Formation of 4-arylpyridines from pyridinium salts under the action of methylammonium sulfite

Article abstract of DOI:10.1023/A:1025657529140

Reactions of pyridinium salts or nonquaternized pyridine with 4-methylpyridinium salts in the presence of methylammonium sulfite in aqueous methylamine afford 4-phenylpyridhie in 29-57% yields. The probable mechanism of ring transformation in simplest pyr

Full text of DOI:10.1023/A:1025657529140

1
606
Russian Chemical Bulletin, International Edition, Vol. 52, No. 7, pp. 1606—1609, July, 2003
Formation of 4ꢀarylpyridines from pyridinium salts
under the action of methylammonium sulfite
ꢀ
S. P. Gromov and N. A. Kurchavov
Center of Photochemistry, Russian Academy of Sciences,
7
A ul. Novatorov, 119421 Moscow, Russian Federation.
Fax: +7 (095) 936 1255. Eꢀmail: gromov@photonics.ru
Reactions of pyridinium salts or nonquaternized pyridine with 4ꢀmethylpyridinium salts in
the presence of methylammonium sulfite in aqueous methylamine afford 4ꢀphenylpyridine in
2
9—57% yields. The probable mechanism of ring transformation in simplest pyridine derivaꢀ
tives under the action of nucleophiles is discussed.
Key words: 4ꢀmethylpyridines, pyridine, pyridinium salts, methylammonium sulfite, ring
transformation, 4ꢀarylpyridines.
Various known transformations of heterocycles involve
are based on the Chichibabin reaction19 (e.g., by catalytic
condensation of benzaldehyde with acetaldehyde and
ammonia at 300—400 °C). However, all of the reactions
yield considerable amounts of byꢀproducts (including
ring opening, expansion, contraction, exchange of a
heteroatom, etc. They are mainly initiated by nucleoꢀ
philic reagents and have been studied most thoroughly for
electronꢀdeficient heterocycles containing two and more
nitrogen atoms (such as pyrimidine, pyrazine, pyridazine,
triazines, and their fused analogs).1
2
0,21
highꢀboiling alkylpyridines
rate off.
), which are hard to sepaꢀ
Earlier,3,8,22 we found that 1,2ꢀdimethylpyridinium
salts undergo recyclization into Nꢀalkylanilines under the
action of alkylammonium sulfite. One could assume that
addition of sulfite or bisulfite ions to 1ꢀalkylpyridinium
salts would allow an intermolecular ring transformation
involving another pyridinium salt containing a methyl
group in position 4. Indeed, heating a mixture of 1ꢀalkylꢀ
pyridinium 1a—d and 1ꢀalkylꢀ4ꢀmethylpyridinium salts
2a—d with methylammonium sulfite afforded 4ꢀphenylꢀ
pyridine (3a) in 29—57% yields (Scheme 1). A similar
reaction occurs between salts 1a and 2a in the presence of
dimethylammonium sulfite, but the yield is lower (24%).
Pyridine and 4ꢀmethylpyridine, which are formed in
the side Nꢀdealkylation of pyridinium salts 1a—d and
2a—d, can be quaternized and used in the synthesis of
compound 3a. This allows one to obtain the target prodꢀ
uct in up to 68% yield (from the pyridine bases consumed
in the reaction).
Pyridine is relatively resistant to ring opening, although
to a lower extent than benzene.2 Such a transformation
,3
4
was first represented by the Zincke—König reaction, in
which quaternized pyridine undergoes ring opening unꢀ
der the action of aromatic amines to give glutaconaldehyde
dianils. Later, a great number of reactions of pyridine
derivatives with nucleophiles causing ring opening and
3
,5
transformations were studied. Mention should be given
6
,7
to some new rearrangements (amidine rearrangement,
3
,8
enamine rearrangement of pyridine derivatives, and an
unusual conversion of nitropyridinium salts into inꢀ
9
,10
doles ); the latter two reactions were discovered by us.
Arylpyridines are used in the preparation of liquid crysꢀ
1
1,12
tals and as ligands and biologically active compounds.
ꢀPhenylpyridine can be obtained by the reaction of
2
phenyllithium or the Grignard reagent with pyridine or its
Nꢀoxide followed by oxidation or disproportionation of
the resulting 1,2ꢀdihydropyridine derivative or thermal
elimination of lithium hydride (e.g., see Refs. 13, 14).
The nature of the counterion was found to have a
certain effect on the efficiency of the ring transformation.
