Novel method for the synthesis of furo[2,3-d]pyrimidines by cyclization of4-(phenacyloxy)pyrimidine-5-carbonitriles

Full text of DOI:10.1007/s10593-010-0520-3

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
NOVEL METHOD FOR THE SYNTHESIS OF
FURO[2,3-d]PYRIMIDINES BY CYCLIZATION OF
4-(PHENACYLOXY)PYRIMIDINE-5-CARBONITRILES
V. Gefenas1*, Ž. Stankevičiūtė1,2, and A. Malinauskas2
Keywords:
2-methylsulfanyl-4-(phenacyloxy)pyrimidine-5-carbonitriles,
furo[2,3-d]pyrimidines,
Thorpe-Ziegler cyclization, sodium ethoxide.
It is known that alkylation of 4(3H)-pyrimidinones occurs with the formation of a mixture of N(1)-, N(3)-,
and O-alkylation products [1, 2]. We have previously found [3, 4] that reaction of 5-cyano-2-methylsulfanyl-
4(3H)-pyrimidinone (1) with 4-substituted -bromoacetophenones 2a,b in the presence of potassium carbonate
and a catalytic amount of potassium iodide in anhydrous acetonitrile medium readily gives all three of the O-,
N(1)-, and N(3)- alkylations. The main reaction course (O-alkylation) gives the 2-methylsulfanyl-
4-(phenacyloxy)pyrimidine-5-carbonitriles 3a,b in preparative yields of 37-50%. In continuing our study of the
alkylation of 4(3H)-pyrimidinones we report here a novel synthetic route to the furo[2,3-d]pyrimidine system
via cyclization of 2-methylsulfanyl-4-(phenacyloxy)pyrimidine-5-carbonitriles 3a,b. Interest in the method of
synthesis of furo[2,3-d]pyrimidines is due to the wide spectrum of biological activity of these compounds [5-8].
The synthesis of the previously unknown 5-amino-6-(4'-R-benzoyl)-2-methylfulfanylfuro[2,3-d]pyrimi-
dines 4a,b from carbonitriles 3a,b was carried out under Thorpe-Ziegler cyclization conditions using the system
ethanol–sodium ethoxide. According to our data, such a transformation has only been studied for O-(-oxo)alkyl
derivatives of 3-cyano-2(1H)-pyridinone [9] (forming 3-aminofuro[2,3-d]pyridines) and the investigation of the
routes of synthesis of furo[2,3-b]pyrimidines by cyclization of pyrimidines has been mainly reported in the
literature through closing the side chain of 5-alkynyl derivatives [8] with only a single example of the
cyclization of 5-alkoxycarbonyl [5] and 5-cyano derivatives [10].
1
13
Elemental analysis, IR, and H and C NMR spectra obtained for compounds were fully in agreement
1
with the structures of the furo[2,3-d]pyrimidines 4a,b. For these compound the H NMR spectra show singlets
for the protons of the 5-amino group and H-4 of the pyrimidine ring at 7.67-7.84 and 9.26-9.27 ppm respectively
together with the absence of a signal for the OCH2 group appearing in the region 5.99-6.04 ppm in the 1H NMR
13
spectra of the starting carbonitriles 3a,b. The C NMR spectra of the furopyrimidines 4a,b show a shift of the
carbonyl carbon atom of 10.95-12.57 ppm to higher field when compared with those in compounds 3a,b and the
C-4a signal is seen near 131.5 ppm (the corresponding C-5 signal in the spectrum of carbonitriles 3a,b
_______
* To whom correspondence should be addressed, e-mail: vladasg@vpu.lt.
1Chemistry Department, Faculty of Natural Sciences, Vilnius Pedagogical University, Vilnius LT-08106,
Lithuania.
2 Institute of Chemistry, Vilnius LT-01108, Lithuania.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 464-467. March, 2010. Original
article submitted November 23, 2009.
372
0009-3122/10/4603-0372©2010 Springer Science+Business Media, Inc.

