Some aspects of reaction of 6-aminouracil and 6-amino-2-thiouracil with α,β-unsaturated ketones

Article abstract of DOI:10.1135/cccc20050350

A number of 5,7-diaryl-5,8-dihydropyrido[2,3-d]pyrimidines and 5,7-diarylpyrido[2,3-d]-pyrimidines were obtained by the reaction of 6-aminouracil derivatives with α,β-unsaturated ketones. Basic catalysts decrease yields of the dihydro derivatives whereas

Full text of DOI:10.1135/cccc20050350

350
Chebanov et al.:
SOME ASPECTS OF REACTION OF 6-AMINOURACIL AND
6-AMINO-2-THIOURACIL WITH α,β-UNSATURATED KETONES
1,
2
3
Valentin A. CHEBANOV *, Vyacheslav E. SARAEV , Ekaterina A. GURA ,
4
5
Sergey M. DESENKO and Vladimir I. MUSATOV
Department of Photoactive Heterocyclic Compounds, Scientific and Technological Corporation
“Institute for Single Crystals”, Institute for Scintillation Materials of National Academy of Science
1
of Ukraine, Lenin Ave 60, 61001 Kharkiv, Ukraine; e-mail: chebanov@isc.kharkov.com,
2 saraev@isc.kharkov.com, 3 k_gura@mail.ru, 4 desenko@isc.kharkov.com, 5 musatov@isc.kharkov.com
Received August 31, 2004
Accepted Jan uary 9, 2005
A n um ber of 5,7-diaryl-5,8-dih ydropyrido[2,3-d]pyrim idin es an d 5,7-diarylpyrido[2,3-d]-
pyrim idin es were obtain ed by th e reaction of 6-am in ouracil derivatives with α,β-un saturated
keton es. Basic catalysts decrease yields of th e dih ydro derivatives wh ereas acids in crease it.
In th e reaction s of keton es con tain in g th e dim eth ylam in o group, elim in ation of th e aryl
substituen t from position 5 of th e pyridopyrim idin e system was observed. Som e aspects of
oxidation of 5,8-dih ydropyrido[2,3-d]pyrim idin es an d syn th esis of pyrido[2,3-d]pyrim idin es
were also in vestigated.
Keyw ord s: Nitrogen h eterocycles; Pyrido[2,3-d]pyrim idin es; Pyrim idin es; Oxidation ; NMR
spectroscopy; Cyclization s; α,β-Un saturated keton es; Heteroan n ulation s.
It is well kn own th at m an y pyrido[2,3-d]pyrim idin e derivatives possess in -
terestin g ph ysiological properties. Th ey h ave been proved to posses an tibac-
terial1, an tiviral2, diuretic3 an d oth er activities4. As a result, com poun ds of
th is class presen t a con siderable in terest for research . On e of th e facile syn -
th etic path ways to such com poun ds is reaction of 6-am in ouracil an d its de-
rivatives with β-ketoesters5,6, β-diketon es7–10 or α,β-un saturated carbon yl
com poun ds11–14. Th e reaction s of 6-am in ouracil with α,β-un saturated car-
bon yl com poun ds are th e m ost gen eral-purpose m eth ods because th ey al-
low to obtain both pyrido[2,3-d]pyrim idin es an d th eir dih ydro derivatives
with differen t substituen ts in position s 5 an d 7 of th e h eterocyclic system .
Altern ative path ways are n ot suitable for syn th esis of th e dih ydro deriva-
tives an d pyrido[2,3-d]pyrim idin es con tain in g various substituen ts.
As it was previously reported11, refluxin g of 2-th io-6-am in ouracil 2 in
DMF with a series of ch alcon es leads to 5,7-diaryl-2-th ioxopyrido[2,3-d]-
pyrim idin -4-on es. Syn th esis of th eir 5,8-dih ydro derivatives was carried out
Collect. Czech. Chem. Commun. (Vol. 70) (2005)
doi:10.1135/cccc20050350

Reaction of 6-Aminouracil and 6-Amino-2-Thiouracil
351
in argon atm osph ere. Th e structures of com poun ds syn th esized were con -
1
firm ed by H an d 13C NMR spectroscopy. In support of th e position s of aryl
substituen ts, a series of NOE experim en ts was m ade.
In th e fram ework of th e presen t in vestigation , th e in fluen ce of reaction
con dition s an d electron ic n ature of substituen ts on th e com position of re-
action products was studied. Elaboration of a facile syn th etic procedure for
5,7-diaryl-5,8-dih ydropyrido[2,3-d]pyrim idin es an d th eir oxidation were
also goals of th e research .
