Fused pyridothienopyrimidine heterocycles. 2. A facile and efficient synthesis of the annelated pyrido[3,2:4,5]thieno-[2,3-e]pyrimido[3,2-c] pyrimidones

Article abstract of DOI:10.1007/s10593-009-0351-2

The cyclocondensation reactions of 4-aminopyridothienopyrimidine with malonates and their acetylation were studied. All structures were determined by ¹H NMR and mass spectra techniques.

Full text of DOI:10.1007/s10593-009-0351-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
FUSED PYRIDOTHIENOPYRIMIDINE
HETEROCYCLES. 2*. A FACILE AND
EFFICIENT SYNTHESIS OF THE
ANNELATED PYRIDO[3',2':4,5]THIENO-
[2,3-e]PYRIMIDO[3,2-c]PYRIMIDONES
F. A. El-Essawy1**
The cyclocondensation reactions of 4-aminopyridothienopyrimidine with malonates and their
acetylation were studied. All structures were determined by 1H NMR and mass spectra techniques.
Keywords: fused pyrimidines, pyridothienopyrimidines, pyridothienopyrimidopyrimidines.
We have previously reported the synthesis of new tetracyclic compounds containing the pyridothieno-
pyrimidine moiety in order to search for new pharmacological or biologically active compounds [1]. The
pyridothienopyrimidine ring system represents an important class of heterocyclic compounds owing to their
medicinal interest [2, 3]. In addition, certain pyrimidines and annelated pyrimidine derivatives are known to
display anticancer, antimalarial, and antifilarial activitives [4, 5]. These features prompted us to design a specific
program aimed at constructing novel tetracyclic ring systems containing a pyrimidine moiety, which condensed
with pyridothienopyrimidine derivatives. The cyclocondensation reaction of diethyl malonates with sufficiently
reactive 1,3-dinucleophiles such as amidines and amides is a known reaction [6]. In continuation of our ongoing
search for new heterocycles by the cyclocondensation reaction of enamines or amidines with malonate
derivatives [7–11], we here wish to report a simple and efficient method, utilizing 4-aminopyrido-
thienopyrimidine 4, which is a typical heterocyclic amidine, for the synthesis of a new tetracyclic system,
namely pyrido[3',2':4,5]thieno[2,3-e]pyrimido[3,2-c]pyrimidines. The newly synthesized tetracyclic compounds,
pyridothienopyrimidopyrimidines, seem promising for biological activity evaluation studies, but to the best of our
knowledge, this ring system has remained totally unexplored.
As depicted in Scheme 1, the required key intermediate 4 was obtained in three steps. Thus, the chloro
compound 1 [12] reacted with sodium azide in DMF to give the corresponding azido derivative 2. The structure of
compound 2 was supported by its IR spectrum, which showed the presence of azide absorption at 2144 cm–1.
_______
* For communication 1 see [1].
** To whom correspondence should be addressed, e-mail: el-essawy2000@yahoo.com.
1Chemistry Department, Faculty of Science, Menoufia University, Shebin El-Koam, Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1054-1060, June, 2009. Original
article received January 7, 2009.
0009-3122/09/4507-0837©2009 Springer Science+Business Media, Inc.
837

An elegant method for the reduction of azides to amines is offered by the Staudinger reaction [13], in which
azide reacts with phosphane to yield phosphazene. Hydrolysis of phosphazene with aqueous acids or bases leads
to the corresponding amine and phosphane oxide [14].
Consequently, this reaction has been applied in the present investigation to synthesize 4-amino-
7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine 4 by reduction of azido derivative 2 via the formation of
phosphazene intermediate 3 in excellent yields. The structures of compounds 3 and 4 were established on the
basis of elemental analysis and spectral data.
