The p-(dimethylamino)benzaldehyde modification of Hantzsch reaction: Synthesis of 6-(1H-benzimidazol-2-yl)pyrido[2,3-d]pyrimidino-2,4(1H, 3H)-diones

Article abstract of DOI:10.1007/s10593-007-0069-y

The reaction between p-(dimethylamino)benzaldehyde and 2-acylmethyl-1H- benzimidazoles and 6-amino-1,3-dimethylpyrimidino-2,4(1H,3H)-dione has given previously unknown 5-unsubstituted 6-(1H-benzimidazol-2-yl)pyrido[2,3-d] pyrimidino-2,4(1H,3H)-diones. The reaction occurs on boiling in acetic and acid and includes the formation of 1,4-dihydropyridine-bearing compounds in accordance with the Hantzsch reaction scheme and aromatization as a result of cleavage of N,N-dimethylaniline.

Full text of DOI:10.1007/s10593-007-0069-y

Chemistry of Heterocyclic Compounds, Vol. 43, No. 4, 2007
THE p-(DIMETHYLAMINO)BENZALDEHYDE MODIFICATION
OF HANTZSCH REACTION: SYNTHESIS OF 6-(1H-BENZIMIDAZOL-
2-YL)PYRIDO[2,3-d]PYRIMIDINO-2,4(1H, 3H)-DIONES
I. B. Dzvinchuk and M. O. Lozinskii
The reaction between p-(dimethylamino)benzaldehyde and 2-acylmethyl-1H-benzimidazoles and 6-amino-
1,3-dimethylpyrimidino-2,4(1H,3H)-dione has given previously unknown 5-unsubstituted 6-(1H-
benzimidazol-2-yl)pyrido[2,3-d]pyrimidino-2,4(1H,3H)-diones. The reaction occurs on boiling in acetic and
acid and includes the formation of 1,4-dihydropyridine-bearing compounds in accordance with the Hantzsch
reaction scheme and aromatization as a result of cleavage of N,N-dimethylaniline.
Keywords: aldehydes, benzimidazoles, pyrido[2,3-d]pyrimidines, pyrimidines, pyrazoles,
aromatization, Hantzsch reaction, selectivity.
Substituted pyridines are frequently made by Hantzsch reaction in various modifications [1, 2]. We have
found that the reaction between p-(dimethylamino)benzaldehyde (1), dimedone, and ammonium acetate on
boiling in acetic acid is accompanied by the formation of an aromatic pyridine ring without the use of an
oxidizing agent: the reaction occurs through the combination of acridine with the 1,4-dihydropyridine fragment
containing the 4-(dimethylamino)phenyl substituent in the γ-position, and ends with the aromatization by the
splitting off of N,N-dimethylaniline [3]. There are attractive prospects for using this as a new approach to
synthesis of compounds containing γ-unsubstituted pyridine rings, but the situation is not entirely clear. We have
examined this on the reactions in a three-component system: the aldehyde 1, the 2-acylmethyl-
1H-benzimidazoles 2a-h, and 6-amino-1,3-dimethylpyrimidino-2,4(1H,3H)-dione (3). The reaction of
compound 3 with various 1,3-dielectrophils has recently been used extensively in the synthesis of
pyrido[2,3]d]pyrimidines [4-18], but the reactions with compounds 1 and 2 has not been examined before.
We found that boiling reagents 1-3 in acetic acid did not end with the formation of typical compounds in
the 1,4-dihydropyridine series 4a-h. The reaction was accompanied by aromatization, which probably occurs via
the C-protonated forms 5a-h, which readily split off N,N-dimethylaniline, and these to 5-unsubstituted 6-(1H-
benzimidazol-2-yl)pyrido[2,3-d]pyrimidino-2,4(1H,3H)-diones 6a-h. The reaction goes to completion in 2 h.
The products are readily isolated by diluting the reaction mixtures with water. The yields are 78-93%.
The process occurs highly selectively under relatively mild conditions and is of fairly general character.
It is not complicated by substantial side-reactions such as disproportionation, oxidation, or dehydrogenization of
the 1,4-dihydropyridine compounds 4, or the interaction of the aldehyde 1 with products from the nucleophile
reaction centers in them. Correspondingly, the substituent R in position 7 of the pyridopyrimidines 6 may vary
__________________________________________________________________________________________
Institute of Organic Chemistry, Ukrainian National Academy of Sciences, Kiev 02094; e-mail:
Rostov@bpci.kiev.ua Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 585-589, April 2007.
Original article submitted July 31, 2006.
480
0009-3122/07/4304-0480©2007 Springer Science+Business Media, Inc.