Th e startin g m aterials were prepared by th e followin g literature proce-
dures. Th us, 6-am in ouracil derivatives 1 an d 2 were obtain ed by treatm en t
of eth yl cyan oacetate with urea or th iourea in th e presen ce of sodium
eth oxide15. α,β-Un saturated keton es 3a–3h an d 8a, 8b were prepared by a
kn own m eth od16 from correspon din g aldeh ydes an d acetoph en on es.
Th e reaction s of am in o derivatives 1, 2 with ch alcon es 3a–3h were per-
form ed by refluxin g in DMF in th e presen ce of basic or acidic catalysts an d
also by h eatin g in glacial acetic acid (Sch em e 1). After a sh ort open -air h eat-
in g (10–20 m in ) of am in es 1, 2 with keton es 3a–3h in DMF, on ly th e start-
in g com poun ds could be isolated from th e reaction m ixture. A prolon ged
reflux (2 h an d m ore) led to pyrido[2,3-d]pyrim idin es 6a, 6b, 7a, 7c–7h
(com poun ds 6b, 7a, 7c–7e were isolated in a m ixture with 5,8-dih ydro-
pyrido[2,3-d]pyrim idin es 4b, 5a, 5c–5e). A furth er in crease of th e h eatin g
tim e to 6–10 h an d passin g air th rough th e reaction m ixture did n ot lead to
an y ch an ge of both th e yield an d th e ratio of pyridopyrim idin es 6b, 7a,
7c–7e an d th eir dih ydro derivatives 4b, 5a, 5c–5e in th e reaction products.
R1
R1
R1
O
O
O
HN
HN
HN
+
+
X
N
H
N
H
O
X
N
H
N
X
N
H
NH2
R2
R2
R2
1, X= O
2, X = S
3
4, X = O
5, X = S
6, X = O
7, X = S
R1
3–7
a
R1
H
R2
H
3–7
e
R2
Me2N
NO2
Cl
Cl
H
b
Cl
Me
Cl
f
F
c
H
g
CO2Me
d
MeO
Cl
h
H
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

352
Chebanov et al.:
Th e treatm en t of am in o derivatives 1, 2 with keton es 3a, 3f–3h in th e
presen ce of trieth ylam in e or potassium h ydroxide yielded sufficien tly pure
correspon din g pyrido[2,3-d]pyrim idin es 6a, 7a, 7f–7h , wh ereas th e reaction
of 1, 2 with ch alcon es 3c–3e un der th e sam e con dition s led to th e form a-
tion of m ixtures of 5c–5e an d 7c–7e, wh ich could be h ardly separated.
An addition of several drops of acetic acid to DMF in creased con ten t of
th e dih ydro derivatives in th e resultin g m ixture. Refluxin g am in ouracils 1,
2 an d ch alcon es 3b –3e in glacial acetic acid led to th e form ation of
5,8-dih ydropyrim idin es 4b, 5c–5e. However, in th e case of ch alcon es 3a,
3f–3h un der th e sam e con dition s, on ly pyridopyrim idin es 6a, 7a, 7f–7h
were isolated.
Th e results obtain ed in th is way sh ow th at th e ratio of 5,7-diarylpyrido-
[2,3-d]pyrim idin es to th eir dih ydro derivatives in th e product m ixture de-
pen ds on reaction con dition s: basic catalysts decrease th e yields of th e
dih ydro derivatives, wh ereas acid catalysts in crease th em . Th is is possibly
closely related to proton ation an d deproton ation of th e dih ydro derivatives,
wh ich are reflected in th eir ability to arom atize. On th e oth er h an d, a de-
pen den ce of th e product com position on th e electron ic n ature of substitu-
en ts in th e h eterocycle was observed. In troduction of electron -with drawin g
substituen ts in to position 5 in creases th e con ten t of pyrido- [2,3-d]pyrim i-
din es, wh ereas electron -don atin g groups h ave an opposite effect.
In th e presen ce of stron g electron don or groups, elim in ation of th e aryl
substituen t from position 5 of th e pyridopyrim idin e m oiety could be ob-
served. Th us, in th e reaction of 2 with ch alcon es 8a, 8b in acetic acid on ly
com poun ds 10a, 10b were isolated (Sch em e 2). Sim ilar processes h ave been
NMe2
Me2N
O
O
HN
HN
+
S
N
H
N
H
S
N
H
NH2
O
R
R
2
8
9
O
8–10
R
H
HN
a
b
S
N
H
N
Me
R
10
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Reaction of 6-Aminouracil and 6-Amino-2-Thiouracil
353
described in literature17 just in th e case of h eterocycles with electron -rich
elim in ated aryl substituen ts.
