Cyclization of δ-[(S)-1-phenylethyl]-amino alcohols to form chiral 1,3-disubstituted phthalanes [1]

Full text of DOI:10.1007/s10593-005-0078-7

Chemistry of Heterocyclic Compounds, Vol. 40, No. 10, 2004
CONDENSED PYRIDOPYRIDIMINES.
8*. SYNTHESIS OF NEW DERIVATIVES OF
PYRANO[3',4':6,7]PYRIDO[2,3-d]PYRIMIDINE
A. Sh. Oganessyan, A. S. Noravyan, and M. Zh. Grigoryan
New substituted 8,8-dimethyl-4-oxopyrano[3',4':6,7]pyrido[2,3-d]pyrimidines have been synthesized
from 2-amino-3-ethoxycarbonyl-7,7-dimethylpyrano[4,3-b]pyridine.
Keywords: pyranopyridine, pyranopyridopyrimidine, pyridine, pyridopyrimidine, pyridimine,
tetrahydropyran, synthesis.
We have previously prepared some derivatives of pyrano[3',4':6,7]pyrido[2,3-d]pyrimidine [2,3]. In a
continuing search for biologically active compounds, we have synthesized new examples of this series
containing various substituents in positions 2 and 3 of the pyrimidine ring.
3-Substituted 4-oxo-2-thiopyranopyridopyrimidines 1a-c were synthesized by two methods: A) by
boiling ethanolic solutions of 2-amino-3-ethoxycarbonylpyrano[4,3-b]pyridine 2 [2] with the isothiocyanates 3a-
c with subsequent heterocyclization of the 2-(N'-R-thioureido) derivatives 4a-c under the influence of KOH; B)
by condensation of pyranopyridine 2 with the isothiocyanates 3a-c at 130-140°C.
RNCS
COOEt
COOEt
NH2
O
O
3a–c
EtOH,
boiling
C
NH
R
N
NH
N
4a–c
2
S
3a–c
KOH
130–140 oC
O
N
O
R1X
5a–c
R
S
R
O
N
N
O
1
N
N
N
H
S
R
1a–c
6a–i
1a, 3a, 4a, 6a,d,g R = CH2Ph; 1b, 3b, 4b, 6b,e,h R = CH2CH=CH2; 1c, 3c, 4c, 6c,f,i
R = C6H4OMe-4; 5a, 6a−c R1 = Et, X = I; 5b, 6d−f R1 = CH2COPh, X = Br;
5c, 6g−i R1 = CH2CONH2, X = Cl
_______
* For part 7 see [1].
__________________________________________________________________________________________
A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Armenian
Republic, Erevan 375014; e-mail: west@msrc.am. Translated from Khimiya Geterotsiklicheskikh Soedinenii,
No. 10, 1554-1557, October, 2004. Original article submitted May 19, 2000; revision submitted March 5, 2004.
1342
0009-3122/04/4010-1342©2004 Springer Science+Business Media, Inc.

