Compound 1c

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Compound data: CIF

Synthetic procedure: See article for the definitive version of this procedure and for full experimental details.

Methyl-(S)-1-benzyl-4-oxopyrrolidine-2-carboxylate S2 (3.02 g, 12.95 mmol, 1.00 equiv.), synthesized according to a procedure reported in the literature¹, was added to an oven dried, argon purged 2-neck round bottomed flask fitted with an argon inlet and septum, followed by the addition of CH₂Cl₂ (130.0 mL). Then, diethylaminosulfur trifluoride (DAST, 4.11 mL, 31.1 mmol, 2.40 equiv.) was added dropwise at 0 ºC. The resulting yellow solution was allowed to warm slowly up to ambient temperature. After 40 hours stirring, the orange solution was cooled to 0 ºC and NaHCO₃ (sat., aq., 200 mL) was carefully added. The mixture was allowed to warm to ambient temperature and vigorously stirred for 15 min. The layers were separated and the aqueous layer was extracted with CH₂Cl₂ (3 x 200 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a dark yellow oil, which was purified by column chromatography (c-hexane/EtOAc 20:1) to furnish S3 as a light yellow liquid (2.38 g; 72% yield). R_f = 0.49 (c-hexane/EtOAc 10:1); [α]_D²⁶ = -68.3 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 7.30-7.18 (m, 5H, Ph), 3.93 (d, J = 13.1 Hz, 1H, C6HH), 3.67 (s, 3H, CH₃), 3.55 (d, J = 12.7 Hz, 1H, C6HH), 3.53 (d, J = 7.8 Hz, 1H, C2H), 3.30 (q, J = 11.5 Hz, 1H, C5HH), 2.79 (dt, J = 16.7 Hz, 11.5 Hz, 1H, C5HH), 2.61-2.36 (m, 2H, C3H₂). ¹³C NMR (101 MHz, CDCl₃): δ 172.0 (CO₂Me), 137.1 (ipso), 129.0 and 128.6 (4C, ortho and meta), 128.0 (dd, J_CF = 250.1 Hz, 246.5 Hz, C4), 127.7 (para), 63.2 (t, J_CF = 3.8 Hz, C2), 60.0 (t, J_CF = 29.0 Hz, C5), 57.6 (C6), 52.2 (CH₃), 39.9 (t, J_CF = 26.0 Hz, C3). ¹⁹F NMR (376 MHz, CDCl₃): δ -93.0 (dm, J_FF = 230.0 Hz), -94.2 (dm, J_FF = 230.0 Hz). HRMS: calculated for C₁₃H₁₆F₂NO₂: 256.1144, found: 256.1151.

