Reaction of 2-polyfluoroalkylchromones with 1,3,3-trimethyl-3,4-dihydroisoquinolines and methylketimines as a direct route to zwitterionic axially chiral 6,7-dihydrobenzo[a]quinolizinium derivatives and 2,6-diaryl-4-polyfluoroalkylpyridines

Article abstract of DOI:10.1021/ol0351448

(Matrix presented) 2-Polyfluoroalkylchromones react with 1,3,3-trimethyl-3,4-dihydroisoquinolines to give zwitterionic axially chiral 6,7-dihydrobenzo[a]quinolizinium derivatives in high yields. In addition, performing this reaction with aromatic methylke

Full text of DOI:10.1021/ol0351448

ORGANIC
LETTERS
2003
Vol. 5, No. 17
3123-3126
Reaction of 2-Polyfluoroalkylchromones
with 1,3,3-Trimethyl-3,4-dihydroiso-
quinolines and Methylketimines as a
Direct Route to Zwitterionic Axially
Chiral 6,7-Dihydrobenzo[a]quinolizinium
Derivatives and 2,6-Diaryl-4-polyfluoro-
alkylpyridines
,†
Vyacheslav Ya. Sosnovskikh,* Boris I. Usachev,† Aleksei Yu. Sizov,†
Ivan I. Vorontsov,‡ and Yurii V. Shklyaev§
Department of Chemistry, Ural State UniVersity, 620083 Ekaterinburg, Russia,
A. N. NesmeyanoV Institute of Organoelement Compounds, Russian Academy of
Sciences, 119991 Moscow, Russia, and Institute of Technical Chemistry,
Ural Branch of the Russian Academy of Sciences, 614600 Perm, Russia
VyacheslaV.sosnoVskikh@usu.ru
Received June 20, 2003
ABSTRACT
2-Polyfluoroalkylchromones react with 1,3,3-trimethyl-3,4-dihydroisoquinolines to give zwitterionic axially chiral 6,7-dihydrobenzo[a]quinolizinium
derivatives in high yields. In addition, performing this reaction with aromatic methylketimines is a simple and convenient synthesis of 2,6-
diaryl-4-polyfluoroalkylpyridines.
Much attention has recently been given to the development
of new methods for synthesis of RF-containing heterocycles,
because they find wide use in various areas of industry,
medicine, and agriculture due to their unique physicochem-
ical and biological properties.1,2 In addition, the introduction
of the RF group substantially affects the electron density
distribution in organic molecules, and as a result some
partially fluorinated substances have become valuable syn-
thons for the construction of novel fluorine-containing
heterocyclic compounds.3
In continuation of our studies on the chemical properties
of 2-polyfluoroalkylchromones,4 which turned out to be
(1) (a) Organofluorine Compounds in Medicinal Chemistry and Biomedi-
cal Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. M., Eds.;
Elsevier: Amsterdam, 1993. (b) Welch, J. T.; Eswarakrishnan, S. Fluorine
in Bioorganic Chemistry; Wiley: New York, 1991.
† Ural State University.
‡ Russian Academy of Sciences.
(2) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555.
(b) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
§ Ural Branch of the Russian Academy of Sciences.
10.1021/ol0351448 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/30/2003

Scheme 1
highly reactive substrates in the reactions with N-,5a,b S-,5c,d
We have found that 6-nitro-2-polyfluoroalkylchromones
1 react with isoquinolines 2 in a THF solution for 4 days at
∼20 °C and afford colored (from orange to dark red)
crystalline products in high yields. On the basis of the data
and C-nucleophiles,5e we investigated the reaction of these
compounds with 1,3,3-trimethyl-3,4-dihydroisoquinolines
capable of reacting with electrophilic substrates as C-nucleo-
philes6a,b or 1,3-C,N-dinucleophiles6b-d due to the enamine
tautomeric form.