481

TABLE 1. Characteristics of Synthesized Compounds 6a-h
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
mp, °С
С
Н
N
6a
6b
6c
6d
6e
6f
C17H15N5O2
C22H17N5O2
C23H19N5O3
C25H23N5O5
C22H16BrN5O2
C22H16N6О4
C22H16N6О4
C20H15N5О3
63.29
63.54
68.73
68.92
66.69
66.82
63.18
63.42
57.07
57.16
61.49
61.68
61.53
61.68
64.18
64.34
4.88
4.71
4.55
4.47
4.78
4.63
5.02
4.90
3.55
3.49
3.84
3.76
3.89
3.76
3.94
4.05
21.58
21.79
18.16
18.27
16.77
16.94
14.55
14.79
15.13
15.15
19.41
19.62
19.44
19.62
18.57
18.76
248.5-250
303-304.5
337-338.5
272-273.5
>350
93
78
85
79
85
85
82
83
304-305.5
>350
6g
6h
306-307.5
from alkyl to various aryl species, including the furan type. The yield trend in the series 6a-h indicates that the
reaction is only slightly dependent on the nature of the substituent R (when one corrects for the losses on
isolation arising from differences in solubility).
TABLE 2. 1H NMR Spectra of Synthesized Compounds
Com-
pound
δ, ppm (J, Hz)
6a
6b
2.98 (3H, s, 7-CH3); 3.31 (3H, s, 1-CH3); 3.58 (3H, s, 3-CH3); 7.22-7.23 (2H, m, H-5',6');
7.53-7.55 (1H, m, H-7'); 7.67-7.68 (1H, m, H-4'); 8.72 (1H, s, H-5); 12.90 (1H, s, NH*)
3.36 (3H, s, 1-CH3); 3.65 (3H, s, 3-CH3); 7.15-7.22 (2H, m, H-5',6'); 7.29 (2H, t, J = 7.5,
C6H5: H-3,5); 7.35 (1H, t, J = 7.5, C6H5: H-4); 7.38 (1H, d, J = 7.8, H-7'); 7.44 (1H, d,
J = 7.5, C6H5: H-4); 7.60 (1H, d, J = 7.5, H-4'); 8.61 (1H, s, H-5); 12.59 (1H, s, NH)
6c
6d
6e
6f
3.34 (3H, s, 1-CH3); 3.62 (3H, s, 3-CH3); 3.69 (3H, s, CH3O); 6.78 (2H, d, J = 8.4, C6H4O:
H-3,5); 7.18-7.21 (2H, m, H-5',6'); 7.34 (2H, d, J = 9.0, C6H4O: H-2,6);
7.50 (2H, m, H-4',7'); 8.53 (1H, s, H-5); 12.68 (1H, s, NH)
3.36 (3H, s, 1-CH3); 3.41 (6H, s, 3,5-CH3O); 3.63 (3H, s, 3-CH3); 3.68 (3H, s, 4-CH3O);
6.73 (2H, s, C6H2); 7.21-7.23 (2H, m, H-5',6'); 7.45 (1H, m, H-7'); 7.64 (1H, m, H-4');
8.55 (1H, s, H-5); 12.62 (1H, s, NH)
3.35 (3H, s, 1-CH3); 3.63 (3H, s, 3-CH3); 7.19-7.21 (2H, m, H-5',6'); 7.33 (2H, d,
J = 8.4, C6H4Br: H-3,5); 7.42-7.48 (3H, m, H-7' + C6H4Br: H-3,5); 7.59 (1H, m, H-4');
8.63 (1H, s, H-5); 12.72 (1H, s, NH)
3.34 (3H, s, 1-CH3); 3.61 (3H, s, 3-CH3); 7.16-7.18 (2H, m, H-5',6'); 7.36 (1H, d,
J = 7.8, H-7'); 7.46-7.50 (2H, m, H-4' + 3-O2NC6H4: H-5); 7.65 (1H, d, J = 8.4,
3-O2NC6H4: H-6); 8.11 (1H, d, J = 8.4, 3-O2NC6H4: H-4); 8.21 (1H, s, 3-O2NC6H4: H-2);
8.72 (1H, s, H-5); 12.89 (1H, s, NH)
6g
6h
3.34 (3H, s, 1-CH3); 3.61 (3H, s, 3-CH3); 7.16-7.18 (2H, m, H-5',6');
7.59 and 7.05 (2×2H, two d, J = 9.0, 4-O2NC6H4); 8.74 (1H, s, H-5); 12.96 (1H, s, NH)
3.33 (3H, s, 1-CH3); 3.67 (3H, s, 3-CH3); 6.60-6.62 (1H, m, furyl: H-4); 6.84 (1H, d,
J = 3.3, furyl: H-3); 7.21-7.29 (2H, m, H-5',6'); 7.54 (1H, d, J = 8.1, H-7'); 7.71 (1H, d,
J = 7.2, H-4'); 7.77 (1H, d, J = 0.9, furyl: H-5); 8.46 (1H, s, H-5); 12.82 (1H, s, NH)
_______
* Undergoes deuterium exchange.
482