Scheme 1
Me
N
Me
N
N
S
N
S
N
N
NaN3, DMF
Cl
N3
Me
Me
1
2
Me
Me
N
S
N
N
N
TPP
toluene
MeCO2H
H2O
N
PPh3
NH2
S
Me
N
Me
N
3
4
A general method for the preparation of 3-substituted 4-hydroxy-7,9-dimethylpyrido[3',2':4,5]thieno-
[2,3-e]pyrimido[3,2-c]pyrimidin-2-ones 6a-d is outlined in Scheme 2 by thermal reaction of amino derivative 4
with substituted diethylmalonates at 220-250°C, the method without restrictions described in [15]. This probably
formed throughout the synthesis of ketene intermediate 5a-d as described earlier [16]. The yields range between
71 and 95%, which showed that no further activation of malonates is necessary. The only disadvantage of this
reaction sequence is its high reaction temperature, which prevents its use for sensitive substrates and
substituents. The structures of compounds 6a-d were established on the basis of elemental analysis and spectral
data. The existence of a 2,4-dioxo structure can be excluded because of the appearance of OH signals of the
1
4-hydroxy group in the H NMR spectra at δ 11.80-12.21 ppm and the lack of aliphatic signals deriving from
hydrogen at C-3. Acetylation of compounds 6a-d with acetic anhydride gave the acetyl derivatives 7a-d, whose
combustion analysis indicated the acetylation of the OH group.
Scheme 2
O
R1
Me
N
Me
N
N
S
N
S
C
N
H
N
R
RCH(CO2Et)2
Ph2O
R
4
N
N
O
Me
Me
O
6a-d R1 = OH
7a-d R1 = COMe
Ac2O/reflux
5a-d
5-7 a R = Me, b R = Et, c R = n-Bu, d R = Ph
Their IR spectra showed absorptions at 1781, 1764, 1765, and 1787 cm–1 corresponding to OAc groups.
The 1H NMR spectra of compounds 7a-d confirmed the presence of OAc group as a singlet signal at δ 1.86-1.91
ppm and lack of OH signals.
838

In a further investigation of the cyclocondensation scope of malonates with amidines to synthesize new
heterocyclic system, we studied the reaction of amino derivative 4 with ethoxymethylene malonic ester
(EMME). Thus, condensation of an equimolar amount of compound 4 with EMME in refluxing ethanol yielded
the corresponding pyridothienopyrimidylaminomethylene malonate 8, which underwent intramolecular
cyclization in boiling diphenyl ether to give ethyl 7,9-dimethyl-4-oxo-pyrido[3',2':4,5]thieno[2,3-e]pyrimido-
[3,2-c]pyrimidine-3-carboxylate 9 (Scheme 3). Alternatively, pyridothienopyrimidopyrimidine derivative 9
could also be obtained in one step by refluxing amino derivative 4 with EMME in diphenyl ether. The structure
of compound 9 was established on the basis of elemental analysis and spectral data (see Experimental). The
reaction of compound 9 with either an equimolar or excess amount of hydrazine hydrate in absolute ethanol at
reflux temperature led to the formation of the unexpected 4-amino-7,9-dimethylpyrido[3',2':4,5]thieno-
Scheme 3
Me
N
N
EMME
CO2Et
CO2Et
4
N
H
78°C
EMME,
Ph2O
S
Me
N
reflux
8
Ph2O, reflux
O
Me
N
N
S
N
CO2Et
N
Me
9
TABLE 1. Experimental Characteristics of Compounds 6a-d and
Acetylated Compounds 7a-d
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, ºC*
Yield, %
C
N
6a
6b
C15H12N4O2S
C16H14N4O2S
57.37
57.68
3.94
3.87
17.63
17.94
>330
>330
95
77
58.62
58.88
4.58
4.32
16.86
17.17
6c
6d
7a
7b
7c
7d
C18H18N4O2S
C20H14N4O2S
C17H14N4O3S
C18H16N4O3S
C20H20N4O3S
C22H16N4O3S
61.32
61.00
5.33
5.12
16.13
15.81
>330
>330
86
71
80
72
72
83
64.16
64.30
3.77
3.53
14.96
14.73
57.34
57.62
4.21
3.98
15.64
15.81
282-285
272-275
209-212
>300
58.92
58.68
4.62
4.38
15.42
15.21
60.73
60.59
5.32
5.08
14.42
14.13
63.15
63.45
3.96
3.87
13.26
13.45
_______
* Solvents: DMF (compounds 6a,d) and AcOH (compounds 6b,c and 7a-d).
