A novel ring transformation of pyridinium salts as a route to 4-arylpyridines

Article abstract of DOI:10.1002/1099-0690(200212)2002:24<4123::AID-EJOC4123>3.0.CO;2-M

Regiospecific phenylation of pyridine derivatives at the 4-position takes place in the reaction of 4-methylpyridinium salts 1 with other pyridinium salts 2 by intermolecular transformation of the pyridine ring in 1 and participation of the methyl group of 2. The method developed makes it possible to carry out ring transformation not only for pyridinium salts 1 but even for pyridine itself. 4-Phenylpyridine (3) was produced in 29-57% yields. The new reaction proceeds in an aqueous medium on heating and on treatment with methylammonium sulfite. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2002.

Full text of DOI:10.1002/1099-0690(200212)2002:24<4123::AID-EJOC4123>3.0.CO;2-M

SHORT COMMUNICATION
A Novel Ring Transformation of Pyridinium Salts as a Route to
4-Arylpyridines
Sergey P. Gromov*[a] and Nikolai A. Kurchavov[a]
Keywords: Nitrogen heterocycles / Synthetic methods / Pyridinium salts / Ring transformation / 4-Arylpyridines
Regiospecific phenylation of pyridine derivatives at the 4-po-
sition takes place in the reaction of 4-methylpyridinium salts
even for pyridine itself. 4-Phenylpyridine (3) was produced
in 29−57% yields. The new reaction proceeds in an aqueous
1 with other pyridinium salts 2 by intermolecular transforma- medium on heating and on treatment with methylammo-
tion of the pyridine ring in 1 and participation of the methyl
group of 2. The method developed makes it possible to carry
out ring transformation not only for pyridinium salts 1 but
nium sulfite.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2002)
Introduction
(R2 ϭ H) and 1-alkyl-4-methylpyridinium salts 2aϪc with
methylammonium sulfite, we obtained 4-phenylpyridine 3a
in yields of up to 57% (see Scheme 1).
As it is an aromatic system, the pyridine ring is relatively
resistant to cleavage, although to a lesser extent than ben-
zene.[1,2] Historically, the first thoroughly studied reaction
of this type was the ZinckeϪKönig reaction[3] — cleavage
of the quaternized pyridine ring by aromatic amines to form
glutacondialdehyde dianils. Subsequently, a large number of
reactions with ring opening and ring transformation of pyr-
idine derivatives induced by nucleophilic reagents have been
discovered and studied.[2,4,5] In particular, a number of new
rearrangements, some of which are general for the chem-
istry of heterocyclic compounds, such as the amidine re-
arrangement[6,7] and the enamine rearrangement[2,8] of pyr-
idine derivatives, and the unusual ring transformation of
nitropyridinium salts into indoles[9] have been described in
our previous publications. The main structural factors and
conditions influencing the ring transformation pathway that
have been identified to date provide grounds to expect great
prospects for further research along these lines.
Reactions of this type can also be induced by dimethyl-
ammonium sulfite, for example the reaction between 1a and
2a, although the yield of 4-phenylpyridine (3a) is lower
(about 24%).
Pyridine and 4-methylpyridine resulting from the side N-
dealkylation reaction of pyridinium salts 1 and 2aϪc can
be used once again for the synthesis of 4-phenylpyridine
(3a) after quaternization.
As shown previously,[10] sulfite ion, which is a soft nucle-
ophile, appears to add preferably to the 4-position of pyridi-
nium salts 1aϪc, giving rise to 1,4-dihydropyridines as in-
termediates. The violation of aromaticity of the pyridine
ring promotes its opening. The glutacondialdehyde derivat-
ive thus produced condenses under the action of a base with
the active methyl group of the 4-methylpyridinium salt
2aϪc. Subsequent ring-closure furnishes a benzene ring and
affords, correspondingly, a quaternary 4-phenylpyridinium
salt 4. The last step is N-dealkylation to yield 4-phenylpyr-
idine (3a).
A study of the effect of steric factors on the efficiency of
formation of 4-arylpyridines 3a,b provides evidence sup-
porting the proposed reaction scheme. Thus, an increase in
the steric bulk of the alkyl group at the nitrogen atom of
the 4-methylpyridinium salt 2aϪc leads to a considerable
increase in the yield of 4-phenylpyridine (3a; see Table 1).
Apparently, the introduction of alkyl groups (R3) de-
creases the electron deficiency of the pyridine ring and cre-
ates steric hindrance to the addition of nucleophiles at the
2-position; this reduces the degree to which side reactions
with pyridine ring-opening proceed. The creation of hind-
rance to the parallel N-dealkylation giving 4-methylpyridine
might be yet another reason.
Results and Discussion
It was found previously that 1-alkyl-2-methylpyridinium
salts undergo nucleophilic recyclization into N-alkylanilines
on treatment with alkylammonium sulfite.[2,8,10] It was
assumed that the addition of sulfite or bisulfite ions to
1-alkylpyridinium salts would provide the possibility of an
intermolecular ring transformation with another pyridin-
ium salt containing the methyl group in the 4-position. In-
deed, by heating a mixture of 1-alkylpyridinium salts 1aϪc
[a]
Photochemistry Center of Russian Academy of Sciences,
ul. Novatorov 7a, Moscow 119421, Russia
Fax: (internat.) ϩ7-095/936-1255
E-mail: gromov@photonics.ru
Eur. J. Org. Chem. 2002, 4123Ϫ4126  2002 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/02/1224Ϫ4123 $ 20.00ϩ.50/0
4123

