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Synlett 2007(5): 0733-0736  
DOI: 10.1055/s-2007-970756
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Reformatsky Conjugate Additions to Alkylidene Malonates and Malonamides

Emilie Bentza, Mark G. Moloney*a, Susan M. Westawayb
a The Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
Fax: +44(1865)285002; e-Mail: mark.moloney@chem.ox.ac.uk;
b GlaxoSmithKline Research & Development Ltd, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Further Information

Publication History

Received 28 December 2006
Publication Date:
08 March 2007 (online)

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Abstract

Conditions for the effective conjugate addition of ­Reformatsky reagents to activated α,β-unsaturated systems under thermal and microwave irradiation conditions have been identified.

Key words

organometallic reagents - addition reactions - zinc

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Typical Procedure for the Reformatsky Reaction1- tert -Butyl 3,3-Diethyl 2-methylpropane-1,3,3-tricarboxylate ( 3) Zinc powder was activated by shaking with a sat. solution of NH4Cl for 5 min, followed by washing with H2O, EtOH, Et2O and then drying under high vacuum at r.t. for 3 h.
Thermal Conditions To a suspension of activated zinc (350 mg, 5.4 mmol) in THF (5 mL) were added a few crystals of iodine, followed by tert-butyl 2-bromopropionate (520 mL, 3.2 mmol). The mixture was sonicated at 35-40 °C for 15 min. With stirring, diethyl ethylidenemalonate (2, 182 mL, 1.1 mmol) was added and the mixture was sonicated at 35-40 °C for 15 min. After 18 h at reflux, the mixture was quenched with a solution of sat. NH4Cl (5 mL) and EtOAc (5 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified by flash chromatography (PE-EtOAc, 90:10) to afford 1-tert-butyl 3,3-diethyl 2-methylpropane-1,3,3-tricarboxylate (3) as a yellow oil (283 mg, 87%).
Microwave Conditions To a suspension of activated zinc (65 mg, 1.0 mmol) in THF (2 mL) were added a few crystals of iodine, followed by tert-butyl 2-bromopropionate (97 mL, 0.6 mmol) and diethyl ethylidenemalonate (37 mL, 0.2 mmol). The mixture was placed into the microwave reactor to achieve a temperature of 100 °C for 10 min. The reaction mixture was quenched with a sat. solution of NH4Cl (3 mL) and extracted with EtOAc (4 mL). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography (PE-EtOAc, 70:30) to afford the desired product 3 (60 mg, 100%). R f = 0.50 (PE-EtOAc, 70:30). IR (film): νmax = 2980, 2938, 1732 (s), 1369, 1256, 1155 cm-1. 1H NMR (400 MHz, CDCl3): δ = 1.00 [3 H, d, J = 6.8 Hz, C(2)CH3], 1.20 (6 H, t, J = 7.1 Hz, OCH2CH3), 1.39 [9 H, s, C(CH3)], 2.16-2.25 [1 H, m, C(1)H2], 2.41-2.48 [1 H, m, C(1)H2], 2.65-2.72 [1 H, m, C(2)H], 3.32 [1 H, d, J = 7.3 Hz, C(3)H], 4.12 (4 H, q, J = 7.1 Hz, OCH2CH3). 13C NMR (100.6 MHz, CDCl3): δ = 14.0 (OCH2CH3), 17.2 [C(2)CH3], 27.9, 28.0, 28.1 [C(CH3)], 30.2 [C(2)], 39.9 [C(3)], 56.7 [C(1)], 61.2 (OCH2CH3), 80.4 [C(CH3)], 168.4, 168.4, 171.3 (C=O). MS (ESI+): m/z (%) = 325 (100)[M + Na)+]. HRMS: m/z calcd for C15H26O6Na: 325.1627; found: 325.1610 [M + Na]+.

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Crystal data and data collection parameters for compound 11: C17H20ClNO4, T = 150 K, M = 337.80, monoclinic, a = 33.7267(9), b = 5.6388(2), c = 18.2387(5) Å, V = 3458.36(18) Å3. Space group C2/c, Z = 8, D x = 1.297 mg m-3, µ = 0.240 mm-1 R = 0.0375, wR = 0.0399. The compound was crystallised from EtOAc-PE.