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Synlett 2009(16): 2617-2620  
DOI: 10.1055/s-0029-1217953
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 8-Oxo-3-acetylenic-5,6,7,8-tetrahydroindolizines via Sonogashira Coupling

Stéphanie Gracia, Estelle Métay, Stéphane Pellet-Rostaing*, Marc Lemaire*
Laboratoire de Catalyse et Synthèse Organique, ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS, UMR 5246, Université de Lyon, 69622 Villeurbanne, France
Fax: +33(4)72431408; e-Mail: pellet@univ-lyon1.fr;
Further Information

Publication History

Received 24 June 2009
Publication Date:
03 September 2009 (online)

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Abstract

A selective alkynylation of 3-bromoindolizinone, involving the first copper-free Sonogashira coupling on pyrrole ring, has been developed to afford 8-oxo-3-acetylenic-5,6,7,8-tetra­hydroindolizinone.

Key words

cross-coupling - pyrrole - palladium - alkynylation - alkaloid

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11

Synthesis of 3-Bromo-8-oxo-5,6,7,8-tetrahydro-indolizine (2) To a solution of 8-oxo-5,6,7,8-tetrahydroindolizine in CH2Cl2 (0.12 M) was added NBS (1 equiv) portionwise.
The resulting mixture was stirred for 10 min (as monitored by TLC). After removal of the solvent in vacuum, the
crude product was purified by column chromatography (cyclohexane-EtOAc, 9:1). A white powder is obtained with 95% yield. ¹H NMR (300 MHz, CDCl3): δ = 2.26 (m, 2 H), 2.54 (m, 2 H), 4.02 (t, 2 H, J = 5.85 Hz), 6.26 (d, 1 H, J = 4.32 Hz), 6.96 (d, 1 H, J = 4.14 Hz). ¹³C NMR (75 MHz, CDCl3): δ = 23.2 (CH2), 35.7 (CH2), 44.4 (CH2), 109 (Cq), 113.2 (CH), 114.7 (CH), 131.9 (Cq), 131.8 (Cq), 186.5 (CO). HRMS (EI): m/z calcd for C8H8BrNO: 212.9789; found: 212.9791.

17

General Procedure for Copper-Free Sonogashira Coupling (See Supporting Information)
To a solution of 2 and PdCl2 (PPh3)2 (10 mol%) in dry MeCN (0.5 M) under argon were added Et3N (1.5 equiv) then acetylene (1.2 equiv). The resulting mixture was heated at 80 ˚C in a sealed tube for the required time (as monitored by GC). The mixture was cooled at r.t. then diluted with CH2Cl2. The organic layer was washed with H2O, brine, dried over Na2SO4, concentrated, and finally purified on column chromatography (cyclohexane and cyclohexane-EtOAc = 9:1).
3-(Phenylethynyl)-8-oxo-5,6,7,8-tetrahydro-indolizine (3a)
Yield 82%; yellow powder. ¹H NMR (300 MHz, CDCl3): δ = 2.32 (m, 2 H), 2.62 (dd, 2 H, J = 6.21, 7.53 Hz), 4.22 (dd, 2 H, J = 5.64, 7.14 Hz), 6.53 (d, 1 H, J = 4.32 Hz), 7.00 (d, 1 H, J = 4.14 Hz), 7.37 (m, 3 H), 7.52 (m, 2 H). ¹³C NMR (75 MHz, CDCl3): δ = 23.6 (CH2), 36.4 (CH2), 43.7 (CH2), 80.1 (Cq), 95.6 (Cq), 114.1 (CH), 116.1 (CH), 120.1 (Cq), 122.6 (Cq), 128.8 (CH), 129.2 (CH), 131.8 (Cq), 131.8 (CH), 187.2 (CO). HRMS (EI): m/z calcd for C16H13NO: 235.0997; found: 235.0995.