Application of the Intramolecular Didehydro-Diels–Alder (IMDDA) Reaction for the Synthesis of Thieno[2,3-f]isoindole-4(8)-carboxylic Acids

Abstract

The reaction of 3-(thienyl)propargylamines with maleic anhydride, followed by a domino sequence involving successive acylation/[4+2] cycloaddition steps, leads to the formation of the thieno[2,3-f]isoindole core. The key step, the intramolecular didehydro-Diels–Alder (IMDDA) reaction, proceeds with a high level of selectivity, yielding the target products – 7-oxo-5,6,7,8-tetrahydro-4H-thieno[2,3-f]isoindole-4(8)-carboxylic acids – in good yields. X-ray analysis and DFT calculations have revealed that the key step, the IMDDA reaction, proceeds via an exo transition allene state, resulting in the exclusive formation of a single isomer of the target heterocycle.

Key words

intramolecular didehydro-Diels–Alder reaction - propargylamine - IMDDA reaction - thieno[2,3-f]isoindole - thiophene - thienylacetylene

Publication History

Received: 27 September 2024

Accepted after revision: 10 February 2025

Article published online:
06 May 2025

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• 10 General Procedure for the Synthesis of Products 10a–l and Characterization Data Maleic anhydride (1 equiv) was added to the corresponding propargylamine 12 diluted in PhCH₃ (3 mL). The resulting mixture was heated at reflux for 5 h and then cooled to room temperature. The resulting precipitate was filtered off, washed with PhCH₃ (3 mL), Et₂O (2 × 3 mL), and air dried to give the title acids 10a–n as colorful solid powders. 5-Oxo-6-phenyl-5,6,7,8-tetrahydro-4H-thieno[3,2-f]isoindole-4-carboxylic acid (10a) For the reaction 48 mg (0.225 mmol) of thienylpropargylamine 12a and 22 mg (0.225 mmol) of maleic anhydride were taken. Yield 31.5 mg (45%); colorful powder; mp 213–214 °C. ¹H NMR (700.2 MHz, DMSO-d ₆, 25 °C): δ = 12.77 (br s, 1 H, CO₂H), 7.79 (d, J = 7.8 Hz, 2 H, H-2,6 Ph), 7.52 (d, J = 4.7 Hz, 1 H, H-Thien), 7.40 (d, J = 7.3 Hz, 2 H, H-3,5 Ph), 7.10 (m, 2 H, H-4Ph, H-Thien), 4.70 (d, J = 18.6 Hz, 1 H, NHCH₂), 4.62 (d, J = 18.6 Hz, 1 H, NHCH₂), 4.48 (br s, 1 H, CH), 3.91 (m, 2 H, CH₂) ppm. ¹³C NMR (176.1 MHz, DMSO-d ₆, 25 °C): δ = 171.9, 168.7, 150.0, 139.9, 132.9, 130.6, 129.5 (2 C), 129.2, 126.5, 125.3, 123.8, 118.4 (2 C), 53.0, 41.0, 25.9 ppm. IR (KBr): ν_max = 1737 (СО₂), 1650 (N–C = O) сm^–1. MS (ESI): m/z 312 [M + H]⁺. Anal. Calcd for C₁₇H₁₃NO₃S: C, 65.58; H, 4.21; N, 4.50; S, 10.30. Found: C, 65.27; H, 4.69; N, 4.81; S, 10.04.