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DOI: 10.1055/s-2008-1077966
1,3-Dipolar Cycloaddition of Difluoro(methylene)cyclopropanes with Nitrones: Efficient Synthesis of 3,3-Difluorinated Tetrahydropyridinols
Publication History
Publication Date:
15 July 2008 (online)
Abstract
Difluoro-substituted spirocyclopropaneisoxazolidines were formed by 1,3-dipolar cycloaddition of difluoro(methylene)cyclopropanes (F2MCPs) with nitrones in high yields. The [3+2]-cycloaddition reactions exhibited good regioselectivity and high stereoselectivity. The cycloadducts could rearrange further to form highly substituted 3,3-difluorinated tetrahydropyridinols.
Key words
fluorine - difluoro(methylene)cyclopropanes - 3,3-difluorinated tetrahydropyridinols - ring rearrangement - 1,3-dipolar cycloaddition - nitrone
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References and Notes
Preparation of 1,1-Difluoro-2,2,5-trimethyl-6-phenyl-7-tosyl-4-oxa-5-azaspiro[2.4]heptane (3a): Into a 5-mL sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-methylnitrone (2a; 30 mg, 0.22 mmol) and PE (1.5 mL). The mixture was stirred at 50 ˚C for 12 h. After cooling to r.t., the solvent was removed under reduced pressure. The residue was purified by chromatography on a silica gel column (PE-EtOAc, 10:1) to yield 3a as a viscous oil (70 mg, 95%). ¹H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.53 (s, 3 H), 2.48 (s, 3 H), 2.55 (s, 3 H), 3.89 (d, J = 4.8 Hz, 1 H), 4.06 (d, J = 4.8 Hz, 1 H), 6.91-6.97 (m, 2 H), 7.15-7.25 (m, 3 H), 7.33 (d, J = 8.2 Hz, 2 H), 7.72 (d, J = 8.2 Hz, 2 H). ¹9F NMR (282 MHz, CDCl3): δ = -144.9 (d, J = 151 Hz, 1 F), 158.2 (d, J = 151 Hz, 1 F). IR (film): 3066, 3035, 3008, 2969, 2933, 2878, 1597, 1496, 1479, 1457, 1436, 1325, 1305, 1249, 1209, 1188, 1149, 1125, 1087, 1078 cm-¹. MS (ESI): m/z = 430.0 [M + Na+]. Anal. Calcd for C21H23F2NO3S: C, 61.90; H, 5.69; N, 3.44. Found: C, 61.87; H, 5.80; N, 3.05.
11The single-crystal X-ray structural data for 4a have been deposited at the Cambridge Crystallographic Data Centre and allocated the deposition number CCDC 684886.
12Preparation of 3,3-Difluoro-1,2,2-trimethyl-6-phenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol (4a): Into a 5-mL sealed tube were added 1 (50 mg, 0.184 mmol), phenyl-N-methylnitrone (2a; 24 mg, 0.184 mmol) and PE (2.5 mL). The mixture was stirred at 100 ˚C for 8 h. After cooling to r.t., 3,3-difluoro-1,2,2-trimethyl-6-phenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol (4a) was precipitated. After removing the solvent by filtration, the residue was recrystallized in CHCl3 by slow evaporation. Yield: 52 mg, 70%. ¹H NMR (300 MHz, CDCl3): δ = 1.16 (s, 3 H), 1.30 (s, 3 H), 1.93 (s, 3 H), 2.32 (s, 3 H), 4.11 (d, J = 9.8 Hz, 1 H), 6.87-7.01 (m, 9 H), 10.6 (s, 1 H). ¹9F NMR (282 MHz, CDCl3): δ = -109.0 (dd, J = 9.7, 269 Hz, 1 F), -125.6 (d, J = 269 Hz, 1 F). ¹³C NMR (75 MHz, CDCl3): δ = 12.7, 20.2 (d, J FC = 4 Hz), 21.4, 32.1, 59.0 (dd, J FC = 15, 18 Hz), 62.7, 113.9 (m), 115.4 (t, J FC = 184 Hz), 126.3, 127.7, 127.9, 129.4, 130.3, 137.8, 138.3 (d, J FC = 2 Hz), 143.8, 152.3 (t, J FC = 19 Hz). IR (film): 3235, 2995, 2821, 1643, 1598, 1496, 1456, 1369, 1317, 1289, 1276, 1249, 1217, 1175, 1148, 1125, 1101, 1070, 1057, 1017, 994 cm-¹. MS (ESI): m/z = 408.1 [M + H+].