Haloboration of Internal Alkynes with Boronium and Borenium Cations as a Route to Tetrasubstituted Alkenes

Hail boration! 2-Dimethylaminopyridine-ligated dihaloborocations [X2B(2-DMAP)](+) with a strained four-membered boracycle were used for the haloboration of terminal and dialkyl internal alkynes (see scheme). Esterification then provided vinyl boronate esters as useful precursors to tetrasubstituted alkenes. Following mechanistic studies, the scope of the haloboration was expanded simply by variation of the amine. Pin = 2,3-dimethyl-2,3-butanedioxy.


General Considerations
All manipulations of air and moisture sensitive species were performed under an atmosphere of argon or nitrogen using standard Schlenk and glovebox techniques. Glassware was dried in a hot oven overnight and heated before use. Hexane, ortho -dichlorobenzene, d 1 -chloroform, d 2 -dichloromethane, 2,6-lutidine, Et 3 N and were dried over calcium hydride and distilled under vacuum. Pentane and dichloromethane were dried by passing through an alumina drying column incorporated into an MBraun SPS800 solvent purification system. All solvents were degassed and stored over molecular sieves (3Å) under inert atmosphere or in the glovebox. 2, 6- To a 1M solution of BCl 2 Ph (0.83 ml, 6.33 mmol) in anhydrous CH 2 Cl 2 , 2-dimethylaminopyridine (79 ml, 6.33 mmol) was added. NMR spectroscopy was used to confirm the reaction, to which Aluminium trichloride (0.84 g, 6.33 mmol) was added. A solid precipitated out of solution, and the solvent was removed under reduced pressure, leaving a white solid. This was washed with CH 2 Cl 2 (10 ml, x3) and 3 was isolated as a white powder (2.02 g, 4.89 mmol, 77%). 2DMAP (0.13 ml, 1 mmol) was added to a solution of Chlorocatecholborane (154 mg, 1 mmol) in DCM (2 ml) in a greased schlenk, giving immediate formation of a yellow colour. The solvent was removed in vacuo, and AlCl 3 (133 mg, 1 mmol) was added. The mixture was dissolved in oDCB (3 ml) and stirred until dissolution occurred to give a bright yellow solution. The mixture was layered with n Hexane and crystals grown over 5 days. The crystals were isolated by filtration, washed with oDCB (3 ml) and n Hexane (2x5 ml) and dried in vacuo to give 4 as yellow plates (218 mg, 0.53 mmol, 53%) Reaction of 1 with PPh 3 A J. Young's fitted NMR tube fitted with a d 6 -DMSO capillary was charged with 1 (38mg, 0.1mmol) in DCM (1cm 3 ) and PPh 3 (26mg, 0.1mmol) was added and the NMR recorded immediately. The retained sole sharp peak at 103.22ppm in the 27 Al NMR spectrum indicates that the anion [AlCl 4 ] remains the major 27 Al containing species in solution, indicating that halide transfer has not occurred. The 11 B NMR spectrum shows some residual 1 (12.1ppm), and two new signals showing B-P coupling. The minor signal at 3.24ppm ( 1 J B-P =155.3Hz) is the simple Cl 3 B-PPh 3 adduct, with the major signal at 3.85ppm ( 1 J B-2-(3,3-dimethylbut-1-yn- (Z)-2-(2-chloro-3,3-dimethylbut-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a suspension of [Cl 2 B(2DMAP)][AlCl 4 ] (50 mg, 0.14 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, t Bu acetylene (17 µl, 0.14 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a white oil (20 mg, 0.08 mmol, 63%). (Z)-2-(2-chloro-2-phenylvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a suspension of [Cl 2 B(2DMAP)][AlCl 4 ] (50 mg, 0.14 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, phenylacetylene (15 µl, 0.14 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a yellow oil (30 mg, 0.12 mmol, 88%). (Z)-2-(2-chloropent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a suspension of [Cl 2 B(2DMAP)][AlCl 4 ] (50 mg, 0.14 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, 1-pentyne (17 µl, 0.14 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a white oil (26 mg, 0.11 mmol, 73%). (Z)-2-(2-chloro-2-(p-tolyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a suspension of [Cl 2 B(2DMAP)][AlCl 4 ] (50 mg, 0.14 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, 4-ethynyl toluene (17 µl, 0.14 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a yellow oil (24 mg, 0.09 mmol, 65 %). (Z)-2-(2-bromopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a suspension of [Br 2 B(2DMAP)][BBr 4 ] (100 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, 1-pentyne (16 µl, 0.16 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a pale yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a yellow oil (34 mg, 0.12 mmol, 78%).
To a suspension of [Br 2 B(2DMAP)][BBr 4 ] (100 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, 3-hexyne (19 µl, 0.16 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, as evidenced by desymeterisation of the 3-hexyne, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The crude product was then purified using column chromatography in 1:1 DCM:petroleum ether. The product was isolated as a yellow oil (29 mg, 0.10 mmol, 62%). To a suspension of [Br 2 B(2DMAP)][BBr 4 ] (100 mg, 0.16 mmol) in anhydrous CH 2 Cl 2 in a J.Young's NMR tube, 2-methyl-4-pentyne (0.16 mmol) was added, turning light yellow and dissolving some of the precipitate. The reaction mixture was then stirred at room temperature for 18 hours, during which time the precipitate fully dissolved. NMR spectroscopy was used to confirm reaction completion, as evidenced by desymeterisation of the 3-hexyne, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities, and did not require further purification. The product was isolated as a colourless oil (24 mg, 0.08 mmol, 52 %). (E)-2-(4-chlorohex-3-en-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane LutBCl 3 (50 mg, 0.22 mmol) was suspended in anhydrous o-C 6 H 4 Cl 2 in a J.Young's NMR tube, to which AlCl 3 (25 µl, 0.22 mmol) was added, causing dissolution to a clear yellow solution. To this [LutBCl 2 ][AlCl 4 ], 3-hexyne (25 µl, 0.22 mmol) was added, turning dark brown. The reaction mixture was then stirred at room temperature for 24 hours, NMR spectroscopy confirmed reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving an orange oil. Pentane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a yellow/orange oil (44 mg, 0.18 mmol, 81 %).