To fin d an altern ative syn th esis of pyrido[2,3-d]pyrim idin e derivatives,
th e th ree-com pon en t reaction of am in es 1, 2 with syn th etic precursors of
ch alcon es was attem pted. It was foun d th at th e on e-pot h eatin g of alde-
h ydes 11a–11c an d acetoph en on e 12 with am in o derivatives 1, 2, both in
DMF an d in acetic acid, led to th e form ation of 6,6′-diam in o-5,5′-(aryl-
m eth ylen e)bispyrim idin es 13a, 14b, 14c (Sch em e 3). In th is case, th e reac-
tion proceeded with out participation of acetoph en on e wh ich was deter-
m in ed in th e reaction m ixtures by HPLC.
R
O
O
O
HN
H
CH3
NH2
NH2
NH
+
+
X
N
H
NH2
R
HN
X
X
N
H
N
H
O O
1, X = O
2, X = S
11
12
+ 12
11, 13, 14
R
13, X = O
14, X = S
a
b
c
Me
Cl
F
SCHEME 3
On e of th e goals of th e in vestigation was to study oxidation of 5,8-
dih ydro derivatives 4b, 5c–5e to th e correspon din g pyrido[2,3-d]pyrim i-
din es. As it was earlier m en tion ed, passin g air th rough th e reaction m ixture
was n ot an effective oxidation m eth od of 5,8-dih ydropyrido[2,3-d]pyrim i-
din es. Com m on m eth ods of h eteroarom atization , such as treatm en t 4b,
5c–5e with sodium n itrite or with brom in e in acetic acid led to pyrido-
[2,3-d]pyrim idin es 6b , 7c–7e, but th e products con tain ed con siderable
am oun ts of startin g com poun ds.
Th e use of N-brom osuccin im ide (NBS) turn ed out to be a preparative
m eth od for th e oxidation of 5,8-dih ydropyrido[2,3-d]pyrim idin es. Reflux of
equim olar am oun ts of com poun ds 4b, 5c–5e an d NBS in dry DMF for 3 h
led to sufficien tly pure pyrido[2,3-d]pyrim idin es 6b, 7c–7e (Sch em e 4).
Th e results obtain ed allowed to elaborate a sim ple m eth od for syn th esis
of 5,7-diarylpyrido[2,3-d]pyrim idin es by th e reaction of am in o derivatives
1, 2 with ch alcon es in DMF in th e presen ce of equim olar am oun ts of NBS.
Usin g th is m eth od, com poun ds 6b, 7c–7e were obtain ed.
Th e com position of com poun ds 4b, 5c–5e, 6a, 6b, 7a, 7c–7h , 10a, 10b,
13a an d 14b, 14c was con firm ed by elem en tal an alysis an d th eir structures
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

354
Chebanov et al.:
1
were proved by H NMR an d 13C NMR spectral data (see Experim en tal). Th e
1H NMR spectra of 5,8-dih ydropyrido[2,3-d]pyrim idin es 4b, 5c–5e sh ow
sign als of fun ction al groups an d aryl substituen ts, a doublet of m eth in e
3
3
proton s (ca. 4 ppm , J ≈ 5 Hz), a doublet of eth ylen e proton (ca. 5 ppm , J ≈
5 Hz), a broad sin glet of NH group of pyridin e rin g n ear 8 ppm , sign als of
pyrim idin e am in o groups at 11.5 an d 12.0 ppm . Th e 1H NMR spectra of
com poun ds 6a, 6b an d 7a, 7c–7h sh ow sign als of term in al groups, sin glet
of pyridin e proton at ca. 8 ppm an d broad sign als of am in o groups, wh ich
are low-field-sh ifted (ca. 1 ppm ) relative to com poun ds 4b, 5c–5e. In th e
1H NMR spectra of 10a, 10b, besides sign als of arom atic proton s an d pyrim -
idin e NH groups, two doublets at 7.9 an d 8.3 ppm (3J = 8.2 Hz) are presen t.
A sin glet of m eth in e proton in Mich ael adducts 13a an d 14a, 14b is located
at ca. 5.3 ppm . 13C NMR spectroscopic data are n ot in con tradiction with
th e proposed structures 4b, 5c–5e, 6a, 6b, 7a, 7c–7h , 10a, 10b.
