Synthesis of new pyridines with oligocations and oxygen nucleophiles.

Article abstract of DOI:10.1021/ol0256926

Nucleophilic substitution of 4-(dimethylamino)pyridine on pentachloropyridine yielded pentakis(pyridine-2,3,4,5,6-pentayl)pyridinium, tris-(3,5-dichloropyridine-2,4,6-triyl)pyridinium, or (tetrachloropyridin-4-yl)pyridinium depending on the reaction conditions. Nucleophilic substitution with water, hydroxides, and alcoholates resulted in new betaines and highly substituted pyridines. [structure: see text]

Full text of DOI:10.1021/ol0256926

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1375-1377
Synthesis of New Pyridines with
Oligocations and Oxygen Nucleophiles
Andreas Schmidt,* Thorsten Mordhorst, and Tobias Habeck
Technische UniVersita¨t Clausthal, Institut fu¨r Organische Chemie, Leibnizstrasse 6,
D-38678 Clausthal-Zellerfeld, Germany
schmidt@ioc.tu-clausthal.de
Received February 8, 2002
ABSTRACT
Nucleophilic substitution of 4-(dimethylamino)pyridine on pentachloropyridine yielded pentakis(pyridine-2,3,4,5,6-pentayl)pyridinium, tris-(3,5-
dichloropyridine-2,4,6-triyl)pyridinium, or (tetrachloropyridin-4-yl)pyridinium depending on the reaction conditions. Nucleophilic substitution
with water, hydroxides, and alcoholates resulted in new betaines and highly substituted pyridines.
Neutral as well as charged pyridine derivatives play key roles
in numerous biological processes and are very interesting
molecules in the field of pharmacology. The muscarinic
acetylcholine receptor antagonist cyclostellettamine 11 and
the epidermal growth factor active polymeric pyridinium
alkaloids 22 (Scheme 1) are among the di- and oligocationic
pyridines isolated from natural sources. In addition, highly
charged systems were examined as semiconductors,3 precur-
sors of novel polymers3 and stable radicals,4 acetylcholine
esterase reactivators,5 herbicides,6 and novel oxidizing
agents.7 However, despite intense studies directed toward the
synthetic potential of heteroaromatics,8 numerous substituted
pyridines remain unknown to date.
As a continuation of our interest in charge-cumulated
heteroaromatic systems,9 we report the syntheses of 3-fold
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5925.
Scheme 1
(3) Koch, A. S.; Feng, A. S.; Hopkins, T. A.; Streitwieser, A. J. Org.
Chem. 1993, 58, 1409. DiMagno, S. G.; Waterman, K. C.; Speer, D. V.;
Streitwieser, A. J. Am. Chem. Soc. 1991, 113, 4679.
(4) Okada, K.; Matsumoto, K.; Oda, M.; Murai, H.; Akiyama, K.;
Ikegami, Y. Tetrahedron Lett. 1995, 36, 6689. Ikegami, Y.; Muramatsu,
T.; Hanaya, K. J. Am. Chem. Soc. 1989, 111, 5782. Akiyama, K.; Tero-
Kubota, S.; Ikegami, Y. J. Am. Chem. Soc. 1983, 105, 3601.
(5) Boon, W. R.Chem. Ind. (London) 1965, 782. Dodge, A. D. EndeaVour
1970, 111, 130. Black, A. L.; Summers, L. A. J. Chem. Soc. C 1969, 610.
Campbell, E. C.; Glover, E. E.; Trenholm, G. J. Chem. Soc. 1969, 1987.
(6) Ashani, Y.; Cohen, S. J. Med. Chem. 1971, 14, 621. Barfknecht, C.
F.; Benz, F. W.; Long, J. P. J. Med. Chem. 1971, 14, 1003. Corder, C. N.;
Way, J. L. J. Med. Chem. 1966, 9, 638.
(7) Weiss, R.; May, R.; Pohmrehn, B. Angew. Chem. 1996, 108, 1319;
Angew. Chem., Int. Ed. Engl. 1996, 35, 1232.
(8) Spitzner, D. In Houben-Weyl, Methoden der organischen Chemie,
Vol. E7b; Thieme Verlag: Stuttgart, 1992; p 286.
10.1021/ol0256926 CCC: $22.00 © 2002 American Chemical Society
Published on Web 03/19/2002

