Iridium- and Rhodium-Catalyzed [2+2+2] Cycloadditions of Diynes with Maleimide: A New Synthetic Route to Highly Substituted Phthalimides

Abstract

The [2+2+2] cycloaddition of maleimide with α,ω-diynes in the presence of [IrCl(cod)]₂ or [RhCl(cod)]₂ and DPPE gives cyclohexadiene derivatives which are readily aromatized with DDQ or MnO₂. This two-step procedure gives access to highly substituted phthalimides in good yields.

Key words

alkyne cycloaddition - phthalimides - iridium - rhodium - dehydrogenations

References and Notes

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9

General Procedures for Iridium- and Rhodium-Catalyzed [2+2+2] Diyne-Maleimide Cycloadditions (Table 2)
Diyne 1 (0.25 mmol), [IrCl(cod)]₂ or [RhCl(cod)]₂ (0.025 mmol) and DPPE (0.050 mmol) were dissolved in degassed THF (5 mL) under an Ar atmosphere and the mixture was stirred at r.t. for 5 min. Maleimide (0.25 mmol) was then added in one portion and the reaction mixture was refluxed for 3 h in the case of iridum catalysis or 24 h in the case of rhodium catalysis. After cooling, the resulting reaction mixture was concentrated under reduced pressure and cyclohexadiene 3 was isolated by column chromatography.

10

General Procedure for the Preparation of Diynes 1 by Sonogashira Coupling
An oven-dried flask was charged with the corresponding aryl iodide (15 mmol), PdCl₂(PPh₃)₂ (350 mg, 0.50 mmol), anhyd CuI (38 mg, 0.2 mmol), dried Et₃N (15 mL) and anhyd THF (15 mL) under Ar. The mixture was then stirred at r.t. for 10 min. Afterwards, a solution of the corresponding diacetylene (5 mmol) in anhyd THF (15 mL) and dried Et₃N (15 mL) was added dropwise. The reaction mixture was stirred at r.t. for 48 h under Ar. The reaction mixture was poured into an aq soln of 10% HCl and was extracted with Et₂O. The organic phases were washed with H₂O, brine, and dried over Na₂SO₄. Evaporation of the solvent gave a brown oil or solid from which the product was separated by column chromatography over silica gel using a mixture of EtOAc-pentane (1:1) to give the product 1 with analytical purity in 80-95% yield. All diynes 1 gave analytical and spectral data in accordance with the structure.

11

All cyclohexadienes 3 gave analytical and spectral data in accordance with the structure.
Data for Products 3
Compound 3a: mp 171.5 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (br s, 1 H), 7.28-7.43 (m, 10 H), 4.28 (s, 2 H), 4.17 (q, 2 H, J = 8.0 Hz), 4.03 (q, 2 H, J = 8.0 Hz), 3.15 and 3.08 (ABq, 4 H, J = 20.0 Hz), 1.21 (t, 3 H, J = 8.0 Hz), 1.08 (t, 3 H, J = 8.0 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 176.4, 170.9, 170.8, 138.5, 135.1, 128.4, 128.1, 127.7, 124.0, 61.9, 61.7, 58.3, 47.9, 39.5, 14.1, 14.0. IR (neat): 3153, 3052, 1779, 1751, 1697, 1574, 1493, 1235, 1183 cm^-1. Anal. Calcd for C₂₉H₂₇NO₆: C, 71.74; H, 5.61; N, 2.88. Found: C, 71.48; H, 5.66; N, 2.53.
Compound 3b: mp 253.5 °C (dec.). ¹H NMR (400 MHz, DMSO-d ₆): δ = 11.36 (br s, 1 H), 7.29-7.42 (m, 10 H), 4.74 and 4.30 (ABq, 4 H, J = 13.2 Hz), 4.69 (s, 2 H). ¹³C NMR (100 MHz, DMSO-d ₆): δ = 177.8, 138.2, 135.2, 134.1, 128.1, 127.3, 122.7, 70.5, 46.2. IR (neat): 3148, 3058, 1774, 1712, 1574, 1494, 1182 cm^-1. Anal. Calcd for C₂₂H₁₇NO₃: C, 76.95; H, 4.99; N, 4.08. Found: C, 76.70; H, 5.10; N, 3.85.
Compound 3e: mp 205 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.18 (br s, 1 H), 7.29 (d, 4 H, J = 12.0 Hz), 6.94 (d, 4 H, J = 12.0 Hz), 4.24 (s, 2 H), 4.18 (q, 2 H, J = 8.0 Hz), 4.05 (q, 2 H, J = 8.0 Hz), 3.84 (s, 6 H), 3.14 and 3.09 (ABq, 4 H, J = 16.0 Hz), 1.22 (t, 3 H, J = 8.0 Hz), 1.09 (t, 3 H, J = 8.0 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 176.6, 171.0, 170.8, 159.0, 134.4, 130.9, 129.4, 123.1, 113.9, 61.9, 61.6, 58.4, 55.3, 47.8, 39.6, 14.1, 14.0. Anal. Calcd for C₃₁H₃₁NO₈: C, 68.25; H, 5.73; N, 2.57. Found: C, 68.14; H, 5.66; N, 2.41.

15

General Procedure for Aromatization of Cyclohexadienes 3
With DDQ: Cyclohexadiene 3 (0.15 mmol) and DDQ (0.15 mmol) were dissolved in anhyd toluene (5 mL) and the reaction mixture was stirred under reflux for 24 h. Once cooled, the resulting reaction mixture was washed with distilled H₂O, dried with Na₂SO₄, and evaporated under reduced pressure. Phthalimide 4 was obtained after chromatographical purification using SiO₂.
With MnO₂: Cyclohexadiene 3 (0.15 mmol) and activated MnO₂ (1.5 mmol) were added to anhyd toluene (5 mL). The black suspension was stirred under reflux for 48 h or until completion of the reaction (TLC monitoring). After cooling, the solid was filtered off and the filtrate evaporated under reduced pressure, giving pure 4 in quantitative yields.

16

All phthalimides 4 gave analytical and spectral data in accordance with the structure.
Data for Product 4a
Mp 179.5 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (br s, 1 H), 7.38-7.51 (m, 10 H), 4.15 (q, 4 H, J = 7.2 Hz), 3.52 (s, 4 H), 1.19 (t, 6 H, J = 7.2 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 170.9, 166.9, 146.9, 136.5, 134.8, 129.1, 129.0, 128.5, 128.4, 62.2, 60.1, 40.3, 14.1. Anal. Calcd for C₂₉H₂₅NO₆: C, 72.04; H, 5.21; N, 2.90. Found: C, 72.35; H, 5.59; N, 3.12.