Multicomponent Syntheses to Alkene- and Alkyne-Functionalized Benzopyrans via Alkynylation and [4+2] Cyclization in One-Pot Process

Abstract

A novel multicomponent synthesis was found to be an efficient and elegant approach to 2,4-difunctionalized benzopyrans. This sequence includes ZnMe₂-promoted alkynylation of salicylaldehyde and ZnCl₂-mediated [4+2] cyclization proceeding in sequence of a one-pot process, providing a series of benzopyrans with good diastereoselectivities and moderate yields (dr 20:1 to 4:1). These products are potential precursors and bioactive core skeletons of natural products.

Key words

one-pot - multicomponent - alkynylation - [4+2] cyclization - benzopyran

• References and Notes

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• 22 General Procedure for the Syntheses of 1–14 N-Ts-Proline (15.8 mg, 0.0588 mmol) and Cu(OTf)₂ (21.2 mg, 0.0588 mmol) were mixed in dry toluene (2.0 mL) under Ar atmosphere. Then, ZnMe₂ in toluene (1.2 M, 3.06 mL) was added. After 10 min, terminal alkyne (2.94 mmol) was added; 2 h later, the solution was cooled to 0 °C and treated with substituted salicylaldehyde (0.735 mmol) and dissolved in toluene (2.0 mL). The resulting mixture was stirred at 40 °C for 12 h. After salicylaldehyde was disappeared (monitoring with TLC), the solution was opened to atmosphere, 4 Ǻ MS and functionalized 1,3-butadiene (3.675 mmol) was added. Then, 5 min later, ZnCl₂·OEt₂ (1 M, 1.10 mL, 1.10 mmol) was dropped. The mixture was stirred 12 h at 40 °C and filtered through short diatomite columns to afford the crude product. Further purification by flash column chromatography afforded the product. Selected Data for 1 A light yellow liquid (54% yield). ¹H NMR (400 MHz, CDCl₃): δ = 7.41–7.43 (m, 2 H), 7.27–7.29 (m, 3 H), 7.09 (d, 1 H, J = 2.4 Hz), 6.74–6.82 (m, 2 H), 6.06 (dd, 1 H, J = 10.8, 17.2 Hz), 5.35 (dd, 1 H, J = 0.8, 17.6 Hz), 5.14 (dd, 1 H, J = 0.8 Hz, 10.8 Hz), 4.10 (dd, 1 H, J = 6.0, 10.4 Hz), 3.76 (s, 3 H), 2.22 (dd, 1 H, J = 6.0, 13.6 Hz), 2.10 (dd, 1 H, J = 10.4, 13.6 Hz), 1.37 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.4, 146.7, 142.5, 131.6, 128.2, 127.9, 123.4, 121.2, 118.1, 114.7, 113.5, 113.2, 90.5, 82.0, 75.6, 55.7, 38.5, 26.5, 23.6. IR: ν_max = 3059, 2929, 2855, 2375, 2226, 2066, 1954, 1878, 1689, 1598, 1492, 1427, 1373, 1266, 1219, 1146, 1093, 1039, 927, 911, 812, 757, 692, 531, 485 cm^–1. ESI-HRMS: m/z calcd: 305.1536 [M + H]⁺; found: 305.1529.