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. 2022 Nov;8(11):3096-3108.
doi: 10.1016/j.chempr.2022.07.022. Epub 2022 Aug 22.

General and Selective Metal-Free Radical α-C-H Borylation of Aliphatic Amines

Sumon Sarkar  1 , Sidhant Wagulde  1 , Xiangqing Jia  1 , Vladimir Gevorgyan  1   2
Affiliations

General and Selective Metal-Free Radical α-C-H Borylation of Aliphatic Amines

Sumon Sarkar et al. Chem. 2022 Nov.

Abstract

Despite recent developments, selective C(sp3)-H borylation of feedstock amines remains a formidable challenge. Herein, we have developed a general, mild, and photoinduced transition metal- and strong base-free method for α-C(sp3)-H borylation of amines. This protocol features a regioselective 1,5-hydrogen atom transfer process to access key α-aminoalkyl radical intermediate using commercially available easy-to-install/remove iodobenzoyl radical translocating group. Remarkably, this general, efficient, and operationally simple method allows activation of primary and secondary α-C-H sites of a broad range of acyclic and cyclic amines toward highly regio- and diastereoselective synthesis of valuable α-aminoboronates. Utility of this protocol has been demonstrated by its employment in late-stage borylation of structurally complex amines and formal C-H arylation reaction of amines. Thus, it is expected that this operationally simple, general, and practical method will find broad application in organic synthesis and drug discovery.

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Conflict of interest statement

DECLARATION OF INTERESTS The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. α-Aminoboronic Acid-Containing Drugs
Related to introduction section, describes importance of α-aminoboronates.
Figure 2.
Figure 2.. Optimization of Reaction Conditions
Related to results and discussion, describes reaction optimization.
Figure 3.
Figure 3.. Scope of Radical α-C(sp3)–H Borylation of Aminesa
Related to results and discussion, describes generality of the developed protocol. a0.2 mmol scale, isolated yields of 3 from corresponding 2. b1.75 equiv of B2Cat2 was used. cGC-MS yields for semi-one pot borylation from the corresponding amine. dIsolated after Boc protection. eYield based on recovered starting materials.
Scheme 1.
Scheme 1.. Directed α-C–H Borylation of Amines
Related to introduction section, describes directed borylation approaches and our reaction design.
Scheme 2.
Scheme 2.. Complementarity of the Developed Approach with Existing Direct Borylation Methods
Related to results and discussion, describes complementary regioselectivity of new approach with that of previously reported direct borylation methods.
Scheme 3.
Scheme 3.. Further Transformations of Obtained Boronates
Related to results and discussion, describes scale-up experiments, derivatization of products, and removal of benzoyl group.
Scheme 4.
Scheme 4.. Mechanistic Studies
Related to results and discussion, describes a series of mechanistic studies.
Scheme 5.
Scheme 5.. Proposed Reaction Mechanism
Related to results and discussion, describes proposed mechanistic cycle.
See this image and copyright information in PMC

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