R1
R1
O
O
NBS, ∆
HN
HN
DMF
X
N
H
N
X
N
H
N
H
R2
R2
4b, 5c-5e
6b, 7c-7e
NBS, ∆
1, 2
+
3b-3e
6b, 7c-7e
DMF
SCHEME 4
Thus, a num ber of 5,7-diarylpyrido[2,3-d]pyrim idines and their 5,8-dihydro
derivatives were syn th esized by th e reaction of 6-am in ouracil (1) an d
2-th io-6-am in ouracil (2) with ch alcon es. Th e obtain ed experim en tal data
sh owed an in fluen ce of th e catalyst type on th e com position of reaction
products: basic catalysts decreased yields of th e dih ydro derivatives wh ereas
acids in creased th em . Syn th etic procedures for 5,8-dih ydropyrido[2,3-d]-
pyrim idin es by refluxin g of α,β-un saturated keton es with 6-am in ouracil de-
rivatives in glacial acetic acid were developed. Th e syn th esis of pyrido-
[2,3-d]pyrim idin es by th e treatm en t of th e sam e startin g com poun ds in
dry DMF with NBS was also proposed. In th e case of ch alcon es con tain -
in g dim eth ylam in o group, elim in ation of aryl substituen t from position 5
of th e pyridopyrim idin e rin g system was observed. An attem pted th ree-
com pon en t reaction of arom atic aldeh ydes an d acetoph en on es with
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Reaction of 6-Aminouracil and 6-Amino-2-Thiouracil
355
6-am in ouracil derivatives led to 6,6′-diam in o-5,5′-(arylm eth ylen e)bis-2-
(th ioxopyrim idin -4-on e)s or 6,6′-diam in o-5,5′-(arylm eth ylen e)bis(pyrim i-
din e-2,4-dion e)s in stead of pyrido[2,3-d]pyrim idin es.
EXPERIMENTAL
Startin g arom atic aldeh ydes, acetoph en on es, eth yl cyan oacetate, urea an d th iourea are com -
m ercially available. All reaction s were m on itored by TLC on Silufol UV-254 plates usin g
eth yl acetate–ch loroform (1:1). Meltin g poin ts were determ in ed with a Kofler apparatus. IR
spectra (in cm –1) were m easured on Specord 75-IR in KBr pellets. Th e 1H an d 13C NMR spec-
tra were recorded in DMSO-d6 at 200 MHz (50 MHz for 13C) on a Varian Mercury VX-200
spectrom eter an d an alyzed with ADVASP(tm ) An alyzer program (Um atek In tern ation al In c.).
Ch em ical sh ifts are reported in ppm (δ-scale), couplin g con stan ts (J) in Hz, in tern al stan dard
was Si(CH3)4. Meltin g poin ts an d spectral ch aracteristics for com poun ds 3a–3h , 8a, 8b are
correspon din g to th e literature data16,18–23. Elem en tal an alysis for C, H, N, S an d h alogen s
was m ade at th e Departm en t of An alytical Ch em istry of th e In stitute.
5-(4-Ch loroph en yl)-7-(4-m eth ylph en yl)-5,8-dih ydropyrido[2,3-d]pyrim idin e-2,4-dion e (4b),
5,7-Diaryl-2-th ioxo-5,8-dih ydropyrido[2,3-d]pyrim idin -4-on es (5c–5e) an d
7-Aryl-2-th ioxopyrido[2,3-d]pyrim idin -4-on es (10a, 10b). Gen eral Procedure (Meth od A)
A solution of 6-am in ouracil derivative (1, 2; 0.01 m ol) an d appropriate ch alcon e (0.01 m ol)
in glacial acetic acid (10 m l) was refluxed for 3 h . Th en th e reaction m ixture was cooled
down an d poured on to crush ed ice. Th e precipitate form ed was filtered off an d crystallized
from eth an ol.
5-(4-Chlorophenyl)-7-(4-methylphenyl)-5,8-dihydropyrimido[2,3-d]pyrimidine-2,4-dione (4b ).
