Synthesis of Trifluoromethylated Azetidines, Aminopropanes, 1,3-Oxazinanes, and 1,3-Oxazinan-2-ones Starting from 4-Trifluoromethyl-β-lactam Building Blocks

Abstract

This paper reports on the preparation of 4-(trifluoromethyl)azetidin-2-ones and their synthetic potential as eligible new building blocks for the construction of CF₃-containing azetidines, diaminopropanes, aminopropanol derivatives, 1,3-oxazinanes, and 1,3-oxazinan-2-ones. This β-lactam building block approach provides a convenient new entry into trifluoromethylated scaffolds as useful synthetic intermediates en route to a variety of CF₃-functionalized target structures.

Key words

β-lactams - azetidines - aminopropanes - oxazinanes - fluorine - CF₃

• References and Notes

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• 13 syn-2-Methoxy-3-[N-(4-methoxyphenyl)-N-methylamino]-4,4,4-trifluorobutyl Acetate (6b) In a flame-dried flask under nitrogen atmosphere, Me₃O·BF₄ (0.17 g, 1.14 mmol, 2 equiv) was added to an ice-cooled solution of cis-3-methoxy-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidine (4b, 0.15 g, 0.57 mmol, 1 equiv) in dry CH₂Cl₂ (4 mL). After stirring for 2 h at room temperature, the solvent was evaporated, and the resulting residue was redissolved in MeCN (5 mL), after which NaOAc (0.19 g, 2.28 mmol, 4 equiv) was added. After stirring at reflux temperature for 2 h, the reaction mixture was poured into a sat. solution of NaHCO₃ (5 mL), extracted with CH₂Cl₂ (3 × 5 mL), and washed with brine (3 × 5 mL). Drying (MgSO₄), filtration of the drying agent, and evaporation of the solvent afforded syn-4,4,4-trifluoro-2-methoxy-3-[N-(4-methoxyphenyl)-N-methylamino]butyl acetate (6b), which was purified by means of preparative TLC (hexane–EtOAc); pale yellow oil, yield 86%; R_f = 0.07 (PE–EtOAc, 95:5). IR (ATR): ν_max = 1745 (CO), 1512, 1242, 1097, 1053, 1038, 818 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.01 (3 H, s), 3.02 (3 H, s), 3.48 (3 H, s), 3.76 (3 H, s), 3.91 (1 H, qd, J = 5.5, 1.1 Hz), 4.14 (1 H, dd, J = 12.1, 6.6 Hz), 4.21–4.27 (2 H, m), 6.82 (4 H, br s). ¹³C NMR (75 MHz, CDCl₃): δ = 20.6, 34.7, 55.6, 59.4, 61.9 (q, J = 26.9 Hz), 77.8, 114.6, 116.0, 125.9 (q, J = 288.5 Hz), 145.0, 152.9, 170.4. ¹⁹F NMR (282 MHz, CDCl₃): δ = –68.36 (3 F, d, J = 7.9 Hz). MS (70 eV): m/z (%) = 336 (80) [M⁺ + H], 321 (100) [M⁺ – CH₃]. ESI-HRMS: m/z calcd for C₁₅H₂₁F₃NO₄ ⁺: 336.1417 [M + H]⁺; found: 336.1433.
• 14 syn-2-Benzyloxy-4,4,4-trifluoro-N ³-(4-methoxyphenyl)-N ³-methyl-N ¹-tert-butylbutane-1,3-diamine (7a) In a flame-dried flask under nitrogen atmosphere, Me₃O·BF₄ (0.13 g, 0.88 mmol, 2 equiv) was added to an ice-cooled solution of cis-3-benzyloxy-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidine (4a, 015 g, 0.44 mmol, 1 equiv) in dry CH₂Cl₂ (3 mL). After stirring for 2 h at room temperature, the solvent was evaporated, and the residue was redissolved in MeCN (3 mL), followed by the addition of tert-butylamine (0.13 g, 1.76 mmol, 