Synthesis and reactivity of pyridylpyridone derivatives

Full text of DOI:10.1021/jo991294d

J . Org. Chem. 2000, 65, 1225-1226
1225
Sch em e 1
Syn th esis a n d Rea ctivity of
P yr id ylp yr id on e Der iva tives
Noriyasu Sakamoto,† Yasuyuki Kurita,‡
Kazunori Yanagi,§ and Noritada Matsuo*,†
Agricultural Chemicals Research Laboratory and
Biotechnology Laboratory, Sumitomo Chemical Co., Ltd.
4-2-1 Takatsukasa, Takarazuka, Hyogo 665-8555, J apan
Received August 16, 1999
In tr od u ction
It is well-known that the incorporation of fluorine
atoms into biologically active molecules often leads to
increased activity compared to that of the parent com-
pounds. 2,3-Dichloro-5-(trifluoromethyl)pyridine (1) is an
important starting material for various agrochemicals
and pharmaceuticals.1 The very high levels of activity of
compounds derived from 1 can in part be attributed to
the presence of the trifluoromethyl group. In our continu-
ing research to find new insecticides, we synthesized the
novel insecticidal dimeric product 2.2 Further modifica-
tion of compound 2 via nucleophilic substitution reactions
with KF and KCN proceeded in a highly regioselective
manner to afford the novel pyridylpyridones 3 and 4,
respectively.
Resu lts a n d Discu ssion
The dimeric product 2 was initially obtained ac-
cidentally in low yield (30%) from 2,3-dichloro-5-(trifluo-
romethyl)pyridine 1 (DMF-CH3CO2Na, 120 °C). How-
ever, an alternative procedure (1, K2CO3 in DMSO, 120
°C, 24 h) led to the isolation of the desired product in
greatly improved yield (82%) (Scheme 1).3
tures of both new compounds were confirmed by means
of X-ray analysis.
Nucleophilic substitution at the 3-position of pyridine
derivatives under such mild reaction conditions is
unusualssuch reactions typically require temperatures
in excess of 200 °C. Thus we were very interested in the
nucleophilic substitution of the chlorine atom by fluorine
at the 3-position on the pyridine ring.
First, we attempted to relate the chemical regioselec-
tivity to a particular MO index such as charges, electron
densities, orbital energies, and heats of formation. In
addition, we studied the comparison of energies of
Meizenheimer-type intermediates. These procedures,
however, did not account for the regioselectivity of a
fluoride anion nor a cyanide anion to the pyridylpyridone
2.
Second, we turned our attention to the HSAB prin-
ciples.4 It is well-known that a fluoride anion is a hard
base and a cyanide anion is a soft base, and hard bases
prefer to coordinate with hard acids and soft bases prefer
soft acids. Klopman and Fleming showed that hard acids
are recognized, as small sized, highly positively charged,
not easily polarizable, and characterized by a low value
for the frontier electron density of LUMO.5 On the other
Further investigations for the derivatives of 2 revealed
that 2 undergoes facile and highly regioselective nucleo-
philic substitution with KF and KCN to give the novel
pyridylpyridone 3 and 4, respectively (Scheme 1). We
initially assumed that the 3 and 4 were pyridylpyiridones
arising from substitution at the 3′-carbon atom of the
pyridone ring, which is activated by R-carbonyl group.
In fact, KCN did indeed react (25 °C, 12 h) at the
3′-carbon atom of 2 to give the corresponding 3′-cyano
compound 4 in good yield (71%). However, KF unexpect-
edly reacted at the 3-carbon atom of 2 (120 °C, 5 h) to
give the novel pyridylpyridone 3. The yield of 3 was
moderate (40%), but no other fluorine-containing com-
pounds, for example, 3′-fluoro-substituted or 3,3′-difluoro-
substituted pyridylpyridones were detected. The struc-
* To whom correspondence should be addressed.
† Agricultural Chemicals Research Laboratory.
‡ Tsukuba Research Laboratory, Sumitomo Chemical Co.,Ltd. 6
Kitahara,Tsukuba, Ibaraki 300-3294, J apan.
§ Biotechnology Laboratory.
(1) (a) Haga, T.; Toki, T.; Nishiyama, R.; Koyanagi, T. Nippon
Noyaku Gakkaishi 1985, 10, 217. (b) Smith, L. L.; J ohnston, H. J .;
Gerwick, C. B.; Egli, A. E. Abstr. Weed Sci. Soc. Am. 1982, 107.
