Improved Palladium-Catalysed Synthesis of α-Benzyl-β-keto Esters

Abstract

This paper describes the development of an imporved protocol for the synthesis of α-benzyl-β-keto esters from aryl bromides via Heck reaction. The use of this protocol to synthesise a variety of diverse α-benzyl-β-keto esters for use in the preparation of new pharmaceutical agents is demonstrated.

palladium - Heck reaction - arylation - Baylis-Hillman - α-benzyl-β-keto ester

References and Notes

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4 Gilchrist TL. Heterocyclic Chemistry   3rd ed.:  Addison Wesley Longman; Harlow: 1997. 

5

The reaction was completed in a closed tube with a bursting disc fitted in the top of the tube. The reaction was completed behind a blast screen and these important safety measures should be implemented when completing this reaction particularly when scaling up the procedure.

6

Typical Procedure for Heck Reaction
1-Bromo-2-methoxybenzene (0.958 mL, 7.75 mmol), methyl 3-hydroxy-2-methylenebutyrate (0.942 ml, 7.75 mmol) and N-methyldicyclohexylamine (4.98 mL, 23.26 mmol) were added to a suspension of Pd(dbpf)Cl₂ (0.126 g, 0.19 mmol) and TBAC (0.431 g, 1.55 mmol) in DMF (10 ml) under nitrogen. The resulting suspension was stirred
at 100 ˚C in a closed tube for 18 h (see ref. 5 for safety measures). The solution was diluted with EtOAc (50 mL) and extracted with H₂O (50 mL) and brine (2 × 50 mL). The organic phase was dried over MgSO₄, filtered, and evaporated. The residue was diluted with MeCN (30 mL) and loaded on to a 70 g SCX cartridge. The product was washed through with MeCN (100 mL) and the filtrate evaporated to give methyl 2-(2-methoxybenzyl)-3-oxo-butanoate (1.558 g, 85%) as an orange oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.20 (ddd, J = 8.9, 7.6, 2.1 Hz, 1 H, CH), 7.11 (dd, J = 6.8, 3.0 Hz, 1 H, CH) 6.87-6.82 (m, 2 H, CH), 3.92 (dd, J = 8.4, 7.2 Hz, 1 H, CH), 3.83 (s, 3 H, CH₃), 3.67 (s, 3 H, CH₃), 3.19 (dd, J = 13.9, 7.2 Hz, 1 H, CH₂), 3.10 (dd, J = 13.9, 8.2 Hz, 1 H, CH₂), 2.18 (s, 3 H, CH₃). ^¹³C NMR (125 MHz, CDCl₃): δ = 203.1, 169.9, 157.3, 130.8, 128.1, 126.2, 120.5, 110.2, 59.0, 55.2, 52.2, 29.5, 29.4. HRMS (TOF-LCMS): m/z calcd for C₁₃H₁₇O₄ [M + H]⁺: 237.1121; found: 237.1122.

7 Aggarwal VK. Emme I. Fulford SY. J. Org. Chem.  2003,  68:  692