4 equiv). After heating for 4 h at reflux temperature, the reaction mixture was poured into a sat. solution of NaHCO₃ (4 mL), extracted with CH₂Cl₂ (3 × 3 mL), and washed with brine (3 × 3 mL). Drying (MgSO₄), filtration of the drying agent, and evaporation of the solvent yielded syn-2-benzyloxy-4,4,4-trifluoro-N ³-(4-methoxyphenyl)-N ³-methyl-N ¹-tert-butylbutane-1,3-diamine (7a), which was purified by means of preparative TLC (hexane–EtOAc, 95:5); pale yellow oil, yield 78%; R_f = 0.04 (PE–EtOAc, 95:5). IR (ATR): ν_max = 3308 (NH), 1512, 1243, 1144, 1113, 1029, 814, 739 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 0.95 (9 H, s), 2.68 (1 H, dd, J = 12.1, 7.2 Hz), 2.77 (1 H, dd, J = 12.1, 5.5 Hz), 3.04 (3 H, s), 3.77 (3 H, s), 3.98–4.01 (1 H, m), 4.51 (1 H, dq, J = 8.4, 5.0 Hz), 4.59 and 4.67 (2 × 1 H, 2 d, J = 11.6 Hz), 6.83 and 6.89 (2 × 2 H, 2 d, J = 8.8 Hz), 7.29–7.36 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 28.9, 34.8, 42.4, 50.5, 55.8, 62.1 (q, J = 26.6 Hz), 73.6, 79.1, 114.7, 115.7, 126.4 (q, J = 288.4 Hz), 127.9, 128.5, 138.2, 145.2, 152.6. ¹⁹F NMR (282 MHz, CDCl₃): δ = –67.85 (3 F, d, J = 9.2 Hz). MS (70 eV): m/z (%) = 425 (100) [M⁺ + H]. ESI-HRMS: m/z calcd for C₂₃H₃₂F₃N₂O₂ ⁺: 425.2410 [M + H]⁺; found: 425.2421.
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• 18 syn-2-Benzyloxy-4,4,4-trifluoro-3-(4-methoxyphenylamino)butan-1-ol (8a) To an ice-cooled solution of cis-3-benzyloxy-1-(4-methoxyphenyl)-4-(trifluoromethyl)azetidin-2-one (3a; 0.39 g, 1.1 mmol, 1 equiv) in Et₂O (7 mL) was added LiAlH₄ (2.2 mL, 2.2 mmol, 2 equiv, 1 M in Et₂O) in small portions whilst stirring under N₂. After heating for 2 h at reflux temperature, the reaction mixture was cooled to 0 °C, quenched with H₂O (5 mL) and filtered through a short pad of Celite^®. Extraction with Et₂O (3 × 5 mL), drying (MgSO₄), filtration of the drying agent, and evaporation of the solvent afforded syn-2-benzyloxy-4,4,4-trifluoro-3-(4-methoxyphenylamino)butan-1-ol (8a), which was purified by recrystallization (heptane–EtOAc = 8:2); white crystals, yield 74%; mp 104 °C (from heptane–EtOAc 8:2). IR (ATR): ν_max = 3418 (NH), 3372 (OH), 1516, 1246, 1151, 1122, 1065, 1031, 818 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 2.16 (1 H, br s), 3.50–3.56 and 3.60–3.66 (2 × 1 H, 2 m), 3.70 (3 H, s), 3.95 (1 H, dd, J = 6.6, 6.1 Hz), 4.00–4.04 (1 H, m), 4.15 (1 H, d, J = 9.9 Hz), 4.59 (1 H, d, J = 11.0 Hz), 4.66 (1 H, d, J = 11.0 Hz), 6.63 and 6.74 (2 × 2 H, 2 d, J = 8.8 Hz), 7.31–7.37 (5 H, m). ¹³C NMR (75 MHz, CDCl₃): δ = 55.7, 56.4 (q, J = 28.8 Hz), 61.1, 73.6, 76.3, 114.9, 115.1, 126.0 (q, J = 285.0 Hz), 128.20, 128.25, 128.6, 137.4, 140.6, 152.9. ¹⁹F NMR (282 MHz, CDCl₃): δ = –73.13 (3 F, d, J = 6.6 Hz). MS (70 eV): m/z (%) = 356 (100) [M⁺ + H]. ESI-HRMS: m/z calcd for C₁₈H₂₁F₃NO₃ ⁺: 356.1468 [M + H]⁺; found: 356.1476.
