Mechanistic Insights into Copper Catalyzed sp3 C-H Functionalization
Jang, Eun Sil
Warren, Timothy H
Direct C-H functionalization offers opportunities to modify carbon centers normally inert to traditional methods that rely on functional group manipulations, diversifying methods for complex organic molecule synthesis. Traditional synthetic methods often require activated carbon centers. For instance, the most common organic route to C-N bond formation is the nucleophilic substitution of R-X (X = halide, activated-OH) or reductive amination of carbonyl functional groups, R1COR2. Similarly, in C-O and C-C bond formation, a nucleophilic functional group attacks an electrophilic carbon. More economical and efficient C-N, C-O, and C-C bond formation would directly aminate C-H bonds with corresponding functional groups, H-NR1R2, H-OR’, and H-CH2E (E = C(O)R or NO2). The use of transition metal catalysts can allow such transformations for even relatively strong sp3-C-H bonds. The development of such selective transformations, however, is still in its infancy. Though many mechanisms have been proposed for transition metal catalyzed C-H functionalization, few are well understood. Thus, improved mechanistic insights can lead to more rapid advancements in synthetic methodologies.Herein we describe the mechanistic understanding of -diketiminato copper(I) complexes, [CuI], in catalytic intramolecular sp3 C-H functionalization using tBuOOtBu as an oxidant. With initial success in C-H amination using unactivated alkyl and arylamines, H-NR1R2, each step in the proposed catalytic cycle underwent rigorous analysis, largely devoted to understanding the role of -diketiminato copper(II) amide intermediates [CuII]-NR1R2. Previous studies proposed [CuII]-NHAd (Ad = adamantyl) as the intermediate responsible for a key step in our catalysis, capable of performing both hydrogen atom abstraction (HAA) of R-H to give R as well as radical capture (RC) of this alkyl radical R to give R-NHAd and [CuI]. With other copper(II) amides bearing aromatic N-substituents, the role of such [CuII]-NHAr species is primarily to capture the R radical formed via HAA of R-H by •OtBu (released by [CuI] catalyzed homolytic cleavage of tBuOOtBu). This amino variant Kharasch-Sosnovsky reaction has been effectively applied to other functional groups such as alcohols, nitroalkanes, and aryl ketones to introduce new methods for sp3-C-O and sp3-sp3 C-C bond formation.
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Bakhoda, Abolghasem (Georgetown University, 2019)sp3 C−H functionalization represents a paradigm shift from the conventional rationality of organic synthesis. Classical organic synthesis relies on the manipulation of functional groups while the new logic of C−H ...