A facile synthesis of functionalized 1,2,6,7-tetrahydroimidazo[1,5-C] pyrimidine-3,5-diones

Article abstract of DOI:10.1080/00397911.2012.707738

A Pd-mediated hydrogenation of ethyl 6-azidomethyl-1,2,3,4-tetrahydro-4-R- 2-oxo-5-pyrimidinecarboxylates leads to the corresponding ethyl 6-aminomethyl1,2,3,4-tetrahydro-4-R-2-oxo-5-pyrimidinecarboxylates. The latter react with bis(trichloromethyl) carbonate, yielding the title ethyl 1,2,3,5,6,7-hexahydro-7-R-3,5-dioxoimidazo[1,5-c] pyrimidine-8-carboxylates. Copyright

Full text of DOI:10.1080/00397911.2012.707738

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A Facile Synthesis of Functionalized 1,2,6,7-
Tetrahydroimidazo[1,5-c]pyrimidine-3,5-diones
Pavlo S. Lebed' a , Pavlo O. Kos a , Andrey Tolmachev b , Mykhaylo V. Vovk a , Alexander N.
Boyko b & Alexey Chekotylo b
a Institute of Organic Chemistry National Academy of Sciences of Ukraine, Kyiv, Ukraine
b ChemBioCenter, National Taras Shevchenko University, Kiev, Ukraine
Accepted author version posted online: 20 Mar 2013.
To cite this article: Pavlo S. Lebed' , Pavlo O. Kos , Andrey Tolmachev , Mykhaylo V. Vovk , Alexander N. Boyko &
Alexey Chekotylo (2013): A Facile Synthesis of Functionalized 1,2,6,7-Tetrahydroimidazo[1,5-c]pyrimidine-3,5-
diones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.707738
To link to this article: http://dx.doi.org/10.1080/00397911.2012.707738
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A FACILE SYNTHESIS OF FUNCTIONALIZED 1,2,6,7-
TETRAHYDROIMIDAZO[1,5-C]PYRIMIDINE-3,5-DIONES
Pavlo S. Lebed’1, Pavlo O. Kos1, Andrey Tolmachev2, Mykhaylo V. Vovk1, Alexander N.
Boyko2, Alexey Chekotylo2
1Institute of Organic Chemistry National Academy of Sciences of Ukraine, Kyiv,
Ukraine, 2ChemBioCenter, National Taras Shevchenko University, Kiev, Ukraine
Address correspondence to Pavlo S. Lebed’, Institute of Organic Chemistry National
Academy of Sciences of Ukraine, Murmanskaya st. 5, 02094, Kyiv, Ukraine. E-mail:
p_lebed@rambler.ru.
Abstract
A Pd-mediated hydrogenation of ethyl 6-azidomethyl-1,2,3,4-tetrahydro-4-R-2-oxo-5-
pyrimidinecarboxylates leads to the corresponding ethyl 6-aminomethyl1,2,3,4-
tetrahydro-4-R-2-oxo-5-pyrimidinecarboxylates. The latter react with
bis(trichloromethyl)carbonate yielding the title ethyl 1,2,3,5,6,7-hexahydro-7-R-3,5-
dioxoimidazo[1,5-c]pyrimidine-8-carboxylates.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications® to view the free supplemental file.
KEYWORDS: ethyl 6-azidomethyl-2-oxo-5-pyrimidinecarboxylates; ethyl 6-
aminomethyl-2-oxo-5-pyrimidinecarboxylates; bis(trichloromethyl)carbonate; ethyl 3,5-
dioxoimidazo[1,5-c]pyrimidine-8-carboxylates.
