Synthesis of new isolated and fused tri- and tetracyclic pyridine derivatives

Article abstract of DOI:10.1007/s10593-013-1219-z

A number of functionalized pyridine derivatives in which the pyridine ring is linked to triazole, thiadiazole, thiazole, and tetrazole moieties were synthesized by cyclization with carbon disulfide, phenylisothiocyanate, and sodium azide. Benzylation of the synthesized tetrazolylmethylpyridone derivative afforded the N(1)-benzylated product; its crystal structure is reported. The substituted fused tetracyclic pyridofuropyrimidine was synthesized by sequential reactions starting from the 2-pyridone derivative.

Full text of DOI:10.1007/s10593-013-1219-z

Chemistry of Heterocyclic Compounds, Vol. 48, No. 12, March, 2013 (Russian Original Vol. 48, No. 12, December, 2012)
SYNTHESIS OF NEW ISOLATED AND FUSED TRI-
AND TETRACYCLIC PYRIDINE DERIVATIVES
F. A. El-Essawy1*, W. A. El-Sayed2,3, A. Sh. El-Etrawy4, and M. N. El-Bayaa1
A number of functionalized pyridine derivatives in which the pyridine ring is linked to triazole,
thiadiazole, thiazole, and tetrazole moieties were synthesized by cyclization with carbon disulfide,
phenylisothiocyanate, and sodium azide. Benzylation of the synthesized tetrazolylmethylpyridone
derivative afforded the N(1)-benzylated product; its crystal structure is reported. The substituted fused
tetracyclic pyridofuropyrimidine was synthesized by sequential reactions starting from the 2-pyridone
derivative.
Keywords: pyridine, tetrazole, thiazole, triazole, alkylation, cyclization, tetracyclic system.
The synthesis of functionalized heterocycles, as well as tri- and tetracyclic nitrogen-containing
compounds, is one of the major objectives for various laboratories because of their interesting biological
properties. Derivatives of pyridones occur as alkaloids and have been isolated from the leaves and bark of
various trees; for example, nudifluorine, recinine, and piericidin A (Fig. 1) have been isolated from Trewia
nudiflora L., Cator plant, and mycelia of Streptomyces mobaraensis [1, 2], respectively. 2-Pyridones are
biologically interesting molecules, and their chemistry has received considerable attention. Natural products
with this structure have emerged as potent antitumor and antiviral agents, and 2-pyridones have proved useful as
intermolecular connectors between building blocks in material science [3-9].
Multisubstituted pyridine derivatives and fused pyridines occupy a central position in modern
heterocyclic chemistry, particularly in the pharmaceutical and agrochemical fields [10-14]. Furthermore, it has
been reported that certain compounds bearing the thiadiazole, tetrazole, thiazole, and triazole nucleus possess
significant anti-inflammatory activity [15-17]. The functionalization of pyridone and pyrimidine rings with
substituents such as cyano, amino, and hydroxy groups and halogen permits cyclization to fused bi-, tri-, or
tetracyclic systems. In view of these observations, and in continuation of our previous work on the synthesis of
2-pyridone derivatives [18-21] and other functionalized heterocycles, we aim herein to synthesize new five-
membered rings linked to 2-pyridone in addition to functionalized condensed tri- and tetracyclic pyridine ring
systems.
_______
*To whom correspondence should be addressed, e-mail: farag.eleswi@science.menofia.edu.eg.
1Menoufia University, Abdel Naser St., Shebin El-Koam, Egypt.
2NBU University Salhia St., Arar, Kingdom of Saudi Arabia; e-mail: waelshendy@nbu.sa.edu.
3National Research Centre, Tahrir St., El-Dokki, Cairo, Egypt; e-mail: waelshendy@gmail.com.
4College of Pharmacy, Misr University for Science and Technology, Outstanding Neighborhood St., 6th October
City, Egypt; e-mail: etrawy@yahoo.com.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1977-1986, December, 2012.
Original article submitted May 20, 2012.
0009-3122/13/4812-1853©2013 Springer Science+Business Media New York
1853

Fig. 1. Some natural derivatives of pyridones.
In the present investigation, the pyridone derivative 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbo-
nitrile (1), synthesized by treatment of acetylacetone with cyanoacetamide [22], was alkylated with 2-chloro-
acetonitrile to give two alkylnitrile derivatives, O- and N-alkylnitriles 2 and 3, respectively. The O- and
N-alkylated derivatives were separated by column chromatography to give pure compounds 2 and 3 in 34 and
1
49% yields, respectively. The H NMR spectrum of the carbonitrile 2 showed that the methylene group was
shifted downfield compared to that of N-alkyl derivative 3. The methylene group singlet appeared at 5.32 ppm
for the O-alkylated product and at 5.14 ppm for the N-alkylated one. Also, the IR spectra confirmed the absence
of the carbonyl group in the O-alkylated derivative, which appeared at 1654 cm-1 in the N-alkylated product.
