Direct Enantioselective C(sp³)–H Acylation for the Synthesis of α-Amino Ketones

Abstract

A direct enantioselective acylation of α-amino C(sp 3 )−H bonds with carboxylic acids has been achieved via the merger of transition metal and photoredox catalysis. This straightforward protocol enables cross-coupling of a wide range of carboxylic acids, one class of feedstock chemicals, with readily available N-alkyl benzamides to produce highly valuable α-amino ketones in high enantioselectivities under mild conditions. The synthetic utility of this method is further demonstrated by gram scale synthesis and application to late-stage functionalization. This method provides an unprecedented solution to address the challenging stereocontrol in metallaphotoredox catalysis and C(sp 3 )−H functionalization. Mechanistic studies suggest the α-C(sp 3 )−H bond of the benzamide coupling partner is cleavage by photocatalytically generated bromine radicals to form α-amino alkyl radicals, which subsequently engages in nickel-catalyzed asymmetric acylation.

Asymmetric benzylic C(sp3)−H acylation via dual nickel and photoredox catalysis

“…It has been reported that single-electron oxidation of bromide anion by photoexcited photocatalyst can generate bromine radical ( E 1/2 [Ir(III*/II)] = +1.21 V vs SCE in CH 3 CN; E 1/2 ox [Br − /Br·] = +0.80 V vs SCE in DME) 51 – 54 . According to the literature precedent and our previous mechanistic experiments 38 , 51 – 54 , we hypothesize that the catalytic reaction is initiated by oxidative addition of Ni(0) catalyst I to an in situ-activated carboxylic acid to afford Ni(II) species II . Subsequent trapping of prochiral benzylic radicals generated from the bromine-radical-mediated HAT process provides Ni(III) complex III , which undergoes reductive elimination to yield the desired product and Ni(I) species IV .…”

“…Our investigation began with an exploration of reaction conditions for the coupling of 4-ethylbiphenyl and 3-phenylpropanoic acid (Table 1 ). Based on previously reported elegant strategies and our recent conditions for carboxylic acid activation in ketone synthesis 38 , 56 – 60 , dimethyl dicarbonate (DMDC) was chosen as the activating agent to generate mixed anhydride in situ from carboxylic acids. After an extensive study of reaction parameters (also see Supplementary Table 1 ), we were delighted to find that a simple chiral nickel/bis(oxazoline) catalyst and a known Ir-photocatalyst could provide the acylation product in 85% yield and 94% ee (entry 1).…”

“…Recently, our laboratory reported a direct enantioselective C(sp 3 )−H acylation of N -alkyl benzamides for the synthesis of α-amino ketones; wherein, a chiral nickel catalyst could engage photocatalytically generated α-amino radicals and in situ-activated carboxylic acids in acyl cross-couplings 38 . We reasoned that this strategy could be applied to the asymmetric benzylic C−H acylation of alkylarenes to address the challenges described above for the synthesis of α-aryl ketones via radical C(sp 3 )−H functionalization 36 – 38 . Despite that initial progress 38 , no examples of enantioselective benzylic C−H acylation have been reported.…”

“…We reasoned that this strategy could be applied to the asymmetric benzylic C−H acylation of alkylarenes to address the challenges described above for the synthesis of α-aryl ketones via radical C(sp 3 )−H functionalization 36 – 38 . Despite that initial progress 38 , no examples of enantioselective benzylic C−H acylation have been reported. In addition, there is an increasing demand for the development of benzylic C−H functionalization reactions for the synthesis of high value-added molecules from simple alkylarenes 39 – 50 .…”

Visible-Light-Promoted Asymmetric Catalysis by Chiral Complexes of First-Row Transition Metals

“…In 2020, Huo and co-workers reported a direct enantioselective acylation of -amino C(sp 3 )-H bonds for the synthesis of -amino ketones (Scheme 9). 25 The reaction was catalyzed by an iridium-based photocatalyst and a nickel cocatalyst containing a chiral bisoxazoline ligand L10 in the presence of dimethyl dicarbonate (DMDC) as the activator, and converted a carboxylic acid into a mixed anhydride in situ. Mechanistic investigations suggested that the C(sp 3 )-H bond of 33 is cleavage by photocatalytically generated bromine radicals to produce an -aminoalkyl radical, which is involved in the further stereoselective transformation governed by the chiral nickel catalyst.…”