Condensed pyridopyrimidines. 6*. Synthesis of novel pyrano-[3′,4′:6,7]pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1023/B:COHC.0000008266.92949.ba

The previously unreported pyrano[3′,4′ :6,7]pyrido[2,3-d]pyrimidines have been synthesized from 2-ethyl-2-methyltetrahydropyran-4-one.

Full text of DOI:10.1023/B:COHC.0000008266.92949.ba

Chemistry of Heterocyclic Compounds, Vol. 39, No. 9, 2003
CONDENSED PYRIDOPYRIMIDINES.
6*. SYNTHESIS OF NOVEL PYRANO-
d
[3',4':6,7]PYRIDO[2,3- ]PYRIMIDINES
A. Sh. Oganisyan, A. S. Noravyan, and M. Zh. Grigoryan
The previously unreported pyrano[3',4':6,7]pyrido[2,3-d]pyrimidines have been synthesized from
2-ethyl-2-methyltetrahydropyran-4-one.
Keywords: pyranopyridine, pyranopyridopyrimidine, pyridine, pyrimidine, pyridopyrimidine,
tetrahydropyran, synthesis.
Condensed pyranopyridine derivatives are of great interest as the basis for the preparation of novel
condensed heterocyclic systems [2].
This work concerns the synthesis of novel condensed pyrido[2,3-d]pyrimidines starting from 2-ethyl-2-
methyltetrahydropyran-4-one. The reaction of the pyrrolidinyl enamine of ketone 1 with ethyl
ethoxymethylenecyanoacetate gave the ethyl ester of 3-(6-ethyl-6-methyl-4-pyrrolidino-5,6-dihydro-2H-pyran-3-
yl)-2-cyanoacrylic acid (2) which was cyclized in the presence of aqueous ammonia solution to 2-amino-3-
carbethoxypyrano[4,3-b]pyridine (3). Refluxing an alcohol solution of the latter with phenyl- and
benzylisothiocyanates gave the corresponding 2-N'-thioureido derivatives 4a,b which underwent
heterocyclization to the 2-thio-3-substituted pyranopyrido[2,3-d]pyrimidines 5a,b (Scheme 1).
Compounds 5a,b were also prepared in a single stage from the pyranopyridine 3 and the indicated
isothiocyanates at a temperature of 130-140°C. The reaction of the thiopyranopyridopyrimidines 5a,b with ethyl
chloroacetate or with phenacyl bromide gave the corresponding S-alkyl derivatives 6a-d.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Mercury 300 (300 MHz) instrument using chloroform-d1
(compounds 1-3, 5a,b) or DMSO-d6 (compounds 4a,b, 6a,b). TLC was carried out using Silufol UV-254 plates
and revealed using iodine vapor.
The characteristics for the compounds synthesized are given in Table 1.
Pyrrolidinyl Enamine of 2-Ethyl-2-methyltetrahydropyran-4-one (1). A mixture of pyrrolidine
(7.1 g), ketone (14.2 g, 0.1 mol) and p-toluenesulfonic acid (0.01 g) in absolute toluene (30 ml) was refluxed
using a Dean–Stark apparatus until the calculated amount of water had collected. After evaporation of solvent
_______
* For Communication 5 see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute for Fine Organic Chemistry, Armenian Republic National Academy of
Sciences, Yerevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 9, pp. 1372-1375, September, 2003. Original article submitted May 19, 2000.