Compound 2 was cyclized by treatment with sodium ethoxide in absolute ethanol, affording the furopyridine
derivative 4. The structure of furopyridine 4 was proved by IR, 1H NMR, and mass spectral data, which were in
1
agreement with the assigned structure. Moreover, the signal of CH2 protons was not seen in the H NMR
spectrum, proving that the methylene group was involved in the cyclization step through addition to the nitrile
group. The N-alkylated derivative 3 reacted with phenylisothiocyanate in the presence of sulfur, according to a
reported method [23], to give the thiazolylpyridine 5. The IR spectrum of compound 5 showed absorption bands
1
at 3300-3430 (NH2) and 1342 (C=S) cm-1. Its H NMR spectrum showed new signals at 4.52 ppm for the NH2
group and at 7.15-7.57 ppm for the phenyl group.
1854

On the other hand, the substituted pyridine 1 reacted with acrylonitrile in the presence of triethylamine,
affording 1-(2-cyanoethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (6) in 95% yield. The
aminothiazole derivative 7 was synthesized by the reaction of nitrile 6 with PhNCS and sulfur under the same
conditions used to synthesize compound 5. The 1H NMR spectrum of thiazole 7 showed two singlets at 4.25 and
4.61 ppm for CH2 and NH2 protons, respectively.
The tetrazole derivative 8 was prepared by treatment of nitrile 3 with sodium azide in DMF in the
presence of ammonium chloride. Concerning the intermolecular cycloaddition reaction of nitriles and azides, it
was shown that in the case of using azide salts, they react with nitriles through an anionic two-step mechanism
leading regioselectively to 1H-tetrazoles [24]. The formation of tetrazoles from nitriles and azides was
investigated regarding the scope and reaction kinetics. In the formation of the tetrazole using azide and
ammonium salts, the proton transferred to the nitrile nitrogen in the formed intermediate originates from the
ammonium azide. In previous studies the calculations showed that in reactions where a proton is available, a
stepwise reaction through an intermediate is more favorable than the concerted spontaneous attack in [2+3]
cycloaddition, either neutral or ionic. In this mechanism, the key to lowering the transition state is the activation
of the nitrile by a proton, which is provided by the ammonium salt [24].
The reaction of compound 3 with hydrazine hydrate in ethanol afforded the imidrazone derivative 9.
The structures of compounds 8 and 9 were confirmed by their chemical reactions in addition to their spectral
and analytical data. Benzylation of the NH group of the tetrazole derivative 8 by benzyl chloride afforded the
N-benzylated tetrazole 10 as the only product in 82% yield. The structure of tetrazole 10 was also proved by
single crystal X-ray structural analysis (Fig. 2), which showed that the benzyl group is located on N(2) and not
on N(3) atom. This may be explained by the nature of the starting tetrazole in which the tetrazole ring is not
directly attached to the pyridine ring and is separated by a methylene group, which decreased the possibility of
attachment at the N(3) atom.
1855

Fig. 2. The molecular structure of compound 10 with representation
of the atoms by thermal vibration ellipsoids with 50% probability.
Cyclization of the imidrazone 9 was performed by refluxing it with carbon disulfide in an alcoholic
solution of potassium hydroxide, carbon disulfide in methanol, or PhNCS in dry pyridine to afford the 1,2,4-tri-
azole derivatives 11, 13, and 1,3,4-thiadiazole-2-thione 12, respectively, which is in agreement with previously
reported results [23]. Compounds 11 and 12 were obtained selectively. The presence of potassium hydroxide
resulted, chemoselectively, in the formation of compound 11 in a base-catalyzed cyclization mechanism leading
to the 1,2,4-triazole ring system. The mass spectra of derivatives 11-13 showed the molecular ion peak in
1
agreement with the assigned structure. The H NMR spectra revealed the chemical shifts corresponding to NH
groups and the aromatic protons.
Me
N
Me
N
NH2
N
NH
O
1) ClCH2CO2Et
2) EtONa
HCONH2
Ac2O
1
CO2Et
O
O
Me
Me
14
15
POCl3
Py
N
NaN3
DMF
N
PPh3
N
N
aq. AcOH
C6H4Cl2
PPh3
Cl
N3
N
NH2
16
17
18
19
OH
Me
N
N
PhCH(CO2Et)2
Ph2O
Ph
N
O
Me
N
O
20
For the preparation of fused pyridofuropyrimidine derivatives, we examined the conversion of the
furopyridine derivative 14, prepared according to the reported method [25], to the 4-aminopyridofuropyrimidine
19. The known aminoester 14 was cyclized by fusion with formamide to give the pyrimidin-4(3H)-one derivative
1856

15. Chlorination by treatment with phosphoryl chloride in dry pyridine afforded 4-chloro-7,9-di-methyl-3,4-
dihydropyrido[3',2':4,5]furo[3,2-d]pyrimidine (16) in 73% yield. Compound 16 was treated with sodium azide
in DMF at room temperature to give azide 17 in 65% yield. The IR spectrum of compound 17 showed
absorption at 2140 cm-1 due to the azide group, which indicated that compound 17 is in the azide and not the
tetrazole form. Refluxing the azidopyrido[3',2':4,5]furo[3,2-d]pyrimidine derivative 17 with triphenyl phosphine
in 1,2-dichlorobenzene afforded the aminophosphorane 18. Hydrolysis of compound 18 with 80% aqueous
acetic acid produced the amino derivative 19. The structures of compounds 15-19 were confirmed by their
analytical and spectral data. The structure of amine 19 was confirmed also by reaction with diethyl
phenylmalonate to obtain the tetracyclic compound 20 [26]. The structure of pyrimido[3,2-c]pyrimidin-2-one
derivative 20 was confirmed by the mass spectrum which showed the molecular ion peak corresponding to its
1
molecular weight. The H NMR spectrum of compound 20 showed a signal at 12.43 ppm due to the OH group
and the absence of the broad signal at 7.53 ppm for NH2 protons, which was present in the spectrum of
compound 19.