It turned out that the use of bromides instead of iodides
somewhat increases the yield of 4ꢀphenylpyridine (3a).
Probably, this is due to the fact that bromides are more
stable than iodides under rather drastic reaction conꢀ
ditions.
As shown by us earlier,22 a sulfite ion as a soft nucleoꢀ
phile seems to add predominantly at position 4 of salts
1a—d, which affords an intermediate 1,4ꢀdihydropyridine
derivative. The disturbance of the aromaticity of the pyriꢀ
dine ring facilitates its opening. The resulting glutaconꢀ
4
ꢀPhenylpyridine cannot be obtained by direct
phenylation of pyridine because the nucleophilic addition
of corresponding organometallic reagents occurs excluꢀ
sively at position 2 of the pyridine ring.1
3
Current methods for the synthesis of 4ꢀphenylpyridine
include different versions of the Suzuki reaction, freeꢀ
radical arylation, and regioselective addition of the
Grignard reagents, but the starting reagents for these methꢀ
ods are toxic or difficultly accessible.1
5—18
The known
commercial methods for the synthesis of 4ꢀphenylpyridine
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1522—1525, July, 2003.
066ꢀ5285/03/5207ꢀ1606 $25.00 © 2003 Plenum Publishing Corporation
1

A novel route to 4ꢀarylpyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1607
Scheme 1
1
2
i
1
4
, 2: R , R = Me (a), Et (b, c), Pr (d); X = I (a, b, d), Br (c)
2
: R = Me, X = I
aldehyde derivative undergoes condensation with a reacꢀ
tive methyl group of 4ꢀmethylpyridinium salt 2a—d under
the action of a base. Subsequent ring closure gives quaꢀ
ternary 4ꢀphenylpyridinium salt 4, which is converted to
In contrast, a bulkier alkyl substituent bound to the
nitrogen atom in salts 1a—d seems to considerably hinder
the opening of the pyridine ring.
According to the proposed reaction mechanism, a
methyl group in position 4 of the pyridine ring presents
considerable steric hindrances to addition of a sulfite ion,
which sharply reduces the yield of the reaction product
(Scheme 2). For instance, the reaction of 1,4ꢀdimethylꢀ
pyridinium iodide (2a) with 1ꢀisopropylꢀ4ꢀmethylpyriꢀ
dinium iodide (2d) gives 4ꢀ(4ꢀmethylphenyl)pyridine (3b)
only in 5% yield.
The reaction of 1,3ꢀdimethylpyridinium iodide (1e)
with 1ꢀisopropylꢀ4ꢀmethylpyridinium iodide (2d) affords
a 3 : 1 mixture of 4ꢀ(3ꢀmethylphenyl)pyridine (3c) and
4ꢀ(4ꢀmethylphenyl)pyridine (3b) in a total yield of 8%
(see Scheme 2); i.e., the methyl group in position 3 of salt
1e also prevents the addition of a sulfite ion at position 4.
The competitive formation of 4ꢀ(4ꢀmethylphenyl)pyridine
4
ꢀphenylpyridine (3a) as a result of Nꢀdealkylation.
The data obtained in the study of the effect of steric
factors on the efficiency of the formation of 4ꢀarylpyridines
confirm the proposed reaction scheme. A bulkier alkyl
group bound to the nitrogen atom in 4ꢀmethylpyridinium
salts 2a—d favors an increase in the yield of 4ꢀphenylꢀ
pyridine (3a) (Table 1). Apparently, the presence of the
alkyl group at the nitrogen atom in salts 2a—d reduces the
electron deficiency of the pyridine ring and presents steric
hindrances to addition of nucleophiles at position 2; this
in turn reduces the probability of the side opening of the
pyridine ring and prevents competitive Nꢀdealkylation
yielding 4ꢀmethylpyridine.
Table 1. Effects of the substituents and counterions in pyridinium
salts 1a—d and 2a—d on the yield of 4ꢀphenylpyridine (3a)
(
3b) can be explained by selfꢀcondensation of salt 2d,
which proceeds as in the preceding example.
A further increase in the number of methyl groups in
positions 3—5 makes the pyridinium ring unable to addiꢀ
tion and opening under the action of nucleophiles, which
prevents its transformation.
