Synthesis of two new heterocyclic systems: Furo[3',2':5,6]pyrimido[2,1-c] [1,2,4]triazines and furo[3,2-e][1,2,3,4]tetrazolo[1,5-a]pyrimidine

Article abstract of DOI:10.1007/BF03246571

Two novel heterocyclic triazines and tetrazole systems were synthesized through cyclization of 2-hydrazino-furo[2,3-d]pyrimidine with α-haloketones and nitrous acid respectively in high yields. The starting 2-hydrazino-pyrimidine was synthesized from 4-im

Full text of DOI:10.1007/BF03246571

J. Iran. Chem. Soc., Vol. 8, No. 4, December 2011, pp. 1135-1138.
JOURIrNaAnLiaOnF THE
Chemical Society
Synthesis of Two New Heterocyclic Systems: Furo[3',2':5,6]pyrimido[2,1-
c][1,2,4]triazines and Furo[3,2-e][1,2,3,4]tetrazolo[1,5-a]pyrimidine
M. Rahimizadeha,*, M. Bakavolia, Z. Gordia,b and S.M. Seyedia
aDepartment of Chemistry, Ferdowsi University of Mashhad, Mashhad 91775-1436, Iran
bDepartment of Chemistry, Payame Noor University (PNU), Torbat-e-Heydarieh, Iran
(Received 31 August 2010, Accepted 10 June 2011)
Two novel heterocyclic triazines and tetrazole systems were synthesized through cyclization of 2-hydrazino-furo[2,3-
d]pyrimidine with α-haloketones and nitrous acid respectively in high yields. The starting 2-hydrazino-pyrimidine was
synthesized from 4-imino-3,6-diphenyl-furo[2,3-d]pyrimidine-2(1H)-thione by methylation and subsequent nucleophilic
displacement of methylthio group with hydrazine hydrate.
Keywords: Furo[2,3-d]pyrimidine, α-Haloketones, Triazines, Tetrazole
INTRODUCTION
of some novel tricyclic fused furo[3,2-e][1,2,3,4]tetrazolo[1,5-
a]pyrimidine and furo[3',2':5,6]pyrimido [2,1-c][1,2,4]
4
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 receptor2) and EGFR (epidermal
growth factor receptor) [9] inhibitors. Furthermore, a wide
range of biological activities [10-13] has been attributed to
fused triazoles, triazines and tetrazoles. In connection with our
interest in the synthesis of polyheterocyclic systems [14], we
recently reported [15,16] the synthesis of substituted 2-amino-
3-furonitriles and 3,6-disubstituted-furo[2,3-d]pyrimidines as
key-precursors for this purpose. Arising from these studies, we
now report here the utility of 4-imino-3,6-diphenyl-3,4-
dihydrofuro[2,3-d]pyrimidine-2(1H)-thione 1 for the synthesis
triazines 5-8 as shown in Schemes 1 and 2.
EXPERIMENTAL
All melting points recorded are uncorrected open capillary
measurements. IR spectra were recorded on a Shimadzu-IR
1
470 spectrophotometer. H NMR spectra were recorded on
Bruker-80 and 100 MHz instruments using tetramethylsilane
(TMS) as an internal standard. 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.
4-Imino-3,6-diphenyl-3,4-dihydrofuro[2,3-d]pyrimidine-2
(1H)-thione 1 is a known compound and was prepared
according to the previously reported method [16].
Synthesis of 2-(Methylsulfanyl)-3,6-diphenylfuro[2,3-
d]pyrimidine-4(3H)-imine 2
To a solution of 4-imino-3,6-diphenyl-3,4-dihydrofuro[2,
3-d]pyrimidine-2(1H)-thione 1 (1.59 g, 5 mmol) in sodium
*Corresponding author. E-mail: rahimizh@yahoo.com

Rahimizadeh et al.
NH
N
105, 90, 86 (base peak), 77, 65.
Ph
CH3I, 1.5 eq.
