Reaction of 2-alkylthio-6-amino-pyrimidin-4(3H)-ones with ethyl bromopyruvate. Synthesis of furo-[2,3-d]-pyrimidine and furo[3,2-e]imidazo-[1,2- c]pyrimidine carboxylates

Article abstract of DOI:10.1007/s10593-009-0264-0

Reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones with ethyl bromopyruvate to give ethyl 2-alkyl-thio-4-aminofuro[2,3-d]pyrimidine-5- carboxylates has been shown to proceed under neutral or acidic conditions. The obtained furo[2,3-d]pyrimidines underwen

Full text of DOI:10.1007/s10593-009-0264-0

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
REACTION OF 2-ALKYLTHIO-6-AMINO-
PYRIMIDIN-4(3H)-ONES WITH ETHYL
BROMOPYRUVATE. SYNTHESIS OF FURO-
[2,3-d]-PYRIMIDINE AND FURO[3,2-e]IMIDAZO-
[1,2-c]PYRIMIDINE CARBOXYLATES
V. Masevicius1, G. Petraityte1, S. Tumkevicius1*
Reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones with ethyl bromopyruvate to give ethyl 2-alkyl-
thio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates has been shown to proceed under neutral or acidic
conditions. The obtained furo[2,3-d]pyrimidines underwent further cyclocondensation reaction with
ethyl bromopyruvate to afford diethyl 5-alkylthiofuro[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxy-
lates.
Keywords: furo[3,2-e]imidazo[1,2-c]pyrimidines, furo[2,3-d]pyrimidines, pyrimidin-4(3H)-ones,
cyclization.
Recently we showed that esters of thieno[2,3-d]pyrimidine-6-carboxylic acids are useful precursors for
the synthesis of analogues of folic acid and other 6-(arylamino)methylthieno[2,3-d]pyrimidines – potential
inhibitors of dihydrofolate reductase [1, 2]. Continuing our work on the synthesis of fused heterocycles with
anticipated biological and pharmaceutical activities we present herein some findings on the synthesis of 2-alkyl-
thio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates by the reaction of 2-alkylthio-6-aminopyrimidin-4(3H)-ones
(1) with ethyl bromopyruvate. There are only few examples of such an approach to furo-[2,3-d]pyrimidine-
5-carboxylates [3, 4] in the literature and they show that such a cyclocondensation reaction can be performed
under basic conditions. However, attempts to apply the described procedures for the synthesis of 3a,b, using
triethylamine or K2CO3 as basic reagents, failed. Nevertheless, it was found that the cyclocondensation reaction
of 1a,b with an equivalent amount of ethyl bromopyruvate proceeds under neutral or acidic conditions to give
furopyrimidines 2a,b in good yields. Formation of the corresponding pyrrolo-[2,3-d]pyrimidines was not
observed. When an excess of ethyl bromopyruvate was used and the reaction was carried out at room
temperature together with furopyrimidines 2, formation of furo[3,2-e]imidazo[1,2-c]pyrimidines 3 was also
observed. For example, 3b was isolated as a side product (0.4%) from the reaction of 1b with 2 eq. of ethyl
bromopyruvate.
_______
* To whom correspondence should be addressed, e-mail: sigitas.tumkevicius@chf.vu.lt.
1Vilnius University Department of Organic Chemistry, Vilnius LT-03225, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 440-443, March, 2009. Original
article received February 17, 2009.
0009-3122/09/4503-0357©2009 Springer Science+Business Media, Inc.
357

