Synthesis of novel condensed pyridines and pyrido[2,3-d]pyrimidines

Article abstract of DOI:10.1007/s10593-010-0612-0

Methods have been developed for the synthesis of novel derivatives of pyrano[3,4-c]pyridines, 2,7-naphthyridines, and condensed pyrido[2,3-d] pyrimidines by condensation of thiopyranthiones.

Full text of DOI:10.1007/s10593-010-0612-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
SYNTHESIS OF NOVEL CONDENSED PYRIDINES
AND PYRIDO[2,3-d]PYRIMIDINES
E. G. Paronikyan1, A. S. Noravyan1, and A. S. Harutunyan1*
Methods have been developed for the synthesis of novel derivatives of pyrano[3,4-c]pyridines,
2,7-naphthyridines, and condensed pyrido[2,3-d]pyrimidines by condensation of thiopyranthiones.
Keywords: 2,7-naphthyridines, pyrano[3,4-c]pyridines, pyrido[2,3-d]pyrimidines, thiopyranthione,
cyclization.
Derivatives of pyranopyridines and isoquinolines show antibacterial activity [1] whereas 2,7-naphthyri-
dines are phosphodiesterase inhibitors [2]. With the aim of searching for biologically active compounds we have
carried out in this study the synthesis of novel condensed pyridine derivatives (pyranopyridines,
2,7-naphthyridines, isoquinolines, and pyrido[2,3-d]pyrimidines). In order to prepare these compounds we have
broadened the area of use of a previously reported recyclization of pyrano(pyrido)[3,4-c]thiopyran-1-thiones to
pyrano[3,4-c]pyridines and 2,7-naphthyridines [3]. Hence the reaction of the known condensed thiopyranthiones
1a-d [4, 5] with hydrazine hydrate or methylamine gave the corresponding pyridinethiones 2a-f.
CN
CN
R1
R1
NH2
NH2
R2
R2–NH2
R
R
X
S
X
N
S
S
2a–f
1a–d
1a, 2a,b X = O, R = Me, R1 = Et; 1b, 2c,d X = NMe, R = R1 = H; 1c, 2e X = O, R = Pr-i,
R1 = H; 1d, 2f X = NCH2Ph, R = R1 = H; 2 a,c R2 = NH2; b,d–f R2 = Me
The reaction of the compound 2b prepared and also the previously reported pyridinethiones 2g,h [3, 6]
with triethyl orthoformate gave the ethoxymethylideneamino derivatives of tetrahydro-1H-pyrano-
[3,4-c]pyridine 3a,c and hexahydroisoquinoline 3b. Compounds 3a-c can be treated with ammonia to give the
corresponding amino derivatives 4a-c and compound 3c with methylamine gave the methylamino derivative 4d.
Cyclization of the derivatives 4a-d using sodium ethylate gave the condensed 1-amino(aminomethyl)pyrido-
[2,3-d]pyrimidines 5a-d. It should be noted that compound 3c and hydrazine hydrate gave the 1-hydrazino
derivative 5e immediately and the corresponding intermediate compound 4e was not separated.
_______
* To whom correspondence should be addressed, e-mail: harutyunyan_arpi@mail.ru.
1A. L. Mndzhoyan Institute of Fine Organic Chemistry, Scientific Technological Center of Organic and
Pharmaceutical Chemistry of the National of Academy of Sciences of the Republic of Armenia, Yerevan
375014, Armenia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1222-1226, August, 2010.
Original article submitted August 25, 2009; revision submitted March 31, 2010.
0009-3122/10/4608-0987©2010 Springer Science+Business Media, Inc.
987

CN
CN
S
R1
R1
NH2
Me
N
CHOEt
HC(OEt)3
R
R
X
N
X
N
Me
S
3a–c
R2NH2
2b,g,h
R1
R
CN
NHR2
N
R1
X
N
CHNHR2
EtONa
R
X
N
Me
N
S
N
Me
S
4a–d
5a–e
2b, 3a–5a X = O, R = Me, R1 = Et; 2g, 3b–5b X = CH2, R = R1 = H;
2h, 3c, 4c,d, 5c,d,e X = O, R = R1 = Me; 4, 5 a–c R2 = H, d R2= Me; 5e R2= NH2
The composition and structure of the compounds prepared were confirmed by the results of elemental
analysis (see Table 1) as well as from IR and 1H NMR spectroscopic data (see Experimental).
