Synthesis of perfluoroalkyl-substituted azines via nucleophilic substitution of hydrogen with perfluoroisopropyl carbanions

Article abstract of DOI:10.1021/jo062254u

(Chemical Equation Presented) Perfluoroisopropyl carbanions generated in situ by treatment of perfluoropropene (HFP) with solid KF in the appropriate solvents add to N-alkylpyridinium, quinolinium, and other azinium salts to give reasonably stable N-alkyl

Full text of DOI:10.1021/jo062254u

Synthesis of Perfluoroalkyl-Substituted Azines via Nucleophilic
Substitution of Hydrogen with Perfluoroisopropyl Carbanions
Rafał Loska and Mieczysław Ma¸kosza*
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw 42, Poland
icho-s@icho.edu.pl
ReceiVed October 31, 2006
Perfluoroisopropyl carbanions generated in situ by treatment of perfluoropropene (HFP) with solid KF
in the appropriate solvents add to N-alkylpyridinium, quinolinium, and other azinium salts to give
reasonably stable N-alkyldihydroazines containing a perfluoroisopropyl group. In most cases, addition
proceeds in position 2 of the heterocyclic ring. Stability of these dihydroazines depends on the nature of
the N-alkyl group and other substituents present in the azine ring. The least stable of them were converted
into their stable C-trifluoroacetyl derivatives in reaction with trifluoroacetic anhydride. Treatment of
N-benzyl- or N-p-methoxybenzyl-2-perfluoroisopropyl dihydroazines with oxidizing agents such as DDQ
or cerium(IV) ammonium nitrate results in cleavage of the benzylic C-N bond followed by oxidation of
the ring, giving pyridines or quinolines with a perfluoroisopropyl group in the aromatic ring. On the
basis of these findings, a new protocol for introduction of perfluoroalkyl substituents into azine rings
was elaborated via oxidative nucleophilic substitution of hydrogen. It involves three chemical steps: (i)
alkylation of azine with p-MeOC6H4CH2Br, (ii) reaction of the resulting salt with fluorinated carbanions
generated in situ from HFP and KF, and (iii) N-deprotection and aromatization of the isolated dihydroazine
on treatment with CAN. The first two reactions, (i) and (ii), can be performed as a one-pot operation.
Introduction
presence of palladium catalysts.4,5 Procedures that allow direct
introduction of a perfluoroalkyl group into aromatic rings but
are applicable mainly on a laboratory scale include (i) nucleo-
philic oxidative substitution of hydrogen in nitroarenes by a
trifluoromethyl carbanion (from the Ruppert reagent, CF3SiMe3
Perfluoroalkyl-substituted heterocyclic compounds are of
prominent importance among currently used pharmaceuticals,
agrochemical agents, and liquid crystalline compounds.1-3 They
owe their unique properties to the special character of perfluo-
roalkyl groupsslow polarizability, high lipophilicity and elec-
tronegativity, and significant metabolic stability. For many years,
the most widely used methods of introduction of perfluoroalkyl
substituents into aromatic systems were transformations of CCl3
and CO2H groups into CF3 upon treatment with fluorinated
Lewis acids (SbF3, SbF5, etc.sthe Swarts process) or SF44 and
reactions of aryl halides (primarily iodides) with perfluoroalkyl-
copper reagents or with perfluoroalkylzinc reagents in the
-
and (Me2N)3S+Me2SiF3 , TASF) with dimethyldioxirane (DMD)
as an oxidant, affording trifluoromethylated phenols6 (this
procedure was recently developed in our laboratory); (ii) a
reaction of electron-rich arenes with perfluoroalkylphenyliodo-
nium7 or trifluoromethyldibenzothiophenium and similar re-
agents;8 and (iii) addition of n-perfluoroalkyllithiums to BF3-
complexed azaarenes, leading to 1,2-dihydro-2-n-perfluoro-
alkylquinolines and diazines (but to pyridines only in very low
(4) (a) Dmowski, W. In Houben-Weyl Methods in Organic Chemistry;
Baasner, B., Hagemann, H., Tatlow, J. C., Eds.; Georg Thieme Verlag:
Stuttgart, Germany, 1999; Vol. E10a, pp 321-405. (b) McClinton, M. A.;
McClinton, D. A. Tetrahedron 1992, 48, 6555.
(5) (a) McLoughlin, V. C. R.; Thrower, J. Tetrahedron 1969, 25, 5921.
(b) Kondratenko, N. V.; Vechirko, E. P.; Yagupolskii, L. M. Synthesis 1980,
932. (b) Matsui, K.; Tobita, E.; Ando, M.; Kondo, K. Chem. Lett. 1981,
1719. (c) Duan, J.-X.; Su, D.-B.; Wu, J.-P.; Chem, Q.-Y. J. Fluorine Chem.
1994, 66, 167. (d) Cottet, F.; Schlosser, M. Eur. J. Org. Chem. 2002, 327.
(6) Surowiec, M.; Ma¸kosza, M. Tetrahedron 2004, 60, 5019.
* To whom correspondence should be addressed. Fax: +48 226326681.
(1) (a) Chambers, R. D. Fluorine in Organic Chemistry; Blackwell
Publishing: Oxford, U.K., 2004. (b) Kirsch, P. Modern Fluoroorganic
Chemistry; Wiley-VCH: Weinheim, Germany, 2004. (c) Hiyama, T.; Kanie,
K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M.; Organofluorine Com-
pounds: Chemistry and Applications; Springer-Verlag: Berlin-Heidelberg,
Germany, 2000.
(2) Langlois, B. R.; Billard, T. Synthesis 2003, 185.
(3) Lin, P.; Jiang, J. Tetrahedron 2000, 56, 3635.
10.1021/jo062254u CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/23/2007
1354
J. Org. Chem. 2007, 72, 1354-1365

Synthesis of Perfluoroalkyl-Substituted Azines
SCHEME 1. Oxidative Nucleophilic Substitution of
Hydrogen in Nitroarenes by Trifluoromethyl Carbanions
yields), followed by a spontaneous air oxidation to the corre-
sponding perfluoroalkyl-containing heteroaromatic derivatives.9
Attempts to replace halogens or a nitro group in halodinitroben-
zenes or halocyanonitrobenzenes with CF3-, generated from the
Ruppert reagent without a metal catalyst, gave mixtures of the
expected trifluoromethylnitroarenes in low yields.10 Oxidative
nucleophilic replacement of hydrogen in trinitrobenzene by a
trifluoromethyl carbanion was also reported.11
The limitations of most of the methods mentioned above are
either the harsh conditions needed to effect the desired
transformations or the application of expensive, high molecular
weight or not environmentally benign reagents. For these
reasons, alternative ways to synthesize perfluoroalkylated
aromatic compounds should be of significant interest. We thus
turned our attention to the process of generation of perfluoro-
carbanions from simpler perfluoroolefins and potassium fluoride
and their possible use for direct nucleophilic perfluoroalkylation
of aromatic compounds. We envisioned that these carbanions
could react with electrophilic arenes to provide products of the
aromatic nucleophilic substitution of hydrogen (vicarious or
oxidative)12 in a manner analogous to trifluoromethylation of
nitroarenes by a CF3SiMe3/TASF system (Scheme 1).6
Polyfluorinated alkenes readily add fluoride anions and other
nucleophiles leading to the formation of perfluorocarbanions.1,13
Synthetic application of these intermediates is partially impeded
by the competing fluoride-catalyzed oligomerization of the
starting fluoroalkenes; however, there are reports on their
successful reactions with electrophiles such as alkyl14 and acyl15
halides, chloromethyl ethers,16 carbon dioxide,17 HgCl2,18 etc.
Their potential use in nucleophilic perfluoroalkylation of
heteroaromatic compounds was explored only in a very specific
case of perfluorinated aromatics (mainly pyridines) by Chambers
and co-workers.19 These highly electrophilic arenes are very
prone to undergo a nucleophilic aromatic displacement of
fluorine. They were reported to react with tetrafluoroethylene,
hexafluoropropene, and, to some extent, with CF2dCFX (X )
H, Cl, Br) in the presence of KF or CsF at high temperatures
or tetrakis(dimethylamino)ethylene (TDAE) at room temperature
in solvents like sulfolane or tetraglyme to provide mixtures of
mono- and polysubstituted products. However, this approach
suffers from low selectivity and narrow applicability; all
positions of the aromatic ring of the product are occupied by
either a fluorine atom or a fluoroalkyl group.
Herein, we report results of our investigation of the reactions
of perfluoroisopropyl carbanions generated from hexafluoro-
propene (HFP, a fluoroolefin manufactured at an industrial scale)
and solid potassium fluoride with electrophilic arenes. In
preliminary experiments, we have found that nitroarenes, even
those as active as 1,3-dinitrobenzene, do not react with the
(CF3)2CF- carbanion; no products were formed with HFP and
KF(s) in various solvents, at various temperatures, and in the
presence of crown ethers or tetraalkylammonium salts. Presum-
ably, due to a strong stabilization of these carbanions by two
CF3 substituents, they are not sufficiently nucleophilic to add
to nitroarenes and form σ-adducts.
(7) (a) Umemoto, T. DE Patent 3021226, 1980; Chem. Abstr. 1981, 94,
208509. (b) Umemoto, T.; Kuriu, Y.; Shuyama, H. Chem. Lett. 1981, 1663.
(c) Umemoto, T.; Kuriu, Y.; Shuyama, H.; Miyano, O.; Nakayama, S.-I. J.
Fluorine Chem. 1982, 20, 695. (d) Umemoto, T.; Kuriu, Y.; Shuyama, H.;
Miyano, O.; Nakayama, S.-I. J. Fluorine Chem. 1986, 31, 37. (e)
Yagupolskii, L. M.; Maletina, I. I.; Kondratenko, N. V.; Orda, V. V.
Synthesis 1978, 835. (f) Yagupolskii, L. M.; Mironova, A. A.; Maletina, I.
I.; Orda, V. V. Zh. Org. Khim. 1980, 16, 232. (g) Yagupolskii, L. M. J.
Fluorine Chem. 1987, 36, 1. (h) Mironova, A. A.; Orda, V. V.; Maletina,
I. I.; Yagupolskii, L. M. J. Org. Chem. USSR 1989, 25, 597. (i) Eisenberger,
P.; Gischig, S.; Togni, A. Chem.sEur. J. 2006, 12, 2579/
(8) (a) Yagupolskii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. J.
Org. Chem. USSR 1984, 20, 103. (b) Umemoto, T.; Ishihara, S.; Adachi,
K. Tetrahedron Lett. 1990, 31, 3579. (c) Umemoto, T.; Ishihara, S. J. Am.
Chem. Soc. 1993, 115, 2156. (d) Umemoto, T.; Ishihara, S.; Adachi, K. J.
Fluorine Chem. 1995, 74, 77. (e) Umemoto, T.; Ishihara, S. J. Fluorine
Chem. 1998, 92, 181. (f) Yang, J.-J.; Kirchmeier, R. L.; Shreeve, J. M. J.
Org. Chem. 1998, 63, 2656. (g) Magnier, E.; Blazejewski, J.-C.; Tordeux,
M.; Wakselman, C. Angew. Chem., Int. Ed. 2006, 45, 1279, 1301.
(9) (a) Uno, H.; Okada, S.; Shiraishi, Y.; Shimokawa, K.; Suzuki, H.
Chem. Lett. 1988, 1165. (b) Uno, H.; Okada, S.; Suzuki, H. Tetrahedron
1991, 47, 6231. (c) Uno, H.; Suzuki, H. Synlett 1993, 91.