Compounds 3a,b in reasonable yields were obtained by heating 2a,b with ethyl bromopyruvate in
toluene or o-xylene. Performing reaction of 2b with ethyl bromopyruvate at room temperature in
dichloromethane allowed us to isolate a small amount of intermediate 5 which under crystallization from
2-propanol quantitatively underwent conversion to furo[3,2-e]imidazo[1,2-c]pyrimidine 3b. Reaction of 2a,b
iv
O
EtO
1
O
9
O
N
OEt
2
OEt
NH2
O
3
i
N
5
N
HN
4
+
8
O
O
RS
N
RS
N
RS
N
NH2
7
6
1a,b
2a,b
ii
3a,b
iii
OEt
O
N
O
1
2
3
O
O
NH
OEt
N
OEt
O
9
N
5
4
8
EtO
O
PhCH2S
N
O
RS
N
6
7
5
4a,b
1–5 a R = Me, b R = CH2Ph
not formed
Reagents and conditions: i – BrCH2COCO2Et, DMF, r.t.; ii – BrCH2COCO2Et, CH2Cl2, r.t.;
iii – 2-propanol, ∆; iv – BrCH2COCO2Et, toluene or o-xylene, ∆
with ethyl bromopyruvate can give either compounds 3a,b or their isomers 4a,b. Notable difference in the NMR
spectra between these compounds must be chemical shifts of imidazole carbon atoms with attached proton (C-3
in compounds 3a,b and C-2 in compounds 4a,b). The signal for this carbon in the 13C NMR spectra of the
13
synthesized compounds was clearly identified from C NMR DEPT (45°) spectra. To make a choice between
possible products of this reaction, calculations of the NMR spectra were performed with Gausian 98 program [5]
13
using the DFT B3LYP method with 6-31G(d,p) basis set. Chemical shift of the calculated C NMR spectrum for
C-3 of compound 3a was found to be 117.7 ppm. This value is in good match with δexp(C-3) = 115.2 ppm of the
synthesized furo[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxylate 3a, whereas the calculated value of chemical shift
for C-2 of compound 4a is 146.7 ppm. Analogous results were also obtained for compound 3b: δexp(C-3) = 115.3
ppm, δcalc(C-3) = 118.4 ppm, while δcalc(C-2) for compound 4b is 145.9 ppm. Thus, it can be unambiguously
concluded that diethyl furo[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxylates 3a,b are formed in the reaction of
2-alkylthio-4-aminofuro[2,3-d]pyrimidine-5-carboxylates 2a,b with ethyl bromopyruvate.
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected. IR spectra were run on a
1
13
Perkin–Elmer FT-IR spectrophotometer Spectrum BX II in nujol. H and C NMR spectra were recorded on a
Varian Unity Inova spectrometer (300 and 75 MHz, respectively) in CDCl3 using residual CHCl3 signals (7.29 and
358

