TY - JOUR
T1 - A general N-alkylation platform via copper metallaphotoredox and silyl radical activation of alkyl halides
AU - Dow, Nathan W.
AU - Cabré, Albert
AU - MacMillan, David W.C.
N1 - Funding Information:
The authors are grateful for financial support provided by the National Institute of General Medical Sciences (NIGMS), the NIH (under award R35GM134897-01 ), the Princeton Catalysis Initiative , and kind gifts from Merck , Janssen , BMS , Genentech , Celgene , and Pfizer . N.W.D. acknowledges Princeton University , N. Brink, and the Brink Family for a Brink Graduate Fellowship and acknowledges Princeton University, E. Taylor, and the Taylor family for an Edward C. Taylor Fellowship. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS. The authors thank M.N. Lavagnino, Y. Liang, W. Liu, H.A. Sakai, and X. Zhang for helpful scientific discussions.
Publisher Copyright:
© 2021 Elsevier Inc.
PY - 2021/7/8
Y1 - 2021/7/8
N2 - The catalytic union of amides, sulfonamides, anilines, imines, or N-heterocycles with a broad spectrum of electronically and sterically diverse alkyl bromides has been achieved via a visible-light-induced metallaphotoredox platform. The use of a halogen abstraction-radical capture (HARC) mechanism allows for room temperature coupling of C(sp3)-bromides using simple Cu(II) salts, effectively bypassing the prohibitively high barriers typically associated with thermally induced SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with >10 classes of medicinally relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary, and tertiary alkyl bromides. Furthermore, the capacity of HARC methodologies to engage conventionally inert coupling partners is highlighted via the union of N-nucleophiles with cyclopropyl bromides and unactivated alkyl chlorides, substrates that are incompatible with nucleophilic substitution pathways. Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.
AB - The catalytic union of amides, sulfonamides, anilines, imines, or N-heterocycles with a broad spectrum of electronically and sterically diverse alkyl bromides has been achieved via a visible-light-induced metallaphotoredox platform. The use of a halogen abstraction-radical capture (HARC) mechanism allows for room temperature coupling of C(sp3)-bromides using simple Cu(II) salts, effectively bypassing the prohibitively high barriers typically associated with thermally induced SN2 or SN1 N-alkylation. This regio- and chemoselective protocol is compatible with >10 classes of medicinally relevant N-nucleophiles, including established pharmaceutical agents, in addition to structurally diverse primary, secondary, and tertiary alkyl bromides. Furthermore, the capacity of HARC methodologies to engage conventionally inert coupling partners is highlighted via the union of N-nucleophiles with cyclopropyl bromides and unactivated alkyl chlorides, substrates that are incompatible with nucleophilic substitution pathways. Preliminary mechanistic experiments validate the dual catalytic, open-shell nature of this platform, which enables reactivity previously unattainable in traditional halide-based N-alkylation systems.
KW - N-alkylation
KW - SDG12: Responsible consumption and production
KW - SDG9: Industry innovation and infrastructure
KW - copper catalysis
KW - cyclopropylation
KW - halogen abstraction
KW - organochloride activation
KW - photoredox
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U2 - 10.1016/j.chempr.2021.05.005
DO - 10.1016/j.chempr.2021.05.005
M3 - Article
C2 - 34423174
AN - SCOPUS:85108992845
SN - 2451-9294
VL - 7
SP - 1827
EP - 1842
JO - Chem
JF - Chem
IS - 7
ER -