Introduction of substituents into azine rings via N-acylation
followed by addition of nucleophiles to such activated N-
acylazinium rings is a methodology widely used in organic
synthesis. There are several reports on addition of nucleophiles
to N-acylpyridinium salts and subsequent oxidation of the
resulting 1-acyl-1,2- and 1-acyl-1,4-dihydropyridines with dichlo-
rodicyanobenzoquinone (DDQ) to obtain readily hydrolyzable,
ring-substituted N-acylated salts.20,21 Aromatization of such
1-acyldihydropyridines was also effected using chloranil,22
sulfur,23 atmospheric oxygen,24 triphenylcarbenium tetrafluoro-
(10) (a) Adams, D. J.; Clark, J. H.; Hansen, L. B.; Sanders, V. C.; Stewart,
J. T. J. Chem. Soc., Perkin Trans. 1 1998, 3081. (b) Adams, D. J.; Clark,
J. H.; Heath, P. A.; Hansen, L. B.; Sanders, V. C.; Tavener, S. J. J. Fluorine
Chem. 2000, 101, 187.
(11) Stahly, G. P. J. Fluorine Chem. 1989, 45, 431.
(12) (a) Terrier, F. Chem. ReV. 1982, 82, 78. (b) Terrier, F. Nucleophilic
Aromatic Displacement; Chemie: Weinheim, Germany, 1991. (c) Chupa-
khin, O. N.; Charushin, V. N.; van der Plas, H. C. Nucleophilic Aromatic
Substitution of Hydrogen; Academic Press: San Diego, CA, 1994. (d)
Makosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20, 282. (e) Makosza,
M. Russ. Chem. Bull. 1996, 45, 491. (f) Makosza, M.; Wojciechowski, K.
Liebigs Ann./Recl. 1997, 1805. (g) Makosza, M.; Wojciechowski, K. Chem.
ReV. 2004, 104, 2631.
(13) (a) Brunskill, W.; Flowers, W. T.; Gregory, R.; Haszeldine, R. N.
J. Chem. Soc., Chem. Commun. 1970, 1444. (b) Dixon, D. A.; Fukunaga,
T.; Smart, B. E. J. Am. Chem. Soc. 1986, 108, 4027. (c) Smart, B. E.;
Middleton, W. J.; Farnham, W. B. J. Am. Chem. Soc. 1986, 108, 4905. (d)
Farnham, W. B.; Dixon, D. A.; Calabrese, J. C. J. Am. Chem. Soc. 1988,
110, 2607. (e) Bayliff, A. E.; Chambers, R. D. J. Chem. Soc., Perkin Trans.
1 1988, 201. (f) For a review, see: Farnham, W. B. Chem. ReV. 1996, 96,
1633.
(14) Dmowski, W.; Wozniacki, R. J. Fluorine Chem. 1987, 36, 385.
(15) (a) Smith, R. D.; Fawcett, F. S.; Coffman, D. D. J. Am. Chem. Soc.
1962, 84, 4285. (b) Ishikawa, N.; Shin-ya, S. Bull. Chem. Soc. Jpn. 1975,
48, 1339. (c) Ishikawa, N.; Iwamoto, K.; Ishiwata, T.; Kitazume, T. Bull.
Chem. Soc. Jpn. 1982, 55, 2956.
(16) Ikeda, I.; Watanabe, H.; Hirao, T.; Kurosawa, H. J. Fluorine Chem.
1994, 69, 97.
(17) Graham, D. P.; McCormack, W. B. J. Org. Chem. 1966, 31, 958.
(18) Dyatkin, B. L.; Sterlin, S. R.; Martynov, B. I.; Mysov, E. I.;
Knunyants, I. L. Tetrahedron 1971, 27, 2843.
(19) Chambers, R. D.; Gray, W. K.; Korn, S. R. Tetrahedron 1995, 51,
13167 and references therein.
J. Org. Chem, Vol. 72, No. 4, 2007 1355

Loska and Ma¸kosza
SCHEME 2. Oxidative Nucleophilic Substitution of Hydrogen in N-Alkylazinium Salts by Perfluoroisopropyl Carbanions
borate,22d or anodic oxidation.25 However, perfluorocarbanions
have never been used in these reactions as nucleophiles. Our
attempts of reactions of a perfluoroisopropyl carbanion generated
from KF(s) and HFP with N-acylpyridinium salts were unsuc-
cessful; only acyl fluorides, perfluoroisopropyl ketones, and
unreacted pyridines were recovered from such experiments.
Apparently, F- and (CF3)2CF- anions reacted preferentially with
the activated carbonyl group of the N-acylazinium salts rather
than with the heterocyclic ring.
SCHEME 3. Addition of C3F7- Carbanions to a Simple
N-Alkylpyridinium Salt 1a and Stabilization of the Product
by Acylation with TFAAa
On the other hand, preliminary experiments indicated that
N-alkylazinium salts 1, which are much more stable entities,
undergo addition of such carbanions when exposed to HFP and
KF(s) and afford the respective dihydro adducts 2 and 3 (Scheme
2). Furthermore, we have found that the 1,2-dihydroazine
derivatives 2 yield the perfluoroisopropyl-substituted azaarenes
5 when treated with appropriate oxidants, thus completing a
process of formal oxidative aromatic substitution of hydrogen
by a perfluorinated carbanion. Herein, we provide an account
of the scope and limitations of this novel and potentially useful
synthesis of perfluoroalkylated heterocycles. The intermediate
dihydroazines20 are interesting by themselves since they can be
potentially transformed into a multitude of other fluoroalkylated
heterocyclic systems, for example, via reduction, cycloaddition,
reactions with electrophiles, etc.20a,26
a Conditions: (i) 5.0 equiv of KF(s), ca. 4 equiv of HFP, rt, CH2Cl2, 24
h; (ii) TFAA, i-Pr2NEt, 0 °C, 30 min.
Results and Discussion
Initial Studies. Reactions of N-Benzyl and N-Benzhydryl
Salts. Reaction of N-benzylpyridinium chloride with perfluor-
oisopropyl carbanions generated from hexafluoropropene and
solid potassium fluoride gave the expected adduct in low yield
(<5%). Although the addition proceeded, the product was very
unstable and decomposed rapidly during the reaction.
(20) Revievs on the chemistry of dihydropyridines: (a) Lavilla, R. J.
Chem. Soc., Perkin Trans. 1 2002, 1141. (b) Eisner, U.; Kuthan, J. Chem.
ReV. 1972, 72, 1. (c) Kuthan, J.; Kurfu¨rst, A. Ind. Eng. Chem. Prod. Res.
DeV. 1982, 21, 191. (d) Stout, D. M.; Meyers, A. I. Chem. ReV. 1982, 82,
223. (e) Comins, D. L.; O’Connor, S. AdV. Heterocycl. Chem. 1988, 44,
199. (f) Sausin¸sˇ, A.; Duburs, G. Heterocycles 1988, 27, 291.
In our previous studies on reactions of trichloromethyl
carbanions generated at the interface between chloroform and
aqueous NaOH, we observed that adducts of these carbanions
to N-benzylpyridinium chloride decomposed rapidly, whereas
the adducts to N-benzhydrylpyridinium chloride 1a were more
stable and could be isolated in high yields.27 Indeed, treatment
of 1a with an excess of HFP and KF(s) in CH2Cl2 in a closed
pressure tube at room temperature for 24 h (Scheme 3) provided
the expected adducts 2a and 3a. The 1,4-dihydropyridine isomer
3a was the major product, and only traces of 1,2-dihydropyridine
isomer 2a were detected by the 1H NMR analysis of the crude
reaction mixture. Compound 3a could be isolated in 58% yield,
but it decomposed rapidly during chromatographic purification
on silica gel and was rather unstable on standing at room
temperature (dark-red products of decomposition appeared after
less than 24 h). 1,2-Dihydropyridine 2a was also unstable and
was not isolated in pure form.
(21) (a) Gundersen, L.-L.; Rise, F.; Undheim, K. Tetrahedron 1992, 48,
5647. (b) Lavilla, R.; Gotsens, T.; Guerrero, M.; Bosch, J. Synthesis 1995,
382. (c) Lavilla, R.; Gotsens, T.; Guerrero, M.; Masdeu, C.; Santano, M.
C.; Minguillo´n, C.; Bosch, J. Tetrahedron 1997, 53, 13959. (d) Wallace,
D. J.; Gibb, A. D.; Cottrell, I. F.; Kennedy, D. J.; Brands, K. M. J.; Dolling,
U. H. Synthesis 2001, 1784. (e) Bergman, J.; Goonewardena, H. Acta Chem.
Scand., Ser. B 1980, 34, 763. (f) For oxidation of a 1-alkyl-2-fluoro-1,4-
dihydropyridine and its hydrolisis to a 2-pyridone, see: Bennasar, M.-L.;
Juan, C.; Bosch, J. Chem. Commun. 2000, 2459.
(22) (a) Weller, D. D.; Stirchak, E. P.; Weller, D. L. J. Org. Chem. 1983,
48, 4597. (b) Comins, D. L. Tetrahedron Lett. 1983, 24, 2807. (c) Comins,
D. L.; Stroud, E. D.; Herrick, J. J. Hetrocycles 1984, 22, 151. (d) Ho¨sl, C.
E.; Wanner, K. T. Heterocycles 1998, 48, 2653.
(23) (a) Comins, D. L.; Stroud, E. D. Hetrocycles 1986, 24, 3199. (b)
Comins, D. L.; Smith, R. K.; Stroud, E. D. Hetrocycles 1984, 22, 339. (c)
Shing, T.-L.; Chia, W.-L.; Shiao, M.-J.; Chau, T.-Y. Synthesis 1991, 849.
(d) Krapcho, A. P.; Waterhouse, D. J.; Hammach, A.; Di Domenico, R.;
Menta, E.; Oliva, A.; Spinelli S. Synth. Commun. 1997, 27, 781. (e) Comins,
D. L.; King, L. S.; Smith, E. D.; Fe´vrier, F. C. Org. Lett. 2005, 5059.
(24) (a) Akiba, K.; Iseki, Y.; Wada, M. Tetrahedron Lett. 1982, 23, 429.
(b) Shiao, M.-J.; Tarng, K.-Y. Heterocycles 1990, 31, 637. (c) Chia, W.-
L.; Shiao, M.-J. Tetrahedron Lett. 1991, 32, 2033. (d) Mangeney, P.;
Gosmini, R.; Raussou, S.; Commerc¸on, M. Tetrahedron Lett. 1993, 34, 6399.
(e) Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang, M. Org. Lett. 2001, 2807.
(f) Corey, E. J.; Tian, Y. Org. Lett. 2005, 7, 5535.
(26) Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1681 and references therein.
(25) Comins, D. L.; Killpack, M. O. Hetrocycles 1990, 31, 2025.
(27) Makosza, M.; Kryłowa, I. Tetrahedron 1999, 55, 6395.
1356 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Perfluoroalkyl-Substituted Azines
SCHEME 4. Reaction of 3-Methylpyridinium Salt 1b with
HFP and KF(s) under Various Conditionsa
SCHEME 5. Reactions of N-Benzhydryl- and
N-Benzylazinium Salts with Perfluoroisopropyl Carbanionsa
a Conditions: (i) 5.0 equiv of KF(s), ca. 4 equiv of HFP, rt; (ii) TFAA,
i-Pr2NEt, 0 °C, 30 min.
These results clearly demonstrate that perfluoroisopropyl
carbanions generated via addition of fluoride anions to HFP
under relatively mild conditions add efficiently to pyridinium
cations, providing the respective adducts in a synthetically useful
yield; however, the problem of stability of the products still
remained to be solved. Since it is known that dihydropyridines
containing electron-withdrawing substituents in position 3 are
reasonably stable compounds,20 we acylated crude 3a with
trifluoroacetic anhydride (TFAA) directly after the reaction with
HFP and KF (performed in CH2Cl2 for 4.5 h) to obtain
compound 4a with an overall yield of 49% (Scheme 3).28 Indeed,
the presence of the strongly electron-withdrawing trifluorom-
ethylcarbonyl group made this product sufficiently stable to
obtain an analytical sample. The yield of the two-step procedure
(reaction with KF(s) and HFP and then with TFAA) is lower
than the yield of the initial dihydropyridine, presumably because
of partial decomposition upon treatment with the acylating agent.