Thus, new pyridine derivatives, linked to triazole, thiadiazole, thiazole, and tetrazole ring systems, were
synthesized. An efficient method to synthesize tricyclic and tetracyclic pyridine derivatives has been
demonstrated. Benzylation of the synthesized tetrazolylmethylpyridone derivative afforded the N(1)-benzylated
product.
EXPERIMENTAL
The IR spectra were recorded in KBr pellets on a Pye Unicam SP 3300 spectrophotometer. The 1H and
13C NMR spectra were recorded on a Varian Mercury VX-300 spectrometer (300 and 75 MHz, respectively);
residual signals of the solvent were used as the standard. Mass spectra were recorded on a Shimadzu GCMS-
QP1000 EX mass spectrometer at 70 eV. Elemental analyses were carried out at the Micro Analytical Center of
Cairo University, Egypt. Melting points were measured on an Electrothermal IA 9000 Series digital melting
point apparatus. The progress of the reactions was monitored by TLC (silica gel 60 F254, Merck). The
aminoester 14 was synthesized by the known method [25].
Alkylation of 4,6-Dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (1). A mixture of 2-pyri-
dinone 1 (2.10 g, 14.0 mmol) and 60% NaH (0.56 g, 14.0 mmol) in anhydrous DMF (20 ml) was stirred at room
temperature for 2 h. Then, 2-chloroacetonitrile (1.07 g, 14.1 mmol) was added dropwise at 0°C and the reaction
mixture was stirred for an additional 12 h at room temperature. The solvent was removed by evaporation in
vacuo, and the resulting residue was co-evaporated with anhydrous toluene (3×10 ml). The resulting residue
was treated with ice-cooled water, with stirring, to crystallize the mixture of O- and N-alkylated compounds.
The obtained compounds were separated by column chromatography using EtOAc–CHCl3 (gradient 0-10%
EtOAc) as eluent to give pure compounds 2 and 3.
2-(Cyanomethoxy)-4,6-dimethylnicotinonitrile (2). Yield 0.90 g (34%). Colorless powder. Mp 116-118°C.
Rf 0.7 (EtOAc–CHCl3, 1:10). IR spectrum, ν, cm-1: 3060, 3009 (C–H), 2223 (CN). 1H NMR spectrum (CDCl3),
δ, ppm: 2.45 (3H, s, CH3); 2.47 (3H, s, CH3); 5.32 (2H, s, CH2); 7.13 (1H, s, H-5). 13C NMR spectrum (CDCl3),
δ, ppm: 19.5 (CH3); 23.8 (CH3); 51.3 (CH2); 83.0 (CH2CN); 110.4 (CN); 113.4; 116.1; 119.4; 160.3; 160.6.
Mass spectrum, m/z (Irel, %): 187 [M]+ (99). Found, %: C 64.22; H 4.66; N 22.61. C10H9N3O. Calculated, %:
C 64.16; H 4.85; N 22.45.
1-(Cyanomethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (3). Yield 1.30 g (49%).
Pale-yellow crystals. Mp 230-231°C. Rf 0.2 (EtOAc–CHCl3, 1:10). IR spectrum, ν, cm-1: 3076, 3041 (C–H), 2214
(CN), 1654 (C=O). 1H NMR spectrum (CDCl3), δ, ppm: 2.35 (3H, s, CH3); 2.51 (3H, s, CH3); 5.14 (2H, s, CH2);
6.94 (1H, s, H-5). Mass spectrum, m/z (Irel, %): 188 [M+H]+ (98). Found, %: C 64.33; H 4.71; N 22.59.
C10H9N3O. Calculated, %: C 64.16; H 4.85; N 22.45.
1857

3-Amino-4,6-dimethylfuro[2,3-b]pyridine-2-carbonitrile (4). To a solution of O-alkylated compound
2 (1.89 g, 10 mmol) in abs. EtOH (30 ml), a few drops of NaOEt solution were added. The solution was
refluxed for 30 min and left to cool. The solid obtained was filtered off and recrystallized from EtOH. Yield
1.70 g (88%). Pale yellow crystals. Mp 159-160°C. IR spectrum, ν, cm-1: 3410, 3350 (NH2), 2210 (CN).
1H NMR spectrum (CDCl3), δ, ppm: 2.50 (3H, s, CH3); 2.61 (3H, s, CH3); 6.27 (2H, br. s, NH2); 7.01 (1H, s,
H-5). 13C NMR spectrum (CDCl3), δ, ppm: 22.3 (CH3); 23.8 (CH3); 105.4 (CN); 109.4; 114.0; 120.8; 142.5;
145.0; 158.1; 159.9. Mass spectrum, m/z (Irel, %): 187 [M]+ (100), 147 (40), 240 (31). Found, %: C 64.28;
H 4.69; N 22.59. C10H9N3O. Calculated, %: C 64.16; H 4.85; N 22.45.