and 5-fold positively charged pyridine derivatives. Their
synthetic potential for the preparation of highly substituted
and hitherto unknown pyridine derivatives is examined.
Due to the limited leaving group tendency, halogenated
pyridines are usually not very susceptible to more than one
nucleophilic displacement by neutral nucleophiles.10 Substi-
tutions on pentachloropyridine with amines generally require
high temperatures to produce 2-amino-substituted tetra-
chloropyridines.11 High temperature (180 °C) and pressure
results in 3,4-diamino-substituted trichloropyridines.12 Per-
aminations of halogenopyridines are therefore not often
described in the literature.13 However, successive nucleophilic
substitutions of the chlorine atoms of pentachloropyridine 3
by heteroaromatic nucleophiles cause increased activation
due to the formation of strong electron-withdrawing hetare-
nium substituents. In contrast to chloropyrimidines,14 the
outcome of the reaction can easily be influenced by the
reaction conditions which allow for the syntheses of penta-
cationic, tricationic, or monocationic compounds. In contrast
to the reaction with aliphatic amines, heating a concentrated
solution of pentachloropyridine 3 and DMAP in 1,2-
dichlorobenzene (1,2-DCB) to 60 °C resulted in the forma-
tion of a slightly yellow precipitate of 1-(4-dimethylamino)-
[2,3,5,6-tetrachloropyridin-4-yl]pyridinium chloride 4a with
an 87% yield (Scheme 2). Under Finkelstein-analogous
NMR spectra displays seven signals. The C(2)-Cl and C(3)-
Cl atoms of 4b appear at δ ) 146.22 and 129.31 ppm,
respectively. In either case, the formation of a monocationic
system is confirmed by electrospray ionization mass spec-
trometry (ESIMS) which gives the base peaks at m/z ) 338.0
amu in the positive mode. The iodine derivative 4b shows
an additional peak at m/z ) 802.8 amu at fragmentor voltages
between 0 and 10 V which obviously corresponds to a
monocationic π-sandwich complex between two molecules
of 4+ and one iodine anion.
Heating the same solution for 40 min at reflux temperature
in an inert atmosphere resulted in the almost quantitative
formation of a yellow precipitate of 1,1′,1′′-tris[4-(dimethyl-
amino)-(3,5-dichloropyridine-2,4,6-triyl)pyridinium] tri-
chloride 5, which can be stored under nitrogen. The 1H NMR
spectrum, the peaks for the â-protons appear at 8.83 and
8.66 ppm and the R-protons at 7.49 and 7.34 ppm in 2:1
and 1:2 ratios, respectively.
We then focused our interest on the synthetic potential of
this new tricationic system. More vigorous reaction condi-
tions converted pentachloropyridine 3 or trication 5 and
DMAP into a 5-fold positively charged species. Thus,
treatment of 3 with 4-(dimethylamino)pyridine in 1,2-
dichlorobenzene in the presence of 5-6 equiv of trifluoro-
methylsulfonic acid trimethylsilyl ester (TMSOTf) at reflux
temperature resulted in the formation of a slightly yellow
precipitate of 1,1′,1′′,1′′′,1′′′′-pentakis[4-(dimethylamino)-
(pyridine-2,3,4,5,6-pentayl)pyridinium] pentakis(trifluoro-
methylsulfonate) 6 in a yield of 31%, which proved stable
in air (Scheme 3). The leaving group is trapped as volatile
Scheme 2
Scheme 3
TMSCl when this method is applied. Molecular mass as well
as the 5-fold positive charge is unambiguously confirmed
(9) Schmidt, A.; Kindermann, M. K. J. Org. Chem. 1998, 63, 4636.
Schmidt, A. Heterocycles 1998, 48, 865. Schmidt, A.; Nieger, M.
Heterocycles 1999, 51, 2119. Ma¨kinen, M.; Schmidt, A.; Vainiotalo, P.
Eur. J. Mass Spectrom. 2000, 6, 259. Schmidt, A.; Nieger, M. Heterocycles
2001, 55, 827.
(10) Vorbru¨ggen, H. AdV. Heterocycl. Chem. 1990, 49, 117. Collins, I.;
Suschitzky, H. J. Chem. Soc. C 1970, 1523. Roberts, S. M.; Suschitzky, H.
Chem. Commun. 1967, 893.
(11) Bratt, J.; Iddon, B.; Mack, A. G.; Suschitzky, H.; Taylor, J. A.;
Wakefield, B. J. J. Chem. Soc., Perkin Trans. 1 1980, 648. Julia, L.; Rius,
J.; Suschitzky, H. Heterocycles 1992, 34, 1539.
(12) Sell, W. J.; Dootson, F. W. J. Chem. Soc. 1900, 77, 772.
(13) Foces-Foces, C.; Llamas-Saiz, A. L.; Escola´stico, C.; Claramunt,
R.; Elguero, J. J. Phys. Org. Chem. 1996, 9, 137.
reaction conditions, refluxing a 1:1 mixture in the presence
of sodium iodide in anhydrous acetone, monosubstitution at
C(4) to the iodide 4b could be observed with a 65% yield.
Two resonance frequencies of heteroaromatic protons at δ
) 7.43 and 8.34 ppm can be seen in the 1H NMR spectrum.
In accordance with the symmetric structure of 4a,b, the 13
C
(14) Schmidt, A.; Hetzheim, A. Tetrahedron 1997, 53, 1295.
1376
Org. Lett., Vol. 4, No. 8, 2002