In an attempt to improve the yield of the process, we increased
the time of the reaction of 1a with HFP and KF(s), but it turned
out to be slightly detrimental for the yield, presumably due to
decomposition of dihydropyridine 3a (45% of 4a after 24 h of
reaction with HFP and KF and subsequent acylation). We also
tried to use DMF instead of CH2Cl2, as it is a much better
solvent for pyridinium salts, and it can also partially dissolve
solid KF. Indeed, the reaction in DMF was significantly faster
(46% of 4a after 1.5 h and acylation); however, under these
conditions, decomposition of 3a is also faster (only 35% of 4a
obtained after 24 h of reaction with HFP and KF(s)).
We then turned our attention to the reactions of N-benzyl-
3-methylpyridinium bromide 1b, as we expected that the adducts
to this salt might be more stable, owing to the ring substituent.
Unfortunately, reaction in DMF resulted in complete decom-
position and formation of unidentified tarry material, whereas
reaction in CH2Cl2 afforded only 23% of compound 3b as one
regioisomer (Scheme 4). Product 3b, once isolated by flash
column chromatography, was significantly more stable at room
temperature than 2a or 3a. This prompted us to perform the
reaction of the salt 1b with HFP and KF(s) over a longer time.
Indeed, after 13 h at room temperature, 3b was isolated in a
54% yield. An even better result was obtained with 1,2-
dimethoxyethane (DME) as the solvent; 90% of 3b was obtained
a Conditions: (i) HFP, KF(s), CH2Cl2, rt, 24 h; (ii) HFP, KF(s), DMF,
rt, 2 h.
after 13 h. In each case, the reaction proceeded with complete
regioselectivity. Similar to the case of 1,4-dihydropyridine
adduct 3a, compound 3b could be acylated in situ with TFAA,
giving completely stable 4b in a 23 or 31% yield in two steps,
depending on the solvent.
Encouraged by the results obtained with 1a and 1b, we
performed similar reactions with N-benzyl and benzhydryl salts
1c-f, obtaining the respective C3F7-substituted dihydroazines
in high yields as mixtures of readily separable 1,2- and 1,4-
dihydro isomers 2 and 3 (with the 1,2-dihydro isomers favored
in most cases, Scheme 5). The solvent of choice for these
reactions was DMF rather than CH2Cl2; the reactions were much
faster because of better solubility of salts 1, and the addition
products obtained from 1c-f did not decompose, in contrast to
2a, 3a, and 3b. The products of the addition at the position
adjacent to the nitrogen atom of quinoline, isoquinoline, and
pyridines containing an EWG substituent (CO2Me, CN) in
position 3 were stable and readily characterizable compounds;
their stability is also increased by the bulky and electron-
withdrawing perfluoroisopropyl substituent. The 1,4-dihydro
isomers 3 decomposed very slowly upon standing at ambient
temperature and could also be readily isolated and characterized.
1
In addition to standard H, 13C, and 19F NMR 1D spectra,
the structures of the products 2, 3, and 4 (described previously
and in the next sections) were confirmed using COSY, DEPT,
1
HMBC, and HSQC NMR experiments. A simple H NMR
spectrum does not allow one to distinguish between the isomeric
products obtained in the reactions of quinolinium and 3-sub-
stituted pyridinium salts. The signals of the proton R of the
perfluoroisopropyl group and of one of the vinyl protons have
structures of apparent triplets or poorly resolved doublets of
doublets and have very similar chemical shifts in the spectra of
both 1,2- and 1,4-dihydro isomers. On the other hand, it is
possible to assign the 13C NMR signals of the benzylic and of
the ring sp3 carbon atoms (the former with the help of a DEPT
(28) Acylation of dihydropyridines with trifluoroacetic or trichloroacetic
anhydride: (a) Bennasar, M.-L.; Vidal, B.; Bosch, J. J. Org. Chem. 1995,
60, 4280. (b) Bennasar, M.-L.; Roca, T.; Monerris, M.; Juan, C.; Bosch, J.
Tetrahedron 2002, 58, 8099. (c) Bennasar, M.-L.; Vidal, B.; Bosch, J. J.
Org. Chem. 1997, 62, 3597.
J. Org. Chem, Vol. 72, No. 4, 2007 1357

Loska and Ma¸kosza
SCHEME 6. Oxidative Deprotection/Aromatization of
N-Benzyl-1,2-dihydroazines in the Presence of DDQa
spectrum) and then to determine, unambiguously, the connectiv-
ity of the whole molecule based on the 2D 1H-13C HSQC and
HMBC correlation spectra. An interesting feature of the 13C
NMR spectra of compounds 2, 3, and 4 is that the doublet of
the sp3 ring carbon atom (the one connected to the perfluor-
oisopropyl group) of 1,4-dihydropyridines 3 and 4 always
appears in a lower chemical shift range (33-44 ppm) than that
in the spectra of 1,2-dihydropyridines 2 (57-63 ppm). This
observation is in agreement with literature reports,21c and it
provides a simpler means of discriminating the 1,2- and 1,4-
dihydro isomers.
We have not observed any isomerization of 1,2- to 1,4-
dihydropyridines during chromatographic purification27 or after
several months of storage.
a Conditions: (i) 4.0 equiv of DDQ, CH2Cl2, 0 °C to rt, 24 h.
The success of the addition reaction of carbanions generated
from HFP and solid KF performed in a polar solvent like DMF
could be explained by the partial solubility of potassium fluoride;
fluoride anions present in a low concentration in the organic
phase can add to the fluoroalkene leading to the formation of
perfluoroisopropyl carbanions, which in turn add to the pyri-
dinium cations giving the final product. On the other hand, the
solubility of KF in apolar solvents like CH2Cl2 is negligible. A
different type of mechanism must be operating for the addition
process in such solvents. Perfluorocarbanions are formed on
the surface of solid potassium fluoride and, via interfacial ion
exchange, form ion pairs with pyridinium cations, which
subsequently collapse to the addition products in the organic
phase; thus, the pyridinium salt itself acts as a kind of a phase-
transfer catalyst in a solid-liquid system. A similar “autocata-
lytic” effect of such salts in the process of dihydropyridine
formation was studied in our laboratory for the case of the
addition of trichloromethyl carbanion to the N-benzhydryl- and
N-(2,4,6-trimethylbenzyl)pyridinium salts in a CHCl3/50%
NaOH(aq) system.27 It was also proposed by Lavilla, Bosch,
and co-workers for the reaction of N-benzylpyridine bromides
with 2-methylindole in CH2Cl2 or PhMe/50% NaOH.21c In the
case of DMF, simple solubility of KF (formation of (CF3)2CF-
in the bulk of the organic phase) and phase-transfer (PT)
catalysis may be of comparable importance. It has been reported
that the rate of alkylation of chloromethyl ethers with carbanions
generated from perfluoro-2-methyl-2-pentene and KF/DMF
increased significantly in the presence of tetrabutylammonium
chloride, but it could proceed without a PT catalyst as well.16
The addition of perfluorocarbanions to azinium salts proceeds
readily when they contain a variety of substituents, but a methyl
group in position 2 or 4 hinders the reaction. For example,
reaction of 1-benzyl-2-methylpyridinium bromide with perflu-
oroisopropyl carbanions generated under standard conditions did
not give any addition products, although the reaction mixture
rapidly turned violet and an exothermic effect was noticed.
These observations can probably be ascribed to a facile proton
abstraction from the methyl substituent by a highly basic fluoride
or perfluorocarbanion and formation of an exomethylene
pyridine derivative.29
substituted aromatic heterocycles by a process of a formal
substitution of hydrogen by a perfluorocarbanion. While the first
step of this process, that is, a nucleophilic addition to the
aromatic ring, could be performed successfully, we still sought
for a method of transforming these adducts into the aromatic
and completely stable final products. To this end, we subjected
the dihydroazine adducts 2-4 to oxidizing conditions. In
general, N-alkylated dihydroazines are known to give the
corresponding N-alkyl-substituted salts upon treatment with
oxidizing agents.20 On the other hand, oxidants like DDQ or
cerium(IV) ammonium nitrate (CAN) are widely applied for
deprotection of benzylic ethers and amines.30 We therefore
attempted a reaction of a N-benzyl compound 2c with 4 equiv
of DDQ in CH2Cl2, as depicted in Scheme 6. After 24 h, we
were pleased to observe formation of aromatized, perfluoroiso-
propyl-substituted quinoline 5c31 isolated in 42% yield. Other
widely used oxidizing reagents were not applicable for this
transformation; chloranil did not react, trichloroisocyanuric acid
(TCCA)32 gave only poor conversion, whereas KMnO4 led to
a complete decomposition of the substrate. The reaction could
also be successfully performed in the pyridine series (conversion
of 2f into 5f in 70% yield).
Unfortunately, 1,4-dihydro isomers 3 failed to undergo a
similar reaction, although they were totally consumed in the
presence of DDQ. We suppose that, in this case, the final
product is a C3F7-substituted azinium salt. However, we were
unable to separate it in a pure form from the mixture of products
of DDQ decomposition or to liberate a free azine upon treatment
with nucleophiles like triphenylphosphine or to transform this
salt into a pyridone derivative upon treatment with NaOH.
According to the literature data, 1,2-dihydropyridines undergo
oxidation much slower than their 1,4-dihydro isomers.20b,33 We
suppose that, in our case, 1,2-dihydropyridines 2 in the presence
of DDQ are first deprotected and subsequently oxidized to
pyridines, while isomers 3 are quickly oxidized to the corre-
(30) (a) Fukuyama, T.; Laird, A. A.; Hotchkiss, L. M. Tetrahedron Lett.
1985, 26, 6291. (b) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885. (c) Murakata, C.; Ogawa, T. Carbohydr. Res. 1992,
234, 75. (d) Bull, S. D.; Davies, S. G.; Fenton, G. A.; Mulvaney, W.; Prasad,
R. S.; Smith, A. D. Chem. Commun. 2000, 337. (e) Bull, S. D.; Davies, S.
G.; Kelly, P. M.; Gianotti, M.; Smith, A. D. J. Chem. Soc., Perkin Trans.
1 2001, 3106.
(31) Kobayashi, Y.; Kumadaki, I.; Hanzawa, Y.; Mimura, M. Chem.
Pharm. Bull. 1975, 23, 2044.
(32) Tilstam, U.; Weinmann, H. Org. Process Res. DeV. 2002, 6, 384.
(33) (a) Wallenfels, K.; Gellrich, M. Justus Liebigs Ann. Chem. 1959,
621, 149. (b) Eisner, U.; Sadeghi, M. M.; Hambright, W. P. Tetrahedron
Lett. 1978, 3, 303. (c) Bodor, N.; Kamin´ski, J. J. THEOCHEM 1988, 163,
315.
Oxidative Deprotection/Aromatization of 1,2-Dihydroazines.
Although the C3F7-substituted dihydroazine derivatives de-
scribed in the preceding sections were, in most cases, stable
and could be of interest by themselves, our primary goal was
to elaborate a new synthetic way toward perfluoroalkyl-
(29) For a similar deprotonation of a 2-alkylquinolinium salt under basic
conditions, see: Diaba, F.; Lewis, I.; Grignon-Dubois, M.; Navarre, S. J.
Org. Chem. 1996, 61, 4830.
