CaltechAUTHORS
  A Caltech Library Service

Investigation of the C–N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N–Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe

Lee, Heejun and Ahn, Jun Myun and Oyala, Paul H. and Citek, Cooper and Yin, Haolin and Fu, Gregory C. and Peters, Jonas C. (2022) Investigation of the C–N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N–Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe. Journal of the American Chemical Society, 144 (9). pp. 4114-4123. ISSN 0002-7863. doi:10.1021/jacs.1c13151. https://resolver.caltech.edu/CaltechAUTHORS:20220216-527740512

This is the latest version of this item.

[img] PDF (Synthesis procedures for all compounds and experiments, additional experimental details, spectroscopic characterization data including 1H NMR and EPR data, and details of DFT calculations) - Supplemental Material
See Usage Policy.

9MB
[img] Plain Text (Molecular coordinates) - Supplemental Material
See Usage Policy.

159kB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20220216-527740512

Abstract

Whereas photoinduced, copper-catalyzed couplings of nitrogen nucleophiles with alkyl electrophiles have recently been shown to provide an attractive approach to achieving a variety of enantioselective C–N bond constructions, mechanistic studies of these transformations have lagged the advances in reaction development. Herein we provide mechanistic insight into a previously reported photoinduced, copper-catalyzed enantioconvergent C–N coupling of a carbazole nucleophile with a racemic tertiary α-haloamide electrophile. Building on the isolation of a copper(II) model complex whose EPR parameters serve as a guide, we independently synthesize two key intermediates in the proposed catalytic cycle, a copper(II) metalloradical (L*Cu^(II)(carb′)₂) (L* = a monodentate chiral phosphine ligand; carb′ = a carbazolide ligand), as well as a tertiary α-amide organic radical (R·); the generation and characterization of R· was guided by DFT calculations, which suggested that it would be stable to homocoupling. Continuous-wave (CW) and pulse EPR studies, along with corresponding DFT calculations, are among the techniques used to characterize these reactive radicals. We establish that these two radicals do indeed combine to furnish the C–N coupling product in good yield and with significant enantiomeric excess (77% yield, 55% ee), thereby supporting the chemical competence of these proposed intermediates. DFT calculations are consistent with R· initially binding to copper(II) via a dative interaction from the closed-shell carbonyl oxygen atom of the radical, which positions the α-carbon for direct reaction with the copper(II)-bound carbazole N atom, to generate the C–N bond with enantioselectivity, without the formation of an alkylcopper(III) intermediate.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.1c13151DOIArticle
https://www.ccdc.cam.ac.uk/services/structure_request?pid=ccdc:2128480&issn=0002-7863&id=doi:10.1021/jacs.1c13151&sid=ACSRelated ItemCrystallographic data
ORCID:
AuthorORCID
Lee, Heejun0000-0002-0439-3863
Oyala, Paul H.0000-0002-8761-4667
Citek, Cooper0000-0001-9376-8200
Yin, Haolin0000-0002-2063-8605
Fu, Gregory C.0000-0002-0927-680X
Peters, Jonas C.0000-0002-6610-4414
Additional Information:© 2022 American Chemical Society. Received 14 December 2021. Published online 15 February 2022. Support has been provided by the National Institutes of Health (National Institute of General Medical Sciences: R01-109194). We are grateful to the Dow Innovation Fund for support of our EPR facility and to the Beckman Institute X-ray Crystallography Facility. The Resnick Sustainability Institute at Caltech is acknowledged for its support of enabling facilities. J.M.A. acknowledges the National Sciences and Engineering Research Council (NSERC) of Canada for a graduate research fellowship. J.C.P. and G.C.F. dedicate this contribution to the memory of our colleague, mentor, and friend Robert H. Grubbs. The authors declare no competing financial interest. CCDC 2128476–2128480 contain the supplementary crystallographic data for this paper.
Group:Resnick Sustainability Institute
Funders:
Funding AgencyGrant Number
NIHR01109194
Dow Innovation FundUNSPECIFIED
Resnick Sustainability InstituteUNSPECIFIED
Natural Sciences and Engineering Research Council of Canada (NSERC)UNSPECIFIED
Issue or Number:9
DOI:10.1021/jacs.1c13151
Record Number:CaltechAUTHORS:20220216-527740512
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20220216-527740512
Official Citation:Investigation of the C–N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N–Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe. Heejun Lee, Jun Myun Ahn, Paul H. Oyala, Cooper Citek, Haolin Yin, Gregory C. Fu, and Jonas C. Peters. Journal of the American Chemical Society 2022 144 (9), 4114-4123; DOI: 10.1021/jacs.1c13151
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:113477
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:16 Feb 2022 10:04
Last Modified:08 Apr 2022 22:05

Available Versions of this Item

  • Investigation of the C–N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N–Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe. (deposited 16 Feb 2022 10:04) [Currently Displayed]

Commentary/Response Threads

  • Lee, Heejun and Ahn, Jun Myun and Oyala, Paul H. and Citek, Cooper and Yin, Haolin and Fu, Gregory C. and Peters, Jonas C. Investigation of the C–N Bond-Forming Step in a Photoinduced, Copper-Catalyzed Enantioconvergent N–Alkylation: Characterization and Application of a Stabilized Organic Radical as a Mechanistic Probe. (deposited 16 Feb 2022 10:04) [Currently Displayed]

Repository Staff Only: item control page