Synthesis of Novel Chiral Thiophene-, Benzothiophene- and Benzofuran-
Oxazoline Ligands and their Use in the Enantioselective Pd-Catalyzed
Allylation

Abstract

Novel thiophene, benzothiophene and benzofuran-oxazoline ligands 6-11 containing a diphenylphosphino group at different positions of the heterocyclic skeleton have been prepared and used in the enantioselective allylation. The advantage of these new ligands is their easy accessibility and their high reactivity. The best results were obtained with ligand 9 to give the product 13 in 97.0% ee with 92% yield in 2 hours at 0 °C.

Key words

allylation - asymmetric catalysis - furan - ligands - palladium - thiophene

References

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7

Synthesis of Ligand 9: To a suspension of benzothiophene-3-carboxylic acid (1.0 g, 5.6 mmol) in DMF (0.5 mL) and toluene (10 mL), oxalyl chloride (2.13 g, 16.8 mmol) was added dropwise at 0 °C with stirring, which was continued for 3 h at r.t. The solvent was removed in vacuo and the crude acid chloride dissolved in CH₂Cl₂ (20 mL). This solution was added dropwise to a mixture of (S)-valinol (865 mg, 6.7 mmol) and Et₃N (1.41 g, 14 mmol) in CH₂Cl₂ (50 mL). After stirring overnight, 1 N HCl (50 mL) was added, the aqueous phase extracted twice with CH₂Cl₂ (50 mL) and the combined organic layers dried over MgSO₄. The solvent was removed in vacuo and the residue dissolved in CH₂Cl₂ (50 mL). After the addition of NEt₃ (1.41 g, 14 mmol) the solution was cooled to 0 °C and MsCl (767 mg, 6.7 mmol) added dropwise. After complete conversion (TLC, n-pentane/EtOAc = 1:1) the solvent was removed in vacuo, MeOH (20 mL) added followed by powdered KOH (1.56 g, 28 mmol) and the mixture stirred for 3 h. After removal of methanol in vacuo water (60 mL) was added and the mixture extracted with ether (2 × 50 mL). Drying of the organic layers over MgSO₄ gave the crude oxazoline, which was purified by column chromatography (Et₂O/pentane = 1:10) to afford 900 mg (3.7 mmol, 66% over 3 steps) of a yellow oil, which solidified at -20 °C. The oxazoline was dissolved in dry Et₂O (50 mL) and treated with n-BuLi (4.1 mmol of a 2.2 M solution in hexane) at -78 °C. After 5 min PPh₂Cl (977 mg, 4.4 mmol) was added and the cooling bath removed with continuation of stirring for 1 h. Afterwards the solvent was removed in vacuo and the residue purified by column chromatography (n-pentane:Et₂O = 10:1) to give ligand 9, as a white foam (1.15 g, 2.7 mmol, 73%). [α]_D ²⁰
-72.5 (c 1.0, CHCl₃); R_f 0.26 (n-pentane/Et₂O = 10:1);
¹H NMR (300 MHz, CDCl₃): δ = 0.80 (d, J = 7.0 Hz, 3 H, CH₃), 0.89 (d, J = 7.0 Hz, 3 H, CH₃), 1.64 (oct, J = 7.0 Hz,
1 H, CHMe₂), 3.87 (t, J = 8.0 Hz, 1 H, 4-H_a), 3.98 (ddd, J = 9.0, 8.0, 7.0 Hz, 1 H, 3-H), 4.14 (dd, J = 9.0, 8.0 Hz, 1 H, 4-H_b), 7.27-7.48 (m, 12 H, Ph-H, 5′-H, 6′-H), 7.66 (d, J = 8.0 Hz, 1 H, 4′-H*), 8.56 (d, J = 8.0 Hz, 1 H, 7-H*), (the assignments of the signals with an asterisk may have to be exchanged); ¹³C NMR (150 MHz, CDCl₃): δ = 18.39 (CH₃), 18.67 (CH₃), 32.82 [CH(CH₃)₂], 69.50 (C-3′), 72.37 (C-4′), 123.39 (C-H), 124.58 (Ph-C₄), 124.59 (Ph-C₄), 124.80 (CH), 127.95 (d, J = 16.4 Hz, C-3), 128.26 (d, J = 2.7 Hz, Ph-C₃), 128.31 (d, J = 2.3 Hz, Ph-C₃), 129.00 (C-H), 129.20 (C-H), 133.46 (d, J = 20.9 Hz, Ph-C₂), 133.87 (d, J = 21.0 Hz, Ph-C₂), 136.74 (d, J = 9.9 Hz, Ph-C₁), 137.05 (d, J = 10.3 Hz, Ph-C₁), 139.39 (d, J = 2.1 Hz, C-3a), 141.69 (C-7a), 147.55 (d, J = 41.8 Hz, C-2), 159.47 (d, J = 3.3 Hz, C-1′); ³¹P NMR (80 MHz, CDCl₃): δ = -13.19; MS (EI): m/z = 429 (M⁺), 358, 338; Anal. Calcd for C₂₆H₂₄NOPS: C, 72.70; H, 5.63%. Found: C, 73.11; H, 5.65%.

8

Cozzi et al. have also prepared the ligand 9 and used it with similar results in the Pd-catalyzed allylation: Cozzi, P. G.; Dipietro, P.; End, N.; Berens, U. IUPAC ICOS-14 in Christchurch, New Zealand, July 16^th, 2002.