TABLE 1. Physicochemical Characteristics of Compounds 2-5
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp,°C
Yield, %
C
N
S
2a
2b
2c
2d
2e
2f
C12H16N4OS
C13H17N3OS
C10H13N5S
54.39
54.52
59.42
59.29
51.24
51.04
56.21
56.38
59.04
59.29
65.92
65.78
60.31
60.16
61.25
61.06
58.72
58.99
58.11
57.91
58.74
58.51
56.69
56.50
57.81
57.91
58.05
57.91
58.78
58.51
56.63
56.50
6.21
6.10
6.22
6.51
5.43
5.57
6.18
6.02
6.70
6.51
5.70
5.84
6.84
6.63
6.07
6.22
6.42
6.27
6.02
6.25
5.58
5.73
6.03
5.84
6.37
6.25
6.01
6.25
5.85
5.73
6.05
5.84
21.28
21.19
15.84
15.95
29.92
29.76
24.02
23.91
16.08
15.95
18.19
18.05
13.03
13.15
15.38
15.26
13.54
13.76
19.41
19.29
22.88
22.74
20.12
20.27
19.08
19.29
19.36
19.29
22.94
22.74
20.02
20.27
12.21
12.13
12.23
12.18
13.51
13.63
13.60
13.69
12.07
12.18
10.26
10.33
10.24
10.04
11.41
11.64
10.61
10.50
11.19
11.04
12.89
13.02
11.69
11.60
10.95
11.04
11.19
11.04
13.11
13.02
11.47
11.60
232-234
220-222
240-243
221-224
208-210
228-229
105-107
109-110
127-128
237-239
256-257
240-241
242-244
251-253
292-294
270-272
259-262
254-256
56.8
63.5
64.1
66.7
67.6
60.3
69.4
70.4
71.2
72.1
65.1
69.1
65.7
70.1
72.4
74.1
70.2
71.3
C11H14N4S
C13H17N3OS
C17H18N4S
3a
3b
3c
4a
4b
4c
4d
5a
5b
5c
5d
5e
C16H21N3O2S
C14H17N3OS
C15H19N3O2S
C14H18N4OS
C12H14N4S
C13H16N4OS
C14H18N4OS
C14H18N4OS
C12H14N4S
C13H16N4OS
C14H18N4OS
C13H17N5OS
57.72
57.91
53.43
53.59
6.14
6.25
6.01
5.88
19.12
19.29
24.21
24.04
10.88
11.04
11.18
11.00
988

EXPERIMENTAL
The IR spectra were recorded on a UR-20 spectrometer for a suspension in vaseline oil. 1H NMR spectra for
the compounds synthesized were recorded on a Varian Mercury 300 VX instrument (300 MHz) using DMSO-d6
solvent and with TMS as internal standard. Mass spectra were taken on an MX-1320 instrument with direct
introduction of the sample into the ion source and an electron ionization energy of 70 eV. The purity of the
compounds was monitored by TLC on Silufol UV-254 plates using the systems: ethanol–chloroform, 1:2 (2a,c),
ethanol–chloroform, 1:1 (2b,d-f), acetone–hexane, 1: 1 (3a-c), or butanol–acetic acid–water, 4:2:5 (4a-d, 5a-e).
The characteristics for the compounds prepared are given in Table 1.
6,7-Diamino-3-ethyl-3-methyl-8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile
(2a) and 2,3-Diamino-7-methyl-1-thioxo-1,2,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitrile (2c)
(General Method). A mixture of compound 1a or 1b (5 mmol) and an 80% aqueous solution of hydrazine
hydrate (10 ml) was held on a boiling water bath for 4 h. The cooled reaction mixture was treated with water (50
ml) and the crystals of the corresponding product formed were filtered off, washed with water, dried, and
recrystallized from dioxane.
IR spectrum of compound 2a or 2c (basic spectroscopic data identical), , cm-1: 3150-3460 (NH2), 2220
(CN), 1580-1590 (C=C Ar). 1H NMR spectrum, , ppm (J, Hz): compound 2a – 0.96 (3H, t, J = 7.4, CH2CH3);
2
3
2
3
1.18 (3H, s, CH3); 1.50 (1H, dq, J1 = 14.0, J2 = 7.4, CH2CH3); 1.62 (1H, dq, J1 = 14.0, J2 = 7.4, CH2CH3);
2.42 (1H, d, 2J = 17.2, CH2); 2.52 (1H, d, 2J = 17.2, CH2); 4.35 (1H, d, 2J = 16.2, OCH2); 4.40 (1H, d, 2J = 16.2,
OCH2); 6.45 (2H, s, NNH2); 7.45 (2H, br. s, NH2); compound 2c – 2.44 (3H, s, CH3); 2.61 (2H, t, 3J = 5.8, CH2);
2.75 (2H, t, 3J = 5.8, NCH2CH2); 3.36 (2H, s, NCH2); 6.50 (2H, s, NNH2); 7.36 (2H, br. s, NH2).
