A Novel Palladium-Catalyzed Coupling of Thiol Esters with 1-Alkynes

Abstract

A new method for synthesizing α,β-acetylenic ketones by palladium-mediated coupling of thiol esters with 1-alkynes is described. The reaction could be applied to coupling of thiol esters bearing various functional groups, such as aromatic bromides, and ketones, with functionalized terminal acetylenes.

Key words

1-alkynyl ketones - thiol esters - Sonogashira-type coupling reaction - palladium - copper

References

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16

Typical Procedure: To a solution of thiol ester 1 (1.00 g, 4.48 mmol), PdCl₂(dppf) (365 mg, 0.448 mmol), CuI (1.45 g, 7.61 mmol), and tri-2-furylphosphine (260 mg, 1.12 mmol) in a mixture of DMF (7.5 mL) and Et₃N (1.5 mL) was added 1-hexyne (1.02 mL, 892 mmol) at r.t. After stirring for 3 h at 50 °C, Celite was added to the mixture and the resulting suspension was stirred for 5 min. The mixture was diluted with Et₂O (50 mL) and the reaction was quenched by addition of H₂O (50 mL). The mixture was filtered through a pad of Celite and separated. The aqueous layer was extracted with Et₂O (20 mL × 2). The combined organic extracts were washed with brine (20 mL), dried over anhyd MgSO₄ and concentrated in vacuo. Purification by flash column chromatography on silica gel (40 g, 5-8% Et₂O/hexanes) gave 1.03 g (4.21 mmol, 94%) of α,β-alkynyl ketone 2 as a brown oil. Compound 2: IR(film): 2958, 2871, 2214, 1671, 1513, 1247, 1178, 1036, 825 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.11 (d, J = 8.3 Hz, 2 H), 6.82 (d, J = 8.5 Hz, 2 H), 3.78 (s, 3 H), 2.92 (t, J = 6.8 Hz, 2 H), 2.83 (t, J = 7.1 Hz, 2 H), 2.37 (t, J = 6.8 Hz, 2 H), 1.58-1.52 (m, 2 H), 1.46-1.40 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 187.1, 158.0, 132.4, 129.2, 113.9, 94.8, 80.8, 55.2, 47.3, 29.7, 29.1, 21.9, 18.6, 13.5. HRMS (FAB): m/z calcd for C₁₆H₂₀O₂: 244.1463. Found: 244.1458.

17

The reaction using trimethylsilylacetylene gave only recovered starting material 1.

20

Since the aryl alkynyl ketone products are relatively active Michael-acceptors, the ethyl thiolate adducts were obtained as byproducts. For this reason, the reactions using those substrates were quenched while some starting material remained (Figure [1] ).

Figure 1

21

The yield of 2 increased as the amount of CuI increased. The yields of 2 with no CuI, 0.5, 1.0, 1.5, 2.0, and 2.5 equiv are 11%, 25%, 33%, 62%, 65%, and 87%, respectively. However, addition of more than 3.0 equiv of CuI did not improve the yield.