Unprecedented Intramolecular Nucleophilic Aromatic Additions of Allyloxy Anions to Diphenylphosphinoyl-Substituted Benzene Rings: A Facile Method for Preparing Multisubstituted Benzopyrans

Abstract

A new synthetic method for the preparation of multisubstituted benzopyrans that involves an intramolecular conjugate addition of allyloxy anions to diphenylphosphinoyl-substituted benzene rings is described. The intermediate anion is trapped with electrophiles providing benzopyrans that are readily oxidized with O₂ to intermediates containing a peroxide that is easily converted into benzopyran-2-ones (i.e. coumarins).

nucleophilic aromatic additions - cyclizations - benzopyrans - coumarins

References and Notes

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<A NAME="RS07907ST-4">4</A>

Interestingly, selection of a different proton source significantly improved both selectivity of the reaction and yield. For example, adding N-Boc-2-methylalanine methyl ester to anion 16 instead of H₂O improved the isomeric ratio to 14:1:1.4 in favor of trans-11 and the yield from 48% to 85%.

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<A NAME="RS07907ST-9">9</A>

7-Benzyl-6-dimethoxymethyl-3-methyl-4 H -chromene (19a): To a solution of allylbenzene 1c (0.61 g, 1.45 mmol) in THF (15 mL) was added a solution LDA over 5 min (1.74 mmol) in THF (6 mL) at -78 °C. After 4 h at this temperature a solution of benzaldehyde (0.21 g, 2.0 mmol) in THF (3 mL) was added at -78 °C over 5 min upon which the dark cherry color disappeared. After 15 min of stirring at this temperature the reaction mixture was allowed to warm to r.t. for 1 h and quenched with aq sat. NH₄Cl solution (5 mL) and H₂O (5 mL) under stirring. After 10 min the organic phase was separated and the aqueous one was extracted with CH₂Cl₂ (2 × 40 mL). The combined organic extract was washed with brine (20 mL), dried over Na₂SO₄ and concentrated in vacuo. The residue was forwarded to silica gel column chromatography (35 g, hexanes-EtOAc-Et₃N, 135:15:1) to give oily 19a (0.28 g, 62% yield). Please note 19a was easily oxidized to the corresponding peroxide (like 9) if left exposed to air. ¹H NMR (200 MHz, C₆D₆): δ = 7.58 (s, 1 H, CH), 7.05-7.25 (m, 5 H, CH), 6.91 (s, 1 H, CH), 6.24 (q, J = 1.5 Hz, 1 H, CH), 5.50 [s, 1 H, CH(OMe)₂], 4.10 (s, 2 H, Bn), 3.17 (s, 6 H, MeO), 3.05 (s, 2 H, CH₂Ar), 1.32 (s, 3 H, Me). ¹³C NMR (50 MHz, C₆D₆): δ = 151.2 (C), 140.6 (C), 138.5 (C), 135.1 (CH), 130.7 (C), 128.9 (CH), 128.4 (CH), 128.3 (CH), 125.9 (CH), 118.3 (CH), 116.8 (C), 108.3 (C), 100.9 [CH(OMe)₂], 52.0 (MeO), 37.7 (CH₂), 28.3 (CH₂), 17.5 (Me). IR (film): 3326, 2939, 2908, 2830, 1691, 1626, 1573, 1496, 1452, 1356, 1186, 1108, 1047, 987, 956, 735, 696 cm^-1. MS (EI): m/z (rel. intensity) = 165 (11), 178 (14), 231 (11), 247 (100), 277 (11), 278 (100), 310 (38) [M⁺]. HRMS: m/z [M⁺] calcd for C₂₀H₂₂O₃: 310.1569; found: 310.1546.

<A NAME="RS07907ST-10">10</A>

The moderate yields of this reaction were due to the products being easily oxidized to their corresponding peroxides upon workup.

<A NAME="RS07907ST-11">11</A> Compounds with similar structures to 24 have displayed interesting fragrances: Demyttenaere J. Van Syngel K. Markusse AP. Vervisch S. Debenedetti S. De Kimpe N. Tetrahedron  2002,  58:  2163 

<A NAME="RS07907ST-12">12</A>

The peroxides did not survive silica gel purification so they were used immediately in the next reaction. The peroxide was formed in 80-85% yield (by ¹H NMR spectroscopy).