Synthesis of 3,5-diaroylpyridines

Article abstract of DOI:10.1007/s10593-011-0784-2

Previously unknown 3,5-diaroylpyridines have been synthesized by the condensation of 1,3-diketones according to the Hantzsch reaction.

Full text of DOI:10.1007/s10593-011-0784-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 4, July 2011 (Russian original Vol. 47, No. 4, April, 2011)
SYNTHESIS OF 3,5-DIAROYLPYRIDINES
K. Garkushenko1, M. A. Makarova1,
O. P. Sorokina1, N. V. Poendaev1,
M. A. Vorontsova1, and G. P. Sagitullina1*
Previously unknown 3,5-diaroylpyridines have been synthesized by the condensation of 1,3-diketones
according to the Hantzsch reaction.
Keywords: 3,5-diaroylpyridines, 1,4-dihydropyridines, 1,3-diketones, Hantzsch pyridines.
The main method of synthesizing pyridines of symmetrical and unsymmetrical structure with various
sets of acceptor substituents (nitro, alkanoyl, aroyl, ethoxycarbonyl, cyano, carbamoyl, etc.) in positions 3 and 5
of the pyridine nucleus is the two-stage synthesis of Hantzsch [1–6]. The stage of cyclization of 1,4-dihyd-
ropyridines, which have a broad spectrum of biological activity [7–10], is constantly being improved, and has
several experimental modifications [11]. The stage of aromatization of the 1,4-dihydropyridines is carried out by
chemical, electrochemical, and enzymatic oxidation [12, 13]. The chemical oxidation of 1,4-dihydropyridines
has been well studied and a wide range of both organic and inorganic reagents have been used [14–18].
Progress in the investigation of the oxidation of dihydropyridines and the fundamental knowledge of
establishing the mechanism of the cleavage of the hydride-mobile hydrogen from dihydropyridines, for the
understanding of the most important biological processes involving nicotinamide-adenine dinucleotides and
their phosphates, is considered systematically and fully in a review [19].
The aim of the present work was the synthesis of previously unknown symmetrical 3,5-diaroylpyridines.
Interest in the synthesis of new representatives of 3,5-diaroyl-1,4-dihydro-pyridines is caused by the
recently discovered ability of certain 3,5-diacetyl- and 3,5-dibenzoyl-1,4-dihydropyridines to display the
properties of effective inhibitors of P-glycoprotein. An increase in the expression of P-glycoprotein and other
transmembrane transporters of medicinal preparations affects the emergence of drug resistance in various
illnesses, including many forms of cancer. One of the means of suppressing medicinal resistance is the use of
inhibitors of transport proteins, blocking the transport of medicinal substances from cells, and increasing their
intracellular concentration [20–22].
____________
Dedicated to bright memories of Professor Reva Safarovich Sagitullin
*To whom correspondence should be addressed; e-mail: Sagitullina@orgchem.univer.omsk.su.
1 F. M. Dostoevsky Omsk State University, Department of Organic Chemistry, 55a Mira Pr., Omsk 644077,
Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 586–590, April, 2011. Original
article submitted March 7, 2011.
0009-3122/11/4704-0482©2011 Springer Science+Business Media, Inc.
482

For the synthesis of 3,5-diaroyl-1,4-dihydropyridines 2a–g, having no substituent in position 4, the sim-
plest and most effective preparative method is the modified method of cyclocondensation of β-diketones 1a–g
according to Hantzsch. In place of formaldehyde and ammonia in the classical variant of the Hantzsch synthesis,
hexamethylenetetramine and ammonium acetate are used [11]. Only 3,5-dibenzoyl-1,4-dihydropyridine 2a of
the 1,4-dihydropyridines 2a–g synthesized by us by the procedure of [11], has been described previously [18].
HCHO
+
O
O
O
O
O
O
[O]
Ar
Ar
Ar
Ar
Ar
Ar
Me
N
H
2ag
Me
O
O
NH3
Me
Me
Me
N
Me
1ag
3ag
13 a Ar = Ph, b Ar = 4-ClC6H4, c Ar = 4-BrC6H4, d Ar = 4-MeOC6H4,
e Ar = 3-MeOC6H4, f Ar = 1-naphthyl, g Ar = 2-naphthyl
TABLE 1. Characteristics of the Synthesized Dihydropyridines 2a–g and
Pyridines 3b–g
Found, %
Calculated, %
Com-
pound
Yield,
%
Empirical formula
mp, °С*
С
H
N
–
2а
2b
2c
2d
2e
2f
C21H19NO2
C21H17Cl2NO2
C21H17Br2NO2
C23H23NO4
–
–
195–196
65
52
84
41
50
80
71
72
73
62
40
95
91
195–200 [18]
65.38
65.30
4.46
4.44
3.70
3.63
192–193
202–203
181–182
138–139
252–253
229–230
139–140
155–156
161–162
100–101
153–154
126–127
52.98
53.08
3.62
3.61
2.90
2.95
73.26
73.19
6.18
6.14
3.79
3.71
C23H23NO4
73.15
73.19
6.05
6.14
3.67
3.71
C29H23NO2
83.37
83.43
5.48
5.55
3.39
3.35
2g
3b
3c
3d
3e
3f
C29H23NO2
83.40
83.43
5.56
5.55
3.32
3.35
C21H15Cl2NO2
C21H15Br2NO2
C23H21NO4
65.70
65.64
3.95
3.93
3.71
3.65
53.38
53.31
3.18
3.20
3.05
2.96
73.57
73.58
5.61
5.64
3.68
3.73
C23H21NO4
73.62
73.58
5.60
5.64
3.76
3.73
C29H21NO2
83.88
83.83
5.13
5.09
3.44
3.37
3g
C29H21NO2
83.84
83.83
5.07
5.09
3.32
3.37
__________
*Solvent: dioxane (compound 2a), ethanol (compounds 2b–e, 3f,g), ace-
tic acid (compounds 2f,g), hexane (compounds 3b,c,e), 2-propanol (com-
pound 3d).
483

