F
X. Lai et al.
Letter
Synlett
(14) (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis Reactiv-
ity, Applications; Wiley-VCH: Weinheim, 2013. (b) Ojima, I. Flu-
orine in Medicinal Chemistry and Chemical Biology; Wiley-
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Bioorganic and Medicinal Chemistry of Fluorine; Wiley-VCH:
Hoboken, 2008. (d) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (e) Müller, K.;
Faeh, C.; Diederich, F. Science 2007, 317, 1881. (f) Jeschke, P.
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(London, U.K.) 2011, 473, 470.
(15) For recent reviews, see: (a) Nie, J.; Guo, H. C.; Cahard, D.; Ma, J.
A. Chem. Rev. 2011, 111, 455. (b) Tomashenko, O. A.; Grushin, V.
V. Chem. Rev. 2011, 111, 4475. (c) Roy, S.; Gregg, B. T.; Gribble,
G. W.; Le, V. D. Tetrahedron 2011, 67, 2161. (d) Qing, F. L.; Zheng,
F. Synlett 2011, 1052. (e) Besset, T.; Schneider, C.; Cahard, D.
Angew. Chem. 2012, 124, 5134. (f) Ye, Y.; Sanford, M. S. Synlett
2012, 23, 2005. (g) Qing, F. L. Chin. J. Org. Chem. 2012, 32, 815.
(h) Studer, A. Angew. Chem. 2012, 124, 9082. (i) He, Z.; Huang,
Y.; Verpoort, F. Acta Chim. Sin. 2013, 71, 700. (j) Liang, T.;
Neumann, C. N.; Ritter, T. Angew. Chem. 2013, 125, 8372.
(k) Massolo, E.; Benaglia, M.; Orlandi, M.; Rossi, S.; Celentano, G.
Chem. Eur. J. 2015, 21, 3589.
(20) Synthesis of 4-(3-Amino-1,1,1-trifluoro-2-phenylpropan-2-
yl)-3-methyl-1-phenyl-1H-pyrazol-5-ol (4)
To a dried small bottle were added 3aa (0.2 mmol) in AcOH (4.0
mL) and excessive zinc powder. The mixture was stirred at room
temperature for 6 h until TLC showed the reaction was com-
pleted. Then the precipitate was filtered off. The filtrate was
adjusted pH to 5–6 with a sat. K2CO3 solution. The organic phase
was separated, and the aqueous phase was extracted with
CH2Cl2 (2 × 10 mL). The combined organic phase was washed
with water (20 mL), then dried (Na2SO4). Removal of the solvent
under reduced pressure gave a white crude residue, and the
residue was purified with silica gel column chromatography,
eluting with EtOAc–PE (1:5, v/v), to afford the desired product
4. Colorless solid, 70.8 mg (98% yield), mp 216–217 °C. HPLC
[Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID), n-
hexane–i-PrOH = 90:10, 1.0 mL/min, 254 nm; tR (major) = 9.6
min, tR (minor) = 12.2 min] 93% ee. IR (KBr): ν = 3314, 3060,
3033, 2999, 1598, 1498, 1448, 1424, 1352, 1313, 1287, 1274,
1203, 1170, 1140, 1034, 996, 957, 911, 841, 769, 756, 730, 701,
655, 640, 616, 546 cm–1. 1H NMR (500 MHz, DMSO-d6): δ = 9.88
(s, 3 H), 7.99 (d, J = 7.8 Hz, 2 H), 7.48–7.38 (m, 4 H), 7.38–7.29
(m, 3 H), 7.06 (t, J = 7.3 Hz, 1 H), 3.37 (d, J = 13.8 Hz, 1 H), 3.22
(d, J = 13.6 Hz, 1 H), 1.18 (s, 3 H) ppm. 13C NMR (126 MHz,
DMSO-d6): δ = 160.87, 147.31, 141.10, 139.32, 129.06, 128.72,
128.62 (q, JC–F = 286.0 Hz), 127.98, 127.83, 123.44, 119.43,
93.22, 53.49 (q, JC–F = 25.2 Hz), 47.56, 15.42 ppm. 19F NMR (471
MHz, DMSO-d6): δ = –64.84 (s, 3 F) ppm. ESI-HRMS: m/z calcd
for C19H19F3N3O [M + H]+: 362.1480; found: 362.1428.
(16) (a) Gao, J. R.; Wu, H.; Xiang, B.; Yu, W. B.; Han, L.; Jia, Y. X. J. Am.
Chem. Soc. 2013, 8, 2983. (b) Liu, F.; Chen, J.; Feng, B.; Hu, X. Q.;
Ye, L. H.; Lu, L. Q.; Xiao, W. J. Org. Biomol. Chem. 2014, 7, 1057.
(c) Chen, Q.; Wang, G. Q.; Jiang, X. X.; Xu, Z. Q.; Lin, L.; Wang, R.
Org. Lett. 2014, 5, 1394.
(21) Synthesis
of
3-Methyl-1-phenyl-4-[1,1,1-trifluoro-3-(4-
(17) Vakulya, B.; Varga, S.; Csampai, A.; Soós, T. Org. Lett. 2005, 7,
1967.
nitrobenzamido)-2-phenylpropan-2-yl]-1H-pyrazol-5-yl-4-
nitrobenzoate (5)
(18) Wang, H. X.; Wang, Y. M.; Song, H. B.; Zhou, Z. H.; Tang, C. C. Eur.
