A convenient route for the synthesis of some new Bi-and triheterocondensed uracils

Article abstract of DOI:10.1007/s10593-010-0507-0

Some bifunctional heterocyclic systems having vicinal chlorocyano, chloroacetyl, and chloro-ethoxycarbonyl groups in their structures reacted with 6-amino-1,3-dimethyluracil to afford novel triheterocyclic systems having a pyrimidinedione moiety. Enaminones and a-cyanocinnamic acid derivatives in this reaction gave pyrido[2,3-d]pyrimidinediones. The antimicrobial activity of some new synthesized triheterocyclic systems was studied. 2010 Springer Science+Business Media, Inc.

Full text of DOI:10.1007/s10593-010-0507-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 3, 2010
A CONVENIENT ROUTE FOR THE SYNTHESIS OF SOME
NEW BI- AND TRIHETEROCONDENSED URACILS
M. Abdel-Megid1*
Some bifunctional heterocyclic systems having vicinal chlorocyano, chloroacetyl, and chloro-
ethoxycarbonyl groups in their structures reacted with 6-amino-1,3-dimethyluracil to afford novel
triheterocyclic systems having a pyrimidinedione moiety. Enaminones and α-cyanocinnamic acid
derivatives in this reaction gave pyrido[2,3-d]pyrimidinediones. The antimicrobial activity of some new
synthesized triheterocyclic systems was studied.
Keywords: bi-, triheterocycles, enaminones, uracil, antimicrobial activity.
Several bi- and oligocycles containing uracil rings were found to be an important class of compounds
exhibiting biological and pharmacological activities. These compounds showed antitumor [1, 2], cardiotonic [3, 4],
antifungal [5, 6], antibronchitic [7], antibacterial [6], and antifolate [8] activities. There are ample precedents for the
synthesis of these fused heterocycles [9-14]. Most of these methods usually require rigorous conditions [15], long
reaction times [16,17], and complex synthetic pathways [2]. As a part of our studies on diazines [18-22], the present
investigation aims to search for simple and efficient routes for the synthesis of polynuclear heterocyclic systems
having an uracil nucleus in their structure starting with 6-amino-1,3-dimethyluracil (1), which is considered as a
versatile starting material of a typical synthon leading to the target polynuclear heterocyclic systems. The newly
synthesized triheterocycles appear to be promising antimicrobial agents.
It was found that the reaction of compound 1 with some heterocyclic systems having vicinal chlorocyano
groups is an interesting one. Thus, when compound 1 was subjected to reaction with 2-chloro-4,6-dimethyl-
pyridine-3-carbonitrile (2) in boiling ethanol containing triethylamine as a base, three possible compounds 3-5 may
be produced. The structure of compound 4 was ruled out on the basis of spectral data as IR spectrum of the product
exhibited a peak at 2222 cm–1 attributed to the CN function and elemental analysis showed the absence of chlorine.
1
The H NMR spectrum (DMSO-d6) excluded the formation of compound 3 as it displayed a signal at δ 4.70 ppm
corresponding to the NH2 group with the absence of the H-5 signal at δ 5.73 ppm. These confirmed the formation
of 2-(6-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4,6-dimethylpyridine-3-carbonitrile (5).
Fusion of compound 5 above its melting point or increasing the reaction time between compounds 1 and 2 led to
cycloaddition of the amino group of uracil to the cyano group of the other ring giving rise to 5-amino-
2,4,7,9-tetramethylpyrimido[4,5-h][1,6]naphthyridine-8,10(7H,9H)-dione (6) (Scheme 1).
_______
* To whom correspondence should be addressed, e-mail: mabdelmegid@yahoo.com.
1 Chemistry Department, Faculty of Education, Ain-Shams University, Roxy, Cairo, A. R. Egypt.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 405-414, March, 2010. Original
article received June 16, 2009. Revised version received September 6, 2009.
316
0009-3122/10/4603-0316©2010 Springer Science+Business Media, Inc.