839

TABLE 2. Spectral Characteristics of Compounds 6a-d and 7a-d
Com-
pound
MS, m/z
(I, %)
IR ν, cm–1
1H NMR δ, ppm (J, Hz)
6a
3482 (OH);
1671 (CO);
1583 (C=N)
1.93 (3H, s, CH3); 2.55 (3H, s, CH3); 2.84 (3H, s, CH3); 312 [M]+
7.22 (1H, s, H-8); 9.34 (1H, s, H-5);
12.21 (1H, br. s, OH)
(10)
6b
6c
3440 (OH);
1671 (CO);
1602 (C=N)
1.08 (3H, t, J = 7, CH2-CH3);
326 [M]+
(5)
2.5 (2H, q, J = 7, CH3-CH2); 2.54 (3H, s, CH3);
2.88 (3H, s, CH3); 7.38 (1H, s, H-8); 9.53 (1H, s, H-5);
11.90 (1H, br. s, OH)
3438 (OH);
1667 (CO);
1583 (C=N)
0.91 (3H, t, J = 7.2, -CH3); 1.34 (2H, m, -CH2);
1.94 (2H, m, -CH2); 2.5 (2H, t, J = 6, -CH2);
2.58 (3H, s, CH3); 2.9 (3H, s, CH3); 7.28 (1H, s, H-8);
9.43 (1H, s, H-5); 11.80 (1H, br. s, OH)
354 [M]+
(100)
6d
7a
7b
7c
3436 (OH);
1667 (CO);
1579 (C=N)
2.56 (3H, s, CH3); 2.89 (3H, s, CH3);
7.26-7.56 (6H, m, H-8 and C6H5); 9.46 (1H, s, H-5);
12.03 (1H, br. s, OH)
374 [M]+
(10)
1781 (COCH3); 1.90 (3H, s, COCH3); 1.95 (3H, s, CH3);
1693 (CO);
1607 (C=N)
354 [M]+
(20)
2.60 (3H, s, CH3); 2.91 (3H, s, CH3);
7.33 (1H, s, H-8); 9.5 (1H, s, H-5)
1764 (COCH3); 1.10 (3H, t, J = 7, -CH3); 1.91 (3H, s, COCH3);
1699 (CO);
1602 (C=N)
368 [M]+
(15)
2.43 (2H, q, J = 7, -CH2); 2.59 (3H, s, CH3);
2.88 (3H, s, CH3); 7.21 (1H, s, H-8); 9.36 (1H, s, H-5)
1765 (COCH3); 0.91 (3H, t, J = 7.2, -CH3); 1.34 (2H, m, CH2);
1699 (CO);
1602 (C=N)
396 [M]+
(30)
1.86 (3H, s, COCH3); 1.94 (2H, m, CH2);
2.54 (2H, t, J = 6, CH2); 2.62 (3H, s, CH3);
2.91 (3H, s, CH3); 7.48 (1H, s, H-8); 9.63 (1H, s, H-5)
7d
1787 (COCH3); 1.91 (3H, s, COCH3); 2.59 (3H, s, CH3);
1670 (CO);
1600 (C=N)
416 [M]+
(20)
2.92 (3H, s, CH3); 7.28–7.58 (6H, m, H-8 and C6H5);
9.5 (1H, s, H-5)
[3,2-d]pyrimidine 4 in acceptable yield. The validity of this product structure was deduced from its correct
elemental analysis and compatible spectral data, which was in accordance with an authentic sample prepared by
hydrolysis of phosphazene 3. A reasonable mechanism for this transformation involves the nonisolable
intermediate 10, which is formed via nucleophilic attack by one site of the binucleophile hydrazine hydrate on
the activated carbonyl group at C-4 with concomitant ring opening to form acyclic intermediate 10, followed by
attack of the second site on C-2, forming pyrazolinone ester, which may be decomposed through the reaction
mixture (Scheme 4).
Scheme 4
H N–NH2
2 ..
H2N
..
O
NH
C
Me
N
Me
N
N
N
N
NH
O
CO2Et
N H ·
H2O
2
4
N
N
CO2Et
S
S
Me
Me
9
10
O
H
N
HN
CO2Et
Me
Me
N
N
S
N
N
NH
NH
NH2
S
Me
N
Me
4
840

EXPERIMENTAL
Melting points were determined on a Buchi melting point apparatus. NMR spectra were recorded (300
and 75 MHz, respectively) on a Varian Germini-2000 apparatus and registered in DMSO-d6, ppm to internal
Me4Si. IR spectra were recorded on a Nicolet FT-IR spectrophotometer. Mass spectra were measured on Kratos
50 tc spectrometers. Microanalysis was performed in the microanalysis lab at Cairo University. Common
reagent-grade chemicals are either commercially available and used without further purification, or prepared by
standard literature procedure. All reactions were monitored by TLC, carried out on 0.2 mm silica gel 60 F-254
(Merck) plates using UV light (254 and 360 nm) for detection.
