A practical guide for using lithium halocarbenoids in homologation reactions

Abstract Lithium halocarbenoids are versatile reagents for accomplishing homologation processes. The fast α-elimination they suffer has been considered an important limitation for their extensive use. Herein, we present a series of practical considerations for an effective employment in the homologation of selected carbon electrophiles. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00706-018-2232-9) contains supplementary material, which is available to authorized users.


Materials and methods
All 1 H NMR and 13 C NMR spectra were recorded on Bruker Avance spectrometers operating at 200, 300, 400 or 500 MHz and at 50, 75, 100, or 125 MHz, respectively, from CDCl3 solutions. The (residual) solvent signal was used as an internal standard which was related to TMS with δ 7.26 ppm ( 1 H) and δ 77.0 ppm ( 13 C). Spin-spin coupling constants (J) are given in Hz. In some cases, full and unambiguous assignment of all 1 H, 13 C, resonances was performed by combined application of standard NMR techniques, such as APT, DEPT, HSQC, HMBC and NOESY experiments.
All melting points are uncorrected. Column chromatography purifications were conducted on silica gel 60 (40-63 μm). TLC was carried out on aluminum sheets pre-coated with silica gel 60F254; the spots were visualized under UV light (λ = 254 nm) and/or KMnO4 (aq.) was used as revealing system.
Starting materials were supplied from commercial sources otherwise indicated.
Elementary microanalyses were carried out using a Leco® CHNS 932 equipment.

Procedure A:
To a solution of ketone 7 (200 mg, 2.08 mmol, 1.0 equiv) in THF (2 mL) cooled at -78 °C was added freshly distilled chloroiodomethane (997 mg, 0.41 mL, 5.65 mmol, 3.0 equiv), followed by the addition of a solution of MeLi-LiBr complex (1.5 M, 3.52 mL, 5.28 mmol, 2.8 equiv) operated by syringe pump with flow of 0.2 ml/min. The mixture was stirred for 1 hour before it was quenched with saturated aq. NH4Cl (2 mL) and extracted with Et2O (3 x 5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and after removing the solvent under reduced pressure, analytically pure chlorohydrin 7a (260 mg, 85% yield) was obtained as a colourless oil.

Procedure B:
To a solution of ketone 7 (200 mg, 2.08 mmol, 1.0 equiv) and an additive (3.0 equiv) in THF (2 mL) cooled at -35 °C was added freshly distilled chloroiodomethane (997 mg, 0.41 mL, 5.65 mmol, 3.0 equiv), followed by the addition of a solution of MeLi-LiBr complex (1.5 M, 3.52 mL, 5.28 mmol, 2.8 equiv) operated by syringe pump with flow of 0.2 ml/min. The mixture was stirred for 1 hour before it was quenched with saturated aq. NH4Cl (2 mL) and extracted with Et2O (3 x 5 mL). The organic layer was washed with brine (5 mL), dried over Na2SO4, filtered and after removing the solvent under reduced pressure, analytically pure chlorohydrin 7a was obtained as a colourless oil.