Enantiospecific sp2–sp3 Coupling of ortho‐ and para‐Phenols with Secondary and Tertiary Boronic Esters

Abstract The coupling of ortho‐ and para‐phenols with secondary and tertiary boronic esters has been explored. In the case of para‐substituted phenols, after reaction of a dilithio phenolate species with a boronic ester, treatment with Ph3BiF2 or Martin's sulfurane gave the coupled product with complete enantiospecificity. The methodology was applied to the synthesis of the broad spectrum antibacterial natural product (−)‐4‐(1,5‐dimethylhex‐4‐enyl)‐2‐methyl phenol. For ortho‐substituted phenols, initial incorporation of a benzotriazole on the phenol oxygen atom was required. Subsequent ortho‐lithiation and borylation gave the coupled product, again with complete stereospecificity.


General Information
Solvents and Reagents: All air and water-sensitive reactions were carried out in flame-dried glassware under a nitrogen atmosphere using standard Schlenk manifold technique. Bulk solutions were evaporated under reduced pressure using a Büchi rotary evaporator. All solvents were commercially supplied or provided by the communal stills of the School of Chemistry, University of Bristol. Petroleum ether (pet. ether) refers to the fraction collected between 40 -60 °C. TMEDA was distilled over CaH2. (+)-Sparteine and (-)-sparteine were obtained from the commercially available sulfate pentahydrate salt (99%, Acros) and distilled before use. The sparteine free base readily absorbs atmospheric carbon dioxide (CO2) and should be stored under argon/nitrogen at −20 °C in a Schlenk tube. sec-BuLi was purchased from Acros. PhLi was purchased from Sigma-Aldrich. The molarity of organolithium solutions was determined by titration using N-benzyl benzamide as an indicator. All other reagents were purchased from commercial sources and used as sold, unless noted.
Chromatography and Spectroscopy: Flash column chromatography (FCC) was carried out using fluorochem silica gel LC60A-40 (63 μm). Auto-column chromatography was carried out on a Biotage, Isolera One using Biotage SNAP cartridge KP Sil 5 g, unless otherwise stated. All reactions were followed by thin-layer chromatography (TLC) when practical, using Merck Kieselgel 60 F254 fluorescent treated silica which was visualised under UV light or by staining with aqueous basic potassium permanganate or phosphomolybdic acid. 1 H and 13 C NMR spectra were recorded using Jeol ECP(Eclipse) 300 MHz, Jeol ECS 400 MHz, Varian VNMR 400 MHz and Varian VNMR 500 MHz spectrometers. Chemical shifts (δ) are given in parts per million (ppm), and coupling constants (J) are given in Hertz (Hz). The 1 H NMR spectra are reported as follows: ppm (multiplicity, coupling constants, number of protons, assignment). Data are reported as follows: chemical shift, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, qi = quintet, sx = sextet, sp = septet, m = multiplet, dd = doublet of doublets, etc.) and integration. NMR assignments are made according to spin systems, using two-dimensional (COSY, HSQC, HMBC) NMR spectroscopy to assist the assignment.
Where an assignment could not be made unambiguously, possible assignments are listed.
High resolution mass spectra (HRMS) were recorded on a VG Analytical Autospec by Electron Ionisation (EI) or Chemical Ionisation (CI) or on a Brüker Daltonics Apex IV by Electrospray Ionisation (ESI). IR spectra were recorded on a Perkin Elmer Spectrum One FT-IR as a thin film. Only selected absorption maxima (νmax) are reported in wavenumbers (cm -1 ). Melting points were recorded in degrees Celsius (°C), using a Kofler hot-stage microscope apparatus and are reported uncorrected. Optical rotation ( [α] D T ) was measured on a performed on a HP Agilent 1100 with a Chiralpak columns and monitored by DAD (Diode Array Detector). Chiral SFC was performed on a Waters TharSFC system using a Diacel Chiralpak columns (4.6 m × 250 mm × 5 μm) and monitored by DAD (Diode Array Detector). GC-MS was performed on an Agilent 7820A using a HP-5MS UI column (30 m x 0.25 mm x 0.25 μm).
Naming of compounds: Compound names are those generated by ChemBioDraw 15.0 software (PerkinElmer), following the IUPAC nomenclature.
Solution of Martin's sulfurane: Due its hydroscopic nature, a solution of Martin's sulfurane was employed in this chemistry. This solution was made by emptying the contents of a full (5 g) bottle of Martin's sulfurane reagent into a pre-weighed dry schlenk tube. Dry THF was added to the schlenk tube to make a 0.5 M solution, based on the weight of Martin's sulfurane reagent in the schlenk tube. This solution was found to be active for months when stored at room temperature under N2 atmosphere.

Synthesis of Boronic Ester Synthesis
Please see the references below for the synthesis and determination of the enantiomeric excesses (where applicable) of boronic esters 6 and 8a-8j. Substrates available from commercial sources (8b-8c and 8n) are not listed here.
Then, solid iodonium triflate (A, 1.05 equiv.) was added to the reaction mixture in one portion and stirred.
After 16 h, the reaction was quenched by the addition of water (20 mL) and diluted with DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over MgSO 4 , filtered and concentrated under vacuum. The crude material was purified by flash column chromatography on silica gel to afford C.
Compound 10a was prepared following the literature report. [9]

Electrophile Screening and Additional Information on Reaction Development
The combined organic layers were washed with brine (30 mL), dried over MgSO 4 , filtered and concentrated under vacuum. The crude material was purified by automated flash column chromatography on silica gel (Biotage SNAP KP -5 g) eluting with a slow gradient of pet. ether:EtOAc (100:0 to 95:0).

4-Isobutylphenol (9a)
The starting boronic ester (0.16 mmol) was reacted according to General Procedure A (63% NMR yield) to afford the title compound as oil. The spectral data matched with the commercially available sample. [12] Rf (10% EtOAc/pet.

4-Cyclohexylphenol (9c)
The starting boronic ester (0.16 mmol) was reacted according to General Procedure A (16 mg; 58%) to afford the title compound as off-white solid. The spectral data matched with the commercially available sample.

2-Cyclohexylphenol (15a)
The starting boronic ester (0.20 mmol) was reacted according to General Procedure C (21 mg; 60%) to afford the title compound as gummy liquid. The spectral data matched with the commercially available sample.

Reversible Boronate Complex Formation with Benzotriazoles
With strong electron-withdrawing substituents on the aromatic ring of the aryl halide of the ortho-ArOBt substrates (e.g. CF3-substituted example S4 in the scheme below), the resultant anion S5 from the lithiumhalogen exchange is more stabilized than the boronate complex S6. Hence, a reversible boronate complex formation was observed. After 16 h, upon quenching the reaction with water, only a very low yield of the coupled product S7 was obtained and the protonated phenoxybenzotriazole S8 and boronic ester starting material 6 were isolated. Similar low reactivity was observed with sterically hindered tertiary pinacol boronic esters such as 8g. In this case, the reaction of aryl lithium 12 with boronic ester 8g is, presumably, reversible due to destabilization of boronate complex S9 as a result of the large steric hindrance. As a result, low yields of the coupled product 15c were obtained and the protonated phenoxybenzotriazole S9 and boronic ester starting material 8g were isolated.
An improvement in the yield was generally observed when the lithiated species in used in excess, which is also indicative of a reversible boronate complex.