Direct Aldehyde C–H Arylation and Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis

Abstract

A mechanism that enables direct aldehyde C–H functionalization has been achieved via the synergistic merger of photoredox, nickel, and hydrogen atom transfer (HAT) catalysis. This mild, operationally simple protocol transforms a wide variety of commercially available aldehydes, along with aryl or alkyl bromides, into the corresponding ketones in excellent yield. This C–H abstraction coupling technology has been successfully applied to the expedient synthesis of the medicinal agent haloperidol.

The Persistent Radical Effect in Organic Synthesis

“…Along these lines, MacMillan introduced quinuclidine as an efficient mediator (Figure a). Quinuclidine reduces Ni I by Ir photoredox catalysis, and the resulting ammonium radical cation abstracts an H‐atom in α‐position to nitrogen, oxygen, or an aldehydic H atom . The thus generated C radicals then engage in Ni‐mediated cross‐couplings according to the general mechanism depicted in Figure a.…”

Asymmetric Synthesis of 1,4‐Dicarbonyl Compounds from Aldehydes by Hydrogen Atom Transfer Photocatalysis and Chiral Lewis Acid Catalysis

“…Thea cyl radical I is generated smoothly by ap olarity-matched HAT [27] between photo-activated *eosin Yand an aldehyde.R adical I in turn adds to N,O-rhodium-coordinated N-acyl pyrazole substrate II to produce the secondary radical intermediate III,w hich subsequently undergoes reverse HATwith eosin Y-Htoturn over the HATc atalytic cycle.L igand exchange between intermediate IV and the starting unsaturated amide delivers the chiral product and regenerates the active complex II. Thea cyl radical I is generated smoothly by ap olarity-matched HAT [27] between photo-activated *eosin Yand an aldehyde.R adical I in turn adds to N,O-rhodium-coordinated N-acyl pyrazole substrate II to produce the secondary radical intermediate III,w hich subsequently undergoes reverse HATwith eosin Y-Htoturn over the HATc atalytic cycle.L igand exchange between intermediate IV and the starting unsaturated amide delivers the chiral product and regenerates the active complex II.…”

“…Secondary alkyl aldehydes,e ither acyclic (13)o rc yclic (14,15), were viable coupling partners.C ompound 16,amasked aldehyde,was synthesized in good yield (73 %) with excellent enantioselectivity (98 %) by using readily available 1,3dioxolane as the solvent. Cyclic ethers such as tetrahydrofuran (THF) and Entry Deviation from standard conditions [a] Yield [%] [b] ee [%] [c] 1w ithout L-Rh < 5r acemic 2w ithout neutral eosin Y < 58 7 3n one 52 (50) [ 2-methyl tetrahydrofuran delivered products 23 and 24 with excellent enantioselectivity.B oth acyclica nd cyclic tertiary amines were good candidates for this asymmetric transformation, which provided effective and convenient method direct access to chiral g-aminoacid skeletons (25)(26)(27). However,all electron-neutral (17), electron-rich (18,19), and electron-deficient (20,21)aryl aldehydes proceeded to afford the desired products in moderate yields (32-46 %) with good to excellent enantioselectivity (76-99 % ee).…”

Alkyl‐C‐C‐Bindungsbildung durch Nickel/Photoredox‐Kreuzkupplung

“…[74] Aufd ieser Grundlage wurde die duale Ni/ Photoredox-Katalyse zur Kupplung zahlreicher Acyl-Elektrophile mit Alkylradikalvorstufen eingesetzt. HAT-Strategien fürd ie Acylierung wurden auch beschrieben und schließen die Kupplung von Aldehyden mit Alkylbromiden [79] sowie die Synthese von Alkylthioestern ein. Ein selektiver Acyltransferm it gemischten Anhydriden kann beim Vorhandensein von zwei C(sp 2 )-O-Bindungen problematisch sein, da sie von dem Ni-Katalysator unterschieden werden müssen.…”