J. Org. Chem. 2013, 4844.
To a dried small bottle were added 4 (0.125 mmol) and p-nitro-
benzoyl chloride (0.3 mmol) in DMF (2.0 mL). The mixture was
stirred at room temperature for 15 min, and Et3N (0.025 mmol)
was then added. The mixture was stirred at room temperature
for 6 h until TLC showed the reaction was completed. Then
water (10 mL) and CH2Cl2 (10 mL) were added. After stirring for
30 min, the organic phase was separated, and the aqueous
phase was extracted with CH2Cl2 (2 × 10 mL). The combined
organic phase was washed with water (20 mL), then dried
(Na2SO4). Removal of the solvent under reduced pressure gave a
white crude residue, and the residue was purified with silica gel
column chromatography, eluting with EtOAc–PE (1:5, v/v), to
afford the desired product 5. Colorless solid, 79.1 mg (96%
yield), mp 158–161 °C. HPLC [Daicel Chiralpak AD-H column (25
cm × 0.46 cm ID), n-hexane–i-PrOH = 70:30, 1.0 mL/min, 254
nm; tR (minor) = 15.8 min, tR (major) = 26.5 min] 88% ee. IR
(KBr): ν = 3421, 3110, 3074, 2960, 2867, 1767, 1675, 1598,
1530, 1506, 1488, 1441, 1386, 1348, 1320, 1296, 1237, 1215,
1171, 1109, 1059, 1012, 926, 867, 845, 854, 767, 714, 592, 533,
(19) General Procedure for Asymmetric Michael Reactions
To a dried small bottle were added (E)-β-F3C-β-disubstituted
nitroalkene 1 (0.2 mmol), pyrazolone 2 (0.2 mmol), catalyst VI
(0.04 mmol, 20 mol%), and NaOH (0.01 mmol, 5 mol%) in CH2Cl2
(2.0 mL). The mixture was stirred at ice-bath for 24–50 h until
TLC showed the reaction was completed, the reaction mixture
was concentrated and directly purified by silica gel column
chromatography, eluting with EtOAc–PE (1:2, v/v), to afford the
corresponding desired product 3.
5-Methyl-2-phenyl-4-(2,2,2-trifluoro-1-nitromethyl-1-
phenylethyl)-2H-pyrazol-3-ol (3aa)
The title compound 3aa was obtained according to the general
procedure as a colorless solid, 73.4 mg (81% yield), mp 188–190
°C. HPLC [Daicel Chiralpak AD-H column (25 cm × 0.46 cm ID),
n-hexane–i-PrOH = 90:10, 1.0 mL/min, 254 nm; tR (major) =
12.4 min, tR (minor) = 32.1 min] 97% ee. IR (KBr): ν = 3053,
2615, 1606, 1559, 1500, 1459, 1407, 1374, 1332, 1314, 1298,
1215, 1172, 1148, 1120, 1030, 833, 763, 701 cm–1. 1H NMR (500
MHz, DMSO-d6): δ = 11.87 (s, 1 H), 7.71 (d, J = 7.9 Hz, 2 H), 7.61–
7.36 (m, 7 H), 7.27 (t, J = 7.3 Hz, 1 H), 6.26 (d, J = 12.9 Hz, 1 H),
5.78 (d, J = 13.2 Hz, 1 H), 1.47 (s, 3 H) ppm. 13C NMR (126 MHz,
DMSO-d6): δ = 149.09, 136.93, 135.52, 129.47, 129.04, 128.69,
128.49, 127.18 (q, JC–F = 286.0 Hz), 125.92, 120.26, 99.54, 77.68,
53.96 (q, JC–F = 26.5 Hz), 13.13 ppm. 19F NMR (471 MHz, DMSO-
1
498 cm–1. H NMR (500 MHz, DMSO-d6): δ = 8.53 (s, 1 H), 8.38
(d, J = 8.6 Hz, 2 H), 8.31 (d, J = 8.6 Hz, 2 H), 8.19 (s, 2 H), 7.84 (d,
J = 8.7 Hz, 2 H), 7.51 (dd, J = 13.5, 7.9 Hz, 4 H), 7.44–7.26 (m, 6
H), 4.58 (dd, J = 13.9, 5.9 Hz, 1 H), 4.50 (dd, J = 14.2, 6.6 Hz, 1 H),
1.79 (s, 3 H) ppm. 13C NMR (126 MHz, DMSO-d6): δ = 166.20,
161.60, 151.70, 149.46, 148.40, 142.23, 140.75, 137.79, 136.88,
131.99, 131.93, 131.17, 129.91, 129.29, 128.95, 128.91, 128.66,
128.20, 127.20 (q, JC–F = 283.5 Hz) 124.79, 123.00, 105.73, 53.19
(q, JC–F = 23.9 Hz), 42.13, 15.46 ppm. 19F NMR (471 MHz, DMSO-
d6):
C
δ = –66.61 (s, 3 F) ppm. ESI-HRMS: m/z calcd for
19H16F3N3NaO3 [M + Na]+: 414.103597; found: 414.103795.
d6):
C
δ = –66.96 (s, 3 F) ppm. ESI-HRMS: m/z calcd for
33H25F3N5O7 [M + H]+: 660.1700; found: 660.1547.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F