Reaction of 5-Nitroso-6-Aminouracils with Glyoxylic Acid – A Simple Synthetic Pathway to Uric Acid Derivatives

Full text of DOI:10.1007/s10600-017-2065-5

DOI 10.1007/s10600-017-2065-5
Chemistry of Natural Compounds, Vol. 53, No. 3, May, 2017
REACTION OF 5-NITROSO-6-AMINOURACILS WITH
GLYOXYLIC ACID – A SIMPLE SYNTHETIC PATHWAY
TO URIC ACID DERIVATIVES
*
Yu. A. Azev, O. S. Ermakova, and V. S. Berseneva
Purines are commonly synthesized by the method proposed by Traube that is based on cyclization of
4,5-aminopyrimidines with urea, formamide, or formic acid [1]. The reaction of 4,5-aminopyrimidines with C cyclizing
2
agents (glyoxal, glyoxylic acid derivatives, etc.) synthesized pteridine derivatives [1, 2]. Heating 5-nitroso-6-aminouracils
with aldehydes formed 7-hydroxyxanthine derivatives [3]. Uric acid is the final product from oxidation (metabolism) of
purines in living organisms. Its level characterizes the metabolic condition. Serious diseases can manifest if its in vivo content
increases. Therefore, monitoring of the secretion level of uric-acid and its derivatives is especially significant [4]. Practically
the whole set of natural purine bases or the nucleic acids incorporated into the structure or resulting from purine metabolism
can be synthesized from uric acid [1].
The reactions of uracil amine derivatives with C cyclizing agents were investigated in order to develop simple and
2
convenient synthetic pathways to purine and pteridine derivatives. An unusual transformation of 5-nitroso-6-aminouracils 1a
and 1b during the reaction with glyoxylic acid was discovered during the work. Thus, brief heating of 1a and 1b and glyoxylic
acid in formic acid formed smoothly and in high yield uric-acid derivatives 2a and 2b (Scheme 1).
_
O
O
O
O
O
O
R
R
R
+
NH
NH
NO
NH
O
2
2
N
OH
N
N
N
-H O
2
N
H
OH
O
N
CH
O
N
O
N
2
CH
CH
3
3
3
3a, b
1a, b
I
1
O
R = CH
3
Cl
OCH
3
O
O
OH
N
O
H
H
N
H
N
H C
O
R
3
R
O
- CH OH
3
N
N
O
N
O
OCH
- CO
3
2
N
H
2a, b
N
H
O
N
CH
O
N
CH
3
O
N
CH
OH
NH
2
- H O
2
3
3
4
I
2
a: R = H; b: R = CH
3
Scheme 1
The masses of 2a and 2b that were determined by mass spectrometry agreed with those calculated. PMR spectra of
2a and 2b exhibited resonances for the corresponding methyl protons. Furthermore, the structures of 2a and 2b were confirmed
by convergent syntheses. Thus, heating known 5,6-diamino-1,3-dimethylpyrimidine-2,4-(1H,3H)-dione (3b) and methyl
chloroformate produced methyl (6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)carbamate (4), the structure
of which was confirmed using PMR spectroscopy and mass spectrometry.
Heating 4 to the melting point (225–230°C) formed dimethyluric acid that was identical to 2b.
Yeltsin Ural Federal University, 19 Mira St., Ekaterinburg, 620002, Russia, e-mail: azural@yandex.ru. Translated
from Khimiya Prirodnykh Soedinenii, No. 3, May–June, 2017, pp. 509–510. Original article submitted August 23, 2016.
©
0009-3130/17/5303-0603 2017 Springer Science+Business Media New York
603

