A Novel One-Pot Synthesis of Phthalic Acid Derivatives Involving a Three-Component Coupling Reaction of β-Arylcrotonate and Alkynes

Abstract

Based on a versatile three-component coupling methodology, a novel synthesis of highly substituted phthalic acid derivatives is reported.

Diels-Alder reaction - annulation - β-arylcrotonate - multicomponent reaction - dimethyl acetylenedicarboxylate

References

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<A NAME="RD06605ST-12">12</A>

General Procedure for the One-Pot Synthesis of Phthalic Acid Derivatives.
The DMF·DMA (1.7 mL, 2.5 mmol) was added to β-phenylethylcrotonate (1.0 g, 1 mmol) at r.t. under N₂. The resulting solution was refluxed at 120 °C for 5 h. After completion of the enamine formation (monitored by TLC), the reaction mixture was cooled to 60 °C, DMAD (0.97 mL, 1.5 mmol) was added and stirred for 30 min. The reaction was quenched by adding 5% ice cold HCl (50 mL), extracted with CH₂Cl₂ (2 × 25 mL). The combined extracts were washed with brine (2 × 20 mL) and dried (Na₂SO₄). Removal of the solvent followed by flash column chromatographic purification (silica gel, hexane-EtOAc, 5:1) afforded 2a as pale-yellow liquid (0.94 g, 52%).
Spectral Data of Selected Compounds. Compound 2b: ¹H NMR (300 MHz, CDCl₃): δ = 1.02 (t, J = 7.1 Hz, 3 H), 2.40 (s, 3 H), 3.93 (s, 3 H), 3.94 (s, 3 H), 4.09 (q, J = 7.1 Hz, 2 H), 7.24 (s, 4 H), 7.51 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.0 Hz, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 13.49, 21.16, 52.73, 52.88, 61.71, 127.88, 127.98, 129.11, 129.24, 131.26, 131.96, 134.35, 136.26, 138.17, 144.97, 165.72, 167.42, 168.11. MS (EI): m/z (%) = 356 (100) [M⁺], 325 (52), 311 (42), 279 (20).
Compound 2g: ¹H NMR (400 MHz, CDCl₃): δ = 0.87 (t, J = 7.2 Hz, 3 H), 3.94 (s, 3 H), 3.95 (s, 3 H), 4.02 (q, J = 7.2 Hz, 2 H), 7.45-7.47 (m, 1 H), 7.50-7.55 (m, 2 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.82-7.89 (m, 4 H), 8.08 (d, J = 8.0 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.45, 52.77, 52.91, 61.77, 125.97, 126.59, 126.63, 127.39, 127.68, 127.89, 128.14, 131.28, 131.40, 131.54, 132.28, 132.79, 133.03, 134.58, 136.64, 144.94, 165.71, 167.36, 168.06. MS (EI): m/z (%) = 392 (100) [M⁺], 347 (16), 315 (25), 202 (32).
Compound 2h: ¹H NMR (500 MHz, CDCl₃): δ = 1.11 (t, J = 7.4 Hz, 3 H), 3.89 (s, 3 H), 3.90 (s, 3 H), 4.17 (q, J = 7.4 Hz, 2 H), 7.04-7.10 (m, 2 H), 7.38 (d, J = 5.1 Hz, 1 H), 7.58 (d, J = 8.0 Hz, 1 H), 7.96 (d, J = 8.0 Hz, 1 H). ¹³C NMR (125 MHz, CDCl₃): δ = 13.74, 52.95, 52.99, 53.10, 62.13, 127.51, 127.63, 128.28, 131.17, 131.62, 132.40, 134.29, 137.06, 139.79, 165.68, 167.35, 167.82. MS (EI): m/z (%) = 348 (100) [M⁺], 303 (61), 257 (58), 186 (26).
Compound 2d′: ¹H NMR (400 MHz, CDCl₃): δ = 1.03 (t, J = 7.2 Hz, 3 H), 3.88 (s, 3 H), 4.09 (q, J = 7.2 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.30-7.35 (m, 3 H), 8.09 (d, J = 6.8 Hz, 1 H), 8.42 (s, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.74, 52.18, 61.31, 121.64, 128.29, 129.48, 129.56, 130.79, 131.17, 131.40, 131.99, 133.98, 135.01, 138.92, 145.49, 165.95, 167.39. MS (EI): m/z (%) = 318 (100) [M⁺], 287 (18), 273 (85), 186 (21).