The Kulinkovich reaction allows the preparation of cyclopropanol derivatives by the reaction of Grignard reagents with carboxylic esters in the presence of titanium(IV) isopropoxide.
Reaction mechanism of Kulinkovich reaction
Suggested reaction mechanism:
- Dialkylation of the titanium catalyst with two equivalents of ethylmagnesium bromide.
- β-hydride elimination gives ethane and titanacyclopropane.
- This titanacyclopropane reacts with the carboxylic ester to produce a cyclopropanol derivative.
- Addition of ethylmagnesium bromide to the titanium complex delivers the magnesium cyclopropoxide product while regenerating the diethyltitanium intermediate.
- Aqueous/acidic workup yields the 1-cyclopropanol product.
For additional details on the chemistry of cyclopropanols, refer to Chem. Rev. 2003, 103, 2597.
Examples and experimental procedures of Kulinkovich reaction
Example 2: Angew. Chem. Int. Ed. 2022, 61, e202115633.
The methyl ester (9.98 mmol, 1.0 equiv) was combined with ClTi(OiPr)3 (0.46 M in THF, 4.8 equiv) under argon. The solution was cooled to 0 ºC, and then EtMgBr (1.0 M in THF, 9.6 equiv) was added dropwise over a 1.5 h period. The solution was left to stir at 0 ºC for another 1 h, and then to room temperature for 30 min. The reaction was quenched by the addition of EtOAc followed by saturated aqueous NH4Cl. The solution was filtered through a Celite pad, followed by EtOAc, and the filtrate was concentrated under reduced pressure and diluted with EtOAc and brine. The organic phase was collected, and the aqueous phase was washed with additional EtOAc. The combined organic phases were dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography to afford the desired cyclopropanol (86% yield).
Example 1: Angew. Chem. Int. Ed. 2018, 57, 15209.
To a solution of the lactone (4.6 mmol, 1.0 equiv) in THF (16 mL), a solution of ClTi(OiPr)3 (1.0 M in THF, 2.4 equiv) was added at room temperature. The reaction mixture was cooled to 0 ºC, and a solution of EtMgBr (1.0 M in THF, 4.8 equiv) was added dropwise from a syringe over 10 min. After gas evolution ceased, the reaction mixture was warmed to room temperature. The flask was then tightly sealed with a plastic cap and stirred vigorously at room temperature for 36 h. The reaction mixture was diluted with EtOAc and quenched with sat. aq. NH4Cl. Triethylamine was added, and the reaction mixture was stirred for 30 min. The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated to yield a crude residue, which was purified by flash column chromatography to afford the cyclopropanol product.
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