Ph
Ph
NaOH 5 %,
10 min.
O
SCH3
N
NH
N
Synthesis
of
4,7-Diphenylfuro[3,2-e][1,2,3,4]
Ph
2
NH2-NH2, 2 eq.
EtOH, reflux, 24 h
Ph
tetraazolo[1,5-a]pyrimidine-5(4H)-imine 4
O
S
N
H
To a stirred cold (0-5 °C) suspension of 2-hydrazino-3,6-
1
NH
Ph
NH2-NH2, 4 eq.
EtOH, reflux, 24 h
diphenylfuro[2,3-d]pyrimidine-4(3H)-imine
3 (0.32 g, 1
N
mmol) in glacial acetic acid (10 ml), a solution of sodium
nitrite (0.07 g, 1 mmol) in water (5 ml) was added dropwise.
After stirring for 10 min. at room temperature, the resulted
solid was filtered off, washed thoroughly with water and
recrystallized from ethanol to give compound 4 in 85% yields
as pale yellow needles; m.p.: 230-231 °C; IR (KBr): ν = 3300,
2260, 2250, 1660, 1620, 1550, 1510, 1460, 1380, 1300, 1250,
O
NH
NH2
N
3
NaNO2
CH3COOH
10 min.
NH
NH
Ph
N
Ph
N
Ph
Ph
1
N
N
750, 700 cm-1. H NMR (DMSO-d6, 100 MHz): δ = 7.3-7.7
O
O
N3
N
N
N
(m, 5H), 7.7-8.0 (m, 6H), 8.7 (br s, 1H). MS (m/z): 328 (M+),
327, 316, 302, 283, 281, 267, 249, 235, 223, 207, 191, 183,
169, 147, 140, 121, 105, 91, 81, 71 (base peak), 57.
4'
4
Scheme 1
General Procedure for the Synthesis of Furo
hydroxide solution (5%, 40 ml), methyl iodide (1.06 g, 7.5
mmol) was added and stirred for 10 min. The resulted solid
was filtered, and recrystallized from ethanol to give compound
2 in 95% yields as pale yellow needles; m.p.: 230-231 °C; IR
(KBr): ν = 3400, 1640, 1520, 1500, 1475, 1275, 1120, 1050,
750, 700 cm-1. 1H NMR (CDCl3, 100 MHz): δ = 2.50 (s, 3H),
7.05 (s, 1H), 7.2-7.7 (m, 9H), 7.85 (dd, 2H, J1 = 8 Hz, J2 = 1.5
Hz). MS (m/z): 333 (M+), 332, 185, 183 (base peak), 157,155,
77, 75.
[3',2':5,6]pyrimido[2,1-c][1,2,4]triazines 5-8
A
solution of 2-hydrazino-3,6-diphenylfuro[2,3-d]
pyrimidine-4(3H)-imine 3 (0.32 g, 1 mmol), α-halo ketone (1
mmol), and a drop glacial acetic acid (0.1 ml) in DMF (15 ml)
was heated in 90 °C for 24 h. After the completion of the
reaction, water (50 ml) was added, the resulted solid filtered
off, washed thoroughly with water and recrystallized from
ethanol to give compounds (5-8) in 60-95 % yields.
2,5,9-Triphenyl-5,7-dihydro-4H-Furo[3',2':5,6]
pyrimido[2,1-c][1,2,4]triazin-4-imine 5. was obtained from
phenacyl bromide in 95% yield; white solids; m.p.: 257-258
°C; IR (KBr): ν = 3300, 1630, 1600, 1580, 1490, 1450, 1380,
Synthesis of 2-Hydrazino-3,6-diphenylfuro[2,3-d]
pyrimidine-4(3H)-imine 3
1
1320, 1220, 1180, 1150, 1070, 1020, 920, 750, 700 cm-1. H
A mixture of 2-(methylsulfanyl)-3,6-diphenylfuro[2,3-d]
pyrimidine-4(3H)-imine
2
or
4-imino-6-phenyl-3,4-
NMR (DMSO-d6, 100 MHz): δ = 4.95 (br s, 1H, NH), 7.4-7.9
(m, 15H), 8.05 (d, 2H, J = 8 Hz). MS (m/z): 418, 417 (M+),
386, 367, 359, 344, 335, 316, 299, 288, 271 (base peak), 255,
243, 227, 213, 184, 155, 140, 127, 105, 77.
