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Synlett 2007(1): 0136-0140  
DOI: 10.1055/s-2006-956492
LETTER
© Georg Thieme Verlag Stuttgart · New York

Effective Pathway to the α-CF3-Substituted Azahistidine Analogues

Grigorii T. Shchetnikov, Alexander S. Peregudov, Sergej N. Osipov*
A.N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, Vavilov str. 28, 119991 Moscow, Russia
Fax: +7(495)1355085; e-Mail: osipov@ineos.ac.ru;
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Publication History

Received 16 October 2006
Publication Date:
20 December 2006 (online)

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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

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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.

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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.

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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.