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Synlett 2025; 36(10): 1358-1362
DOI: 10.1055/s-0043-1773527
letter

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

Evgeniya R. Shelukho
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
,
Elizaveta D. Yakovleva
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
,
Nikita A. Logvinenko
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
,
Victor N. Khrustalev
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
b   Zelinsky Institute of Organic Chemistry of RAS, 47 Leninsky Prospect, 119991 Moscow, Russian Federation
,
Roman A. Novikov
с   V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilov St., Moscow, 119991, Russian Federation
,
Fedor I. Zubkov 
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
,
Vladimir P. Zaytsev  ∗
a   RUDN University, 6 Miklukho-Maklaya St., Moscow 117198, Russian Federation
› Author Affiliations
This publication has been supported by the Russian Science Foundation (project no. 24-23-00212), see https://rscf.ru/project/24-23-00212/.
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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

Supporting Information

    Supporting information for this article is available online at https://doi.org/10.1055/s-0043-1773527.
  • Supporting Information


Publication History

Received: 27 September 2024

Accepted after revision: 10 February 2025

Article published online:
06 May 2025

© 2025. Thieme. All rights reserved

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  • References and Notes

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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): νmax = 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.