Asymmetric Organocatalytic Synthesis of cis-Substituted ­Dihydrobenzofuranols via Intramolecular Aldol Reactions

Abstract

The diastereo- and enantioselective synthesis of 3-hydroxy 2,3-dihydrobenzofurans via an intramolecular cis-selective aldol reaction employing proline-type organocatalysts is described enabling a new entry to coumarine natural products.

organocatalysis - aldol reaction - asymmetric synthesis - proline - dihydrobenzofuran

References and Notes

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17

Aldehyde ketones of type 4 can be synthesized by reaction of the corresponding salicyl aldehydes, K₂CO₃ and α-bromo ketones in DMF at r.t.

18

CCDC 617162 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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20

All new compounds were fully characterized (IR, NMR, MS, elemental analysis, optical rotation, melting point).
Asymmetric Organocatalytic Intramolecular cis -Aldol Reaction to 5b - Typical Procedure.
To a suspension of (S)-proline (17.3 mg, 0.15 mmol, 30 mol%) in DMF (0.5 mL) was added the aldehyde-ketone 4b (96 mg, 0.5 mmol) and stirred at r.t. for 24 h. The mixture was quenched with a pH 7 buffer solution, extracted with Et₂O (3 ×) and dried over MgSO₄. The solvent was evaporated and the crude product was purified by flash chromatography on silica gel (Et₂O-n-pentane, 1:2) to yield 5b (71 mg, 74%) as a colorless solid; mp. 106 °C; de 88% (99% after recrystallization, determined by GC); ee 77% [99% after recrystallization, determined by chiral stationary phase HPLC (Daicel Chiralpak IA)]; [α]_D ²³ -149.5 (c 1.7, CHCl₃). IR (KBr): 3363, 2971, 2927, 1720, 1601, 1469, 1394, 1311, 1237, 1166, 1024, 981, 939, 847, 748, 634, 490 cm^-1. ¹H NMR (400 MHz, CDCl₃, TMS): δ = 1.09 (t, 3 H, J = 7.3 Hz, CH₃), 2.58 (s, 1 H, OH), 2.63 (dq, 1 H, J = 7.2, 18.7 Hz, CHH), 2.80 (dq, 1 H, J = 7.2, 18.7 Hz, CHH), 4.98 (d, 1 H, J = 6.6 Hz, CH), 5.54 (d, 1 H, J = 6.6 Hz, CH), 6.95-6.97 (m, 1 H, ArH), 6.98-7.01 (m, 1 H, ArH), 7.29-7.33 (m, 1 H, ArH), 7.40-7.42 (m, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): d = 6.7 (CH₃), 34.1 (CH₂), 73.0, 89.9, 110.6, 121.6, 125.7 (CH), 126.6 (C), 131.0 (CH), 159.3 (C), 208.7 (CO). MS (EI): m/z (%) 192 (25) [M⁺], 121 (7), 119 (9), 118 (100), 107 (7), 79 (10), 77 (11), 57 (13). Anal. Calcd for C₁₁H₁₂O₃: C, 68.74; H, 6.29. Found: C, 68.96; H, 6.65.