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INTRODUCTION
The imidazo[1,5-с]pyrimidine unit, a structural analogue of purine, is found in
compounds exhibiting a wide spectrum of biological activities. For example, 6-
methylimidazo[1,5-с]tetrahydropyrimidine-5-thion (Zapotidine)[1,2] possesses hypnotic,
sedative, and hypotensive activity. Additionally, some derivatives of imidazo[1,5-
с]tetrahydropyrimidin-5-one were shown to be efficient adenosine antagonists.[3]
Recently a semi-synthetic glycopeptide antibiotic containing tetrahydroimidazo[1,5-
с]pyrimidine fragment was found to exhibit exceptional antibacterial activity that was
higher than that of the widely used vancomycin.[4]
A most popular synthetic approach to the imidazo[1,5-c]pyrimidines consists of
cyclocondensation of histamine with N,N’-carbonyldiimidazole,[5-11] N,N’-
thiocarbonyldiimidazole,[12] bis(4-nitrophenyl)carbonate,[13] and S-phenyl ester of
chlorothiocarbonic acid.[14] This methods allow a straightforward preparing of 5-oxo- or
5-thio-derivatives of imidazo[1,5-c]pyrimidines. At the same time there is a limited
number of synthetic procedures for the preparation of imidazo[1,5-c]pyrimidine
derivatives bearing multiple functional groups. Available examples of the multiply
functionalized imidazo[1,5-c]pyrimidines include esters of imidazo[1,5-c]pyrimidine-7-
cabroxylic and imidazo[1,5-c]pyrimidine-8-carboxylic acids.[15,16] It is therefore of
importance to develop synthetic routes to the imidazo[1,5-c]pyrimidine derivatives
bearing several functional groups serving as diversity points for the rational design of
libraries of biologically potent compounds. We have recently reported[16] a convenient
approach to a functionalized imidazo[1,5-c]pyrimidine system. The approach consisted of
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an annulation of imidazole unit to 6-azidomethyl-5-ethoxycarbonyl-3,4-
dihydropyrimidin-2-ones resulting in ethyl esters of 3-amino-5-
oxotetrahydroimidazo[1,5-c]pyrimidine-8-carboxylic acids. In this contribution we
improve and expand this method to prepare 3,5-dioxo-derivatives of imidazo[1,5-
c]pyrimidine-8-carboxylic acids.
RESULTS AND DISCUSSION
The presented synthetic route is summarized in Scheme 1. In the first step readily
available 6-azidomethyl-2-oxo-3,4-dihydropyrimidine-5-carboxylates 1a-e are reduced
into corresponding 6-aminomethyl derivatives 2a-e. Analysis of the literature[17-20] shows
that the catalytic hydrogenation under Pd/С is the most suited technique to smoothly
convert various azidomethyl heterocycles into corresponding amines. The data presented
in Table 1 demonstrate that in our hands the reduction was indeed successful with yields
of 54-83%. Prepared compounds 2a-e, although contain both the nucleophilic amino-
group and the electrophilic ethoxycarbonyl functionality, do not undergo self-
condensation under ambient conditions.[21] The annulation of imidazolidin-2-one unit in
2a-e takes place through the reaction with bis(trichloromethyl)carbonate.[22] As depicted
in Scheme 1 6-aminomethylpryrimidines 2a-e readily react with
bis(trichloromethyl)carbonate leads to ethyl 1,2,3,5,6,7-hexahydro-7-R-3,5-
dioxoimidazo[1,5-c]pyrimidine-8-carboxylates 3а-е with moderate to high yields (Table
1).
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According to available literature reports on the reaction of the
bis(trichloromethyl)carbonate with amines[22] the conversion of compounds 2 to 3
proceeds with displacement of bis(trichloromethyl) groups from
bis(trichloromethyl)carbonate to give tetrahydroimidazo[1,5-c]pyrimidine-3,5-diones 3.
This constitutes a significant improvement of our formerly reported procedure[16] in
which carbodiimide intermediates underwent cyclization in boiling chlorobenzene with
low yields on account of a side reaction, that was 1,3-prototropic shift in the allyl subunit
of the tetrahydroimidazopyrimidine.
1H and 13C NMR spectroscopy, liquid chromatography / mass spectrometry (LC/MS),
and elemental analyses of compounds 2 and 3 confirmed their structural integrity and
high purity.
CONCLUSIONS
An efficient and smooth approach to the novel functionalized hexahydroimidazo[1,5-
c]pyrimidine derivatives was developed. The approach consists of two reaction steps
occurring under mild conditions. First, the 6-azidomethylpyrimidine-2-ones are reduced
catalytically to the 6-aminomethylpyrimidine-2-ones. The latter undergo
cyclocondensation by treatment with bis(trichloromethyl)carbonate.
EXPERIMENTAL
Melting points were measured with Tomas Hoover apparatus and uncorrected. IR spectra
were recorded on a Nexus-470 spectrophotometer in KBr tablets. 1H and 13C NMR
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spectra were registreted in DMSO-d6 on Bruker AVANCE DRX 500, Varian UNITY
Plus 400, and Varian VRX-300 instruments with TMS as an internal standard.
