2-Alkyl-4-oxohexahydropyrimido[4,5-d]- and -[5,4-d]azocines

Article abstract of DOI:10.1007/s10593-011-0744-x

It has been established that 2-R-4-oxotetrahydropyrido[4,3-d]pyrimidines, under the action of activated alkynes in methanol, form a mixture of 2-R-4-oxohexahydropyrimido[4,5-d]azocines and products of decomposition of the tetrahydropyridine ring, the 2-R-5-methoxymethyl-4-oxo-6-vinylaminoethyl- pyrimidines. Tetrahydropyrido[3,4-d]pyrimidine, isomeric at the junction of the pyrimidine and tetrahydropyridine rings, forms only the corresponding pyrimido[5,4-d]azocine, the product of expansion, under the action of methyl propiolate.

Full text of DOI:10.1007/s10593-011-0744-x

Chemistry of Heterocyclic Compounds, Vol. 47, No. 2, May, 2011 (Russian Original Vol. 47, No. 2, February, 2011)
2-ALKYL-4-OXOHEXAHYDROPYRIMIDO[4,5-d]- AND
-[5,4-d]AZOCINES
L. G. Voskressensky1*, M. V. Ovcharov1, T. N. Borisova1, L. N. Kulikova,
A. V. Listratova1, R. S. Borisov1, and A. V. Varlamov1
It has been established that 2-R-4-oxotetrahydropyrido[4,3-d]pyrimidines, under the action of activated
alkynes in methanol, form a mixture of 2-R-4-oxohexahydropyrimido[4,5-d]azocines and products of
decomposition of the tetrahydropyridine ring, the 2-R-5-methoxymethyl-4-oxo-6-vinylaminoethyl-
pyrimidines. Tetrahydropyrido[3,4-d]pyrimidine, isomeric at the junction of the pyrimidine and
tetrahydropyridine rings, forms only the corresponding pyrimido[5,4-d]azocine, the product of
expansion, under the action of methyl propiolate.
Keywords: activated alkyne, pyrimidoazocine, tandem expansion, tandem decomposition.
The synthesis of 2-methyl(phenyl)-4-oxotetrahydropyrimido[4,5-d]azocines were described for the first
time by us in [1]. The reaction used for this was the expansion of the tetrahydropyridine ring in
tetrahydropyrido[4,3-d]pyrimidines under the action of activated alkynes in methanol. Pyridopyrimidines with a
methyl and phenyl groups in position 2 of the pyrimidine ring, and benzyl or methyl groups at the nitrogen atom
of the tetrahydropyridine fragment have been studied. To determine the synthetic limits of the conversions
indicated above it was necessary to establish the effect of the steric bulk of a substituent at the nitrogen atom of
the hydrogenated pyridine fragment, the electronic effects of the substituents in position 2 of the pyrimidine
fragment, and the order of joining the oxopyrimidine and tetrahydropyridine rings. For this purpose in the present
work we have studied tandem conversions of 6-isopropyl-2-methyl- (1) and 6-isopropyl-2-phenyl-
tetrahydropyrido[4,3-d] pyrimidines 2, 6-benzyl-2-methylthiotetrahydropyrido[4,3-d]pyrimidine 3, 6-benzyl-
2-morpholinotetrahydropyrido[4,3-d]pyrimidine 4, and 7-benzyl-2-morpholinotetrahydropyrido[3,4-d]pyrimidine 5,
which is isomeric at the ring junction.
O
O
R
NH
R1
HN
N
+
N
R1
N
H2N
R
CO2Et
1–3
1 R = i-Pr, R1 = Me; 2 R = i-Pr, R1 = Ph; 3 R = Bn, R1 = SMe
_______
Dedicated to L. I. Belen'kii on the occasion of his eightieth birthday.
* To whom correspondence should be addressed, e-mail: lvoskressensky@sci.pfu.edu.ru.
1Peoples' Friendship University of Russia, 6 Miklukho-Maklaya St., Moscow 117198, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 279-286, February, 2011. Original
article submitted January 24, 2011.