Scheme 1
O
N
Me
Me
O
CN
Cl
N
+
NH2
Me
N
Me
2
1
O
Me
N
O
NH
Me
N
Me
O
NC
Me
O
N
N
N
N
H
Me
N
Me
N
NH
2 Cl
Me
Me
4
Me
3
Me
O
O
N
Me
O
Me
N
Me
NH2
N
Me
CN
NH2
N
N
O
N
Me
Me
5
6
A similar reaction of aminouracil 1 with substituted chloropyridazine carbonitrile 7 or with
chloropyrimidinecarbonitrile 8 under the same reaction conditions with increasing reaction time led to the
formation of pyridazinopyridopyrimidine 9 and dipyrimidopyridine 10, respectively.
Moreover, pyridazinopyridopyrimidine derivatives 13 and 14 were obtained on treatment of compound
1 with pyridazine having vicinal chloroacetyl groups like compound 11 or having vicinal chloroethoxycarbonyl
groups like compound 12, where 6-aminouracil is attacked at C-5 followed by cyclocondensation of the amino
group with the acetyl or ethoxycarbonyl group with elimination of water and ethanol, respectively. The structure
of the obtained triheterocyclic systems 6, 9, 10, 13, and 14 was deduced from their correct elemental analyses
and spectral data (Scheme 2).
Recently an analogous method for the synthesis of pyrido[2,3-d]pyrimidines was proposed via the
reaction of 6-amino-2-thiouracil with activated olefinic systems possessing a leaving group such as
dimethylamino [23]. Motivated by this fact and as a part of our reaction on enaminones [24-27], we studied
herein the effect of some enaminones of pyrazoles and simple enaminones on aminouracil 1. For this purpose a
novel enaminone, 3-(dimethylamino)-2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]prop-2-enenitrile (16), was
obtained from the reaction of 1-cyanoacetyl-3,5-dimethylpyrazole (15) with DMF/dimethylacetal (DMFDMA) in
boiling xylene. The interaction of enaminone 16 with aminouracil 1 in boiling ethanol containing a few drops of
triethylamine involves the removal of 3,5-dimethylpyrazole as a result of nucleophlic attack at the oxo group of
the side chain by the electron-rich 5-position of the uracil or by its amino group. Formation of intermediate 17
was difficult due to a steric factor. Instead, intermediate 18 was formed and underwent ring closure to give
compound 20 and not compound 19.
317

Scheme 2
N
Ph
Ph
O
N
Ph
Ph
Ph
Ph
N
Me
O
COMe
Cl
Ph
O
N
N
N
CN
Cl
Ph
Me
O
N
N
N
N
Me
N
N
N
Me
11
13
NH2
7
N
Me
9
1
Me
Ph
Ph
Ph
Ph
N
CN
Cl
Ph
CO2Et
Cl
O
N
N
O
N
N
Me
Me
O
N
N
Me
N
N
12
Ph
NH2
N
8
N
H
O
O
N
N
N
Me
Me
10
14
The structure of compound 19 was ruled out on the basis of the product being identical with an authentic
sample of compound 20 previously prepared from compound 1 and ethyl ethoxymethylenecyanoacetate [28]
(Scheme 3).
Scheme 3
NMe2
CN
Me
Me
DMFDMA
N
N
CN
Me
Me
Me
N
N
O
O
16
15
–
N
Me
N
1
+
O
O
O
NMe2
Me
CN
Me
O
NC
N
N
N
O
NH2 NMe2
N
N
H
O
Me
N
Me
18
17
O
O
O
CN
O
Me
Me
CN
N
O
N
N
O
N
N
Me
Me
20
19
1
+ EtOCH=C(CN)COOEt
318

Furthermore, pyrazolopyridopyrimidinediones 22a,b were synthesized on treatment of compound 1 with
4-methylidenedimethylaminopyrazolones 21a,b, while 5-arylpyrido[2,3-d]pyrimidinedione derivatives 23a,b
and 7-amino-6-(1H-benzimidazol-2-yl)-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (25) were
obtained via interaction of compound 1 with 1-aryl-3-dimethylaminoprop-2-en-1-ones and enamine 24,
respectively (Scheme 4). The formation of compounds 22a,b and 23a,b is assumed to proceed by the Michael
type addition of the most nucleophilic ring carbon, C-5 of uracil, to the activated double bond of the vinyl
ketone, forming a Michael adduct as an intermediate, which undergoes cyclocondensation by water elimination.