Yield 78%. M.p. >300 °C. For C20H16ClN3O2 (365.8) calculated: 65.67% C, 4.41% H, 9.69% Cl,
11.49% N; foun d: 65.62% C, 4.47% H, 9.70% Cl, 11.51% N. IR: 3409, 3229, 2843, 2303,
1709, 1662, 1622, 1602, 1542, 1476, 1436, 1396, 1336, 1089, 1016. 1H NMR: 2.32 s, 3 H
(CH3); 4.54 d, 3J = 5.1, 1 H (H-5); 5.21 d, 3J = 5.1, 1 H (H-6); 7.05–7.40 m , 8 H (Ar); 8.10 bs,
1 H (NH-8); 11.58 bs, 1 H (NH-1); 12.00 bs, 1 H (NH-3). 13C NMR: 20.9 (CH3); 36.9 (C-5);
85.0 (C-4a); 103.1 (C-6); 138.6 (C-7); 146.5 (C-8a); 150.0 (C-2); 163.2 (C-4); 126.3, 128.8,
129.0, 130.5 (CHAr); 131.1, 131.3, 137.6, 140.3 (CAr).
7-(4-Chlorophenyl)-5-phenyl-2-thioxo-5,8-dihydropyrido[2,3-d]pyrimidine-4-one (5c). Yield
58%. M.p. >300 °C. For C19H14ClN3OS (367.8) calculated: 62.04% C, 3.84% H, 9.64% Cl,
11.42% N, 8.72% S; foun d: 62.00% C, 3.89% H, 9.67% Cl, 11.40% N, 8.70% S. IR: 3420,
3235, 2843, 2310, 1720, 1635, 1600, 1480, 1442, 1402, 1329, 1070, 1025. 1H NMR: 4.55 d,
3J = 5.1, 1 H (H-5); 5.36 d, 3J = 5.1, 1 H (H-6); 7.26–7.47 m , 9 H (Ar); 8.17 bs, 1 H (NH-8);
11.60 bs, 1 H (NH-1); 11.98 bs, 1 H (NH-3). 13C NMR: 37.1 (C-5); 90.6 (C-4a); 103.6 (C-6);
140.0 (C-7); 146.6 (C-8a); 150.0 (C-4); 163.4 (C-2); 125.8, 127.8, 128.7, 128.8, 129.1 (CHAr);
132.4, 133.6, 142.2 (CAr).
7-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2-thioxo-5,8-dihydropyrido[2,3-d]pyrimidin-4-one (5d ).
Yield 52%. M.p. >300 °C. For C20H16ClN3O2S (397.9) calculated: 60.37% C, 4.05% H, 8.91% Cl,
10.56% N, 8.06% S; foun d: 60.30% C, 4.10% H, 8.90% Cl, 10.50% N, 8.08% S. IR: 3416,
3336, 2849, 2303, 1708, 1658, 1642, 1542, 1509, 1482, 1429, 1402, 1209, 1129, 1002.
1H NMR: 3.67 s, 3 H (OCH3); 4.48 d, 3J = 5.5, 1 H (H-5); 5.33 d, 3J = 5.5, 1 H (H-6);
6.82–7.48 m , 8 H (Ar); 8.13 bs, 1 H (NH-8); 11.60 bs, 1 H (NH-1); 12.01 bs, 1 H (NH-3).
Collect. Czech. Chem. Commun. (Vol. 70) (2005)

356
Chebanov et al.:
13C NMR: 36.8 (C-5); 55.7 (OCH3); 90.7 (C-4a); 105.5 (C-6); 134.1 (C-7); 146.2 (C-8a); 158.5
(C-4); 161.2 (C-2); 114.4, 127.0, 129.2, 129.5 (CHAr); 132.3, 133.9, 139.2, 140.3 (CAr).
7-(4-Chlorophenyl)-5-[4-(dimethylamino)phenyl]-2-thioxo-5,8-dihydropyrido[2,3-d]pyrimidin-
4-one (5e). Yield 67%. M.p. >300 °C. For C21H19ClN4OS (410.9) calculated: 61.38% C, 4.66% H,
8.63% Cl, 13.63% N, 7.80% S; foun d: 61.42% C, 4.62% H, 8.61% Cl, 13.68% N, 7.81% S. IR:
3489, 3215, 2843, 2315, 1706, 1660, 1618, 1600, 1531, 1420, 1391, 1222, 1013. 1H NMR:
2.81 s, 6 H (N(CH3)2); 4.41 d, 3J = 5.2, 1 H (H-5); 5.32 d, 3J = 5.2, 1 H (H-6); 6.60–7.48 m ,
8 H (Ar); 8.10 bs, 1 H (NH-8); 11.34 bs, 1 H (NH-1); 11.98 bs, 1 H (NH-3). 13C NMR: 37.2
(C-5); 40.5 (N(CH3)2); 90.2 (C-4a); 105.1 (C-6); 134.0 (C-7); 145.9 (C-8a); 158.9 (C-4); 165.4
(C-2); 114.3, 124.6, 126.5, 127.4 (CHAr); 132.5, 140.3, 143.0, 147.5 (CAr).
