Reaction of ethyl 3,3-diaminoacrylate with pyrimidine series o-chloro ketones. Synthesis of pyrido[4,3-d]pyrimidines and 6H-1,3,6,7-tetra- azaphenalenes

Article abstract of DOI:10.1007/s10593-013-1269-2

Cyclocondensation of ethyl 3,3-diaminoacrylate with 5-acetyl-4- chloropyrimidines gave ortho- and peri-condensed heterocycles formed through substitution of the chlorine atom by the α-carbon atom of the enediamine and condensation of the amino group with

Full text of DOI:10.1007/s10593-013-1269-2

Chemistry of Heterocyclic Compounds, Vol. 49, No. 3, June, 2013 (Russian Original Vol. 49, No. 3, March, 2013)
REACTION OF ETHYL 3,3-DIAMINOACRYLATE WITH
PYRIMIDINE SERIES o-CHLORO KETONES. SYNTHESIS
OF PYRIDO[4,3-d]PYRIMIDINES AND 6H-1,3,6,7-TETRA-
AZAPHENALENES
O. Yu. Bakulina1, E. M. Igumnova1, D. V. Dar'in, and P. S. Lobanov1*
Cyclocondensation of ethyl 3,3-diaminoacrylate with 5-acetyl-4-chloropyrimidines gave ortho- and
peri-condensed heterocycles formed through substitution of the chlorine atom by the -carbon atom of
the enediamine and condensation of the amino group with the carbonyl or by addition of the amino
group to the pyridine ring.
Keywords: 5-acetyl-4-chloropyrimidines, ethyl 3,3-diaminoacrylate, pyrido[4,3-d]pyrimidines,
6H-1,3,6,7-tetraazaphenalenes, cyclocondensation.
The cyclocondensation of -carbonylacetamidines (which as the free bases exist primarily in the
tautomeric enediamine forms) with aromatic and heteroaromatic dielectrophiles is a convenient method for the
preparation of condensed azines (isoquinolines, naphthyridines, and pyridopyrimidines). Aromatic aldehydes
[1-3], esters [4], nitriles [5-8], and nitro compounds [9, 10] having a mobile halogen in an ortho position can
behave as the dielectrophiles. In these reactions, the -carbon atom of the enediamine (amidine) substitutes the
aromatic halogen, and one of the nitrogen atoms forms a bond to carbonyl (or nitrile) carbon atom of the
aromatic dielectrophile, or to the nitrogen atom of the nitro group.
Only two examples involving ortho-halo ketones in this reaction have been reported [5]. Moreover, if
2-fluoro-5-nitroacetophenone and ethyl 3,3-diaminoacrylate form the expected isoquinoline, then the 5-acetyl-4,6-di-
chloropyrimidine unexpectedly gives a peri-condensed heterocycle similar to compound 8 reported in our work.
In this connection, we have studied in greater detail the behavior of o-halo ketones in their reaction with
3,3-diaminoacrylic acid derivatives.
Me
O
H2N
NH2
N
N
N
Me
+
DMF
NH2
MeS
N
MeS
N
Cl
COR
COR
1
3a,b
2a,b
2, 3 a R = OEt, b R = N(CH2)4
_______
*To whom correspondence should be addressed, e-mail: pslob@mail.ru.
1Saint Petersburg State University, 26 University Ave., Saint Petersburg 198504, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 501-506, March 2013. Original
article submitted August 13, 2012; revision submitted January 17, 2013.
466
0009-3122/13/4903-0466©2013 Springer Science+Business Media New York

Ketone 1 has one chlorine atom in an ortho position to the acetyl group and reacts smoothly with the
ethyl ester 2a and pyrrolidide 2b of 3,3-diaminoacrylic acid to give the expected pyridopyrimidines 3a,b.
The structure of compound 3a has been confirmed from X-ray structural analysis (Fig. 1).
Fig. 1. Molecular structure of compound 3a with representation of atoms by thermal vibration
ellipsoids of 50% probability.
Ketone 4 with two chlorine atoms in ortho positions to the acetyl group reacted with the ethyl 3,3-di-
aminoacrylate (2a) to form the pyridopyrimidine 5a. Its cyclocondensation behavior was clearly different from
that of the analog without the methylsulfanyl substituent at position 2. The latter formed only a tricyclic reaction
product [5] as an analog of compound 8. Such a different result can be rationalized from the fact that compound
5a formed a precipitate and was therefore removed from the reaction medium, whereas its analog without the
methylsulfanyl substituent remained in solution and reacted with a second molecule of the enediamine 2a.
Cl
Me
Cl
O
N
N
N
Me
2a
+
DMF
NH2
MeS
N
MeS
N
Cl
CO2Et
4
5a
In order to examine the possible preparation of the 6H-1,3,6,7-tetraazaphenalene 8 from ketone 4, we
carried out a reaction of the pyridopyrimidine 5a with a second mole of the enediamine 2a and obtained
compound 6a as the product of chlorine atom substitution by the enediamine-carbon atom. Compound 6a
proved fully stable and without a tendency to cyclize spontaneously to the tricyclic isomer 8.
467