The final step of the process could be assumed to be
Nꢀdealkylation of an intermediate compound of type 4 to
give 4ꢀarylpyridines 3a—c. Indeed, heating of 1ꢀmethylꢀ
Comꢀ
pound
R1
X
Comꢀ
pound
R2
X
Yield of 3a
(%)
1
1
1
1
1
1
1
a
a
a
a
b
c
d
Me
Me
Me
Me
Et
I
I
I
I
I
2a
2b
2c
2d
2a
2a
2a
Me
Et
I
I
Br
I
I
I
42
49
53
57
35
37
29
Et
i
Pr
Me
Me
Me
4
ꢀphenylpyridinium iodide (4) in the presence of methylꢀ
Et
Pri
Br
I
ammonium sulfite afforded 4ꢀphenylpyridine (3a) in 93%
yield. It is known that Nꢀalkylpyridinium salts under the
I

1
608
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
Gromov and Kurchavov
Scheme 2
Table 2. Effects of the molar ratio of pyridine to 1ꢀisopropylꢀ4ꢀ
methylpyridinium iodide (2d) and the reaction duration on the
yield of 4ꢀphenylpyridine (3a)
Pyridine : salt 2d
Time/h
Yield of 3a (%)
1
1
2
: 2
: 1
: 1
120
120
120
60
3
7
13
20
2
0 : 1
the yield of 4ꢀphenylpyridine (3a) from the consumed
pyridine can be substantially higher.
3
,8,22
Previously,
we found that pyridine bases can unꢀ
dergo ring opening under the action of methylammonium
sulfite to give Nꢀmethylanilines. The driving force of these
recyclization processes is an exchange of the amine resiꢀ
due for a methylamine one in an acyclic intermediate.
Here, this intermediate seems to undergo condensation
with 4ꢀmethylpyridinium salt 2d under the action of bases
to give 4ꢀphenylpyridine (3a) (Scheme 3).
Scheme 3
action of liquid ammonia, aqueous ammonia, or ammoꢀ
nium sulfite are converted into pyridine bases because of
exchange of the alkylamine residue for an amine in an
acyclic intermediate.2
3—25
In the absence of ammonia or
an ammonium salt, dealkylation can proceed without ring
opening.2
tion sphere contains no ammonia or ammonium ions
nonalkylated) and the Nꢀsubstituent is probably elimiꢀ
2,26
In the case under consideration, the reacꢀ
(
nated as a result of the direct attack of a nucleophile on
the Me—N bond.
The method developed by us allows one to effect the
ring transformation not only in 1ꢀalkylpyridinium salts
1
a—d but also in pyridine itself. Prolonged heating of
Thus, we discovered a novel reaction of simplest pyriꢀ
dine derivatives, which can be important for the chemisꢀ
try of pyridine. The reaction occurs between pyridinium
salts in the presence of alkylammonium sulfite. At the
same time, we found a simple and convenient route to
highꢀpurity 4ꢀphenylpyridine obtained in good yields from
substances available from byꢀproduct coke industry.
pyridine and 4ꢀmethylpyridinium salt 2d with aqueous
methylammonium sulfite gives 4ꢀphenylpyridine (3a) in
up to 20% yield (Table 2). With an excess of salt 2d,
4
4
ꢀ(4ꢀmethylphenyl)pyridine (3b) was formed, along with
ꢀphenylpyridine (3a), as a result of selfꢀcondensation of
1
salt 2d ( H NMR data). The yield of 4ꢀphenylpyridine
(
3a) and its purity were significantly increased when the
molar ratio of pyridine to salt 2d was 20 : 1. In this case,
ꢀ(4ꢀmethylphenyl)pyridine (3b) was not detected by the
Experimental
4
1
1H NMR spectra were recorded on a Bruker DRXꢀ500 specꢀ
trometer in CDCl and DMSOꢀd with Me Si as the internal
H NMR method. Taking into account that a significant
portion of pyridine is recovered, one can conclude that
3
6
4

A novel route to 4ꢀarylpyridines
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 7, July, 2003
1609
standard. Chemical shifts were measured to within 0.01 ppm,
spinꢀspin coupling constants were measured to within 0.01 Hz.
Mass spectra were recorded on a Finnigan MAT 8430 instruꢀ
ment (ionizing voltage 70 eV, direct inlet probe). The course
of the reaction was monitored by TLC on DCꢀAlufolien
Kieselgel 60 F254 plates (Merck). Column chromatography was
carried out on Kieselgel 60 silica gel (0.063—0.100 mm; Merck).
