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Organic & Biomolecular Chemistry
Page 8 of 9
ARTICLE
Journal Name
by flash column chromatography using pentane/Et2O 20:1 as 3H), 2.21 – 2.08 (m, 1H), 2.01 – 1.89 (m, 1H), 1.24 (s, 1H) ppm;
eluent to afford the title product (73 mg, 72 % (corrected for 13C NMR (101 MHz, CDCl3) δ 160.7, 141.D2O, I1: 2108.1.903, 91/2C79O.9B,01226365.9E
residual aryl iodide)) as a yellow oil. Rf: 0.24 (in pentane/Et2O (q, J = 3.7 Hz), 125.9, 124.5 (q, J = 272.0 Hz), 122.9 (q, J = 32.7
20:1); 1H NMR (400 MHz, CDCl3) δ 8.60 (d, J = 5.6 Hz, 1H), 8.31 Hz), 115.9, 78.8, 48.4, 38.9, 36.7 ppm; 19F NMR (376 MHz, CDCl3)
(d, J = 8.4 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 5.6 Hz, 1H), δ -61.5 ppm; HRMS m/z calculated for C17H19F3NO [M + H]+
7.82 – 7.69 (m, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ 146.6 (q, 310.1413, found 310.1423. The NMR data are in agreement
J = 33.2 Hz), 140.9, 137.3, 131.0, 129.0, 127.7, 124.89 – 124.72 with literature.29
(m, 2C), 124.7, 122.4 (q, J = 276.3 Hz) ppm; 19F NMR (376 MHz,
CDCl3) δ -63.0 ppm; HRMS m/z calculated for C10H7F3N [M + H]+
198.0525, found 198.0526. The NMR data are in agreement
with literature.12b
Conflicts of interest
The authors declare the following competing financial interests:
1-Benzyl-4-(trifluoromethyl)-1H-pyrazole (2v). Prepared 1-
benzyl-4-iodo-1H-pyrazole and isolated using Sonogashira
reaction and General workup procedure A. The crude product
purified by flash column chromatography using pentane/EtOAc
(15:1) as eluent to afford the title product (59 mg, 51%) as an
Anders T. Lindhardt is co-owner of SyTracks A/S, which
commercializes the COtube technology.
Acknowledgements
1
yellow oil. Rf: 0.31 (in pentane/EtOAc 15:1); H NMR (400 MHz,
We thank the Independent Research Fund Denmark
–
CDCl3) δ 7.74 (s, 1H), 7.63 (s, 1H), 7.45 – 7.33 (m, 3H), 7.29 –
7.22 (m, 2H), 5.32 (s, 2H) ppm; 13C NMR (101 MHz, CDCl3) δ
137.3, 135.2, 129.2, 128.75, 128.7 – 128.6 (m), 128.1, 122.7 (q,
J = 266.0 Hz), 114.1 (q, J = 39.5 Hz), 56.7 ppm; 19F NMR (376
MHz, CDCl3) δ -56.3 ppm; HRMS m/z calculated for C11H10F3N2
[M + H]+ 227.0791, found 227.0794. The NMR data are in
agreement with literature.12b
Technology and Production (Grant No. 4148-00031), the
Carlsberg Foundation, the Danish National Research
Foundation (Grant No. DNRF 118), and Aarhus University for
financial support. We thank M.Sc. Line Bang for synthesizing
compound 1w (former student, Aarhus University).
2,2,2-Trifluoro-N-methyl-N-(3-phenyl-3-(4-
Notes and references
(trifluoromethyl)phenoxy)propyl)acetamide (2w). Prepared
from 2,2,2-trifluoro-N-(3-(4-iodophenoxy)-3-phenylpropyl)-N-
methylacetamide and isolated using Sonogashira reaction and
General workup procedure A. The crude product purified by
flash column chromatography using pentane/CH2Cl2 (1:1) as
eluent to afford the title product (150 mg, 75%) as a yellow oil.
1
For selected examples for fluorine properties, see: (a) K.
Muller, C. Faeh and F. Diederich, Science, 2007, 317, 1881; (b)
Y. Zhou, J. Wang, Z. Gu, S. Wang, W. Zhu, J. L. Acena, V. A.
Soloshonok, K. Izawa, and H. Liu, Chem. Rev., 2016, 116, 422;
(c) B. R. Langlois and T. Billard, Synthesis (Stuttg), 2003, 185;
(d) J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo, A. E.
Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu, Chem.
Rev., 2014, 114, 2432; (e) P. Jeschke, Chembiochem, 2004, 5,
570; (f) D. O’Hagan, Chem. Soc. Rev., 2008, 37, 308.
