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email.gif - 0.3 KECHET96 Article 007 Nagatoshi Nishiwaki

Nitropyrimidinones: synthetic equivalents of unstable nitromalonaldehyde and diformylamine

Nagatoshi Nishiwaki, Yasuo Tohda and Masahiro Ariga*

Department of Chemistry, Osaka Kyoiku University, Asahigaoka 4-698-1, Kashiwara, Osaka 582, Japan


Synthetic route to nitropyrimidinones

Reaction of 1-methyl-5-nitropyrimidin-2(1H)-one 4 with bidentate ions

Ring transformation of 1-methyl-5-nitropyrimidin-2(1H)-one 4

Reaction of 3-methyl-5-nitro-4-pyrimidin-(3H)-one 5 with bidentate ions




The ring transformation of N-substituted 3,5-dinitropyridin-2(1H)-one 1 affords polyfunctionalized systems such as phenols 3,1 pyridotriazines,1 anilines,2 nitropyridines3 and so on. The stepwise nucleophilic addition of bidentate anion to pyridone 1 produced the bicyclic intermediate 2, from which anionic nitroacetamide is eliminated to give the ring transformed products. In these reactions, pyridone 1 behaves as the synthetic equivalent of unstable nitromalonaldehyde.

scheme 1
Two isomeric nitropyrimidinones 44 and 55 are azaanalogs of pyridone 1, which have a ring nitrogen instead of a nitro group. Thus, these compounds are considered to show similar electron deficiency and reactivities to dinitropyridone 1. Namely, 1-methyl-5-nitropyrimidin-2(1H)-one 4 consists of the masked nitromalonaldehyde and N-methylurea, and 3-methyl-5-nitropyrimidin-4(3H)-one 5 consists of activated diformylamine and N-methylnitroacetamide.

scheme 2

In this poster, we show the synthetic utilities of two isomeric nitropyrimidinones 4 and 5.

Synthetic route to nitropyrimidinones

The preparation of both nitropyrimidinones 4 and 5 are easily achieved in a few steps from commercially available reagents.

1-Methylpyrimidin-2(1H)-one hydrochloride 6 was quantitatively obtained by the condensation6 of N-methylurea and 1,1,3,3-tetramethoxypropane under acidic conditions. The nitration of pyrimidinone 6 with
15 M HNO3 in 18 M H2SO4 at 100 celsius afforded nitropyrimidinone 4 in 84% yield (from urea).


Nitropyrimidinone 5 was obtained from 2-thiouracil by reduction,7 methylation,7 and nitration with fuming HNO3 in 18 M H2SO4 at 100 celsius in 40% overall yield.
scheme 4

Reaction of 1-methyl-5-nitropyrimidin-2(1H)-one 4 with bidentate ions

Reaction of nitropyrimidinone 4 with diethyl acetonedicarboxylate in the presence of NEt3 in EtOH afforded 6,8-bis(ethoxycarbonyl)-7-hydroxy-2-methyl-9-nitro-3-oxo-2,4-diazabicyclo[3.3.1]ona-7-ene (8a) in 66% yield. In this case, the ring transformed product, trisubstituted phenol 3,1 was not detected. The same product 8a was also obtained in 76% yield when NaOEt and pyridine were used as the base and the solvent respectively. However employment of NaOEt was necessary to obtain 9 in the reaction for ethyl acetoacetate which has only one active methylene group.

The structures of bicyclic compounds 8 and 9 were confirmed by comparison of spectral data with those of 2 being a similar structure. The positions of the double bond in the ring skeletons is different. The product 8a was bicyclonona-7-ene derivative since spin-spin coupling was observed between H5 and four protons, H1, H4, H6, and H9, in the 2D 1H-1H COSY spectra. On the other hand, product 9 was bicyclonona-6-ene derivative since NOEs were observed between the proton at the 1-position and the N-methyl group, and between the proton at 9-position and the exo proton at the 8-position in the 2D 1H-1H NOESY spectra.
Based on these facts, the first attack of enolate ions occurred at the less hindered 4-position of pyrimidinone 4 to furnish the Meisenheimer like complex 10. The intramolecular addition of this adduct afforded bicyclic compounds 8 or 9. In the case of diethyl acetonedicarboxylate, enolization occurred towards the less bulky direction affording product 8.
scheme 5

Ring transformation of 1-methyl-5-nitropyrimidin-2(1H)-one 4

We reported that dinitropyridone 1 reacted with ketones in the presence of NH3 to give 3-nitropyridine derivatives in good yields.3) Thus, a similar ring transformation using nitropyrimidinone 4 was examined. 3-Nitropyridine derivatives were obtained but in low yields and the reaction mixture was complicated.
Compared with dinitropyridone 1, ring transformation of nitropyrimidinone 4 barely progressed, and the intermediate bicyclic compound was more readily isolated. The different reactivities were caused by a difference in stability of the leaving group, the anion of urea and nitroacetamide. It was reported that nitropyrimidinone having no substituent at the 1-position also gave a similar product under acidic conditions.4

It was found that nitropyrimidinone 4 behaved as the synthetic equivalent of nitromalonaldehyde, and was an excellent precursor for polyfunctionalized bicyclic compounds.