1
of elemental analysis and IR and H NMR spectroscopies,
we ascribed the zwitterionic structure 3 to these compounds
(Scheme 1).7 The structure was confirmed by the X-ray
diffraction study of crystals 3d.8
According to the X-ray diffraction data, molecule 3d, in
its crystalline form, is a zwitterion with intramolecular charge
separation (Figure 1). Due to steric interactions between the
(3) (a) Ogoshi, H.; Mizushima, H.; Toi, H.; Aoyama, Y. J. Org. Chem.
1986, 51, 2366. (b) Nenaidenko, V. G.; Sanin, A. V.; Balenkova, E. S.
Russ. Chem. ReV. 1999, 68, 437. (c) Sosnovskikh, V. Ya. Uspekhi Khimii
2003, 72, 550.
(4) Whalley,W. B. J. Chem. Soc. 1951, 3235.
(5) (a) Sosnovskikh, V. Ya.; Usachev, B. I. IzV. Acad. Nauk, Ser. Khim.
2001, 1357 (Russ. Chem. Bull. 2001, 50, 1426). (b) Sosnovskikh, V. Ya.;
Vorontsov, I. I.; Kutsenko, V. A. IzV. Acad. Nauk, Ser. Khim. 2001, 1360
(Russ. Chem. Bull. 2001, 50, 1430). (c) Sosnovskikh, V. Ya.; Usachev, B.
I.; Sevenard, D. V.; Ro¨schenthaler, G.-V. Tetrahedron 2003, 59, 2625. (d)
Sosnovskikh, V. Ya.; Usachev, B. I.; Vorontsov, I. I. Tetrahedron 2003,
59, 2549. (e) Sosnovskikh, V. Ya.; Sevenard, D. V.; Usachev, B. I.;
Ro¨schenthaler, G.-V. Tetrahedron Lett. 2003, 44, 2097.
(6) (a) Shklyaev, Yu. V.; Maslivets, A. N. Zh. Organ. Khim. 1996, 32,
319 (Russ. J. Org. Chem. 1996, 32, 302). (b) Sviridov, V. D.; Chkanikov,
N. D.; Galakhov, M. V.; Shklyaev, Yu. V.; Shklyaev, V. S.; Aleksandrov,
B. B.; Gavrilov, M. S. IzV. Acad. Nauk SSSR, Ser. Khim. 1990, 1405 (Bull.
Acad. Sci. USSR. DiV. Chem. Sci. 1990, 39, 1268). (c) Tyutin, V. Yu.;
Chkanikov, N. D.; Shklyaev, Yu. V.; Shklyaev, V. S.; Kolomiets, A. F.;
Fokin, A. V. IzV. Acad. Nauk, Ser. Khim. 1992, 1888 (Bull. Russ. Acad.
Sci. DiV. Chem. Sci. 1992, 41, 1474). (d) Sviridov, V. D.; Chkanikov, N.
D.; Shklyaev, Yu. V.; Kolomiets, A. F.; Fokin, A. V. Khim. Geterotsikl.
Soedin. 1990, 1689 (Chem. Heterocycl. Compd. 1990, 26, 1405).
(7) Preparation of Compounds 3a-i: General Procedure. A mixture
of chromone 1 (1.9 mmol) and dihydroisoquinoline 2 (2.5 mmol) in THF
(3 mL) was allowed to stand at ∼20 °C for 4 days. The resulting orange or
dark red crystalline product was isolated by filtration, washed with THF,
and dried. Compound 3a: yield 82%, mp 223-225 °C (dec.); 1H NMR
(400 MHz, CDCl3) δ 1.67 (s, 3H, Me), 1.85 (s, 3H, Me), 2.97 (d, 1H,
CHH, J ) 16.4 Hz), 3.44 (d, 1H, CHH, J ) 16.4 Hz), 6.63 (d, 1H, H6′, oJ
) 9.6 Hz), 7.40 (d, 1H, H,8 oJ ) 7.4 Hz), 7.63 (t, 1H, H9 or H,10 oJ ) 7.5
Hz), 7.69 (td, 1H, H10 or H,9 oJ ) 7.5 Hz, mJ ) 1.1 Hz), 7.86 (d, 1H, H,11
oJ ) 7.6 Hz), 7.93 (d, 1H, H3′, mJ ) 3.0 Hz), 8.03 (d, 1H, H1 or H3, mJ )
Figure 1. Molecular structure of 3d (solvate with THF and H2O
molecules).