1
Rf: 0.33 (in pentane/ CH2Cl2 1:1); H NMR (400 MHz, CDCl3) δ
Mixture of rotamers (major/minor 1.88:1) 7.48 – 7.40 (m, 2H),
7.40 – 7.24 (m, 5H), 6.92 – 6.84 (m, 2H), 5.26 – 5.15 (m, 1H),
3.65 (t, J = 7.4 Hz, 2H), 3.14 (s, 3H), 3.04 (s, 3H), 2.38 – 2.23 (m,
1H), 2.21 – 2.10 (m, 1H) ppm; 13C NMR (101 MHz, CDCl3) δ
Mixture of rotamers 160.2, 160.1, 157.1 (q, J = 35.8 Hz), 157.1
(q, J = 35.8 Hz), 140.2, 139.8, 129.2, 129.1, 128.5, 128.3, 127.1 –
126.9 (m), 125.8, 125.6, 123.9 – 122.7 (m), 116.6 (q, J = 288.3
Hz), 116.5 (q, J = 288.9 Hz), 115.8 (d, J = 5.4 Hz), 78.2, 77.8, 47.1,
46.7 – 46.4 (m), 37.5, 35.6, 35.5 (q, J = 3.5 Hz), 34.9 ppm; 19F
NMR (376 MHz, CDCl3) δ Mixture of rotamers -61.6, -61.6, -68.9,
-69.9 ppm; HRMS m/z calculated for C19H17F6NNaO2 [M + Na]+
428.1056, found 428.1056.
N-Methyl-3-phenyl-3-(4-(trifluoromethyl)phenoxy)propan-1-
amine (Prozac) (3w). 2,2,2-trifluoro-N-methyl-N-(3-phenyl-3-
(4-(trifluoromethyl)phenoxy)propyl)acetamide (150 mg, 0.37
mmol, 1.0 equiv.) and 2M NaOH (aq) (0.28 mL, 1.5 equiv.) were
dissolved in THF (2 mL) and stirred at room temperature for 5
hours. The reaction mixture was concentrated under reduced
pressure, redissolved in Et2O (30 mL) and washed with water
(2×15 mL), sat. K2CO3 (15 mL) and brine (15 mL). The organic
layer was dried over Na2SO4, filtered and concentrated under
reduced pressure to afford the title compound as a yellow oil
(115 mg, quant.). 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.6 Hz,
2H), 7.30 – 7.26 (m, 4H), 7.23 – 7.18 (m, 1H), 6.85 (d, J = 8.5 Hz,
2H), 5.25 (dd, J = 8.2, 4.7 Hz, 1H), 2.72 – 2.65 (m, 2H), 2.37 (s,
2
3
For selected accounts on organoflourine compounds, see: (a)
G. W. Gribble, Chem. Educ., 2004, 81, 1441; (b) D. O'Hagan
and D. B. Harper, J. Fluorine Chem., 1999, 100, 127; (c) W. R.
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Selected recent examples of aromatic trifluoromethylation,
see: (a) X. Lin, C. Huo, H. Li and Z. Weng, Chem. Eur. J., 2016,
22, 2075; b) J.-J. Dai, C. Fang, B. Xiao, J. Yi, J. Xu, Z.-J. Liu, X. Lu,
L. Liu, and Y. Fu, J. Am. Chem. Soc., 2013, 135, 8436; (c) G. K.
S. Prakash, F. Wang, Z. Zhang, R. Haiges, M. Rahm, K. O.
Christe, T. Mathew, and G. A. Olah, Angew. Chem. Int. Ed.,
2014, 53, 11575; (d) A. I. Konovalov, A. Lishchynskyi, and V. V.
Grushin, J. Am. Chem. Soc., 2014, 136, 13410; (e) J. W. Beatty,
J. J. Douglas, K. P. Coleand C. R. J. Stephenson, Nature Comm.,
2015, 6, 7919; (f) S. T. Keaveney and F. Schoeneback, Angew.
Chem. Int. Ed., 2018, 57, 4073.
4
5
Z. Wang, in Comprehensive Organic Name Reactions and
Reagents, John Wiley & Sons, Inc., Hoboken N.J., 2009, ch.
615: Swarts Reaction, pp. 2744-2747.
Selected examples on radical trifluoromethylation, see: (a) D.
A. Nagib and D. W. C. MacMillan, Nature, 2011, 480, 224; (b)
Y. Ji, T. Brueckl, R. D. Baxter, Y. Fujiwara, I. B. Seiple, S. Su, D.
G. Blackmond and P. S. Baran, Proc. Natl. Acad. Sci. USA, 2011,
108, 14411.
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7
H. Morimoto, T. Tsubogo, N. D. Litvinas and J. F. Hartwig
Angew. Chem. Int. Ed., 2011, 50, 3793.
For selected reviews on trifluoromethylation, see: (a) T.
Furuya, A. S. Kamlet and T. Ritter, Nature, 2011, 473, 470; (b)
X.-F. Wu, H. Neumann and M. Beller, Chem. Asian. J., 2012, 7,
8 | J. Name., 2012, 00, 1-3
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