NH2
EtO2C
N
NH2
R
Cl
N
R
N
N
N
2a
+
DMF
NH2
MeS
NH2
MeS
N
CO2Et
CO2Et
6a,b
5a,b
a R = Me, b R = H
Cyclization did occur upon treatment of compound 6a with picric acid. It is likely that the pyridine ring
nitrogen atom was protonated by the acid, which markedly increased the electrophilicity of the neighboring
carbon atom, thus facilitating cyclization. The picrate 7a was formed, which gave upon treatment with NaOEt
the desired tricyclic product 8, which also was stable and did not open to give the starting compound 6a.
A similar sequence of reactions was also performed starting from the previously reported
pyridopyrimidine 5b [2], lacking a methyl substituent at position 5. The single difference was aromatization of
picrate 7b during isolation of free base, to give compound 9, evidently through the action of atmospheric
oxygen. All of the signals in the 1H NMR spectra of picrates 7a,b were markedly broadened, evidently due to a
rapid proton exchange between several basic centers.
SMe
N
N
EtO2C
H2N
CO2Et
NH2
.
2,4,6-(NO2)3C6H2OH
6a,b + 2,4,6-(NO2)3C6H2OH
, MeCN
N
H
N
H
R
7a,b
a R = Me, b R = H
SMe
N
N
EtONa
EtO2C
H2N
CO2Et
NH2
7a
EtOH
N
H
N
H
Me
8
SMe
N
O
Me
N
N
EtONa, O2
EtO2C
CO2Et
NH2
HN
N
7b
EtOH
MeS
N
NH2
H2N
N
H
CO2Et
10
9
Attempts to prepare compound 6a or its tricyclic isomer 8 directly from ketone 4 were unsuccessful, as
in the study [5]. The reaction was attempted with a large volume of solvent (in order to avoid precipitation of
compound 5a) and over a longer time. Under these conditions a mixture was obtained, containing besides the
1
tricyclic compound 8 also a compound with H NMR spectrum close to that of compound 5a, but with an
additional mobile proton signal at ~12.7 ppm. This compound can be tentatively assigned as the
468

