Ruthenium-Catalyzed Cyclotrimerization of 1,6- and 1,7-Azadiynes: New Access to Fluorinated Bicyclic Amino Acids

Abstract

An efficient access to a variety of trifluoromethyl-substituted cyclic α-amino acid derivatives based on ruthenium-catalyzed cyclotrimerization of appropriate 1,6- and 1,7-diynes with terminal and internal alkynes has been developed.

fluorinated diynes - amino acids - ruthenium catalysis - cyclotrimerization - alkynes

References and Notes

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18

General Procedure for Ru-Catalyzed Cyclotrimerization: The catalyst RuCl(Cp*)(cod) (2 mol%) was added to the solution of diyne (0.15 mmol) and alkyne (0.6 mmol) in degassed DCE under an argon atmosphere. The resulting mixture was stirred at r.t. until the reaction completion (TLC control). The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (eluent: EtOAc-PE).
Data for Compound 6a: oil. ¹H NMR (400 MHz, DMSO-d ₆, 80 ºC): δ = 3.61 (br s, 3 H, OMe), 4.84 (d, J _AB = 15.2 Hz, 1 H, NCH₂), 5.03 (d, J _AB = 15.2 Hz, 1 H, NCH₂), 5.23 (s, 2 H, OCH₂), 7.34-7.56 (m, 9 H, Ar). ¹⁹F NMR (282 MHz, DMSO-d ₆, TFA, 80 °C): δ = 5.3 (s, 3 F, CF₃). Anal. Calcd for C₁₉H₁₆F₃NO₄: C, 60.16; H, 4.25; N, 3.69. Found: C, 60.21; H, 4.35; N, 3.67.
Data for Compound 7a: oil. ¹H NMR (400 MHz, DMSO-d ₆, 80 °C): δ = 3.33 (d, J _AB = 15.4 Hz, 1 H, CH₂), 3.39 (d, J _AB = 15.4 Hz, 1 H, CH₂), 3.50 (s, 3 H, OMe), 4.49 (d, J _AB = 15.1 Hz, 1 H, NCH₂), 4.87 (d, J _AB = 15.1 Hz, 1 H, NCH₂), 5.15 (s, 2 H, OCH₂), 7.29 (m, 4 H, Ar), 7.33-7.43 (m, 5 H, Ph). ¹⁹F NMR (282 MHz, CDCl₃, TFA, 80 °C): δ = 6.32 (s, 3 F, CF₃). ¹³C NMR (150.9 MHz, DMSO-d ₆, 80 ºC): δ = 32.51, 45.15, 56.21, 68.18, 70.10 (q, ² J _C-F = 28.4 Hz), 122.23 (q, ¹ J _C-F = 288.2 Hz), 127.88, 127.91, 128.04, 134.70, 136.51, 139.18, 156.32, 165.81. Anal. Calcd for C₂₀H₁₈F₃NO₄: C, 61.07; H, 4.61; N, 3.56. Found: C, 60.99; H, 4.55; N, 3.67.

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22

Data for Compound 10: mp 234 °C (dec.). ¹H NMR (300 MHz, DMSO-d ₆): δ = 3.35 (d, J _AB = 15.4 Hz, 1 H, CH₂), 3.39 (d, J _AB = 15.4 Hz, 1 H, CH₂), 3.86 (d, J _AB = 15.5 Hz, 1 H, NCH₂), 4.06 (d, J _AB = 15.5 Hz, 1 H, NCH₂), 7.23 (m, 4 H, Ar). ¹⁹F NMR (282 MHz, DMSO-d ₆): δ = 3.07 (s, 3 F, CF₃). ¹³C NMR (150.9 MHz, DMSO-d ₆): δ = 31.03, 45.12, 64.01 (q, ² J _C-F = 29.9 Hz), 120.91 (q, ¹ J _C-F = 281.3 Hz), 127.31, 128.01, 128.41, 129.21, 133.81, 138.14, 168.41. Anal. Calcd for C₁₂H₁₂F₃NO₂: C, 53.88; H, 4.11; N, 5.71. Found: C, 53.61; H, 4.32; N, 5.34.