Synthesis of novel 3,6-disubstituted furo[2,3-d]pyrimidines

Article abstract of DOI:10.3987/COM-08-11422

One-pot base catalyzed heterocyclization of 2-amino-5-phenyl-3- furancarbonitrile with various isothiocyanates afforded the novel furo[2,3-d]pyrimidine derivatives in high yields. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11422

HETEROCYCLES, Vol. 75, No. 10, 2008
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HETEROCYCLES, Vol. 75, No. 10, 2008, pp. 2549 - 2553. © The Japan Institute of Heterocyclic Chemistry
Received, 29th April, 2008, Accepted, 28th May, 2008, Published online, 2nd June, 2008. COM-08-11422
SYNTHESIS OF NOVEL 3,6-DISUBSTITUTED
FURO[2,3-d]PYRIMIDINES
Mehdi Bakavoli,* Mohammad Rahimizadeh, and Zinat Gordi
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad,
Mashhad, 91775-1436, Iran
E-mail: mbakavoli@yahoo.com
Abstract
–
One-pot
base
catalyzed
heterocyclization
of
2-amino-5-phenyl-3-furancarbonitrile with various isothiocyanates afforded the
novel furo[2,3-d]pyrimidine derivatives in high yields.
Furo[2,3-d]pyrimidines have received much attention due to their biological activities. Antifungal,1
antibacterial,2 antiviral,3 antifolate,4 antitumor,5 and anti-HCMV (human cytomegalovirus)6 activities
have been described for these compounds. Recently, some furopyrimidines were shown to be potent LCK
(lymphocyte-specific kinase),7 PI3K (phosphoinositide 3-kinase),8 VEGFR2 (vascular endothelial growth
factor receptor 2) and EGFR (epidermal growth factor receptor)9 inhibitors. Various methods for the
synthesis of furo[2,3-d]pyrimidines have been reported10 in the literature that mainly involve
cyclocondensation of 2-aminofuran derivatives with various electrophilic reagents such as formic acid,7,11
formamide,8,9 orthoesters,12,13 carbon disulfide,14 thiourea15 and isothiocyanates.16 In pursuing our work
on the synthesis of polyheterocyclic systems,17 we wish to report a convenient one-pot synthesis of
new 3-aryl-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thiones (3a-f) as a key precursor for
the synthesis of various furans polyheterocyclic compounds.
In the present work we have employed heterocyclization of 2-amino-5-phenyl-3-furancarbonitrile (1) with
aryl- and alkyl isothiocyanates for the synthesis of new 3,6-disubstitutedfuro[2,3-d]pyrimidines (3a-f).
Cyclocondensation of 2-amino-5-phenyl-3-furancarbonitrile (1) with aryl and alkyl isothiocyanates (2a-f)
in the presence of potassium t-butoxide in t-butanol under reflux gave products identified as
3-aryl-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thiones (3a-f) as shown in Scheme 1.