Although nitromalonaldehyde is a useful building block for constructing polyfunctionalized nitro compounds, it is too unstable to be isolated. As the synthetic equivalent of nitromalonaldehyde, its sodium salt has been employed for many years. Sodium nitromalonaldehyde, however, is used restrictively only in aqueous media, and should be handled as an explosive material before purification.8 Thus, an improvement in the other facile reagent substituting for nitromalonaldehyde is an important goal. From this point of view, nitropyrimidinone 4 and dinitropyridone 1 can be utilized as the synthetic equivalents of nitromalonaldehyde in organic media.9

Reaction of 3-methyl-5-nitro-4-pyrimidin-(3H)-one 5 with bidentate ions

To a solution of nitropyrimidinone 5 in EtOH, diethyl acetonedicarboxylate and NEt3 were added, and heated. During the reaction, 3,5-bis(ethoxycarbonyl)pyridin-4(1H)-one 11a precipitated. The present reaction was applicable to 2,4,6-heptatrione to yield pyridone derivative 11b. In the case of ethyl acetoacetate, the use of NaOEt was necessary. In these reactions, nitropyrimidinone 5 behaved as the synthetic equivalent of diformylamine.
The present reaction is considered to proceed as follows. Stepwise nucleophilic addition of bidentate ions to the 2- and 6-positions of pyrimidinone 5 furnished bicyclic intermediate 12. The anion of nitroacetamide is eliminated from 12 to give ring transformed products, 3,5-bis(functionalized)pyridones. Although two intermediates 12a and 12b were plausible, it was not determined which compound was produced since the bicyclic intermediate was not isolated. In this case, the stable leaving group, the anion of nitroacetamide, facilitated the ring transformation.
We have reported that the ring transformation of nitropyrimidinone 5 with ketones in the presence of ammonia readily affords disubstituted pyrimidine derivatives in which the C-N-C unit is derived from nitropyrimidinone 5.5
Ring transformations of nitropyrimidines, 5-nitrouracils and 5-nitropyrimidin-2(1H)-ones have been energetically investigated.10 Whereas there is no instance using 5-nitropyrimidin-4(3H)-ones to the best of our knowledge. Although some investigation utilizing diformylamine have been reported, few instances applying it to organic syntheses are known.11 Furthermore, diformylamine reveals greater amide character than formyl, undergoing nucleophilic substitution more readily than nucleophilic addition. In the present reaction, the ring transformed product is formally the latter reaction type, hence nitropyrimidinone 5 would be a useful synthetic reagent for constructing the C-N-C unit.


The present work was supported by a Grant-in Aid for Scientific Research (No. 04855170, No. 05640605, No. 07855107) from the Ministry of Education, Science and Culture of Japan, and supported by Daiichi Pharmaceutical Co Ltd Award in Synthetic Organic Chemistry, Japan.


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3 Tohda, Y.; Eiraku, M.; Nakagawa, T.; Usami, Y.; Ariga, M.; Kawashima, T.; Tani, K.; Watanabe, H.; Mori, Y. Bull. Chem. Soc. Jpn., 1990, 63, 2820.

4 Fox, J. J.; Su, T.-L.; Stempel, L. M.; Watanabe, K. A. J. Org. Chem., 1982, 47, 1081.

5 Nishiwaki, N.; Matsunaga, T.; Tohda, Y.; Ariga, M. Heterocycles, 1994, 38, 249.

6 Fox, J. J.; Praag, D. V. J. Am. Chem. Soc., 1960, 82, 486.

7 Bauer, L; Wright, G. E.; Mikrut, B. A.; Bell, C. L. J. Heterocycl. Chem., 1965, 2, 447.

8 Fanta, P. E.; Stein, R. A. Chem. Rev., 1960, 60, 261.; Fanta, P. E. Org. Synth., Coll. Vol. 4, 844 (1963).

9 Nishiwaki, N.; Tohda, Y.; Ariga, M. Bull. Chem. Soc. Jpn., 1996, 69, in press.; Tohda, Y.; Ariga, M.; Kawashima, T.; Matsumura, E. Bull. Chem. Soc. Jpn., 1987, 60, 201.

10 Rusinov, V. L.; Chupakhin, O. N.; van der Plas, H. C. Heterocycles, 1995, 40, 441.

11 Kashima, C.; Arao, H.; Hibi, S.; Omote, Y. Tetrahedron Lett., 1989, 30, 1561.; Flitsch, W.; Hampel, K.; Hohenhorst, M. Liebigs Ann. Chem., 1990, 397.