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• 20 cis-5-Benzyloxy-3-(4-methoxyphenyl)-4-trifluoromethyl-1,3-oxazinane (9a) To a solution of syn-2-benzyloxy-4,4,4-trifluoro-3-(4-methoxyphenylamino)butan-1-ol (8a; 0.50 g, 1.41 mmol, 1 equiv) in THF (20 mL) was added formaldehyde (0.11 g, 1.41 mmol, 1 equiv, 37% solution in H₂O). The resulting mixture was stirred for 4 h at room temperature, after which the solvent was removed in vacuo. Water (100 mL) was added to the mixture. Extraction with EtOAc (3 × 70 mL), drying (MgSO₄), filtration of the drying agent, and evaporation of the solvent afforded cis-5-benzyloxy-3-(4-methoxyphenyl)-4-trifluoromethyl-1,3-oxazinane (9a), which was purified by means of recrystallization (hexane–EtOAc, 8:1); white crystals, yield 50%; mp 58.5 °C (from hexane–EtOAc, 8:1). IR (ATR): ν_max = 1510, 1360, 1252, 1240, 1171, 1154, 1094, 1029, 983, 909, 810, 737, 696 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.78 (3 H, s), 3.85–3.92 (1 H, m), 3.96–4.03 (2 H, m), 4.08–4.17 (1 H, m), 4.48 and 4.65 (2 × 1 H, 2 d, J = 11.6 Hz), 4.80 and 4.85 (2 × 1 H, 2 d, J = 11.7 Hz), 6.82 and 7.09 (2 × 2 H, 2 d, J = 9.0 Hz), 7.28–7.35 (5 H, m). ¹³C NMR (100.6 MHz, CDCl₃): δ = 55.6, 62.1 (q, J = 27.6 Hz), 65.8, 68.1, 71.9, 77.6, 114.5, 121.7, 125.8 (q, J = 285.0 Hz), 127.6, 128.0, 128.5, 137.3, 144.0, 155.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –64.87 (3 F, d, J = 9.2 Hz). MS: m/z (%) = 368 (100) [M⁺ + H]. ESI-HRMS: m/z calcd for C₁₉H₂₁F₃NO₃ ⁺: 368.1468 [M + H]⁺; found: 368.1480.
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• 22 cis-5-Benzyloxy-4-trifluoromethyl-3-(4-methoxyphenyl)-1,3-oxazinan-2-one (10a) To a solution of syn-2-benzyloxy-4,4,4-trifluoro-3-(4-methoxyphenylamino)butan-1-ol (8a, 0.1 g, 0.28 mmol, 1 equiv) in dry THF (20 mL) was added Et₃N (0.06 g, 0.56 mmol, 2 equiv) at 0 °C. Ethyl chloroformate (0.12 g, 1.13 mmol, 4 equiv) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h, the solvent was removed in vacuo, and the residue was redissolved in EtOAc (20 mL) and washed with H₂O (2 × 20 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). Drying (MgSO₄), filtration of the drying agent, and removal of the solvent in vacuo afforded cis-5-benzyloxy-3-(4-methoxyphenyl)-4-trifluoromethyl-1,3-oxazinan-2-one (10a), which was further purified by means of recrystallization from EtOH to white crystals, yield 66%; mp 141 °C (EtOH). IR (ATR): ν_max = 1700 (CO), 1514, 1415, 1261, 1238, 1136, 1167, 1036, 827, 747 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 3.81 (3 H, s), 4.32–4.43 (3 H, m), 4.47–4.52 (1 H, m), 4.67 and 4.75 (2 × 1 H, 2 d, J = 11.6 Hz), 6.90 and 7.14 (2 × 2 H, 2 d, J = 8.9 Hz), 7.35–7.43 (5 H, m). ¹³C NMR (100.6 MHz, CDCl₃): δ = 55.5, 60.9 (q, J = 28.0 Hz), 65.8, 68.0, 72.5, 114.6, 124.0 (q, J = 285.8 Hz), 128.0, 128.5, 128.7, 128.8, 134.3, 136.1, 151.3, 159.0. ¹⁹F NMR (376 MHz, CDCl₃): δ = –66.96 (3 F, d, J = 7.7 Hz). MS: m/z (%) = 382 (100) [M⁺ + H]. ESI-HRMS: m/z calcd for C₁₉H₁₉F₃NO₄ ⁺: 382.1261 [M + H]⁺; found: 382.1261.
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