1-(2-Cyanoethyl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (6). To a mixture of
acrylonitrile (1.10 g, 20 mmol) and Et3N (1.00 g, 10 mmol) in abs. EtOH (30 ml), 2-pyridone 1 (1.47 g,
10 mmol) was added. The reaction mixture was refluxed for 6 h, and the obtained precipitate, after cooling, was
filtered off, dried, and recrystallized from EtOH. Yield 1.90 g (95%). White powder. Mp 133-134°C. IR
1
spectrum, ν, cm-1: 3076, 3055 (C–H), 2944–2921 (C–H), 2252, 2225 (2CN), 1662 (C=O). H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 2.27 (3H, s, CH3); 2.50 (3H, s, CH3); 2.97 (2H, t, J = 6.9, CH2CH2CN); 4.22 (2H, t,
J = 6.9, CH2CH2CN); 6.37 (1H, s, H-5). Mass spectrum, m/z (Irel, %): 202 [M+H]+ (3), 201 (30), 148 (100), 120
(31), 77 (15). Found, %: C 65.73; H 5.38; N 20.94. C11H11N3O. Calculated, %: C 65.66; H 5.51; N 20.88.
Synthesis of Compounds 5 and 7 (General Method). To a well-stirred solution of compound 3 or 6
(9.3 mmol), finely ground sulfur (0.3 g, 9.3 mmol), solution of Et3N (1.3 ml, 9.3 mmol) in abs. EtOH (30 ml), and
phenylisothiocyanate (1.3 g, 9.3 mmol) was gradually added. The reaction mixture was heated under reflux for
3-4 h, during which a yellowish-green crystalline compound separated. After cooling, the obtained solid was
filtered, washed with Et2O, dried, and recrystallized from MeOH to afford pure compound 5 or 7.
1-(4-Amino-3-phenyl-2-thioxo-2,3-dihydro-1,3-thiazol-5-yl)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-
3-carbonitrile (5). Yield 1.6 g (50%). Yellow powder. Mp 180-182°C. IR spectrum, ν, cm-1: 3430, 3300 (NH2),
1
2220 (CN), 1685 (C=O), 1342 (C=S). H NMR spectrum (DMSO-d6), δ, ppm: 2.29 (3H, s, CH3); 2.42 (3H, s,
CH3); 4.52 (2H, br. s, NH2); 6.99 (1H, s, H-5); 7.15-7.57 (5H, m, H Ph). 13C NMR spectrum (CDCl3), δ, ppm:
20.2 (CH3); 25.2 (CH3); 89.3 (C-5 thiazole); 105.0; 110.6; 113.1; 117.1; 120.4; 128.2; 129.5; 129.7; 133.2;
146.9; 156.1, 160.7; 163.1; 182.7 (C=S). Mass spectrum, m/z (Irel, %): 354 [M]+ (15), 322 (30), 278 (5), 192
(100). Found, %: C 57.77; H 3.80; N 15.92. C17H14N4OS2. Calculated, %: C 57.61; H 3.98; N 15.81.
1-[(4-Amino-3-phenyl-2-thioxo-2,3-dihydro-1,3-thiazol-5-yl)methyl]-4,6-dimethyl-2-oxo-1,2-dihydro-
pyridine-3-carbonitrile (7). Yield 1.9 g (55%). Pale-yellow crystals. Mp 141-142°C. IR spectrum, ν, cm-1:
3366, 3268 (NH2), 2206 (CN), 1338 (C=S). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.24 (3H, s, CH3); 2.53
(3H, s, CH3); 4.55 (2H, s, CH2); 4.61 (2H, br. s, NH2); 6.98 (1H, s, H-5); 7.68-7.80 (3H, m, H Ph); 7.89-8.08
(2H, m, H Ph). Mass spectrum, m/z (Irel, %): 368 [M]+ (3), 278 (2), 256 (10), 192 (5), 160 (5), 96 (10), 64 (100).
Found, %: C 58.75; H 4.26; N 15.33. C18H16N4OS2. Calculated, %: C 58.67; H 4.38; N 15.20.
4,6-Dimethyl-2-oxo-1-(2H-tetrazol-5-ylmethyl)-1,2-dihydropyridine-3-carbonitrile (8). A mixture of
cyanomethylpyridine 3 (3.74 g, 20 mmol), NaN3 (1.30 g, 20 mmol), and NH4Cl (1.10 g, 20 mmol) in DMF
(10 ml) was heated for 7 h at 120-125°C. The solvent was removed under reduced pressure, and the residue was
dissolved in water (100 ml) and carefully acidified with conc. HCl to pH 2. The solution was cooled to 5°C in
an ice bath to precipitate the tetrazole 8, which was then recrystallized from MeOH. Yield 3.80 g (83%).
Pale-yellow crystals. Mp 216-217°C. IR spectrum, ν, cm-1: 3429 (NH), 2216 (CN), 1621, 1598 (C=N), 1662
1
(C=O). H NMR spectrum (DMSO-d6), δ, ppm: 2.34 (3H, s, CH3); 2.51 (3H, s, CH3); 5.50 (2H, s, CH2); 6.98
13
(1H, s, H-5); 10.50 (1H, br. s, NH). C NMR spectrum (DMSO-d6), δ, ppm: 20.3 (CH3); 20.4 (CH3); 42.2
(CH2); 99.2 (CN); 109.2; 115.6; 152.5; 153.0; 159.4; 161.0. Mass spectrum, m/z (Irel, %): 231 [M+H]+ (2), 230
(15), 202 (10), 188 (8), 173 (20), 160 (50), 148 (30), 131 (30), 119 (60), 77 (65), 55 (100). Found, %: C 52.25,
H 4.22; N 36.63. C10H10N6O. Calculated, %: C 52.17; H 4.38; N 36.50.