1358 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Perfluoroalkyl-Substituted Azines
SCHEME 7. Reactions of N-p-Methoxybenzylazinium
A serious drawback of the DDQ oxidation of the perfluor-
oisopropyl-substituted dihydroazines is problems with separation
of the resulting perfluoroisopropyl azaarenes from the products
of DDQ reduction and decomposition. Compounds 5 are not
sufficiently basic to be extracted from the organic phase with
concentrated aqueous HCl, whereas chromatographic purifica-
tion is also ineffective. These problems are completely elimi-
nated when CAN is used as an oxidizing agent. After some
experimentation, we found that slow addition of an aqueous
solution of 2.2 equiv of CAN to a solution of 2-perfluoroiso-
propyl-1,2-dihydropyridine 2 in MeOH at room temperature
results in a clean and almost instantaneous formation of 5. For
example, CAN oxidation of dihydropyridine 2e′ gave 5e in the
isolated yield of 81%. Simple extraction of the product with
Et2O, evaporation, and chromatographic purification on silica
gel using hexanes or hexanes-Et2O as the eluent allows one to
obtain pure perfluoroisopropyl azaarenes. In some cases, chro-
matography on neutral aluminum oxide was necessary to remove
the side products of oxidation, that is, p-methoxybenzyl aldehyde
and alcohol. An additional attractive feature of CAN is its lower
price and better stability than DDQ.
Bromides with Perfluoroisopropyl Carbanionsa
a Conditions: (i) HFP, KF(s), DMF, rt, 2 h.
SCHEME 8. Oxidative Deprotection/Aromatization of
N-p-Methoxybenzyl-1,2-dihydroazines with DDQa
In the course of the experiments described so far, we
established that the optimal way of preparation of perfluoroiso-
propyl-substituted azines from the corresponding azinium salts
is to use a N-PMB salt as a substrate for the perfluoroisopropyl
carbanion addition and CAN as an oxidant in the subsequent
step of deprotection/aromatization. Along with this scheme, we
prepared a series of C3F7-containing azines, as described in the
following sections.
Reactions of N-p-Methoxybenzyl Salts with Perfluoroiso-
propyl Carbanions. Addition of perfluoroisopropyl carbanions
to the N-PMB pyridinium and quinolinium salts 1c′-1m′
proceeded with a comparable efficiency as with their N-
benzylated counterparts, as summarized in Scheme 7 and Table
1. The yields are good to very good, and regioselectivity is
usually high, in most cases in favor of 1,2-dihydroazine. Only
in the case of the 3-benzoylpyridinium salt 1g′ (entry 5) was it
impossible to separate the resulting 1,2- and 1,4-dihydropy-
ridines by column chromatography. Formation of compounds
2g′ and 3g′ in a very high combined yield is particularly notable
considering that the carbonyl group is a widely used electrophile
in reactions with fluorinated carbanions, especially for nucleo-
philic trifluoromethylation. In order to test the scalability of the
reaction of azinium salts with HFP and KF(s), we also performed
a reaction with 10.0 mmol of the salt 1e′ (instead of the usual
0.95 mmol) and obtained compounds 2e′ and 3e′ in the
a Conditions: (i) 4.0 equiv of DDQ, CH2Cl2, 0 °C to rt, 30 min; (ii) 2.2
equiv of DDQ, CH2Cl2, 0 °C to rt, 30 min.
sponding salts, which in turn cannot undergo deprotection of
the benzylic group.
Compound 4a, bearing an N-benzhydryl substituent, was inert
toward DDQ oxidation.
Oxidative cleavage of the N-C bond by DDQ is particularly
facile for a N-p-methoxybenzyl (PMB) substituent.30c In order
to elaborate a more efficient overall process of nucleophilic
substitution of hydrogen in azines by perfluorocarbanions, we
prepared compounds 2c′, 2e′, and 2f′ in a manner analogous to
that of their N-benzylated counterparts (Scheme 7). Indeed,
deprotection and aromatization of perfluoroisopropyl-substituted
N-p-methoxybenzyl-1,2-dihydroazines 2c′, 2e′, and 2f′ by DDQ
was complete in good yields within 30 min instead of 24 h as
required for 2c and 2f (Scheme 8). Similar to the case of
N-benzyl-1,4-dihydroazines, the compounds 3c′, 3e′, and 3f′
could not be transformed into the 4-perfluoroisopropylazines
upon the action of DDQ.
The facile deprotection-aromatization of 1,2-dihydroazines
2 upon the action of DDQ is somewhat unexpected in the view
of the report of Lau and co-workers,34 who failed to affect a
similar transformation with 1-p-methoxybenzyl-2-phenyl-1,2-
dihydroquinoline; they observed no reaction with DDQ even
after 24 h under forcing conditions.
1
combined yield of 92% (1:1 from H NMR).
N-PMB salts are somewhat easier to obtain, owing to a greater
reactivity of PMBBr than BnBr. In fact, we were able to perform
the salt preparation in situ by mixing the starting heterocycle
and PMBBr in DMF and, after the appropriate time at room
temperature, by reacting it with KF and HFP, thus effecting a
one-pot transformation of an azine into a perfluoroalkylated
dihydroazine (Table 1, entries 1, 3, 4, and 6-10).
Pyridines containing electron-withdrawing substituents in
position 2 (like 6 and 7) are weak nucleophiles and do not react
with PMBBr even at high temperatures. Fortunately, this
problem could be overcome by in situ alkylation in the presence
of a stoichiometric amount of silver tetrafluoroborate in MeCN
(Scheme 9). The resulting pyridinium tetrafluoroborates were
subjected to the reaction with HFP and KF(s) without isolation
and underwent addition of perfluoroisopropyl carbanions in
(34) Wiebe, J. M.; Caille´, A. S.; Trimble, L.; Lau, C. K. Tetrahedron
1996, 52, 11705.
J. Org. Chem, Vol. 72, No. 4, 2007 1359

Loska and Ma¸kosza
TABLE 1. Reactions of N-p-Methoxybenzylazinium Bromides with (CF3)2CF- Carbanionsa
1360 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Perfluoroalkyl-Substituted Azines
Table 1 (Continued)
a Conditions: 5.0 equiv of KF(s), ca. 4 equiv of HFP, DMF, rt. b Time needed for salt formation in DMF at rt, followed by TLC. c Azinium chloride was
used instead of bromide. d Reaction of this salt was performed only according to a “one-pot” procedure.
SCHEME 9. Reaction of Pyridinium Salts Formed from Weakly Nucleophilic Pyridines 6 and 7 via Alkylation Promoted by
Silver Tetrafluoroboratea
a Conditions: (i) PMBBr, AgBF4, MeCN, rt; (ii) 5.0 equiv of KF(s), HFP, MeCN, rt, 2 h.
moderate overall yields due to incomplete conversion of the
starting pyridines.
carbon nucleophiles), the addition is reversible, and the kinetic
product 1,2-dihydropyridine rearranges, at least at higher
temperatures or after a prolonged period of time, to the more
stable 1,4-dihydropyridine, which is the observed or predominant
product of the reaction. The example of a trichloromethyl
carbanion is perhaps the most relevant for the present discussion;
it undergoes a reversible addition almost exclusively to the C-2
atom of the pyridinium ring.20b,27,40 In our case, preferential
formation of 1,2-dihydroazines 2 indicates that the (CF3)2CF-
carbanion belongs to the hard nucleophiles like trifluoromethyl6
or difluoro(phenylsulfonyl)methyl carbanions.41 Despite a sig-
nificant stabilizing effect of the two CF3 groups, the process is
irreversible, as we have not observed any interconversion
between 1,2- and 1,4-dihydropyridines even after several months
of storage. Moreover, pure compound 2e′ did not isomerize to
3e′ when subjected to standard reaction conditions (KF(s), HFP,
DMF, rt).
The only examples of opposite regioselectivity are reactions
in which 1,4-dihydropyridines 3a, 3b, and 3h′ were formed.
The first of these results can be explained by steric factors; due
to bulkiness of the perfluoroisopropyl carbanion, it does not
attack the position vicinal to the large N-benzhydryl substituent.28b
The two other cases are less obvious, but they both involve
pyridinium salts with an electron-donating or weakly accepting
substituent at C-3. Formation of their respective 1,4-dihydro
Regioselectivity of Perfluorocarbanion Addition. On the
basis of the results summarized in Schemes 3, 4, 5, 7, and 9
and Table 1, it is possible to draw some conclusions on the
regioselectivity of perfluoroisopropyl carbanions addition to
azinium salts. Due to the special character of these carbanions,
it is difficult to compare the regioselectivity of the reaction with
other nucleophilic additions to N-alkylazinium salts described
in the literature. In general, soft nucleophiles like sodium or
potassium enolates, bis(O-trialkylsilyl)ketene acetals,35 highly
nucleophilic arenes,36 alkyl- and arylcopper28b,37 and organoti-
tanium21a reagents, or sulfur nucleophiles attack predominantly
at the 4 position, while hard nucleophiles like organolithium
and organomagnesium28b compounds, hydroxide, alkoxide, and
cyanide anions, ammonia, and secondary amines add preferen-
tially at the position adjacent to the nitrogen atom.20,38,39 In many
cases (most heteroatom nucleophiles and highly stabilized
(35) Rudler, H.; Denise, B.; Parlier, A.; Daran, J.-C. Chem. Commun.
2002, 940.
(36) Volochnyuk, D. M.; Kostyuk, A. N.; Pinchuk, A. M.; Tolmachev,
A. A. Tetrahedron Lett. 2003, 44, 391.
(37) (a) Bennasar, M.-L.; Juan, C.; Bosch, J. Tetrahedron Lett. 1998,
39, 9275. (b) Bennasar, M.-L.; Juan, C.; Bosch, J. Tetrahedron Lett. 2001,
42, 585.
(38) Bennasar, M.-L.; Alvarez, M.; Lavilla, R.; Zulaica, E.; Bosch, J. J.
Org. Chem. 1990, 55, 1156.
(39) Donohoe, T. J.; Johnson, D. J.; Mace, L. H.; Thomas, R. E.; Chiu,
J. Y. K.; Rodrigues, J. S.; Compton, R. G.; Banks, C. E.; Tomcik, P.;
Bamford, M. J.; Ichihara, O. Org. Biomol. Chem. 2006, 4, 1071.
(40) (a) Kro¨hnke, F.; Duchardt, K. H. Chem. Ber. 1977, 110, 2669. (b)
Grignon-Dubois, M.; Diaba, F.; Grelier-Marly, M.-C. Synthesis 1994, 800.
(41) Li, Y.; Hu, J. Angew. Chem., Int. Ed. 2005, 44, 5882.
J. Org. Chem, Vol. 72, No. 4, 2007 1361

Loska and Ma¸kosza
TABLE 2. Regioselectivity of the Reaction of 3-Methoxycarbonyl-
(1e′) and 3-Cyanopyridinium (1f′) Salts with Perfluorocarbanions in
Various Solvents
TABLE 3. Preparation of Perfluoroisopropyl-Substituted Azines
from 1,2-Dihydroazines Using CAN as the Oxidant
substrate
1e′
solvent
toluene
CH2Cl2
THF
2:3a
yield
substrate (R)
2e′ (5-CO2Me)
product, yield
5e (81%)
5f (99%)
5 g (86%)
5i (87%)
5j (99%)
1
2
3
4
5
6
7
8
9
(>20:1)b
31.4:1
20.6:1
12.6:1
11.0 1c
5.2:1
5%
1
2
3
4
5
6
7
(3-CO2Me)
10%
11%
22%
72%
34%
84%
56%
83%
2f′ (5-CN)
2g′ (5-COPh)
2i′ (4-OEt-5-NO2)
2j′ (4-CN)
DME
DME (24h)
MeCN
DMF
DME (24h)
DMF
2k′ (5-methoxy-1,2-dihydroquinoline) 5k (98%)
1.1:1c
6.9:1
2l′ (1,2-dihydrophenanthroline)
2o′ (3-CO2Me-6-CO2Me)
5l
1f′ (3-CN)
(52%; 37% recovered 2l′)
5o
2.8:1c
8
(68%; 24% recovered 2o′)
a Ratio of isomers was established using 1H and 19F NMR spectroscopy.
b No 1,4-isomer 3e′ was detected. c Ratio of isomers from chromatographic
separation.
somewhat in contradiction to the results reported by Lavilla,
Bosch, and co-workers who investigated addition reactions of
2-methylindole anions to similar salts; in toluene, they always
observed the highest preference for 1,4-dihydropyridine
formation.21c This difference may probably be ascribed to a
different nature of the nucleophiles.