77.3 ppm for 1H and 13C NMR spectra, respectively) as internal standard. Elemental analyses were performed at
the Elemental Analysis Laboratory of the Department of Organic Chemistry of Vilnius University. TLC was
performed with silica gel 60 F254 aluminum plates (Merck), visualisation with UV light.
Ethyl 4-Amino-2-methylthiofuro[2,3-d]pyrimidine-5-carboxylate (2a). A mixture of compound 1a [6]
(9.06 g, 57.7 mmol), DMF (20 ml) and 90% ethyl bromopyruvate (8 ml, 57.38 mmol) was stirred at room
temperature for 24 h. Then water was added and the resulting precipitate was filtered off, washed with diethyl ether,
and recrystallized to give 11.8 g (81%) of compound 2a; mp 167–168.5°C (benzene). IR spectrum, ν, cm-1: 3370,
3295, 3142 (NH2), 1702 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.42 (3H, t, J = 7.2, CH3); 2.60 (3H, s, CH3S);
4.41 (2H, q, J = 7.2, CH2); 5.80 (1H, s, NH); 7.91 (1H, s, NH); 7.97 (1H, s, CH). 13C NMR spectrum, δ, ppm: 14.4;
14.5; 61.9; 95.1; 114.2; 145.8; 158.2; 164.1; 168.3; 169.6. DEPT (45º) spectrum, δ, ppm: 14.3; 14.5; 62.0; 145.8.
Found, %: C 47.61; H 4.46; N 16.79. C10H11N3O3S. Calculated, %: C 47.42; H 4.38; N 16.59.
Ethyl 4-Amino-2-benzylthiofuro[2,3-d]pyrimidine-5-carboxylate (2b) was synthesized from 1b [7]
according to the procedure described for compound 2a. Yield 58%. When 1–2 drops of conc. H2SO4 were added
to the reaction mixture, compound 2b was isolated in 57% yield; mp 184–185 °C (benzene). IR spectrum, ν,
cm-1: 3381, 3297 (NH2), 1708 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.34 (3H, t, J = 7.2, CH3); 4.42 (2H, q,
J = 7.2, CH2); 4.46 (2H, s, CH2S); 5.60 (1H, s, NH); 7.25–7.38 (3H, m, C6H5); 7.46–7.52 (2H, m, C6H5); 7.92
13
(1H, s, NH); 7.98 (1H, s, CH). C NMR spectrum, δ, ppm: 14.5; 35.6; 62.0; 95.5; 114.3; 127.4; 128.7; 129.4;
137.9; 145.8; 158.4; 164.0; 168.3; 168.7. DEPT (45º) spectrum, δ, ppm: 14.5; 35.6; 62.0; 127.4; 128.7; 129.4;
145.9. Found, %: C 58.74; H 4.73; N 12.45. C16H15N3O3S. Calculated, %: C 58.34; H 4.59; N 12.76.
Diethyl 5-Methylthiofuro[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxylate (3a). A mixture of
compound 2a (0.25 g, 0.99 mmol), toluene (50 ml), and 90% ethyl bromopyruvate (0.149 ml, 0.23 g, 1.2 mmol) was
refluxed using a Dean–Stark trap for 9 h. Then toluene was evoparated to dryness and the residue recrystallized to
give 0.14 g (41%) of compound 3a; mp 215–216.5°C (benzene). IR spectrum, ν, cm–1: 1712, 1703 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 1.49 (3H, t, J = 7.2, CH3); 1.54 (3H, t, J = 7.2, CH3); 2.89 (3H, s, SCH3); 4.46–4.55 (4H,
13
m, 2CH2); 8.22 (1H, s, CH); 8.28 (1H, s, CH). C NMR spectrum, δ, ppm: 14.4; 14.5; 61.7; 61.8; 100.9; 115.2;
116.1; 138.2; 141.7; 146.8; 149.7; 157.4; 161.8; 162.9. DEPT (45º) spectrum, δ, ppm: 14.4; 14.5; 61.7; 61.8; 115.2;
146.8. Found, %: C 51.43; H 4.24; N 11.85. C15H15N3O5S. Calculated, %: C 51.57; H 4.33; N 12.03.
Diethyl 5-Benzylthiofuro[3,2-e]imidazo[1,2-c]pyrimidine-2,9-dicarboxylate (3b) was synthesized
according to the procedure described for compound 3a, using o-xylene as a solvent. Reaction time 2 h. Yield
1
45%; mp 154–155°C (methanol). IR spectrum, ν, cm–1: 1739, 1713 (C=O). H NMR spectrum, δ, ppm (J, Hz):
1.48 (3H, t, J = 7.2, CH3); 1.54 (3H, t, J = 7.2, CH3); 4.42–4.56 (4H, m, 2CH2); 4.74 (2H, s, CH2S); 7.35–7.42
(3H, m, C6H5); 7.50–7.56 (2H, m, C6H5); 8.24 (1H, s, CH); 8.25 (1H, s, CH). 13C NMR spectrum, δ, ppm: 14.4;
14.5; 36.4; 61.7; 61.8; 101.2; 115.3; 116.1; 128.5; 129.2; 129.6; 135.1; 138.2; 141.8; 146.9; 148.7; 157.2; 161.8;
162.9. DEPT (45º) spectrum, δ, ppm: 14.4; 14.5; 36.4; 61.7; 61.8; 115.2; 128.5; 129.2; 129.6; 146.9. Found, %:
C 60.05; H 4.43; N 9.82. C21H19N3O5S. Calculated, %: C 59.28; H 4.50; N 9.88.
Ethyl 2-Benzylthio-3-(3-ethoxy-2,3-dioxopropyl)-4-imino-3,4-dihydrofuro[2,3-d]pyrimidine-5-carboxy-
late (5) starts melting at 119oC, then solidifies, with final mp 154–155oC. IR spectrum, ν, cm–1: 1750 (sh), 1736,
1704 (C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.48–1.36 (6H, m, 2CH3); 4.38–4.57 (4H, m, 2CH2); 4.60 (1H, d,
J = 12.9, COCH2N); 4.75 (1H, s, CH2S); 4.79 (1H, s, CH2S); 5.20 (1H, dd, J = 12.9, J = 2, COCH2N); 7.36–7.42
(3H, m, C6H5); 7.44–7.5 (2H, m, C6H5); 8.15 (1H, s, CH); 9.2 (1H, s, NH). 13C NMR spectrum, δ, ppm: 14.3; 14.5;
37.2; 57.2; 63.2; 64.1; 90.0; 95.1; 115.3; 128.8; 129.3; 129.7; 133.7; 148.1; 153.3; 160.5; 161.9; 166.2; 166.3.
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