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HETEROCYCLES, Vol. 75, No. 10, 2008
NH
CN
R1
S
t-BuOK
N
+ R1-N=C=S
t-BuOH
Ph
NH2
Ph
O
O
N
H
2a-f
1
3a-f
d) R1= 3-Br-C6H4
e) R1= 2-Br-C6H4
f) R1= Et
a) R1= Ph
b) R1= 4-Cl-C6H4
c) R1= 4-Br-C6H4
Scheme 1
The structures of new compounds were confirmed by spectral data. For example, the IR spectrum of 3f
was devoid of the stretching vibration bands at 3375, 3280 and 2180 cm-1 for NH2 and CN absorption of
the precursor but instead showed new absorption bands at 3400, 1640 and 1270 cm-1 for NH, C=N and
1
C=S groups, respectively. The H-NMR spectra in DMSO-d6 showed two broad singlets at 4.65 and 8.6
due to NH groups as well as a triplet (1.25) and a quartet (3.5) corresponding to ethyl group and the
characteristic signals at 7.2-7.7 for phenyl group. Furan proton showed a singlet at 7.05 ppm. Mass
spectrum of the compound showed the molecular ion peak at m/z 271 and 273 corresponding to the (M+)
and (M++2). Also this compound gave satisfactory elemental analysis data.
In conclusion, we have developed
a
facile method for one pot synthesis of new
through base-catalyzed
3-aryl-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thiones
cyclocondensation of 2-amino-5-phenyl-3-furancarbonitrile with aryl- and alkyl isothiocyanates. The
efficiency of the present work is apparent from high yields with the lack of side product. It is noteworthy
that the present method is preferred over a similar reported method because of its relative higher yields
and the lack 16 of Dimroth rearrangement.
EXPERIMENTAL
The melting points were recorded on an Electrothermal type 9100 melting point apparatus. The IR spectra
were obtained on a 4300 Shimadzu Spectrometer. The 1HNMR (100 MHz) spectra were recorded on a
Bruker AC 100 spectrometer. The mass spectra were scanned on a Varian Mat CH-7 instrument at 70 eV.
Elemental analyses were obtained on
a
Thermo Finnigan Flash EA microanalyzer.
2-Amino-5-phenyl-3-furonitrile (1) is a known compound and was prepared according to literature.18

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1. General procedure for the synthesis of 3-aryl-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]
pyrimidin-2(1H)-thiones 3a-f
To a solution of the 2-amino-5-phenyl-3-furancarbonitrile (1) (1.84 g, 10 mmol) and potassium t-butoxide
(1.68 g, 15 mmol) in t-butanol (40 mL), aryl or alkyl isothiocyanate (2a-f) (12 mmol) was added. The
reaction mixture was heated under reflux for 4 h. After the completion of the reaction (monitored by TLC
CHCl3 : MeOH 9:1), the solvent was evaporated, the residue was dissolved in water (20 mL) and
subsequently neutralized by 1N HCl. The crude product was filtered, washed with water and
recrystallized from EtOH to give compounds (3a-f) in 75-92 % yields.
1.1. 4-Imino-3,6-diphenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3a). Compound 3a was
obtained in 76 % yield; shining yellow solids; mp 220-221 ˚C; IR (KBr) : 3400, 1640, 1275 cm-1.
1H-NMR (DMSO-d6, 100 MHz) δ: 3.5 (br s, 1H, NH), 7.1-7.7 (m, 11H), 8.3 (br s, 1H, NH). MS (m/z):
319 (M+), 194, 135, 105, 93, 77 (base peak), 65, 51. Anal. Calcd for C18H13N3OS: C, 67.69; H, 4.10; N,
13.16; S, 10.04. Found: C, 67.57; H, 3.97; N, 13.10; S, 9.89.
1.2. 3-(4-Chlorophenyl)-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3b).
Compound 3b was obtained in 90 % yield; white solids; mp 212-213 ˚C; IR (KBr) : 3450, 1650, 1275
cm-1. 1H-NMR (DMSO-d6, 100 MHz) δ: 4.2 (br s, 1H, NH), 7.15 (s, 1H), 7.2-8.0 (m, 9H), 8.4 (br s, 1H,
NH). MS (m/z): 353 (M+, base peak), 295, 169, 140, 127, 105, 77. Anal. Calcd for C18H12ClN3OS: C,
61.10; H, 3.42; N, 11.88; S, 9.06. Found: C, 61.02; H, 3.28; N, 11.84; S, 8.91.
1.3. 3-(4-Bromophenyl)-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3c).
Compound 3c was obtained in 88 % yield; white solids; mp 240-242 ˚C; IR (KBr) : 3450, 1645, 1270
cm-1. 1H-NMR (DMSO-d6, 100 MHz) δ: 4.2 (br s, 1H, NH), 7.20 (s, 1H), 7.41 (AB q, 4H, ∆ν/J = 2.5, J =
6 Hz), 7.5-7.8 (m, 5 H), 8.6 (br s, 1H, NH). MS (m/z): 399 (M++2), 397 (M+, base peak), 341, 339, 260,
259, 173, 159, 140, 130, 115, 105, 77, 63. Anal. Calcd for C18H12BrN3OS: C, 54.28; H, 3.04; N, 10.55; S,
8.05. Found: C, 54.06; H, 2.97; N, 10.35; S, 7.82.
1.4. 3-(3-Bromophenyl)-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3d).
Compound 3d was obtained in 86 % yield; yellow solids; mp 215-216 ˚C; IR (KBr) : 3450, 1650, 1270
1
cm-1. H-NMR (DMSO-d6, 100 MHz) δ: 3.4 (br s, 1H, NH), 7.0-7.9 (m, 10 H), 8.3 (br s, 1H, NH). MS
(m/z): 399 (M++2), 397 (M+, base peak), 340, 339, 260, 259, 171, 158, 140, 130, 116, 103, 77, 51. Anal.
Calcd. for C18H12BrN3OS: C, 54.28; H, 3.04; N, 10.55; S, 8.05. Found: C, 54.09; H, 2.98; N, 10.43; S,
7.99.
1.5. 3-(2-Bromophenyl)-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3e).
Compound 3e was obtained in 90 % yield; yellow solids; mp 185-186 ˚C; IR (KBr) : 3450, 1650, 1270
cm-1. 1H-NMR (DMSO-d6, 100 MHz) δ: 6.75 (s, 1H), 6.7-7.7 (m, 9H), 7.7 (br s, 1H, NH), 8.7 (br s, 1H,

