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. 2019 Apr 24;141(16):6726-6739.
doi: 10.1021/jacs.9b02238. Epub 2019 Apr 16.

A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines

Shengyang Ni  1 , Natalia M Padial  1 , Cian Kingston  1 , Julien C Vantourout  1 , Daniel C Schmitt  2 , Jacob T Edwards  1 , Monika M Kruszyk  1 , Rohan R Merchant  1 , Pavel K Mykhailiuk  1   3   4 , Brittany B Sanchez  5 , Shouliang Yang  6 , Matthew A Perry  2 , Gary M Gallego  6 , James J Mousseau  2 , Michael R Collins  6 , Robert J Cherney  7 , Pavlo S Lebed  3   8 , Jason S Chen  5 , Tian Qin  1 , Phil S Baran  1
Affiliations

A Radical Approach to Anionic Chemistry: Synthesis of Ketones, Alcohols, and Amines

Shengyang Ni et al. J Am Chem Soc. .

Abstract

Historically accessed through two-electron, anionic chemistry, ketones, alcohols, and amines are of foundational importance to the practice of organic synthesis. After placing this work in proper historical context, this Article reports the development, full scope, and a mechanistic picture for a strikingly different way of forging such functional groups. Thus, carboxylic acids, once converted to redox-active esters (RAEs), can be utilized as formally nucleophilic coupling partners with other carboxylic derivatives (to produce ketones), imines (to produce benzylic amines), or aldehydes (to produce alcohols). The reactions are uniformly mild, operationally simple, and, in the case of ketone synthesis, broad in scope (including several applications to the simplification of synthetic problems and to parallel synthesis). Finally, an extensive mechanistic study of the ketone synthesis is performed to trace the elementary steps of the catalytic cycle and provide the end-user with a clear and understandable rationale for the selectivity, role of additives, and underlying driving forces involved.

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Figures

Figure 1.
Figure 1.
Polar-bond disconnections via conventional 2e− logic vs. newly explored radical processes for ketone, alcohol, and amine synthesis.
Figure 2.
Figure 2.
Radical methods for accessing ketones: Historical perspective.
Figure 3.
Figure 3.
(A) Inspiration for a mild ketone and chemoselective ketone synthesis and (B) development and optimization of CCC.
Figure 4.
Figure 4.
Applications of CCC to the formal synthesis of anamarine (A), muscone (B), and parallel library synthesis (C).
Figure 5.
Figure 5.
(A) Synthesis of amines from RAEs previously limited to amino acid synthesis and (B) an alternative protocol to access benzylic amines.
Figure 6.
Figure 6.
(A) Alcohol synthesis through conventional and radical means and (B) the development of an alkyl-NHK reaction employing RAEs.
Figure 7.
Figure 7.
CCC: The complete mechanistic picture and supporting experiments. Phth = phthalimide.
Figure 8.
Figure 8.
Limitations of the described methodologies.
See this image and copyright information in PMC

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