222
0009-3122/11/4702-0222©2011 Springer Science+Business Media, Inc.

O
N
CO2Et
O
HN
HN
O
N
+
N
N
H2N
N
Bn
Bn
O
5
Pyridopyrimidines 1-3, 5 were obtained by the procedure reported in [2] from 3-ethoxycarbonyl-
piperidin-4-ones, 4-ethoxycarbonylpiperidin-3-ones, and the appropriate amidines. Pyridopyrimidine 4 was
synthesized from 2-methylthio-substituted compound 3 by the action of morpholine.
In the reaction of tetrahydropyridopyrimidines 1, 2 with methyl propiolate and acetylacetylene in methanol
only the products of expanding the tetrahydropyridine ring were isolated, viz. hexahydropyrimido[4,5-d]azocines
6-9, the yield of which when using compound 2 (65-73%) was approximately two times greater than from
compound 1. Reaction of compounds 1 and 2 with ADCE (acetylenedicarboxylic ester) was accompanied by the
formation, in addition to the appropriate azocines 10 and 11, of products of opening of the tetrahydropyridine
ring, the methoxymethyl-substituted pyrimidines 12 and 13. The yield of azocine 11 did not exceed 3%. From
the reaction of 2-methylthio-substituted compound 3 with ADCE only 5-methoxymethyl-substituted pyrimidine
14 was isolated. On interacting compound 3 with methyl propiolate and acetylacetylene a mixture was formed of
methoxymethyl-substituted pyrimidines 17, 18 and azocines 15, 16, in which the latter predominated and their
yields reached 65%.
Y
Y
–
Y
O
OMe
O
N
O
4
X
3
HN
+
5а
Y
X
X
X
R
HN
N
HN
5
1–3
R
6b
+
MeOH
N
R1
N
1
R1
R1
N
N
R
2
6
6а
A
6–11, 15, 16
12–14, 17, 18
6, 7 R = Pr-i, R1 = Me, X = H, 6 Y = CO2Me, 7 Y = COMe; 8, 9 R = Pr-i, R1 = Ph, X = H, 8 Y = CO2Me, 9 Y = COMe;
10–13 R = Pr-i, X = Y = CO2Me, 10, 12 R1 = Ph; 11, 13 R1 = Me; 14–18 R = Bn, R1 = SMe, 14 X = Y = CO2Me,
15, 17 X = H, Y = CO2Me; 16, 18 X = H, Y = COMe
The tandem conversion reactions of tetrahydropyridopyrimidines proceed through the formation of
ammonium zwitterion A [3].
CO2Me
–
O
O
N
+2
CO2Me
Bn
+
HN
N
HN
N
Bn
N
N
N
MeOH
O
O
A
4
O
N
OMe
CO2Me
O
CO2Me
HN
HN
+
N
N
N
Bn
N
N
O
Bn
O
20
19
223

The isomeric tetrahydropyrido[4,3-d]- and [3,4-d]pyrimidines 4 and 5 react with methyl propiolate in
methanol equally readily. From pyridopyrimidine 4 a mixture was formed of pyrimido[4,5-d]azocine 19 and
methoxymethylpyrimidine 20 in the ratio ~1:2.
Pyridopyrimidine 5, isomeric at the junction of the pyrimidine and tetrahydropyridine rings, was
converted almost quantitatively under these conditions into tetrahydropyrimido[5,4-d]azocine 21 (89% yield).
O
O
CO2Me
Bn
HN
N
HN
+
N
5
Bn
N
N
N
N
MeOH
+2
O
O
CO2Me
–
21
A1
CO2Me
We assume that the difference in the course of the tandem conversions is caused by the different values
+
of δ2 at the methylene group in the intermediate zwitterions A and A1 (different ability of the pyrimidine
fragment to delocalize this charge). Calculations of charges according to the expanded method of Huckel in the
program Chem Office 2006, Chem3D Ultra 10.0 showed that in the intermediate A1 δ2+ was equal to 0.027, and
in A 0.016. Nucleophilic assistance by the solvent is necessary for the tandem conversions in the latter case,
which was also observed experimentally.