484

Under analogous conditions 3,5-diacetyl-1,4-dihydropyridine was formed from acetylacetone in 65%
yield but the remaining members of the series of 3,5-dialkanoyl-1,4-dihydropyridines were obtained in yields
from 20 to 48% [23]. Oxidative dehydrogenation of 3,5-dibenzoyldihydropyridine 2a to the corresponding
aromatic pyridine 3a was carried out by heating it with chloranil in benzene, but dihydropyridines 2b–g were
oxidized to aromatic pyridines 3b–g with sodium nitrite in acetic acid. It should be mentioned that pyridine 3a
was previously obtained by the reaction of 3,5-dicyano-2,6-dimethylpyridine with phenyl magnesium bromide,
however its melting point, given in [24], differed significantly from the melting point of pyridine 3a, obtained
by us by the oxidation of 3,5-dibenzoyl-1,4-dihydropyridine 2a. The structures of compounds 2b–g, 3b–g
synthesized for the first time, were confirmed by data of 1H NMR and IR spectra, and by elemental analysis. The
characteristics of compounds and the spectral data are given in Tables 1 and 2.
EXPERIMENTAL
The IR spectra were obtained on a Simex FT 801 instrument in the solid phase with an attachment for a
single broken internal reflection. The 1H NMR spectra were recorded on a Bruker Avance DRX-400 (400 MHz)
in CDCl3 and DMSO-d6, internal standard was the residual protons of the solvent (CDCl3 δ 7.25 and DMSO-d6
δ 2.50 ppm). Elemental analysis was carried out on a Perkin-Elmer CHN Analyzer. A check on the progress of
reactions and the purity of the obtained compounds was effected by TLC on Silufol UV-254 plates in the solvent
system benzene-ethyl acetate, 9:1, visualization was with UV light.
1,3-Diketones 1a–g, obtained by the procedures of [25–30] were used.
Synthesis of Dihydropyridines 2a–g (General Method). A mixture of the corresponding 1,3-diketone
1a–g (120 mmol), hexamethylenetetramine (urotropin) (1.54 g, 11 mmol), and ammonium acetate (4.92 g,
60 mmol) in ethanol (60 ml) was boiled for 1 h. After cooling, the precipitated solid was filtered off.
3,5-Dibenzoyl-2,6-dimethylpyridine (3a). A mixture of 1,4-dihydropyridine 2a (3.17 g, 10 mmol) and
chloranil (3.98 g, 16 mmol) in benzene (100 ml) was boiled for 2 h, the mixture was cooled and the precipitated
solid of tetrachlorohydroquinone was filtered off. Hydrochloric acid (15%, 20 ml) was added to the filtrate, the
aqueous layer was separated, neutralized with aqueous ammonia, and the precipitated pyridine was filtered off.
The yield of pyridine 3a 2.74 g (87%); mp 145–146oC (benzene–hexane) (lit. mp 80–81oC [24]).
Preparation of Pyridines 3b–g (General Method). Sodium nitrite (0.69 g, 10 mmol) was added in
portions at room temperature with stirring to a suspension of the corresponding dihydropyridine 2b–g (5 mmol)
in acetic acid (17 ml). After adding all the sodium nitrite the reaction mixture was stirred for 2 h at room
temperature. The mixture was then poured onto ice, neutralized with ammonia, and the precipitated crystals of
pyridines were filtered off, and washed with water.
REFERENCES
1.
A. E. Sausinsh and G. Ya. Duburs, Khim. Geterotsikl. Soedin., 435 (1992). [Chem. Heterocycl. Comp.,
28, 363 (1992)].
2.
3.
4.
5.
6.
U. Eisner and J. Kuthan, Chem. Rev., 72, 1 (1972).
J. Kuthan and A. Kurfűrst, Ind. Eng. Chem. Prod. Res. Dev., 21, 191 (1982).
D. M. Stout and A. I. Meyers, Chem. Rev., 82, 223 (1982).
V. L. Rusinov and O. N. Chupakhin, Nitroazines [in Russian], Nauka, Novosibirsk (1991), p. 85.
I. B. Dzvinchuk, N. A. Tolmachova, A. N. Chernega, and M. O. Lozinskii, Khim. Geterotsikl. Soedin.,
244 (2009). [Chem. Heterocycl. Comp., 45, 194 (2009).
7.
S. Visentin, B. Rolando, A. di Stilo, R. Fruttero, M. Novara, E. Carbone, C. Roussel, N. Vanthuyne, and
A. Gasco, J. Med. Chem., 47, 2688 (2004).
8.
9.
C. Velazquez and E. E. Knaus, Bioorg. Med. Chem., 12, 3831 (2004).
R. Shan, C. Velazquez, and E. E. Knaus, J. Med. Chem., 47, 254 (2004).
485