dihydrofuro[2,3-d]pyrimidine-2(1H)-thione 1 (10 mmol) and
hydrazine hydrate (2 or 4 mmol, respectively) in ethanol (10
ml) was heated under reflux for 24 h. The reaction mixture
was cooled to room temperature and water (10 ml) was added.
The resulted solid was filtered and recrystallized from ethanol
to give compound 3 in 90% yields as white needles; m.p.: 280-
281 °C; IR (KBr): ν = 3445, 3335, 1650, 1620, 1520, 1380,
9-(4-Methoxyphenyl)-2,5-diphenyl-5,7-Dihydro-4H-
Furo[3',2':5,6]pyrimido[2,1-c][1,2,4]triazin-4-imine 6. was
obtained from 4-methoxy-phenacyl bromide in 90% yield;
white solids; m.p.: 262-263 °C; IR (KBr): ν = 3300, 2950,
1650, 1600, 1550, 1490, 1450, 1390, 1280, 1220, 1180, 1050,
1350, 1290, 1150, 900, 820 cm-1. H NMR (DMSO-d6, 100
1
1
850, 800, 700 cm-1. H NMR (DMSO-d6, 100 MHz): δ = 3.85
MHz): δ = 4.35 (br s, 2H), 7.1-7.35 (m, 6H), 7.4-7.6 (m, 5H),
7.7 (br s, 2H). MS (m/z): 317 (M+), 215, 213, 173, 171, 134,
(s, 3H), 4.90 (br s, 1H, NH), 7.1 (d, 2H, J = 8 Hz), 7.5 (m,
1136

Synthesis of Two New Heterocyclic Systems
4H), 7.6-7.9 (m, 8H), 8.05 (d, 2H, J = 8 Hz). MS (m/z): 449,
NH
NH
O
447 (M+), 434, 409, 393, 378, 365, 344, 332, 319, 303, 287,
273, 261, 242, 231, 216, 204, 184, 159, 144, 135 (base peak),
116, 107, 93, 77. Anal. Calcd. for C27H21N5O2: C, 72.47; H,
4.73; N, 15.65. Found: C, 72.75; H, 4.35; N, 15.56.
Ph
N
Ph
Br
N
R1
N
Ph
Ph
DMF, 90 °C, 24 h
CH3COOH (cat.)
O
O
N
NH
NH2
N
NH
R1
5-8
3
5) R1= C6H5-
6) R1= 4-CH3OC6H4-
7) R1= 4-BrC6H4-
8) R1= CH3-
9-(4-Bromophenyl)-2,5-diphenyl-5,7-Dihydro-4H-Furo
[3',2':5,6]pyrimido[2,1-c][1,2,4]triazin-4-imine
7.
was
obtained from 4-bromo-phenacyl bromide in 95% yield; white
solids; m.p.: 207-208 °C; IR (KBr): ν = 3300, 1640, 1600,
1580, 1490, 1450, 1370, 1320, 1250, 1220, 1180, 1070, 1020,
Scheme 2
1
850, 750, 700 cm-1. H NMR (DMSO-d6, 100 MHz): δ = 4.90
ppm for hydrazine and imino groups. Treatment of compound
3 with sodium nitrite in acetic acid at 0 ºC, led to the
furo[3,2-e][1,2,3,4]tetraazolo[1,5-a]
pyrimidine 4 in 85% yield. This new ring system is in
equilibrium with the 2-azido-3-substituted-furo[2,3-d]
(br s, 1H, NH), 7.45 (m, 4H), 7.55-8.10 (m, 12H), 9.50 (br s,
1H, NH). MS (m/z): 449, 496 (M+), 434, 409, 393, 378, 365,
344, 332, 319, 303, 287, 273, 261, 242, 231, 216, 204, 184,
159, 144, 135 (base peak), 116, 107, 93, 77.
