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. 2023 Jul 19;145(28):15207-15217.
doi: 10.1021/jacs.3c02185. Epub 2023 Jul 6.

Copper-Mediated Dehydrogenative C(sp3)-H Borylation of Alkanes

Ruocheng Sang  1 , Wangyujing Han  1 , Hanwen Zhang  1 , Carla M Saunders  1 , Adam Noble  1 , Varinder K Aggarwal  1
Affiliations

Copper-Mediated Dehydrogenative C(sp3)-H Borylation of Alkanes

Ruocheng Sang et al. J Am Chem Soc. .

Abstract

Borylations of inert carbon-hydrogen bonds are highly useful for transforming feedstock chemicals into versatile organoboron reagents. Catalysis of these reactions has historically relied on precious-metal complexes, which promote dehydrogenative borylations with diboron reagents under oxidant-free conditions. Recently, photoinduced radical-mediated borylations involving hydrogen atom transfer pathways have emerged as attractive alternatives because they provide complimentary regioselectivities and proceed under metal-free conditions. However, these net oxidative processes require stoichiometric oxidants and therefore cannot compete with the high atom economy of their precious-metal-catalyzed counterparts. Herein, we report that CuCl2 catalyzes radical-mediated, dehydrogenative C(sp3)-H borylations of alkanes with bis(catecholato)diboron under oxidant-free conditions. This is a result of an unexpected dual role of the copper catalyst, which promotes oxidation of the diboron reagent to generate an electrophilic bis-boryloxide that acts as an effective borylating agent in subsequent redox-neutral photocatalytic C-H borylations.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Borylations of non-activated alkanes with diboron reagents.
Figure 2
Figure 2
Preliminary mechanistic investigations. Yields were determined by GC-FID analysis.
Figure 3
Figure 3
Scope of C–H borylation reactions. Conditions: B2cat2 (0.3 mmol) and CuCl2 (20–100 mol %) in MeCN (1.5 mL, 0.2 M) were pre-stirred for 10 h, then alkane (5 equiv) was added and irradiated (390 nm Kessil lamps) for 16 h. Yields are of isolated products. Regioisomeric ratios (r.r.) and diastereomeric ratios (d.r.) were determined by GC analysis. Only the d.r. of the major regioisomer is shown, and the d.r. of the minor is given in the Supporting Information. The metal-free yields refer to those obtained using the conditions reported in a previous study.aUsing 20 mol % CuCl2. bReactions performed without pre-stirring CuCl2 and B2cat2. cUsing 100 mol % CuCl2. dThe r.r. and d.r. were determined by 1H NMR analysis after oxidation to the corresponding alcohol. eReaction was performed on a 3 mmol scale. fUsing alkane (20 equiv), 200 mol % CuCl2, and 40 mol % pyridine. gThe r.r. was determined by 1H NMR analysis.
Figure 4
Figure 4
C–H borylations of natural products and drug derivatives. Conditions: B2cat2 (0.3 mmol), alkane (5 equiv), CuCl2 (100 mol %), MeCN (1.5 mL, 0.2 M), 390 nm Kessil lamps, 40 °C, 16 h. Yields are of isolated products. Regioisomeric ratios (r.r.) and diastereomeric ratios (d.r.) were determined by GC analysis. The metal-free yields refer to those obtained using the conditions reported in ref (5). aReactions performed by pre-stirring CuCl2 and B2cat2 at r.t. for 10 h before adding the alkane and irradiating. bThe yields in parentheses were obtained using the alkane as the limiting reagent under the following conditions: alkane (0.3 mmol, 1 equiv), B2cat2 (0.6 mmol, 2 equiv), CuCl2 (200 mol %), MeCN (1.5 mL, 0.2 M), 390 nm Kessil lamps, 40 °C, 24 h. N(phth): N-phthalimido.
Figure 5
Figure 5
Proposed mechanism.
Figure 6
Figure 6
Mechanistic studies. Yields were determined by GC-FID analysis. The yield is based on the moles of product per mole of B2cat2; a yield above 100% reflects the conversion of the HOBcat by-product to the boronic ester product.
Figure 7
Figure 7
Mechanistic Investigation on regioselectivity. Yields were determined by GC-FID analysis.
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