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Synlett 2007(2): 0227-0230  
DOI: 10.1055/s-2007-968011
LETTER
© Georg Thieme Verlag Stuttgart · New York

New Indolizine Template from the Ugi Reaction

Laurent El Kaim*, Marie Gizolme, Laurence Grimaud
Laboratoire Chimie et Procédés, Ecole Nationale Supérieure de Techniques Avancées, 32 Bd Victor, 75739 Paris Cedex 15, France
Fax: +33(1)45525587; e-Mail: laurent.elkaim@ensta.fr;
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Publication History

Received 6 October 2006
Publication Date:
24 January 2007 (online)

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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.

Key words

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

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

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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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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.