Oxidative Deprotection/Aromatization of N-PMB-1,2-
Dihydroazines with CAN. This reaction was performed using
the previously described optimal conditions, and it proceeded
in high yields to give a variety of substituted azines 5 containing
a perfluoroisopropyl group in position 2 (in some cases, almost
quantitatively, Table 3). Reaction of 1,2-dihydropyridine 2n′
proceeded reluctantly and afforded a complicated mixture of
products, one of which was the expected 2-methoxycarbonyl-
6-heptafluoroisopropylpyridine (identified by 1H NMR analysis
of the mixture after workup and evaporation). Unfortunately,
on treatment with either CAN or DDQ, 1,2-dihydroisoquinoline
derivatives 2d′ or 2m′ decomposed into complex mixtures of
products instead of giving the expected 1-perfluoroisopropyl-
isoquinolines.
adducts is in agreement with a literature report about addition
of a lithium enolate of 2-acetylindole to 3-substituted N-
methylpyridinium salts with subsequent trapping of the resulting
dihydropyridines by acylation with trichloroacetic anhydride
(TCAA).28a While 3-COMe-, 3-CO2Me-, 3-CHdCHCO2Me-,
3-CN-, and 3-CONEt2-substituted salts all afforded mainly 1,2-
dihydropyridines, the only product detected after the reaction
of 3-ethylpyridinium salt and treatment with TCAA was a
trichloroacylated 1,4-dihydropyridine.
Exclusive formation of only one of the two possible regioi-
someric 1,6-dihydropyridines in the reactions of unsymmetri-
cally substituted 3-CN, 3-CO2Me, and 3-COPh pyridinium salts
is probably for steric reasons; the bulky perfluoroisopropyl group
cannot enter the most hindered position between N-benzyl and
the substituent already present in the ring.
From the preceding discussion, it follows that the regiose-
lectivity of addition of a hard (CF3)2CF- carbanion is determined
by the positive charge distribution in the azinium ring, the
highest partial charge being localized on the two carbon atoms
adjacent to nitrogen. It should then depend on the polarity of
the reaction medium. Indeed, it was clearly demonstrated for
the case of substrates 1e′ and 1f′ (Table 2). In solvents of low
polarity (toluene, CH2Cl2, or THF), highly regioselective
formation of the 1,2-isomer 2e′ was observed, but the overall
yield was very poor due to low solubility of the substrates and
a low reaction rate. From the synthetic point of view, it was
interesting to find that using 1,2-dimethoxyethane (DME), a
solvent of a slightly higher polarity and capable of dissolving
some amount of potassium fluoride, allowed us to obtain 2e′ in
a much better yield without a significant loss of regioselectivity.
Since HFP oligomerization in DME in the presence of KF is
much slower than that in DMF, it was possible to extend the
reaction time to 24 h to obtain 2-perfluoroisopropyl-1,2-
dihydropyridines 2e′ and 2f′ both selectively and in good yields.
In the case of quinoline derivatives, the influence of solvent
on regioselectivity was insignificant. For example, for the
reactions of 1l′ in toluene (24 h), DME (24 h), and DMF (3 h),
the ratio of regioisomers 2l′ and 3l′ was, respectively, 8.0:1,
4.1:1, and 6.1:1 with total yields of 10, 55, and 92%.
Summary and Conclusions
Substituted N-alkylazinium salts were shown to efficiently
add perfluoroisopropyl carbanions generated in situ from
hexafluoropropene and solid potassium fluoride, leading to
perfluoroalkyl-substituted dihydro derivatives that, in turn, are
readily oxidized to perfluoroisopropyl azaarenes. The whole
process can be viewed as an example of a nucleophilic aromatic
substitution of hydrogen. Since it utilizes readily available
substrates and proceeds under mild conditions, it may be a novel,
valuable method of direct introduction of perfluoroalkyl groups
into heterocyclic rings, either simple or already functionalized
with other substituents; other fluoroolefins may probably be
employed instead of HFP. For example, preliminary experiments
show that chlorotrifluoroethene and 2H-pentafluoropropene enter
similar reactions.
Considering the central role of dihydropyridines and dihyd-
roquinolines in the synthesis of heterocyclic compounds,20,21,26
our contribution may open new, versatile synthetic pathways,
leading to previously unknown fluorinated heterocyclic systems.
Experimental Section
The observed influence of reaction medium polarity on the
regioselectivity of nucleophilic addition to pyridinium salts is
General Procedure for Reactions of N-Alkylazinium Salts 1
with HFP and KF(s). Preparation of Dihydroazines 2 and 3.
1362 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Perfluoroalkyl-Substituted Azines
HFP (ca. 0.6 g, 4 mmol) was condensed in a glass pressure tube
(ca. 3.5 mL volume) at -75 °C under an argon atmosphere. DMF
(2.75 mL; or other solvent, see text), azinium salt (0.95 mmol),
and spray-dried KF(s) (276 mg, 4.75 mmol) were introduced, and
the pressure tube was closed with a teflon valve. The contents of
the tube were stirred vigorously at room temperature for 3 h. After
opening of the tube, the reaction mixture was poured into water
(10 mL), and the products were extracted with CH2Cl2 (3 × 5 mL).
Combined organic layers were washed with water (5 × 10 mL),
dried over anhydrous Na2SO4, and concentrated. The products were
purified by column chromatography on silica gel using 10:1 or 5:1
mixtures of hexanes/AcOEt as the eluent (when two isomeric
products were formed, mixtures of hexanes and Et2O of similar
composition were sometimes more effective to separate them, see
below).
Preparation of Trifluoroacetylated 1,4-Dihydropyridines 4a
and 4b. These reactions were performed as described in the
previous paragraph, but after the reaction with HFP and KF (after
the time specified in the text), the contents of the pressure tube
was cooled to 0 °C, and i-Pr2NEt (129 mg, 174 µL, 1.00 mmol)
was added. Trifluoroacetic anhydride (210 mg, 139 µL, 1.00 mmol)
was then added dropwise with vigorous stirring, and the reaction
mixture was allowed to warm to room temperature over about 30
min. Isolation and purification of products was then performed,
analogous to the general procedure described above.
13C NMR (100 MHz) δ 20.5, 37.6 (d, 2JCF ) 21.6 Hz), 59.0, 91.7
1 2 3
(dm, JCF ) 206.9 Hz, JCF ) 31.0 Hz), 96.6 (d, JCF ) 7.7 Hz),
3
1
111.8 (d, JCF ) 5.2 Hz), 117.2 (q, JCF ) 291.4 Hz), 120.7 (qd,
1JCF ) 290.5 Hz, JCF ) 28.5 Hz), 120.8 (qd, JCF ) 287.9 Hz,
2
1
2JCF ) 28.5 Hz), 127.7, 127.8, 128.9, 129.3, 134.1, 145.8 (q, JCF
4
) 5.1 Hz), 177.1 (q, JCF ) 33.6 Hz); 19F NMR (376 MHz) δ
2
-181.77 (1F, m, CF(CF3)2), -74.96 (3F, m, CF(CF3)2), -74.84
(3F, m, CF(CF3)2), -69.4 (3F, s, COCF3); MS (EI 70 eV, m/z, %)
449 (M+, <1), 380 (4), 280 (100); HRMS (EI) calcd for C18H13-
NOF10 (M+), 449.0838; found, 449.0832. Anal. Calcd for C18H13-
NOF10: C, 48.12; H, 2.92; N, 3.12; F, 42.28. Found: C, 48.17; H,
2.98; N, 3.01; F, 41.52.
1-Benzyl-2-heptafluoroisopropyl-1,2-dihydroquinoline (2c).
Pale yellow oil: IR (film, νmax/cm-1) 3066, 3033, 2884, 1650, 1601,
1495, 1453, 1295, 1254, 1224, 1155, 1109, 974, 944, 791, 748,
1
2
707, 525; H NMR (400 MHz) δ 4.46 (1H, d, JHH ) 16.3 Hz,
NCH2), 4.98 (1H, d, 2JHH ) 16.2 Hz, NCH2), 5.09 (1H, ddm, 3JHF
) 10.8 Hz, 3JHH ) 6.0 Hz, CHCF), 5.57 (1H, ddm, 3JHH ) 9.6, 6.0
Hz, CHCHCF), 6.67 (1H, d, 3JHH ) 9.2 Hz, CHdHCHCF), 6.65-
3
4
6.73 (2H, m, Harom), 6.99 (1H, dd, JHH ) 7.4 Hz, JHH ) 1.6 Hz,
3
4
H
arom), 7.06 (1H, ddd, JHH ) 9.0, 7.5 Hz, JHH ) 1.6 Hz, Harom),
7.18-7.24 (3H, m, Harom), 7.25-7.30 (2H, m, Harom); 13C NMR
4
2
(100 MHz) δ 55.9 (d, JCF ) 4.3 Hz), 60.1 (d, JCF ) 19.8 Hz),
92.1 (dm, 1JCF ) 207.8 Hz, 2JCF ) 30.2 Hz), 114.2 (d, JCF ) 6.9
3
1
2
Hz), 114.4, 118.5, 120.7 (qd, JCF ) 287.5 Hz, JCF ) 28.0 Hz),
120.8 (qd, 1JCF ) 287.5 Hz, 2JCF ) 27.2 Hz), 122.1, 127.2, 127.4,
127.4, 128.7, 129.6, 130.9, 137.0, 142.8; 19F NMR (376 MHz) δ
1-Benzhydryl-4-heptafluoroisopropyl-1,4-dihydropyridine (3a).
Yellow oil, becomes dark red after a few hours at rt: 1H NMR
3
3
-179.49 (1F, m, CF(CF3)2), -74.15 (3F, m, JFF ) 7.9 Hz, CF-
(200 MHz) δ 4.22-4.38 (1H, m, CHCF), 4.45 (2H, dd, JHH
)
(CF3)2), -72.84 (3F, m, 3JFF ) 8.6 Hz, CF(CF3)2); MS (EI 70 eV,
m/z, %) 389 (M+, 2), 220 (100), 91 (41); HRMS (EI) calcd for
C19H14NF7 (M+), 389.1014; found, 389.1007. Anal. Calcd for
C19H14NF7: C, 58.62; H, 3.62; N, 3.60; F, 34.16. Found: C, 58.29;
H, 3.77; N, 3.53; F, 34.14.
7.9, 3.6 Hz, NCHdCH), 6.12 (2H, d, 3JHH ) 8.2 Hz, NCHdCH),
7.19-7.30 (4H, m, Harom), 7.30-7.50 (6H, m, Harom); 13C NMR
2
(50 MHz) δ 37.5 (d, JCF ) 22.0 Hz), 69.3, ok. 89 (m), 91.9 (d,
3JCF ) 7.7 Hz), 121.2 (qd, 1JCF ) 288.6 Hz, 2JCF ) 27.5 Hz), 127.8,
128.4, 128.6, 133.0, 139.6.
1-Benzyl-4-heptafluoroisopropyl-1,4-dihydroquinoline (3c).