9-Methyl-2,5-Diphenyl-5,7-dihydro-4H-Furo[3',2':5,6]
pyrimido[2,1-c][1,2,4]triazin-4-imine 8. was obtained from
chloroacetone in 60% yield; shining yellow needled; m.p.:
217-218 °C; IR (KBr): ν = 3400, 3100, 2950, 1660, 1600,
1510, 1480, 1450, 1370, 1250, 1150, 1050, 780, 700 cm-1. 1H-
NMR (DMSO-d6, 100 MHz): δ = 2.3 (s, 3H), 4.25 (br s, 1H,
NH), 7.5 (m, 4H), 7.75 (m, 8H), 8.0 (br s, 1H, NH). MS (m/z):
357, 355 (M+), 333, 332 (base peak), 273, 183, 77.
formation
of
the
pyrimidine tautomer 4′ [17], which confirmed by
a
characteristic absorption of the azido group (2250 cm-1) in IR
1
spectrum. Also, the H NMR spectra confirmed the assigned
structure 4.
The compounds 5-8 were obtained in good to high yields
through the heterocyclization of 3 with some α-haloketones
(chloroacetone and phenacyl bromide derivatives) in DMF at
90 ºC. The structures of these new furo[3',2':5,6]pyrimido[2,1-
c][1,2,4]triazines 5-8 were confirmed by spectral data. For
example, the 1H NMR spectrum of 6 in DMSO-d6 showed two
broad singlets (D2O-exchangable) at 4.9 and 9.2 due to NH
groups as well as two doublets at 7.1 and 8.0 corresponding to
p-methoxy aryl hydrogens. Methoxy group protons showed a
singlet at 3.85 ppm. Mass spectrum of the compound showed
the molecular ion peak (M+) at m/z 447. Also this compound
gave satisfactory elemental analysis data.
RESULTS AND DISCUSSION
The
4-imino-3,6-diphenyl-3,4-dihydrofuro[2,3-d]
pyrimidine-2(1H)-thione 1 reacted with methyl iodide in 5%
aqueous NaOH at room temperature to produce the
methylthio-pyrimidine derivative 2 in 95% yields. The 1H
NMR spectrum of compound 2 in CDCl3 showed a singlet at
2.50 for methylthio group. Nucleophilic displacement of
methylthio group with hydrazine hydrate was carried out using
ethanol as solvent to afford 2-hydrazino-3,6-diphenylfuro[2,3-
d]pyrimidine-4(3H)-imine 3 in 90% yield. The long duration
of reactions (24 h) could be explained by hindrance to
nucleophilic attack in the 2-position of the 3-substituted
pyrimidine rings. However, direct displacement of thione
group of 1 with hydrazine hydrate was achieved in moderate
yield (75%). The formation of 3 was confirmed by the
presence of NH and NH2 signals around 3400 and 3200 cm-1
In conclusion, in this paper, the synthesis of two novel
heterocyclic ring systems, furo[3',2':5,6]pyrimido[2,1-c]
[1,2,4]triazines
and
furo[3,2-e][1,2,3,4]tetraazolo[1,5-a]
pyrimidine, through heterocyclization of the 2-hydrazino-
furo[2,3-d]pyrimidines with α-haloketones and nitrous acid
respectively in high yields are described.
ACKNOWLEDGMENTS
1
We are grateful to Ferdowsi University of Mashhad
Research Council for their financial support of this work.
in the IR spectrum. The H NMR spectrum of this compound
in DMSO-d6 showed D2O-exchangable signals at 4.4 and 7.7
1137

Rahimizadeh et al.
