Efficient Reformatsky Conjugate Additions to Alkylidene Malonates and Malonamides

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.

organometallic reagents - addition reactions - zinc

References and Notes

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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): ν_max = 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) ų. 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.

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