H(18) atom of the nitrophenoxide ring and the hydrogen
atoms of the C(8)H3 methyl group, the nitrophenoxide ring
is not conjugated with the central heterocycle. The planes
of these cycles are turned relative to each other by 67.8(5)°,
and the C(2)-C(17) bond length of 1.488(6) Å corresponds
to the normal nonconjugated Csp2-Car bond (1.488 Å),9
o
2.2 Hz), 8.11 (d, 1H, H3 or H1, mJ ) 2.2 Hz), 8.14 (dd, 1H, H5′, J ) 9.6
Hz, mJ ) 3.0 Hz); IR (Nujol) 1650, 1595, 1570, 1520 cm-1. Anal. Calcd
for C22H17F3N2O3: C, 63.77; H, 4.14; N, 6.76. Found: C, 63.78; H, 4.10;
N, 6.73.
3124
Org. Lett., Vol. 5, No. 17, 2003

indicating that the electron density is not delocalized along
the bond between the cycles considered. A comparison of
the geometric parameters of the p-nitrophenoxide fragment
in structure 3d with the published data on seven p-
nitrophenoxide-containing organic salts found by us in CCDC
(Table 1, see Supporting Information) shows that their
geometries are comparable, but the resonance p-quinoid
structure 3′ contributes more significantly to the zwitterionic
nature of molecule 3d. Thus, compounds 3 might exist as
atropisomers due to restricted rotation about the C(2)-C(17)
bond. Note that atropisomeric compounds are of considerable
interest due to their presence in a number of biologically
active natural products and their utility as directing groups
in asymmetric synthesis.10
formation of the zwitterionic intermediate, bearing an iso-
propyl group at the nitrogen atom, followed by elimination
of propylene. Demethylation of 5 to 2,6-bis(2-hydroxyphe-
nyl)-4-(trifluoromethyl)pyridine (6) can be achieved by
heating with 48% hydrobromic acid at 200 °C in a sealed
tube for 10 h (yield 85%)11 (Scheme 2). Although much
Scheme 2
The chirality and the zwitterionic structure proposed for
compounds 3a-i agree well with the 1H NMR spectroscopic
data. The protons of the CH2 group are diastereotopic and
appear as doublets at δ 2.85-2.97 and 3.33-3.44 ppm with
2JAX ) 16.4-16.5 Hz. In the phenoxide fragment of
zwitterions 3, the H(6′) proton is shielded by ∼0.5 ppm, and
the ortho and meta constants were increased by 0.4-0.5 Hz
compared to those in phenols 4; in the pyridinium ring the
attention has been paid to the chemistry of the CF3-containing
pyridine derivatives,12 these compounds were not described
in the literature and were unavailable by the known 2,6-
diarylpyridines syntheses.12d-f At the same time, pyridines
5 and 6 due to the ortho-OH group are of great interest as
analytical reagents13 and organic electroluminescence sub-
stances.14
The present method could be applicable to the 6-substituted
(MeO, NO2) 2-RF-chromones and N-(1-arylethylidene)-2-
propanamines to afford the corresponding analogues of
pyridine 5 in good to moderate yields. Notably, the nitro
group that appears to be so important in the reaction of 1
m
H(1) and H(3) protons appear as doublets with J ) 1.8-
2.2 Hz, whereas in the pyridine ring they appear as singlets.
Most likely, the reaction includes the nucleophilic attack
of the enamine tautomer of dihydroisoquinoline 2 to C(2)
atom of 2-RF-chromone 1 followed by the pyrone cycle
opening and intramolecular cyclization at the keto group
(Scheme 1). Note that the reaction is typical only for 6-nitro-
2-polyfluoroalkylchromones and does not occur when the
RF group is replaced by the methyl or trichloromethyl group.
