A. M. Shestopalov et al. / Tetrahedron Letters 50 (2009) 5257–5259
5259
D.; Zhou, H.; Liu, H. J. Am. Chem. Soc. 1997, 119, 1809; (e) Dehmlow, E. V.; Schulz,
H.-J. Tetrahedron Lett. 1985, 26, 4903.
R1
N
R1
R2
R3
Z
R2
R3
Z
F
2. (a) Dolci, L.; Dolle, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C. J. Labelled Compd.
Radiopharm. 1999, 42, 975; (b) Zhang, Y.; Horti, A. G. J. Labelled Compd.
Radiopharm. 2004, 47, 947; (c) Jammaz, I. A.; Al-Otaibi, B.; Okarvi, S.; Amartey, J.
J. Labelled Compd. Radiopharm. 2006, 49, 125; (d) Amartey, J. K.; Al-Jammaz, I.;
Al-Otaibi, B.; Esguerra, C. Nucl. Med. Biol. 2002, 29, 817; (e) Pichika, R.;
Easwaramoorthy, B.; Collins, D.; Christian, B. T.; Shi, B.; Narayanan, T. K.;
Potkin, S. G.; Mukherjee, J. Nucl. Med. Biol. 2006, 33, 295.
3. (a) Hoyte, R. M.; Zhang, J.; Lerum, R.; Oluyemi, A.; Persaund, P.; O’Connor, C.;
Labaree, D. C.; Hochberg, R. B. J. Med. Chem. 2002, 45, 5397; (b) Kahn, M. G. C.;
Konde, E.; Dossou, F.; Labaree, D. C.; Hochberg, R. B.; Hoyte, R. M. Bioorg. Med.
Chem. Lett. 2006, 16, 3454.
MW, DMSO
2 KF. 2H2O
Hal
N
2
1a-e,g,h
3a-e,g,h
1: Hal = Br (e,g); Cl (a-d, f, h).
1, 3: Z = CN, R1= R3 = CH3 , R2 = H (a); Z = CN, R1 = H, R2 - R3 = (CH2)4 (b);
Z = CN, R1= R3 = C6H5 , R2 = H ( ); Z = CN, R1 = 4-CH3O-C6H4,
c
R2 = H, R3 = C6H5
(
); Z = CN, R1 = 4-F-C6H4, R2 = H, R3 = C6H5 ( );
d
e
Z = R2 = R3 = H, R1 = CH3 (g); Z = H, R1 = CH3, R2-R3 = (CH=CH)2 (h).
4. Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
5. (a) Shestopalov, A. M.; Shestopalov, A. A.; Rodinovskaya, L. A.; Gromova, A. V. In
Fluorinated Heterocyclic Compounds: Synthesis, Chemistry and Applications;
Petrov, V. A., Ed.; John Wiley & Sons Ltd: New York, 2009; pp 243–271. Part 1;
(b) Kim, D. W.; Jeong, H.-J.; Lim, S. T.; Sohn, M.-H.; Katzenellenbogen, J. K.; Chi, D.
Y. J. Org. Chem. 2008, 73, 957; (c) Adams, D. B.; Kilcoyne, J. P.; MacBride, J. A.;
Hugh, M. M. J. Chem. Res. (S) 1990, 6, 172; (d) Mutterer, F.; Weis, C. D. Helv. Chim.
Acta 1976, 59, 229; (e) Clark, J. H.; Macquarrie, D. J. Tetrahedron Lett. 1987, 28,
111; (f) Finger, G. C.; Starr, L. D. J. Am. Chem. Soc. 1959, 81, 2674; (g) Dolci, L.;
Dolle, F.; Jubeau, S.; Vaufrey, F.; Crouzel, C. J. Labelled Compd. Radiopharm. 1999,
42, 975.
6. Shestopalov, A. M.; Rodinovskaya, L. A.; Fedorov, A. E.; Kalugin, V. E.; Nikishin, K.
G.; Shestopalov, A. A.; Gakh, A. A. J. Fluorine Chem. 2009, 130, 236.
7. Shestopalov, A. M.; Kalugin, V. E.; Fedorov, A. E.; Nikishin, K. G.; Rodinovskaya, L.
A.; Gakh, A. A. The 232nd ACS National Meeting of the American Chemical
Society, San Francisco, CA, September 10–14, 2006.
Scheme 1. Microwave-assisted synthesis of 2-fluoropyridines 3.
Cl
F
MW, DMSO
N
2 KF.2H2O
N
S
N
2
S
N
1f
3f
Scheme 2. Synthesis of substituted fluorothienopyridine 3f.
8. Berdonosov, S. S.; Berdonosova, D. G.; Znamenskaya, I. V. Chem. Technol. 2000, 3,
2. in Russian.
