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Synlett 2008(9): 1386-1390  
DOI: 10.1055/s-2008-1072739
LETTER
© Georg Thieme Verlag Stuttgart · New York

Di-tert-Butylmagnesium as an Atom-Efficient, Carbon-Centred Base Reagent for the Preparation of Silyl Enol Ethers from Ketones

William J. Kerr*a, Allan J. B. Watsona, Douglas Hayesb
a Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde, 295 Cathedral Street, Glasgow, G1 1XL, UK
e-Mail: w.kerr@strath.ac.uk;
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK
Further Information

Publication History

Received 3 March 2008
Publication Date:
16 April 2008 (online)

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Abstract

Di-tert-butylmagnesium has been found to be a reactive, yet non-nucleophilic and non-reductive, carbon-centred base for the deprotonation of a series of ketones. This reagent demonstrates equally high reactivity when used as either the pre-formed reagent, or in a more accessible one-pot protocol from the parent Grignard reagent, and offers improved atom-efficiency over more traditionally employed bases.

Key words

deprotonations - Grignard reagents - ketones - magnesium - organometallic reagents

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For example, for GaEt3 to perform effectively in deprotonation reactions, 1.5 mol of the complex (i.e., 4.5 equiv of base) was required at 125 °C; see ref. 1a.

6

Kerr, W. J.; Watson, A. J. B. unpublished results.

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Typical Experimental Procedure for the Deprotonation of Ketones Using (Isolated) t -Bu 2 Mg
A Schlenk tube was charged with LiCl (1 mmol, 42.5 mg) and flame-dried under vacuum. The tube was purged three times with N2 before being cooled to r.t. and charged with t-Bu2Mg (0.5 M solution in THF, 0.5 mmol, 1 mL) and THF (9 mL). The mixture was stirred for 15 min at r.t. before being cooled to 0 °C. Then, TMSCl (1 mmol, 109 mg, 0.13 mL) was added and the mixture was stirred for 5 min before addition of cyclohexanone (2a, 1 mmol, 98 mg) as a solution in THF (2 mL) over 1 h via syringe pump. The reaction mixture was stirred at 0 °C under N2 for 1 h before being quenched with sat. aq NaHCO3 solution (10 mL). The mixture was allowed to warm to r.t. before being extracted with Et2O (1 × 40 mL and 2 × 25 mL). The combined organic extracts were dried (Na2SO4) and a representative sample was analysed by GC to obtain the ketone to silyl enol ether. The solution was then filtered and concentrated in vacuo to afford a residue which was purified by column chromatography eluting with 1% Et2O-PE to afford 1-trimethylsiloxycyclohexene (3a, 150 mg, 88%).13 Gas chromatography was carried out using a Hewlett Packard 5890 Series 2 Gas Chromatograph fitted with a Varian WCOT Fused Silica Column containing a CP-SIL 19CB coating and using H2 as carrier gas (80 kPa): (i) injector and detector temperature, 200 °C; (ii) initial oven temperature, 45 °C; (iii) temperature gradient, 20 °C min-1; (iv) final oven temperature, 190 °C; and (v) detection method, FID.

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Typical Experimental Procedure for the Deprotonation of Ketones Using in situ Generated t -Bu 2 Mg
A Schlenk tube was charged with LiCl (1 mmol, 85 mg) and flame-dried under vacuum. The tube was purged three times with N2 before being cooled to r.t. and charged with t-BuMgCl (1 M solution in THF, 1 mmol, 1 mL), 1,4-dioxane (1.05 mmol, 88 mg, 0.09 mL), and THF (9 mL). The mixture was stirred for 15 min at r.t. before being cooled to 0 °C. Then, TMSCl (1 mmol, 109 mg, 0.13 mL) was added and the mixture was stirred for 5 min before addition of 1,4-cyclohexanedione monoethylene ketal (2i, 1 mmol, 156 mg) as a solution in THF (2 mL) over 1 h via syringe pump. The reaction mixture was stirred at 0 °C under N2 for 1 h before being quenched with sat. NaHCO3 aq soln (10 mL). The mixture was allowed to warm to r.t. before being extracted with Et2O (1 × 40 mL and 2 × 25 mL). The combined organic extracts were dried (Na2SO4), and a representative sample was analysed by GC (see ref. 10) to obtain the conversion value of ketone to silyl enol ether. The solution was then filtered and concentrated in vacuo to afford a residue which was purified by column chromatography eluting with 1% Et2O-PE to afford 8-trimethylsilyloxy-1,4-dioxaspiro[4.5]dec-7-ene (3i, 160 mg, 70%).13

