Halogen-Metal Exchange/Cyclization of Iodoketones: A Direct Synthesis of 3-Arylbenzofurans

Abstract

The first synthesis of benzofuran 2 was achieved in 17% overall yield in seven steps. The key step was a halogen-metal exchange/cyclization reaction. Several examples of this reaction were reported.

Key words

benzofuran - halogen-metal exchange/cyclization reaction - arylbenzofuran

References

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14

Typical Procedure.
Five equiv of MeLi (1.6 M solution in Et₂O) were added via syringe to 4 mL of THF at -78 °C. To this solution was added 1 equiv of the iodoketone (in 4 mL of THF) dropwise via syringe. After addition, the reaction was allowed to stir at -78 °C for 15 min. The reaction was allowed to slowly warm to r.t., and was quenched by the addition of 4 mL of aq NH₄Cl solution. After 5 min, the reaction was extracted into EtOAc, washed with brine (2 × 10 mL), dried over MgSO₄, filtered, and concentrated. The crude product was then dissolved in 10 mL of acetone, and 5 mL of a 10% aq PTSA solution was added with continued stirring for 4 h. Removal of acetone, followed by aqueous work up and extraction into EtOAc, afforded the crude benzofuran, which was purified via chromatography.
3-(2,4,5-Trimethoxyphenyl)benzofuran (8d). ¹H NMR (CDCl₃): δ = 7.89 (s, 1 H), 7.74 (d, J = 7.2 Hz, 1 H), 7.55 (d, J = 7.4 Hz, 1 H), 7.31 (t, J = 8.8 Hz, 2 H), 7.17 (s, 1 H), 6.68 (s, 1 H), 3.96 (s, 3 H), 3.91 (s, 3 H), 3.83 (s, 3 H). ¹³C NMR (CDCl₃): δ = 155.4, 151.6, 149.2, 143.5, 127.5, 124.4, 122.9, 122.8, 121.1, 117.6, 114.1, 112.6, 111.8, 98.5, 57.0, 56.7, 56.4. HRMS: m/z calcd for C₁₇H₁₆O₄: 284.1048; found: 284.1053.