New Indolizine Template from the Ugi Reaction

Abstract

Ugi reactions and [3+2] cycloaddition of pyridinium salts have been associated to provide an efficient multicomponent access to indolizines. The pyridinium salts are formed by an Ugi ­reaction using chloroacetic acid and propargylamine followed by pyridine addition on the Ugi adduct. The coupling of these salts with aryl iodides gives directly indolizine derivatives in a Sonogashira-cycloaddition-oxidation reaction cascade.

indolizine - isocyanide - multicomponent reaction - Ugi reaction - Sonogashira coupling

References and Notes

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14

For similar oxidations, see: ref. 10a,c and ref. 11.

15

Typical Procedure (Given for 7c, Table 1): Anisaldehyde 1a (5 mmol, 608 µL), propargylamine (1 equiv, 343 µL), chloroacetic acid (1 equiv, 472 mg) and cyclohexyl iso-cyanide 2b (1 equiv, 622 µL) were added to MeOH (5 mL) and the mixture stirred overnight at r.t. The crude product was purified by flash chromatography using CH₂Cl₂ to give 1.41 g of 3b (70%). To the chloro derivative 3b (3.2 mmol) in EtOH (3 mL) was added 4-picoline (2 equiv, 0.52 mL) and the mixture stirred at 50 °C for 24 h. EtOH was evaporated, the crude product (1.6 mmol) was then added to 1-iodo-4-nitrobenzene (6b, 1.1 equiv, 876 mg) in a mixture THF-i-Pr₂NH (1:1, 6 mL). Then, Pd(OAc)₂ (0.04 equiv, 28 mg), CuI (0.08 equiv, 48 mg) and PPh₃ (0.08 equiv, 66 mg) were added and the mixture was stirred for 2 d. Extraction, evaporation and flash chromatography using Et₂O-PE (50: 50) afford 590 mg of 7c (33%).
¹H NMR (400 MHz, CDCl₃): δ = 8.56 (d, 1 H, J = 7.1 Hz), 8.26 (d, 2 H, J = 9.1 Hz), 7.63 (br s, 1 H), 7.59 (d, 2 H, J = 9.1 Hz), 7.39 (d, 2 H, J = 8.8 Hz), 6.93 (d, 2 H, J = 8.8 Hz), 6.71 (dd, 1 H, J = 7.1, 1.5 Hz), 6.00 (s, 1 H), 5.84 (br s, 1 H), 5.06 (d, 1 H, J = 17.2 Hz), 4.13 (d, 1 H, J = 17.2 Hz), 3.90-3.84 (m, 1 H), 3.82 (s, 3 H), 2.45 (s, 3 H), 1.99-1.93 (m, 2 H), 1.74-1.69 (m, 2 H), 1.39-1.10 (m, 6 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 169.3, 162.0, 160.1, 145.1, 142.3, 138.1, 137.7, 135.0, 130.5, 128.0, 126.9, 125.9, 124.9, 120.7, 116.8, 115.7, 114.8, 106.3, 58.5, 55.7, 49.2, 45.3, 33.3, 25.9, 25.2, 22.3. MS (DI, CI NH₃): m/z = 553. HRMS: m/z calcd for C₃₂H₃₂N₄O₅: 552.2373; found: 552.2385.

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17

Modified Procedure (Table 2): Aldehyde 1a (5 mmol), propargylamine (1 equiv), chloroacetic acid (1 equiv) and the isocyanide (1 equiv) were added to MeOH (5 mL) and the mixture stirred overnight at r.t., pyridine was then added (2 equiv) followed by stirring at 50 °C for 24 h. Addition of Et₂O and filtration gave pyridinium 5 which was further treated as shown for 7c.