by electrospray ionization mass spectrometry (ESIMS).
Spraying an acetonitrile solution at 0 V fragmentor voltage
results in peaks at m/z ) 1280.4 [65+ - OTf-], 565.7 [65+
- 2OTf-], and 327.5 [65+ - 3 OTf-]. 1H NMR spectroscopy
in DMSO-d6 resulted in the detection of resonance frequen-
cies of three distinct types of pyridinium â-hydrogen atoms
at δ ) 8.23, 8.05, and 7.87 ppm, the ratio of which is 2:2:1.
The â-hydrogen atoms form a multiplet at 7.23 ppm.
Water converted the trication 5 under loss of two positive
charges into the tripolar system 7 which is slightly yellow
in color (75% yield). This reaction obviously involves
nucleophilic attack at C-2 of the central pyridine moiety,
extrusion of one DMAP molecule, and subsequent depro-
tonation of the resulting hydroxy group (Scheme 4).
We then directed our attention to alcohols as potential
nucleophiles. It is known that 2- or 4-substitution on
pentachloropyridine proceeds at high temperatures to give
monosubstituted tetrachloropyridines16 or 2,4-disubstituted
trichloropyridines.17 The methoxy derivative 9 was hitherto
available through a two-step procedure starting from 2,4,6-
trichloropyridine which reacts with sodium methoxide (sealed
tube, 135 °C) followed by chlorination of the resulting 2,4,6-
trimethoxypyridine with phosphorus pentachloride,18 or
alternatively by substituting pentachloropyridine 3 with
methanolate in DMF19 with a low yield. Treatment of the
trication 5 with sodium alkoxides in the corresponding
alcohols at reflux temperature over a period of 2 h, however,
resulted in the smooth formation of 2,4,6-trialkoxy-substi-
tuted pyridines. Thus, methanolate in methanol, n-butanolate
in butanol, and tert-butanolate in tert-butanol, respectively,
gave the 3,5-dichloro-2,4,6-trialkoxypyridines 9-11 in good
yields (Scheme 5). In either case, two distinct types of alkoxy
Scheme 4
Scheme 5
1
substituents in a 1:2 ratio can be observed in the H NMR
spectrum.
Two sets of 4-(dimethylamino)pyridinium rings at δ )
8.65/8.49 ppm (â positions) and 7.44/7.32 ppm (R positions)
in a 1:1 ratio and no deuterium-exchangeable protons such
as NH (pyridone) or OH groups (pyridol) are observed in
the 1H NMR spectrum. No dicationic species can be detected
by ESI mass spectrometry. The 13C NMR spectrum suggests
the formation of a nonsymmetric molecule since 13 signals
are detected. The central pyridine ring gives resonance
frequencies at 126.4, 131.1, 146.6, 147.0, and 191.6 ppm.
The last-mentioned signal is due to the C(2)-O group.
After heating at reflux temperature, a diluted aqueous
solution of sodium hydroxide induced the nucleophilic
displacement of two pyridinium rings of the trication 5 to
yield the 2-pyridinium-substituted 4,6-dihydroxypyridine 8
as a cross-conjugated mesomeric betaine.15 The protonation
site cannot unambiguously be determined by NMR spec-
troscopy.
Acknowledgment. We thank the Fonds der Chemischen
Industrie (FCI) for financial support and Wibke Dempwolf,
Hanns-Martin Kaiser, Christoph Leutiger, Nikoloz Koba-
khidze, and Gerrit Oppermann for some experiments. This
work is dedicated to Prof. Heinrich Wamhoff on the occasion
of his 65th birthday.
Supporting Information Available: Spectroscopic data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL0256926
(16) Mack, A. G.; Suschitzky, H.; Wakefield, B. J. J. Chem. Soc., Perkin
Trans. 1 1980, 1682.
(17) Brady, J. H.; Wakefield, B. J. Synthesis 1984, 33.
(18) Den Hertog, H. J.; Schogt, J. C. M.; De Bruyn, J.; De Klerk, A.
Recl. TraV. Chim. Pays-Bas 1950, 69, 673.
(19) Xiaoyong, X. Xuhong, Q.; Zhong, L.; Gonghua S. J. Fluorine Chem.
1998, 88, 9.
(15) Ollis, W. D.; Stanforth, S. P.; Ramsden, C. A. Tetrahedron 1985,
41, 2239.
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