4-Azido-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine (2). Sodium azide (1.63 g, 25 mmol)
was added to a stirred solution of chloro compound 1 (1.25 g, 5 mmol) in DMF (20 ml). Stirring was continued
for a further 12 h at 50-60ºC. Then the reaction mixture was poured into ice water, and the precipitated solid
product was collected by filtration, washed with water, dried, and recrystallized from MeOH to afford the
1
corresponding azido compound 2. (0.90 g, 70%); mp 183-184ºC. IR spectrum, ν, cm–1: 2144 (N3). H NMR
spectrum, δ, ppm: 2.61 (3H, s, CH3); 2.94 (3H, s, CH3); 7.38 (1H, s, H-8); 8.29 (1H, s, ArH). Mass spectrum,
m/z (I, %): 256 [M]+ (20); 228 (100). Found, %: C 51.25; H 3.13; N 32.56. C11H8N6S. Calculated, %: C 51.55;
H 3.15; N 32.79.
7,9-Dimethyl-4-(triphenylphosphoranylideneamino)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine (3). A
solution of azidopyridothienopyrimidine 2 (1.28 g, 5 mmol) and triphenylphosphane (1.31 g, 5 mmol) in toluene
(20 ml) was heated under reflux for 30 min. The solvent was then removed under reduced pressure and the
resulting solid product was collected by filtration and recrystallized from ethanol to afford compound 3 as white
prisms (3.0 g, 88%); mp 273–275ºC. 1H NMR spectrum, δ, ppm: 2.59 (3H, s, CH3); 2.89 (3H, s, CH3); 7.22 (1H,
s, H-8); 7.56–7.89 (15H, m, ArH); 8.36 (1H, s, ArH). Mass spectrum, m/z (I, %): 490 [M]+ (100). Found, %:
C 70.91; H 4.66; N 11.33. C29H23N4PS. Calculated, %: C 71.00; H 4.73; N 11.42.
4-Amino-7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine (4). A solution of iminophosphorane
3 (1.5 g, 3 mmol) in acetic acid (80%, 20 ml)) was heated under reflux for 5 h. The solvent was then removed in
vacuum, and the resulting solid product was digested with MeOH, collected by filtration, washed well with
MeOH to remove Ph3PO, dried, and recrystallized from AcOH to afford compound 4 as white prisms (0.8 g,
89%); mp 287–289ºC (reported, >360°C [17]). IR spectrum, ν, cm–1: 3459, 3288 (NH2). 1H NMR spectrum, δ,
ppm: 2.49 (3H, s, CH3); 2.86 (3H, s, CH3); 7.25 (1H, s, ArH); 7.46 (2H, bs, NH2); 8.38 (1H, s, ArH). 13C NMR
spectrum, δ, ppm: 18.61 (CH3); 23.61 (CH3); 118.08; 122.03; 123.11; 146.01; 145.57; 154.67; 157.89; 159.13;
160.76 (C-ArH). Mass spectrum, m/z (I, %): 230 [M]+ (100). Found, %: C 57.22; H 4.35; N 24.18. C11H10N4S.
Calculated, %: C 57.37; H 4.38; N 24.33.
4-Hydroxy-7,9-dimethyl-3-(methyl, ethyl, n-butyl, phenyl)pyrido[3',2':4,5]thieno[2,3-e]pyrimido-
[3,2-c]pyrimidin-2-ones 6a-d (General Method). A mixture of 4-aminopyridothienopyrimidine 4 (0.46 g,
2 mmol) and the appropriate malonic ester (4 mmol) in diphenyl ether (5 ml) was refluxed in an oil bath for
20-40 min, using a short air condenser to remove the liberated ethanol. After cooling, the reaction mixture was
triturated with diethyl ether, and the obtained precipitate was filtered off, washed with diethyl ether, dried, and
recrystallized from the proper solvent (Tables 1 and 2).