2-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)ethanimidohydrazide (9). To a solution of cyano-
methylpyridine 3 (3.74 g, 20 mmol) in EtOH (20 ml), 80% hydrazine hydrate (2.00 g, 32 mmol) was added. The
mixture was refluxed for 4 h, and the solvent was removed under reduced pressure. The precipitate was
1858

recrystallized from EtOH. Yield 3.50 g (81%). Yellow solid. Mp 249-250°C. IR spectrum, ν, cm-1: 3387, 3295
(NH2), 3226 (NH), 2215 (CN), 1655 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.32 (3H, s, CH3); 2.48
(3H, s, CH3); 3.18 (2H, br. s, NH2); 4.60 (2H, s, CH2); 5.34 (1H, br. s, NHNH2); 7.17 (1H, s, H-5), 8.31 (1H,
br. s, =NH). Mass spectrum, m/z (Irel, %): 219 [M]+ (20), 204 (30), 188 (15), 173 (20), 149 (100). Found, %:
C 54.88, H 5.79; N 31.99. C10H13N5O. Calculated, %: C 54.78, H 5.98; N 31.94.
1-[(1-Benzyl-1H-tetrazol-5-yl)methyl]-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (10).
To a stirred solution of tetrazole 8 (1.33 g, 5.8 mmol) and 60% NaH (0.08 g, 5.8 mmol) in anhydrous DMF
(15 ml), benzyl chloride (0.74 g, 5.8 mmol) was slowly added dropwise. The mixture was stirred at room
temperature for 8 h, then poured into ice water. After cooling the mixture, the resulting precipitate was collected
by filtration and recrystallized from EtOH. Yield 1.50 g (82%). Colorless crystals. Mp 169-170°C. IR spectrum,
ν, cm-1: 3074, 3051 (C–H), 2966-2922 (C–H), 2222 (CN), 1665 (C=O). 1H NMR spectrum (DMSO-d6), δ, ppm:
2.34 (3H, s, CH3); 2.46 (3H, s, CH3); 5.50 (2H, s, NCH2); 5.91 (2H, s, PhCH2); 6.97 (1H, s, H-5); 7.33-7.68
(5H, m, H Ph). 13C NMR spectrum (DMSO-d6), δ, ppm: 20.4 (CH3); 20.5 (CH3); 37.8 (NCH2); 59.0 (PhCH2);
99.2 (CN); 109.4; 115.5; 120.3; 122.2; 124.3; 125.7; 127.9; 128.4; 128.6; 156.8. Mass spectrum, m/z (Irel, %):
321 [M+H]+ (10), 320 (32), 245 (16), 217 (21), 203 (100), 177 (33). Found, %: C 63.81; H 4.98; N 26.41.
C17H16N6O. Calculated, %: C 63.74; H 5.03; N 26.23.
4,6-Dimethyl-2-oxo-1-[(5-thioxo-2,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]-1,2-dihydropyridine-
3-carbonitrile (11). To a stirred suspension of amidrazone 9 (0.48 g, 2.2 mmol) in EtOH (5 ml), KOH (1 mmol)
and CS2 (2 ml) were added gradually. The reaction mixture was then heated under reflux for 6 h. After cooling
and evaporation of the solvent, the obtained potassium salt was dissolved in water and acidified with 2 N
aqueous HCl. The solid product was collected and recrystallized from MeOH. Yield 0.40 g (75%). Yellow crystals.
1
Mp 218-219°C. IR spectrum, ν, cm-1: 3350 (NH), 2220 (CN), 1656 (C=O). H NMR spectrum (DMSO-d6), δ,
ppm: 2.37 (3H, s, CH3); 2.51 (3H, s, CH3); 5.41 (2H, s, NCH2); 6.99 (1H, s, H-5); 10.12 (1H, br. s, NH); 13.15
(1H, br. s, NH). Mass spectrum, m/z (Irel, %): 262 [M+H]+ (80), 261 (80), 201 (25), 148 (100). Found, %:
C 50.71; H 4.22; N 26.91. C11H11N5OS. Calculated, %: C 50.56; H 4.24; N 26.80.
4,6-Dimethyl-2-oxo-1-[(5-thioxo-4,5-dihydro-1,3,4-thiadiazol-2-yl)methyl]-1,2-dihydropyridine-3-carbo-
nitrile (12). To a solution of amidrazone 9 (1.75 g, 8 mmol) in MeOH (30 ml), CS2 (5 ml, 16 mmol) was added.
The mixture was refluxed for 5 h, and the solvent was removed under reduced pressure. The precipitate was
recrystallized from MeOH. Yield 1.6 g (70%). Green powder. Mp 226-227°C. IR spectrum, ν, cm-1: 2229 (CN),
1
1660 (C=O). H NMR spectrum (DMSO-d6), δ, ppm: 2.39 (3H, s, CH3); 2.43 (3H, s, CH3); 5.33 (2H, s, CH2);
7.10 (1H, s, H-5); 12.82 (1H, br. s, NH). 13C NMR spectrum (DMSO-d6), δ, ppm: 20.8 (CH3); 21.3 (CH3); 46.6
(CH2); 101.0 (CN); 115.7; 118.5; 149.0; 151.2; 157.7; 163.1; 179.2 (C=S). Mass spectrum, m/z (Irel, %): 279
[M+H]+ (10), 278 (100), 245 (23), 202 (20). Found, %: C 47.59; H 3.33; N 20.41. C11H10N4OS2. Calculated, %:
C 47.46; H 3.62; N 20.13.