Allowing for the data of [1] it may be proposed that the steric bulk of the substituent at the nitrogen of
the tetrahydropyridine ring has practically no effect on the direction of its tandem transformations. This
direction is determined mainly by electronic effects of substituents in the oxopyrimidine fragment and the order
of its joining with tetrahydropyridine.
Bands were observed in the IR spectra of compounds 6-21 in the 1610-1701 cm-1 region for the
stretching vibrations of the carbonyls of ester, amide, and keto groups. In the mass spectra there were peaks for
1
molecular ions of various intensity corresponding to their empirical formula. The H NMR spectra of
pyrimidoazocines 7-10, 15, 16, 19, 21, obtained by the action on pyridopyrimidines of terminal alkynes, are
characterized by the presence of a singlet signal at 7.41-7.78 ppm, caused by the H-7 or H-8 (for 21) proton of
the enamine fragment of the azocine ring. In the spectra of pyrimidines 12-14 singlet signals in the 4.36-4.95
ppm region were caused by the terminal proton of the vinyl group. In the spectra of compounds 17, 18, 20 the
terminal vinyl group causes the presence of two signals, a doublet at 7.56-7.68 (J = 13.0-13.1 Hz) and a
3
broadened singlet in the 4.36-5.30 ppm region. The value of J indicates the trans configuration of the vinyl
group.
EXPERIMENTAL
1
The IR spectra were obtained on a Infralyum FT 801 Fourier spectrometer in KBr disks. The H NMR
spectra were recorded on a Bruker WP 400 (400 MHz) in CDCl3 (compounds 1-4) and DMSO-d6 (compounds
6-8, 19-21) and a Jeol JNM-ECA 600 (600 MHz) in CDCl3 (compounds 9-18) (Center for Collective Use,
Russian Foreign Students University RUDN), internal standard was TMS. Chromatography / mass spectrometry
analysis was carried out on a system comprising an Agilent 1100 liquid chromatograph, an Agilent
Technologies LC/MSD VL (electrospraying, chemical ionization at atmospheric pressure), ELSD Sedex 75.
High resolution mass spectra of compounds 15 and 17 were obtained on a JEOL JMS-T100LP-DART 100
instrument (DART ionization) (Center for Collective Use, Peoples' Friendship University of Russia). Thin-
224

layer chromatography was carried out on Silufol UV-254 or Sorbfile plates. Acros 60 Å silica gel was used for
preparative chromatography (granule size 0.04-0.06 mm).
5,6,7,8-Tetrahydropyrido[4,3-d]pyrimidin-4-ones 1-3 (General Method). Acetamidine (benz-
amidine, or S-methylisothiouronium iodide) (0.05 mol) and K2CO3 (0.1 mol) were added to a solution of
3-ethoxycarbonylpiperidin-4-one hydrochloride (0.05 mol) in water (100 ml). The mixture was heated for 12 h
at 60oC (check by TLC, Silufol, ethyl acetate–ethanol, 5:1). The precipitated solid was filtered off and
recrystallized from ethyl acetate.
6-Isopropyl-2-methyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (1). Yield 35%; mp
1
163-165oC. IR spectrum, , cm-1: 1658 (C=O). H NMR spectrum, δ, ppm (J, Hz): 1.15 (6H, d, J = 6.5
(CH3)2CH); 2.44 (3H, s, 2-CH3); 2.73-2.82 (4H, m, H-7,8); 2.96 (1H, sept, J = 6.5, (CH3)2CH); 3.51 (2H, s,
H-5); 12.88 (1H, br. s, NH). Found, %: C 63.66; H 8.36; N 20.13. [M+H]+ 208. C11H17N30. Calculated, %:
C 63.74; H 8.27; N 20.27. M 207.