Compounds 1 were synthesized according to reported procedures.[16]
General Procedure For The Preparation Of Ethyl 6-(Aminomethyl)-1,2,3,4-
Tetrahydro-4-R-2-Oxo-5-Pyrimidinecarboxylates (2a-E)
The hydrogen was bubbled slowly into a stirred suspension of 6-azidomethylpyrimidine
1a-e (0.003 mol) and 10 mol % Pd/C (100 mg) in ethanol (10 mL) over a period of 8h.
Then the reaction mixture was heated to reflux and the catalyst was filtered off. The
filtrate solvent was removed under reduced pressure. The solid residue was crystallized
from benzene and dried in vacuum.
Ethyl 6-(aminomethyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (2a). IR (ν,
сm-1): 1705 and 1730 (C=O), 3225 and 3310 (NH), 3360 (NH2). 1H NMR (300 MHz,
DMSO-d6) δ (ppm): 1.18 (t, 3H, J = 6.7 Hz, CH3,), 3.64 (s, 2H, CH2), 3.89 (s, 2Н, СН2),
4.06 (q, 2H, J = 6.7 Hz, CH2), 7.09 (brs, 1H, NH). 13С NMR (125 MHz) δ (ppm): 14.59
(СН3), 40.65 (СН2), 41.04 (СH2), 59.66 (СН2), 93.33 (С), 153.18 (С=O), 153.58 (С),
165.50 (С=О). Anal. calcd. (%) for C8H13N3O3: С, 48.23; Н, 6.58; N, 21.09. Found: С,
48.43; Н, 6.50; N, 21.28.
General Procedure For Preparation Of Ethyl 1,2,3,5,6,7-Hexahydro-7-R-3,5-Dioxo-
Imidazo[1,5-C]Pyrimidine-8-Carboxylates (3a-E)
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To a solution of bis(trichloromethyl)carbonate (1.07 g, 0.0036 mol) in dry
dichloromethane (10 mL) a solution of triethylamine (1.09 g, 0.0108 mol) in dry
dichloromethane (2 mL) was added dropwise at 5 °C. Then 6-aminomethylpyrimidine
2a-e (0.0036 mol) was slowly added to the stirred reaction mixture at 5 °C. The reaction
mixture was stirred at room temperature for 6h. A solid precipitate formed was filtered
and washed with deionized water (25×3 mL). The crude product was crystallized from
methanol and dried in vacuum.
Ethyl 3,5-dioxo-1,2,3,5,6,7-hexahydroimidazo[1,5-c]pyrimidine-8-carboxylate (3a).
IR (ν, сm-1): 1700 and 1765 (C=O), 3280 (NH). 1H NMR (400 MHz, DMSO-d6) δ (ppm):
1.21 (t, 3Н, J = 5.9 Hz, CH2СН3), 3.94 (s, 2H, CH2), 4.10 (m, 2Н, СН2СН3), 4.30 (s, 1H,
CH2), 7.51 (s, 1H, NH), 8.03 (s, 1H, NH). 13C NMR (125 MHz, DMSO-d6) δ (ppm):
14.08 (СН3), 40.30 (СH2), 42.58 (СH2), 59.91 (СН2), 95.19 (С), 146.59 (С), 147.46
(С=O), 152.76 (С=O), 163.95 (С=О). Anal. calcd. (%) for C9H11N3O4: С, 48.00; H, 4.92;
N, 18.66. Found: С, 47.71; Н, 5.08; N, 18.55.
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Table 1. Isolated yields and melting points of ethyl 2-oxo-5-pyrimidine-carboxylates 2a-e
and ethyl 3,5-dioxoimidazo[1,5-c]pyrimidine-8-carboxylates 3a-e.
Entry
R
Yield
(%)
54
Mp (°C) Entry
R
Yield
(%)
63
Mp (°C)
2a
2b
2c
2d
2e
H
161-162 3a
162-163 3b
166-167 3c
159-160 3d
153-154 3e
H
212-213
216-217
226-227
218-219
237-238
Me
Ph
75
Me
Ph
58
80
70
4-ClC6H4 56
4-ClC6H4 61
4-
83
4-
76
MeOC6H4
MeOC6H4
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Scheme 1. Synthetic pathway for the preparation of ethyl 1,2,3,5,6,7-hexahydro-7-R-3,5-
dioxoimidazo[1,5-c]pyrimidine-8-carboxylates 3a-e.
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