Enantiospecific Alkynylation of Alkylboronic Esters

Abstract Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel‐type alkenylation followed by a 1,2‐elimination reaction. The process involves use of α‐lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel‐type reactions has not previously been explored. The resulting functionalized 1,1‐disubstituted alkenes undergo facile base‐mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl‐protected alkynes can be formed by simply introducing a suitable carbon‐ or silicon‐based electrophile after the base‐mediated 1,2‐elimination reaction.


Reaction Optimization
To a stirred solution of 1a (0.15 mmol, 1.0 equiv.) and 2a (1.0 M in THF, 1.3-2.0 equiv.) in solvent (1.0 mL) under N2 at T °C (see table below) was added freshly prepared LDA (0.86 M in THF or Et2O, dropwise (approximately rate of addition = 10 µL every 10 s). The solution was then stirred at T °C for 1 h 3 before the addition of a solution of I-X (1.5-2.2 equiv.) in methanol (2.0 mL) dropwise over 5 min. The reaction was stirred for 5 min at T °C before warming to r.t. and stirred for a further 1 h. After this time a sample was removed and analysed by GCMS.

General Procedure A:
To a stirred solution of 2a (1.0 M in THF, 0.60 ml, 0.60 mmol) and 1 (0.30 mmol) in diethyl ether (2.0 mL) under N2 at -95 °C was added freshly prepared LDA (0.86 M in THF, 0.70 mL, 0.60 mmol) dropwise at a rate of approximately 10 µL every 10 s. The resulting solution was stirred for 1 h at -95 °C before the addition of a solution of I2 (168 mg, 0.66 mmol) in MeOH (2.0 mL) dropwise over 10 min. The reaction was stirred for 5 min at -95 °C before warming to r.t. and stirring for 1 h. The reaction was quenched by the addition of 20% Na2S2O3 (10 mL) and the aqueous phase extracted with Et2O (2 × 15 mL). The combined organic phases were washed with water (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was then re-dissolved in DMF (4.0 mL) and TBAF•3H2O (473 mg, 1.50 mmol) was added. The resulting solution was heated to 60 °C for 1 h before being cooled to r.t. and diluted with H2O (10 mL). The aqueous phase was extracted with Et2O (2 × 15 mL) and the combined organic phases dried over MgSO4, filtered and concentrated in vacuo. The crude product purified by flash column chromatography on silica gel.
Representative TLC example shown below for General Procedure A:

General Procedure B:
To a stirred solution of 2a (1.0 M in THF, 0.60 ml, 0.60 mmol) and 1 (0.30 mmol) in diethyl ether (2.0 mL) under N2 at -95 °C was added freshly prepared LDA (0.86 M in THF, 0.70 mL, 0.60 mmol) dropwise at a rate of approximately 10 µL every 10 s. The resulting solution was stirred for 1 h at -95 °C before the addition of a solution of I2 (168 mg, 0.66 mmol) in MeOH (2.0 mL) dropwise over 10 min. The reaction was stirred for 5 min at -95 °C before warming to r.t. and stirring for 1 h. The reaction was quenched by the addition of 20% Na2S2O3 (10 mL) and the aqueous phase extracted with Et2O (2 × 15 mL). The combined organic phases were washed with water (15 mL), dried over MgSO4, filtered and concentrated in vacuo. The crude product was then re-dissolved in THF (2.0 mL) and cooled to -78 °C before the dropwise addition of LDA (0.86 M, 0.80 mmol, 0.93 mL in THF). The reaction was removed from the cold bath and stirred at r.t. for 1 h before quenching with saturated NH4Cl(aq) (10 mL). The aqueous phase was extracted with Et2O (2 × 15 mL) and the combined organic phases dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel.

General Procedure C:
To a stirred solution of 2b (68 mg, 0.40 mmol) 5 and 1 (0.30 mmol) in THF (2.0 mL) under N2 at -78 °C was added freshly prepared LDA (0.86 M in THF, 0.47 mL, 0.40 mmol) dropwise at a rate of approximately 10 µL every 10 s. The resulting solution was stirred for 1 h at -78 °C before the addition of a solution of I2 (102 mg, 0.40 mmol) in MeOH (2.0 ml) dropwise over 5 min. The reaction was stirred for 5 min at -78 °C before warming to r.t. and stirred for 1 h. The reaction was quenched by the addition of 20% Na2S2O3 (10 mL) and the aqueous phase extracted with Et2O (2 × 15 mL). The combined organic phases were washed with water

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(15 mL), dried over MgSO4, filtered through a short pad of silica gel (2 cm) and concentrated in vacuo. The crude product was then re-dissolved in Et2O (3.0 ml) cooled to -78 °C and t BuLi (1.7 M, 0.44 ml, 0.75 mmol) was added. The reaction was then transferred to a 0 °C bath and stirred for 30 min before the addition of saturated NH4Cl(aq) (10 mL). The aqueous phase was extracted with Et2O (2 × 15 mL) and the combined organic phases dried over MgSO4, filtered and concentrated in vacuo. The crude product purified by flash column chromatography on silica gel.
Representative TLC example shown below for General Procedure C:

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The starting boronic ester 1b (er 98:2, 86 mg, 0.30 mmol) was reacted with vinyl bromide according to General Procedure A. The crude product was purified by column chromatography (petroleum ether) to afford the title compound as a colourless oil in 54% yield (30 mg) and 98:2 er (100% es).
The product 3q' (122 mg, 0.400 mmol) was then dissolved in Et2O (4.0 ml) cooled to -78 °C and t BuLi (1.7 M, 0.26 ml, 0.44 mmol) was added. The reaction was then transferred to a 0 °C bath and stirred for 30 min before the addition of saturated NH4Cl(aq) (10 mL). The aqueous phase was extracted with Et2O (2 × 15 mL) and the combined organic phases dried over MgSO4, filtered and concentrated in vacuo. The crude product purified by preparative TLC on silica gel (petroleum ether/ethyl acetate = 10:1) to give 6q as a colourless oil in 37% yield (24 mg) and 98:2 er (98% es) along with recovered 3q' (42 mg). Yield of 6q based on recovered starting material = 56%.