Magnesium turnings (300 mg, 12.3 mmol, 5.25 equiv.) were added to a 25 mL 2-neck flask equipped with a condenser and stirred under high-vacuum for 5 hours. THF (10 mL, dry) was then added followed by iodine (15 mg, 59 μmol, 0.025 equiv.), affording a brown solution. Commercially available 1-bromo-3,5-bis-(trifluoromethyl)-benzene (2.76 g, 9.40 mmol, 4.00 equiv.) was added to the magnesium-suspension in a first portion of 0.9 g. The speed of addition of the remaining 1.76 g of aryl bromide was controlled to maintain the mixture at reflux. When the exothermic reaction stopped, the reaction mixture was refluxed for 10 additional minutes. The resulting brown mixture was then cooled at 0 ºC and a solution of S3 (2.35 mmol, 600 mg, 1 equiv.) in anhydrous THF (2 mL) was added. The mixture was allowed to warm up to ambient temperature. After 15 hours stirring, the mixture was diluted with NH₄Cl (aq., sat., 100 mL) and extracted with CH₂Cl₂ (3 x 100 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo. Purification by column chromatography (c-hexane/EtOAc 100:1) afforded S4 as a white solid (1.47 g, 2.25 mmol, 96% yield). R_f = 0.71 (c-hexane/EtOAc 5:1); [α]_D²⁶ = +14.0 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 2H, Ar^ortho), 8.04 (s, 2H, Ar’^ortho), 7.80 (s, 1H, Ar^para), 7.77 (s, 1H, Ar’^para), 7.32-7.21 (m, 3H, Bn^para and Bn^meta), 7.01-6.92 (m, 2H, Bn^ortho), 5.21 (br. s, 1H, OH), 4.45 (t, J = 8.3 Hz, 1H, C2H), 3.34-3.15 (m, 3H, NCH₂Ph and C5HH), 3.05-2.92 (m, 1H, C5HH), 2.34-2.19 (m, 1H, C3HH), 2.11 (dtd, J = 18.0 Hz, 13.5 Hz, 8.7 Hz, 1H, C3HH); ¹³C NMR (101 MHz, CDCl₃): δ 148.4 (Ar^ipso), 146.5 (Ar’^ipso), 136.8 (Bn^ipso), 132.6 (2C, q, J_CF = 33.6 Hz, Ar^meta), 132.5 (2C, q, J_CF = 33.5 Hz, Ar’^meta), 129.0 (2C, Bn^meta), 128.3 (2C, Bn^ortho), 128.2 (Bn^para), 126.2 (dd, J_CF = 251.8 Hz, 245.5 Hz, C4), 125.8 (2C, q, J_CF = 3.8 Hz, Ar^ortho), 125.4 (2C, q, J_CF = 4.4 Hz, Ar’^ortho), 123.2 (2C, q, J_CF = 272.9 Hz, CF₃), 123.1 (2C, q, J_CF = 273.0 Hz, CF₃), 122.2-121.9 (2C, m, Ar^para and Ar’^para), 76.1 (C6), 69.2 (dd, J_CF = 4.1 Hz, 2.7 Hz, C2), 60.5 (two signals on top of each other: NCH₂Ph (s) and C5 (t, J_CF = 28.2 Hz)), 38.3 (t, J_CF = 25.0 Hz, C3). ¹⁹F NMR (376 MHz, CDCl₃): δ -63.0 (s, 6F, ArCF₃), -63.1 (s, 6F, Ar’CF₃), -98.1 (dp, J_FF = 232.4 Hz, J_HF = 15.8, 1F, C4FF), -100.6 (br d, J_FF = 232.1 Hz, 1F, C4FF). HRMS: calculated for C₂₈H₂₀F₁₄NO 652.1313, found: 652.1321.

S4 (1.40 g, 2.15 mmol, 1.00 equiv.) was dissolved in a 1:1 mixture of EtOH and EtOAc (12 mL), followed by the addition of Pd/C (10%, wet support, 420 mg). The reaction flask was purged with vacuum/hydrogen cycles (6x). The suspension was vigorously stirred for 26 hours and then filtered over Celite. The plug was washed with CH₂Cl₂ (100 mL) and the solution was concentrated in vacuo to give a colorless oil. This was purified by column chromatography (c-hexane/EtOAc 5:1) to afford S5 as colorless oil which solidified as a white solid upon standing (1.14 g; 94% yield). R_f = 0.54 (c-hexane/EtOAc 5:1); [α]_D²⁶ = -59.5 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.06 (s, 2H, ortho), 7.95 (s, 2H, ortho’), 7.83 (s, 1H, para), 7.80 (s, 1H, para’), 4.70 (s, 1H, OH), 4.65 (dd, J = 9.5 Hz, 7.1 Hz, 1H, C2H), 3.50-3.32 (m, 2H, C5H₂), 2.26-2.08 (m, 1H, C3HH), 2.03-1.88 (m, 1H, C3HH), 1.76 (br s, 1H, NH). ¹³C NMR (101 MHz, CDCl₃): δ 147.6 (ipso), 145.1 (ipso’), 132.7 (2C, q, J_CF = 33.5 Hz, meta), 132.5 (2C, q, J_CF = 33.5 Hz, meta’), 128.4 (dd, J_CF = 252.4 Hz, 245.9 Hz, C4), 126.1 (2C, q, J_CF = 3.7 Hz, ortho), 125.5 (2C, q, J_CF = 3.8 Hz, ortho’), 123.2 (4C, q, J_CF = 272.9 Hz, CF₃), 122.3 (apparent p, J_CF = 3.7 Hz, para), 122.1 (apparent p, J_CF = 3.8 Hz, para’), 76.3 (C6), 62.2 (dd, J_CF = 5.5 Hz, 2.1 Hz, C2), 54.0 (t, J_CF = 29.5 Hz, C5), 35.7 (t, J_CF = 24.8 Hz, C3). ¹⁹F NMR (376 MHz, CDCl₃): δ -63.0 (s, 6F, ArCF₃), -63.1 (s, 6F, Ar’CF₃), -96.6 (ddq, J_FF = 230.7 Hz, J_HF = 20.4 Hz, 16.7 Hz, 1F, C4FF), -100.6 (ddtd, J_FF = 230.8 Hz, J_HF = 14.6 Hz, 9.4 Hz, 5.3 Hz, 1F, C4FF). HRMS: calculated for C₂₁H₁₅F₁₄NO: 562.0846, found: 562.0851.

