使用机械化学生成的钙基重格氏试剂(R-CaX)对有机卤化物进行直接硼化

doi:10.6023/A24090273

摘要/Abstract

钙基重格氏试剂(R-CaX)的研究由于其合成难度大, 至今应用较少. 钙基重格氏试剂相较于镁基格氏试剂(R-MgX)而言, 碳金属键具备更强的极性和离子化特性, 因此可以在某些转化中表现出独特的反应活性. 传统合成钙基重格氏试剂需对金属钙进行预先活化, 例如使用有毒的液氨或者高活性的金属锂, 这些苛刻的反应条件严重阻碍了其在实验室和工业生产中的应用. 本研究利用球磨机产生的持续的机械能破坏金属钙表面的惰性氧化层, 实现钙的原位活化, 随后直接插入卤代烃的碳卤键, 原位生成相应的钙基重格氏试剂. 随后, R-CaX作为碳亲核试剂与频哪醇硼烷(HBpin)反应, 成功合成了有机硼化合物, 并具有良好的底物兼容性; 特别是在使用难溶溴代芳烃作为底物时, 该机械化学方法与传统溶液反应体系相比, 展现出独特的优势.

关键词: 钙基重格氏试剂, 机械化学, 硼化反应, 绿色化学, 无溶剂

The study of calcium-based Grignard reagents (R-CaX) has historically been limited due to the challenges in their synthesis. However, calcium’s biocompatibility and distinct chemical properties make it a highly promising candidate for organic synthesis applications. Unlike their magnesium-based counterparts (R-MgX), calcium-based reagents exhibit stronger polarity and a higher degree of ionic character in the carbon-metal bond. This increased ionic nature can result in unique reactivity, offering advantages in specific transformations where magnesium-based reagents may be less effective. Traditional methods for synthesizing calcium-based Grignard reagents are cumbersome, requiring the pre-activation of metallic calcium through processes involving toxic materials such as liquid ammonia or highly reactive lithium. These harsh conditions not only present safety concerns but also limit the reagents' practicality, particularly in industrial applications where scalability and safety are crucial. In recent years, mechanochemistry has emerged as a sustainable alternative to conventional methods, providing opportunities to improve reaction efficiency and reduce the use of solvents. The mechanical energy generated by ball milling has been shown to disrupt the inert surface layer of metallic calcium, allowing for in situ activation. This enables the calcium to react with organohalides, forming calcium-based Grignard reagents without the need for toxic reagents or complex pre-activation steps. Once formed, these reagents can act as carbon nucleophiles, reacting with pinacolborane (HBpin) to form organoboron compounds, which are valuable intermediates in organic synthesis. This study demonstrates that by utilizing the continuous mechanical energy of ball milling, a variety of boronated products can be synthesized efficiently and with high yields. The method also shows broad substrate compatibility, particularly excelling in reactions involving poorly soluble aryl bromides, where traditional solution-based systems often fail. In conclusion, this work marks the first successful application of calcium-based Grignard reagents in borylation reactions via mechanochemical methods, offering a novel and efficient approach that addresses the limitations of conventional techniques.

Key words: calcium-based heavy Grignard reagent, mechanochemistry, borylation reaction, green chemistry, solvent-free

引用此文

刘雨涵, 高盼. 使用机械化学生成的钙基重格氏试剂(R-CaX)对有机卤化物进行直接硼化[J]. 化学学报, 2024, 82(11): 1114-1119.

Yuhan Liu, Pan Gao. Direct Borylation of Organohalides Using Mechanochemically Generated Calcium-Based Heavy Grignard Reagents (R-CaX)[J]. Acta Chimica Sinica, 2024, 82(11): 1114-1119.

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图/表 8

图式1. 钙基重格氏试剂(R-CaX)的发展

Scheme 1. Development of R-CaX

Entry	Various of standard conditions	Yield of 3a^b/%
1	none	85
2	3.0 equiv. of THF	78
3	5.0 equiv. of THF	60
4	DME instead of THF	66
5	1,4-dioxone instead of THF	45
6	Et₂O instead of THF	71
7	DMF instead of THF	12
8	toluene instead of THF	6
9	hexane instead of THF	19
10	1.0 equiv. of Ca	69
11	2.0 equiv. of Ca	77
12	4.0 equiv. of 2	80
13	2.0 equiv. of 2	55
14	frequency=15 Hz	45
15	80 ℃	84
16	Zn instead of Ca	21
17	Mg instead of Ca	49
18	Li instead of Ca	33
19	under N₂	81
20	in solution^c	0

表1. 机械化学合成芳基硼化物3a的条件优化a

Table 1. Optimization of reaction conditions for the mechanochemical synthesis of arylboronate 3a

表2. 溴代烃的底物范围a

Table 2. Substrate scope of organobromidesa

表3. 微溶溴代芳烃的反应活性

Table 3. Reactivity of slightly soluble arylboronates

图式2. 其它卤代芳烃

Scheme 2. Other aryl halides

图式3. 克级反应a

Scheme 3. Gram-scale reactiona a Reaction conditions: 1a (10.0 mmol), 2 (30.0 mmol), Ca (7.5 mmol), THF (40.0 mmol), in a stainless-steel ball-milling jar (10 mL) with two stainless-steel balls (diameter: 10 mm). Isolated yield.

图式4. 分步实验

Scheme 4. Step-wise experiment

图式5. 使用液氨活化的金属钙制备相应的有机钙试剂

Scheme 5. Preparation of corresponding Ar-CaBr using calcium activated by liquid ammonia

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