2494
S. Yamada, P. Knochel
PRACTICAL SYNTHETIC PROCEDURES
Hz), 41.06, 38.44, 28.95, 17.54, 14.42 (d, J = 3.8 Hz), 10.81 (d,
J = 4.5 Hz).
19F NMR (282 MHz, CDCl3, 25 °C): d = –120.2 to –120.3 (m, 1 F).
MS (EI, 70 eV): m/z (%) = 251 (4) [M+], 194 (16), 176 (11), 166
(12), 98 (100), 57 (14).
13C NMR (75 MHz, CDCl3, 27 °C): d = 158.73, 151.31 (d,
J = 256.5 Hz), 130.45 (d, J = 1.5 Hz), 129.03, 127.57 (d, J = 21.9
Hz), 125.62 (d, J = 3.0 Hz), 113.77, 111.65 (d, J = 19.6 Hz), 55.22,
14.64, 9.95.
19F NMR (282 MHz, CDCl3, 27 °C): d = –133.49 (t, J = 2.8 Hz, 1
F).
HRMS: m/z [M+] calcd for C15H22FNO: 251.1685; found 251.1690.
MS (EI, 70 eV): m/z (%) = 236 (100) [M+], 221 (48), 57 (45), 55
(40), 43 (42).
2-Chloro-5-fluoro-4-(4-methoxyphenyl)pyridine (3n); Typical
Procedure 4
HRMS: m/z [M+] calcd for C13H13FO32S: 236.0671; found
The Grignard reagent was prepared using Method A. In a 100-mL
Schlenk flask under N2 was placed 5-bromo-2-chloro-4-(4-meth-
oxyphenyl)pyridine (1n, 5.951 g, 20 mmol) in THF (10 mL). 1.18
M i-PrMgCl·LiCl in THF (25.4 mL, 30 mmol) was added at 0 °C
and the mixture was stirred at this temperature for 1 h. Then the sol-
vent was removed in vacuo (40 °C/1.0 mbar, 1 h). CH2Cl2 (20 mL)
was added and then NFSI (7.568 g, 24 mmol) in CH2Cl2 (20 mL)
and perfluorodecalin (10 mL) were slowly added at –78 °C. The
mixture was stirred at 0 °C for 30 min and at 25 °C for 2 h; it was
then poured into ice-cooled sat. aq NH4Cl soln (200 mL) and ex-
tracted with CH2Cl2 (3 × 200 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The crude
mixture was passed through a plug of silica and the filtrate was pu-
rified by column chromatography (silica gel, pentane–CH2Cl2, 1:2)
to give a pale yellow solid; yield: 2.61 g (58%); mp 74.3–76.0 °C.
236.0659.
Acknowledgment
S.Y. thanks the Humboldt Foundation for financial support. We
thank the Fonds der Chemischen Industrie, the European Research
Council (ERC) for financial support. We also thank Chemetall
GmbH (Frankfurt), BASF AG (Ludwigshafen) for the generous gift
of chemicals.
References
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V.
Chem. Soc. Rev. 2008, 37, 320. (b) Hagmann, W. K. J. Med.
Chem. 2008, 51, 4359. (c) Kirk, K. L. Org. Process Res.
Dev. 2008, 12, 305. (d) Müller, K.; Faeh, C.; Diederch, F.
Science 2007, 317, 1881.
IR (KBr): 2935 (w), 1597 (m), 1518 (m), 1461 (s), 1359 (m), 1254
(vs), 1178 (s), 1043 (s), 827 cm–1 (vs).
1H NMR (300 MHz, CDCl3, 27 °C): d = 8.27 (d, J = 2.2 Hz, 1 H,
PyH), 7.56 (ABq, J = 9.0, 9.0 Hz, 2 H, ArH), 7.40 (d, J = 5.6 Hz, 1
H, PyH), 7.01 (ABq, J = 9.0, 9.0 Hz, 2 H, ArH), 3.88 (s, 3 H,
OCH3).
13C NMR (75 MHz, CDCl3, 27 °C): d = 160.90, 155.94 (d,
J = 255.8 Hz), 146.52 (d, J = 3.0 Hz), 138.93 (d, J = 12.8 Hz),
138.09 (d, J = 28.7 Hz), 130.14, 130.09, 123.99 (d, J = 2.3 Hz),
123.88 (d, J = 1.5 Hz), 114.43, 55.37.
(2) Jeschke, P. ChemBioChem 2004, 5, 570.
(3) Sandford, G. J. Fluorine Chem. 2007, 128, 90.
(4) (a) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.