1-Benzhydryl-4-heptafluoroisopropyl-3-trifluoroacetyl-1,4-di-
hydropyridine (4a). Pale yellow solid: mp 87-88 °C; IR (film,
Yellow oil, decomposes after a few days at rt: IR (film, νmax/cm-1
)
ν
max/cm-1) 3093, 3068, 3035, 2923, 1667, 1573, 1497, 1454, 1430,
3038, 2922, 1672, 1601, 1492, 1220, 974, 756, 740, 716, 706; MS
(EI 70 eV, m/z, %) 389 (M+, 2), 220 (43), 91 (100); HRMS (EI)
calcd for C19H14NF7 (M+), 389.1014; found, 389.1026. Anal. Calcd
for C19H14NF7: C, 58.62; H, 3.62; N, 3.60; F, 34.16. Found: C,
58.84; H, 3.69; N, 3.53; F, 34.02.
1386, 1291, 1261, 1218, 1129, 993, 975, 924, 876, 789, 750, 724,
1
3
700, 672, 607; H NMR (400 MHz) δ 4.82 (1H, t, J ) 5.5 Hz,
3
CHCF), 5.06 (1H, t, JHH ) 6.9 Hz, NCHdCH), 5.94 (1H, s,
NCHPh2), 6.31 (1H, d, 3JHH ) 7.8 Hz, NCHdCH), 7.13-7.19 (4H,
m, Ph), 7.36-7.45 (6H, m, Ph), 7.46 (1H, s, NCHdCCOCF3); 13
C
2-Benzhydryl-1-heptafluoroisopropyl-1,2-dihydroisoquino-
line (2d). White solid: mp 99-100 °C; IR (KBr, νmax/cm-1) 3069,
3036, 1624, 1492, 1284, 1234, 1107, 982, 771, 732, 697; 1H NMR
NMR (100 MHz) δ 33.5 (d, 2JCF ) 21.5 Hz), 71.2, 90.5 (m), 98.0,
1
1
101.5, 117.0 (q, JCF ) 291.4 Hz), 121.0 (dm, JCF ) 288.0 Hz),
128.2, 128.4, 128.9, 128.9, 129.2, 129.3, 131.6, 136.8, 137.0, 146.6
(d, 4JCF ) 5.1 Hz), 177.5 (q, 2JCF ) 33.7 Hz); 19F NMR (376 MHz)
δ -183.27 (1F, m, CF(CF3)2), -75.62 (3F, m, 3JFF ) 8.3 Hz, CF-
3
(400 MHz) δ 5.57 (1H, d, JHH ) 7.4 Hz, NCHdCH), 5.61 (1H,
d, 3JHF ) 7.0 Hz, CHCF), 5.81 (1H, s, CHPh2), 5.99 (1H, dd, 3JHH
) 7.4 Hz, 4JHH ) 1.2 Hz, NCHdCH), 6.87 (1H, d, 3JHH ) 7.7 Hz,
3
(CF3)2), -73.24 (3F, m, JFF ) 7.6 Hz, CF(CF3)2), -69.7 (3F, s,
H
arom), 6.98-7.11 (4H, m, Harom), 7.15-7.25 (6H, m, Harom), 7.26-
COCF3); MS (EI 70 eV, m/z, %) 511 (M+, <1), 342 (10), 167
(100), 165 (17), 152 (9); HRMS (EI) calcd for C23H15NOF10 (M+),
511.0994; found, 511.0996. Anal. Calcd for C23H15NOF10: C,
54.02; H, 2.96; N, 2.74; F, 37.15. Found: C, 54.05; H, 2.84; N,
2.73; F, 36.51.
2
7.36 (3H, m, Harom); 13C NMR (100 MHz) δ 62.6 (d, JCF ) 20.7
4
1
2
Hz), 71.7 (d, JCF ) 2.6 Hz), 90.7 (dm, JCF ) 204.3 Hz, JCF
)
30.2 Hz), 102.3, 118.7 (d, 3JCF ) 4.3 Hz), 120.5 (qd, 1JCF ) 288.0
Hz, 2JCF ) 27.6 Hz), 123.4, 125.4, 127.4, 127.8, 128.1, 128.6, 128.6,
129.0, 130.1, 131.7, 134.3, 138.4, 140.6; 19F NMR δ (ppm) -179.31
3
1-Benzyl-4-heptafluoroisopropyl-3-methyl-1,4-dihydropyri-
(1F, m, CF(CF3)2), -71.72 (3F, m, JFF ) 8.2 Hz, CF(CF3)2),
dine (3b). Yellow oil, becomes dark red after a few days at rt: 1H
-71.57 (3F, m, 3JFF ) 8.2 Hz, CF(CF3)2); MS (EI 70 eV, m/z, %)
465 (M+, 2), 296 (43), 167 (100), 152 (12); HRMS (EI) calcd for
C25H18NF7 (M+), 465.1328; found, 465.1338. Anal. Calcd for
C25H18NF7: C, 64.52; H, 3.90; N, 3.01; F, 28.57. Found: C, 64.57;
H, 3.66; N, 2.80; F, 28.60.
4
NMR (200 MHz) δ 1.73 (3H, dd, JHH ) 3.0, 1.4 Hz, Me), 4.02
(1H, m, CHCF), 4.29 (2H, s, NCH2), 4.33 (1H, m, NCHdCH),
5.97 (1H, t, 4JHH ) 1.2 Hz, NCHdCMe), 6.13 (1H, dt, 3JHH ) 7.8
4
Hz, JHH ) 2.0 Hz, NCHdCH), 7.10-7.26 (2H, m, Ph), 7.26-
4
7.48 (3H, m, Ph); 13C NMR (50 MHz) δ 21.0 (d, JCF ) 5.5 Hz),
1-Benzyl-2-heptafluoroisopropyl-5-methoxycarbonyl-1,2-di-
hydropyridine (2e). Separated from 3e by chromatography using
10:1 hexanes/Et2O as the eluent; pale yellow solid: mp 60-61 °C;
IR (KBr, νmax/cm-1) 2953, 1702, 1646, 1578, 1442, 1387, 1320,
1288, 1257, 1219, 1185, 1157, 1112, 991, 955, 745, 705; 1H NMR
(400 MHz) δ 3.73 (3H, s, OCH3), 4.50 (1H, AB, 2JHH ) 15.6 Hz,
NCH2), 4.93 (1H, m, CHCHCF), 5.06 (1H, m, CHCF), 6.73 (1H,
dm, 3JHH ) 9.9 Hz, CHdCHCHCF), 7.21-7.26 (2H, m, Ph), 7.32-
2
3
42.5 (d, JCF ) 20.9 Hz), 57.1, 89.5 (d, JCF ) 9.5 Hz), 101.5,
127.2, 127.6, 128.7, 130.3, 134.0, 137.9.
1-Benzyl-4-heptafluoroisopropyl-3-methyl-5-trifluoroacetyl-
1,4-dihydropyridine (4b). Colorless oil, solidified after several
months at -15 °C: mp 39-40 °C; IR (film, νmax/cm-1) 3071, 3036,
2930, 1667, 1575, 1439, 1299, 1225, 1195, 1146, 1004, 735, 718,
676; 1H NMR (400 MHz) δ 1.84 (3H, s, Me), 4.62 (2H, AB, 2JHH
) 15.0 Hz, NCH2), 4.69 (1H, d, 3JHF ) 3.5 Hz, CHCF), 6.14 (1H,
4
7.42 (3H, m, Ph), 7.47 (1H, d, JHH ) 0.9 Hz, NCHdCCO2Me);
4
2
d, JHH ) 0.9 Hz, NCHdCMe), 7.19-7.25 (2H, m, Ph), 7.36-
13C NMR (100 MHz) δ 51.1, 58.7 (d, JCF ) 18.9 Hz), 60.5 (d,
4
7.45 (3H, m, Ph), 7.60 (1H, d, JHH ) 1.1 Hz, NCHdCCOCF3);
4JCF ) 6.0 Hz), 91.7 (dm,1 JCF ) 208.6 Hz, 2JCF ) 29.4 Hz), 101.5,
J. Org. Chem, Vol. 72, No. 4, 2007 1363

Loska and Ma¸kosza
103.7 (dd, 3JCF ) 7.7 Hz, 4JCF ) 1.7 Hz), 120.4 (qd, 1JCF ) 287.1
Hz, 2JCF ) 25.9 Hz), 120.6 (qd, 1JCF ) 287.1 Hz, 2JCF ) 27.6 Hz),
127.3, 127.4, 128.5, 129.2, 135.1, 146.8, 166.1; 19F NMR (376
MHz) δ -177.59 (1F, m, CF(CF3)2), -73.76 (3F, m, CF(CF3)2),
-72.63 (3F, m, CF(CF3)2); MS (EI 70 eV, m/z, %) 397 (M+, <1),
366 (5), 228 (41), 91 (100); HRMS (ESI, MeOH) calcd for C17H14-
NO2F7Na (M + Na+), 420.0805; found, 420.0822. Anal. Calcd for
C17H14NO2F7: C, 51.39; H, 3.55; N, 3.53; F, 33.47. Found: C,
51.23; H, 3.56; N, 3.62; F, 33.28.
Oxidation of 2-Heptafluoroisopropyl-1,2-dihydroazines 2 with
CAN. Dihydroazine 2 (0.40 mmol) was dissolved in MeOH (2.0
mL), and a solution of CAN (439 mg, 0.80 mmol) in water (0.5
mL) was added dropwise at rt with vigorous stirring. The reaction
mixture was then diluted with H2O (10 mL), and the product was
extracted with Et2O (3 × 10 mL). Combined organic layers were
washed with H2O (ca. 20 mL), dried (Na2SO4), and evaporated.
The product was purified by column chromatography or distillation
as specified below.
1-Benzyl-4-heptafluoroisopropyl-3-methoxycarbonyl-1,4-di-
hydropyridine (3e). Separated from 2e by chromatography using
2-Heptafluoroisopropylquinoline (5c).31 Purified by column
chromatography on silica gel using hexanes as the eluent; colorless
oil: IR (film, νmax/cm-1) 3070, 2924, 1597, 1505, 1296, 1280, 1233,
1219, 1167, 1137, 1114, 981, 935, 828, 754; 1H NMR (400 MHz)
10:1 hexanes/Et2O as the eluent; pale yellow oil: IR (film, νmax
/
cm-1) 3069, 3034, 2953, 1704, 1593, 1416, 1304, 1255, 1218, 1172,
1
3
4
1088, 977, 721; H NMR (400 MHz) δ 3.73 (3H, s, OCH3), 4.48
δ 7.66 (1H, ddd, JHH ) 8.2, 7.0 Hz, JHH ) 1.2 Hz, Harom), 7.75
(1H, dd, 3JHH ) 8.7 Hz, 4JHH ) 2.9 Hz, Harom), 7.81 (1H, ddd, 3JHH
) 8.4, 6.9 Hz, 4JHH ) 1.5 Hz, Harom), 7.89 (1H, dd, 3JHH ) 8.1 Hz,
3
(2H, s, NCH2), 4.71 (1H, tm, J ) 5.3 Hz, CHCF), 4.79 (1H, m,
3
NCHdCH), 6.16 (1H, d, JHH ) 7.8 Hz, NCHdCH), 7.18-7.22
4
3
(2H, m, Ph), 7.30-7.41 (3H, m, Ph), 7.47 (1H, d, JHH ) 1.1 Hz,
4JHH ) 1.4 Hz, Harom), 8.19 (1H, dm, JHH ) 8.5 Hz, Harom), 8.34
2
3
4
NCHdCCO2Me); 13C NMR (100 MHz) δ 35.2 (d, JCF ) 21.6
(1H, dd, JHH ) 8.8 Hz, JHH ) 0.7 Hz, Harom); 13C NMR (100
Hz), 51.3, 58.0, 91.2 (dm, 1JCF ) 207.8 Hz, 2JCF ) 28.4 Hz), 93.7
MHz) δ 91.1 (dm, 1JCF ) 202.6 Hz, 2JCF ) 31.9 Hz), 117.7 (d, 3JCF
3
3
1
1
2
(d, JCF ) 5.2 Hz), 97.7 (d, JCF ) 6.0 Hz), 120.9 (qd, JCF
)
)
) 8.6 Hz), 120.3 (qd, JCF ) 287.9 Hz, JCF ) 27.6 Hz), 127.6,
128.1, 128.4, 130.2, 130.6, 137.6 (d, 4JCF ) 2.6 Hz), 147.1 (d, 4JCF
2
1
2
288.8 Hz, JCF ) 28.4 Hz), 121.3 (qd, JCF ) 288.0 Hz, JCF
27.6 Hz), 127.3, 128.3, 129.0, 132.4, 135.9, 143.1, 168.2; 19F NMR
) 2.6 Hz), 147.2 (d, JCF ) 25.9 Hz); 19F NMR (376 MHz) δ
2
3
(376 MHz) δ -183.99 (1F, m, J ) 7.3 Hz, CF(CF3)2), -75.66
-182.54 (1F, sept. of d, 3JFF ) 6.7 Hz, 4JFH ) 2.7 Hz, CF(CF3)2),
-74.74 (6F, d, 3JFF ) 6.7 Hz, CF(CF3)2); MS (EI 70 eV, m/z, %)
297 (M+, 100), 278 (16), 228 (60), 178 (39), 128 (43); HRMS
(EI) calcd for C12H6NF7 (M+), 297.0388; found, 297.0382.