S. P. Gromov, N. A. Kurchavov
SHORT COMMUNICATION
Scheme 1. Reagents and conditions: excess of a mixture of aq. (MeNH3)2SO3 and MeNH2, sealed tube, 230 °C, 60 h
Table 1. Effect of substituents in the pyridinium salts 1aϪc (R2 ϭ
H) and 2aϪc on the formation of 4-phenylpyridine 3a
ticular case, the loss of the N-substituent seems to proceed
along the second pathway, i.e. by direct nucleophilic attack
at the MeϪN bond because no ammonia or (non-alkylated)
ammonium ions are present in the reaction area.
R1
R3
Yield [%] of 3a
[a]
The method developed makes it possible to carry out ring
transformation not only for 1-alkylpyridinium salts 1aϪc
but even for pyridine itself. Prolonged heating (120 h) of
pyridine and the 4-methylpyridinium salt 2c with an aque-
ous solution of methylammonium sulfite gives 4-phenylpyr-
idine (3a) in a satisfactory yield (9Ϫ20%). The yield of 3a
increases substantially with an increase in the pyridine/2c
molar ratio to 20:1.
Previously, we reported that pyridine bases undergo ring
opening under the action of methylammonium sulfite
yielding N-methylanilines.[2,8,10] The driving force of these
recyclizations was the replacement of the amine residue by
the methylamine residue in the intermediate acyclic struc-
ture. In our case, this intermediate appears to condense with
the 4-methylpyridinium salt 2c under the action of bases to
form 4-phenylpyridine (3a; see Scheme 2).
1a
1a
1a
1b
1c
Me
Me
Me
Et
2a
2b
2c
2a
2a
Me
Et
iPr
Me
Me
42
49
57
35
29
iPr
[a]
Isolated yield by chromatography.
In the case of the second component 1aϪc, the size of
the alkyl substituent at nitrogen exerts the opposite effect
on the reaction efficiency. In this case, bulky substituents at
the nitrogen atom appear to hamper opening of the pyrid-
ine ring considerably; this prevents ring transformation. As
is to be expected in terms of the assumed reaction mechan-
ism, the introduction of a methyl group at the 4-position of
the pyridine ring brings about pronounced steric hindrance
to the addition of the sulfite ion, resulting in a sharp de-
crease in the yield of the reaction product. Indeed, the reac-
tion of 1,4-dimethylpyridinium iodide (2a) with 1-isopro-
pyl-4-methylpyridinium iodide (2c) gives 4-(4-methyl-
phenyl)pyridine (3b) in a yield of only 5%.
It could also be that the final step of the process is N-
dealkylation of 4 giving rise to 4-arylpyridines 3a,b. Indeed,
heating 1-methyl-4-phenylpyridinium iodide (4; R2 ϭ H,
R3 ϭ Me) in the presence of methylammonium sulfite un-
der the above reaction conditions resulted in the quantitat-
ive formation of 4-phenylpyridine (3a). N-Alkylpyridinium
salts are known to be converted into pyridine bases on
treatment with liquid ammonia, aqueous solutions of
ammonia, or ammonium sulfite via the exchange of the al-
kylamine residue with the amine group in the intermediate
acyclic structure.[11Ϫ13] When the reagent used does not
contain free ammonia or the ammonium cation, deal-
Scheme 2. Reagents and conditions: excess of a mixture of aq.
kylation can proceed without ring opening.[10,14] In this par- (MeNH3)2SO3 and MeNH2, sealed tube, 230 °C, 120 h
4124
Eur. J. Org. Chem. 2002, 4123Ϫ4126