It is likely that a balance occurs between steric and electronic
effects.
On heating compound 3a to melting or on refluxing 3a in
butanol for 4 h, N-C(6) bond cleavage occurs to a afford a
mixture of isomeric 2,6-diarylpyridines shown as 4a and 4a′
(yield 80%). Steric hindrance in 3a may provide a driving
force for cleavage of the N-C(6) bond. This result clearly
shows that the present methodology could be applicable to
2-polyfluoroalkylchromones and aromatic N-substituted me-
thylketimines, providing the corresponding 2,6-diaryl-4-
polyfluoroalkylpyridines.
(11) 2-(2-Hydroxyphenyl)-6-(2-methoxyphenyl)-4-(trifluoromethyl)-
pyridine (5): yield 41%, yellow needles, mp 130-132 °C; 1H NMR (400
o
MHz, CDCl3) δ 3.93 (s, 3H, MeO), 6.96 (ddd, 1H, H5′, J ) 8.1, 7.2 Hz,
mJ ) 1.2 Hz), 7.04 (dd, 1H, H3′, oJ ) 8.3 Hz, mJ ) 1.2 Hz), 7.07 (dd, 1H,
o
o
H3′′, J ) 8.3 Hz, mJ ) 1.0 Hz), 7.12 (ddd, 1H, H5′′, J ) 7.5, 7.6 Hz, mJ
) 1.0 Hz), 7.36 (ddd, 1H, H4′, J ) 8.5, 7.2 Hz, mJ ) 1.6 Hz), 7.47 (ddd,
o
1H, H4′′, J ) 8.3, 7.5 Hz, mJ ) 1.7 Hz), 7.72 (dd, 1H, H6′′, J ) 7.6 Hz,
o
o
mJ ) 1.7 Hz), 7.85 (dd, 1H, H6′, J ) 8.1 Hz, mJ ) 1.6 Hz), 7.91 (s, 1H,
o
H3 or H5), 8.00 (s, 1H, H5 or H3), 13.87 (s, 1H, OH); IR (Nujol) 2800-
3300, 1620, 1595, 1570 cm-1. Anal. Calcd for C19H14F3NO2: C, 66.09; H,
4.09; N, 4.06. Found: C, 66.15; H, 4.12; N, 3.94. 2,6-Bis(2-hydroxyphe-
nyl)-4-(trifluoromethyl)pyridine (6): yield 85%, dark yellow crystals, mp
170-171 °C (toluene-hexane); 1H NMR (400 MHz, DMSO-d6) δ 7.00
(ddd, 2H, H5′, H5′′, oJ ) 7.9, 7.2 Hz, mJ ) 1.2 Hz), 7.02 (dd, 2H, H3′, H3′′,
Indeed, using this reaction, we were able to obtain 2-(2-
hydroxyphenyl)-6-(2-methoxyphenyl)-4-(trifluoromethyl)py-
ridine (5) in 41% yield from readily available 2-trifluoro-
methylchromone4 and methylketimine, prepared from 2-meth-
oxyacetophenone with isopropylamine (boiling in butanol
for 4 h). Taking into account the results of the reaction of 1
with 2, we can propose that the first step involves the
oJ ) 8.3 Hz, mJ ) 1.2 Hz), 7.37 (ddd, 2H, H4′, H4′′, J ) 8.3, 7.2 Hz, mJ
o
) 1.6 Hz), 7.98 (dd, 2H, H6′, H6′′, oJ ) 7.9 Hz, mJ ) 1.6 Hz), 8.29 (s, 2H,
H3, H5), 11.91 (s, 2H, 2 OH); IR (Nujol) 3300, 1625, 1600, 1565 cm-1
.
Anal. Calcd for C18H12F3NO2: C, 65.26; H, 3.65; N, 4.23. Found: C, 65.14;
H, 3.70; N, 3.98.
