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.

Key words

deprotonations - Grignard reagents - ketones - magnesium - organometallic reagents

References and Notes

• 1a Nishimura Y. Miyake Y. Amemiya R. Yamaguchi M. Org. Lett.  2006,  8:  5077 
• 1b Kerr WJ. Watson AJB. Hayes D. Chem. Commun.  2007,  5049 
• 1c Kerr WJ. Watson AJB. Hayes D. Org. Biomol. Chem.  2008,  6:  1238 
• For applications of alternative carbon-centred organo-metallic reagents in deprotonation reactions, see:
• 2a Ph₃CK: House HO. Kramar V. J. Org. Chem.  1963,  28:  3362 
• 2b Ph₃CLi, Ph₃CK: House HO. Trost BM. J. Org. Chem.  1965,  30:  1341 
• 2c AlMe₃: Jeffery EA. Meisters A. J. Organomet. Chem.  1974,  82:  307 
• 2d MesLi: Woodward RB. Logusch E. Nambiar KP. Sakan K. Ward DE. Au-Yeung B.-W. Balaram P. Browne LJ. Card PJ. Chen CH. Chênevert RB. Fliri A. Frobel K. Gais H.-J. Garratt DG. Hayakawa K. Heggie W. Hesson DP. Hoppe D. Hoppe I. Hyatt JA. Ikeda D. Jacobi PA. Kim KS. Kobuke Y. Kojima K. Krowicki K. Lee VJ. Leutert T. Machenko S. Martens J. Matthews RS. Ong BS. Press JB. Rajan Babu TV. Rousseau G. Sauter HM. Suzuki M. Tatsuta K. Tolbert LM. Truesdale EA. Uchida I. Ueda Y. Uyehara T. Vasella AT. Vladuchick WC. Wade PA. Williams RM. Wong HN.-C. J. Am. Chem. Soc.  1981,  103:  3210 
• 2e n-BuLi, AlMe₃: Seebach D. Ertaş M. Locher R. Schweizer WB. Helv. Chim. Acta  1985,  68:  264 
• 2f n-BuLi, AlMe₃: Ertaş M. Seebach D. Helv. Chim. Acta  1985,  68:  961 
• For both the efficacy and issues with reagents such as the commonly used lithium-based amides, see:
• 3a Bakker WII. Wong PL. Snieckus V. In Encyclopedia of Reagents for Organic Synthesis   Vol. 5:  Paquette LA. Wiley; Chichester: 1995.  p.3096 
• 3b Heathcock CH. In Modern Synthetic Methods   Vol. 3:  Scheffold R. Wiley-VCH; New York: 1992.  p.3 
• 3c Caine D. In Comprehensive Organic Synthesis   Vol. 3:  Trost BM. Fleming I. Pergamon; Oxford: 1991.  p.1 
• 3d Kowalski C. Creary X. Rollin AJ. Burke MC. J. Org. Chem.  1978,  43:  2601 
• 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:
• 4a Brandsma L. Verkruijsse HD. Preparative Polar Organometallic Chemistry   Springer; Berlin: 1987. 
• 4b Brandsma L. Verkruijsse HD. Synthesis of Acetylenes, Allenes and Cumulenes, A Laboratory Manual   Elsevier; Amsterdam: 1981. 
• 4c

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

• 7 Dinsmore A. Billing DG. Mandy K. Michael JP. Mogano D. Patil S. Org. Lett.  2004,  6:  293 
• 8a Starowieyski KB. Lewinski J. Wozniak R. Chrost A. Organometallics  2003,  22:  2458 
• 8b Kamienski CW. Eastham JF. J. Organomet. Chem.  1967,  8:  542 
• 9a Bassindale MJ. Crawford JJ. Henderson KW. Kerr WJ. Tetrahedron Lett.  2004,  45:  4175 
• 9b Carswell EL. Hayes D. Henderson KW. Kerr WJ. Russell CJ. Synlett  2003,  1017 
• 9c Henderson KW. Kerr WJ. Moir JH. Tetrahedron  2002,  58:  4573 
• 9d Anderson JD. García García P. Hayes D. Henderson KW. Kerr WJ. Moir JH. Fondekar KP. Tetrahedron Lett.  2001,  42:  7111 
• 9e Henderson KW. Kerr WJ. Moir JH. Chem. Commun.  2001,  1722 
• 9f Henderson KW. Kerr WJ. Moir JH. Synlett  2001,  1253 
• 9g Henderson KW. Kerr WJ. Moir JH. Chem. Commun.  2000,  479 
• 11 For the preparation of dialkylmagnesium reagents using 1,4-dioxane, see: Wakefield BJ. Organomagnesium Methods in Organic Synthesis   Academic Press; London: 1995. 
• 14 Bonafoux D. Bordeau M. Biran C. Cazeau P. Dunogues J. J. Org. Chem.  1996,  61:  5532 
• 15 House HO. Czuba LJ. Gall M. Olmstead HD. J. Org. Chem.  1969,  34:  2324 
• 16a

  Commercially available from Aldrich Chemical Co., CAS# [6651-36-1], cat. no. 144819;

• 16b

  Commercially available from Aldrich Chemical Co., CAS# [19980-43-9], cat. no. 283126;

• 16c

  Commercially available from Aldrich Chemical Co., CAS# [38858-72-9], cat. no. 540390.

• 17 Kopka I. Rathke MW. J. Org. Chem.  1981,  46:  3771 
• 18 Heathcock CH. Davidsen SK. Hug KT. Flippin LA. J. Org. Chem.  1986,  51:  3027 
• 19 Graf C.-D. Malan C. Knochel P. Angew. Chem. Int. Ed.  1998,  37:  3014 
• 20 Graf C.-D. Malan C. Harms K. Knochel P. J. Org. Chem.  1999,  64:  5581 
• 21 Rathore R. Kochi JK. J. Org. Chem.  1996,  61:  627 
• 22a Crawford JJ. Kerr WJ. McLaughlin M. Morrison AJ. Pauson PL. Thurston GJ. Tetrahedron  2006,  62:  11360 
• 22b Kerr WJ. McLaughlin M. Morrison AJ. Pauson PL. Org. Lett.  2001,  3:  2945 
• 22c Loon H.-Y. Lee S. Kim D. Kim BK. Bahn JS. Kim S. Tetrahedron Lett.  1998,  39:  7713 
• 23 Heathcock CH. Buse CT. Kleschick WA. Pirrung MC. Sohn JE. Lampe J. J. Org. Chem.  1980,  45:  1066 
• 24 Davis FA. Sheppard AC. Chen B.-C. Haque MS. J. Am. Chem. Soc.  1990,  112:  6679 

5

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.

10

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.

12

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

13

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).