A Novel Ring Transformation of Pyridinium Salts as a Route to 4-Arylpyridines
SHORT COMMUNICATION
4-Phenylpyridine (3a): A 40% aqueous solution of CH3NH2 (5 mL),
a 68% solution of CH3NH3HSO3 (4 mL), and water (3 mL) were
added to a mixture of 1-alkylpyridinium salt 1aϪc (3 mmol) and
1-alkyl-4-methylpyridinium salt 2aϪc (3 mmol) dissolved in water
(2 mL). The mixture was heated in a sealed tube in a metal auto-
clave on a Wood-alloy bath at 230 °C for 60 h. After opening the
tube, the contents were diluted with water and extracted with ben-
zene. The extract was dried with Na2SO4 and concentrated. The
resulting 4-phenylpyridine (3a) was separated from pyridine and 4-
methylpyridine by column chromatography on silica gel using ben-
Arylpyridines are an important class of heterocyclic com-
pounds encountered in a number of fields, including liquid
crystals, ligands, and molecules of pharmacological inter-
est.[15,16] The main approaches to the synthesis of 4-phenyl-
pyridine proposed to date include various modifications of
the Suzuki reaction, free-radical arylation and regioselective
addition of Grignard reagents, i.e. they are fairly expensive
or require initial compounds that are often difficult to
prepare.[17Ϫ20] The known industrial methods for the pre-
paration of 4-phenylpyridine are based on catalytic con- zene and a benzene/ethyl acetate mixture (2:1) as eluents. Yield:
1
135Ϫ265 mg (29Ϫ57%). M.p. 72Ϫ74 °C (ref.[25] 74 °C). H NMR
densation of benzaldehyde with acetaldehyde and ammonia
(CDCl3): δ ϭ 7.45 (m, 1 H), 7.49Ϫ7.52 (m, 4 H), 7.65 (m, 2 H),
at 300Ϫ400 °C. However, this reaction always yields consid-
8.67 (m, 2 H) ppm.
erable amounts of by-products that are difficult to separate
(in particular, high-boiling alkylpyridines).[21,22]
4-(4-Methylphenyl)pyridine (3b): The procedure for the reaction of
salt 2a with salt 2c to give 4-(4-methylphenyl)pyridine (3b) was sim-
ilar to that described above. Yield: 25 mg (5%). M.p. 88Ϫ89 °C
1
(ref.[26] 89.5Ϫ90.5 °C). H NMR (CDCl3): δ ϭ 2.42 (s, 3 H), 7.30
(d, 2 H), 7.50 (m, 2 H), 7.55 (d, 2 H), 8.64 (d, 2 H) ppm. MS (EI,
Conclusion
70 eV): m/z ϭ 169 (100) [Mϩ], 168 (86), 167 (45), 166 (11), 142
(22), 141 (29), 139 (14), 115 (29), 91 (32), 51 (13).
We have found a new reaction of pyridine derivatives
which could be of high value in pyridine chemistry. This
process is based on the interaction of pyridinium salts with
one another in the presence of alkylammonium sulfite. Sim-
ultaneously, we found a simple and convenient method for
the synthesis of 4-phenylpyridine, formed with high purity
and in high yields from readily available substances (prod-
ucts and wastes of the coke industry).
General Procedure for the Reaction of Pyridine and Pyridinium Salt
2c: The general procedure for the reaction of pyridine with salt 2c
was similar to that described above. Mixtures of pyridine and 1-
isopropyl-4-methylpyridinium iodide (2c) in various molar ratios
were heated for the same or longer periods of time. 4-Phenylpyrid-
ine (3a) was isolated as described above. Yield: 42Ϫ93 mg
(9Ϫ20%).
Acknowledgments
Experimental Section
We thank the Photochemistry Center of the Russian Academy of
Sciences for financial support.
General Remarks: Unless stated otherwise, reagents and solvents
were obtained from commercial sources and used as received. The
pyridinium salts 1aϪc were prepared according to a known proced-
ure.[23] 1-Ethyl-4-methylpyridinium iodide (2b) was also synthesised
according to a known procedure.[24] TLC was performed with