Pyridinium salts 1a—e were prepared according to a common
procedure.27 1ꢀEthylꢀ4ꢀmethylpyridinium iodide 2b and 1ꢀmeꢀ
thylꢀ4ꢀphenylpyridinium iodide (4) were synthesized according
to the known procedures.2
Reaction of pyridine with salt 2d (general procedure). The
reaction was carried out by analogy with procedure A by heating
a mixture of pyridine and 1ꢀisopropylꢀ4ꢀmethylpyridinium ioꢀ
dide (2d) (see Table 2). 4ꢀPhenylpyridine (3a) was also isolated
according to procedure A.
References
1
2
3
. H. C. van der Plas, Ring Transformations of Heterocycles,
Academic Press, London, New York, 1973, 1, 2.
. D. M. Smith in Comprehensive Organic Chemistry, Ed. P. G.
Sammes, Pergamon, Oxford, 1979, 4, p. 3.
8,29
1
ꢀIsopropylꢀ4ꢀmethylpyridinium iodide (2d). 4ꢀMethylpyriꢀ
dine (5 mL, 50 mmol) was added to isopropyl iodide (15 mL,
50 mmol). The reaction mixture was left for a month. The
. A. N. Kost, S. P. Gromov, and R. S. Sagitullin, Tetrahedron,
1
1
981, 37, 3423.
precipitate that formed was washed with hexane and dried in
vacuo. The yield of 2d was 8.2 g (60%), m.p. 130—132 °C.
4
5
. J. Becher, Synthesis, 1980, 589.
. H. C. van der Plas, J. Heterocycl. Chem., 2000, 37, 427.
1
H NMR (DMSOꢀd ), δ: 1.59 (d, 6 H, 2 Me, J = 6.71 Hz); 2.62
6
6. M. Wahren, Z. Chem., 1969, 7, 241.
(
s, 3 H, Me); 4.94—5.02 (m, 1 H, CH); 8.00 (d, 2 H, H(2),
7
. E. S. H. El Ashry, Y. El Kilany, N. Rashed, and H. Assafir,
H(6), J = 6.27 Hz); 9.02—9.08 (m, 2 H, H(3), H(5)). Found (%):
Adv. Heterocycl. Chem., 1999, 75, 79.
C, 41.01; H, 5.44; N, 5.28. C H IN. Calculated (%): C, 41.08;
9
14
8. S. P. Gromov and A. N. Kost, Heterocycles, 1994, 38, 1127.
. S. P. Gromov, Heterocycles, 2000, 53, 1607.
H, 5.36; N, 5.32.
9
4
3
ꢀPhenylpyridine (3a). A. A 68% solution of MeNH HSO3
10. S. P. Gromov and Yu. G. Bundel´, Dokl. Akad. Nauk SSSR,
1985, 281, 585 [Dokl. Chem., 1985, 281, 93 (Engl. Transl.)].
(
4 mL), aqueous 40% MeNH (5 mL) and water (3 mL) were
2
added to a 1ꢀalkylpyridinium salt 1a—d (3 mmol) and a 1ꢀalkylꢀ
ꢀmethylpyridinium salt 2a—d (3 mmol) dissolved in 2 mL of
1
1
1. S. P. Stanforth, Tetrahedron, 1998, 54, 263.
2. S. G. Speciale, C. L. Liang, P. K. Sonsalla, R. H. Edwards,
and D. C. German, Neuroscience, 1998, 84, 1177.
4
water. The reaction mixture was heated in a sealed tube placed
in a metal autoclave on a Wood´s alloy bath at 230 °C for 60 h.
After the tube was opened, the contents was diluted with water
1
3. L. A. Walters and S. M. McElvain, J. Am. Chem. Soc., 1933,
5
5, 4625.
14. R. A. Abramovitch and C. S. Giam, Can. J. Chem., 1962,
0, 213.
5. I. Fenger and C. Le Drian, Tetrahedron Lett., 1998, 39, 4287.
16. O. Lohse, P. Theverin, and E. Waldvogel, Synlett, 1999, 45.
2
and extracted with benzene. The extract was dried with Na SO4
and concentrated. The resulting 4ꢀphenylpyridine was separated
from pyridine and 4ꢀmethylpyridine by column chromatograꢀ
phy on SiO2 with benzene and then benzene—ethyl acetate
4
1
(
1
2 : 1) as eluents. M.p. 72—74 °C (cf. Ref. 13: m.p. 74 °C).
1
1
1
7. V. MartinezꢀBarrasa, A. Garcna de Viedma, C. Burgos, and
J. AlvarezꢀBuilla, Org. Lett., 2000, 2, 3933.
8. A. R. Katritzky, H. Beltrami, and M. P. Sammes, J. Chem.
Soc., Perkin Trans. 1, 1980, 2480.
