Synthesis of Chiral L₂/Z-Type Ligands Featuring a Bisoxazoline Framework and Their Application to Palladium-Catalyzed Asymmetric Allylic Alkylation

Abstract

Chiral L₂/Z*-type ligands featuring a bisoxazoline framework have been successfully synthesized and applied in asymmetric allylic alkylation. These ligands, designed based on an oxazoline skeleton and derived from chiral amino acid derivatives, incorporate antimony and bismuth as Z-type ligands. Ligands with bulky, electron-withdrawing groups on antimony and bismuth showed enhanced catalytic performance. This research highlights the potential of these novel chiral L₂/Z*-type ligands to improve asymmetric catalysis.

Key word

asymmetric catalyst - Z-type ligand - chiral oxazoline - transition metal - allylic alkylation

Publication History

Received: 27 June 2024

Accepted after revision: 31 July 2024

Accepted Manuscript online:
31 July 2024

Article published online:
26 August 2024

• References and Notes

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• 11 Synthesis of L₂/Z*-Type Ligands 2 (2b) n-BuLi (1.05 equiv., 1.52 M in hexane) was added to a solution of 2-(2-bromophenyl)-oxazoline substrate (1.0 equiv.) in Et₂O (0.1 M) at –78 °C. The reaction mixture was stirred for 30 min to form the lithium species in situ, then SbCl₃ (0.5 equiv.) was added. The resulting mixture was stirred overnight at room temperature. The solvent was then filtered through a Celite pad to remove LiCl. The filtrate was evaporated to dryness, and the residue was purified by GPC (CHCl₃). Ligand 2b was obtained as a white powder in 55% yield. Analytical Data of 2b Mp 161–164 °C. ¹H NMR (500 MHz, DMSO): δ = 7.90 (d, J = 7.6 Hz, 2 H), 7.54 (br, 6 H), 4.70 (br, 2 H), 4.46 (br, 2 H), 4.19 (br, 2 H), 1.01 (br, 18 H). ¹³C NMR (100 MHz, DMSO): δ = 169.5, 152.8, 135.2, 133.0, 130.7, 129.5, 128.6, 74.9, 71.5, 33.6, 26.2. IR (ATR): 2962, 1654, 1630, 1475, 1380, 1364, 1256, 1132, 1083, 1039, 955, 776, 742 cm^–1. [α]_D ²⁵ 117.3 (c 1.0, CH₂Cl₂). HRMS (ESI): m/z calcd for C₂₆H₃₂ClN₂O₂Sb [M – Cl]⁺: 525.1496; found: 525.1496.
• 12 Synthesis of L₂/Z*-Type Ligands 4 (4b) n-BuLi (1.05 equiv., 1.52 M in hexane) was added to a solution of 3b (1.0 equiv.) in Et₂O (0.05 M) at –78 °C. The reaction mixture was then transferred to a solution of 2b (1.0 equiv.) in Et₂O (0.05 M) using a cannula and stirred at room temperature for 15 h. The solvent was filtered through a Celite pad to remove LiCl. The filtrate was evaporated to dryness, and the residue was recrystallized from CH₃CN. Ligand 4b was obtained as a white powder in 31% yield. Analytical Data of 4b Mp 201–203 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.90–7.82 (m, 4 H), 7.50–7.46 (m, 1 H), 7.37–7.31 (m, 4 H), 7.24–7.18 (m, 2 H), 4.23 (t, J = 9.2 Hz, 1 H), 4.13 (m, 2 H), 3.99 (t, J = 9.2 Hz, 1 H), 3.79 (br, 2 H), 0.52 (s, 18 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –54.5, –56.0. ¹³C NMR (100 MHz, CDCl₃): δ = 164.7, 164.6, 151.4 (2 C), 148.1 (br), 138.7, 138.5, 137.8 (q, J _CF = 30.2 Hz), 137.5 (q, J _CF = 30.2 Hz), 133.0, 132.8, 130.5, 130.4, 129.2 (t, J = 6.7 Hz, 2 C), 128.1, 127.7, 127.6, 127.5, 127.2, 124.6 (q, J = 274.8 Hz), 124.2 (q, J = 273.9 Hz), 75.8, 75.7, 69.1, 68.7, 33.3, 33.2, 25.5 (3 C), 25.5 (3 C). IR (ATR): 2954, 1645, 1355, 1330, 1285, 1181, 1139, 1127, 1109, 1083, 967, 815, 784, 737, 728 cm^–1. [α]_D ²⁵ 32.7 (c 0.5, CH₂Cl₂). HRMS (ESI): m/z calcd for C₃₄H₃₅F₆N₂O₂Sb [M – Ar]⁺: 525.1496; found: 525.1496. Synthesis of Complex 6 CuCl (1.0 equiv.) was added to a CH₂Cl₂ solution of 2b (0.05 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was then filtered through a Celite pad, and the solvent was removed under reduced