铜催化的烷基溴和芳基硼酸酯的羰基化的铃木-宫浦反应

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

摘要/Abstract

摘要：

过渡金属催化的羰基化反应是构建含羰基化合物重要的手段之一, 使用不同种类的亲核试剂作为反应组分, 对应的各种不同类别的含羰基类产品, 比如羧酸、酰胺、酯、醛等都可以被高效地制备. 在使用碳亲核试剂作为反应组分的时候, 酮类化合物就可以成为目标产品. 酮作为非常重要的中间体原料, 被广泛的应用于精细化学品及高端材料的制备. 但是其羰基化合成的挑战在于碳亲核试剂的弱亲核性, 与氮或者氧亲核试剂相比, 其对催化体系的要求更高. 另一方面, 在亲电试剂方面, 烷基类底物由于底物中β-氢的存在, 使得其高选择性的化学转化更加具有挑战. 同时, 由于在一氧化碳的氛围下, 一氧化碳分子对金属中心的络合配位会降低催化中心的电子云密度, 使得亲电试剂的活化更加困难, 进而烷基溴的羰基化活化进一步受限. 在催化剂的使用方面, 目前绝大多数的工作都是以贵金属铑、铱和钯等为主. 对于丰产金属, 如铜、镍、铁和钴等的研究比较少. 其中铜催化剂具有成本低廉和低毒性等特点, 虽然它在材料领域有着广泛应用, 但是在羰基化反应中的探索还相对较少.

本文实现了真正意义上的铜催化的烷基溴的羰基化的铃木-宫浦反应. 以未活化的烷基溴(包括一级溴代物、二级溴代物、三级溴代物)和芳基硼酸酯作为原料, 以常见的铜盐作为催化剂, 可以高效高选择性制得各种官能团及多位点取代的烷基芳基酮. 以二级溴代物为例, 各种张力环底物都能被高效的转化为对应的烷基芳基酮产品. 在官能团的兼容性方面, 酯基、醚、醛基、氰基等官能团都能被很好的兼容. 通过自由基控制实验, 我们可以检测到各种相关的自由基被捕获的中间体化合物, 证明了该反应经历了自由基中间体. 另外, 通过中间体配合物的研究, 我们发现反应应该从催化剂和亲核试剂的反应开始. 在合适的配体及反应环境下, 芳基硼酸酯先和铜催化剂反应得到芳基铜中间体, 继而活化烷基溴得到最终产品.

后续工作也在开展中, 主要分为三个方面: 分别是1)底物适应性的拓展，更加惰性的烷基氯或者脂肪醇的直接活化; 2)反应机理的进一步探索, 为新的反应设计提供思路; 3)手性版本的转化. 这些工作的展开将极大的加深对铜催化剂在烷基类底物羰基化中应用的理解, 也将开启铜催化羰基化的新篇章.

关键词: 铜催化剂, 烷基溴, 羰基化反应, 铃木-宫浦反应, 芳基硼酸酯

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

张佳骏, 吴小锋. 铜催化的烷基溴和芳基硼酸酯的羰基化的铃木-宫浦反应[J]. 催化学报, 2025, 73: 146-152.

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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链接本文: https://www.cjcatal.com/CN/10.1016/S1872-2067(25)64700-0

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

图/表 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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