Elemental Analysis
Calculated: C 58.93; H 9.07. Observed: C 59.00; H 9.09 nOe spectroscopy shows through space interaction between points 1.05 and 0.93.

Elemental Analysis
Calculated: C 61.16; H 6.84; Observed: C 61.14; H 6.80; (nOe shows through space interaction between the vinylic proton (5.94 ppm) and phenyl (7.56 ppm) resonance, but no interaction between phenyl and pinacol resonances) (E)-2-(1-chloro-1-phenylpenta-1,4-dien-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane LutBCl 3 (50 mg, 0.22 mmol) was suspended in anhydrous o-C 6 H 4 Cl 2 in a J.Young's NMR tube, to which AlCl 3 (30 mg, 0.22 mmol) was added, causing dissolution to a clear yellow solution. To this [LutBCl 2 ][AlCl 4 ], 1-phenyl-4-penten-1-yne (34 µl, 0.22 mmol) was added, turning dark brown. The reaction mixture was then stirred at room temperature for 4 hours, NMR spectroscopy confirmed reaction completion, and the solution was esterified with excess triethylamine and 2 equivalents of pinacol. The solvent was removed under reduced pressure, leaving a yellow/orange oil. Hexane was used to extract the product, which was passed through a 1 inch plug of silica to remove pinacol impurities. The product was isolated as a colourless oil (35 mg, 0.12 mmol, 53% (nOe shows through space interaction between the CH 2 (2.81 ppm) and pinacol (1.27 ppm) resonances, but no interaction between pinacol and any phenyl resonances) Reaction of 6 with PhCCH -Thermal stability test A J. Young's NMR tube fitted with a d6 0.18mmol) and AlCl 3 (24mg, 0.18mmol) and DCM (1cm dissolution was complete. Phenylacetylene (20 immediately. Formation of the haloborated alkylboreniu then refluxed at 60°C for 85 hours, after which the crude NMR spectra were found to be largely unchanged as seen in the example 1H NMR Thermal stability test A J. Young's NMR tube fitted with a d6-DMSO capillary was charged with Lutidine (24mg, 0.18mmol) and DCM (1cm 3 ) added, the tube then gently inverted until dissolution was complete. Phenylacetylene (20µl, 0.18mmol) was added and a red colour formed immediately. Formation of the haloborated alkylborenium was quantitative. The reaction mixture was then refluxed at 60°C for 85 hours, after which the crude NMR spectra were found to be largely unchanged as seen in the example 1H NMR spectra below.
DMSO capillary was charged with Lutidine-BCl 3 adduct (40mg, ) added, the tube then gently inverted until l, 0.18mmol) was added and a red colour formed m was quantitative. The reaction mixture was then refluxed at 60°C for 85 hours, after which the crude NMR spectra were found to be largely Reaction progress based on consumption of alkynyl C-H resonance and growth of vinylic C-H resonance by 1 H NMR spectroscopy (Vs. an internal standard), expressed as a percentage.
To the product, Pd 2 (dba) 3 ( 0.05 eq), P t Bu 3 (0.2 eq), 4-fluorophenyl boronic acid (1 eq) were added in THF. To this, 3M KOH (3 eq) was added and the reaction stirred for 18 hours. The reaction was quenched with aqueous ammonium chloride and extracted with ether. The extract was washed with water, dried over MgSO 4 , and concentrated under reduced pressure to yield a yellow/brown oil. This crude product was purified with column chromatography using 2:1 hexane:DCM eluent. The major product shows an R f value of 0.60, and presented as a colourless oil (249 mg, 51 %) X-ray Crystallography Data for compounds 1, 4 and 5 were recorded on an Oxford Xcalibur Sapphire2 diffractometer, with Mo Kα radiation (graphite monochromator, λ=0.71073). The CrysAlisPro [2] software package was used for data collection, cell refinement and data reduction. Empirical absorption corrections were applied using spherical harmonics, implemented in SCALE3 ABSPACK scaling algorithm. Data for compound 3 were recorded on a Bruker APEX-II diffractometer, with Cu Kα radiation (graphite monochromator, λ= 1.54178). The Bruker APEX2 software package was used for data collection, and the Bruker SAINT [3] software package was used for cell refinement and data reduction. Empirical absorption corrections were applied using SADABS-2008/1 -Bruker AXS area detector scaling and absorption correction All structures were solved using direct methods [4] and refined against F 2 using the Crystals [5] software package. Non-hydrogen atoms were refined anisotropically. Hydrogen atoms were all located in a difference map and repositioned geometrically. Experimental details are given below in Table 1.