The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

Tim G. Kilroy; Pier Giorgio Cozzi; Nicole End; Patrick J. Guiry

doi:10.1055/s-2003-43345

LETTER

The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

Tim G. Kilroy^a, Pier Giorgio Cozzi^b, Nicole End^c, 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

Abstract

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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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References

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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.

Kilroy, T. G.; End, N.; Cozzi, P. G.; Guiry, P. J. unpublished results.