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Product Data
1-Trimethylsilyloxycyclohexene (3a):14,15,16a,17 IR (CH2Cl2): νmax = 1668 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.18 [s, 9 H, Si(CH3)3], 1.48-1.54 (m, 2 H, CH2), 1.63-1.69 (m, 2 H, CH2), 1.97-2.03 (m, 4 H, 2 × CH 2), 4.86-4.88 (m, 1 H, CH).
1-Trimethylsiloxycyclopentene (3b):14,15,16b,18 IR (CH2Cl2): νmax = 1645 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.20 [s, 9 H, Si(CH3)3], 1.82-1.90 (m, 2 H, CH2), 2.24-2.29 (m, 4 H, 2 × CH 2), 4.62-4.63 (m, 1 H, CH).
6-Methyl-1-trimethylsilyloxy-1-cyclohexene (3c):14,15,17 IR (CH2Cl2): νmax = 1660 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 0.19 [s, 9 H, Si(CH3)3], 1.04 (d, 3 H, CH 3, J = 7.0 Hz), 1.36-1.41 (m, 1 H, CH), 1.45-1.49 (m, 1 H, CH), 1.57-1.59 (m, 1 H, CH), 1.78-1.82 (m, 1 H, CH), 1.98-2.02 (m, 2 H, CH2), 2.14-2.15 (m, 1 H, CH), 4.81 (td, 1 H, CH, J = 3.95, 1.20 Hz).
4-tert-Butyl-1-trimethylsilyloxy-1-cyclohexene (3d):9c,19,20 IR (CH2Cl2): νmax = 1672 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.19 [s, 9 H, Si(CH 3)3], 0.90 (s, 9 H, 3 × CH 3), 1.21-1.29 (m, 2 H, CH2), 1.78-1.85 (m, 2 H, CH 2), 1.98-2.09 (m, 3 H, CH and CH2), 4.84-4.86 (m, 1 H, CH).
4-Methyl-1-trimethylsilyloxy-1-cyclohexene (3e):9c,19,20 IR (CH2Cl2): νmax = 1669 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 0.18 [s, 9 H, Si(CH3)3], 0.95 (d, 3 H, CH3, J = 6.3 Hz), 1.29-1.34 (m, 1 H, CH), 1.62-1.73 (m, 3 H, CH and CH2), 1.93-2.00 (m, 1 H, CH), 2.05-2.09 (m, 2 H, CH2), 4.82-4.83 (m, 1 H, CH).
4-(tert-Butyldimethylsiloxy)-1-trimethylsilyloxy-1-cyclo-
hexene (3f):20 IR (CH2Cl2): νmax = 1668 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.06 {s, 3 H, Si[C(CH3)3]CH 3}, 0.07 {s, 3 H, Si[(C(CH3)3]CH 3}, 0.18 [s, 9 H, Si(CH3)3], 0.89 [s, 9 H, Si(C(CH3)3], 1.60-1.83 (m, 2 H, CH2), 1.97-2.16 (m, 3 H, CH and CH2), 2.17-2.27 (m, 1 H, CH), 3.84-3.93 (m, 1 H, CH), 4.66-4.73 (m, 1 H, C=CH).
1-Trimethylsilyloxycycloheptene (3g):21 IR (CH2Cl2): νmax = 1660 cm-1. 1H NMR (400 MHz, CDCl3): δ = 0.18 [s, 9 H, Si(CH3)3], 1.50-1.59 (m, 4 H, 2 × CH 2), 1.66-1.70 (m, 2 H, CH2), 1.97-2.01 (m, 2 H, CH2), 2.22-2.24 (m, 2 H, CH2), 4.86-4.88 (m, 1 H, CH).
4-Phenyl-1-trimethylsilyloxy-1-cyclohexene (3h):19,20 IR (CH2Cl2): νmax = 1669 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 0.24 [s, 9 H, Si(CH3)3], 1.86-1.93 (m, 1 H, CH), 1.96-1.99 (m, 1 H, CH), 2.06-2.11 (m, 1 H, CH), 2.19-2.34 (m, 3 H, CH and CH2), 2.76-2.78 (m, 1 H, CH), 4.97-4.98 (m, 1 H, CH), 7.19-7.34 (m, 5 H, C6H5).
8-Trimethylsilyloxy-1,4-dioxaspiro[4.5]dec-7-ene (3i):22 IR (CH2Cl2): νmax = 1671 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 0.15 [s, 9 H, Si(CH3)3], 1.81 (t, 2 H, CH 2, J = 6.6 Hz), 2.20-2.23 (m, 2 H, CH2), 2.25-2.28 (m, 2 H, CH2), 3.95-4.01 (m, 4 H, CH), 4.73 (m, 1 H).
1-Phenyl-1-trimethylsilyloxyprop-1-ene (3j):14,18,23,24 IR (CH2Cl2): νmax = 1686, 1652 cm-1. 1H NMR (400 MHz, CDCl3): δ (Z-isomer) = 0.17 [s, 9 H, Si(CH3)3], 1.76 (d, 3 H, CH3, J = 6.9 Hz), 5.35 (q, 1 H, CH, J = 6.9 Hz), 7.23-7.49 (m, 5 H, 5 × ArCH); δ (E-isomer) = 0.15 [s, 9 H, Si(CH3)3], 1.73 (d, 3 H, CH3, J = 7.3 Hz), 5.13 (q, 1 H, CH, J = 7.3 Hz), 7.23-7.49 (m, 5 H, C6H5).
(3,4-Dihydro-1-naphthyloxy)trimethylsilane (3k):16c,21 IR (CH2Cl2): νmax = 1638 cm-1. 1H NMR (400 MHz, CDCl3):
δ = 0.38 [s, 9 H, Si(CH3)3], 2.42-2.47 (m, 2 H, CH2), 2.89 (t, 2 H, CH2, J = 7.8 Hz), 5.32 (t, 1 H, CH, J = 4.6 Hz), 7.21-7.36 (m, 3 H, 3 × ArCH), 7.54 (d, 1 H, ArCH, J = 7.4 Hz).