Scheme 4
O
O
Me
N
Me
O
Me
O
N
N
N
N
N
N
N
Ar
R
Me
Me
O
22a,b
23a,b
Me
NMe2
Ar
NMe2
1
N
CN
H
N
N
O
R
N
NMe2
21a,b
24
H
N
NH2
N
N
Me
O
N
O
N
Me
25
CHPh
21, 22 a R = H, b R = Ph; 23 a Ar = Ph, b Ar = CH
Also, pyrido[2,3-d]pyrimidinetriones 27a,b could be obtained on refluxing compound 1 with 3-aryl-
2-cyanoprop-2-enoic acids in ethanol containing piperidine as a base. Compound 26 was not formed as the product
did not give an acid reaction and the IR spectrum of the product showed CN at 2212 cm–1. In addition, when
compound 1 was subjected to reaction with 2-cyano-3,3-bis(methylthio)acrylonitrile (28), 5,6,7-trisubstituted
pyrido[2,3-d]pyrimidinedione 29 was obtained [29], which reacted with hydrazine hydrate in boiling ethanol to
yield the hydrazino derivative 31 but not the triheterocyclic system, pyrazolopyridopyrimidinedione 30, as the IR
spectrum of the product exhibited an absorption band at 2211cm–1 corresponding to the CN function.
On the other hand, when sodium hypochlorite reacted with compound 1, 6-amino-5-chloro-1,3-di-
methyluracil (32) was produced in a better yield than that obtained previously [30]. Boiling of compound 32 in
DMF containing triethylamine afforded 1,3,6,8-tetramethyl-1,5,6,10-tetrahydropyrimido[4,5-g]pteridine-
2,4,7,9(3H,8H)-tetrone (33), while its dehydrated form was previously obtained by photodecomposition of
6-azido-1,3-dimethyluracil [31] (Scheme 5).
The antimicrobial activity of the synthesized triheterocyclic systems against two Gram-positive bacteria
(Bacillus subtilis and Streptococcus faecalis) and a Gram-negative bacteria (Escherichia coli) was investigated
in comparison with ampicillin as an antibacterial standard agent. Also, the compounds were tested against
fungus (Candida albicans) in comparison with nystatin as an antifungal standard agent using a filter paper disc
method [32, 33]. The results are recorded in Table 1.
319

Scheme 5
O
Ar
O
Ar
Me
N
CN
O
Me
O
COOH
NH2
N
O
N
N
H
N
N
Me
Me
27a,b
26a,b
CN
Ar
O
N
O
NH2
N
COOH
Me
O
Cl
Me
CN
N
NaOCl
N
1
SMe
NH2
O
N
SMe
NC
SMe
28
Me
32
Me
CN
29
N2H4
Me
N
O
H
O
NH2
O
NH2
NH2
N
Me
O
N
Me
O
CN
Me
O
N
N
N
N
Me
N
N
N
H
O
N
N
NHNH2
N
N
H
O
Me
Me
Me
30
31
33
26,27 a Ar = 3-O2NC6H4, b Ar = 2,4-Cl2C6H3
The results show that all the tested compounds are capable of inhibiting the growth of all the used
microorganisms. Compounds 9 and 13 having a pyridazine moiety in their structure showed a higher
antibacterial activity compared with those having pyrazole, pyridine, and pyrimidine in their structure, while
compound 22a exhibited antifungal activity greater than those having pyridine, pyridazine, and pyrimidine in
their structure. Therefore, compounds 9 and 13 can be used as antibacterial agents and compound 22a can be
used as an antifungal agent.
TABLE 1. The Inhibition Zone Expressed in mm/mg Sample
Antibacterial activity
Antifungal activity
Compound
B. subtilis
S. faecalis
E. coli
Candida albicans
6
12
16
10
15
11
11
12
10
18
—
12
18
12
16
10
10
11
11
28
—
12
15
10
15
11
11
12
10
11
—
12
11
11
10
15
16
14
12
—
12
9
10
13
14
22a
22b
31
Ampicillin
Nystatin
320

EXPERIMENTAL
All reported melting points are uncorrected. The IR spectra were recorded on a FTIR Bruker Vector 22
spectrometer using the KBr wafer technique. 1H NMR spectra (DMSO-d6) were measured on a Varian Gemini
spectrophotometer 200 MHz using TMS as an internal standard. Mass spectra were obtained using a GCMS QP
1000 ex Shimadzu instrument (EI, 70 eV). Elemental analyses were carried out at the Micro Analytical Center,
Cairo University.