TABLE 1. Characteristics of the Compounds Synthesized, 1, 4, and 6
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °C
Rf *
Yield, %
C
H
N
S
1a
1b
1c
C19H19N3O2S
C15H17N3O2S
C19H19N3O3S
64.5
64.6
5.4
5.4
11.8
11.9
9.1
9.1
310-312
238-240
300
0.61
88 (A)
92 (B)
59.5
59.4
5.6
5.6
13.8
13.9
10.6
10.6
0.64 75.5 (A)
89 (B)
62.1
61.8
5.7
5.2
11.8
11.4
8.1
8.7
0.67
87 (A)
90 (B)
4a
4b
4c
6a
6b
6c
6d
6e
6f
C21H25N3O3S
C17H23N3O3S
C21H25N3O4S
C21H23N3O2S
C17H21N3O2S
C21H23N3O3S
C27H25N3O3S
C23H23N3O3S
C27H25N3O4S
C21H22N4O3S
C17H20N4O3S
C21H22N4O4S
63.2
63.1
58.6
58.4
61.0
60.7
63.65
63.5
61.8
61.6
63.6
63.5
68.7
68.8
65.7
65.6
67.1
66.5
61.6
61.5
56.5
56.7
60.0
59.2
6.1
6.3
6.5
6.6
6.0
6.2
5.5
5.8
6.2
6.3
5.6
5.8
5.0
4.9
5.7
5.9
4.8
5.1
5.3
5.4
5.6
5.6
4.9
5.2
10.6
10.5
12.1
12.0
10.8
10.1
10.7
10.6
13.0
12.7
11.1
10.6
8.7
8.9
10.3
10.0
8.4
8.6
13.5
13.7
15.9
15.6
13.4
13.2
8.1
8.0
9.0
9.2
6.7
7.7
8.2
8.1
9.6
9.8
7.9
8.1
7.1
6.8
6.8
7.6
6.8
6.6
7.9
7.8
8.4
8.8
7.3
7.5
191-192
155-156
157-159
181-183
123-125
175-177
210-212
165-167
194-196
150-152
162-164
208-210
0.58
0.61
0.63
0.57
0.60
0.64
0.58
0.53
0.57
0.62
0.63
0.67
50
51.2
52
92.3
90.3
75.7
89.3
82.5
80
6g
6h
6i
81.5
73.5
75
_______
*Solvent systems: chloroform–benzene–ether, 2:1:1 (1a-c); chloroform–
ether, 1:2 (4a); chloroform–ether–isooctane, 1:2:1 (4b,c]; chloroform–ether–
heptane, 1:1:1 (6a-i).
It should be noted that the single stage route B gave higher yields of the required products 1.
The corresponding S-alkylsubstituted 6a-i were obtained as the result of interaction of compounds 1a-c
with the halogeno derivatives 5a-c.
EXPERIMENTAL
IR spectra of nujol mulls were recorded on a UR-20 spectrometer, 1H NMR spectra of DMSO-d6 (1a-c,
4a,c, 6a,c,d), CDCl3 (4b), and pyridine-d5 (6h,i) solutions were recorded with a Varian Mercury 300 (300 MHz)
machine. TLC was carried out on Silufol UV-254 plates with development with iodine vapor.
Characteristics of the compounds synthesized are given in Table 1.
2-(N'-benzylthioureido)-3-ethoxycarbonyl-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (4a).
A mixture of 2 (2.5 g, 0.01 mol) and benzyl isothiocyanate 3a (3.2 g, 0.02 mol) in ethanol (50 ml) was boiled
for 10 h. The crystalline product 4a which separated on cooling was filtered off, washed with ether and
recrystallized from ethanol. IR spectrum (thin film), ν, cm-1: 1470 (C=S), 1630 (C=N), 1690 (C=O), 3200 (NH).
1H NMR spectrum, δ, ppm (J, Hz): 11.90 (1H, s, HNHet); 8.20 (1H, s, H-4), 7,17 (5H, s, C6H5); 6.86 (1H, t,
1343