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HETEROCYCLES, Vol. 75, No. 10, 2008
NH). MS (m/z): 399 (M++2), 397 (M+, base peak), 341, 339, 260, 259, 170, 155, 140, 130, 114, 105, 77,
63. Anal. Calcd for C18H12BrN3OS: C, 54.28; H, 3.04; N, 10.55; S, 8.05. Found: C, 53.94; H, 2.98; N,
10.83; S, 7.92.
1.6. 3-Ethyl-4-imino-6-phenyl-3,4-dihydrofuro[2,3-d]pyrimidin-2(1H)-thione (3f). Compound 3f was
1
obtained in 92 % yield; white solids; mp 246-245 ˚C; IR (KBr) : 3450, 1640, 1275 cm-1. H-NMR
(DMSO-d6, 100 MHz) δ: 1.25 (t, 3H, J = 8 Hz), 3.45 (q, 2H, J = 8 Hz), 4.6 (br s, 1H, NH), 7.05 (s, 1H),
7.2-7.7 (m, 5H), 8.6 (br s, 1H, NH). MS (m/z): 273 (M++2), 271 (M+, base peak), 255, 243, 227, 213, 212,
185, 184, 155, 140, 127, 105, 77, 51. Anal. Calcd for C14H13N3OS: C, 61.97; H, 4.83; N, 15.49; S, 11.82.
Found: C, 62.01; H, 4.71; N, 15.33; S, 11.64.
REFERENCES
1. M. M. H. Bhuiyan, K. M. M. Rahman, M. K. Hossain, M. A. Rahim, and M. I. Hossain, Croat.
Chem. Acta, 2005, 78, 633.
2.
C. G. Dave and R. D. Shah, Molecules, 2002, 7, 554.
3. (a) Z. Janeba, J. Balzarini, G. Andrei, R. Snoeck, E. DeClercq, and M. J. Robins, J. Med. Chem.,
2005, 48, 4690. (b) F. Amblard, V. Aucagne, P. Guenot, R. F. Schinazi, and L. A. Agrofoglio,
Bioorg. Med. Chem., 2005, 13, 1239.
4. (a) A. Gangiee, Y. Zeng, J. J. McGuire, and R. L. Kisliuk, J. Med. Chem., 2005, 48, 5329. (b)
Gangiee, Y. Zeng, J. J. McGuire, F. Mehraein, and R. L. Kisliuk, J. Med. Chem., 2004, 47, 6893.
5. (a) A. Gangjee, Y. Zeng, M. Ihnat, L. A. Warnke, D. W. Green, R. L. Kisliuk, and F.-T. Lin, Bioorg.
Med. Chem., 2005, 13, 5475. (b) A. Gangiee, Y. Zeng, J. J. McGuire, and R. L. Kisliuk, J. Med.
Chem., 2000, 43, 3125.
6. M. J. Robins, K. Miranda, V. K. Rajwanshi, M. A. Peterson, G. Andrei, R. Snoeck, E. DeClercq,
and J. Balzarini, J. Med. Chem., 2006, 49, 391.
7. E. F. DiMauro, J. Newcomb, J. J. Nunes, J. E. Bemis, C. Boucher, J. L. Buchanan, W. H. Buckner,
A. Cheng, T. Faust, F. Hsieh, X. Huang, J. H. Lee, T. L. Marshall, M. W. Martin, D. C. McGowan,
S. Schneider, S. M. Turci, R. D. White, and X. Zhu, Bioorg. Med. Chem. Lett., 2007, 17, 2305.
8. M. Hayakawa, H. Kaizawa, H. Moritomo, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta,
S.-I. Tsukamoto, F. I. Raynaud, P. Workman, M. D. Waterfield, and P. Parker, Bioorg. Med. Chem.
Lett., 2007, 17, 2438.
9. A. Martin-Kohler, J. Widmer, G. Bold, T. Meyer, U. Séquin, and P. Traxler, Helv. Chem. Acta, 2004,
87, 956.
10. (a) D. Dauzonne and A. Adam-Launay, Tetrahedron, 1992, 48, 3069. (b) R. G.
Melik-Ogandzhanyan, V. E. Khachatryan, and A. S. Gapoyan, Usp. Khim., 1985, 54, 450.

