Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2H in Continuous Flow

Wai Chung Fu; Timothy F. Jamison

doi:10.1002/anie.202004260

Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF₂H in Continuous Flow

Wai Chung Fu, Timothy F. Jamison

Research output: Journal article publication › Journal article › Academic research › peer-review

33 Citations (Scopus)

Abstract

The deuteriodifluoromethyl group (CF₂D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF₂H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D₂O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.

Original language	English
Pages (from-to)	13885-13890
Number of pages	6
Journal	Angewandte Chemie - International Edition
Volume	59
Issue number	33
DOIs	https://doi.org/10.1002/anie.202004260
Publication status	Published - 10 Aug 2020
Externally published	Yes

Keywords

chlorodifluoromethane
continuous flow
deuteration
difluoromethylation
gem-difluoroalkene

ASJC Scopus subject areas

Catalysis
General Chemistry

More information

10.1002/anie.202004260

Cite this

@article{4d9405bc702f49cca4adb8d797865491,

title = "Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2H in Continuous Flow",

abstract = "The deuteriodifluoromethyl group (CF2D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF2H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D2O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.",

keywords = "chlorodifluoromethane, continuous flow, deuteration, difluoromethylation, gem-difluoroalkene",

author = "Fu, \{Wai Chung\} and Jamison, \{Timothy F.\}",

note = "Funding Information: We thank Dr. Rachel L. Beingessner (MIT), Dr. Mohan Kumar (MIT), Dr. Long V. Nguyen (MIT) and Dr. Timothy M. Monos (MIT) for helpful discussions. This work was supported by the Croucher Foundation (Hong Kong), and the Defense Advanced Research Project Agency (DARPA) under contract number ARO W911NF‐16‐2‐0023. Funding Information: We thank Dr. Rachel L. Beingessner (MIT), Dr. Mohan Kumar (MIT), Dr. Long V. Nguyen (MIT) and Dr. Timothy M. Monos (MIT) for helpful discussions. This work was supported by the Croucher Foundation (Hong Kong), and the Defense Advanced Research Project Agency (DARPA) under contract number ARO W911NF-16-2-0023. Publisher Copyright: {\textcopyright} 2020 Wiley-VCH Verlag GmbH \& Co. KGaA, Weinheim",

year = "2020",

month = aug,

day = "10",

doi = "10.1002/anie.202004260",

language = "English",

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pages = "13885--13890",

journal = "Angewandte Chemie - International Edition",

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publisher = "John Wiley and Sons Ltd",

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T1 - Deuteriodifluoromethylation and gem-Difluoroalkenylation of Aldehydes Using ClCF2H in Continuous Flow

AU - Fu, Wai Chung

AU - Jamison, Timothy F.

N1 - Funding Information: We thank Dr. Rachel L. Beingessner (MIT), Dr. Mohan Kumar (MIT), Dr. Long V. Nguyen (MIT) and Dr. Timothy M. Monos (MIT) for helpful discussions. This work was supported by the Croucher Foundation (Hong Kong), and the Defense Advanced Research Project Agency (DARPA) under contract number ARO W911NF‐16‐2‐0023. Funding Information: We thank Dr. Rachel L. Beingessner (MIT), Dr. Mohan Kumar (MIT), Dr. Long V. Nguyen (MIT) and Dr. Timothy M. Monos (MIT) for helpful discussions. This work was supported by the Croucher Foundation (Hong Kong), and the Defense Advanced Research Project Agency (DARPA) under contract number ARO W911NF-16-2-0023. Publisher Copyright: © 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

PY - 2020/8/10

Y1 - 2020/8/10

N2 - The deuteriodifluoromethyl group (CF2D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF2H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D2O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.

AB - The deuteriodifluoromethyl group (CF2D) represents a challenging functional group due to difficult deuterium incorporation and unavailability of precursor reagents. Herein, we report the use of chlorodifluoromethane (ClCF2H) gas in the continuous flow deuteriodifluoromethylation and gem-difluoroalkenylation of aldehydes. Mechanistic studies revealed that the difluorinated oxaphosphetane (OPA) intermediate can proceed via alkaline hydrolysis in the presence of D2O to provide α-deuteriodifluoromethylated benzyl alcohols or undergo a retro [2+2] cycloaddition under thermal conditions to provide the gem-difluoroalkenylated product.

KW - chlorodifluoromethane

KW - continuous flow

KW - deuteration

KW - difluoromethylation

KW - gem-difluoroalkene

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DO - 10.1002/anie.202004260

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