Angew. Chem. Int. Ed. 2008, 47, 8404. (b) Sun, H.;
DiMagno, S. G. Chem. Commun. 2007, 528. (c) Sun, H.;
DiMagno, S. G. Angew. Chem. Int. Ed. 2006, 45, 2720.
(d) Sun, H.; DiMagno, S. G. J. Am. Chem. Soc. 2005, 127,
2050. (e) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999,
28, 225.
19F NMR (282 MHz, CDCl3, 27 °C): d = –136.25 to –136.32 (m, 1
F).
MS (EI, 70 eV): m/z (%) = 239 (33), 237 (100) [M]+, 222 (11), 222
(5) Balz, G.; Schiemann, G. Ber. Dtsch. Chem. Ges. 1927, 60,
1186.
(6) For other recent fluorination methods, see: (a) Anbarasan,
P.; Neumann, H.; Beller, M. Angew. Chem. Int. Ed. 2010, 49,
2219. (b) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang,
Y.; García-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
2009, 325, 1661. (c) Furuya, T.; Ritter, T. Org. Lett. 2009,
11, 2860. (d) Furuya, T.; Strom, A. E.; Ritter, T. J. Am.
Chem. Soc. 2009, 131, 1662. (e) Cazorla, C.; Métay, E.;
Andrioletti, B.; Lemaire, M. Tetrahedron Lett. 2009, 50,
3936. (f) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem.
Int. Ed. 2008, 47, 5993. (g) Hull, K. L.; Anani, W. Q.;
Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 7134.
(7) (a) Krasovskiy, A.; Straub, B. F.; Knochel, P. Angew. Chem.
Int. Ed. 2006, 45, 159. (b) Ila, H.; Baron, O.; Wagner, A. J.;
Knochel, P. Chem. Commun. 2006, 583. (c)Krasovskiy, A.;
Knochel, P. Angew. Chem. Int. Ed. 2004, 43, 3333.
(8) (a) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.;
Gavryushin, A.; Knochel, P. Chem. Eur. J. 2009, 15, 7192.
(b) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm,
M.; Knochel, P. Angew. Chem. Int. Ed. 2008, 47, 6802.
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Ed. 2010, 49, 2215.
(10), 194 (22).
HRMS: m/z [M]+ calcd for C12H9ClFNO: 237.0357; found
237.0457.
3-Fluoro-2,5-dimethyl-4-(4-methoxyphenyl)thiophene (3s);
Typical Procedure 5
The Grignard reagent was prepared using Method A. In a 100-mL
Schlenk flask under N2 was placed 3-bromo-2,5-dimethyl-4-(4-
methoxyphenyl)thiophene (1s, 5.944 g, 20 mmol) in THF (10 mL).
1.18 M i-PrMgCl·LiCl in THF (25.4 mL, 30 mmol) and dioxane
(2.0 mL) were added at 0 °C and the mixture was stirred at 50 °C for
12 h. Then, the solvent was removed in vacuo (40 °C/1.0 mbar, 1 h).
CH2Cl2 (20 mL) was added and NFSI (7.568 g, 24 mmol) in CH2Cl2
(20 mL) and perfluorodecalin (10 mL) were slowly added at –78 °C.
The mixture was stirred at 0 °C for 30 min and at 25 °C for 2 h; it
was then poured into ice-cooled sat. aq NH4Cl soln (200 mL) and
extracted with CH2Cl2 (3 × 200 mL). The combined organic layers
were dried (Na2SO4), filtered, and concentrated in vacuo. The crude
mixture was passed through a plug of silica and the filtrate was pu-
rified by column chromatography (silica gel, pentane–CH2Cl2, 4:1)
to give a yellow oil; yield: 3.58 g (76%).
(11) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Burel, E. E.; Faul, M. M.; Larsen, R. D.;
Martinell, M. J.; Reider, P. J. Org. Lett. 2006, 8, 1787.
IR (film): 2920 (w), 1599 (m), 1529 (m), 1497 (m), 1244 (vs), 1177
(s), 1150 (m), 1035 (s), 833 cm–1 (vs).
1H NMR (300 MHz, CDCl3, 27 °C): d = 7.32 (ABq, J = 9.0, 9.0 Hz,
2 H, ArH), 7.01 (ABq, J = 9.0, 9.0 Hz, 2 H, ArH), 3.90 (s, 3 H,
OCH3), 2.40 (s, 3 H, CH3), 2.35–2.75 (m, 3 H, CH3).
Synthesis 2010, No. 14, 2490–2494 © Thieme Stuttgart · New York