6-Amino-3-ethyl-3,7-dimethyl-8-thioxo- (2b) and 6-Amino-3-isopropyl-7-methyl-8-thioxo-1,2,7,8-
tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (2e), 3-Amino-2,7-dimethyl- (2d) and 3-Amino-7-benzyl-
2-methyl-1-thioxo-1,2,5,6,7,8-hexahydro-2,7-naphthyridine-4-carbonitrile (2f) (General Method). A mixture of
compound 1a,c,d or 1f (5 mmol) and a 25% aqueous solution of methylamine (20 ml) was held for 5 h at
70-80ºC. The cooled mixture was treated with water (50 ml), and the crystals of the products 2b,d,e or 2f
formed respectively were filtered off, washed with water, and recrystallized from ethanol. IR spectrum of
1
compounds 2b,d-f, , cm-1: 3190-3450 (NH2), 2220 (CN), 1600 (C=C Ar). H NMR spectrum, , ppm (J, Hz):
3
compound 2b – 0.96 (3H, t, J = 7.4, CH2CH3); 1.17 (3H, s, CH3); 1.50 (1H, m) and 1.59 (1H, m, CH2CH3);
2.39 (1H, d, 2J = 17.3, CH2); 2.49 (1H, d, 2J = 17.3, CH2); 3.94 (3H, s, NCH3); 4.32 (1H, d, 2J = 16.4, OCH2); 4.38
2
3
(1H, d, J = 16.4, OCH2); 7.43 (2H, br. s, NH2); compound 2d – 2.40 (3H, s, NCH3); 2.54 (2H, t, J = 5.8, CH2);
2.70 (2H, t, 3J = 5.8, NCH2CH2); 3.30 (2H, s, NCH2); 3.95 (3H, s, NCH3); 7.36 (2H, br. s, NH2); compound 2e – 1.00
(3H, d, 3J = 6.1, CH3); 1.02 (3H, d, 3J = 6.1, CH3); 1.78 (1H, m, CH); 2.43 (1H, dd, 2J1 = 17.0, 2J2 = 10.1, CH2); 2.52
(1H, m, CH2); 3.19 (1H, m, OCH); 3.93 (3H, s, NCH3); 4.18 (1H, d, 2J = 15.7, OCH2); 4.71 (1H, d, 2J = 15.7, OCH2);
7.43 (2H, br. s, NH2); compound 2f – 2.58 (2H, t, 3J = 5.6, CH2CH2N); 2.69 (2H, t, 3J = 5.6, CH2CH2N); 3.45 (2H, s,
NCH2); 3.68 (2H, s, NCH2); 3.95 (3H, s, NCH3); 7.17-7.33 (5H, m, Ph); 7.36 (2H, br. s, NH2).
3-Ethyl-3,7-dimethyl-8-thioxo- (3a) and 6-[(E)-(Ethoxymethylidene)amino]-3,3,7-trimethyl-8-thioxo-
3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (3c), 3-[(E)-(Ethoxymethylidene)amino]-2-methyl-
1-thioxo-1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (3b) (General Method). A mixture of compound
2b,g or 2h (5 mmol) and triethyl orthoformate (25 ml) was refluxed using a reflux condenser for 3 h. The excess
ester was distilled off and the residue was treated with hexane (10 ml). The crystalline products 3a-c were
filtered off, washed with hexane, dried, and recrystallized from hexane. IR spectrum of compounds 3a-c, ,
cm-1: 2230 (CN), 1650 (C=N), 1600 (C=C Ar). 1H NMR spectrum, , ppm (J, Hz): compound 3b – 1.46 (3H, t,
3J = 7.1, CH2CH3); 1.79 (4H, m, CH2CH2); 2.67 (2H, m, CH2); 2.71 (2H, m, CH2); 3.86 (3H, s, NCH3); 4.48
(2H, q, 3J = 7.1, CH2CH3); 8.20 (1H, s, CH); compound 3c – 1.29 (6H, s, 2CH3); 1.47 (3H, t, 3J = 7.5, CH2CH3);
2.61 (2H, s, CH2); 3.83 (3H, s, NCH3); 4.40-4.60 (4H, m, CH2O, CH2CH3); 8.22 (1H, s, CHO).