pyridopyrimidone 10, which is a hydrolysis product of the pyridopyrimidine 5a (while noting that water was
formed in the course of the cyclocondensation).
Hence it was shown that the formation of the peri-condensed 6H-1,3,6,7-tetraazaphenalenes via an
intramolecular addition of enediamine amino group to the C=N formal double bond of the pyridine ring is quite
general and occurred in all of the reactions studied.
EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker DPX 300 instrument (300 and 75 MHz,
respectively) using CDCl3 (compounds 1 and 4) or DMSO-d6 (remaining compounds) with the residual signals
1
1
13
of CDCl3 (7.26 ppm for the H nuclei) and DMSO-d6 (2.50 ppm for the H nuclei and 39.7 ppm for the C
nuclei) as internal standards. Elemental analysis was performed on a Hewlett-Packard HP-185B CHN analyzer.
High-resolution mass spectra were recorded on a Bruker micrOTOF instrument (electrospray ionization).
Melting points were determined on a Stuart SMP30 Melting Point Apparatus.
1-(4-Chloro-2-methylsulfanylpyrimidin-5-yl)ethanone (1). MeI (2.25 ml, 33.7 mmol) was added to a
solution of 5-acetylthiouracil [11] (5.0 g, 29.4 mmol) in 10% aqueous NaOH solution (30 ml) and stirred for
24 h at room temperature. The reaction mixture was then acidified with HCl, cooled, the precipitate filtered off
and dried to give the S-methyl derivative (5.4 g, 100%), which was used in the following stage without
additional purification. The S-methyl derivative (2.0 g) was mixed with POCl3 (4 ml, 43 mmol). The mixture
was stirred for 2 h at 80°C. The excess POCl3 was distilled off in vacuo without heating above 60°C. The
residue was poured onto ice (50 g) and stirred thoroughly. CH2Cl2 (25 ml) was added, the organic layer was
separated, and filtered through a silica gel layer. The CH2Cl2 was distilled off in vacuo to give ketone 1. Yield
1.58 g (72%); mp 50-52°C. 1H NMR spectrum, , ppm: 2.58 (3H, s, COCH3); 2.66 (3H, s, SCH3); 8.73 (1H, s,
H-6). Found, m/z: 203.0046 [M+H]+. C7H8ClN2OS. Calculated, m/z: 203.0046.
1-(4,6-Dichloro-2-methylsulfanylpyrimidin-5-yl)ethanone (4) was prepared from 4,6-dichloro-2-me-
thylsulfanylpyrimidine-5-carbaldehyde [2] by the method [12]. Yield 55%; mp 92-94°C. 1H NMR spectrum, ,
ppm: 2.57 (3H, s, COCH3); 2.59 (3H, s, SCH3). Found, m/z: 236.9651 [M+H]+. C7H7Cl2N2OS. Calculated, m/z:
236.9656.
Ethyl 7-Amino-5-methyl-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylate (3a). A solution
of ketone 1 (500 mg, 2.47 mmol) and the acrylate 2a (706 mg, 5.42 mmol) in absolute DMF (5 ml) was
maintained at room temperature for 1 day. The mixture was poured into water, and the precipitate was filtered
off and dried. Yield 580 mg (84%). White crystals; mp 234-236°C (MeCN). 1H NMR spectrum, , ppm (J, Hz):
1.33 (3H, t, J = 7.0, CH2CH3); 2.57 (3H, s, SCH3); 2.72 (3H, s, 5-CH3); 4.33 (2H, q, J = 7.0, CH2CH3); 7.80
13
(2H, br. s, NH2); 9.14 (1H, s, Н-4). C NMR spectrum, , ppm: 14.5 (SCH3); 15.2 (CH2CH3); 21.8 (5-CH3);
61.3 (CH2CH3); 94.6 (C-8); 111.3 (С-4a); 154.5 (C-8a); 159.1 (C-4); 161.7 (C-7); 166.6 (C-5); 168.3 (CO);
173.4 (C-2). Found, %: С 51.77; Н 4.86; N 20.22. С12H14N4O2S. Calculated, %: С 51.78; Н 5.07; N 20.13.
7-Amino-5-methyl-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylic acid pyrrolidide (3b)
1
was prepared similarly. Yield 69%. White crystals; mp 281-282°C (MeCN). H NMR spectrum, , ppm:
1.70-2.00 (4H, m, CH2CH2); 2.49 (3H, s, SCH3); 2.72 (3H, s, 5-CH3); 3.00-3.25 (2Н, m, NCH2); 3.45-3.65 (2Н,
13
m, NCH2); 6.75 (2H, br. s, NH2); 9.15 (1H, s, Н-4). C NMR spectrum, , ppm: 14.3 (SCH3); 21.4 (5-CH3);
25.1, 26.3, 46.2, 47.4 (pyrrolidine); 102.7 (C-8); 110.9 (С-4a); 151.7 (C-8a); 158.4 (C-4); 159.1 (C-7); 163.3
(C-5); 165.3 (CO); 172.6 (C-2). Found, %: С 55.53; Н 5.63; N 22.93. С14H17N5OS. Calculated, %: С 55.42;
Н 5.65; N 23.08.
Ethyl 7-Amino-4-chloro-5-methyl-2-methylsulfanylpyrido[4,3-d]pyrimidine-8-carboxylate (5a). A
solution of ketone 4 (600 mg, 2.53 mmol) and the acrylate 2a (750 mg, 5.76 mmol) in absolute DMF (4.5 ml)
was maintained at room temperature for 2 days. The precipitate formed was filtered off, washed with water, and
469