HETEROCYCLES, Vol. 75, No. 10, 2008
2553
11. J. I. Pyo, E. J. Hwang, C. S. Cheong, S.-H. Lee, S. W. Lee, I. T. Kim, and S. H. Lee, Synthetic
Metals, 2005, 155, 461.
12. Y. Miyazaki, J. Tang, Y. Maeda, M. Nakano, Y. Okamoto, A. T. Truesdale, D. F. Hassler, E. N.
Nartey, D. R. Patrick, M. L. Ho, and K. Ozawa, Bioorg. Med. Chem. Lett., 2007, 17, 1773.
13. R. M. Shaker, ARKIVOC, 2006, part (xiv), 68.
14. M. G. Testa, G. Perrini, U. Chiacchio, and A. Corsaro, J. Chem. Res. (S), 1993, 302.
15. M. Kidwai, A. D. Mishra, and S. Saxena, Indian J. Chem., 2005, 44B, 581.
16. K. R. Jyothikumari and K. N. Rajasekharan, J. Indian Chem. Soc., 1991, 68, 660.
17. (a) M. Bakavoli, F. A. Sani, A. Davoodnia, M. Roshani, and F. Pirouzi, Heterocyclic Commun.,
2007, 13(6), 371. (b) M. Bakavoli, B. Reihani, M. Rahimizadeh, and M. Nikpour, Phosphorus
Sulfur Silicon, 2006, 181, 99. (c) A. Davoodnia, M. Bakavoli, A. Vahedinia, M. Rahimizadeh, and
M. Roshani, Heterocycles, 2006, 68, 801. (d) M. M. Heravi, M. Bakherad, M. Rahimizadeh, M.
Bakavoli, and M. Ghassemzadeh, Heterocyclic Commun., 2004, 10, 335.
18. X. Feng, J.-C. Lancelot, A.-C. Gillard, H. Landelle, and S. Rault, J. Heterocycl. Chem., 1998, 35,
1313.