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Synlett 2004(9): 1503-1508  
DOI: 10.1055/s-2004-829079
LETTER
© Georg Thieme Verlag Stuttgart · New York

Unexpected Tandem Sonogashira-Carbopalladation-Sonogashira Coupling Reaction of Benzyl Halides with Terminal Alkynes: A Novel Four-Component Domino Sequence to Highly Substituted Enynes

Laurent Romain Pottier, Jean-François Peyrat, Mouâd Alami*, Jean-Daniel Brion
Laboratoire de Chimie Thérapeutique, BioCIS - CNRS (UMR 8076), Université Paris Sud XI, Faculté de Pharmacie, rue J.B. Clément 92296 Châtenay-Malabry Cedex, France
Fax: +33(1)46835828; e-Mail: mouad.alami@cep.u-psud.fr;
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Received 7 April 2004
Publikationsdatum:
29. Juni 2004 (online)

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Abstract

Unexpected reactivity of benzyl halides with 1-alkynes in Sonogashira reaction promotes in a single-step process the construction of three carbon-carbon bonds regio- and stereoselectively and afforded highly substituted enynes in fair to good yields. The formation of the coupling adduct in this palladium-mediated four-component domino procedure is rationalized by an unprecedented tandem Sonogashira benzylpalladation Sonogashira sequence.

Key words

Sonogashira - palladium - enynes - benzyl halides - alkynes - four-component coupling

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Typical Procedure for the Coupling of 1-Alkynes with Benzyl Halides:
To a stirred mixture of CuCl (10 mol%), bis(triphenylphosphine)-palladium chloride (5 mol%), tetrabutylammonium iodide (10 mol%) and Et3N (1.5 mmol) in anhydrous THF (5 mL) was added, under a nitrogen atmosphere, at r.t. successively benzyl halide 1 (1 mmol) and terminal alkyne 4 (1.3 mmol). The resulting mixture was warmed at 50 °C and monitored by TLC until complete consumption of the benzyl halide (2-3 h). Et2O (10 mL) was added and then the mixture was filtered through a pad of celite, the filtrate was washed with aq NH4Cl (3 × 10 mL) dried over Na2SO4 and the solvent was then concentrated in vacuo. Purification by flash chromatography on silica gel afforded pure enyne product 3.
3a: 1H NMR (270 MHz, DMSO-d 6): δ = 7.29-7.16 (m, 10 H), 5.16 (t, 1 H, OH, J = 5.9 Hz), 4.91 (t, 1 H, OH, J = 5.3 Hz), 4.17 (d, 2 H, J = 5.9 Hz), 3.98 (d, 2 H, J = 5.3 Hz), 3.77 (s, 2 H), 3.56 (s, 2 H). 13C NMR (67.5 MHz, DMSO-d 6): δ = 145.8, 139.3, 139.2, 128.7, 128.6, 128.5, 126.4, 120.6, 91.4, 86.2, 60.3, 51.6, 39.3, 37.9. ESI-MS: m/z (%) = 310 (100) [M + NH4 +]. Anal. Calcd for C20H20O2: C, 82.16; H, 6.89. Found: C, 81.59; H, 6.83.
3b: 1H NMR (270 MHz, CDCl3): δ = 7.46-7.41 (m, 2 H), 7.35-7.20 (m, 16 H), 7.11-7.06 (m, 2 H), 4.22 (s, 2 H), 3.60 (s, 2 H). 13C NMR (67.5 MHz, CDCl3): δ = 148.0, 140.2, 139.8, 139.1, 131.3, 128.9, 128.7, 128.4, 128.2, 128.0, 127.9, 127.1, 126.0, 123.6, 119.9, 94.0, 92.2, 44.0, 39.2. ESI-MS: m/z (%) = 402 (100) [M + NH4 +], 385 (80) [MH+]. Anal. Calcd for C30H24: C, 93.71; H, 6.29. Found: C, 93.53; H, 6.48.