1
dried. Yield 560 mg (71%). Yellow crystals; mp 162-163°C (MeCN). H NMR spectrum, , ppm (J, Hz): 1.40
(3H, t, J = 7.0, CH2CH3); 2.60 (3H, s, SCH3); 2.94 (3H, s, 5-CH3); 4.41 (2H, q, J = 7.0, CH2CH3); 6.90 (2H,
br. s, NH2). 13C NMR spectrum, , ppm: 14.8, 14.9 (SCH3, CH2CH3); 29.6 (5-CH3); 61.6 (CH2CH3); 96.1 (С-8);
110.7 (С-4a); 157.5; 160.5; 160.7; 165.3; 168.5 (CO); 172.2 (С-2). Found, %: С 46.11; Н 3.98; N 17.69.
С12H13ClN4O2S. Calculated, %: С 46.08; Н 4.19; N 17.91.
Ethyl 7-Amino-4-(2,2-diamino-1-ethoxycarbonylvinyl)-5-methyl-2-methylsulfanylpyrido[4,3-d]-pyri-
midine-8-carboxylate (6a). A solution of the pyridopyrimidine 5a (500 mg, 1.6 mmol) and enediamine 2a
(454 mg, 3.5 mmol) in absolute DMF (3 ml) was maintained for 5 days at room temperature, poured into water;
the precipitate was filtered off, washed with water, and dried. Yield 500 mg (77%). Yellow crystals; mp
1
216-218°C (MeCN). H NMR spectrum, , ppm (J, Hz): 0.80 (3Н, t, J = 7.0, (NH2)2С=CCO2CH2CH3); 1.32
(3Н, t, J = 7.5, 8-СО2CH2CH3); 2.45 (3Н, s, 5-СН3); 2.53 (3Н, s, SCH3); 3.70-3.85 (2Н, m,
(NH2)2С=ССO2CH2CH3); 4.31 (2Н, q, J = 7.5, 8-СО2CH2CH3); 7.25 (2Н, s, 7-NH2); 7.30 (4Н, br. s, С(NH2)2).
13C NMR spectrum, , ppm: 14.3, 15.0, 15.1 (SCH3, СО2CH2CH3); 25.6 (5-СН3); 58.7, 61.1 (СО2CH2CH3);
81.7 (С=С(NH2)2); 95.6 (С-8); 113.2 (С-4а); 156.2; 159.0; 161.7; 165.1; 166.9; 168.5; 169.0; 169.3. Found, %:
С 50.11; Н 5.50; N 20.44. С17H22N6O4S. Calculated, %: С 50.24; Н 5.46; N 20.68.
Ethyl 7-Amino-4-(2,2-diamino-1-ethoxycarbonylvinyl)-2-methylsulfanylpyrido[4,3-d]pyrimidine-
8-carboxylate (6b) was prepared similarly to compound 6a. Yield 79%. Yellow crystals; mp 192-195°C
(decomp., MeCN). 1H NMR spectrum, , ppm (J, Hz): 0.89 (3Н, t, J = 7.0, (NH2)2С=ССO2CH2CH3); 1.33 (3Н,
t, J = 7.5, 8-СО2CH2CH3); 2.53 (3Н, s, SCH3); 3.87 (2Н, q, J = 7.0, (NH2)2С=ССО2CH2CH3); 4.33 (2Н, q,
J = 7.5, 8-СО2CH2CH3); 7.34 (2Н, s, 7-NH2); 7.30-7.65 (4Н, br. s, С(NH2)2); 8.54 (1Н, s, Н-5). 13C NMR
spectrum, , ppm: 14.4, 15.1 (SCH3, 2СО2CH2CH3); 58.8, 61.3 (СО2CH2CH3); 76.4 (С=С(NH2)2 ); 97.3 (С-8);
111.7 (С-4а); 154.5; 156.8; 160.8; 162.7; 167.7; 168.3; 169.6; 171.2. Found, %: С 49.09; Н 5.21; N 21.47.
С16H20N6O4S. Calculated, %: С 48.97; Н 5.14; N 21.41.
Diethyl
5,8-Diamino-6a-methyl-2-methylsulfanyl-6a,7-dihydro-6H-1,3,6,7-tetraazaphenalene-
4,9-dicarboxylate Picrate (7a). Compound 6a (50 mg, 0.12 mmol) was dissolved in refluxing MeCN (30 ml),
and picric acid (30 mg, 0.13 mmol) was added. A precipitate was formed. The mixture was refluxed for a
further 30 min, cooled, and the precipitate was filtered off. Yield 63 mg (82%). Orange crystals; mp 256-262°C
1
(decomp., MeCN). H NMR spectrum, , ppm: 1.23-1.35 (6Н, m, 2СО2CH2CH3); 1.37 (3Н, s, 6а-СН3); 2.66
(3Н, s, SCH3); 4.15-4.32 (4Н, m, 2СО2CH2CH3); 7.2-8.3 (6Н, br. s, 2NH2, 2NH); 8.58 (2Н, s), 12.55 (1Н, br. s,
picric acid). Found, %: С 43.60; Н 3.89; N 19.86. С23H25N9O11S. Calculated, %: С 43.46; Н 3.96; N 19.83.
Diethyl 5,8-diamino-2-methylsulfanyl-6a,7-dihydro-6H-1,3,6,7-tetraazaphenalene-4,9-dicarboxy-
late picrate (7b) was obtained similarly to compound 7a. Yield 90%. Yellow crystals; mp 201-205°C
(decomp., MeCN). 1H NMR spectrum, , ppm: 1.22-1.35 (6Н, m, 2СО2CH2CH3); 2.64 (3Н, s, SCH3); 4.12-4.32
(4Н, m, 2СО2CH2CH3); 5.55 (1H, s, H-6a); 7.4-8.8 (6Н, br. s, 2NH2, 2NH); 8.58 (2Н, s), 12.51 (1Н, br. s, picric
acid). Found, %: С 42.84; Н 3.73; N 20.24. С22H23N9O11S. Calculated, %: С 42.51; Н 3.73; N 20.28.
Diethyl
5,8-Diamino-6a-methyl-2-methylsulfanyl-6a,7-dihydro-6H-1,3,6,7-tetraazaphenalene-
4,9-dicarboxylate (8). Picrate 7a (130 mg, 0.205 mmol) was added to a solution of NaOEt (0.22 mmol,
prepared from Na (5 mg) and absolute EtOH (40 ml)). The suspension formed was stirred to dissolution at room
temperature (1 h). Ethanol was removed in vacuo, and the residue was washed with water and dried. Yield 62
1
mg (74%). Yellow crystals; mp 175-180°C (decomp., MeCN). H NMR spectrum, , ppm (J, Hz): 1.23 (6Н, t,
J = 7.5, 2СO2CH2CH3); 1.29 (3Н, s, 6а-СН3); 2.43 (3Н, s, SCH3); 4.09 (4Н, m, 2СО2CH2CH3); 6.80-8.50 (4Н,
13
br. s, 2NH2); 7.21 (2Н, s, 2NH). C NMR spectrum, , ppm: 14.0; 15.4; 27.1; 59.2; 66.5; 79.1; 103.8; 154.2;
159.1; 168.2; 169.3. Found, m/z: 407.1468 [M+H]+. C17H23N6O4S. Calculated, m/z: 407.1496.
Diethyl 5,8-Diamino-2-methylsulfanyl-6H-1,3,6,7-tetraazaphenalene-4,9-dicarboxylate (9) was
1
obtained similarly. Yield 90%. White crystals; mp 266-273°C (decomp.). H NMR spectrum, , ppm (J, Hz):
1.30 (6Н, t, J = 7.5, 2СО2CH2CH3); 2.52 (3Н, s, SCH3); 4.24 (4Н, q, J = 7.5, 2СО2CH2CH3); 6.80-8.20 (5Н, br.
s, 2NH2, NH). Found, %: С 49.17; Н 4.67; N 21.11. С16H18N6O4S. Calculated, %: С 49.22; Н 4.65; N 21.53.
Found, m/z: 391.1194 [M+H]+. С16H19N6O4S. Calculated, m/z: 391.1183.
470