6-Isopropyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (2). Yield 58%; mp
1
199-201oC. IR spectrum, , cm-1: 1641 (C=O). H NMR spectrum, δ, ppm (J, Hz): 1.19 (6H, d, J = 6.5,
(CH3)2CH); 2.79-2.92 (4H, m, H-7,8); 2.99 (1H, sept, J = 6.5, (CH3)2CH); 3.62 (2H, s, H-5); 7.45-7.58 (3H, m,
H Ph); 8.12 (2H, d, J = 6.9, H Ph). Found, %: C 71.43; H 7.31; N 15.58. [M+H]+ 270. C16H19N3O. Calculated,
%: C 71.35; H 7.11; N 15.60. M 269.
6-Benzyl-2-methylthio-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)one (3). Yield 59%; mp 210-
1
213oC (decomp.). IR spectrum, , cm-1: 1642 (C=O). H NMR spectrum, δ, ppm (J, Hz): 2.53 (3H, s, CH3S);
2.65-2.75 (4H, m, H-7,8); 3.47 (2H, s, H-5); 3.70 (2H, s, CH2Ph); 7.25-7.45 (5H, m, H Ph). Found, %: C 62.80;
H 5.84; N 14.80. [M+H]+ 288. C15H17N3OS. Calculated, %: C 62.69; H 5.96; N 14.62. M 287.
6-Benzyl-2-(4-morpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4(3H)-one (4). A solution of
compound 3 (0.2 g, 0.69 mmol) and morpholine (1 ml) in dioxane (5 ml) was boiled for 32 h (check by TLC,
Sorbfile, ethyl acetate). The mixture was cooled, and heptane (20 ml) was added. The solid was filtered off,
washed with ether, and dried. Compound 4 (0.18 g, 79%) was obtained as colorless crystals; mp 230-232oC. IR
1
spectrum, , cm-1: 1645 (C=O). H NMR spectrum, δ, ppm (J, Hz): 2.60 (2H, t, J = 5.7, H-8); 2.71 (2H, t,
J = 5.7, H-7); 3.28 (2H, br. s, H-5); 3.59-3.62 (4H, m, CH2–N–CH2); 3.64-3.69 (4H, m, CH2–O–CH2); 3.70 (2H,
s, CH2Ph); 7.25-7.37 (5H, m, H Ph). Found, %: C 66.35; H 6.90; N 17.38. [M+H]+ 327. C18H22N4O2. Calculated,
%: C 66.24; H 6.79; N 17.13. M 326.
7-Benzyl-2-(4-morpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (5).
A
sample
obtained by this method was given by "ASINEKS Medkhim" [4].
5,8,9,10-Tetrahydropyrimidin[4,5-d]azocin-4(3H)-ones 6-11, 15, 16, and 5-Methoxymethylpyrimidin-
4(3H)-ones 12-14, 17, 18 (General Method). ADCE, methyl propiolate, or acetylacetylene (1.0-1.16 mmol)
was added to a solution of pyridopyrimidine 1-3 (0.2 g) in methanol (20 ml) at 20oC. At the end of the reaction
(check by TLC, Silufol, chloroform–methanol, 9:1) the solvent was distilled in vacuum to 2 ml. The crystals of
azocine were filtered off and recrystallized from ethyl acetate. If the crystals did not form the reaction mixture
was evaporated to dryness, and the residue was chromatographed on silica gel in the system hexane–ethyl
acetate, 20:1 to 3:1.
Methyl 8-Isopropyl-2-methyl-4-oxo-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6-carboxylate (6).
1
Yield 37%, colorless crystals; mp 220-222oC. IR spectrum, , cm-1: 1646, 1648 (C=O). H NMR spectrum, δ,
ppm (J, Hz): 1.38 (6H, d, J = 6.8, (CH3)2CH); 2.38 (3H, s, 2-CH3); 3.19 (2H, t, J = 6.8, H-10); 3.38 (1H, sept,
J = 6.8, (CH3)2CH); 3.66 (3H, s, OCH3); 3.71 (2H, t, J = 6.8, H-9); 3.89 (2H, s, H-5); 7.49 (1H, s, H-7). Found,
%: C 61.71; H 7.38; N 14.62. [M+H]+ 292. C15H21N3O3. Calculated, %: C 61.84; H 7.27; N 14.42. M 291.