7-Phenyl-2-thioxopyrido[2,3-d]pyrimidin-4-one (10a ). Yield 74%. M.p. >300 °C. For
C
13H9N3OS (255.3) calculated: 61.16% C, 3.55% H, 16.46% N, 12.56% S; foun d: 61.21% C,
3.50% H, 16.48% N, 12.52% S. IR: 3395, 3160, 3050, 2891, 2791, 2309, 1699, 1679, 1612,
1601, 1575, 1500, 1372, 1239, 1177, 1125. 1H NMR: 7.53–8.16 m , 4 H (Ar); 7.87 d, 3J = 8.2,
1 H (H-6); 8.28 d, 3J = 8.2, 1 H (5-H); 12.56 bs, 1 H (NH-1); 13.08 bs, 1 H (NH-3). 13C NMR:
112.6 (C-4a); 121.7 (C-6); 137.1 (C-5); 154.8 (C-8a); 158.9 (C-4); 161.2 (C-7); 171.5 (C-2);
129.5, 130.0, 133.4 (CHAr); 140.1 (CAr).
7-(4-Methylphenyl)-2-thioxopyrido[2,3-d]pyrimidin-4-one (10b). Yield 68%. M.p. >300 °C. For
C
14H11N3OS (269.3) calculated: 62.43% C, 4.12% H, 15.60% N, 11.91% S; foun d: 62.49% C,
4.18% H, 15.58% N, 11.89% S. IR: 3389, 3176, 3050, 2883, 2796, 2316, 1695, 1682, 1615,
1600, 1555, 1502, 1415, 1368, 1242, 1168, 1115, 1068. 1H NMR: 2.36 s, 3 H (CH3);
7.34–8.06 m , 5 H (Ar); 7.92 d, 3J = 8.2, 1 H (H-6); 8.33 d, 3J = 8.2, 1 H (H-5); 12.57 bs, 1 H
(NH-1); 13.12 bs, 1 H (NH-3). 13C NMR: 22.1 (CH3); 112.8 (C-4a); 121.9 (C-6); 137.0 (C-5);
154.5 (C-8a); 158.8 (C-4); 161.4 (C-7); 171.4 (C-2); 126.4, 128.5 (CHAr); 129.0, 137.9 (CAr).
5,7-Diph en ylpyrido[2,3-d]pyrim idin e-2,4-dion e (6a) an d
5,7-Diaryl-2-th ioxopyrido[2,3-d]pyrim idin -4-on e (7a, 7f–7h ).
Gen eral Procedure (Meth od B)
A solution of 6-am in ouracil derivative (1, 2; 0.01 m ol), appropriate ch alcon e (0.01 m ol) an d
trieth ylam in e (0.01 m ol) in dry DMF (5 m l) was refluxed for 3 h . Th en th e reaction m ixture
was cooled down an d diluted with m eth an ol. Th e precipitate form ed was filtered off an d
crystallized from eth an ol.
5-(4-Ch loroph en yl)-7-(4-m eth ylph en yl)pyrido[2,3-d]pyrim idin e-2,4-dion e (6b) an d
5,7-Diaryl-2-th ioxopyrido[2,3-d]pyrim idin -4-on e (7a, 7c–7h ).
Gen eral Procedure (Meth od C)
A solution of 6-am in ouracil derivative (1, 2; 0.01 m ol), appropriate ch alcon e (0.01 m ol) an d
NBS (0.01 m ol) in of dry DMF (5 m l) was refluxed for 3 h . Th en th e reaction m ixture was
cooled down an d diluted with m eth an ol. Th e precipitate form ed was filtered off an d crystal-
lized from eth an ol.
5,7-Diphenylpyrido[2,3-d]pyrimidine-2,4-dione (6a). Yield 75%. M.p. 275 °C. For C19H13N3O2
(315.3) calculated: 72.37% C, 4.16% H, 13.33% N; foun d: 72.40% C, 4.10% H, 13.34% N.
