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. 2020 Mar 18;142(11):5117-5125.
doi: 10.1021/jacs.9b12320. Epub 2020 Mar 9.

Iridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated Azacycles

Pritha Verma  1 , Jeremy M Richter  2 , Nikita Chekshin  1 , Jennifer X Qiao  3 , Jin-Quan Yu  1
Affiliations

Iridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated Azacycles

Pritha Verma et al. J Am Chem Soc. .

Abstract

Saturated azacycles are commonly encountered in bioactive compounds and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, especially in drug discovery. While much effort has been dedicated toward this goal by using a directed C-H activation approach, the development of directing groups that are both general as well as practical remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of saturated azacycles using readily available olefins as coupling partners. This protocol extends the scope of saturated azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive disubstituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also observed for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further adds to the utility of amidoxime directing groups.

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Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Some biologically significant compounds containing α-alkylated saturated azacycles.
Scheme 1.
Scheme 1.
Palladium(II)-and Iridium(I)-catalyzed Directed α-C(sp3)‒H Activation Reactions of Saturated Azacycles. DG = Directing Group.
Scheme 2.
Scheme 2.
Evolution of Directing Groups for Transition-metal-catalyzed α-C(sp3)‒H Alkylation of Amines with Olefin Coupling Partners.
Scheme 3.
Scheme 3.
Design Principles of Amidoxime Directing Groups.
Scheme 4.
Scheme 4.
Evaluation of the Trifluoromethyl O-Benzyl Amidoxime Directing Group for α-C(sp3)‒H Alkylation of Azetidine, Piperidine, and Azepane. aYield was determined by 1H NMR analysis of the crude product using mesitylene as the internal standard. bYield after isolation by chromatography is shown.
Scheme 5.
Scheme 5.
Installation and Removal of Amidoxime Directing Groups.a aReaction conditions: (a) Azacycle (1.0 equiv), 6 (1.2 equiv), triethylamine (1.2 equiv), DCM, 50 °C, under air, 12 h. (b) Azacycle (1.0 equiv), 7 (1.2 equiv), DMF, 70 °C, under air, 12 h. (c) 2k or 5h (0.1 mmol, 1.0 equiv), DIBAL-H (0.5 mmol, 5.0 equiv), toluene (0.5 mL), 0 °C, under N2, 30 min. (d) CbzCl (0.3 mmol, 3.0 equiv), Et3N (0.3 mmol, 3.0 equiv), DCM (1.0 mL), rt, under N2, 12 h.
Scheme 6.
Scheme 6.
Deuterium labelling experiments.
Scheme 7.
Scheme 7.
Proposed Mechanistic Pathways.
See this image and copyright information in PMC

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