Direct Borylation of Organohalides Using Mechanochemically Generated Calcium-Based Heavy Grignard Reagents (R-CaX)

doi:10.6023/A24090273

Abstract

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

Cite this article

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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Fig. & Tab. 8

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

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

Table 2. Substrate scope of organobromidesa

Table 3. Reactivity of slightly soluble arylboronates

Scheme 2. Other aryl halides

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.

Scheme 4. Step-wise experiment

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

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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