4,6-Dimethyl-2-oxo-1-[(3-phenylamino-1H-1,2,4-triazol-5-yl)methyl]-1,2-dihydropyridine-3-carbonitrile
(13). A suspension of amidrazone 9 (0.22 g, 1 mmol) and phenylisothiocyanate (0.14 g, 1 mmol) in anhydrous
pyridine (10 ml) was heated under reflux for 5 h. After cooling, the reaction mixture was poured into ice water
and neutralized with diluted 10% HCl to give a buff solid precipitate. Triazole 13 was collected and
recrystallized from EtOH–DMF (3:1). Yield 0.2 g (65%). Buff powder. Mp 116-117°C. IR spectrum, ν, cm-1:
1
3100 (NH), 2222 (CN), 1639 (C=O). H NMR spectrum (DMSO-d6), δ, ppm: 2.49 (3H, s, CH3); 2.51 (3H, s,
CH3); 5.65 (2H, s, CH2); 6.46 (1H, s, H-5); 6.93-7.68 (5H, m, H Ph); 9.05 (1H, br. s, NH); 9.88 (1H, br. s, NH).
Mass spectrum, m/z (Irel, %): 320 [M]+ (15), 242 (33), 216 (10), 187 (70), 161 (100). Found, %: C 63.90;
H 4.98; N 26.41. C17H16N6O. Calculated, %: C 63.74; H 5.03; N 26.23.
7,9-Dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-one (15). A suspension of ethyl 3-amino-
4,6-dimethylfuro[2,3-b]pyridine-2-carboxylate (14) (2.34 g, 10 mmol) in formamide (5 ml) in the presence of
2-3 drops of Ac2O was heated under reflux for 2 h. After cooling, the precipitate was triturated with MeOH to
afford compound 15, which was recrystallized from AcOH. Yield 1.60 g (75%). Brownish-yellow solid. Mp
1
~320°C. IR spectrum, ν, cm-1: 3412 (NH), 3109–3064 (C–H), 2956, 2864 (C–H), 1703 (C=O). H NMR
1859

spectrum (DMSO-d6), δ, ppm: 2.57 (3H, s, CH3); 2.75 (3H, s, CH3); 7.24 (1H, s, H-8); 8.24 (1H, s, H-2); 9.84
(1H, br. s, OH). 13C NMR spectrum (DMSO-d6), δ, ppm: 17.6, 24.0 (2CH3); 111.0; 121.7; 137.1; 143.2; 145.8;
146.9; 152.2; 158.8; 161.9. Mass spectrum, m/z (Irel, %): 215 [M]+ (60), 187 (15), 168 (15), 153 (100). Found,
%: C 61.51; H 4.13; N 19.64. C11H9N3O2. Calculated, %: C 61.39; H 4.22; N 19.53.
4-Chloro-7,9-dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidine (16). To a suspension of pyridofuro-
pyrimidone 15 (3.29 g, 15.3 mmol) in anhydrous pyridine, POCl3 (15 ml, 20.0 mmol) was added, and the
reaction mixture was refluxed for 4 h. The excess POCl3 was removed under reduced pressure. The residue was
dissolved in ice water (100 ml), and the precipitate was collected by filtration and recrystallized from EtOH.
Yield 2.60 g (73%). Colorless solid. Mp 167-168°C. IR spectrum, ν, cm-1: 3100, 3050 (C–H), 2970, 2890 (C–H),
1
1608 (C=N). H NMR spectrum (DMSO-d6), δ, ppm: 2.71 (3H, s, CH3); 2.92 (3H, s, CH3); 7.18 (1H, s, H-8);
8.68 (1H, s, H-2). Mass spectrum, m/z (Irel, %): 234 [M+H]+ (40), 233 (20), 198 (100), 183 (19), 155 (20).
Found, %: C 56.71; H 3.29; N 18.08. C11H8ClN3O. Calculated, %: C 56.54; H 3.45; N 17.98.
4-Azido-7,9-dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidine (17). NaN3 (1.63 g, 25 mmol) was added
to a stirred solution of compound 17 (1.17 g, 5 mmol) in DMF (20 ml). Stirring was continued for a further 10 h
at room temperature. The reaction mixture was poured into ice-cooled water, and the precipitated solid was
collected by filtration, washed with water, dried, and recrystallized from EtOH. Yield 0.90 g (76%). Pale-yellow
1
crystals. Mp 160-161°C. IR spectrum, ν, cm-1: 3090, 3033 (C–H), 2945, 2886 (C–H), 2140 (N3). H NMR
spectrum (DMSO-d6), δ, ppm: 2.51 (3H, s, CH3); 2.63 (3H, s, CH3); 7.13 (1H, s, H-8); 8.56 (1H, s, H-2). Mass
spectrum, m/z (Irel, %): 240 [M]+ (11), 212 (20), 198 (100), 171 (31). Found, %: C 55.08; H 3.19; N 35.04.