6-Acetyl-8-isopropyl-2-methyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocin-4(3H)-one (7). Yield 30%,
colorless crystals; mp 208-210oC. IR spectrum, , cm-1: 1610, 1655 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
1.13 (6H, d, J = 6.7, (CH3)2CH); 2.29 (3H, s, CH3CO); 2.34 (3H, s, 2-CH3); 3.18 (2H, t, J = 6.5, H-10); 3.40
225

(1H, sept, J = 6.7, (CH3)2CH); 3.71 (2H, t, J = 6.5, H-9); 3.86 (2H, s, H-5); 7.41 (1H, s, H-7). Found, %:
C 65.31; H 7.44; N 15.46. [M+H]+ 276. C15H21N3O2. Calculated, %: C 65.43; H 7.69; N 15.26. M 275.
Methyl 8-Isopropyl-4-oxo-2-phenyl-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6-carboxylate
1
(8). Yield 55%, light-yellow crystals; mp 253-255oC. IR spectrum, , cm-1: 1642, 1697 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 1.31 (6H, d, J = 6.7, (CH3)2CH); 3.48 (2H, t, J = 6.6, H-10); 3.54 (1H, sept, J = 6.7,
(CH3)2CH); 3.74 (3H, s, CH3O); 3.90 (2H, t, J = 6.6, H-9); 4.15 (2H, s, H-5); 7.65-7.75 (3H, m, H Ph); 7.78 (1H,
s, H-7); 8.44 (2H, d, J = 7.8, H Ph). Found, %: C 68.09; H 6.66; N 11.63. [M+H]+ 354. C20H23N3O3. Calculated,
%: C 67.97; H 6.56; N 11.89. M 353.
6-Acetyl-8-isopropyl-2-phenyl-5,8,9,10-tetrahydropyrimido[4,5-d]azocin-4(3H)-one (9). Yield 24%,
1
colorless crystals, mp 255-257oC (decomp.). IR spectrum, , cm-1: 1632, 1697 (C=O). H NMR spectrum, δ,
ppm (J, Hz): 1.21 (6H, d, J = 6.7 (CH3)2CH); 2.25 (3H, s, CH3CO); 3.37 (2H, t, J = 6.7, H-10); 3.46 (1H, sept, J
= 6.7, (CH3)2CH); 3.80 (2H, t, J = 6.7, H-9); 4.01 (2H, s, H-5); 7.45 (1H, s, H-7); 7.55 (2H, t, J = 7.7, H Ph);
7.65 (1H, m, H Ph); 8.25 (2H, d, J = 7.7, H Ph). Found, %: C 71.31; H 6.77; N 12.61. [M+H]+ 338. C20H23N3O2.
Calculated, %: C 71.19; H 6.77; N 12.45. M 337.
Dimethyl 8-Isopropyl-4-oxo-2-phenyl-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6,7-dicarboxy-
1
late (10). Yield 15%, yellow crystals; mp 248-250oC. IR spectrum, , cm-1: 1648, 1690 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 1.30 (6H, d, J = 6.8, (CH3)2CH); 3.24 (2H, m, H-10); 3.38 (1H, br. s, (CH3)2CH); 3.74
3H, s, OCH3); 3.85 (2H, m, H-9); 3.95 (3H, s, OCH3); 4.45 (2H, s, H-5); 7.64-7.66 (2H, m, H Ph); 7.76 (1H, m,
H Ph); 8.42 (2H, m, H Ph). Found, %: C 64.37; H 6.05; N 10.45. [M+H]+ 412. C22H25N3O5. Calculated, %:
C 64.22; H 6.12; N 10.21. M 411.
Dimethyl 8-Isopropyl-2-methyl-4-oxo-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6,7-dicarboxy-
1
late (11). Yield 3%, yellow crystals; mp 217-220oC. IR spectrum, , cm-1: 1643, 1692 (C=O). H NMR
spectrum, δ, ppm (J, Hz): 1.32 (6H, d, J = 6.8, (CH3)2CH); 2.37 (3H, s, 2-CH3); 3.23 (2H, t, J = 6.5, H-10); 3.38
(1H, br. s, (CH3)2CH); 3.70 (3H, s, OCH3); 3.72 (2H, t, J = 6.5, H-9); 3.87 (2H, s, H-5); 3.90 (3H, s, OCH3).
