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

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.

deprotonations - Grignard reagents - ketones - magnesium - organometallic reagents

References and Notes

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For applications of alternative carbon-centred organo-metallic reagents in deprotonation reactions, see:

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For both the efficacy and issues with reagents such as the commonly used lithium-based amides, see:

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For example, n-BuLi will deliver mostly addition products when used in a general sense with ketones. Only in specific cases will n-BuLi act solely as a base reagent. For general information on the reactivity of n-BuLi, see:

<A NAME="RD06707ST-4A">4a</A> Brandsma L. Verkruijsse HD. Preparative Polar Organometallic Chemistry   Springer; Berlin: 1987. 

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For the use of base reagent mixtures with n-BuLi, see ref. 2e and 2f.

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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.

<A NAME="RD06707ST-6">6</A>

Kerr, W. J.; Watson, A. J. B. unpublished results.

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<A NAME="RD06707ST-10">10</A>

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.

<A NAME="RD06707ST-11">11</A> For the preparation of dialkylmagnesium reagents using 1,4-dioxane, see: Wakefield BJ. Organomagnesium Methods in Organic Synthesis   Academic Press; London: 1995. 

<A NAME="RD06707ST-12">12</A>

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

<A NAME="RD06707ST-13">13</A>

Product Data
1-Trimethylsilyloxycyclohexene (3a):^14,15,16a,17 IR (CH₂Cl₂): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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): ν_max = 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).

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