SCHEME 6
General Procedure for the Reductive Ring-Opening. Method
A. To an EtOH solution (30 mL) of pyridine 9a (1.01 g, 2.30 mmol)
was added PtO2 (42 mg, 0.19 mmol). The mixture was hydrogenated
at room temperature under atmospheric pressure. After 12 h, the
catalyst was removed by filtration, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane-AcOEt) to give pyridine 10a
(1.00 g, 99%) as yellow crystals.
Method B. To a CH3CN (61.4 mL) and H2O (6.8 mL) solution
of pyridine 9a (1.50 g, 3.41 mmol) was added Mo(CO)6 (0.45 g,
1.7 mmol). The mixture was heated under reflux. After 2 h, the
volatile compounds were removed under reduced pressure. The
residue was filtered by a Celite pad, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (hexane-AcOEt) to give pyridine 10a
(1.29 g, 86%): colorless needles (AcOEt-hexane); mp 120.4-
1
121.2 °C; H NMR (500 MHz, CDCl3) δ 1.71 (s, 3H), 4.71 (s,
on the pyridine ring to produce a bicyclic intermediate, 15.
Successively, the similar aromatization of the formed dihydro-
pyridine derivative 15 would occur to produce the corresponding
1,6-naphythyridin-4-one derivative 11.
1H), 5.18 (br s, 1H), 7.24-7.41 (m, 3H), 7.59-7.61 (m, 2H), 9.62
(br s, 1H); 13C NMR (125 MHz, CDCl3) δ 22.2, 98.5, 109.8-
110.7 (m), 114.5 (tqd, JCF ) 3.5, 35, and 260 Hz), 118.8 (qt, JCF
) 35 and 260 Hz), 121.4 (qd, JCF ) 6.5 and 260 Hz), 128.1, 129.3,
130.1, 135.2 (dd, JCF ) 3.5 and 6.5 Hz), 137.0, 140.3 (t, JCF ) 35
Hz), 158.9 (d, JCF ) 260 Hz), 160.2 (d, JCF ) 14 Hz), 163.2, 187.5;
19F NMR (470 MHz, CDCl3) δ -94.5 (m, 2F), -75.1 (s, 3F), -60.6
(m, 1F), -55.7 (s, 3F); MS (FAB) m/z 443 (M + H, 100). Anal.
Calcd for C18H11N2F9O: C, 48.88; H, 2.51; N, 6.33. Found: C,
49.14; H, 2.25; N, 6.42.
A simple and convenient method was developed for the
synthesis of fluorocarbon-containing pyridine derivatives via the
intermolecular cyclization of a variety of 1-azaallylic anion
intermediates with the perfluoroalkene. Also developed was the
facile reductive ring-opening reaction of the isoxazole ring.
Moreover, it was found that the â-aminoenone group formed
by the reduction undergoes a consecutive intramolecular cy-
clization with the perfluoroethyl group on the pyridine ring,
providing a practical preparation for the perfluoroalkyl group-
containing 1,6-naphthyridin-4-one derivatives. This combined
procedure appeared to be an efficient and practical method to
produce a new type of fluorine-containing quinolone framework.
Further investigations toward the biological evaluation of fluoro-
containing pyridine derivatives synthesized are currently in
progress.
General Procedure for the Synthesis of 1,6-Naphthyridin-
4(1H)-one. A solution of pyridine 10a (345 mg, 0.782 mmol) in
THF (10 mL) was added to 3 N NaOH(aq) (0.800 mL, 2.35 mmol)
at room temperature. The reaction mixture was stirred for 24 h at
the same temperature. The reaction mixture was then quenched and
neutralized by a 1 N HCl aqueous solution. Then CHCl3 (20 mL)
and brine (20 mL) were added to the reaction mixture, and the
organic layer was extracted with CHCl3. The combined organic
layer was dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel chroma-
tography (AcOEt) to give 1,6-naphthyridin-4(1H)-one (11a; 249
mg, 99%): colorless solids (AcOEt-hexane); mp 174.5-175.8 °C;
1H NMR (500 MHz, CDCl3) δ 2.34 (s, 3H), 6.10 (s, 1H), 7.37-
7.48 (m, 5H), 8.42 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 20.4,
Experimental Section
General Procedure for the Synthesis of Perfluoro-Substituted
Pyridine 9. To a THF solution (50 mL) of 3-methyl-5-[(trimeth-
ylsilyl)methyl]isoxazole (5a; 2.30 g, 13.6 mmol) was added n-BuLi
(15.9 mmol, in hexane) at -70 °C, and the reaction mixture was
stirred at the same temperature. After 1 h, benzonitrile (6a; 1.64 g,
15.9 mmol) was added to the solution via a syringe, and the solution
was stirred for 1 h at -70 °C and then 2 h at room temperature.