4-Acetyl-7,9-dimethyl-3-(methyl, ethyl, n-butyl, phenyl)pyrido[3',2':4,5]thieno[2,3-e]pyrimido-
[3,2-c]pyrimidin-2-ones 7a-d (General Method). A suspension of compounds 6a-d (1.5 mmol) in acetic
anhydride (10 ml) was refluxed for 24 h. After cooling, the separated crystals from the obtained clear solution
were filtered off, washed with ethanol, dried, and recrystallized from acetic acid (Tables 1 and 2).
Diethyl (7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine-4-imino)methylene Malonate (8). A
mixture of amino derivative 4 (0.46 g, 2 mmol), diethyl ethoxymethylenemalonate (0.43 g, 2 mmol), and
2-3 drops of piperidine in absolute ethanol (5 ml) was refluxed for 24 h. After cooling, the reaction mixture was
841

evaporated under reduced pressure, and the residue was triturated with diethyl ether (10 ml). The resulting solid
product was collected by filtration, washed with diethyl ether, dried, and recrystallized from methanol to give
compound 8 (0.3 g, 60%); mp 210-212ºC. IR spectrum, ν, cm–1: 3414 (NH); 1721 (CO); 1664 (CO); 1622
1
(C=C). H NMR spectrum δ, ppm (J, Hz): 1.22 (3H, t, J = 7.1, CH3CH2); 1.38 (3H, t, J = 7.1, CH3CH2); 2.60
(3H, s, CH3); 2.91 (3H, s, CH3); 4.25 (2H, q, J = 7.1, CH3CH2); 7.31 (1H, s, H-8); 8.41 (1H, s, H-2); 8.94 (1H,
d, J = 13.5, CH=C); 10.83 (1H, d, J = 13.5, NH). Found, %: C 56.63; H 5.21; N 13.68. C19H20N4O4S.
Calculated, %: C 56.99; H 5.03; N 13.99.
Ethyl 7,9-dimethyl-4-oxo-pyrido[3',2':4,5]thieno[2,3-e]pyrimido[3,2-c]pyrimidine-3-carboxylate (9).
A. A suspension of compound 8 (0.4 g, 1 mmol) in diphenyl ether (4 ml) was heated under reflux for
1 h. After cooling, the reaction mixture was digested with diethyl ether, and the brown solid product was
collected by filtration, washed with diethyl ether, and recrystallized from acetic acid to afford compound 9
(0.3 g, 86%).
B. A suspension of compound 4 (0.46 g, 2 mmol) and diethyl ethoxymethylenemalonate (0.43 g,
2 mmol) in diphenyl ether (5 ml) was heated under reflux for 20 min; after cooling, the reaction mixture was
triturated with diethyl ether (10 ml) to give a brown solid, which was filtered off, washed with diethyl ether,
dried, and recrystallized from acetic acid to yield compound 9 (0.5 g, 72%); mp 300–303ºC. IR spectrum,
ν, cm-1: 1731 (COOEt); 1693 (CO). 1H NMR spectrum, δ, ppm (J, Hz): 1.33 (3H, t, J = 7.1, CH3CH2); 2.64 (3H,
s, CH3); 2.96 (3H, s, CH3); 4.32 (2H, q, J = 7.1, CH3CH2); 7.42 (1H, s, H-8); 8.89 (1H, s, H-5); 9.73 (1H, s,
H-2). Found, %: C 57.43; H 3.68; N 15.68. C17H14N4O3S. Calculated, %: C 57.62; H 3.98; N 15.81.
Reaction of Carboxylate 9 with Hydrazine Hydrate. A mixture of either equimolar quantities
(1 mmol) or excess (5 mmol) of hydrazine hydrate (80%) and carboxylate 9 (1 mmol) in absolute ethanol
(10 ml) was refluxed for 2 h. The resulting mixture was evaporated and the residue was triturated with acetone.
The obtained colorless solid was filtered off, dried, and recrystallized from AcOH to yield a compound that was
identical in all physical and spectroscopic data to compound 4 (0.3 g, 60%); mp and mixed mp (with a sample
prepared from compound 3) 286-288ºC.
The author thanks DANIDA for financial support of this work at the Faculty of Science, Menoufia
University, through the project "Development of New Drugs against Hepatitis".
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