Found, %: C 58.29; H 6.79; N 12.23. [M+H]+ 350. C17H23N3O5. Calculated, %: C 58.44; H 6.64; N 12.03.
M 349.
Dimethyl (2E)-2-(Isopropyl{2-[5-(methoxymethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-4-yl]ethyl}-
amino))but-2-enedioate (12). Yield 54%, yellow crystals; mp 195-197oC. IR spectrum, , cm-1: 1646, 1696
1
(C=O). H NMR spectrum, δ, ppm (J, Hz): 1.19 (6H, d, J = 6.8, (CH3)2CH); 3.05 (2H, d, J = 6.7, H-6a); 3.40
(3H, s, OCH3); 3.45 (1H, m, (CH3)2CH); 3.50 (2H, t, J = 6.7, H-6b); 3.62 (3H, s, CO2CH3); 3.95 (3H, s,
CO2CH3); 4.50 (2H, s, CH2−OCH3); 5.15 (1H, s, C=HCCO2CH3); 7.50-7.61 (3H, m, H Ph); 8.31 (2H, d, J = 6.9,
H Ph). Found, %: C 62.46; H 6.33; N 9.31. [M+H]+ 444. C23H29N3O6. Calculated, %: C 62.29; H 6.59; N 9.47.
M 443.
Dimethyl (2E)-2-(Isopropyl{2-[5-(methoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-4-yl]ethyl}-
amino))but-2-enedioate (13). Yield 54%, yellow crystals; mp 146-148oC. IR spectrum, , cm-1: 1650, 1701
(C=O). 1H NMR spectrum, δ, ppm (J, Hz): 1.19 (6H, d, J = 6.8, (CH3)2CH); 2.44 (3H, s, 2-CH3); 2.88 (2H, t, J =
6.7, H-6a); 3.38 (2H, t, J = 6.7, H-6b); 3.40 (3H, s, OCH3); 3.46 (1H, m, (CH3)2CH); 3.59 (3H, s, CO2CH3); 3.92
(3H, s, CO2CH3); 4.37 (2H, s, CH2−OCH3); 4.90 (1H, s, C=CHCO2CH3). Found, %: C 56.81; H 7.25; N 11.25.
[M+H]+ 382. C18H27N3O6. Calculated, %: C 56.68; H 7.13; N 11.02. M 381.
Dimethyl (2E)-2-(Benzyl{2-[5-(methoxymethyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-4-yl]-
ethyl}amino))but-2-enedioate (14). Yield 91%, colorless crystals; mp 170-171oC. IR spectrum, , cm-1: 1651,
1
1695 (C=O). H NMR spectrum, δ, ppm (J, Hz): 2.45 (3H, s, SCH3); 2.71 (2H, m, H-6a); 3.09 (3H, s, OCH3);
3.18 (3H, s, CO2CH3); (2H, t, J = 7.4, H-6b); 3.80 (3H, s, CO2CH3); 4.16 (2H, s, CH2Ph); 4.36 (2H, s,
CH2−OCH3); 4.86 (1H, br. s, C=CHCO2CH3); 7.26 (2H, d, J = 7.0, H Ph); 7.30 (1H, d, J = 7.3, H Ph); 7.37 (2H,
t, J = 7.3, H Ph). Found, %: C 57.41; H 5.73; N 9.19. [M+H]+ 462. C22H27N3O6S. Calculated, %: C 57.25;
H 5.90; N 9.10. M 461.
