Copper-catalyzed methylative difunctionalization of alkenes

Abstract

Trifluoromethylative difunctionalization and hydrofunctionalization of unactivated alkenes have been developed into powerful synthetic methodologies. On the other hand, methylative difunctionalization of olefins remains an unexplored research field. We report in this paper the Cu-catalyzed alkoxy methylation, azido methylation of alkenes using dicumyl peroxide (DCP), and di-tert-butyl peroxide (DTBP) as methyl sources. Using functionalized alkenes bearing a tethered nucleophile (alcohol, carboxylic acid, and sulfonamide), methylative cycloetherification, lactonization, and cycloamination processes are subsequently developed for the construction of important heterocycles such as 2,2-disubstituted tetrahydrofurans, tetrahydropyrans, γ-lactones, and pyrrolidines with concurrent generation of a quaternary carbon center. The results of control experiments suggest that the 1,2-alkoxy methylation of alkenes goes through a radical-cation crossover mechanism, whereas the 1,2-azido methylation proceeds via a radical addition and Cu-mediated azide transfer process.

Fig. 1

Functionalization of unactivated alkenes. a Trifluoromethylative difunctionalization of alkenes; b hydrofunctionalization of alkenes. c hydromethylation of alkenes; d Example of 1,2-hydroxy methylation of alkene in natural product synthesis. Five steps were required to accomplish this transformation; e methylative difunctionalization of electron-rich alkenes: radical-metal mediated ligand transfer and radical-cation crossover processes. Abbreviations: Fe(acac)₃ iron (III) acetylacetonate; LAH lithium aluminum hydride; CDMT 2-chloro-4,6-dimethoxy-1,3,5-triazine; NMM N-methyl morpholine; AIBN azobisisobutyronitrile

Fig. 2

1,2-Alkoxy methylation of unactivated alkenes. Unless specified, MeOH was used as solvent. (i) 140 °C; (ii) DTBP (4.0 equiv) was used instead of DCP; (iii) EtOH (2.0 mL, c 0.1 M); (iv) iPrOH (2.0 mL, c 0.1 M). Abbreviations: DTBP di-tert-butyl peroxide; DCP dicumyl peroxide

Fig. 3

1,2-Azido methylation of unactivated alkenes. The reaction scheme is shown above the table

Fig. 4

Methylative heterocyclization of alkenes. a Methylative cycloetherification: 4 (0.2 mmol), Cu(OTf)₂ (0.2 equiv), L1 (0.3 equiv), Na₃PO₄ (0.2 equiv), DTBP (4.0 equiv), CF₃CH₂OH (c 0.1 M), 120 °C. Yields refer to isolated products. b Methylative lactonization: 6 (0.2 mmol), CuSO₄ (0.2 equiv), L2 (0.3 equiv), Na₃PO₄ (0.3 equiv), DTBP (4.0 equiv), tBuOH (c 0.1 M), 120 °C. c Methylative cycloamination: 8, Cu(OAc)₂ (0.2 equiv), L2 (0.3 equiv), Na₃PO₄ (0.2 equiv), DTBP (4.0 equiv), tBuOH (c 0.1 M), 120 °C

Fig. 5

Mechanistic proposal and control experiments. a Possible reaction pathways. b Radical trapping experiment. c Radical clock experiment. d Super sensitive radical probe experiment. Conditions a: 1a (0.2 mmol), Cu(BF₄)₂•6H₂O (0.2 equiv), L1 (0.3 equiv), DCP (4.0 equiv), Na₂HPO₄ (0.2 equiv), MeOH (2.0 mL, c 0.1 M), 120 °C, 4 h; Conditions b: 1a (0.2 mmol), DTBP (0.8 mmol), LiN₃ (0.5 mmol), CuSO₄ (0.002 mmol, 0.1 equiv), L2 (0.06 mmol), tBuOH (2.0 mL, c 0.1 M), 120 °C

Fig. 6

Mechanistic divergence between methoxy methylation and azido methylation. a: 21 (0.2 mmol), Cu(BF₄)₂•6H₂O (0.2 equiv), L1 (0.3 equiv), DCP (4.0 equiv), Na₂HPO₄ (0.2 equiv), MeOH (2.0 mL, c 0.1 M), 120 °C, 4 h; b: 21 (0.2 mmol), DTBP (0.8 mmol), LiN₃ (0.5 mmol), CuSO₄ (0.002 mmol, 0.1 equiv), L2 (0.06 mmol), tBuOH (2.0 mL, c 0.1 M), 120 °C