LETTER
a-CF3-Azahistidine
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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): d = 2.09 (s,
1 H, ≡CH), 3.10 (d, JAB = 16.6 Hz, 1 H, CH2), 3.71 (d,
JAB = 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): d (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):
d = 1.46 [s, 9 H, C(CH3)3], 2.06 (s, 1 H, ≡CH), 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):
d (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.
(17) Brandsma, L.; Verkrujsse, H. Preparative Organometallic
Chemistry, Vol. 1; Springer: Berlin, 1987, 63.
(18) See, for example: (a) Kuijpers, B. H. M.; Groothuys, S.;
Keereweer, A. R.; Quaedflieg, P. J. L. M.; Blaauw, R. H.;
Van Delft, F. L.; Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123.
(b) Horne, W. S.; Stout, C. D.; Ghadiri, M. R. J. Am. Chem.
Soc. 2003, 125, 9372. (c) Dondoni, A.; Giovannini, P. P.;
Massi, A. Org. Lett. 2004, 6, 2929. (d) Angelo, N. G.;
Arora, P. S. J. Am. Chem. Soc. 2005, 127, 17134. (e) Paul,
A.; Bittermann, H.; Gmeiner, P. Tetrahedron 2006, 62,
8919.
(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): d = 3.80 (d, 1 H, CH2, JAB = 15.0 Hz), 4.03 (s, 3 H,
OCH3), 4.16 (d, 1 H, CH2, JAB = 15.0 Hz), 6.18 (s, 1 H, NH),
Synlett 2007, No. 1, 136–140 © Thieme Stuttgart · New York