Cyclohexene-1-boronic acid pinacol ester CAS No: 141091-37-4

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Background Technology:
In drug active molecules, cyclopentenyl and cyclohexenyl groups are increasingly common as typical structural units and are often introduced as substituents to investigate structure-activity relationships. In recent years, the Suzuki coupling of cyclopentenylboronic acid pinacol ester and cyclohexen-1-boronic acid pinacol ester with corresponding chlorinated, brominated or iodinated heterocyclic and aromatic compounds has become a commonly used method for introducing cyclohexenyl or cyclohexenyl groups. Therefore, cyclohexen-1-boronic acid pinacol ester, as one of the important raw materials for coupling reactions, has been reported in many literatures for its synthesis methods.

The reaction. Currently known methods for synthesizing cyclohexene-1-boronic acid pinacol ester all involve refluxing cyclohexanone with an equivalent amount of p-toluenesulfonyl hydrazide in ethanol, followed by filtration to obtain cyclohexyl p-toluenesulfonyl hydrazone; then, 4 equivalents of n-butyl lithium are added at -45°C to -60°C to 1 equivalent of cyclohexyl p-toluenesulfonyl hydrazone and 5 equivalents of TMEDA, and the temperature is raised to room temperature. After the raw materials are completely reacted, the temperature is reduced to -70°C, and isopropoxyboronic acid pinacol ester is added dropwise while maintaining the temperature between -60°C and -70°C. After the addition is complete, stir for 2 hours, then allow to warm to room temperature, quench, extract and distill to obtain the product. However, this method has many drawbacks: (1) The reaction requires ultra-low temperatures, making industrial-scale operations cumbersome and increasing refrigeration costs; (2) The selectivity of the reaction is very poor, with many impurities, and the yield is low during vacuum distillation; (3) The literature uses 4 equivalents of n-butyl lithium, and isopropoxyboronic acid pinacol ester needs to be prepared in-house, which increases raw material costs and poses safety risks during operation.

Preparation process:
Step 1: Preparation of 1-chlorocyclohexene:
In a 2L four-necked flask equipped with a magnetic stirrer, thermometer, condenser and tail gas alkali solution absorption device, add 320.30g (1.556mol) of phosphorus pentachloride and 800g of n-heptane, heat to 70℃~74℃, and dropwise add a mixed solution of 150g (1.533mol) of cyclohexanone and 100g of n-heptane over about 2 hours. After the addition is complete, continue the reaction for half an hour. Then, cool to 0℃ and dropwise add 1L of 2mol/L sodium hydroxide solution, stir for 1 hour, separate the upper organic layer, dry with anhydrous magnesium sulfate, and perform vacuum distillation. Collect the middle fraction at 34~36℃ to obtain 1-chlorocyclohexene weighing 148.09g, with a GC purity of 97.9% and a yield of 82.2%.
Step 2: Preparation of 1-cyclohexene-1-boronic acid pinacol ester:
To a 2L four-necked flask equipped with a mechanical stirrer, thermometer, argon gas protection device and reflux condenser, add 1-chlorocyclohexene 148.09g (1.261 mol), palladium chloride 2.22g (0.0126 mol), tricyclohexylphosphine 7.03g (0.0252 mol), bis(pinacolato)borane 336.44g (1.324 mol), potassium acetate 370.12g (3.783 mol), and toluene 1L. Heat to 110°C and reflux for 12 hours, with GC monitoring. After the reaction is complete, filter the reaction mixture using 10g of diatomaceous earth as the main filter aid, and discard the filter cake. Wash the organic layer twice with 400mL of water (200×2), and dry the organic layer with 10g of anhydrous magnesium sulfate for 4 hours. Filter out the drying agent, distill off the toluene from the filtrate under reduced pressure, and obtain 1-cyclohexene-1-boronic acid pinacol ester product 226.62g, with a yield of 86.4% and a purity of 97.9% [1].