2-Chloro-4,6-dimethylpyridine-3-carbonitrile (2) was prepared according to the reported method [18].
2-(6-Amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4,6-dimethylpyridine-3-carbo-
nitrile (5). Equimolar amounts of 6-amino-1,3-dimethyluracil (1) and 2-chloro-4,6-dimethylpyridine-
3-carbonitrile (2) in ethanol (20 ml) containing triethylamine (5 drops) were refluxed for 1 h. The solid obtained
after cooling the reaction mixture was filtered off and recrystallized from ethanol to give compound 5 as
colorless crystals, yield 68%; mp 245-246oC. IR spectrum, ν, cm–1: 3396, 3351, 3229 (NH2), 2950 (aliphatic
CH), 2222 (CN), 1656 (C=O). 1H NMR spectrum, δ, ppm: 2.23 (3H, s, 4-CH3); 2.30 (3H, s, 6-CH3); 3.08 (3H, s,
NCH3); 3.23 (3H, s, NCH3); 4.70 (2H, s, NH2); 6.14 (1H, s, H-5 pyridine). Mass spectrum, m/z (I, %): 268
[M-NH3] (100), 118 (56.3), 101 (43.8). Found, %: C 59.00; H 5.39, N 24.80. C14H15N5O2. Calculated, %:
C 58.94; H 5.26; N 24.65.
Triheterocondensed uracils 6,9,10,13,14 (General Method). A solution of compound 1 and an equimolar
amount of the chloroheterocyclic compound in ethanol (20 ml) with triethylamine (5 drops) were refluxed for
4-8 h and allowed to cool overnight. The solid obtained was filtered off and crystallized from the proper solvent
to afford the triheterocyclic systems.
5-Amino-2,4,7,9-tetramethylpyrimido[4,5-h][1,6]naphthyridine-8,10(7H,9H)-dione
(6)
was
crystallized from DMF–H2O and appeared as pale-yellow crystals, yield 75%; mp 283-285oC. IR spectrum, ν,
cm–1: 3450-3216 (NH2), 2965 (aliphatic CH), 1654 (CO). Mass spectrum, m/z (I, %): 284 [M-1] (11.3). Found,
%: C 58.60; H 5.40; N 24.86. C14H15N5O2. Calculated, %: C 58.94; H 5.26; N 24.56.
5-Amino-7,9-dimethyl-3,4-diphenylpyrimido[5',4':5,6]pyrido[4,3-c]pyridazine-8,10(7H,9H)-dione
(9) was crystallized from ethanol and appears as yellow crystals, yield 66%; mp 261–262oC. IR spectrum, ν,
cm-1: 3410-3290 (NH2), 2942 (CH aliphatic), 1655 (CO). 1H NMR spectrum, δ, ppm: 3.01 (3H, s, NCH3); 3.27
(3H, s, NCH3); 4.8 (2H, br. s, NH2); 6.77-7.42 (10H, m, H Ar). Mass spectrum, m/z (I, %): 408 [M-2] (11.4),
407 (16.2), 322 (29.5), 59 (100). Found, %: C 67.51; H 4.55; N 20.65. C23H18N6O2. Calculated, %: C 67.31;
H 4.39; N 20.48.
5-Amino-2,7,9-trimethyl-4-phenylpyrimido[4',5':4,5]pyrido[2,3-d]pyrimidine-8,10(7H,9H)-dione
(10) was crystallized from ethanol and appears as pale-yellow crystals, yield 82%; mp 210-212oC. IR spectrum,
ν, cm–1: 3397–3230 (NH2), 2949 (CH aliphatic), 1657 (CO). Mass spectrum, m/z (I, %): 348 [M] (9.45), 332
[M-NH2] (16.2), 318 [M-C2H6], 155 (100). Found, %: C 62.36; H 4.56; N 24.66. C18H16N6O2. Calculated, %:
C 62.06; H 4.59; N 24.13.