(2) Matsuo, N.; Takeda, H.; Yano, T.; Nishida, S.; Tsushima, K.
J apanese Patent 6038363 [8538363], 1985; Chem. Abstr. 1985, 103,
6241.
(4) Pearson, R. G. J . Am. Chem. Soc. 1963, 85, 3533.
(5) (a) Klopman, G. J . Am. Chem. Soc. 1968, 90, 223. (b) Fleming,
I. Frontier Orbitals and Organic Chemical Reactions; Wiley: London,
1976; p 37.
(3) Matsuo, N.; Sakamoto, N. J apanese Patent 532628 [9332628],
1993; Chem. Abstr. 1993, 119, 117127.
10.1021/jo991294d CCC: $19.00 © 2000 American Chemical Society
Published on Web 01/21/2000

1226 J . Org. Chem., Vol. 65, No. 4, 2000
Notes
Ta ble 1. Ma xim u m LUMO Den sity (ØLUMO2),
Electr osta tic P oten tia l, a n d Net Ch a r ges of 3- a n d
3′-Ca r bon Atom s in 2
mesh). 1H NMR was performed at 300 MHz in CDCl3 unless
otherwise specified. Chemical shifts are in ppm downfield from
internal tetramethylsilane. 19F NMR were performed at 282
MHz in CDCl3 unless otherwise specified. Chemical shifts are
in ppm downfield from internal fluorotrichloromethane.
max. LUMO
electrostatic
potential
(atomic unit)
net charges
density
2
(ØLUMO
)
Mulliken CHELPG
[1(2H)-3-Ch lor o-5-(tr iflu or om eth yl)-3′-Ch lor o-5′-(tr iflu o-
r om eth yl)-2′-bip yr id in ]-2-on e (2). A solution of 2,3-dichloro-
5-(trifluoromethyl)pyridine (20.0 g, 92.6 mmol) and potassium
carbonate (6.40 g, 46.3 mmol) in N,N-dimethylformamide (50
mL) was stirred at 140 °C for 30 h. The reaction was cooled to
room temperature. The reaction mixture was poured into water
(100 mL) and then extracted with ethyl acetate. The organic
extracts were combined, washed with water and saturated
aqueous sodium chloride solution, dried over MgSO4, and
filtered, and the solvent was evaporated, yielding a residue that
was chromatographed on silica gel. Elution with 5% EtOAc/
hexane yielded the title compound 2 as white crystals: 13.30 g
3-C
2.26 × 10-4 -0.0148 to +0.0481
-0.178
-0.303
-0.232
-0.282
3′-C 2.89 × 10-4 -0.0021 to +0.0345
hand, soft acids are defined as those possessing the
reverse properties.5 Therefore, to investigate the proper-
ties of 3- and 3′-carbon atoms, the possible reacting
centers, we calculated the maximum LUMO densities,
electrostatic potentials and net charges of 3- and 3′-
carbon atoms in 2.6 The results are summarized in Table
1.
(76.0% yield); mp 107.8 °C; IR (CHCl3) 1680 cm-1 1H NMR
;
The maximum value of the electrostatic potential
around 3-carbon atom is greater than that around
3′-carbon atom, and the net charges of 3-carbon atom
obtained from both Mulliken and CHELPG methods are
relatively more positive than those on 3′-carbon atom.
On the other hand, the maximum density of LUMO
(φLUMO2) around 3′-carbon atom is greater than that
around 3-carbon atom. These results indicate that 3-car-
bon atom on the pyridyl pyridone 2 is a harder acid, and
3′-carbon atom on the pyridylpyridone 2 is a softer acid.
Thus a fluoride anion (a hard nucleophile) reacted at
3-carbon atom (a harder electrophile) on the pyridylpy-
ridone 2 to give the pyridyl pyridone 3 and a cyanide
anion (a soft nucleophile) reacted at 3′-carbon atom (a
softer electrophile) on the pyridylpyridone 2 to give the
pyridyl pyridone 4. All pyridylpyridones 2-4 show sig-
nificant insecticidal activity, and the results will be
published in future.
(CDCl3, 300 MHz) δ 7.72 (bs, 1H), 7.77 (bs, 1H), 8.20 (bs, 1H),
8.80 (bs, 1H); 19F NMR (CDCl3, 282 MHz) δ -63.3 (s, CF3), -62.8
(s, CF3). Anal. Calcd for C12H4Cl2N2O: C, 38.22; H, 1.07; N, 7.43.
