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Synlett 2004(1): 106-110  
DOI: 10.1055/s-2003-43345
LETTER
© Georg Thieme Verlag Stuttgart · New York

The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

Tim G. Kilroya, Pier Giorgio Cozzib, Nicole Endc, Patrick J. Guiry*a
a Centre for Synthesis and Chemical Biology, Conway Institute of Biomolecular and Biomedical Research, Department of Chemistry, ­University College Dublin, Belfield, Dublin 4, Ireland
e-Mail: P.Guiry@ucd.ie;
b Dipartimento di Chimica , ‘G. Ciamician’, Via Selmi 2, 40126 Bologna, Italy
c Ciba Speciality Chemicals, Group Research, K-420.2.18, 4002 Basel, Switzerland
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Publication History

Received 29 September 2003
Publication Date:
26 November 2003 (online)

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Abstract

Two new heterocyclic diphenylphosphinooxazolines derived from thiophene and benzothiophene were prepared in moderate to good yield and these, and a range of related HETPHOX ligands, were applied in the intermolecular asymmetric Heck reaction. Phenylation of 2,3-dihydrofuran with the t-butyl-substituted thiophene-oxazoline ligand gave (R)-2-phenyl-2,3-dihydrofuran highly regioselectively with excellent enantioselectivity (91-95% ee) and in good yields (70-97%). In addition, cyclohexenylation of 2,3-dihydrofuran proceeded with enantioselectivities of up to 97% ee in excellent (97%) yields, again with the t-butyl-substituted thiophene-oxazoline ligand proving optimal over a range of reaction conditions investigated.

Key words

P,N ligands - oxazoline - asymmetric catalysis - inter­molecular Heck reaction - palladium

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Typical Experimental Procedure for the Preparation of 2-(2-Diphenylphosphino)-benzo[ b ]thiophene-3-yl-4 S -phenyl-4,5-dihydrooxazole (11).
To a solution of the benzo[b]thiophene-oxazoline (1.0 g, 3.58 mmol) in Et2O (10 mL) at -78 °C a solution of 1.6 M BuLi in hexane (2.3 mL, 3.70 mmol) were added and the resulting suspension was agitated at -78 °C for 1 h and 30 min. Diphenylchlorophosphine (0.62 mL, 3.36 mmol) was added at -78 °C and the reaction mixture was warmed at r.t. and stirred for 30 min. The reaction was quenched by adding pentane (40 mL) and H2O (30 mL). The organic phase was separated and dried over Na2SO4 and purified by chromato-graphy (hexane:Et2O, 9:1). Yield 78%; [α]D -5.4 (c 0.92, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 3.96 (dd, 1 H, J = 8.3, 8.8 Hz), 4.56 (dd, 1 H, J = 8.3, 10.3 Hz), 5.34 (dd, 1 H, J = 8.8, 10.3 Hz), 7.04-7.09 (m, 2 H), 7.22-7.52 (m, 15 H), 7.58-7.72 (m, 1 H), 8.60-8.66 (m, 1 H). 13C NMR (75 MHz, CDCl3): δ = 70.1, 74.1, 121.7, 125.0, 125.1, 125.3, 126.9, 127.5, 127.8, 128.7, 128.8 (d, J = 7.7 Hz), 129.6 (d, J = 10.9 Hz), 133.9 (d, J = 21.3 Hz), 134.3 (d, J = 21.3 Hz), 137.0 (J = 20.6 Hz), 137.2 (d, J = 16.6 Hz), 139.8, 142.0, 142.6, 148.9 (d, J = 42.8 Hz), 161.3. 31P (124 MHz, CDCl3): δ = -12.4. MS (EI): m/z (%) = 463 (4) [M+], 358 (100), 296 (12) and 239 (18).
Typical Experimental Procedure for the Preparation of 4- iso- Propyl-2-(3-diphenylphosphino-thiophene-2-yl)-4,5-dihydrooxazole (12). Thiophene-2-oxazoline (0.418 g, 2.14 mmol) was dissolved in Et2O (5 mL) and the resultant solution was cooled at -78 °C. A solution of 2.5 M n-BuLi in hexane (1.6 mL, 4 mmol) was added dropwise and the yellow solution was stirred at
-78 °C for 30 min. The reaction was warmed up at 0 °C and stirred at this temperature for 30 min. The yellow-green solution was finally cooled to -78 °C then ClPPh2 (0.74 mL, 4 mmol) was added. The reaction was allowed to warm to r.t. during 20 h and then quenched with H2O. The phases were separated and the aqueous phase was extracted with Et2O (2 × 5 mL) the the organic phases were combined, dried over Na2SO4 and evaporated under reduced pressure to give an oil then was purified by chromatography (cyclohexane: Et2O, 9:1) to give a clear oil that slowly turned into a waxy white solid, yield 34%; [α]D -99.0 (c 0.99, CHCl3). 1H NMR (300 MHz, CDCl3): δ = 0.71 (d, 1 H, J = 6.6 Hz), 0.74 (d, 3 H, J = 6.6 Hz), 1.6 (m, 1 H), 3.92 (q, 1 H, J = 7.8 Hz), 4.02 (q, 1 H, J = 7.8 Hz), 4.22 (dt, 1 H, J = 7.8, 1.8 Hz), 6.38 (dd, 1 H, J = 5.2, 0.8 Hz), 7.40-7.30 (m, 11 H). 13C NMR (75 MHz, CDCl3): δ = 17.10, 17.78, 31.86, 71.61, 126.20, 127.41, 127.17 (d, J = 13 Hz), 126.60 (d, J = 6 Hz), 132.10, 132.11 (d, J = 23.4 Hz), 132.50 (d, J = 20.8 Hz), 136.15 (d, J = 10.3 Hz), 137 (d, J = 11.8 Hz), 140.00 (d, J = 27 Hz), 157.11 (d, J = 3.5 Hz). 31P NMR (124 MHz, CHCl3): δ = -13.15. MS (EI): m/z (%) = 379 (2) [M+], 364 (4), 336 (19), 308 (100), 288 (53), 234 (9) and 89 (18).

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Typical Experimental Procedure for the Asymmetric Heck Reaction. A solution of aryl or alkenyl trifluoromethanesulfonate (0.13 mmol) and n-tridecane (10.0 mg, 0.054 mmol) in benzene (0.5 mL) was added to a schlenk containing Pd2(dba)3 (2.3 mg, 0.004 mmol) and ligand (0.008 mmol) under nitrogen. To this was then added the 2,3-dihydrofuran (0.65 mmol) and base (0.39 mmol). The resulting solution was then degassed by three freeze-thaw cycles at 0.01 mbar and then left to stir under nitrogen at 80 °C for 7 d giving a red solution with precipitation of Base·HOTf. Pentane (10 mL) was then added to the reaction mixture and the resulting suspension was filtered through 2 cm of silica with further elution using Et2O (10 mL). This solution was then concentrated and the yield calculated using GC (Se-30, 11 psi, 50 °C, 4 min, 15 °C/min, 170 °C, 10 min) by the internal standard method.

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Kilroy, T. G.; End, N.; Cozzi, P. G.; Guiry, P. J. unpublished results.