To a colorless solution of S5 (2.0 g, 3.56 mmol, 1.0 equiv.) in THF (dry, 18 mL) at 0 ºC was added NaH (60% in mineral oil, 713 mg, 17.8 mmol, 5.0 equiv.) portionwise. The reaction mixture was stirred for 15 min until gas evolution had ceased, then chloro-(2,3-dimethylbutan-2-yl)-dimethylsilane (1.40 mL, 7.13 mmol, 2.0 equiv.) was added dropwise and the mixture was allowed to warm up to ambient temperature. After 5 hours stirring, water (50 mL) was carefully added and the mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were dried over MgSO₄ and concentrated in vacuo to give a yellow oil. Purification by column chromatography (c-hexane/EtOAc 100:1) afforded catalyst 1c as a white solid (2.35 g, 94%). R_f = 0.53 (c-hexane/EtOAc 10:1); [α]_D²⁶ = +1.9 (c = 0.5, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 2H, ortho), 7.91 (s, 2H, para and para’), 7.72 (s, 2H, ortho’), 4.46 (t, J = 8.3 Hz, 1H, C2H), 3.15 (td, J = 13.9 Hz, 7.2 Hz, 1H, C5HH), 2.62 (ddd, J = 20.2 Hz, 12.9 Hz, 7.9 Hz, 1H, C5HH), 2.31-2.08 (m, 2H, C3HH and NH), 1.95-1.69 (m, 2H, C3HH and SiCCH), 0.95 (d, J = 3.0 Hz, 3H, SiCCHCH₃), 0.93 (d, J = 3.0 Hz, 3H, SiCCHCH₃’), 0.89 (s, 3H, SiCCH₃), 0.87 (s, 3H, SiCCH₃’), -0.14 (s, 3H, SiCH₃), -0.47 (s, 3H, SiCH₃). ¹³C NMR (101 MHz, CDCl₃): δ 146.6 (ipso), 145.0 (ipso’), 132.2 (2C, q, J_CF = 33.6 Hz, meta), 131.4 (2C, q, J_CF = 33.5 Hz, meta’), 129.7 (dd, J_CF = 254.0 Hz, 246.9 Hz, C4), 129.5 (2C, q, J_CF = 4.1 Hz, ortho), 128.8 (2C, q, J_CF = 4.1 Hz, ortho’), 123.4 (2C, q, J_CF = 272.8 Hz, ArCF₃), 123.2 (2C, q, J_CF = 272.9 Hz, Ar’CF₃), 122.6 (apparent p, J_CF = 3.8 Hz, para), 122.4 (apparent p, J_CF = 3.8 Hz, para’), 82.2 (C6), 62.8 (dd, J_CF = 6.5 Hz, 1.3 Hz, C2), 53.9 (t, J_CF = 28.8 Hz, C3), 37.6 (t, J_CF = 25.0 Hz, C5), 33.9 (SiCCH), 26.0 (SiCCH), 20.4 (SiCCH₃), 20.2 (SiCCH₃’), 18.7 (2C, SiCCHCH₃), -0.03 (SiCH₃), -0.80 (SiCH₃’). ¹⁹F NMR (376 MHz, CDCl₃): δ -63.06 (s, 6F, ArCF₃), -63.11 (s, 6F, Ar’CF₃), -97.7 (dp, J_FF = 229.6 Hz, J_HF = 17.8 Hz, 1F, C4FF), -100.6 (br d, J_FF = 228.8 Hz, 1F, C4FF). HRMS: calculated for C₂₉H₃₂F₁₄NOSi: 704.2024, found: 704.2031. Catalyst 1c was characterized by X-ray single-crystal analysis, see Section G of the Supplementary Information for details.