9. General procedure for the synthesis fluoroazines 3: Chloro- or bromoazines 1
(2 mmol) and KFÁ2H2O (2) (0.4 g, 4 mmol) were mixed together in DMSO (4 mL)
in a 10-mL Pyrex glass sample holder (CEM). The reaction was carried out in a
closed vessel using
a focused microwave synthesis system (CEM Discover
BenchMate) under continuous stirring. The incubation time was 1.5–4 min with
a fixed microwave irradiation power of 300 W and a maximum temperature of
120–180 °C. After completion, the reaction mixture was cooled, poured into
water (50 ml), extracted with chloroform, and purified by column
chromatography on silica gel (eluent: CHCl3–hexane, 3:2) (Table 1). Physical
data of representative compounds: 3-Cyano-2-fluoro-4-(4-methoxyphenyl)-6-
phenylpyridine (3d): Yield: 75%; mp 193 °C (from CHCl3–MeOH, 1:1). 1H NMR
(300 MHz, DMSO-d6), d: 3.88 (s, 3H, CH3O); 7.19 (d, 2H, C6H4, 3J = 8.3 Hz); 7.56–
8.25 (m, 3H, C6H5); 7.84 (d, 2H, C6H4, 3J = 8.3 Hz); 8.19 (s, 1H, C5H); 8.23–8.26
(m, 2H, C6H5). 13C NMR (50 MHz, DMSO-d6), d: 55.52; 96.28; 113.72 (CN);
114.51; 118.06; 126.82; 127.63; 129.12; 130.52; 131.31; 135.47; 157.44;
1
157.90; 161.32; 163.17 (d, JCF = 239.9 Hz). 19F NMR (188 MHz, DMSO-d6), d: -
61.4. MS (EI, 70 eV) m/z: 304 [M]+ (100). 3-Cyano-2-fluoro-4-(4-fluorophenyl)-6-
phenylpyridine (3e): Yield: 68%; mp 192 °C (from EtOH). 1H NMR (300 MHz,
DMSO-d6), d: 7.49 (m, 2H, C6H4); 7.58 (m, 3H, C6H5); 7.91 (m, 2H, C6H4); 8.24 (m,
3H, C5H, C6H5). 13C NMR (50 MHz, DMSO-d6), d: 96.33; 113.20 (CN); 116.04;
118.50; 127.82; 129.09; 131.27; 131.39; 131.45; 135.29; 153.91; 158.52; 159.20
Figure 1. Desolvation of the FÀ anion under microwave irradiation.
1
(d, JCF = 247.0 Hz); 163.60 (1JCF = 242.7 Hz). 19F NMR (282 MHz, DMSO-d6), d:
À62.95, À110.88. MS (EI, 70 eV) m/z: 292 [M]+ (100). 4-Fluoro-5,6,7,8-
tetrahydro[1]benzothieno[2,3-d]pyrimidine (3f): Yield: 81%; mp 87 °C (from
EtOH). 1H NMR (300 MHz, DMSO-d6), d: 1.84 (m, 4H, CH2CH2); 2.86 (m, 4H,
CH2, CH2); 8.73 (s, 1H, C2H).). 13C NMR (50 MHz, DMSO-d6), d: 21.47; 22.24;
24.50; 24.96; 117.51; 125.55; 138.34; 152.12; 159.83; 167.59 (1JCF = 269.7 Hz).
19F NMR (188 MHz, DMSO-d6), d: À64.43. MS (EI, 70 eV) m/z: 208 [M]+ (57), 180
(100). 4-Methyl-2-fluoropyridine (3g): Yield: 67%; oil (eluent: toluene–hexane,
1:1). 1H NMR (300 MHz, DMSO-d6), d: 2.35 (s, 3H, CH3); 6.97 (s, 1H, C3H), 7.15
(m, 1H, C5H), 8.08 (d, 1H, C6H, J = 5.14 Hz). 13C NMR (50 MHz, DMSO-d6), d:
20.25 (CH3); 109.53 (d, C3H, J = 37.59 Hz), 122.86 (d, C5H, J = 4.42 Hz), 146.93 (d,
Acknowledgments
This research was supported by the Global IPP program through
the International Science and Technology Center (ISTC). Oak Ridge
National Laboratory is managed and operated by UT-Battelle, LLC,
under U.S. Department of Energy contract DE-AC05-00OR22725.
This Letter is a contribution from the Discovery Chemistry Project.
1
C4H, J = 15.48 Hz), 153.50 (d, C6H, J = 8.85 Hz), 163.87 (d, C2H, JCF = 244.43 Hz).
19F NMR (282 MHz, DMSO-d6), d: -71.08. MS (EI, 70 eV) m/z: 111 [M]+ (100). 4-
Methyl-2-fluoroquinoline (3h): Yield: 62%; oil (eluent: toluene–hexane, 1:1). 1H
NMR (300 MHz, CDCl3), d: 2.61 (s, 3H, CH3); 7.15 (s, 1H, C3H), 7.51 (dd, 1H, C7H,
J = 8.06 Hz, J = 7.25 Hz), 7.67 (dd, 1H, C6H, J = 8.06 Hz, J = 7.25 Hz), 7.88 (d, 1H,
C5H, J = 8.06 Hz), 7.98 (d, 1H, C8H, J = 8.06 Hz), 13C NMR (75 MHz, CDCl3), d:
18.79, 109.8, 123.80, 125.92, 126.74, 128.67, 130.15, 150.93, 161.17 (d, C2H,
1JCF = 256.18 Hz). 19F NMR (282 MHz, CDCl3), d: À63.80. MS (EI, 70 eV) m/z: 161
[M]+ (69), 143 (100).
References and notes
1. (a) Dolle, F.; Valette, H.; Bottlaender, M.; Hinnen, F.; Vaufrey, F.; Guenther, I.;
Crouzel, C. J. Labelled Compd. Radiopharm. 1998, 41, 451; (b) Schirrmacher, R.;
Mühlhausen, U.; Wängler, B.; Schirrmacher, E.; Reinhard, J.; Nagel, G.; Kaina, B.;
Piel, M.; Wießler, M.; Rösch, F. Tetrahedron Lett. 2002, 43, 6301; (c) Minakawa,
N.; Kojima, N.; Matsuda, A. J. Org. Chem. 1999, 64, 7158; (d) Pieper, P. A.; Yang,