226

Methyl 8-Benzyl-2-(methylthio)-4-oxo-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6-carboxy-
late (15). Yield 65%, yellow crystals; mp 224-226oC. IR spectrum, , cm-1: 1677 (C=O). 1H NMR spectrum, δ,
ppm (J, Hz): 2.35 (3H, s, SCH3); 3.34 (2H, m, H-10); 3.55 (3H, s, CO2CH3); 3.75 (2H, m, H-9);
4.25 (2H, s, CH2Ph); 4.41 (2H, s, H-5); 7.12-7.13 (2H, m, H Ph); 7.28-7.29 (3H, m, H Ph); 7.35 (1H, s, H-7).
Found, %: C 61.68; H 5.82; N 11.39. [M+H]+ 372.1383. C19H21N3O3S. Calculated, %: C 61.44; H 5.70; N 11.31.
[M+H]+ 372.1376.
6-Acetyl-8-benzyl-2-(methylthio)-5,8,9,10-tetrahydropyrimido[4,5-d]azocin-4(3H)-one (16). Yield
1
58%, yellow crystals; mp 248-250oC. IR spectrum, , cm-1: 1613, 1656 (C=O). H NMR spectrum, δ, ppm (J,
Hz): 2.14 (3H, s, SCH3); 2.34 (3H, s, COCH3); 2.94 (2H, t, J = 6.3, 10-CH2); 3.73-3.76 (4H, m, 5,9-CH2); 4.46
(2H, s, CH2Ph); 7.15-7.17 (2H, m, H Ph); 7.25-7.32 (3H, m, H Ph); 7.60 (1H, s, H-7); 12.31 (1H, br. s, NH).
Found, %: C 64.11; H 6.09; N 11.61. [M+H]+ 356. C19H21N3O2S. Calculated, %: C 64.20; H 5.95; N 11.82.
M 355.
Methyl (2E)-3-((Benzyl{2-[5-(methoxymethyl)-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-4-yl]ethyl}-
amino))acrylate (17). Yield 15%, yellow crystals; mp 169-171oC. IR spectrum, , cm-1: 1651, 1670 (C=O). 1H
NMR spectrum, δ, ppm (J, Hz): 2.48 (3H, s, SCH3); 2.75 (2H, t, J = 7.4, H-6a); 3.27 (3H, s, OCH3); 3.40-3.49
(2H, m, H-6b); 3.60 (3H, s, CO2CH3); 4.22 (2H, s, CH2Ph); 4.26 (2H, s, CH2OCH3); 4.77 (1H, m,
CH=CHCO2CH3); 7.10-7.25 (2H, m, H Ph); 7.26-7.30 (3H, m, H Ph); 7.56 (1H, d, J = 13.0, CH=CHCO2CH3).
Found, %: C 59.75; H 6.30; N 10.28. [M+H]+ 404.1646. C20H25N3O4S. Calculated, %: C 59.53; H 6.25; N 10.41.
M 404.1648.
6-(2-{Benzyl[(1E)-3-oxobut-1-en-1-yl]amino}ethyl)-5-(methoxymethyl)-2-(methylthio)pyrimidin-
4(3H)-one (18). Yield 13%, yellow crystals; mp 172-174oC. IR spectrum, , cm-1: 1611, 1650 (C=O). 1H NMR
spectrum, δ, ppm (J, Hz): 2.11 (3H, s, COCH3); 2.54 (3H, s, SCH3); 2.79-2.85 (2H, m, H-6a); 3.34 (3H, s,
OCH3); 3.44-3.62 (2H, m, H-6b); 4.31 (2H, s, CH2Ph); 4.37 (2H, s, CH2OCH3); 5.24-5.41 (1H, br. s,
CH=CHCO2CH3); 7.19 (2H, d, J = 7.3, H Ph); 7.28-7.36 (3H, m, H Ph); 7.68 (1H, d, J = 13.0,
CH=CHCO2CH3). Found, %: C 61.84; H 6.43; N 10.64. [M+H]+ 388. C20H25N3O3S. Calculated, %: C 61.99;
H 6.50; N 10.84. M 387.
