Copper-catalyzed carbonylative Suzuki-Miyaura coupling of un-activated alkyl bromides with aryl boronates

doi:10.1016/S1872-2067(25)64700-0

Abstract

Abstract:

Herein, we present a copper-catalyzed carbonylative cross-coupling of unactivated alkyl bromides with aryl boronates under CO atmosphere which enabling the efficient synthesis of C(sp³)-C(sp²) ketones with extensive functional group compatibility. This strategy represents a significant advance in copper-catalyzed carbonylation involving alkyl bromides and C(sp²)-nucleophiles. The protocol addresses key challenges commonly encountered in the coupling of C(sp³)-alkyl halides with aryl boron reagents, such as sluggish oxidative addition of alkyl halides, competing Suzuki-Miyaura cross-coupling, undesired dehalogenation and so on. Distinguished by its broad substrate scope and high functional group tolerance, this approach offers a robust and versatile platform for the streamlined synthesis of alkyl aryl ketones.

Key words: Copper catalysis, Unactivated alkyl bromides, Carbonylation, Suzuki-Miyaura coupling, Arylborons

Jiajun Zhang, Xiao-Feng Wu. Copper-catalyzed carbonylative Suzuki-Miyaura coupling of un-activated alkyl bromides with aryl boronates[J]. Chinese Journal of Catalysis, 2025, 73: 146-152.

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URL: https://www.cjcatal.com/EN/10.1016/S1872-2067(25)64700-0

https://www.cjcatal.com/EN/Y2025/V73/I6/146

Figures/Tables 6

Scheme 1. Transition metal-catalyzed carbonylative cross coupling of unactivated alkyl halides.

Table 1 Optimization of the reaction conditions a.

Entry	Ligand	[Cu]	Base	Yield^b (%)
1	L1	CuBr·SMe₂	KO^tBu	77
2	L2	CuBr·SMe₂	KO^tBu	82（80）
3	L3	CuBr·SMe₂	KO^tBu	25
4	L4	CuBr·SMe₂	KO^tBu	49
5	L5	CuBr·SMe₂	KO^tBu	17
6	L8	CuBr·SMe₂	KO^tBu	70
7	L9	CuBr·SMe₂	KO^tBu	71
8	L10	CuBr·SMe₂	KO^tBu	59
9	L2	CuOTf	KO^tBu	79
10	L2	CuBr	KO^tBu	80
11	L2	CuBr₂	KO^tBu	<1
12	L2	CuBr·SMe₂	NaO^tBu	58
13	L2	CuBr·SMe₂	LiO^tBu	<1
14	L2	CuBr·SMe₂	KOMe	<1
15	L2	CuBr·SMe₂	K₂CO₃	<1
16 ^c	L2	CuBr·SMe₂	NaO^tBu	35
17 ^d	L2	CuBr·SMe₂	KO^tBu	59

Scheme 2. Unactivated alkyl electrophile scope of copper-catalyzed carbonylative Suzuki-Miyaura reaction. Reaction conditions: alkyl bromide (0.20 mmol), arylboronic acid esters (0.40 mmol, 2.0 equiv), CuBr·SMe2 (0.01 mmol, 5.0 mol%), L2 (0.015 mmol, 7.5 mol%), KOtBu (0.40 mmol, 2.0 equiv), CO (40 atm), 1,4-dioxane (0.50 mL) under 100 °C for 20 h.

Scheme 3. Arylboronic acid esters scope of copper-catalyzed carbonylative Suzuki-Miyaura reaction. Reaction conditions: alkyl bromide (0.20 mmol), arylboronic acid esters (0.40 mmol, 2.0 equiv), CuBr·SMe2 (0.01 mmol, 5.0 mol%), L2 (0.015 mmol, 7.5 mol%), KOtBu (0.40 mmol, 2.0 equiv), CO (40 atm), 1,4-dioxane (0.50 mL) under 100 °C for 20 h.

Scheme 4. Preliminary mechanistic studies.

Scheme 5. Possible mechanism.

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