Perfluoro-2-methyl-2-pentene (8; 12.2 g, 40.8 mmol) was gradually
added to the solution at -70 °C, and the mixture was stirred at the
same temperature and then for 24 h at room temperature. To quench
the reaction, a saturated aqueous solution of NH4Cl (50 mL) was
added to the mixture. The organic layer was extracted with Et2O,
and the separated organic layer was dried over Na2SO4, filtered,
and then concentrated under reduced pressure. The residue was
purified by silica gel chromatography (hexane-AcOEt) to give
perfluoro-substituted pyridine 9a (4.89 g, 82%): colorless needles
95.0-95.5 (m), 114.4 116.7 (d, JCF ) 3.5 Hz), 123.0 (qd, JCF
)
6.0 and 270 Hz), 127.7, 128.7, 129.5, 138.9, 146.9 (d, JCF ) 3.5
Hz), 147.6, 159.2 (d, JCF ) 260 Hz), 166.1 (d, JCF ) 14 Hz), 176.6;
19F NMR (470 MHz, acetone-d6) δ -65.2 (m, 1F), -56.1 (m, 3F);
MS (FAB) m/z 323 (M + H, 100). Anal. Calcd for C16H10N2F4O:
C, 59.63; H, 3.13; N, 8.69. Found: C, 59.45; H, 3.11; N, 8.54.
Acknowledgment. This work was partially supported by a
grant from the Japan Private School Promotion Foundation
(1997-1999) and a grant for the “High-Tech Research Center”
Project for Private Universities, a matching fund subsidy from
MEXT, 2000-2004 and 2005-2007. We thank Neos Co., Ltd.
for the gift of perfluoro-2-methyl-2-pentene and also acknowl-
edge the staff of the High Technology Research Center of the
Tokyo University of Science for the performance of the
elemental analyses.
1
(hexane); mp 89.4-89.9 °C; H NMR (500 MHz, CDCl3) δ 2.21
(s, 3H), 5.84 (s, 1H), 7.30-7.38 (m, 5H); 13C NMR (125 MHz,
CDCl3) δ 11.1, 108.1, 110.9-117.8 (m), 113.5 (tqd, JCF ) 3.5,
35, and 260 Hz), 118.4 (qt, JCF ) 35 and 260 Hz), 120.8 (dd, JCF
) 3.5 and 10 Hz), 121.0 (qd, JCF ) 10 and 260 Hz), 128.3, 128.8,
130.4, 135.9, 142.9 (t, JCF ) 35 Hz), 159.8, 160.6 (d, JCF ) 240
Hz), 162.7, 164.3 (d, JCF ) 14 Hz); 19F NMR (470 MHz, CDCl3)
δ 56.9 (m, 4F), 36.4 (s, 3F), 15.1 (m, 2F); MS (FAB) m/z 441 (M
+ H, 100). Anal. Calcd for C18H8N2F9O: C, 49.10; H, 2.06; N,
6.36. Found: C, 49.10; H, 2.10; N, 6.40.
Supporting Information Available: Detailed procedures and
spectroscopic data for novel compounds in Tables 1 and 2, ORTEP
diagrams of 9k and 11k, X-ray data for 9k and 11k, and 1H NMR
of novel compounds prepared. This material is available free of
JO070564M
J. Org. Chem, Vol. 72, No. 15, 2007 5881