Attempts to replace the aldehyde 1 by formaldehyde, paraformaldehyde, or urotropine in the three-
component reaction, including with the addition of nitrobenzene as oxidizing agent, have been unsuccessful:
such reactions show little selectivity and it has proved impossible to isolate compounds of type 6 or their
precursors of 1,4-dihydropyridine structure.
The compositions and structures of the synthesized pyrido[2,3-d]pyridines are confirmed by elemental
analysis (Table 1) and by the 1H NMR spectra (Table 2).
The structures of compounds 6a-h are of the same type, since the signals from the protons in the
fragments appearing in each of them occur in narrow ranges in the chemical shifts, and they vary quite regularly
with the nature of substituent R. In particular, the H-5 singlet signal (corresponding to the γ-position in the
pyridine ring) appears clearly in weak fields at 8.46-8.74 mp, and it shifts towards the weak-field side as we pass
from electron-donor substituents R to electron-acceptor ones.
We thus confirm the practical usefulness of the p-dimethylaminobenzaldehyde modification of the
reaction in the synthesis of previously unknown 5-unsubstituted 6-(1H-benzimidazol-2-yl)pyrido[2,3-d]-
pyrimidino-2,4(1H,3H)-diones, but it is likely that the topic is not completely exhausted by this particular
example.
EXPERIMENTAL
The reactions were monitored and the purity of the synthesized compounds was verified by TLC on
1
Silufol UV-254 plates in the benzene-ethanol solvent system, 9:1, development in UV light. The H NMR
spectra were recorded with a Varian VXR-300 spectrometer (300 MHz) in DMSO-d6, standard TMS. All the
compounds were dried for 5 h at 145°C before elemental analysis and spectral test.
6-(1H-benzimidazol-2-yl)-1,3,7-trimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (6a). A mixture
of aldehyde 1 (0.149 g, 1 mmol), 2-acetonylbenzimidazole (2a) (0.174 g, 1 mmol), and compound 3 (0.155 g,
1 mmol) was mixed with 2 ml of glacial acetic acid and kept at 120°C for 2 h. Water was added by drops with
stirring to the boiling solution until the reaction mixture became thick. After cooling, the precipitate was filtered
off and washed with a mixture of 2-propanol and water, 1:1. Yield 0.297 g. The product was recrystallized from
a 2:1 pyridine–water mixture.
Similarly, compounds 6b-h were made from compounds 1, 2b-h, and 3. Compounds 6c-e were
recrystallized from a 2:1 dimethylformamide–water mixture.
REFERENCES
1.
2.
3.
K. V. Vatsuro and G. L. Mishchenko, Named Reactions in Organic Chemistry [in Russian], Khimiya,
Moscow (1976).
F. E. Sausin'sh and G. Ya. Dubur, Khim. Geterotsikl. Soed., 435 (1992) [Chem. Heterocycl. Comp., 28,
363 (1992)].
I. B. Dzvinchuk and N. A. Tolmacheva, Khim. Geterotsikl. Soed., 554 (2001) [Chem. Heterocycl.
Comp., 37, 506 (2001)].
4.
5.
6.
7.
8.
9.
A. Agarwal and P. M. S. Chauhan, Tetrahedron Lett., 46, 1345 (2005).
A. Agarwal and P. M. S. Chauhan, Synth. Commun., 34, 4447 (2004).
U. Girreser, D. Heber, and M. Schuett, Tetrahedron, 60, 11511 (2004).
M. Takahashi, H. Nagaoka, and K. Inoue, J. Heterocycl. Chem., 41, 525 (2004).
I. Devi and P. J. Bhuyan, Synlett, 283 (2004).
E. C. Taylor and B. Bhatia, Heterocycles, 61, 113 (2003).
483

10.
11.
I. Devi, B. S. D. Kumar, and P. J. Bhuyan, Tetrahedron Lett., 44, 8307 (2003).
D. M. Volochnyuk, A. O. Pushechnikov, D. G. Krotko, D. A. Sibgatulin, S. A. Kovalyova, and
A. A. Tolmachev, Synthesis, 10, 1531 (2003).
12.
13.
14.
15.
16.
T. Kuwada, K. Harada, J. Nobuhiro, T. Choshi, and S. Hibino, Heterocycles, 57, 2081 (2002).
D. D. Hughes and M. C. Bagley, Synlett, 1332 (2002).
R. B. Nicewonger, L. Ditto, D. Kerr, and L. Varady, Bioorg. Med. Chem. Lett., 12, 1799 (2002).
M. Nitta and H. Kanda, Heterocycles, 57, 491 (2002).
N. Rosas, P. Sharma, C. Alvarez, A. Cabrera, R. Ramires, A. Delgado, and H. Arzoumanian, J. Chem.
Soc., Perkin Trans. 1, 19, 2341 (2001).
17.
18.
A. A. S. El-Ahl, S. A. A. E. Bialy, and M. A. Ismail, Heterocycles, 55, 1315 (2001).
P. Srivastava, A. S. Saxena, and V. J. Ram, Synthesis, 541 (2000).
484