Effective Pathway to the α-CF₃-Substituted Azahistidine Analogues

Abstract

An efficient method for the preparation of functionalized α-trifluoromethyl-substituted azahistidine analogues has been ­developed. The method is based on the regioselective addition of ­allenylmagnesiumbromide to highly electrophilic imines of tri­fluoropyruvates and subsequent 1,3-dipolar Huisgen cycloaddition between α-propargyl-α-trifluoromethyl-α-amino esters and organic azides.

Key words

fluorinated imines - amino acids - histidine - click reaction - organic azides

References and Notes

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16

General Procedure for the Preparation of 2.
Allenylmagnesiumbromide¹⁷ (solution in THF, 10.0 mmol) was added dropwise to a stirred solution of an imine (10.0 mmol) in dry THF (25 mL) at -78 °C. After 1 h at -78 °C the reaction mixture was allowed to warm to r.t. within 2 h. The reaction was quenched with 1 N HCl and extracted with Et₂O (2 × 25 mL). The combined organic layer was washed with brine (25 mL), dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (EtOAc-PE).
Data for Compounds 2a,b. Compound 2a: oil. ¹H NMR (300 MHz, CDCl₃): δ = 2.09 (s, 1 H, ºCH), 3.10 (d, J _AB = 16.6 Hz, 1 H, CH₂), 3.71 (d, J _AB = 16.6 Hz, 1 H, CH₂), 3.96 (s, 3 H, OCH₃), 5.22 (m, 2 H, OCH₂), 6.10 (s, 1 H, NH), 7.43 (m, 5 H, Ph). ¹⁹F NMR (282 MHz, CDCl₃): δ (TFA) = 3.38 (s, 3 F, CF₃). Anal. Calcd for C₁₅H₁₄F₃NO₄ (%): C, 54.71; H, 4.29; F, 17.33. Found: C, 55.02; H, 4.38; F, 16.99.
Compound 2b: mp 70-71 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.46 [s, 9 H, C(CH₃)₃], 2.06 (s, 1 H, ºCH), 3.10 (d_, J = 16.9 Hz, 1 H, CH₂), 3.71 (m, 1 H, CH₂), 3.90 (s, 3 H, OCH₃), 5.70 (s, 1 H, NH). ¹⁹F NMR (282 MHz, CDCl₃): δ (TFA) = 3.44 (s, 3 F, CF₃). Anal. Calcd for C₁₂H₁₆F₃NO₄: C, 48.81; H, 5.47; N, 4.74. Found: C, 48.74; H, 5.47; N, 4.68.

19

Typical Procedure for the Preparation of 3. Method A. A mixture of organic azide (1.0 mmol), amino ester 2 (1.0 mmol), DIPEA (3.0 mmol) and CuI (0.1 mmol) in THF (10 mL) was stirred at r.t. for 6-8 h. The resulted reaction mixture was treated with 1 N HCl (15 mL), and extracted with Et₂O (3 × 15 mL). Combined organic layers were dried over MgSO₄ and filtered. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography on silica gel (EtOAc-PE). Method B. Organic azide (2.0 mmol) and amino ester 2 (2.0 mmol) were suspended in 1:1 H₂O-t-BuOH (8 mL). To this was added CuSO₄·5H₂O (5 M solution, 0.1 mmol, 5 mol%) and sodium ascorbate (0.6 mmol). The mixture was stirred at r.t. for 24 h, at which time TLC (silica, PE-EtOAc) indicated complete conversion. The resulted solution was concentrated under reduced pressure (rotary evaporator). The residue was dissolved in 30 mL of brine and then extracted with CH₂Cl₂ (3 × 30 mL). Combined organic layers were washed with 5% aq NH₄OH (2 × 10 mL), dried over MgSO₄, filtered and solvent was removed under vacuum to give analytically pure product.
Data for Compounds 3a,g. Compound 3a: mp 158-159 °C. ¹H NMR (300 MHz, CDCl₃): δ = 3.80 (d, 1 H, CH₂, J _AB = 15.0 Hz), 4.03 (s, 3 H, OCH₃), 4.16 (d, 1 H, CH₂, J _AB = 15.0 Hz), 6.18 (s, 1 H, NH), 7.53-7.90 (m, 10 H, Ar), 8.22 (s, 1 H, H-triazole). ¹⁹F NMR (282 MHz, CDCl₃): δ (TFA) = 5.38 (s, 3 F, CF₃). Anal. Calcd for C₁₉H₁₇F₃N₄O₄S (%): C, 50.22; H, 3.77; N, 12.33. Found: C, 50.07; H, 3.84; N, 12.28.
Compound 3g: mp 78-79 °C. ¹H NMR (300 MHz, CDCl₃): δ = 1.84 and 1.88 (2 × s, 3 H, OAc), 2.12 (m, 9 H, 3 × OAc), 3.67 (dd, J = 14.8, 2.5 Hz, 1 H, CH), 3.95 and 3.98 (2 × s, 3 H, OMe), 4.02 (m, 1 H, CH), 4.26 (m, 3 H, CH, CH₂), 5.11-5.51 (m, 5 H, 3 × CH, OCH₂), 5.78 (t, ² J _H-H = 8.9 Hz, 1 H), 6.09 (br s, 1 H, NH), 7.45 (m, 6 H, 1 H-triazole, 5 H-Ar). ¹⁹F NMR (282 MHz, CDCl₃): δ (TFA) = 3.87 (br s, 3 F, CF₃). Anal. Calcd for C₂₉H₃₃F₃N₄O₁₃: C, 49.58; H, 4.73; N, 7.97. Found: C, 49.12; H, 4.57; N, 7.57.

20

Data for Compound 6.
Mp 216-217 °C. ¹H NMR (300 MHz, D₂O): δ = 3.38 (d, J _AB = 15.3 Hz, 1 H), 3.64 (d, J _AB = 15.3 Hz, 1 H), 7.73 (s, 1 H, H-triazole). ¹⁹F NMR (282 MHz, D₂O): δ (TFA) = 3.55 (s, 3 F, CF₃). ¹³C NMR (150.9 MHz, D₂O): δ = 26.5, 65.3 (q, ² J _C-F = 25.4 Hz), 123.5 (q, ¹ J _C-F = 228.9 Hz), 128.1, 137.9, 166.0. Anal. Calcd for C₆H₇F₄N₄O₂: C, 32.15; H, 3.15; N, 25.00. Found: C, 32.12; H, 3.04; N, 24.67.