2-Heptafluoroisopropyl-5-methoxycarbonylpyridine (5e). Pu-
rified by chromatography on silica gel using hexanes and then 10:1
hexanes/AcOEt; colorless liquid: IR (film, νmax/cm-1) 3009, 2961,
2854, 1739, 1599, 1440, 1313, 1294, 1279, 1235, 1216, 1169, 1125,
3
3
(3F, m, JFF ) 7.3 Hz, CF(CF3)2), -73.14 (3F, m, JFF ) 8.1 Hz,
CF(CF3)2); MS (EI 70 eV, m/z, %) 366 (4), 228 (42), 91 (100);
HRMS (ESI, MeOH) calcd for C17H15NO2F7 (M + H+), 398.0986;
found, 398.0986. Anal. Calcd for C17H14NO2F7: C, 51.39; H, 3.55;
N, 3.53; F, 33.47. Found: C, 51.20; H, 3.49; N, 3.63; F, 33.41.
1-Benzyl-3-cyano-6-heptafluoroisopropyl-1,6-dihydropyri-
dine (2f). Pale yellow oil: IR (film, νmax/cm-1) 3066, 3033, 2210,
1
1
1646, 1577, 1385, 1292, 1258, 1226, 1111, 958, 750; H NMR
1027, 984, 966, 739, 711; H NMR (400 MHz) δ 4.00 (3H, s,
3
4
5
(400 MHz) δ 4.50 (2H, s, NCH2), 4.98 (1H, m, CHCHCF), 5.08
(1H, m, CHCF), 6.24 (1H, d, 3JHH ) 9.6 Hz, CHdCHCHCF), 6.98
(1H, m, NCHdCCN), 7.20-7.25 (2H, m, Ph), 7.35-7.44 (3H, m,
OCH3), 7.82 (1H, ddd, JHH ) 8.2 Hz, JHF ) 2.8 Hz, JHH ) 0.7
Hz, CHCdN), 8.50 (1H, dd, 3JHH ) 8.2 Hz, 4JHH ) 2.0 Hz, CHd
CHCdN), 9.31 (1H, dm, 4JHH ) 2.0 Hz, CHdCCO2Me); 13C NMR
2
1
2
Ph); 13C NMR (100 MHz) δ 58.2 (d, JCF ) 19.8 Hz), 60.7 (d,
(100 MHz) δ 52.8, 90.9 (dm, JCF ) 203.5 Hz, JCF ) 32.8 Hz),
4JCF ) 6.0 Hz), 82.3, 91.5 (dm, 1JCF ) 208.6 Hz, 2JCF ) 29.3 Hz),
120.0 (qd, 1JCF ) 287.1 Hz, 2JCF ) 26.7 Hz), 121.6 (d, 3JCF ) 9.5
3
1
2
4
4
105.4 (d, JCF) 6.0 Hz), 119.1, 120.2 (qd, JCF ) 287.9 Hz, JCF
Hz), 127.7, 138.5 (d, JCF ) 2.6 Hz), 150.5 (d, JCF ) 2.6 Hz),
1
2
) 25.0 Hz), 120.5 (qd, JCF ) 287.1 Hz, JCF ) 27.6 Hz), 126.6,
127.7, 128.9, 129.4, 134.3, 147.8; 19F NMR (376 MHz) δ -178.24
(1F, m, CF(CF3)2), -73.91 (3F, m, CF(CF3)2), -72.80 (3F, m, CF-
(CF3)2); MS (EI 70 eV, m/z, %) 364 (M+, <1), 195 (24), 91 (100);
HRMS (EI) calcd for C16H11N2F7 (M+), 364.0810; found, 364.0820.
Anal. Calcd for C16H11N2F7: C, 52.76; H, 3.04; N, 7.69; F, 36.51.
Found: C, 52.76; H, 3.00; N, 7.60; F, 35.82.
151.0 (d, 2JCF ) 25.9 Hz), 164.6; 19F NMR (376 MHz) δ -182.87
3
4
(1F, sept. of d, JFF ) 6.8 Hz, JFH ) 2.7 Hz, CF(CF3)2), -74.94
(6F, d, 3JFF ) 6.8 Hz, CF(CF3)2); MS (EI 70 eV, m/z, %) 305 (M+,
46), 286 (19), 274 (100), 246 (62); HRMS (EI) calcd for C10H6-
NO2F7 (M+), 305.0287; found, 305.0281. Anal. Calcd for C10H6-
NO2F7: C, 39.36; H, 1.98; N, 4.59; F, 43.58. Found: C, 39.62; H,
1.84; N, 4.63; F, 43.63.
1-Benzyl-3-cyano-4-heptafluoroisopropyl-1,4-dihydropyri-
3-Cyano-6-heptafluoroisopropylpyridine (5f). Purified by chro-
matography on neutral aluminum oxide using pentane as the eluent
and by subsequent distillation under reduced pressure (bp 77 °C at
22 mmHg); colorless liquid: IR (film, νmax/cm-1) 3077, 2929, 2241,
1595, 1567, 1478, 1319, 1295, 1273, 1237, 1219, 1196, 1171, 1121,
dine (3f). Yellow solid: mp 49-50 °C; IR (CH2Cl2, νmax/cm-1
)
3068, 3036, 2935, 2205, 1679, 1594, 1418, 1295, 1257, 1223, 1122,
978, 748, 728; 1H NMR (400 MHz) δ 4.31 (1H, tm, 3J ) 6.4 Hz,
4JHF ) 0.8 Hz, CHCF), 4.42 (2H, s, NCH2), 4.72 (1H, m, NCHd
CH), 6.12 (1H, d, 3JHH ) 8.1 Hz, NCHdCH), 6.89 (1H, d, 4JHH
)
986, 967, 849, 751, 713; H NMR (400 MHz) δ 7.88 (1H, ddd,
1
1.5 Hz, NCHdCCN), 7.16-7.20 (2H, m, Ph), 7.33-7.45 (3H, m,
3JHH ) 8.2 Hz, 4JHF ) 2.4 Hz, 5JHH ) 0.8 Hz, CHCdN), 8.20 (1H,
dd, 3JHH ) 8.4 Hz, 4JHH ) 2.1 Hz, CHdCHCdN), 9.00 (1H, dm,
4JHH ) 2.0 Hz, CHdCCN); 13C NMR (100 MHz) δ ca. 92 (m),
2
Ph); 13C NMR (100 MHz) δ 37.5 (d, JCF ) 21.6 Hz), 58.0, 74.7
3
1
2
(d, JCF ) 6.2 Hz), 91.2 (dm, JCF ) 206.9 Hz, JCF ) 28.4 Hz),
96.5 (d, 3JCF ) 6.9 Hz), 119.9, 120.7 (qd, 1JCF ) 287.9 Hz, 2JCF
)
112.2, 115.3, 119.8 (qd, JCF ) 286.2 Hz, JCF ) 28.5 Hz), 122.0
3 4 2
1
2
27.6 Hz), 120.7 (qd, 1JCF ) 287.9 Hz, 2JCF ) 28.4 Hz), 127.4, 128.6,
(d, JCF ) 10.4 Hz), 140.9 (d, JCF ) 2.5 Hz), 151.0 (d, JCF
)
129.2, 132.1, 135.0, 145.6; 19F NMR (376 MHz) δ -179.76 (1F,
25.9 Hz), 151.9 (d, 4JCF ) 2.6 Hz); 19F NMR (376 MHz) δ -182.76
3
4
3
4
md, JFF ) 7.4 Hz, JFH ) 1.4 Hz, CF(CF3)2), -74.62 (3F, m,
CF(CF3)2), -72.58 (3F, m, CF(CF3)2); MS (EI 70 eV, m/z, %) 364
(M+, 1), 195 (29), 91 (100); HRMS (ESI, MeOH) calcd for
C16H11N2F7Na (M + Na+), 387.0703; found, 387.0715. Anal. Calcd
for C16H11N2F7: C, 52.76; H, 3.04; N, 7.69; F, 36.51. Found: C,
52.44; H, 3.03; N, 7.43; F, 36.45.
(1F, sept. of d, JFF ) 7.0 Hz, JFH ) 2.4 Hz, CF(CF3)2), -74.67
(6F, d, 3JFF ) 7.0 Hz, CF(CF3)2); MS (EI 70 eV, m/z, %) 272 (M+,
35), 253 (12), 203 (72), 153 (100), 103 (89), 69 (64); HRMS (EI)
calcd for C9H3N2F7 (M+), 272.0184; found, 272.0187. Anal. Calcd
for C9H3N2F7: C, 39.72; H, 1.11; N, 10.29; F, 48.87. Found: C,
38.90; H, 1.15; N, 10.17; F, 47.33.
Oxidation of 2-Heptafluoroisopropyl-1,2-dihydroazines 2 with
DDQ. Dihydroazine 2 (0.40 mmol) was dissolved in CH2Cl2 (4.0
mL), and DDQ (363 mg, 1.6 mmol) was added in one portion at 0
°C. The reaction mixture was stirred at rt for 24 h for N-benzyl-
containing dihydroazines and for 30 min in the case of N-p-
methoxybenzyldihydroazines. After evaporation, the product was
purified using column chromatography on silica gel.