Merck Kieselgel 60 F254 plates, with viewing under ultraviolet light
(254 nm). Column chromatography was performed with Merck
Kieselgel 60 (0.063Ϫ0.100 mm). Melting points were determined
with a MEL-Temp II apparatus in a capillary and are uncorrected.
[1]
D. M. Smith, in Comprehensive Organic Chemistry (Ed.: P. G.
Sammes), Pergamon, Oxford, 1979, vol. 4, pp. 3Ϫ84.
A. N. Kost, S. P. Gromov, R. S. Sagitullin, Tetrahedron 1981,
37, 3423Ϫ3454.
J. Becher, Synthesis 1980, 8, 589Ϫ612.
H. C. van der Plas, Ring Transformations of Heterocycles, Aca-
[2]
[3]
[4]
demic Press, London, New York, 1973, vols. 1 and 2.
[5]
H. C. van der Plas, J. Heterocycl. Chem. 2000, 37, 427Ϫ438.
[6]
1H NMR spectra were recorded with
a Bruker DRX-500
M. Wahren, Z. Chem. 1969, 7, 241Ϫ252.
[7]
E. S. H. El Ashry, Y. El Kilany, N. Rashed, H. Assafir, Adv.
(500 MHz) spectrometer as solutions in CDCl3 or [D6]DMSO; δ
values are reported in ppm downfield from tetramethylsilane; J
values are in Hz. Mass spectra were measured at an ionizing voltage
of 70 eV by electron impact with a Finnigan MAT 8430 instrument.
Elemental analysis was performed at the microanalytical laboratory
of the A. N. Nesmeyanov Institute of Organoelement Compounds
in Moscow, Russia.
Heterocycl. Chem. 1999, 75, 79Ϫ165.
[8]
S. P. Gromov, A. N. Kost, Heterocycles 1994, 38, 1127Ϫ1155.
[9]
S. P. Gromov, Heterocycles 2000, 53, 1607Ϫ1630.
[10]
R. S. Sagitullin, S. P. Gromov, A. N. Kost, Dokl. Akad. Nauk
SSSR 1978, 243, 937Ϫ940 [Dokl. Chem. 1978, 243, 573Ϫ576
(Engl. Transl.)].
J. A. Zoltewicz, S. Helmick, J. K. O’Halloran, J. Org. Chem.
[11]
1976, 41, 1303Ϫ1308.
[12]
1-Isopropyl-4-methylpyridinium iodide (2c): 4-Methylpyridine
(5 mL, 50 mmol) was added to isopropyl iodide (15 mL,
150 mmol). The reaction mixture was plugged with a stopper and
left for one month. The precipitate was then washed with hexane
and dried under vacuum. Yield: 8.2 g (60%). M.p. 130Ϫ132 °C. 1H
NMR ([D6]DMSO, 30 °C): δ ϭ 1.59 (d, J ϭ 6.71 Hz, 6 H, 2 CH3),
2.62 (s, 3 H, CH3), 4.94Ϫ5.02 (m, 1 H, CH), 8.00 (d, J ϭ 6.27 Hz,
2 H, C(2)-H, C(6)-H), 9.02Ϫ9.08 [m, 2 H, C(3)-H, C(5)-H] ppm.
C9H14IN (263.12): calcd. C 41.08, H 5.36, N 5.32; found C 41.01,
H 5.44, N 5.28.
R. S. Sagitullin, S. P. Gromov, A. N. Kost, Tetrahedron 1978,
34, 2213Ϫ2216.
[13]
ˇ
R. Lukes, J. Jizba, Chem. Listy 1958, 52, 1131Ϫ1136.
[14]
[15]
[16]
A. R. Katritzky, Tetrahedron 1980, 36, 679Ϫ699.
S. P. Stanforth, Tetrahedron 1998, 54, 263Ϫ303.
S. G. Speciale, C. L. Liang, P. K. Sonsalla, R. H. Edwards, D.
C. German, Neuroscience 1998, 84, 1177Ϫ1185.
[17]
[18]
[19]
I. Fenger, C. Le Drian, Tetrahedron Lett. 1998, 39, 4287Ϫ4290.
O. Lohse, P. Theverin, E. Waldvogel, Synlett 1999, 45Ϫ48.
V. Martinez-Barrasa, A. Garcıa de Viedma, C. Burgos, J. Alva-
´
rez-Builla, Org. Lett. 2000, 2, 3933Ϫ3935.
Eur. J. Org. Chem. 2002, 4123Ϫ4126
4125

S. P. Gromov, N. A. Kurchavov
SHORT COMMUNICATION
[20]
[24]
[25]
[26]
A. R. Katritzky, H. Beltrami, M. P. Sammes, J. Chem. Soc.,
M. Katcka, T. Urbanski, Bull. Acad. Pol. Sci. Ser. Sci. Chem.
Perkin Trans. 1 1980, 2480Ϫ2484.
A. Avots, E. Lavrinovics, I. Lazdins, M. Sile, SU Patent 512209,
1967, 15, 413Ϫ421.
[21]
L. A. Walters, S. M. McElvain, J. Am. Chem. Soc. 1933, 55,
1976; Chem. Abstr. 1976, 85, 108537z.
A. Avots, I. Lazdins, M. Sile, E. Lavrinovics, SU Patent 527425,
4625Ϫ4629.
[22]
R. A. Abramovitch, J. G. Saha, J. Chem. Soc. 1964,
1977; Chem. Abstr. 1977, 86, 29647c.
2175Ϫ2187.
[23]
E. M. Kosower, J. A. Skorcz, J. Am. Chem. Soc. 1960, 82,
Received July 23, 2002
[O02416]
2195Ϫ2201.
4126
Eur. J. Org. Chem. 2002, 4123Ϫ4126