Methyl
8-Benzyl-2-morpholino-4-oxo-3,4,5,8,9,10-hexahydropyrimido[4,5-d]azocine-6-carboxylate
(19) and Methyl (2E)-3-(Benzyl{2-[5-(methoxymethyl)-2-morpholino-6-oxo-1,6-dihydropyrimidin-4-
yl]ethyl}-amino)acrylate (20). A suspension of pyridopyrimidine 4 (0.15 g, 0.46 mmol) and methyl propiolate
(0.048 ml, 0.55 mmol) in methanol (10 ml) was boiled for 2 h (check by TLC, Silufol, methanol–chloroform,
9:1). The precipitated crystals (0.065 g) of azocine 19 were filtered off, yield was 35%; mp 290-295oC. IR
1
spectrum, , cm-1: 1645, 1687 (C=O). H NMR spectrum, δ, ppm: 3.23-3.32 (2H, m, H-10); 3.42-3.48 (4H, m,
CH2NCH2); 3.54 (3H, s, CO2CH3); 3.59-3.69 (4H, m, CH2OCH2); 3.68-3.75 (4H, m, H-5,9); 4.39 (2H, s,
CH2Ph); 7.12-7.18 (2H, m, H Ph); 7.24-7.32 (3H, m, H Ph); 7.50 (1H, s, H-7); Found, %: C 64.48; H 6.22; N
13.25. [M+H]+ 411. C22H26N4O4. Calculated, %: C 64.37; H 6.38; N 13.65. M 410.
The filtrate was evaporated to dryness and the crystals were washed with ether. Pyrimidine 20 (0.12 g,
60%) was obtained; mp 208-210oC. IR spectrum, , cm-1: 1640, 1683 (C=O). 1H NMR spectrum, δ, ppm (J, Hz):
2.74 (2H, t, J = 7.3, H-6a); 3.29 (3H, s, OCH3); 3.47 (2H, m, H-6b); 3.66 (3H, s, CO2CH3); 3.70 (4H, m,
CH2NCH2); 3.76 (4H, m, CH2OCH2); 4.21 (2H, s, CH2Ph); 4.34 (2H, s, CH2OCH3); 4.81 (1H, br. s,
CH=CHCO2CH3); 7.17-7.21 (2H, m, H Ph); 7.27-7.35 (3H, m, H Ph); 7.50 (1H, s, H-7); 7.62 (1H, d, J = 13.1,
CH=CHCO2CH3). Found, %: C 62.29; H 6.71; N 12.72. [M+H]+ 443. C23H30N4O5. Calculated, %: C 62.43; H
6.83; N 12.66. M 442.
Methyl
7-Benzyl-2-morpholino-4-oxo-3,4,5,6,7,10-hexahydropyrimido[5,4-d]azocine-9-carboxy-
late (21) was obtained analogously to azocine 19 on boiling pyridopyrimidine 5 (0.2 g, 0.61 mmol) and methyl
propiolate (0.065 ml, 0.74 mmol) in methanol (10 ml). Yield 0.22 g (89%), colorless crystals; mp 292-294oC
1
(decomp.). IR spectrum, , cm-1: 1642, 1685 (C=O). H NMR spectrum, δ, ppm: 2.87 (2H, m, 10-CH2);
227

3.40-3.60 (8H, m, 4CH2 morpholine); 3.62 (3H, s, CO2CH3); 3.65-3.80 (4H, m, H-5,6); 4.39 (2H, s, CH2Ph;
7.09-7.22 (2H, m, H Ph); 7.27-7.42 (3H, m, H Ph); 7.50 (1H, br. s, H-8). Found, %: C 64.20; H 6.19; N 13.53.
[M+H]+ 411. C22H26N4O4. Calculated, %: C 64.37; H 6.38; N 13.65. M 410.
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A. H. Cook and K. Y. Reed, J. Heterocycl. Chem., 399 (1945).
L. G. Voskressensky, T. N. Borisova, A. V. Listratova, L. N. Kulikova, A. A. Titov, and
A. V. Varlamov, Tetrahedron Lett., 47, 4585 (2006).
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A. Yu. Kuznetsov, Yu. A. Kholopov, S. V. Chapyshev, and N. L. Nam, Izv. Timirjazev. Selsko-Khoz.
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