10.
11.
R. Shan. S. E. Howlett, and E. E. Knaus, J. Med. Chem., 45, 955 (2002).
Ya. R. Uldrikis, G. Ya. Dubur, I. V. Dipan, and B. S. Chekavichus, Khim. Geterotsikl. Soedin., 1230
(1975). [Chem. Heterocycl. Comp., 11, 1070 (1975)].
12.
13.
14.
15.
16.
S. P. Chavan, R. K. Kharul, U. R. Kalkote, and I. Shivakumar, Synth. Commun., 33, 1333 (2003).
R. H. Boecker and F. P. Guengerich, J. Med. Chem., 29, 1596 (1986).
J. S. Yadav, B. V. Subba Reddy, G. Sabitha, and G. S. Kiran Kumar Reddy, Synthesis, 1532 (2000).
X.-Q. Zhu, B.-J. Zhao, and J.-P. Cheng, J. Org. Chem., 65, 8158 (2000).
J. Stradin, R. Gavars, L. Baumane, B. Vigante, and G. Dubur, Khim. Geterotsikl. Soedin., 1079 (1993).
[Chem. Heterocycl. Comp., 29, 918 (1993)].
17.
18.
J.-J. Vanden Eynde, R. D’Orazio, and Y. Van Heverbeke, Tetrahedron, 50, 2479 (1994).
Ya. R. Uldrikis, A. O. Kumerova, and G. Ya. Dubur, Khim. Geterotsikl. Soedin., 691 (1973). [Chem.
Heterocycl. Comp., 9, 636 (1973)].
19.
20.
A. I. Matern, V. N. Charushin, and O. N. Chupakhin, Usp. Khim., 76, 27 (2007).
S. Saponara, A. Ferrara, B. Gorelli, A. Shah, M. Kawase, N. Motohashi, J. Molnar, G. Sgaragli, and
F. Fusi, Eur. J. Pharmacol., 563, 160 (2007).
21.
22.
23.
S. Saponara, M. Kawase, A. Shah, N. Motohashi, J. Molnar, K. Ugocsai, G. Sgaragli, and F. Fusi, Brit.
J. Pharmacol., 141, 415 (2004).
M. Kawase, A. Shah, H. Gaveriya, N. Motohashi, H. Sakagami, A. Varga, and J. Molnar, Bioorg. Med.
Chem., 10, 1051 (2002).
J. Ozols, R. Dubure, B. Vigante, M. Bundule, I. Zuika, Z. Brūveris, and G. Dubur, Latv. J. Chem., 209
(1991).
24.
25.
26.
27.
28.
29.
30.
J. Palacek, K. Vondra, and J. Kuthan, Coll. Czech. Chem. Commun., 34, 2991 (1969).
W. Hao, Y. Zhang, T. Ying, and P. Lu, Synth. Commun., 26, 2421 (1996).
A. Sieglitz and O. Horn, Chem. Ber., 84, 607 (1951).
K. V. Auwers and P. Heimke, Liebigs Ann. Chem., 458, 186 (1927).
Z. Budesinsky and V. Musil, Coll. Czech. Chem. Commun., 26, 2865 (1961).
T. Sanae and K. Siniti, Nippon Kagaku Zasshi, 80, 1183 (1959); Chem. Abstr., 55, 4466 (1961).
M. Regitz and A. Liedhegener, Chem. Ber., 99, 3128 (1966).
486