X-Ray Structural Study of Compound 3a. A crystal was grown from DMF. C12H14N4O2S. The
crystals were monoclinic with space group C 2/c, a 22.907(2), b 9.4779(9), c 14.0696(13) Å,  125.942(2)°;
V 2473.1(4) Å3; F(000) 1168,  0.266 mm-1, Z 8; dcalc 1.495 g/cm3. The cell parameters and set of experimental
reflections were measured on a Bruker AXS Smart 1000 CCD automatic diffractometer (monochromatic
MoKradiation,  0.71073 Å, /2 scanning in the angle range 2.20<29.00°). Of the 9585 total reflections
3259 were independent with Rint 0.0358 and 2699 with I > 2 (I). The experimental completeness for the angle
 29.00° was 99.1%. The structure was solved by a direct statistical method and refined using F2 full-matrix
least-squares analysis in anisotropic approximation for all non-hydrogen atoms. The hydrogen atoms were
placed in geometrically calculated positions and refined in the isotropic approximation. All of the calculations
were carried out using the SHELXTL software package [13]. The final refinement results were R1 0.0386, wR2
0.0953 for reflections with I > 2(I) and R1 0.0428, wR2 0.1024 for all of the reflections. The results of this
X-ray structural analysis have been deposited in the Cambridge Crystallographic Data Center (deposit CCDC
920033).
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