9. R. S. Sagitullin, G. P. Shkil´, I. I. Nosonova, and A. A.
Ferber, Khim. Geterotsikl. Soedin., 1996, 147 [Chem.
Heterocycl. Compd., 1996 (Engl. Transl.)].
H NMR (CDCl ), δ: 7.45 (m, 1 H); 7.49—7.52 (m, 4 H); 7.65
3
and 8.67 (both m, 2 H each). Pyridine and 4ꢀmethylpyridine
were converted into hydrochlorides, and their ratio in the mixꢀ
1
ture was determined by H NMR spectroscopy.
B. A 68% solution of MeNH HSO (4 mL), aqueous 40%
3
3
MeNH2 (5 mL), and water (3 mL) were added to iodide 4
197 mg, 1 mmol) dissolved in 2 mL of water. The reaction was
(
2
2
0. Author´s Certificate 512 209 USSR; Byul. izobret., 1976, 61.
1. Author´s Certificate 527 425 USSR; Byul. izobret., 1977, 71.
carried out as described above. The yield was 144 mg (93%),
1
m.p. 72—74 °C (cf. Ref. 13: m.p. 74 °C). H NMR (CDCl ), δ:
3
22. R. S. Sagitullin, S. P. Gromov, and A. N. Kost, Dokl. Akad.
Nauk SSSR, 1978, 243, 937 [Dokl. Chem., 1978, 243, 573
7
.45 (m, 1 H); 7.49—7.52 (m, 4 H); 7.65 (m, 2 H); 8.67 (m, 2 H).
ꢀ(4ꢀMethylphenyl)pyridine (3b) was obtained by analogy
4
(
Engl. Transl.)].
with 3a (procedure A) from 1,4ꢀdimethylpyridinium iodide (2a)
2
2
2
3. J. A. Zoltewicz, S. Helmick, and J. K. O´Halloran, J. Org.
Chem., 1976, 41, 1303.
4. R. S. Sagitullin, S. P. Gromov, and A. N. Kost, Tetrahedron,
1978, 34, 2213.
and 1ꢀisopropylꢀ4ꢀmethylpyridinium iodide (2d). The yield was
1
5
%, m.p. 88—89 °C (cf. Ref. 30: m.p. 89.5—90.5 °C). H NMR
(
(
CDCl ), δ: 2.42 (s, 3 H, Me), 7.30 (d, 2 H, H(3´), H(5´)); 7.50
3
m, 2 H, H(3), H(5)); 7.55 (d, 2 H, H(2´), H(6´)); 8.64 (d, 2 H,
5. R. Lukeš and J. Jizba, Chem. Listy, 1958, 52, 1131.
+
H(2), H(6)). MS (m/z, Irel (%)): 169 (100) [M ], 168 (86),
26. A. R. Katritzky, Tetrahedron, 1980, 36, 679.
1
(
67 (45), 166 (11), 142 (22), 141 (29), 139 (14), 115 (29), 91
32), 51 (13).
ꢀ(3ꢀMethylphenyl)pyridine (3c) was obtained by analogy
2
2
2
3
7. E. M. Kosower and J. A. Skorcz, J. Am. Chem. Soc., 1960,
2, 2195.
8. M. Katcka and T. Urbanski, Bull. Acad. Pol. Sci., Ser. Sci.
Chim., 1967, 15, 413.
9. B. Emmert and O. Varenkamp, Ber. Deutsch. Chem. Ges.,
1923, 56, 491.
0. R. A. Abramovitch and J. G. Saha, J. Chem. Soc., 1964, 2175.
8
4
with 3a (procedure A) from 1,3ꢀdimethylpyridinium iodide (1e)
and 1ꢀisopropylꢀ4ꢀmethylpyridinium iodide (2d). The total yield
1
of a mixture of 3c and 3b (3 : 1) was 8%. H NMR (CDCl ), δ:
3
2
7
.45 (s, 3 H, Me); 7.27 (m, 1 H, H(4´)); 7.39 (m, 1 H, H(5´));
.45 (d, 1 H, H(6´)); 7.46 (s, 1 H, H(2´)); 7.51 (m, 2 H, H(3),
H(5)); 8.66 (m, 2 H, H(2), H(6)). Chemical shifts of the signals
Received December 20, 2002;
for isomer 3b are identical with those presented above.
in revised form February 17, 2003