C11H8N6O. Calculated, %: C 55.00; H 3.36; N 34.98.
7,9-Dimethy-3-(triphenylphosphoranylideneamino)pyrido[3',2':4,5]furo[3,2-d]pyrimidine (18). A
solution of azide 17 (1.20 g, 5 mmol) and Ph3P (1.31 g, 5 mmol) in 1,2-dichlorobenzene (10 ml) was heated under
reflux for 40 min. The solvent was removed in vacuum, and the resulting solid was filtered and recrystallized from
MeOH. Yield 2.00 g (85%). White powder. Mp 244-246°C. IR spectrum, ν, cm-1: 3043, 3024 (C–H), 2985, 2918
(C–H), 1606 (C=N). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.59 (3H, s, CH3); 2.77 (3H, s, CH3); 7.22 (1H, s, H-8);
7.60-7.66 (5H, m, H Ph); 7.75-7.89 (10H, m, H Ph); 8.76 (1H, s, H-2). Mass spectrum, m/z (Irel, %): 474 [M]+ (14),
402 (10), 330 (9), 260 (10), 230 (100). Found, %: C 73.57; H 4.68; N 11.95. C29H23N4OP. Calculated, %: C 73.41;
H 4.89; N 11.81.
7,9-Dimethylpyrido[3',2':4,5]furo[3,2-d]pyrimidin-4-amine (19). A solution of iminophosphorane 18
(1.42 g, 3 mmol) in AcOH (80%, 20 ml) was heated under reflux for 5 h. The solvent was removed in vacuum,
and the resulting solid product was digested with MeOH and collected by filtration, dried, and recrystallized
from AcOH. Yield 0.50 g (78%). White prisms. Mp 293-294°C. IR spectrum, ν, cm-1: 3444, 3317 (NH2), 3163
(C–H), 2953, 2852 (C–H), 1612 (C=N). 1H NMR spectrum (DMSO-d6), δ, ppm: 2.56 (3H, s, CH3); 2.77 (3H, s,
CH3); 7.20 (1H, s, H-8); 7.53 (2H, br. s, NH2); 8.40 (1H, s, H-2). 13C NMR spectrum (DMSO-d6), δ, ppm: 17.4
(CH3); 23.9 (CH3); 110.6; 121.0; 132.1; 144.8; 145.5; 149.7; 153.4; 158.3; 161.9. Mass spectrum, m/z (Irel, %):
214 [M]+ (4), 197 (0.4), 179 (0.5), 125 (4), 111 (10), 97 (20), 71 (60), 57 (100). Found, %: C 61.73; H 4.64;
N 26.31. C11H10N4O. Calculated, %: C 61.67; H 4.71; N 26.15.
4-Hydroxy-7,9-dimethyl-3-phenylpyrido[3',2':4,5]furo[3,2-e]pyrimido[3,2-c]pyrimidin-2-one (20). A
mixture of compound 19 (0.43 g, 2 mmol) and diethyl 2-phenylmalonate (0.47 g, 2 mmol) in diphenyl ether
(5 ml) was refluxed in an oil bath for 20 min, using a short air condenser to remove the liberated ethanol. After
cooling, the reaction mixture was triturated with Et2O and the obtained precipitate was filtered off, washed with
Et2O, dried, and recrystallized from DMF. Yield 0.50 g (75%). Brownish-yellow crystals. Mp ~320°C. IR
1
spectrum, ν, cm-01: 3433–3298 (OH), 1665 (C=O), 1610 (C=N). H NMR spectrum (DMSO-d6), δ, ppm: 2.55
(3H, s, CH3); 2.88 (3H, s, CH3); 7.33-7.63 (6H, m, H-8, H Ph); 8.62 (1H, s, H-5); 12.43 (1H, br. s, OH). Mass
spectrum, m/z (Irel, %): 359 [M+H]+, (20), 358 (50), 330 (20), 269 (10), 231 (100). Found, %: C 67.12; H 3.79;
N 15.76. Calculated, %: C 67.03; H 3.94; N 15.63.
X-Ray Structural Investigation of Compound 10. The crystal of compound 10 (C17H16N6O,
M 320.35) is block-shaped and colorless; crystal dimensions 0.3×0.3×0.3 mm. Crystal structure parameters at
1860

20°C: crystal system monoclinic, space group P21/c. Unit cell dimensions: a 9.1474(9), b 12.206(2), c 15.334(2)
Å; β 97.719(7)°; V 1696.5(3) Å3; Z 4; dcalc 1.254 g/cm–3; μ(MoKα) 0.838 cm-1; F(000) 672.00. Measurements
were carried out on an R-Axis Rapid diffractometer. The data were collected to a maximum 2θ value of 50.6°. A
total of 44 oscillation images was collected. A sweep of data was done using ω-scans from 130.0 to 190.0° in
5.0° step, at χ 45.0° and φ 0.0°. The exposure rate was 36.0 sec/deg. A second sweep was performed using ω-
scans from 0.0 to 160.0° in 5.0° step, at χ 45.0° and φ 180.0°. The exposure rate was 36.0 sec/deg. Of the 13526
reflections that were collected, 3088 were independent (Rint 0.0265); equivalent reflections were merged. An
empirical absorption correction was applied, which resulted in transmission factors ranging from 0.836 to 0.975.