0009-3122/03/3909-1203$25.00©2003 Plenum Publishing Corporation
1203

Scheme 1
O
O
COOEt
NH2
N
O
N
NH3
COOEt
CN
EtO–CH=C–COOEt
+
+
CH=C
RNCS
KOH
N
N
H
CN
3
O
O
2
1
RNCS
130–140 oC
O
O
O
N
COOEt
–R
R1X
–R
S
N
O
N
O
N
–C–NHR
S
R1
N
H
S
NH
N
5a,b
N
6a–d
4a,b
4, 5 a R = Ph, b R = CH2Ph; 6 a, c R = Ph, b, d R = CH2Ph; a, b R1 = CH2COOEt, c, d R1 = CH2COPh
TABLE 1. Characteristics of Compounds 1-6
Found, %
——————
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °C
Rf *2
Calculated, %
C
H
N
S
C12H21NO
74.25
73.85
9.87
7.59
7.18
0.61
0.62
0.56
0.57
0.59
0.65
90
80
76
65
60
1
10.77
C18H26N2O3
C14H20N3O3
C21H22N3O3S
C22H24N3O3S
C19H19N3O2S
67.28
8.3
7.9
103-106
125-127
194-196
157-159
290
2
67.92
8.17
8.8
62.87
63.63
8.02
10.3
10.6
3
7.58
62.6
6.03
5.6
9.58
8.15
8.08
4a
4b
5a
63.63
10.6
65.08
5.10
9.11
8.3
64.4
5.85
10.24
7.8
9.81
9.07
65.10
64.59
6.05
5.38
12.20
80 (A),
92 (B)
11.89
C20H21N3O2S
64.75
6.25
12.08
11.44
8.12
300
0.63
82 (A),
5b
65.40
5.72
8.72
91 (B)
C23H25N3O4S
C24H27N3O4S
C27H25N3O3S
C28H27N3O3S
63.5
6.3
5.7
10.23
8.03
7.29
186-188
157-160
185-187
168-170
0.62
0.58
0.57
0.65
82
80
75
77
6a
6b
6c
6d
62.87
9.57
64.3
5.15
10.20
9.27
7.87
63.58
5.96
7.06
69.13
4.81
5.3
9.21
6.15
6.79
68.79
8.91
68.72
69.28
6.22
8.12
8.66
7.23
5.57
6.60
_______
* Compound 1, bp 110-112°C (3 mm Hg)
*2 Solvent systems: chloroform–ether, 2:1 (1); benzene–ether–methanol,
1:1:1 (2); benzene–ether, 1:3 (3); chloroform–ether, 1:2 (4a,b); chloroform–
benzene–ether, 1:1:1 (5a,b); chloroform–ether–heptane, 1:1:2 (6a,b);
benzene–ether–heptane, 1:1:1 (6c,d).
1204

20
20
1
the residue was distilled in vacuo to give product 1 with nD 1.543 an d4 0.953. H NMR spectrum, δ, ppm,
(J, Hz): 8.12 (1H, s, =CH); 4.83 (2H, s, C(6)H2); 3.65 (4H, m, –CH2NCH2–); 2.45 (2H, q, C(3)H2); 2.05 (4H, s,
–CH2CH2–); 1.22 (5H, t, J = 7, 2-CH3, CH2CH3); 1.01 (3H, t, J = 7, CH2CH3).
Ethyl 3-(2-Ethyl-2-methyl-4-pyrrolidino-5,6-dihydro-2H-pyran-5-yl)-2-cyanoacrylate (2).
A
solution of ethyl ethoxymethylenecyanoacetate (16.9 g, 0.1 mol) in THF (60 ml) was added portionwise with
stirring to a solution of the enamine 1 (19.5 g, 0.1 mol) in THF (40 ml) at room temperature. The mixture was
held at the same temperature for about 16 h. After evaporation of the solvent, cold absolute alcohol (20 ml) was
added to the viscous mass. The precipitated crystals of the product 2 were filtered off, recrystallized from
1
absolute ethyl alcohol, and dried. H NMR spectrum, δ, ppm (J, Hz): 8.05 (1H, s, =CH); 4.82 (2H, s, C(6)H2);
4.23 (2H, q, J = 7, OCH2CH3); 3.68 (4H, m, –CH2NCH2–); 2.48 (2H, q, C(3)H2); 2.0 (4H, s, –CH2CH2–);
1.62-1.20 (8H, t, J = 7, OCH2CH3, 2-CH3, 2-CH2CH3); 0.8 (3H, t, J = 7, 2-CH2CH3).
