Synthesis of 3-Oxoisoindoline-1-carboxamides through Sequential Four-Component Ugi Reaction/Oxidative Nucleophilic Substitution of Hydrogen

Abstract

This paper describes a diversity-oriented approach to the formation of 3-oxoisoindoline-1-carboxamide derivatives utilizing the potential of the nitro group as a directing group. The reaction proceeds through a novel class of post-transformation reactions through a sequential four-component Ugi reaction/oxidative nucleophilic substitution of hydrogen. The 3-oxoisoindoline-1-carboxamide derivatives were synthesized in the presence of a base under mild reaction conditions with high regio- and chemoselectivity. The aerobic oxidation, high bond-forming efficiency, high atom economy, and good to excellent yields are the main advantages of this approach.

Key words

oxoisoindolinecarboxamides - Ugi reaction - multicomponent reaction - nucleophilic substitution

• References and Notes

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• 16 3-Oxoisoindoline-1-carboxamides 6a–k: General ProcedureA 25 mL one-necked flask containing a magnetic stirrer bar was charged with the appropriate primary amine (1.0 mmol) and arylcarboxaldehyde (1.0 mmol) in MeOH (2.0 mL) at rt, and the mixture was stirred for 20 min. 3-Nitrobenzoic acid (4) (1.0 mmol) was then added and stirring was continued for 20 min. The appropriate isocyanide (1.0 mmol) was then added and the mixture was stirred for another 24 hours at rt. When the reaction was complete (TLC), the solvent was removed under vacuum and, without any purification, dry toluene was added to the residue. Cs₂CO₃ (2.0 mmol) was then added, and the mixture was stirred at rt until the reaction was complete. H₂O (5 mL) was added and the aqueous phase was extracted with Et₂O (3 × 10 mL). The organic phase was separated and washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo. Further purification was performed by column chromatography (silica gel). N-[1-(3-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl]-3-nitro-N-phenylbenzamide (5a)White solid; yield: 236 mg (88%); mp 231 °C. IR (KBr): 1351 and 1531 (NO₂), 1649 (C=O) cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 8.19 (s, 1 H, H-Ar), 8.06 (d, J = 7.3 Hz, 1 H, H-Ar), 7.65 (d, J = 7.7 Hz, 1 H, H-Ar), 7.45 (s, 1 H, H-Ar), 7.41 (d, J = 7.9 Hz, 1 H, H-Ar), 7.33 (t, J = 8.0 Hz, 1 H, H-Ar), 7.18 (d, J = 7.7 Hz, 1 H, H-Ar), 7.11 (s, 1 H, H-Ar), 7.10–6.93 (m, 5 H, H-Ar), 6.17 [s, 1 H, −C(sp³)−H], 5.76 (d, J = 8.1 Hz, 1 H, NH), 3.92–3.86 (m, 1 H, H-Cy), 2.02–1.99 (m, 1 H, H-Cy), 1.95–1.89 (m, 1 H, H-Cy), 1.74–1.66 (m, 2 H, H-Cy), 1.63–1.60 (m, 1 H, H-Cy), 1.40–1.33 (m, 2 H, H-Cy), 1.23–1.07 (m, 3 H, H-Cy). ¹³C NMR (151 MHz, CDCl₃): δ = 168.7, 167.6, 147.4, 139.9, 137.5, 136.4, 134.3, 133.4, 131.9, 130.5, 130.1, 128.9, 128.9, 128.8, 128.1, 124.3, 123.7, 122.5, 65.8, 49.1, 32.8, 25.4, 24.8, 24.7. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₇ ⁷⁹BrN₃O₄: 536.1554; found: 536.1559.1-(3-Bromophenyl)-N-cyclohexyl-5-nitro-3-oxo-2-phenylisoindoline-1-carboxamide (6a)Pale-yellow solid; yield: 248 mg (93%); mp 277 °C. IR (KBr): 1350 and 1524 (NO₂), 1651 (C=O) cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 8.75 (s, 1 H, H-Ar), 8.46 (d, J = 8.6 Hz, 1 H, H-Ar), 7.80 (d, J = 8.4 Hz, 1 H, H-Ar), 7.40 (d, J = 7.7 Hz, 1 H, H-Ar), 7.36 (s, 1 H, H-Ar), 7.31–7.27 (m, 2 H, H-Ar), 7.23 (t, J = 7.3 Hz, 1 H, H-Ar), 7.17 (d, J = 8.1 Hz, 2 H, H-Ar), 7.08 (t, J = 7.7 Hz, 1 H, H-Ar), 7.06 (t, J = 7.7 Hz, 1 H, H-Ar), 6.20 (d, J = 8.1 Hz, 1 H, NH), 3.78–3.71 (m, 1 H, H-Cy), 1.88–1.83 (m, 1 H, H-Cy), 1.64–1.57 (m, 3 H, H-Cy), 1.34–1.23 (m, 3 H, H-Cy), 1.10–0.99 (m, 2 H, H-Cy), 0.90–0.84 (m, 1 H, H-Cy). ¹³C NMR (151 MHz, CDCl₃): δ = 166.6, 165.8, 151.6, 149.2, 138.4, 135.7, 132.2, 131.5, 131.3, 130.1, 129.4, 128.2, 127.6, 127.1, 125.5, 125.4, 122.8, 119.9, 77.0, 49.4, 32.5, 32.2, 25.1, 24.5, 24.4. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₇H₂₅ ⁷⁹BrN₃O₄: 534.1165; found: 534.1173.2-Buta-2,3-dien-1-yl-N-cyclohexyl-5-nitro-1-(3-nitrophenyl)-3-oxoisoindoline-1-carboxamide (8a)Pale-yellow solid; yield: 212 mg (89%); mp 285 °C. IR (KBr): 1345 and 1533 (NO₂), 1953 (C=C=C), 1656 (C=O) cm^–1.¹H NMR (600 MHz, CDCl₃): δ = 8.63 (s, 1 H, H-Ar), 8.50 (d, J = 8.4 Hz, 1 H, H-Ar), 8.26 (d, J = 9.0 Hz, 1 H, H-Ar), 8.05 (s, 1 H, H-Ar), 7.85 (d, J = 8.4 Hz, 1 H, H-Ar), 7.56 (t, J = 8.1 Hz, 1 H, H-Ar), 7.38 (d, J = 7.9 Hz, 1 H, H-Ar), 6.56 (d, J = 8.0 Hz, 1 H, –NH), 5.14 (p, J = 6.7 Hz, 1 H, allenic H), 4.76–4.72 (m, 1 H, allenic H), 4.66–4.62 (m, 1 H, allenic H), 4.13–4.08 (m, 1 H, –CH₂-N), 3.89–4.80 (m, 2 H, –CH₂-N and H-Cy), 2.12–2.05 (m, 1 H, H-Cy), 1.83–1.77 (m, 1 H, H-Cy), 1.76–1.61 (m, 3 H, H-Cy), 1.46–1.39 (m, 1 H, H-Cy), 1.35–1.24 (m, 2 H, H-Cy), 1.18–1.10 (m, 1 H, H-Cy), 1.04–0.97 (m, 1 H, H-Cy). ¹³C NMR (151 MHz, CDCl₃): δ = 208.8, 167.2, 165.7, 151.0, 149.4, 148.4, 138.2, 134.5, 131.7, 129.9, 128.2, 125.5, 124.1, 124.0, 119.3, 85.6, 77.5, 75.3, 49.7, 41.3, 32.9, 32.4, 25.2, 24.8, 24.7. HRMS-ESI: m/z [M + H]⁺ calcd for C₂₅H₂₅N₄O₆: 477.1680; found: 477.1686.Crystallographic data for 6a and 6b were collected by using APEX-II software, integrated by using SAINT, and corrected for absorption by using a multiscan approach (SADABS). Final cell constants were determined from full least-squares refinement of all observed reflections. The structure was solved by using intrinsic phasing (SHELXT). All non-H atoms were located in subsequent difference maps and refined anisotropically with SHELXL-2014/7.¹⁹ H atoms were added at calculated positions and refined with a riding model.
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