Iron‐Catalyzed ortho C−H Arylation and Methylation of Pivalophenone N−H Imines

Abstract

Iron-catalyzed ortho CÀHa rylation and methylation reactions of pivalophenone NÀHi mines are reported.T he pivaloyl NÀH imine proveda ne xcellentd irecting group for the arylation with diarylzinc reagents in the presence of an iron-diphosphine catalysta nd 2,3-dichlorobutane at room temperature.Asimilar catalytic system also allowed methylation with Me 3 Al at 70 8C. The pivaloyl imine of the product could be readily converted to ac yano group, thus allowing convenient preparation of ortho-functionalized benzonitriles.The transition-metal-catalyzed, directing-group-assisted CÀH functionalization of arenes has been extensively studied over the last few decades, leadingt oanumber of methods for the synthesis of functionalized aromatic compounds. [1] Although this area of research has long been dominated by precious transition metals, recent years have witnessed significant progress in the use of more cost-effective first-row transition metals, [2] among which iron has received particulara ttention for its high naturala bundance and low toxicity. [3] The ortho-arylation of 2-arylpyridine with ad iarylzinc reagent by using an iron-phenanthrolinec atalyst and av icinal-dichloroalkane oxidant, reported by Nakamura and co-workersi n2 008, represents am ilestone in this context. [4] Since then, the scope of iron-catalyzed oxidative CÀH/CÀMc oupling has been significantly extended in terms of the directing group and the coupling partner (Scheme 1a). Monodentate directing groups such as N-heterocycles, N-aryl imines,and N-methylamides wereemployed for CÀHa rylation with diarylzinc and aryl Grignardr eagents with bidentate nitrogen ligands. [5] Bidentate amide directing groups [6] enabledt he use of various organometallic coupling partners such as organozinc reagents, [7] organoboron reagents, [8] and trimethylaluminum [9] together with iron-diphosphine catalysts. Furthermore, Nakamura and co-workers recently developed an ew tridentate phosphine to achieve ortho-methylation directed by simple carbonyl functionalities such as carboxylic acid, ester,amide, and ketone. [10] ChemSusChem

Allenes for Versatile Iron-Catalyzed C–H Activation by Weak O-Coordination: Mechanistic Insights by Kinetics, Intermediate Isolation, and Computation

“…These unique features have sparked intense interest, leading to great advances in the field of iron-catalyzed C–H activation. − However, despite considerable progress, major challenges remain. Hence, the majority of iron-catalyzed C–H activations require strongly coordinating directing groups and typically a series of overstoichiometric additives, including organic oxidants, zinc salts, and highly reactive Grignard reagents. − Specifically, the excess of Grignard reagents translates into a limited functional group tolerance, diminishing the viable applications of the C–H functionalization approach.…”

Installing the “magic methyl” – C–H methylation in synthesis

“…In 2019, Yoshikai further expanded the repertoire of Fe-catalysed ortho C-H methylations (Scheme 24D). 84 Pivalophenone N-H imines were used as monodentate directing groups given their downstream value as intermediates towards ketones and nitriles. This method also exclusively displayed mono-methylation, supposedly due to steric repulsions between the t-Bu group and the initially introduced methyl group.…”

Recent Progress on the Synthesis of CF2H-Containing Derivatives

“…Xu et al reported a metal-catalyst-free electrochemical 1,2-hydroxydifluoromethylation of acrylamides using CF 2 HSO 2 NHNHBoc as a CF 2 H source. 74 Using Et 4 NPF 6 as an electrolyte at 70 °C in an acetone/H 2 O (1:2) mixture, secondary N-aryl acrylamides furnished the corresponding hydroxydifluoromethylation difunctionalized products from the corresponding alkene substrates (Scheme 19, B1). The reaction was compatible with electron-donating and mildly electron-withdrawing aryl para substituents (Cl, Br) as the R 1 group.…”