3J = 5.0, NHR); 4.60 (2H, d, 3J = 5.0, CH2C6H5); 4.53 (2H, s, 2H-5); 4.13 (2H, q, 3J = 7.0, OCH2CH3); 2.60 (2H,
s, 2H-8); 1.25 (3H, t, 3J = 7.0, OCH2CH3); 1.20 (6H, br. s, 2CH3-7).
2-(N'-Allylthioureido)-3-ethoxycarbonyl-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]pyridine (4b)
was obtained from compound 2 (2.5 g, 0.01 mol) and allyl isothiocyanate 3b (2.0 g, 0.02 mol) by the method
described above. IR spectrum (thin film), ν, cm-1: 1460 (C=S), 1630 (C=N), 1680 (C=O), 3250 (NH). 1H NMR
spectrum, δ, ppm (J, Hz): 11.90 (1H, s, NHHet); 8.20 (1H, s, H-4); 6.93 (1H, t, 3J = 5.8, NHR); 6.22-4.95 (3H,
m, CH=CH2); 4.60 (2H, s, 2H-5); 4.23 (2H, q, 3J = 6.0, OCH2CH3); 4.02 (2H, t, 3J = 5.8, NHCH2); 2.67 (2H, s,
2H-8); 1.28 (3H, t, 3J = 6.0, OCH2CH3); 1.23 (6H, s, 2CH3-7).
3-Ethoxycarbonyl-2-[(N'-4-methoxyphenyl)thioureido]-7,7-dimethyl-7,8-dihydro-5H-pyrano[4,3-b]-
pyridine (4c) was obtained from compound 2 (2.5 g, 0.01 mol) and 4-methoxyphenyl isothiocyanate 3c (3.3 g,
0.01 mol) by the method described above. IR spectrum (thin film), ν, cm-1: 1470 (C=S), 1620 (C=N), 1680
(C=O), 3300 (NH). 1H NMR spectrum, δ, ppm (J, Hz): 13.60 (1H, s, NHR); 11.21 (1H, s, NHHet); 8.20 (1H, s,
3
3
H-4); 7.60-6.85 (4H, m, C6H4); 4.75 (2H, s, 2H-5); 4.40 (2H, q, J = 7.0, OCH2CH3); 3.80 (3H, t, J = 7.0,
OCH3); 2.80 (2H, s, 2H-8); 1.40 (3H, t, 3J = 7.0, OCH2CH3); 1.20 (6H, s, 2CH3-7).
3-Substituted
8,8-Dimethyl-4-oxo-2-thioxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]-
pyrimidines 1a-c. A. A mixture of thioureide 4a-c (0.01 mol), KOH (0.02 mol), and 70% ethanol (50 ml) was
boiled for 1 h, cooled, and treated with 10% hydrochloric acid until slightly acidic. The crystals of the products
1a-c which precipitated were filtered off, washed with water, dried, and recrystallized from butanol.
B. A mixture of compound 2 (2.5 g) and an isothiocyanate 3a-c (3 ml) was maintained at 130-140°C for
7h. The crystals of compound 1a-c which separated on cooling after treating with ethanol were filtered off,
washed with ether, and recrystallized from butanol. IR spectrum (thin film), ν, cm-1, 1a-c: 1460 (C=S), 1670
1
(C=O). H NMR spectra, δ, ppm (J, Hz): 1a: 8.20 (1-H, s, 5-H); 7.70-7.20 (5H, m, C6H5); 6.00 (2H, s, NCH2);
4.73 (2H, s, 2H-6); 2.98 (2H, s, 2H-9); 1.26 (6H, s, 2CH3-8); 1b: 8.50 (1H, s, NH); 8.15 (1H, s, H-5); 6.35-5.15
(3H, m, CH=CH2); 5.03 (2H, br. s, NCH2); 4.63 (2H, s, 2H-6); 2.82 (2H, s, 2H-9); 1.23 (6H, s, 2CH3-8),; 1c:
13.17 (1H, s, NH); 8.02 (1H, s, H-5); 7.09-6.83 (4H, m, C6H4); 4.80 (2H, s, 2H-6); 3.80 (3H, s, OCH3); 2.80
(2H, s, 2H-9); 1.24 (6H, s, 2CH3-8).
3-Substituted 2-Ethylthio-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido[2,3-d]-
pyrimidines 6a-c. Ethyl iodide 5a (1.56 g, 0.01 mol) was added dropwise with stirring to a solution of
compound 1a-c (0.01 mol) and KOH (0.56 g, 0.01 mol) in 90% ethanol (20 ml) heated to 40°C. The crystals of
the product 6a-c which separated were filtered off, washed with water and ether, and recrystallized from ethanol.
1H NMR spectra, δ, ppm (J, Hz): 6a: 8.20 (1H, s, H-5); 7.21 (5H, s, C6H5); 5.25 (2H, s, CH2C6H5); 4.80 (2H, s,
2H-6); 3.38 (2H, m, SCH2); 2.81 (2H, s, 2H-9); 1.42 (3H, m, CH2CH3); 1.26 (6H, s, 2CH3-8); 6c: 8.20 (1H, s, H-
5); 7.10, 7.20 (4H, two d, 3J1 = 3J2 = 8.8, C6H4); 4.81 (2H, s, H-6); 3.90 (3H, s, OCH3); 3.19 (2H, m, SCH2); 2.87
(2H, s, 2H-9); 1.40-1.22 (9H, m, CH2CH3, 2CH3-8).
3-Substituted 2-(Benzoylmethyl)thioxo-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]pyrido-
[2,3-d]pyrimidines 6d-f were obtained from a mixture of compound 1a-c (0.01 mol) and bromoacetophenone
5b (2.0 g, 0.01 mol) by the method used for the synthesis of compounds 6a-c. IR spectrum (thin film), ν, cm-1,
6d-f: 1620 (C=N), 1680 (amide C=O), 1700 (C=O). 1H NMR spectrum, δ, ppm (J, Hz), 6d : 8.20-7.40 (11H, m,
H-5, CH2C6H5, O=CC6H5); 6.00 (2H, s, CH2C6H5); 4.80 (4H, s, CH2-6, SCH2); 2.82 (2H, s, 2H-9); 1.30 (6H, s,
2CH3-8).
3-Substituted 2-(Carbamoylmethyl)thioxo-8,8-dimethyl-4-oxo-8,9-dihydro-6H-pyrano[3',4':6,7]-
pyrido[2,3-d]pyrimidines 6g-i. A mixture of compound 1a-c (0.01 mol), chloroacetamide 5c (1.0 g, 0.01 mol),
and KOH (0.56 g, 0.01 mol) in 90% ethanol (20 ml) was boiled for 4 h. The crystals of product 6g-i which
formed on cooling the reaction mixture was filtered off, washed with water, and recrystallized from ethanol.
1
IR spectra (thin film), ν, cm-1, 6g-i: 1630 (C=N), 1670, 1680 (amide C=O), 3400 (NH2). H NMR spectrum,
δ, ppm (J, Hz), 6h: 8.33 (2H, br. s, NH2); 6.20-5.07 (3H, m, CH=CH2); 4.93 (2H, m, NCH2); 4.83 (2H, s, 2H-6);
4.43 (2H, s, SCH2); 3.13 (2H, s, 2H-9); 1.28 (6H, s, 2CH3-8); 6i, 8.20 (1H, s, H-5); 7.41-7.00 (6H, m, NH2,
C6H4); 4.81 (2H, s, 2H-6); 3.83 (5H, m, SCH2, OCH3); 2.90 (2H, s, 2H-9); 1.33 (6H, s, 2CH3-8).
1344

This work was carried in the program of the International Scientific and Technical Union.
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