Mechanistic Investigation, Wavelength-Dependent Reactivity, and Expanded Reactivity of


Journal

Journal of the American Chemical Society
ISSN: 1520-5126
Titre abrégé: J Am Chem Soc
Pays: United States
ID NLM: 7503056

Informations de publication

Date de publication:
12 Feb 2024
Historique:
medline: 13 2 2024
pubmed: 13 2 2024
entrez: 12 2 2024
Statut: aheadofprint

Résumé

Under mild blue-light irradiation, α-acylated saturated heterocycles undergo a photomediated one-atom ring contraction that extrudes a heteroatom from the cyclic core. However, for nitrogenous heterocycles, this powerful skeletal edit has been limited to substrates bearing electron-withdrawing substituents on nitrogen. Moreover, the mechanism and wavelength-dependent efficiency of this transformation have remained unclear. In this work, we increased the electron richness of nitrogen in saturated azacycles to improve light absorption and strengthen critical intramolecular hydrogen bonding while enabling the direct installation of the photoreactive handle. As a result, a broadly expanded substrate scope, including underexplored electron-rich substrates and previously unsuccessful heterocycles, has now been achieved. The significantly improved yields and diastereoselectivities have facilitated reaction rate, kinetic isotope effect (KIE), and quenching studies, in addition to the determination of quantum yields. Guided by these studies, we propose a revised ET/PT mechanism for the ring contraction, which is additionally corroborated by computational characterization of the lowest-energy excited states of α-acylated substrates through time-dependent DFT. The efficiency of the ring contraction at wavelengths longer than those strongly absorbed by the substrates was investigated through wavelength-dependent rate measurements, which revealed a red shift of the photochemical action plot relative to substrate absorbance. The elucidated mechanistic and photophysical details effectively rationalize empirical observations, including additive effects, that were previously poorly understood. Our findings not only demonstrate enhanced synthetic utility of the photomediated ring contraction and shed light on mechanistic details but may also offer valuable guidance for understanding wavelength-dependent reactivity for related photochemical systems.

Identifiants

pubmed: 38347659
doi: 10.1021/jacs.3c13982
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Auteurs

Sojung F Kim (SF)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Henrik Schwarz (H)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Justin Jurczyk (J)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Bailey R Nebgen (BR)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.
Lawrence Berkeley National Laboratory, Materials Sciences Division, Berkeley, California 94720, United States.

Hailey Hendricks (H)

Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.

Hojoon Park (H)

Department of Process Research and Development, Merck & Co., Inc., Boston, Massachusetts 02115, United States.

Andrew Radosevich (A)

Small Molecule Therapeutics & Platform Technologies, Abbvie Inc., North Chicago, Illinois 60064, United States.

Michael W Zuerch (MW)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.
Lawrence Berkeley National Laboratory, Materials Sciences Division, Berkeley, California 94720, United States.

Kaid Harper (K)

Process Chemistry, Abbvie Inc., North Chicago, Illinois 60064, United States.

Michaelyn C Lux (MC)

Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.

Charles S Yeung (CS)

Department of Discovery Chemistry, Merck & Co., Inc., Boston, Massachusetts 02115, United States.

Richmond Sarpong (R)

Department of Chemistry, University of California, Berkeley, Berkeley, California 94720, United States.

Classifications MeSH