][18][19][20][21] -catalyzed couplings of aldehydes and organohalides. Importantly, each of these systems are proposed to proceed via Grignard-type mechanisms, generating organometallic nucleophiles that undergo formal additions to carbonyl electrophiles.…”