Transposition of Aromaticity from a Furan to a Cyclohexane Ring in Furoisoindoles During the Interaction of 3-(Furyl)allylamines with Bromomaleic Anhydride

Abstract

An unexpected four-step reaction sequence was discovered in the course of investigation of the interaction between 3-(furan-2-yl)allylamines and bromomaleic anhydride. This conversion begins with the initial N-acylation of the allylamines by the anhydride, followed by intramolecular Diels–Alder reaction, which is accompanied by a dehydrohalogenation, and ends with the formation of partially unsaturated furo[2,3-f]isoindoles followed by transposition of aromaticity from the furan moiety to the neighboring cyclohexane ring. The reaction between 3-(furan-3-yl)allylamines and bromomaleic anhydride does not stop at a furo[2,3-f]isoindole formation step, but proceeds further with the cleavage of the furan ring in a 100% atom-efficient fashion to provide polysubstituted isoindoline-4-carboxylic acids.

Key words

furan - Diels–Alder reaction - transposition of aromaticity - furo[2,3-f]isoindole - IMDAV reaction - atom-efficient reaction

• References and Notes


Recent examples of synthesis of furo[2,3-f]isoindoles:
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Bromomaleic anhydride as an internal dienophile:
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• 10 General Procedure for the Synthesis of the Initial Allylamines 2 and 15 Powdered anhydrous MgSO₄ (1.97 g, 16.4 mmol) was added to a stirred solution of 2-furylacrolein or 3-furylacrolein (1.00 g, 8.2 mmol) and the corresponding amine (8.2 mmol) in CH₂Cl₂ (20 mL) at r.t. After approx. 12 h, MgSO₄ was filtered off through a fine layer of SiO₂, washed with CH₂Cl₂ (2 × 15 mL), and the solution was concentrated under reduced pressure. The residue was diluted with MeOH (20 mL), and then NaBH₄ (0.62 g, 16.4 mmol) was added in small portions within 10 min. The solution was vigorously stirred for 3 h at r.t., then the reaction mixture was poured into H₂O (80 mL) and extracted with CH₂Cl₂ (3 × 30 mL); the combined organic layers were dried over anhydrous MgSO₄, concentrated, and the residue was used in the next stage after purification via flash chromatography (a mixture of hexane/EtOAc was used as eluent). Selected Physical and Spectral Data for Compound 2b Brown oil; 68% yield (0.92 g). ¹H NMR (600.2 MHz, CDCl₃, 22 °C): δ = 7.31 (br d, J = 1.7 Hz, 1 H, H-5-Fur), 6.36–6.33 (m, 2 H, H-4-Fur and H-3-Vinyl), 6.23 (d t, J = 6.1, 15.6 Hz, 1 H, H-2-Vinyl), 6.18 (br d, J = 3.5 Hz, 1 H, H-3-Fur), 3.36 (d d, J = 1.0, 6.1 Hz, 2 H, N-C H ₂ -CH=), 2.87 (hept, J = 6.1 Hz, 1 H, CHMe₂), 1.73 (br s, 1 H, NH), 1.08 (d, J = 6.1 Hz, 6 H, CHMe₂ ) ppm. ¹³C NMR (150.9 MHz, CDCl₃, 24 °C): δ = 152.8, 141.7, 127.7, 119.5, 111.2, 107.1, 49.1, 48.0, 23.0 (2 C) ppm. General Procedure for the Synthesis of the Target Furo[2,3-f]isoindolecarboxylic Acids 3 and 19 Bromomaleic anhydride (0.27 g, 1.5 mmol) was added to a solution of the appropriate allylamine 2 or 15 (1.5 mmol) in abs. 1,4-dioxane (10 mL). The mixture was heated at reflux (ca. 100 °C) for 1 h. The reaction mixture was cooled to r.t., and the obtained solid was filtered off, washed with ethanol (3 × 3 mL), and dried in the air. If necessary, the target compounds may be recrystallized from a mixture of EtOH/DMF. Selected Physical and Spectral Data for Compound 3b Beige needles; 76% yield (0.30 g), mp 286.3–286.5 °C (with decomp.). ¹H NMR (600.2 MHz, DMSO-d ₆, 140 °C): δ = 7.15 (s, 1 H, H-8), 4.69 (t, J = 8.7 Hz, 2 H, H-2), 4.53 (s, 2 H, H-7), 4.44 (hept, J = 6.7 Hz, 1 H, CHMe₂), 3.61 (t, J = 8.7 Hz, 2 H, H-3), 1.34 (d, J = 6.7 Hz, 6 H, CHMe ₂) ppm. ¹³C NMR (100.5 MHz, DMSO-d ₆, 140 °C): δ = 169.3, 165.1, 164.9, 146.1, 134.3, 126.5, 122.0, 107.2, 73.2, 47.01, 44.9, 31.1, 20.4 (2 C) ppm.