5,7,9-Trimethyl-3,4-diphenylpyrimido[5',4':5,6]pyrido[4,3-c]pyridazine-8,10-(7H,9H)-dione (13)
was crystallized from aqueous ethanol and appears as yellow crystals, yield 72%; mp 279-281oC. IR spectrum,
ν, cm–1: 3107 (aromatic CH), 2950 (aliphatic CH), 1656 (CO). 1H NMR spectrum, δ, ppm: 3.07 (3H, s, 5-CH3);
3.24 (3H, s, NCH3); 3.34 (3H, s, NCH3); 6.76-7.89 (10H, m, H Ar). Mass spectrum, m/z (I, %): 409 [M] (1.2),
311 (16.9), 208 (1.7), 155 (100). Found, %: C 70.30; H 4.55; N 17.34. C24H19N5O2. Calculated, %: C 70.14;
H 4.64; N 17.11.
7,9-Dimethyl-3,4-diphenylpyrimido[5',4':5,6]pyrido[4,3-c]pyridazine-5,8,10-(6H,7H,9H)-trione (14)
was crystallized from DMF–H2O and appeared as pale-yellow crystals, yield 67%; mp 297-299oC. IR spectrum,
1
ν, cm–1: 3213 (NH2), 3109 (aromatic CH), 2950 (aliphatic CH), 1657 (CO). H NMR spectrum, δ, ppm: 3.06
(3H, s, NCH3); 3.24 (3H, s, NCH3); 6.76-7.34 (10H, m, H Ar); 8.01 (1H, s, NH). Found, %: C 67.45; H 4.35;
N 17.36. C23H17N5O3. Calculated, %: C 67.15; H 4.13; N 17.03.
321

Enaminones 16 and 21a,b (General Method). A mixture of the active methylene compound
(10 mmol) and DMF/dimethylacetal (1.5 ml, 12 mmol) in xylene (20 ml) was refluxed for 6 h, and the solid
obtained on evaporating the excess solvent was collected and crystallized from the proper solvent.
3-(Dimethylamino)-2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]prop-2-enenitrile
(16)
was
crystallized from ethanol and appears as yellow crystals, yield 86%; mp 210–212oC. IR spectrum, ν, cm–1: 2956
(aliphatic CH), 1668 (CO), 2218 (CN). Mass spectrum, m/z (I, %): 218 [M] (23.15). Found, %: C 60.98; H 6.31;
N 26.01. C11H14N4O. Calculated, %: C 60.55; H 6.42; N 25.68.
3-Methyl-4-methylidenedimethylamino-1H-pyrazol-5-one (21a) was crystallized from methanol and
appears as pale-yellow crystals, yield 78%; mp 158-159oC. IR spectrum, ν, cm–1: 3215 (NH), 2964 (aliphatic
CH), 1665 (CO). Mass spectrum, m/z (I, %): 154 [M+1] (1.13), 153 [M] (12.13). Found, %: C 55.15; H 7.32;
N 27.56. C7H11N3O. Calculated, %: C 54.90; H 7.18; N 27.45.
3-Methyl-4-methylidenedimethylamino-1-phenylpyrazol-5-one (21b) was crystallized from ethanol
and appears as orange crystals, yield 86%; mp 187-188oC. IR spectrum, ν, cm–1: 3095 (aromatic CH), 2965
1
(aliphatic CH), 1668 (CO). H NMR spectrum, δ, ppm: 2.21 (3H, s, CH3); 2.95 (3H, s, NCH3); 3.22 (3H, s,
NCH3); 6.11 (1H, s, olefinic H); 7.43-7.91 (5H, m, H Ar). Mass spectrum, m/z (I, %): 229 [M] (6.09), 77 (100).
Found, %: C 68.36; H 6.50; N 18.58. C13H15N3O. Calculated, %: C 68.12; H 6.55; N 18.34.
