Stereo- and Regiocontrolled Methylboration of Terminal Alkynes

A scalable and operationally simple synthesis of trisubstituted alkenyl boronic esters has been achieved using a Zr-catalyzed carboalumination of terminal alkynes followed by in situ transmetalation with i-PrOBpin. The products are formed in good yields and with excellent regioselectivity and perfect stereoselectivity. The new procedure provides a significant improvement over the previously reported syntheses.


General Procedure, Small Scale
Zirconocene dichloride (29 mg, 0.1 mmol, 0.2 eq) was placed into a non-dry 25 mL pear-shaped flask and the atmosphere was exchanged with nitrogen 3 times. Reagent-grade CH 2 Cl 2 (500 ppm water, as stated by the vendor) was added (1.1 mL) to give a clear colorless solution, which was then cooled to 0 °C. If necessary, modified methylaluminoxane (MMAO-12, 7wt% in toluene, 0.22 mL, 0.50 mmol, 1 eq) was added at 0 °C at this point (see the main text for the discussion). AlMe 3 (2 M in toluene, 0.50 mL, 1.0 mmol, 2 eq) was added dropwise at 0 °C and the resulting clear yellowish solution was stirred for 5-10 min. Neat starting alkyne 1 (0.50 mmol) was then added with a syringe, the ice bath was removed, and the mixture was stirred at 23 °C overnight (14 hr). If GCMS analysis indicated incomplete consumption of the starting material, the reaction mixture was stirred further (in some cases, the carboalumination took up to 96 hr, as reported below). The reaction typically turned clear yellow by this point.
Neat i-PrOBpin (0.12 mL, 0.6 mmol, 1.2 eq) was then added at 0 °C in one portion, the ice bath was removed, and the mixture was stirred at 23 °C for 60 min. The Al-B exchange is fast (typically <5 min) and exothermic. In the absence of cooling, 10-30% of proto-demetallated side-product was observed.
The reaction mixture was then cooled to 0 °C and diluted with 5 mL of reagent-grade CH 2 Cl 2 . A solution of HCl (1 M in H 2 O, 1 mL) was added dropwise (caution: gas evolution!) and the mixture was stirred at 0 °C for 10 min, until gas evolution ceased. The mixture was then diluted with 1 M HCl (10 mL) and extracted with CH 2 Cl 2 (4×3 mL). The combined organic layer was washed with brine (4 mL) and dried over Na 2 SO 4 . The solution was passed through a plug of silica (w×h 1×2 cm), washing the plug with 10 mL of CH 2 Cl 2 , then concentrated. A 3-5 mg aliquot was submitted for NMR analysis to measure regioselectivity. Purification of the crude sample by silica chromatography then provided the target vinyl boronate (2% diethyl ether-pentane with a gradient to 10 or 20% of diethyl ether-pentane, as appropriate, over 10 column volumes).
Acid-sensitive substrates (silyl ethers) were worked up similarly, using pure water instead of HCl. Hardto-separate suspensions were observed in these cases.

General Procedure, Gram Scale
Zirconocene dichloride (350 mg, 1.2 mmol, 0.2 eq) was placed into a non-dry 100 mL round-bottom flask and the atmosphere has been exchanged for nitrogen 3 times. Reagent-grade CH 2 Cl 2 (13 mL; 500 ppm water, as stated by the vendor) was added to give a clear colorless solution. AlMe 3 (2 M in toluene, 6.0 mL, 12.0 mmol, 2 eq) was added dropwise at 0 °C and the resulting clear yellowish solution was stirred for 5-10 min. Neat starting alkyne 1 (6.0 mmol) was then added with a syringe over ca. 30 sec, the ice bath was removed and the mixture was stirred at 23 °C for 14 hr, until GCMS analysis indicated complete consumption of the starting material. The reaction turned clear yellow by this point.
The reaction mixture was then cooled to −50 °C (dry ice bath), and neat i-PrOBpin (1.48 mL, 7.2 mmol, 1.2 eq) was added to the rapidly stirred reaction mixture in one portion over ca. 5 sec (CAUTION: strong exotherm!) After 10 min, the ice bath was removed, and the mixture was stirred at 23 °C for 30-60 min. Note: in the absence of cooling, 30-40% of proto-demetallated side-product was observed; conversely, an attempt to control the exotherm by the slow addition of i-PrOBpin at 0 °C also resulted in diminished yieldsthis reagent should be added in one portion, presumably to avoid side reactions with the excess of vinyl aluminum species.
The reaction mixture was then cooled to 0 °C and diluted with 25 mL of reagent-grade CH 2 Cl 2 (~5 reaction volumes). Water (1 mL) was slowly added in 0.2 mL portions to quench reactive aluminum species, while avoiding thermal runaway (CAUTION: gas liberation). After 10 min, another 1 mL of water was added, and the mixture was stirred at 0 °C for 10 min, until bubbling ceased.
The reaction mixture was then diluted either with 1 M HCl (15 mL, for acid-stable products; allows to avoid [Al] precipitation) or water (15 mL, for acid-labile products), and extracted with CH 2 Cl 2 (3×10 mL). The combined organic layer was washed with brine (10 mL) and dried over Na 2 SO 4 , filtered, and concentrated. A 5 mg aliquot was submitted for 1 H NMR analysis to measure regioselectivity. Purification of the crude sample by silica chromatography then provided the target vinyl boronate (2% diethyl etherpentane with a gradient to 10 or 20% of diethyl ether-pentane, as appropriate, over 10 column volumes).
The reaction mixture was then placed into ice bath (0 °C) and the unreacted materials were carefully quenched with water (10 mL; CAUTION: intense gas liberation). The product was then extracted with pentane (4×8 mL), washed with brine (5 mL), dried over Na 2 SO 4 and carefully concentrated (200 Torr, 25 °C). Careful fractional distillation in Kugelrohr (80 °C/300 Torr to remove impurities, then 80→100 °C/225 Torr to distill the product) then afforded the product as a clear colorless, volatile, oil.
Clear colorless oil.
Clear colorless oil.
Clear yellow oil.