Found: C, 38.33; H, 1.16; N, 7.46.
[1(2H)-3-F lu or o-5-(tr iflu or om eth yl)-3′-ch lor o-5′-(tr iflu o-
r om eth yl)-2′-bip yr id in ]-2-on e (3). A solution of 2 (0.963 g,
2.55 mmol) and spray-dried KF (0.155 g, 2.67 mmol) in dimethyl
sulfoxide (10 mL) was stirred at 120-125 °C for 5 h. The reaction
was cooled to room temperature. The reaction mixture was
poured into water (50 mL) and then extracted with ethyl acetate.
The organic extracts were combined, washed with water and
saturated aqueous sodium chloride solution, dried over MgSO4,
and filtered, and the solvent was evaporated, yielding a residue
(0.879 g) that was chromatographed on silica gel. Elution with
5% EtOAc/hexane yielded crude compound 3 (0.403 g). Recrys-
tallization from hexane furnished the title compound 3 as a
white crystals: 0.368 g (40.0% yield); mp 110.2 °C; 1H NMR
(CDCl3, 300 MHz) δ 8.77 (d, J ) 35.5 Hz, 1H), 7.94-7.53 (m,
3H); 19F NMR (CDCl3, 282 MHz) δ -62.2 (s, CF3), -63.5 (s, CF3),
-115.9 (s, 1F) Anal. Calcd for C12H4ClFN2O: C, 39.97; H, 1.12;
N, 7.77. Found: C, 39.65; H, 1.22; N, 7.84.
[1(2H)-3-Ch lor o-5-(tr iflu or om eth yl)-3′-cya n o-5′-(tr iflu o-
r om eth yl)-2′-bip yr id in ]-2-on e (4). A solution of 2 (0.954 g,
2.53 mmol) and potassium cyanide (0.173 g, 2.66 mmol) in
dimethyl sulfoxide (10 mL) was stirred at room temperature for
12 h. The reaction mixture was poured into water (50 mL) and
then extracted with ethyl acetate. The organic extracts were
combined, washed with water and saturated aqueous sodium
chloride, dried over MgSO4, and filtered, and the solvent was
evaporated, yielding a residue that was chromatographed on
silica gel. Elution with 5% EtOAc/hexane yielded the title
compound 4 as a white crystals: 0.659 g (71.0% yield); mp 144.2
°C; 1H NMR (CDCl3, 300 MHz) δ 8.00 (bs, 1H), 8.08 (bs, 1H),
8.22 (bs, 1H), 8.81 (bs, 1H); 19F NMR (CDCl3, 282 MHz) δ -63.1
(s, CF3), -62.9 (s, CF3). Anal. Calcd for C13H4ClN3O: C, 42.45;
H, 1.09; N, 11.43. Found: C, 42.64; H, 0.96; N, 11.24.
Exp er im en ta l Section
Gen er a l. Unless otherwise noted, reagents and solvents were
used as received from commercial suppliers. TLC was performed
on Kiesegel 60 F254 plates (Merck) using reagent grade solvents.
Chromatography was performed using Kieselgel 60 (70-230
(6) Ab initio molecular orbital calculations were performed with the
GAUSSIAN94 program.7 Geometries were fully optimized at the HF/
6-31G* level. The electrostatic potential and the density of LUMO
(ØLUMO2) were obtained at 167 points around the 3-carbon and 204
points around the 3′-carbon in compound 2. These points were on the
2 Å radius spheres the centers of which were the 3-carbon and
3′-carbon, respectively. There were 1632 points primarily located on
each sphere uniformly, and the points more than 2 Å apart from any
other nuclei were selected as the surface points of each atom. The net
charges of the atoms were calculated by using the method of Mulliken
and the CHELPG method of Breneman and Wiberg.8
(7) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheese-man, J . R.; Keith, T. A.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Oritiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzales, C.; Pople, J . A. GAUSSI-
AN94 (Revision A.1); Gaussian, Inc.: Pittsburgh, PA, 1995.
Su p p or tin g In for m a tion Ava ila ble: Copies of ORTEP
diagrams and X-ray crystallographic data for compound 3 and
4. This material is available free of charge via the Internet at
http://pubs.acs.org.
J O991294D
(8) (a) Mulliken, R. S. J . Chem. Phys. 1955, 23, 1833. (b) Breneman,
C. M.; Wiberg, K. B. J . Comput. Chem. 1990, 11, 361.