b
An aqueous
2-Amino-3-carbethoxy-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3- ]pyridine (3).
solution of ammonia (25%, 10 ml) was added to a solution of the ester 2 (3.18 g, 0.01 mol) in THF (15 ml). The
mixture was held in a closed, round bottomed flask at 50°C for 6 h. The crystals of 3 obtained after distillation
1
of THF were filtered off, washed with water, and recrystallized from ethyl alcohol. H NMR spectrum, δ, ppm
(J, Hz): 7.80 (1H, s, 4-H); 6.30 (2H, br. s, NH2); 4.71 (2H, s, C(5)H2); 4.34 (2H, t, J = 7, OCH2CH3); 2.70 (2H, q,
8-CH2); 1.72 (3H, t, J = 7, OCH2CH3); 1.30 (5H, s, 7-CH3, 7-CH2CH3); 1.0 (3H, t, J = 7, 7-CH2CH3).
b
3-Carbethoxy-7-ethyl-7-methyl-2-(N'-phenylthioureido)-7,8-dihydro-5H-pyrano[4,3- ]pyridine (4a).
A mixture of compound 3 (2.64 g, 0.01 mol) and phenylisothiocyanate (3.0 g, 0.02 mol) in ethanol (50 ml) was
refluxed for 8 h. After cooling, the precipitated crystalline product 4a was filtered off, washed with ether, and
1
recrystallized from ethanol. H NMR spectrum, δ, ppm (J, Hz): 13.79 (1H, s, NHC6H5); 8.20 (1H, s, 4-H);
7.19-7.73 (5H, m, C6H5); 4.71 (2H, s, C(5)H2); 4.42 (2H, q, J = 7, OCH2CH3); 2.85 (2H, s, C(8)H2); 1.61 (3H, t,
J = 7, OCH2CH3); 1.45 (2H, q, 7-CH2CH3); 1.22 (3H, s, 7-CH3); 1.00 (3H, t, J = 7, 7-CH2CH3).
b
2-(N'-Benzylthioureido)-3-carbethoxy-7-ethyl-7-methyl-7,8-dihydro-5H-pyrano[4,3- ]pyridine (4b).
From a mixture of compound 3 (2.64 g, 0.01 mol) and benzylisothiocyanate (3.0 g, 0.02 mol) as described in the
method given above to give the product 4b. 1H NMR spectrum, δ, ppm (J, Hz): 12.05 (1H, s, NH); 11.08 (1H, s,
NH); 8.10 (1H, s, 4-H); 7.32 (5H, s, –C6H5); 4.82 (2H, d, CH2C6H5); 4.62 (2H, s, C(5)H2); 4.40 (2H, q, J = 7,
OCH2CH3); 2.60 (2H, s, C(8)H2); 1.48 (5H, q, J = 7, OCH2CH3, 7-CH2CH3); 1.20 (3H, s, 7-CH3); 0.90 (3H, t,
J = 7, 7-CH2CH3).
d
3-Substituted 8-Ethyl-8-methyl-4-oxo-2-thioxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3- ]-
pyrimidines (5a,b). A. A mixture of the thioureide 4a,b (0.01 mol) and potassium hydroxide (0.02 mol) in
aqueous ethanol (70%, 50 ml) was refluxed for 2 h. After cooling, the reaction mixture was neutralized with
hydrochloric acid solution (10%). The precipitate crystals of 5a,b were filtered off, washed with water, dried,
1
and recrystallized from butanol. H NMR spectrum of product 5a, δ, ppm (J, Hz): 8.09 (1H, s, 5-H); 7.22-7.57
(5H, m, –C6H5); 4.82 (2H, s, C(6)H2); 3.00 (2H, m, C(9)H2); 1.71 (2H, m, 8-CH2CH3); 1.31 (3H, s, 8-CH3); 1.00
(3H, t, J = 7, 8-CH2CH3).