IR: 3363, 3189, 3036, 2843, 2309, 1702, 1682, 1600, 1550, 1490, 1444, 1400, 1370, 1288,
1150, 1009. 1H NMR: 7.40–8.16 m , 10 H (Ar); 7.48 s, 1 H (H-6); 12.10 bs, 1 H (NH-1); 12.88 bs,
1 H (NH-3). 13C NMR: 106.1 (C-4a); 118.2 (C-6); 150.5 (C-8a); 153.7 (C-2); 154.1 (C-5);
159.1 (C-7); 161.6 (C-4); 127.7, 127.8, 128.2, 128.8 (CHAr); 129.1, 130.8, 137.0, 139.1 (CAr).
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357
5-(4-Chlorophenyl)-7-(4-methylphenyl)pyrido[2,3-d]pyrimidine-2,4-dione (6b). Yield 69%. M.p.
>300 °C. For C20H14ClN3O2 (363.8) calculated: 66.03% C, 3.88% H, 9.75% Cl, 11.55% N;
foun d: 66.13% C, 3.85% H, 9.72% Cl, 11.54% N. IR: 3416, 3016, 3043, 2850, 2309, 1715,
1695, 1655, 1599, 1575, 1548, 1488, 1408, 1362, 1262, 1188, 1088, 1015. 1H NMR: 2.37 s, 3 H
(CH3); 7.08–8.22 m , 8 H (Ar); 7.59 s, 1 H (H-6); 12.12 bs, 1 H (NH-1); 12.94 bs, 1 H (NH-3).
13C NMR: 21.0 (CH3); 106.0 (C-4a); 119.3 (C-6); 150.8 (C-8a); 153.6 (C-2); 154.8 (C-5); 156.3
(C-7); 161.7 (C-4); 123.2, 127.2, 128.6, 132.8 (CHAr); 133.4, 136.6, 137.8, 145.3 (CAr).
5,7-Diphenyl-2-thioxopyrido[2,3-d]pyrimidin-4-one (7a ). Yield 60%. M.p. >300 °C. For
C
19H13N3OS (331.4) calculated: 68.86% C, 3.95% H, 12.68% N, 9.68% S; foun d: 68.80% C,
3.99% H, 12.69% N, 9.64% S. IR: 3397, 3170, 3043, 2855, 2329, 1708, 1688, 1648, 1600,
1548, 1488, 1402, 1368, 1255, 1168, 1122, 1062, 1028. 1H NMR: 7.41–8.20 m , 10 H (Ar);
7.63 s, 1 H (H-6); 12.29 bs, 1 H (NH-1); 13.05 bs, 1 H (NH-3). 13C NMR: 106.2 (C-4a); 118.6
(C-6); 150.7 (C-8a); 153.6 (C-5); 158.7 (C-4); 162.3 (C-7); 175.2 (C-2); 123.1, 126.1, 126.6,
128.7 (CHAr); 128.5, 129.0, 141.7, 146.0 (CAr).
7-(4-Chlorophenyl)-5-phenyl-2-thioxopyrido[2,3-d]pyrimidin-4-one (7c). Yield 66%. Meltin g
poin t an d spectral data correspon d to literature data11
.
7-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2-thioxopyrido[2,3-d]pyrimidin-4-one (7d ). Yield 52%.
M.p. >300 °C. For C20H14ClN3O2S (395.9) calculated: 60.68% C, 3.56% H, 8.96% Cl, 10.61% N,
8.10% S; foun d: 60.72% C, 3.52% H, 8.97% Cl, 10.58% N, 8.12% S. IR: 3376, 3229, 3069,
2829, 2323, 1715, 1708, 1682, 1601, 1548, 1515, 1455, 1402, 1362, 1242, 1182, 1168, 1082,
1022, 1008. 1H NMR: 3.81 s, 3 H (OCH3); 6.97–8.25 m , 8 H (Ar); 7.58 s, 1 H (H-6); 12.33 bs,
1 H (NH-1); 13.02 bs, 1 H (NH-3). 13C NMR: 55.2 (OCH3); 106.4 (C-4a); 118.2 (C-6); 151.7
(C-8a); 153.8 (C-5); 158.4 (C-4); 162.0 (C-7); 175.2 (C-2); 117.9, 129.5, 130.0, 133.4 (CHAr);
134.7, 138.7, 144.9, 158.2 (CAr).
7-(4-Chlorophenyl)-5-[4-(dimethylamino)phenyl]-2-thioxopyrido[2,3-d]pyrimidin-4-one (7e).