The data were corrected for Lorentz and polarization effects. The structure was solved by direct methods and
expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms
were refined using the "rider" model. The final cycle of full-matrix least-squares refinement on F2 was based on
3088 observed reflections and 217 variable parameters and converged (largest parameter shift was 0.00 times its
estimated standard deviation) with unweighted and weighted agreement factors R1 0.0648 and wR2 0.2423. All
calculations were performed using the CrystalStructure [27] crystallographic software package except for
refinement, which was performed using the SHELXL-97 program [28]. Crystallographic data of compound 10
has been deposited at the Cambridge Crystallographic Data Center (deposit CCDC 864666).
REFERENCES
1.
2.
3.
A. Alert and G. B. Barlin, J. Chem. Soc., 2384 (1959).
B. D. Battas and E. Spinner, Aust. J. Chem., 22, 2581 (1969).
V. Åberg, P. Das, E. Chorell, M. Hedenström, J. S. Pinkner, S. J. Hultgren, and F. Almqvist, Bioorg.
Med. Chem. Lett., 18, 3536 (2008).
4.
S. J. Pinkner, H. Remaut, F. Buelens, E. Miller, V. Åberg, N. Pemberton, M. Hedenström, A. Larsson,
P. Seed, G. Waksman, S. J. Hultgrem, and F. Almqvist, Proc. Natl. Acad. Sci. U. S. A., 103, 17897
(2006).
5.
6.
V. Åberg, M. Sellstedt, M. Hedenström, J. S. Pinkner, S. J. Hultgren, and F. Almqvist, Bioorg. Med.
Chem., 14, 7563 (2006).
V. Åberg, M. Hedenström, J. S. Pinkner, S. J. Hultgren, and F. Almqvist, Org. Biomol. Chem., 3, 3886
(2005).
7.
8.
Y. Fujita, H. Oguri, and H. Oikawa, Tetrahedron Lett., 46, 5885 (2005).
E. Verissimo, N. Berry, P. Gibbons, M. L. S. Cristiano, P. J. Rosenthal, J. Gut, S. A. Ward, and P. M.
O'Neill, Bioorg. Med. Chem. Lett., 18, 4210 (2008).
9.
K. Barral, J. Balzarini, J. Neyts, E. De Clercq, R. C. Hider, and M. Camplo, J. Med. Chem., 49, 43
(2006).
10.
11.
D. Yildiz, Toxicon, 43, 619 (2004).
N. S. Cutshall, K. A. Kucera, R. Ursino, J. Latham, and N. C. Ihle, Bioorg. Med. Chem. Lett., 12, 1517
(2002).
12.
13.
14.
M. Nakanishi, H. Imamura, Y. Maruyama, and H. Hoshino, Yakugaku Zasshi, 90, 272 (1970).
M. Nakanishi, H. Imamura, and K. Goto, Yakugaku Zasshi, 90, 548 (1970).
M. D. Mullican, M. W. Wilson, D. T. Connor, C. R. Kostlan, D. J. Schrier, and R. D. Dyer, J. Med.
Chem., 36, 1090 (1993).
15.
16.
B. Tozkoparan, N. Gökhan, G. Aktay, E. Yeşilada, and M. Ertan, Eur. J. Med. Chem., 35, 743 (2000).
M. Amir, M. S. Y. Khan, and M. S. Zaman, Indian J. Chem., Sect. B: Org. Chem. Incl. Med. Chem.,
43B, 2189 (2004).
17.
18.
B. Tozkoparan, E. Küpeli, E. Yeşilada, and M. Ertan, Biorg. Med. Chem., 15, 1808 (2007).
A. F. Khattab, I. A. El-Sakka, S. M. Yassin, and F. A. El-Essawy, Sulfur Lett., 19, 23 (1995).
1861

19.
20.
F. A. El-Essawy and A. F. Khattab, J. Hetrocycl. Chem., 41, 311 (2004).
F. A. El-Essawy, W. A. El-Sayed, S. A. El-Kafrawy, A. S. Morshedy, and A.-H. Abdel-Rahman,
Z. Naturforsch. C: J. Biosci., 63c, 667 (2008).
21.
22.
23.
H.-A. S. Abbas, W. A. El Sayed, and N. M. Fathy, Eur. J. Med. Chem., 45, 973 (2010).
U. Schmidt and H. Kubitzek, Chem. Ber., 93, 1559 (1960).
M. M. Ramla, M. A. Omar, A.-M. M. El-Khamry, and H. I. El-Diwani, Bioorg. Med. Chem., 14, 7324
(2006).
24.
A. Hassner, in: R. R. Gupta (editor), Topics in Heterocyclic Chemistry, Vol 12, Springer-Verlag, Berlin
(2008), p. 83.
26.
27.
27.
K. Gewald and H. J. Jänsch, J. Prakt. Chem., 318, 313 (1976).
F. A. El-Essawy, Khim. Geterotsikl. Soedin., 1054 (2009). [Chem. Heterocycl. Compd., 45, 837 (2009).]
CrystalStructure 4.0: Crystal Structure Analysis Package, Rigaku Corporation (2000–2010), Tokyo
196–8666.
28.
G. M. Sheldrick, Acta Crystallogr., Sect. A: Found. Crystallogr., A64, 112 (2008).
1862