Synlett 2017; 28(18): 2401-2406
DOI: 10.1055/s-0036-1588805
cluster
© Georg Thieme Verlag Stuttgart · New York

Bu4N+-Controlled Addition and Olefination with Ethyl 2-(Trimethylsilyl)acetate via Silicon Activation

Manas Dasa, Atul Manvara, Ian Foxa, b, Dilwyn J. Robertsb, Donal F. O’Shea*a
  • aDepartment of Pharmaceutical and Medicinal Chemistry, Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Ireland   Email: donalfoshea@rcsi.ie
  • bIpsen Manufacturing Ireland Ltd, Blanchardstown Industrial Park, Blanchardstown, Dublin 15, Ireland
Further Information

Publication History

Received: 30 January 2017

Accepted after revision: 27 March 2017

Publication Date:
02 May 2017 (eFirst)

Published as part of the Cluster Silicon in Synthesis and Catalysis

Abstract

Catalytic Bu4NOAc as silicon activator of ethyl 2-(trimethylsilyl)acetate, in THF, was utilized for the synthesis of β-hydroxy esters, whereas employing catalytic Bu4NOTMS gave α,β-unsaturated esters. The established reaction conditions were applicable to a diverse range of aromatic, heteroaromatic, aliphatic aldehydes and ketones. Reactions were achieved at room temperature without taking any of the specialized precautions that are in place for other organometallics. A stepwise olefination pathway via silylated β-hydroxy esters with subsequent elimination to form the α,β-unsaturated ester has been demonstrated. The key to selective product formation lies in use of the weaker acetate activator which suppresses subsequent elimination whereas stronger TMSO activator (and base) facilitates both addition and elimination steps. The use of tetrabutyl ammonium salts for both acetate and trimethylsilyloxide activators provide enhanced silicon activation when compared to their inorganic cation counterparts.

Supporting Information

 
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  • 21 General Procedure for Addition Reactions A solution of ethyl 2-(trimethylsilyl)acetate (1, 137 μL, 0.75 mmol) and aldehyde (0.50 mmol) in anhydrous THF (2.5 mL) was treated with dried Bu4NOAc (0.05 mmol) under N2. The resulting solution was stirred at r.t. for 1 h. Aqueous HCl (2 M, 10 mL) was added and stirred for 30 min. The residue was extracted with Et2O (3 × 15 mL), organic layers combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure gave the crude product. Ethyl 3-(2-chlorophenyl)-3-hydroxypropanoate (3b) A solution of ethyl 2-(trimethylsilyl)acetate (1, 137 μL, 0.75 mmol) and 2-chlorobenzaldehyde (70 mg, 0.50 mmol) in anhydrous THF (2.5 mL) was treated with dried Bu4NOAc (15 mg, 0.05 mmol) under N2. The resulting solution was stirred at r.t. for 1 h. Aqueous HCl (2 M, 10 mL) was added and stirred for 30 min. The residue was extracted with Et2O (3 × 15 mL), organic layers combined, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography eluting with cyclohexane–EtOAc (90:10) afforded 3b as a colorless oil (91 mg, 80%). 1H NMR (400 MHz, CDCl3): δ = 7.63 (dd, J = 7.7, 1.6 Hz, 1 H), 7.36–7.27 (m, 2 H), 7.22 (td, J = 7.6, 1.7 Hz, 1 H), 5.49 (dd, J = 9.7, 2.5 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H), 3.61 (br s, 1 H), 2.86 (dd, J = 16.6, 2.7 Hz, 1 H), 2.58 (dd, J = 16.6, 9.7 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 172.7, 140.0, 131.5, 129.5, 128.9, 127.3, 127.2, 67.2, 61.1, 41.5, 14.3 ppm. ESI–MS: m/z cald for C11H14O3Cl [M + H]+: 229.1; found: 229.0.
  • 22 General Procedure for Olefination Reactions A solution of ethyl trimethylsilylacetate (1, 137 μL, 0.75 mmol) and aldehyde (0.50 mmol) in THF (2.5 mL) was treated with dried Bu4NCl (0.15 mmol) and TMSOK (0.15 mmol) under N2, and the resulting reaction mixture was stirred at r.t. for 2 h. The reaction mixture was quenched with aq 2 M HCl (10 mL) and stirred for 5 min at r.t. The residue was extracted with EtOAc (3 × 15 mL). Organic layers were combined and washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give the crude product.
  • 23 (E)-Ethyl-3-(3,4,5-trimethoxyphenyl)acrylate (4l) A solution of 3,4,5-trimethoxybenzaldehyde (98 mg, 0.50 mmol) and ethyl trimethylsilylacetate (1, 137 μL, 0.75 mmol) in THF (2.5 mL) was treated with dried Bu4NCl (42 mg, 0.15 mmol) and TMSOK (19 mg, 0.15 mmol) under N2, and the resulting reaction mixture was stirred at r.t. for 2 h. The reaction mixture was quenched with 2 M aq HCl (10 mL) and stirred for 5 min at r.t. The residue was extracted with EtOAc (3 × 15 mL). Organic layers were combined and washed with water and brine, dried over Na2SO4, and concentrated under reduced pressure. Purification by Al2O3 chromatography eluting with cyclohexane–EtOAc (90:10) yielded 4l (95 mg, 71%) as a colorless solid, mp 53–55 °C. 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 16.0 Hz, 1 H), 6.74 (s, 2 H), 6.33 (d, J = 16.0 Hz, 1 H), 4.25 (q, 2 H), 3.87 (s, 9 H), 1.33 (t, 3 H). 13C NMR (100 MHz, CDCl3): δ = 166.9, 153.4, 144.5, 140.1, 129.9, 117.5, 105.2, 60.9, 60.4, 56.1, 26.9, 14.3. MS (EI): m/z calcd for C14H18O5 [M]+: 266.1; found: 266.2.