A multicomponent approach for the preparation of homoallylic alcohols

The generation of transient boronic acid species followed by their subsequent trapping with aldehydes as electrophiles to yield homoallylic alcohols, in a multicomponent and metal-free fashion.


General experimental details
All batch reactions were performed using oven-dried glassware (200 °C) under an atmosphere of argon unless otherwise stated. All flow reactions were performed using a Uniqsis FlowSyn platform 1 or a Vapourtec R2+R4 system. 2 Solvents were freshly distilled over sodium benzophenone ketyl (THF) or calcium hydride (CH 2 Cl 2 , hexane and EtOAc). All reagents were obtained from commercial sources and used without further purification.
Flash column chromatography was performed using high-purity grade silica gel (Merck grade 9385) with a pore size 60 Å and 230-400 mesh particle size under air pressure. Analytical thin layer chromatography (TLC) was performed using silica gel 60 F 254 pre-coated glass backed plates and visualized by ultraviolet radiation (254 nm) and/or potassium permanganate solution as appropriate. 1 H NMR spectra were recorded on a 600 MHz Avance 600 BBI Spectrometer as indicated. Chemical shifts are reported in ppm with the resonance resulting from incomplete deuteration of the solvent as the internal standard (CDCl 3 : 7.26 ppm). 13 C NMR spectra were recorded the same spectrometer with complete proton decoupling. Chemical shifts are reported in ppm with the solvent resonance as the internal standard ( 13 CDCl 3 : 77.16 ppm, t). 19 F NMR spectra were recorded on a 376 MHz Avance III HD Spectrometer. Chemical shifts are reported in ppm with CFCl 3 as the external standard (CFCl 3 : 0.00 ppm). Data are reported as follows: chemical shift δ/ppm, integration ( 1 H only), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, br = broad, m = multiplet or combinations thereof; 13 C signals are singlets unless otherwise stated), coupling constants J in Hz, assignment. Spectra are assigned as fully as possible, using 1 H-COSY, DEPT-135, HMQC and HMBC where appropriate to facilitate structural determination. Signals that cannot be unambiguously assigned are reported with all possible assignments separated by a slash (e.g. H1/H2) or descriptions of their environments (e.g. ArH, OH). Multiple signals arising from diastereotopic or (pseudo)axial/equatorial positions are suffixed alphabetically (e.g. H1 a , H1 b ). Overlapping signals that cannot be resolved are reported with their assignments denoted in list format (e.g. H1, H2 and H3). 1 H NMR signals are reported to 2 decimal places and 13 C signals to 1 decimal place unless rounding would produce a value identical to another signal. In this case, an additional decimal place is reported for both signals concerned.
Infrared spectra were recorded neat as thin films on a Perkin-Elmer Spectrum One FTIR spectrometer and selected peaks are reported (s = strong, m = medium, w = weak, br = broad).
High resolution mass spectrometry (HRMS) was performed using positive electrospray ionisation (ESI+), on either a Waters Micromass LCT Premier spectrometer or performed by the Mass Spectrometry Service for the Chemistry Department at the University of Cambridge. All m/z values are reported to 4 decimal places and are within ± 5 ppm of theoretical values.

Homoallylic alcohol synthesis in batch
General batch procedure for homoallylic alcohol synthesis: To a solution of aldehyde (0.3 mmol, 1.0 equiv.) and vinylboronic acid (0.36 mmol, 1.2 equiv.) in CH 2 Cl 2 /THF (4:1, 3 mL) was added (trimethylsilyl)diazomethane (0.3 mL, 2 M in hexanes, 0.6 mmol, 2.0 equiv.) and the mixture subsequently stirred for 2 h. The mixture was quenched with SiO 2 and stirred for a further 10 min, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to provide the desired homoallylic alcohol.
To a solution of 7 (0.250 g, 0.356 mmol, 1 equiv.) in anhydrous THF (8.5 mL) at 0 °C was added a solution of TBAF (1.42 mL, 1.0 M in THF, 1.42 mmol, 4 equiv.). The mixture was then stirred at r.t. for 16 h. The mixture was diluted with brine (5 mL) and EtOAc (5 mL) and the organic layer separated. The aqueous layer was extracted further with EtOAc (3 × 5 mL) and the combined organic extracts dried (MgSO 4 ) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (50% CH 2 Cl 2 /hexane) to provide the title product 9 (0.194 g, 0.352 mmol, 99%) as a white foam.