pressure. The residue was washed with Et₂O, and the resulting product was dried in vacuo at room temperature for 1 h, yielding the Cu complex 6 (33.7 mg, 99%). Analytical Data of Complex 6 Mp 193–198 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.92 (d, J = 7.6 Hz, 2 H), 7.84 (br, 2 H), 7.75 (br, 2 H), 7.55 (br, 2 H), 5.28 (br, 2 H), 4.81 (br, 4 H), 1.17 (s, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 175.2, 148.5, 135.9, 134.1, 130.5, 129.5, 127.8, 74.3, 73.9, 34.1, 26.5. IR (ATR): 2956, 1610, 1554, 1484, 1397, 1370, 942, 738 cm^–1. [α]_D ²⁵ 383.0 (c 0.5, CH₂Cl₂). HRMS (ESI): m/z calcd for C₂₆H₃₂Cl₂N₂O₂SbCu [M – CuCl₂]⁺: 525.1496; found: 525.1493.
• 13 Reaction of L₂/Z*-Type Ligand 4b and PdCl₂(CH₃CN) PdCl₂(CH₃CN)₂ (1.0 equiv.) was added to a CH₂Cl₂ solution of 4b (0.1 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was then filtered through a Celite pad, and the solvent was removed under reduced pressure. The residue was washed with Et₂O, and the resulting product was dried in vacuo at room temperature for 1 h, yielding the Pd complex 9 (23.0 mg, 25%). Analytical Data for Complex 9 Mp 154–157 °C. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (dd, J = 7.6, 1.2 Hz, 1 H), 8.02 (dd, J = 7.6, 1.2 Hz, 1 H), 7.97 (dd, J = 8.0, 1.2 Hz, 1 H), 7.90 (d, J = 6.8 Hz, 1 H), 7.78 (t, J = 7.6 Hz, 1 H), 7.67 (td, J = 7.6, 1.2 Hz, 1 H), 7.52 (tm, J = 7.6 Hz, 2 H), 7.43 (td, J = 7.6, 1.2 Hz, 1 H), 7.38 (d, J = 7.6 Hz, 1 H), 7.33 (d, J = 7.6 Hz, 1 H), 5.33 (dd, J = 10.2, 4.8 Hz, 1 H), 4.99 (dd, J = 10.2, 7.6 Hz, 1 H), 4.50 (dd, J = 10.2, 8.4 Hz, 1 H), 4.44 (d, J = 10.2 Hz, 1 H), 4.37 (dd, J = 9.2, 4.8 Hz, 1 H), 4.24 (dd, J = 8.4, 7.6 Hz, 1 H), 0.75 (s, 9 H), 0.52 (s, 9 H). ¹⁹F NMR (376 MHz, CDCl₃): δ = –51.7, –55.3. ¹³C NMR (100 MHz, CDCl₃): δ = 165.9, 163.9, 147.9 (br), 146.0, 145.3, 139.3 (q, J _CF = 30.9 Hz), 136.7, 136.6, 135.8 (q, J _CF = 30.9 Hz), 135.0, 134.0, 133.2. 132.4, 132.2 131.7 (2C), 131.0, 130.6 (t, J _CF = 5.3 Hz, 2 C), 128.8, 123.7 (q, J _CF = 275.2 Hz), 122.8 (q, J _CF = 273.1 Hz), 75.7, 75.4, 71.1 69.9, 33.4, 33.2, 25.8 (6 C). IR (ATR): 2956, 1651, 1558, 1485, 1332, 1288, 1138, 1109, 961, 909, 820, 776, 731 cm^–1. [α]_D ²⁵ 607.6 (c 0.5, CH₂Cl₂). HRMS (ESI): m/z calcd for C₃₄H₃₅Cl₂N₂O₂SbPd [M – Cl]⁺ = 881.0365; found: 881.0363.
• 14 Asymmetric Allylic Alkylation with Pd-L₂/Z*-Type Ligand Complexes In a nitrogen gas atmosphere, ligand (5 mol%), Pd₂(dba)₃ (2.5 mol%), and CH₂Cl₂ (0.1 M) were placed in a vial containing a magnetic stirring bar. After stirring for 15 min at 25 °C, 11 (0.2 mmol), 10 (2.0 equiv.) and Cs₂CO₃ were added to the mixture. The reaction mixture was further stirred at 25 °C for 20 h. The reaction was quenched with 1 mL of H₂O. The two phases were separated, and the aqueous layer was extracted with CH₂Cl₂ (3 × 1 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. An internal (1,1,2,2-tetrachloroethane) was added to the residue. The yield of the product 12 was determined by ¹H NMR spectroscopy (>99%). The crude material was then purified by silica gel chromatography (hexane/EtOAc = 80:20) to give the corresponding product 12. Compound 12 was obtained as a colorless oil (49% yield). Analytical data for 12 ^{10c 1}H NMR (400 MHz, CDCl₃): δ = 7.33–7.20 (m, 10 H), 6.48 (d, J = 15.6 Hz, 1 H), 6.33 (dd, J = 15.6, 8.8 Hz, 1 H), 4.27 (dd, J = 10.8, 8.8 Hz, 1 H), 3.96 (d, J = 10.8 Hz, 1 H), 3.70 (s, 3 H), 3.52 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 168.2, 167.8, 140.1, 136.8, 131.8, 129.1, 128.8, 128.5, 127.9, 127.6, 127.2, 126.4, 57.5, 52.7, 52.5, 49.2. HPLC: Daicel CHIRALPAK IA-3, hexane/i-PrOH = 97:3, flow rate = 0.5 mL/min, t _R = 13.0 min (minor), 16.2 min (major).