B. A mixture of compound 3 (2.64 g) and the corresponding isothiocyanate (3 ml) was held at
130-140°C for about 7 h. The precipitated crystals obtained after cooling were filtered off, washed with ether,
1
and recrystallized from butanol. H NMR spectrum of product 5b, δ, ppm (J, Hz): 8.42 (1H, s, 5-H); 7.46-7.28
(5H, m, –C6H5); 5.78 (2H, s, CH2C6H5); 4.92 (2H, s, C(6)H2); 3.00 (2H, t, C(9)H2); 1.71 (2H, br. q, 8-CH2CH3);
1.35 (3H, s, 8-CH3); 1.02 (3H, t, J = 7, 8-CH2CH3).
3-Substituted 2-(Carbethoxy)thio-8-ethyl-8-methyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido-
d
Ethyl chloroacetate (1.23 g, 0.01 mol) was added dropwise with stirring to a solution
[2,3- ]pyrimidines (6a,b).
of compound 5a,b (0.01 mol) and potassium hydroxide (0.56 g, 0.01 mol) in ethanol (90%, 20 ml) heated to
40°C. The precipitated crystals were filtered off, washed with water and ether, and recrystallized from ethanol.
1H NMR spectrum, δ, ppm (J, Hz), 6a: 8.18 (1H, s, 5-H); 7.38-7.60 (5H, br. d, –C6H5); 4.80 (2H, s, C(6)H2); 4.19
(2H, t, J = 7, OCH2CH3); 4.02 (2H, s, SCH2); 2.85 (2H, t, C(9)H2); 1.60 (2H, br. q, 8-CH2CH3); 1.28 (6H, t,
1205

J = 7, OCH2CH3, 8-CH3); 1.01 (3H, t, 8-CH2CH3); 6b: 8.20 (1H, s, 5-H); 7.24 (5H, s, –C6H5); 5.36 (2H, s,
CH2C6H5); 4.81 (2H, s, C(6)H2); 4.18 (2H, q, SCH2); 2.90 (2H, s, C(9)H2); 1.61 (2H, br. m, 8-CH2CH3); 1.30 (6H,
t, J = 7, OCH2CH3, 8-CH3); 0.98 (3H, t, 8-CH2CH3).
3-Substituted 2-(Benzoylmethyl)thio-8-ethyl-8-methyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]-
d
From compounds
pyrido[2,3- ]pyrimidines (6c,d).
5a,b
(0.01 mol) and phenacyl bromide (2.0 g, 0.01 mol) as
1
described above to give compounds 6c,d. H NMR spectrum, δ, ppm (J, Hz), 6c: 8.11 (1H, s, 5-H); 7.40-8.07
(10H, –C6H5, COC6H5); 4.81 (4H, d, C(6)H2, SCH2); 3.90 (2H, br. q, C(9)H2); 1.61 (2H, m, 8-CH2CH3); 1.22 (3H,
s, 8-CH3); 0.98 (3H, t, 8-CH2CH3); 6d: 8.20 (1H, s, 5-H); 7.40-7.64 (10H, m, CH2C6H5, COC6H5); 5.78 (2H, s,
CH2C6H5); 4.81 (4H, br. d, C(6)H2, SCH2); 2.88 (2H, m, C(9)H2); 2.60 (2H, m, CH2CH3); 1.22 (3H, s, 8-CH3);
0.98 (3H, t, 8-CH2CH3).
This work was carried out within the framework of the International science and technical association
program.
REFERENCES
1.
2.
M. Zh. Grigoryan, A. Sh. Oganisyan, and A. S. Noravyan, Armenian Chemical Science at the Threshold
of the 21st Century, Symposium summary [in Russian], Yerevan (2000), p. 111.
A. Sh. Oganisyan and A. S. Noravyan, Khim. Geterotsikl. Soedin., 1388 (1998).
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