3-Benzoyl-6-heptafluoroisopropylpyridine (5g). Purified by
chromatography on neutral aluminum oxide using 5:1 hexanes/Et2O
as the eluent; colorless oil: IR (film, νmax/cm-1) 3067, 1668, 1592,
1
1318, 1281, 1234, 1216, 1169, 1116, 983, 966, 924, 738, 716; H
3
NMR (400 MHz) δ 7.55 (2H, t, JHH ) 8.1 Hz, Ph), 7.68 (1H, tt,
4
3
3JHH ) 7.3 Hz, JHH ) 1.8 Hz, Ph), 7.84 (2H, dd, JHH ) 8.4 Hz,
4JHH ) 1.3 Hz, Ph), 7.87 (1H, ddd, 3JHH ) 8.2 Hz, 4JHF ) 2.6 Hz,
1364 J. Org. Chem., Vol. 72, No. 4, 2007

Synthesis of Perfluoroalkyl-Substituted Azines
3
1
2
5JHH ) 0.7 Hz, CHCdN), 8.30 (1H, dd, 3JHH ) 8.3 Hz, 4JHH ) 2.2
Hz, CHdCHCdN), 9.08 (1H, dm, 4JHH ) 2.0 Hz, CHdCCOPh);
105.6, 116.8 (d, JCF ) 8.6 Hz), 120.3 (qd, JCF ) 288.0 Hz, JCF
4
) 27.6 Hz), 120.9, 122.1, 130.6, 132.7 (d, JCF ) 1.7 Hz), 147.5
13C NMR (100 MHz) δ 90.8 (dm, JCF ) 203.5 Hz, JCF ) 32.8
(d, JCF ) 25.0 Hz), 147.9 (d, JCF ) 2.6 Hz), 155.0; 19F NMR
1
2
2
4
3 4
Hz), 120.0 (qd, 1JCF ) 287.9 Hz, 2JCF ) 26.7 Hz), 121.6 (d, 3JCF
)
(376 MHz) δ -182.61 (1F, sept. of d, JFF ) 6.4 Hz, JFH ) 2.8
Hz, CF(CF3)2), -74.65 (6F, d, 3JFF ) 7.0 Hz, CF(CF3)2); MS (EI
70 eV, m/z, %) 327 (M+, 100), 312 (10), 308 (8), 284 (27), 258
(11), 215 (18); HRMS (EI) calcd for C13H8NOF7 (M+), 327.0494;
found, 327.0496. Anal. Calcd for C13H8NOF7: C, 47.72; H, 2.46;
N, 4.28; F, 40.64. Found: C, 47.90; H, 2.21; N, 4.17; F, 40.59.
3-Heptafluoroisopropylphenanthroline (5l). Yellow solid: mp
126-128 °C; IR (KBr, νmax/cm-1) 1590, 1509, 1494, 1313, 1280,
1242, 1211, 1162, 1132, 980, 970, 848, 718; 1H NMR (400 MHz)
4
9.5 Hz), 128.8, 130.0, 133.7, 134.6, 135.9, 138.5 (d, JCF ) 2.6
2
4
Hz), 150.2 (d, JCF ) 25.9 Hz), 150.3 (d, JCF ) 3.4 Hz), 193.6;
19F NMR (376 MHz) δ -182.81 (1F, sept. of d, JFF ) 6.9 Hz,
3
4JFH ) 2.8 Hz, CF(CF3)2), -74.85 (6F, d, 3JFF ) 6.9 Hz, CF(CF3)2);
MS (EI 70 eV, m/z, %) 351 (M+, 61), 332 (16), 282 (5), 274 (8),
246 (11), 182 (61), 105 (100), 77 (48); HRMS (EI) calcd for C15H8-
NOF7 (M+), 351.0494; found, 351.0487. Anal. Calcd for C15H8-
NOF7: C, 51.30; H, 2.30; N, 3.99; F, 37.86. Found: C, 51.43; H,
2.04; N, 3.92; F, 36.57.
3
4
δ 7.68 (1H, dd, JHH ) 8.0 Hz, JHH ) 4.3 Hz, Harom), 7.87 (2H,
3
3
4
4-Ethoxy-2-heptafluoroisopropyl-5-nitropyridine (5i). Purified
by chromatography on silica gel using 10:1 hexanes/EtOAc; pale
yellow oil, solidified on standing at rt: mp 50-51 °C; IR (film,
AB, JHH ) 8.9 Hz, Harom), 7.99 (1H, dd, JHH ) 8.5 Hz, JHH
)
2.2 Hz, Harom), 8.27 (1H, dd, 3JHH ) 8.1 Hz, 4JHH ) 1.8 Hz, Harom),
3
3
8.43 (1H, d, JHH ) 8.5 Hz, Harom), 9.29 (1H, dd, JHH ) 4.4 Hz,
1
ν
max/cm-1) 2995, 1608, 1570, 1535, 1308, 1278, 1234, 1203, 1170,
4JHH ) 1.8 Hz, Harom); 13C NMR (100 MHz) δ 91.1 (dm, JCF
)
2 3
1
1128, 1030, 984, 925, 856, 756, 742; H NMR (400 MHz) δ )
203.5 Hz, JCF ) 31.9 Hz), 120.0 (d, JCF ) 7.8 Hz), 120.4 (qd,
1JCF ) 287.1 Hz, 2JCF ) 26.7 Hz), 123.5, 125.8, 128.8, 129.2, 129.3,
3
3
1.56 (3H, t, JHH ) 7.2 Hz, OCH2CH3), 4.37 (2H, q, JHH ) 7.2
4
4
4
Hz, OCH2CH3), 7.41 (1H, d, JHF ) 2.4 Hz, CHCdN), 9.01 (1H,
136.1, 137.5 (d, JCF ) 2.2 Hz), 145.7 (d, JCF ) 2.6 Hz), 145.9,
d, 5JHF ) 0.6 Hz, CHdCNO2); 13C NMR (100 MHz) δ 14.0, 66.7,
90.6 (dm, 1JCF ) 204.3 Hz, 2JCF ) 32.8 Hz), 107.9 (d, 3JCF ) 11.2
Hz), 119.8 (qd, 1JCF ) 287.9 Hz, 2JCF ) 26.7 Hz), 137.4, 146.5 (d,
146.6 (d, 2JCF ) 24.1 Hz), 151.3; 19F NMR (376 MHz) δ -182.25
3
(1F, m, CF(CF3)2), -74.55 (6F, d, JFF ) 7.6 Hz, CF(CF3)2); MS
(EI 70 eV, m/z, %) 348 (M+, 100), 329 (10), 279 (68), 229 (28),
179 (29); HRMS (EI) calcd for C15H7N2F7 (M+), 348.0498; found,
348.0505. Anal. Calcd for C15H7N2F7: C, 51.74; H, 2.03; N, 8.04;
F, 38.19. Found: C, 51.52; H, 1.91; N, 7.76; F, 37.96.
4JCF ) 2.6 Hz), 152.2 (d, JCF ) 25.0 Hz), 159.1 (d, JCF ) 1.7
2
4
Hz); 19F NMR (376 MHz) δ -181.50 (1F, sept. of d, JFF ) 6.6
3
Hz, 4JFH ) 2.6 Hz, CF(CF3)2), -74.81 (6F, d, JFF ) 6.6 Hz, CF-
3
(CF3)2); MS (EI 70 eV, m/z, %) 336 (M+, 6), 308 (33), 292 (74),
262 (100); HRMS (EI) calcd for C10H7N2O3F7 (M+), 336.0345;
found, 336.0350. Anal. Calcd for C10H7N2O3F7: C, 35.73; H, 2.10;
N, 8.33; F, 39.56. Found: C, 35.97; H, 2.04; N, 8.15; F, 37.52.
4-Cyano-2-heptafluoroisopropylpyridine (5j). Pale yellow
oil: IR (film, νmax/cm-1) 3076, 2992, 2937, 2840, 2243, 1613, 1601,
1514, 1467, 1311, 1284, 1231, 1171, 1136, 1098, 1036, 1012, 986,
2-Heptafluoroisopropyl-3,6-bis(methoxycarbonyl)pyridine (5o).
Purified by chromatography on silica gel using 5:1 hexanes/AcOEt;
yellow solid: mp 60-61 °C; IR (KBr, νmax/cm-1) 2968, 1761, 1736,
1429, 1312, 1268, 1246, 1214, 1163, 1092, 1002, 977, 960, 710;
1H NMR (400 MHz) δ 3.97 (3H, s, OCH3), 4.01 (3H, s, OCH3),
3
3
8.00 (1H, d, JHH ) 8.0 Hz, Harom), 8.28 (1H, d, JHH ) 8.0 Hz,
arom); 13C NMR (100 MHz) δ 53.2, 53.4, 91.9 (dm, 1JCF ) 206.0
Hz, 2JCF ) 32.8 Hz), 119.9 (qd, 1JCF ) 288.8 Hz, 2JCF ) 26.7 Hz),
H
1
3
814, 752, 716; H NMR (400 MHz) δ 7.74 (1H, dd, JHH ) 4.8
4
2
3
Hz, JHH ) 1.3 Hz, CHdCHCN), 7.94 (1H, m, CHCdN), 8.94
125.9, 132.7, 138.4, 143.4 (d, JCF ) 25.9 Hz), 148.2 (d, JCF )
(1H, dm, JHH ) 5.0 Hz, CHdCHCN); 13C NMR (100 MHz) δ
3.4 Hz), 163.9, 166.3; 19F NMR (376 MHz) δ -181.64 (1F, sept.,
3JFF ) 5.4 Hz, CF(CF3)2), -74.19 (6F, d, 3JFF ) 5.4 Hz, CF(CF3)2);
MS (EI 70 eV, m/z, %) 363 (M+, <1), 344 (10), 332 (24), 305
(100), 273 (12); HRMS (EI) calcd for C12H8NO4F7 (M+), 363.0342;
found, 363.0348. Anal. Calcd for C12H8NO4F7: C, 39.69; H, 2.22;
N, 3.86; F, 36.62. Found: C, 40.36; H, 2.39; N, 3.94; F, 35.44.
3
1
2
90.5 (dm, JCF ) 204.3 Hz, JCF ) 32.8 Hz), 115.3, 119.8 (qd,
1JCF ) 287.9 Hz, 2JCF ) 26.7 Hz), 122.4 (d, 4JCF ) 2.6 Hz), 123.5
3
2
(d, JCF ) 10.4 Hz), 127.2, 149.3 (d, JCF ) 15.9 Hz), 150.7 (d,
4JCF ) 2.6 Hz); 19F NMR (376 MHz) δ -183.02 (1F, sept. of d,
3JFF ) 6.3 Hz, JFH ) 2.8 Hz, CF(CF3)2), -74.55 (6F, d, JFF
)
4
3
7.0 Hz, CF(CF3)2); MS (EI 70 eV, m/z, %) 272 (M+, 69), 253 (26),
203 (100), 153 (100), 103 (57); HRMS (EI) calcd for C9H3N2F7
(M+), 272.0184; found, 272.0179. Anal. Calcd for C9H3N2F7: C,
39.72; H, 1.11; N, 10.29; F, 48.88. Found: C, 39.52; H, 1.13; N,
10.42; F, 48.79.
Acknowledgment. This work was supported by the Polish
Ministry of Science and Higher Education (Grant 3 T09A 043
27).
Supporting Information Available: Analytical data for com-
pounds 2c′, 3c′, 2d′, 2e′, 3e′, 2f′, 3f′, 2g′, 3g′, 3h′, 2i′, 2j′, 2k′, 3k′,
2l′, 3l′, 2m′, 2n′, 2o′, and 3o′, procedure of one-pot synthesis of
dihydroazines 2 and 3, procedure of synthesis of compounds 2n′,
2o′, and 3o′ (Scheme 9), and copies of NMR spectra of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
2-Heptafluoroisopropyl-5-methoxyquinoline (5k). Purified by
chromatography on silica gel using 10:1 hexanes/Et2O; white
solid: mp 80-81 °C; IR (KBr, νmax/cm-1) 2955, 2925, 2856, 1622,
1591, 1476, 1410, 1295, 1275, 1252, 1225, 1169, 1138, 1090, 978,
1
810, 754; H NMR (400 MHz) δ 4.02 (3H, s, OCH3), 6.93 (1H,
dd, 3JHH ) 7.6 Hz, 4JHH ) 0.8 Hz, Harom), 7.66-7.77 (3H, m, Harom),
3
4
8.74 (1H, dd, JHH ) 8.8 Hz, JHH ) 0.8 Hz, Harom); 13C NMR
1
2
(100 MHz) δ 55.9, 91.1 (dm, JCF ) 203.5 Hz, JCF ) 32.8 Hz),
JO062254U
J. Org. Chem, Vol. 72, No. 4, 2007 1365