REFERENCES
Waterfield, P. Parker, Bioorg. Med. Chem. Lett. 17
(2007) 2438.
[1]
M.M.H. Bhuiyan, K.M.M. Rahman, M.K. Hossain,
M.A. Rahim, M.I. Hossain, Croat. Chem. Acta 78
[9]
A. Martin-Kohler, J. Widmer, G. Bold, T. Meyer, U.
Séquin, P. Traxler, Helv. Chem. Acta 87 (2004) 956.
[10] Z.A. Hozien, A.A. Abdel-Wahab, K.M. Hassan, F.M.
Atta, S.A. Ahmed, Pharmazie 52 (1997) 753.
[11] a) E.S. Hand, D.C. Baker, Can. J. Chem. 62 (1984)
2570; b) J.A. Montgomery, A.G. Laseter, K. Hewson, J.
Heterocycl. Chem. 11 (1974) 211.
[12] G. Franco, L. Maria, P. Giueseppe, S.H. Lee, J.
Heterocycl. Chem. 26 (19890 613.
[13] C.J. Shishoo, K.S. Jain, J. Heterocycl. Chem. 29 (1992)
883.
[14] a) M. Rahimizadeh, M. Nikpour, M. Bakavoli, J.
Heterocycl. Chem. 44 (2007) 463; b) M. Bakavoli, F.A.
Sani, A. Davoodnia, M. Roshani, F. Pirouzi,
Heterocyclic Commun. 13 (2007) 371; c) M. Bakavoli,
B. Reihani, M. Rahimizadeh, M. Nikpour, Phosphorus
Sulfur Silicon 181 (2006) 99; d) A. Davoodnia, M.
Bakavoli, A. Vahedinia, M. Rahimizadeh, M. Roshani,
Heterocycles 68 (2006) 801; e) M.M. Heravi, M.
Bakherad, M. Rahimizadeh, M. Bakavoli, M.
Ghassemzadeh, Heterocyclic Commun. 10 (2004) 335.
[15] M. Bakavoli, M. Rahimizadeh, Z. Gordi, J. Chem. Res.
(2008) 564.
(2005) 633.
[2]
[3]
C.G. Dave, R.D. Shah, Molecules 7 (2002) 554.
a) Z. Janeba, J. Balzarini, G. Andrei, R. Snoeck, E. De
Clercq, M.J. Robins, J. Med. Chem. 48 (2005) 4690; b)
F. Amblard, V. Aucagne, P. Guenot, R.F. Schinazi,
L.A. Agrofoglio, Bioorg. Med. Chem. 12 (2005) 1239.
a) A. Gangiee, Y. Zeng, J.J. McGuire, R.L. Kisliuk, J.
Med. Chem. 48 (2005) 5329; b) A. Gangiee, Y. Zeng,
J.J. McGuire, F. Mehraein, R.L. Kisliuk, J. Med. Chem.
47 (2004) 6893.
a) A. Gangjee, Y. Zeng, M. Ihnat, L.A. Warnke, D.W.
Green, R.L. Kisliuk, F.-T. Lin, Bioorg. Med. Chem. 13
(2005) 5475; b) A. Gangiee, Y. Zeng, J.J. McGuire,
R.L. Kisliuk J. Med. Chem. 43 (2000) 3125.
[4]
[5]
[6]
[7]
M.J. Robins, K. Miranda, V.K. Rajwanshi, M.A.
Peterson, G. Andrei, R. Snoeck, E. De Clercq, J.
Balzarini, J. Med. Chem. 49 (2006) 391.
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, X. Zhu, Bioorg. Med. Chem. Lett.
17 (2007) 2305.
[16] M. Bakavoli, M. Rahimizadeh, Z. Gordi, Heterocycles
75 (2008) 2549.
[17] Z.H. Khalil, A.A. Geies, Phosphorus Sulfur Silicon 60
(1991) 223.
[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.
1138