Reaction of Compound 1 with Enaminones and with Enamines 24 (General Method). A mixture of
compound 1 (10 mmol), enaminone (12 mmol) in absolute ethanol (20 ml), and triethylamine (5 drops) was
refluxed for 4-8 h and left to cool overnight. The solid obtained was collected and crystallized from the proper
solvent.
3,6,8-Trimethyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione
(22a)
was
crystallized from DMF–H2O and appeared as yellow crystals, yield 78%; mp 242-244o C. IR spectrum, ν, cm–1:
3341 (NH2), 2953 (aliphatic CH), 1712, 1642 (2CO). Mass spectrum, m/z (I, %): 245 [M] (1.25), 191 (100).
Found, %: C 53.66; H 4.56; N 28.82. C11H11N5O2. Calculated, %: C 53.87; H 4.48; N 28.57.
3,6,8-Trimethyl-1-phenyl-1H-pyrazolo[4',3':5,6]pyrido[2,3-d]pyrimidine-5,7(6H,8H)-dione (22b)
was crystallized from ethanol and appeared as orange crystals, yield 55%; mp 239-241oC. IR spectrum, ν, cm–1:
1
3052 (aromatic CH), 2950 (aliphatic CH), 1710-1645 (2CO). H NMR spectrum, δ, ppm: 2.26 (3H, s, CH3);
3.22 (3H, s, NCH3); 3.35 (3H, s, NCH3); 7.19-8.06 (5H, m, H Ar); 8.97 (1H, s, H-4). Mass spectrum, m/z (I, %):
322 [M+1] (2.2), 191 (100), 136 (26.6), 84 (22.4). Found, %: C 63.75; H 4.55; N 21.66. C17H15N5O2.
Calculated, %: C 63.55; H 4.67; N 21.80.
1,3-Dimethyl-7-phenylpyrido[2,3-d]pyrimidine-2,4-dione (23a) was crystallized from isopropanol
and appeared as yellow crystals, yield 62%; mp 190-192oC. IR spectrum, ν, cm–1: 3055 (aromatic CH), 2944
(aliphatic CH), 1705, 1658 (2CO). 1H NMR spectrum, δ, ppm (J, Hz): 3.21 (3H, s, NCH3); 3.54 (3H, s, NCH3);
7.47-7.76 (5H, m, H Ar); 7.80 (1H, d, J = 6.4, H-5,); 8.21 (1H, d, J = 6.5, H-6). Mass spectrum, m/z (I, %): 267
[M] (89), 268 [M+] (1.30), 239 (80.6), 191(100). Found, %: C 67.45; H 4.67; N 15.85. C15H13N3O2. Calculated,
%: C 67.41; H 4.86; N 15.73.
1,3-Dimethyl-7-styrylpyrido[2,3-d]pyrimidine-2,4-dione (23b) was crystallized from ethanol and
appeared as yellow crystals, yield 78%; mp 296-298oC. IR spectrum, ν, cm–1: 3065 (aromatic CH), 2946 (CH
aliphatic), 1701, 1646 (2CO). Mass spectrum, m/z (I, %): 293 [M] (11.2), 191 (100). Found, %: C 69.89; H 5.36;
N 14.49. C17H15N3O2. Calculated, %: C 69.62; H 5.11; N 14.33.
7-Amino-6-(1H-benzimidazol-2-yl)-1,3-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (25) was
crystallized from DMF–H2O and appeared as pale-yellow crystals, yield 65%; mp 297-299oC. IR spectrum, ν,
1
cm–1: 3396, 3351, 3228 (NH2, NH); 3108 (aromatic CH); 2948 (aliphatic CH); 1700, 1656 (2CO). H NMR
spectrum, δ, ppm: 3.08 (3H, s, NCH3); 3.24 (3H s, NCH3); 4.7 (2H, s, NH2); 6.71-7.33 (6H, m, H Ar, H-5 and
NH). Mass spectrum, m/z (I, %): 322 [M] (1.2), 155 (100), 82 (64.2), 68 (19.4). Found %: C 59.56; H 4.55;
N 25.96. C16H14N6O2. Calculated, %: C 59.62; H 4.34; N 26.08.
