The Application of HETPHOX Ligands to the Asymmetric Intermolecular Heck Reaction

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.

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

References

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18

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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21

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.

22

Kilroy, T. G.; End, N.; Cozzi, P. G.; Guiry, P. J. unpublished results.