The uric-acid derivatives were presumably formed as a result of initial cyclization of nitrosoaminouracils 1a and 1b
with glyoxylic acid to form intermediate I , which transformed during the reaction into intermediate I . Subsequent hydroxylation
1
2
and simultaneous decarboxylation of intermediate I gave uric-acid derivatives 2a and 2b.
2
The observed transformation of the nitrosoaminouracils represented a simple pathway to uric-acid derivatives under
mild conditions and in one step. The uric-acid derivatives were formed in high yields and could be easily isolated and
identified. Obviously, the observed transformation would be useful for studying purine metabolism in biological systems.
PMR spectra were recorded on a Bruker Avance-400 spectrometer. Mass spectra were obtained on a Shimadzu
GCMS-QP2010 Ultra at ionization potential 75 eV and 200°C.
Starting nitrosoaminouracils 1a and 1b and diaminouracils 3a and 3b were synthesized by the literature methods [2, 5].
Reaction of Nitrosopyrimidines 1a and 1b with Glyoxylic Acid. The appropriate 6-amino-5-nitrosopyrimidine-
2,4-dione 1 (1.5 mmol) and glyoxylic acid (6.0 mmol) in formic acid (5.0 mL) were heated at 50°C for 15–20 min. The
resulting precipitate of the corresponding uric-acid derivative 2 was filtered off and recrystallized from H O.
2
1
3-Methyl-1H-purino-2,6,8(3H,7H,9H)-trione (2a). Yield 67%, mp > 300ꢀÑ. Í NMR spectrum (400 MHz, DMSO-d ,
6
ꢁ, ppm, J/Hz): 3.24 (3Í, s, ÑÍ ), 10.69 (1Í, s, NH), 10.96 (1Í, s, NH), 11.78 (1Í, s, NH). Mass spectrum (EI, 70 eV), m/z
3
+
(I ,%): 182 ([M ], 67), 139 (67), 111 (16), 83 (34), 68 (100). C H N O .
rel
6 6 4 3
1
1,3-Dimethyl-1H-purino-2,6,8(3H,7H,9H)-trione (2b). Yield 70%, mp > 300ꢀÑ. Í NMR spectrum (400 MHz,
DMSO-d , ꢁ, ppm, J/Hz): 3.11 (3H, s, ÑÍ ), 3.21 (3H, s, ÑÍ ), 10.65 (1Í, s, NH), 11.79 (1H, br.s, NH). Mass spectrum
6
3
3
+
(EI, 70 eV), m/z (I ,%): 196 ([Ì ], 95), 139 (43), 111 (15), 83 (36), 68 (100). C H N O . The PMR spectrum of 2b agreed
rel
7 8 4 3
with that in the literature [6].
Methyl (6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)carbamate (4). Compound 3b
(60.0 mg, 0.35 mmol) and methyl chloroformate (0.5 mL, 5.3 mmol) in MeCN (2.0 mL) were heated at 80°C for 4 h.
1
The resulting precipitate of 4 was filtered off. Yield 85%, mp 214–215ꢀÑ. Í NMR spectrum (400 MHz, DMSO-d , ꢁ, ppm,
6
J/Hz): 3.09 (3H, s, ÑÍ ), 3.15 (3H, s, ÑÍ ), 3.61 (3H, s, ÑÍ ), 6.56 (2H, s, NH ), 7.48 (1H, s, NH). Mass spectrum (EI, 70 eV),
3
3
3
2
+
m/z (I ,%): 228 ([M ], 24), 196 (100), 168 (15), 142 (13), 83 (70). C H N O .
rel
8 12 4 4
REFERENCES
1.
D. T. Hurst, An Introduction to the Chemistry and Biochemistry of Pyrimidines, Purines and Pteridines,
John Wiley & Sons, Chichester, New York, Brisbane, and Toronto, 1980, 266 pp.
F. F. Blicke and H. C. Godt, J. Am. Chem. Soc., 76, 2798 (1954).
G. Zvilichovsky, H. Garbi, and E. Nemes, J. Heterocycl. Chem., 19 (1), 205 (1982).
A. Taniguchi and N. Kamatani, Jpn. J. Clin. Med., 12 (66), 2378 (2008).
2.
3.
4.
5.
6.
H. B. Cottam, H. Shih, L. R. Tehrani, D. B. Wasson, and D. A. Carson, J. Med. Chem., 39, 2 (1996).
V. N. Bobkov, T. V. Zvolinskaya, and I. I. Kuzmenko, Chem. Heterocycl. Compd., 27 (5), 560 (1991).
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