Radical-Mediated Remote Functional Group Migration

Abstract

Metrics & MoreArticle Recommendations CONSPECTUS: Alkenes are ubiquitous in natural products and are extensively used as synthetic feedstocks in multiple fields including organic synthesis, medicinal chemistry, and materials science. Radical-mediated difunctionalization of alkenes provides a powerful tactic for alkene utilization. Despite the considerable progress made in the past several decades, state-of-the-art methods are highly dependent upon activated alkenes in which a proximal group with a π-electron system (e.g., aryl, carbonyl, and heteroatom) is requisite to stabilize the nascent alkyl radical intermediate via p−π conjugation or p orbitals of the heteroatom. In contrast, the transformation of unactivated alkenes, such as aliphatic alkenes, remains challenging.To overcome this obstacle, we have recently disclosed the strategy of intramolecular distal functional group migration (FGM), which has been efficiently applied in radical difunctionalization of unactivated alkenes. A portfolio of functional groups, such as cyano, heteroaryl, oximino, formyl, and alkynyl groups, showcase the excellent migratory aptitude. Mechanistically, after the addition of an extrinsic radical to the alkene, the newly formed active alkyl radical is rapidly captured by the intramolecular migratory group to generate a cyclic intermediate. Subsequent cleavage of the cyclic C−C bond of the intermediate leads to the functionalized product through the FGM process. Based on the strategy of FGM, a set of elusive difunctionalizations of unactivated alkenes have been accomplished (Part A). Alongside this research, an upgraded highly efficient synthetic strategy, "dock-migration," is created for intermolecular difunctionalization of alkenes. A diversity of sulfone-based dual-function reagents are developed. The intermolecular transformation is initiated by docking the dual-function reagent to the alkene, followed by intramolecular migration of the functional group.Compared to the original FGM protocol, the scope of alkenes is significantly extended from the strategically placed tertiary alcoholsubstituted alkenes to general alkenes. Both activated and unactivated alkenes are well tolerated. By this approach, radical-mediated fluoroalkylheteroarylation, fluoroalkylalkynylation, and alkylation of alkenes have been achieved (Part B). Direct elaboration of C−H bonds into the targeted functional groups represents one of the most ideal and straightforward methods for molecular functionalization. The FGM strategy proves to be an ingenious tool for radical-mediated functionalization of remote unactivated C(sp 3 )−H bonds. Based on the FGM process, we have accomplished: (a) remote C(sp 3 )−H heteroarylation and cyanation of unprotected alcohols via the cascade of alkoxy radical-enabled hydrogen atom transfer (HAT) and intramolecular functional group (e.g., heteroaryl, cyano) migration, and (b) distal C(sp 3 )−H vinylation of propargylic alcohols through consecutive alkenyl radical-promoted HAT process and subsequent alkenyl migration (Part C).

Heterocyclization Reagents for Rapid Assembly of N‐Fused Heteroarenes from Alkenes

“…Based on the experimental results and our knowledge in radical‐mediated heteroaryl migration, [19a] a plausible mechanism is outlined in Scheme 6. Single electron transfer (SET) between Cu I and the C‐Br bond of 1 generates the intermediate a , and initiates the transformation.…”

Intermolecular Radical Fluoroalkylative Olefination of Unactivated Alkenes

“…[1][2][3][4][5][6][7] Most of the current approaches rely highly on the properties of alkenes; activated alkenes are usually suitable substrates, for example, styrenes, enol ethers, enamines, acrylates, and so forth, owing to the presence of p-π conjugation that stabilizes nascent alkyl radicals arising from radical addition to alkenes. To surmount the obstacles in radical difunctionalization of unactivated alkenes, the strategy of remote functional group migration (FGM) was unveiled, [8][9][10][11][12] and has been applied successfully to a set of elusive alkene transformations, including cyanation, 13,14 (hetero)arylation, [15][16][17][18][19] alkynylation, 20,21 alkenylation, [22][23][24][25][26] acylation, 27,28 and oximination. [28][29][30] Incorporation of a fluoroalkyl group (CF 3 , CF 2 R, or CFRR') to bioactive molecules usually rendered a substantial change in lipophilicity, metabolic stability, and other bioactivities.…”

Difunctionalization of Alkenes and Alkynes via Intermolecular Radical and Nucleophilic Additions

“…In addition to the success of radical polymerization for making synthetic polymers, organic radical reactions have also become an increasing important tools for preparation of small molecules through radical addition, cyclization, cascade bond formation, H-atom and group-transfer, and radical-radical coupling reactions [1,2]. Active researches on direct C-H bond functionalization [3], remote (distal) functionalization [4], Smile-type ipso-group rearrangement [5], cascade reaction [6], photoredox catalysis [7], and electrochemical reaction [8] have significantly fueled the chemistry of synthetic radicals.…”

“…Presented in this article are one-pot radical addition, oxidation and nucleophilic addition reactions to incorporate two functional groups to alkenes or alkynes. The difunctionalization could be accomplished through direct 1,2-addition (Scheme 1I-A), 1,2-functionalization involving Smiles-type ispo aryl group migration (Scheme 1I-B) [4,5], or 1,n-functionalization involving H-atom transfer (Scheme 1I-C) [4][5][6]. The majority examples in this paper are direct 1,2-additions.…”