appearing at 90.9 ppm). The IR spectra show characteristic absorption bands for CO and NH at 1638-1622 and
3411-3200 cm-1 respectively together with the absence of the absorption for CN at 2229-2226 cm-1 which
characterizes compounds 3a,b.
R
Br
CN
O
R
CN
O
N
EtOH / EtONa / 
O
2a,b
N
N
H
MeS
K2CO3 / KI / MeCN
N
MeS
O
1
3a,b
4
4a
NH2
5
R
C
N
3
N
3'
5'
2'
6'
N
6
–
4'
1'
7a O
7
2
N
1
MeS
R
O
N
MeS
O
O
4a,b
2–4 a R = MeO, b R = Cl
1
The IR spectra were taken on a Perkin-Elmer BX-II FT-IR spectrophotometer for KBr tablets. H and
13C NMR spectra were recorded on a Varian INOVA spectrometer (300 and 75 MHz respectively) using
DMSO-d6 and with TMS as internal standard. Monitoring of the course of the reaction and the purity of the
compounds obtained was carried out by TLC on Silica Gel 60 F254 glass plates (Sigma-Aldrich) using the
system chloroform–ethyl acetate (4:1) and were revealed using UV light.
The starting 2-methylsulfanyl-4-(phenacyloxy)pyrimidine-5-carbonitriles 3a,b were prepared by method [4].
Compounds 4a,b (General Method). The corresponding 5-carbonitrile 3a,b (1.0 mmol) was added to a
solution of sodium ethoxide (1 mmol) prepared from metallic sodium (0.023 g, 1.0 mmol) in absolute ethanol
(10 ml) and the product was refluxed with stirring for 6-8 h using TLC to monitor the reaction course. The hot
reaction mixture was filtered and the precipitate on the filter was washed with refluxing ethanol (2×2.5 ml), and
recrystallized. The cooled mother liquor gave an additional amount of the furo[2,3-d]pyrimidines 4a,b.
5-Amino-2-methylsulfanyl-6-(4'-methoxybenzoyl)furo[2,3-d]pyrimidine (4a). Yield 63%; mp
1
238-240ºC (ethanol), Rf 0.43. IR spectrum, , cm-1: 3384, 3299, 3200 (NH), 1638 (C=O). H NMR spectrum, ,
ppm (J, Hz): 2.60 (3H, s, SCH3); 3.88 (3H, s, OCH3); 7.13 (2H, d, J = 9.0, H-3',5'); 7.67 (2H, s, NH2); 8.09 (2H, d,
J = 9.0, H-2',6'); 9.26 (1H, s, H-4). 13C NMR spectrum, , ppm: 14.65 (SCH3), 56.15 (OCH3); 109.33 (C-5); 114.48
(C-3',5'); 130.55 (C-1'); 131.42 (C-2',6'); 131.50 (C-4a); 154.47 (C-6); 162.89 (C-4'); 165.02 (C-7a), 172.92 (C-2);
180.31 (CO). Found, %: C 57.07; H 4.13; N 13.41. C15H13N3O3S. Calculated, %: C 57.13; H 4.15; N 13.32.
5-Amino-(4'-chlorobenzoyl)-2-methylsulfanyl-6-furo[2,3-d]pyrimidine (4b). Yield 50%; mp
246-249ºC (ethanol), Rf 0.39. IR spectrum, , cm-1: 3411, 3296 (NH), 1622 (C=O ketone). 1H NMR spectrum, ,
ppm (J, Hz): 2.59 (3H, s, SCH3); 7.65 (2H, d, J = 8.7, H-3',5'); 7.84 (2H, s, NH2); 8.05 (2H, d, J = 8.7, H-2',6');
13
9.27 (1H, s, H-4); C NMR spectrum, , ppm: 14.66 (SCH3); 109.12 (C-5); 129.28 (C-3',5'); 131.03 (C-2',6');
131.36 (C-4a); 136.65 (C-1'); 137.35 (C-4'); 141.95 (C-4); 154.72 (C-6); 165.18 (C-7a); 173.45 (C-2); 179.71
(CO). Found, %: C 52.46; H 3.23; N 13.02. C14H10ClN3O2S. Calculated, %: C 52.59; H 3.15; N 13.14.
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