(12) (a) Konakahara, T.; Hojahmat, M.; Tamura, S. J. Chem. Soc., Perkin
Trans. 1 1999, 2803. (b) Katsuyama, I.; Ogawa, S.; Yamaguchi, Y.;
Funabiki, K.; Matsui, M.; Muramatsu, H.; Shibata, K. Synthesis 1997, 1321.
(c) Lee, L. F.; Stikes, G. L.; Molyneaux, J. M.; Sing, Y. L.; Chupp, J. P.;
Woodard, S. S. J. Org. Chem. 1990, 55, 2872. (d) Funabiki, K.; Isomura,
A.; Yamaguchi, Y.; Hashimoto, W.; Matsunaga K.; Shibata, K.; Matsui,
M. J. Chem. Soc., Perkin Trans. 1 2001, 2578. (e) Xiong, W.-N.; Yang,
C.-G.; Jiang, B. Bioorg. Med. Chem. 2001, 9, 1773. (f) Lee, L. F. Eur. Pat.
Appl. EP 133612, 1985.
(13) Tong, H.; Zhou, G.; Wang, L.; Jing, X.; Wang, F.; Zhang, J.
Tetrahedron Lett. 2003, 44, 131.
(14) (a) Li, Y.; Liu, Y.; Bu, W.; Guo, J.; Wang, Y. Chem. Commun.
2000, 1551. (b) Yanqin, L.; Ying, W.; Yue, W. Pat. Appl. CN 1245822,
2000. (c) Ueno, K.; Suzuki, K.; Senoo, A.; Tanabe, H.; Yogi, S. Eur. Pat.
Appl. EP 1138683, 2001.
(8) Compound 3d (C22H18F2N2O3‚C4H8O‚0.5H2O; CCDC no. 213183):
triclinic, space group P-1 with a ) 10.032(3) Å, b ) 10.206(3) Å, c )
12.847(3) Å; R ) 74.002(6)°, â ) 85.066(6)°, γ ) 65.669(5)°, V ) 1151.6-
(5) Å3, Z ) 2; R1 ) 0.085 (based on F for 2190 reflections with I > 2σ(I));
wR2 ) 0.288 (based on F2 for all 4000 reflections). Full details on the
crystal structure of 3d are available in Supporting Information.
(9) International Tables for Crystallography; Wilson, A. J. C., Ed.;
Kluwer Academic Publishers: Dordrecht, 1995; Vol. C.
(10) Tulinsky, J.; Cheney, B. V.; Mizsak, S. A.; Watt, W.; Han, F.; Dolak,
L. A.; Judge, T.; Gammill, R. B. J. Org. Chem. 1999, 64, 93, and references
therein (atropisomeric compounds).
Org. Lett., Vol. 5, No. 17, 2003
3125

with 2 is not necessary for the ketimine examples. Further
studies on the regioselective synthesis of polyfluoroalkylated
2,6-disubstituted pyridines are now in progress.
03-32706) and, in part, by the U.S. Civilian Research and
Development Foundation (grant REC-005). The authors are
grateful to Dr. L. N. Bazhenova for carrying out elemental
analyses and Dr. M. I. Kodess for recording the NMR spectra
(Institute of Organic Synthesis, Ural Branch of the Russian
Academy of Sciences).
In conclusion, we have presented zwitterionic 6,7-dihy-
drobenzo[a]quinolizinium derivatives with axial chirality
because of hindered rotation about the C(2)-C(17) bond,
which are easily available from 2-polyfluoroalkylchromones
and 1,3,3-trimethyl-3,4-dihydroisoquinolines. On the other
hand, this reaction with aromatic methylketimines is a simple
and convenient synthesis of 2,6-diaryl-4-polyfluoroalkylpy-
ridines with potential use in the preparation of complexes
with various metals useful as electroluminescence materials.14
Supporting Information Available: X-ray data for
compound 3d; spectral and analytical data of compounds
1
3b-i and 4a; and H NMR spectra for compounds 3b, 3c,
3f, 5, and 6. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported
by the Russian Foundation for Basic Research (grant 02-
OL0351448
3126
Org. Lett., Vol. 5, No. 17, 2003