989

6-[(E)-(Aminomethylidene)amino]-3-ethyl-3,7-dimethyl-8-thioxo- (4a), 6-[(E)-(Aminomethylidene)-
amino]-3,3,7-trimethyl-8-thioxo- (4c) and 3,3,7-Trimethyl-6-[(E)-(methylaminomethylidene)amino]-
8-thioxo-3,4,7,8-tetrahydro-1H-pyrano[3,4-c]pyridine-5-carbonitrile (4d), 3-[(E)-(Aminomethylidene)-
amino]-2-methyl-1-thioxo-1,2,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (4b) (General Method). A
mixture of compound 3a,b or 3c (5 mmol) and a 20% ethanol solution of methylamine (20 ml) was held at 20-22ºC
for 48 h. The crystals formed were filtered off, washed with water, dried, and recrystallized from ethanol. IR
spectrum of compounds 4a-d, , cm-1: 3120-3440 (NH, NH2), 2220 (CN), 1670 (C=N), 1580 (C=C Ar).
1-Amino-9-ethyl-5,9-dimethyl- (5a), 1-Amino-5,9,9-trimethyl- (5c), 5,9,9-Trimethyl-1-methyl-
amino- (5d) and 1-Hydrazino-5,9,9-trimethyl-5,6,9,10-tetrahydro-7H-pyrano[4',3':4,5]pyrido[2,3-d]pyri-
midine-6-thione (5e), and 1-Amino-5-methyl-7,8,9,10-tetrahydropyrimido[4,5-c]isoquinoline-6-thione (5b)
(General Method). Compound 4a-d (5 mmol) was added to a solution of sodium ethylate prepared from
sodium (1.12 g, 5.2 mmol) and absolute ethanol (20 ml). The mixture was refluxed using a reflux condenser for
20 min. After cooling, the crystals of the corresponding product formed were filtered off, washed with water,
dried, and recrystallized from DMSO. IR spectrum of compounds 5a-d, , cm-1: 3320-3500 (NH, NH2); 1600-
1610 (C=C Ar). 1H NMR spectrum, , ppm (J, Hz): compound 5a – 0.96 (3H, t, 3J = 7.4, CH2CH3); 1.16 (3H, s,
2
2
CH3); 1.50 and 1.63 (1H, m and 1H, m, CH2CH3); 2.86 (1H, d, J = 17.3, CH2); 3.03 (1H, d, J = 17.3, CH2);
2
2
4.17 (3H, s, NCH3); 4.53 (1H, d, J = 17.5, OCH2); 4.61 (1H, d, J = 17.5, OCH2); 7.24 (2H, br. s, NH2); 8.26
3
3
(1H, s, NCH); compound 5b – 1.69-1.85 (4H, m, CH2CH2); 2.80 (2H, t, J = 6.2, CH2); 3.05 (2H, t, J = 6.2,
CH2); 4.19 (3H, s, NCH3); 7.16 (2H, br. s, NH2); 8.23 (1H, s, NCH); compound 5d – 1.25 (6H, s, 2CH3); 3.02
(3H, s, NCH3); 3.04 (2H, s, CH2); 4.18 (3H, s, NCH3); 4.60 (2H, s, OCH2); 7.06 (1H, br. s, NH); 8.36 (1H, s,
NCH). Mass spectrum of compound 5c, m/z (Irel, %): 277 (15), 276 [M]+ (74), 261 (37), 260 (91), 243 (50).
1-Hydrazino-5,9,9-trimethyl-5,7,9,10-tetrahydro-6H-pyrano[4',3':4,5]pyrido[2,3-d]pyrimidine-
6-thione (5e). A mixture of compound 3c (1.53 g, 5 mmol), hydrazine hydrate (3 ml), and ethanol (15 ml) was
refluxed using a reflux condenser for 2 h. After cooling, the crystals of product 5e were filtered off, washed with
water, dried, and recrystallized from DMSO. Mass spectrum, m/z (Irel, %): 292 (4), 291 [M]+ (30), 276 (38), 275
(47), 260 (62), 249 (100).
REFERENCES
1.
2.
E. G. Paronikyan, G. V. Mirzoyan, A. S. Noravyan, D. A. Avakimyan, and Yu. Z. Ter-Zakharyan,
Khim.-Farm. Zh., 24, No. 11, 29 (1993).
T. Ukita, Y. Nakamura, A. Kubo, Y. Yamamoto, Y. Moritani, K. Saruta, T. Higashijima, J. Kotera,
K. Fujishige, M. Takagi, K. Kikkawa, and K. Omori, Bioorg. Med. Chem. Lett., 13, 2341 (2003).
E. G. Paronikyan, G. V. Mirzoyan, and A. S. Noravyan, Khim. Zh. Armenii, 48, No. 3, 132 (1995).
E. G. Paronikyan and A. S. Noravyan, Khim. Geterotsikl. Soedin., 914 (1999). [Chem. Heterocycl.
Comp., 35, 799 (1999)].
3.
4.
5.
6.
K. Gewald, J. Prakt. Chem., 31, 209 (1966).
K. Gewald, M. Buchwalder, and M. Peukert, J. Prakt. Chem., 315, 679 (1973).
990