322

1,3-Dimethyl-5-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-6-carbo-
nitrile (27a). A mixture of compound 1 (1.55 g, 10 mmol) and 3-nitrobenzylidene cyanoacetic acid (2.12 g,
12 mmol) in absolute ethanol (20 ml) containing a few drops of piperidine was refluxed for 6 h. The solid
obtained on cooling was filtered off and crystallized from absolute ethanol, yield 82%; mp 297-298oC.
1
IR spectrum, ν, cm–1: 3399 (NH), 2950 (aliphatic CH), 2212 (CN), 1716-1675 (2CO). H NMR spectrum, δ,
ppm: 3.15 (3H, s, NCH3); 3.65 (3H, s, NCH3); 7.35-8.22 (4H, m, H Ar); 8.26 (1H, s, NH). Found %: C 54.83;
H 3.32; N 19.78. C16H11N5O5. Calculated, %: C 54.39; H 3.11; N 19.83.
5-(2,4-Dichlorophenyl)-1,3-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidine-
6-carbonitrile (27b) was obtained applying the same method used for compound 27a and crystallized from
ethanol as yellow crystals, yield 62%; mp 286-288oC. IR spectrum, ν, cm–1: 3314 (NH); 3055 (CH aromatic),
2965 (CH aliphatic), 2222 (CN), 1706, 1745 (2CO). Mass spectrum, m/z (I, %): 378 [M] (12.8), 306 [M-Cl2]
(1.7), 154 (100). Found, %: C 50.66; H 2.66; N 15.01. C16H10Cl2N4O3. Calculated, %: C 0.79; H 2.64; N 14.18.
4-Amino-3-cyano-6,8-dimethyl-2-methylthiopyrido[2,3-d]pyrimidine-5,7-dione (29) was prepared
according to the reported method [29].
5-Amino-7-hydrazinyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbo-
nitrile (31). A mixture of compound 29 (2.66 g, 10 mmol) and hydrazine hydrate (5 ml) in ethanol (20 ml) was
refluxed for 3 h. The solid was obtained upon evaporating, and the excess solvent was collect. Crystallized from
ethanol to give compound 31 as yellow crystals, yield 72%; mp 149–150οC. IR spectrum, ν, cm–1: 3429, 3314,
1
3230, 3144 (NH2, NH); 2978 (aliphatic CH); 2211 (CN); 1700, 1656 (2CO). H NMR spectrum, δ, ppm: 3.11
(3H, s, NCH3); 3.16 (3H, s, NCH3); 3.52 (1H, s, NH); 6.02 (2H, br. s, NH2); 10.96 (2H, br. s, NH2). Mass
spectrum, m/z (I, %): 261 [M] (1.9), 191 (100), 135 (22.5), 68 (19.4). Found, %: C 50.11; H 4.36; N 37.25.
C10H11N7O2. Calculated, %: C 49.97; H 4.21; N 37.54.
6-Amino-5-chloro-1,3-dimethyluracil (32). To a solution of compound 1 (1.55 g, 10 mmol) in ethanol
(10 ml) sodium hypochlorite (5 ml) was added dropwise and the reaction mixture was stirred for 2 h. The solid
obtained was filtered off and crystallized from ethanol to give yellow crystals, yield 92%; mp 155–156oC [30].
1,3,6,8-Tetramethyl-1,5,6,10-tetrahydropyrimido[4,5-g]pteridine-2,4,7,9(3H,8H)-tetrone (33).
A
solution of compound 32 (1.9 g, 10 mmol) in DMF (10 ml) containing triethyl amine (5 ml) was refluxed for 3 h,
then cooled and poured into cold water. The solid obtained was filtered off and crystallized from DMF–water to
give compound 33 as colorless crystals, yield 92%; mp 274-276oC. IR spectrum, ν, cm–1: 3230, 3144 (2NH);
2958 (aliphatic CH); 1700, 1656 (CO). Mass spectrum, m/z (I, %): 306 [M] (11.9), 276(12), 191 (100). Found,
%: C 47.11; H 4.36; N 27.25. C12H14N6O4. Calculated, %: C 47.05; H 4.57; N 27.45.
The author thanks Dr. U. Fahmy, Biology department, Faculty of Education, Ain-Shams University for
evaluation the antimicrobial activity.
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