Yield 65%. M.p. >300 °C. For C21H17ClN4OS (408.9) calculated: 61.68% C, 4.19% H, 8.67% Cl,
13.70% N, 7.84% S; foun d: 61.72% C, 4.15% H, 8.65% Cl, 13.72% N, 7.80% S. IR: 3389,
3129, 3043, 2843, 2316, 1703, 1695, 1642, 1600, 1542, 1495, 1408, 1362, 1248, 1188, 1122,
1095, 1015. 1H NMR: 2.96 s, 6 H (N(CH3)2); 6.72–8.27 m , 8 H (Ar); 7.61 s, 1 H (H-6);
12.27 bs, 1 H (NH-1); 12.93 bs, 1 H (NH-3). 13C NMR: 40.6 (N(CH3)2); 105.8 (C-4a); 118.1
(C-6); 151.4 (C-8a); 153.0 (C-5); 158.1 (C-4); 162.1 (C-7); 175.2 (C-2); 112.1, 130.0, 130.1,
132.4 (CHAr); 133.4, 138.8 146.3, 146.7 (CAr).
7-(4-Chlorophenyl)-5-(4-nitrophenyl)-2-thioxopyrido[2,3-d]pyrimidin-4-one (7f). Yield 40%.
M.p. >300 °C. For C19H11ClN4O3S (410.8) calculated: 55.55% C, 2.70% H, 8.63% Cl, 13.64% N,
7.80% S; foun d: 55.49% C, 2.76% H, 8.62% Cl, 13.66% N, 7.82% S. IR: 3376, 3169, 3070,
2489, 2309, 1708, 1682, 1642, 1600, 1555, 1515, 1402, 1348, 1242, 1175, 1088, 1008.
1H NMR: 7.61–8.27 m , 8 H (Ar); 7.74 s, 1 H (H-6); 12.44 bs, 1 H (NH-1); 13.16 bs, 1 H
(NH-3). 13C NMR: 106.3 (C-4a); 118.0 (C-6); 153.4 (C-8a); 153.6 (C-5); 158.2 (C-4); 162.2
(C-7); 175.3 (C-2); 126.9, 129.5, 129.9, 133.2 (CHAr); 134.4, 138.8, 146.3, 150.5 (CAr).
5-(4-Fluorophenyl)-7-phenyl-2-thioxopyrido[2,3-d]pyrimidin-4-one (7g). Yield 58%. M.p. >300 °C.
For C19H12FN3OS (349.4) calculated: 65.32% C, 3.46% H, 12.03% N, 9.18% S; foun d: 65.28% C,
3.50% H, 12.05% N, 9.14% S. IR: 3403, 3156, 3056, 2849, 2936, 1702, 1675, 1648, 1599,
1548, 1468, 1408, 1362, 1235, 1182, 1135. 1H NMR: 7.22–8.20 m , 9 H (ArH); 7.63 s, 1 H
(H-6); 12.37 bs, 1 H (NH-1); 13.01 bs, 1 H (NH-3). 13C NMR: 107.2 (C-4a); 118.4 (C-6); 153.2
(C-8a); 153.5 (C-5); 158.2 (C-4); 162.6 (C-7); 175.2 (C-2); 119.3, 126.4, 128.7, 129.0, 134.6
(CHAr); 141.7, 144.3, 158.5 (CAr).
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Chebanov et al.:
5-[4-Methoxycarbonyl)phenyl]-7-phenyl-2-thioxopyrido[2,3-d]pyrimidin-4-one (7h ). Yield 52%.
M.p. >300 °C. For C21H15N3O3S (389.4) calculated: 64.77% C, 3.88% H, 10.79% N, 8.23% S;
foun d: 64.82% C, 3.82% H, 10.83% N, 8.24% S. IR: 3416, 3209, 3050, 2843, 2316, 1705,
1680, 1650, 1599, 1550, 1475, 1408, 1368, 1282, 1175, 1135, 1102, 1028. 1H NMR: 3.88 s,
3 H (COOCH3); 7.50–8.24 m , 9 H (Ar); 7.67 s, 1 H (H-6); 12.39 bs, 1 H (NH-1); 13.10 bs, 1 H
(NH-2). 13C NMR: 51.8 (COCH3); 106.5 (C-4a); 118.2 (C-6); 153.7 (C-8a); 153.9 (C-5); 158.2
(C-4); 162.1 (C-7); 166.3 (COOCH3); 175.3 (C-2); 126.4, 128.6 128.7, 129.0, 132.1 (CHAr);
135.0, 141.7, 148.8 (CAr).
5-(4-Ch loroph en yl)-7-(4-m eth ylph en yl)-5,8-dih ydropyrido[2,3-d]pyrim idin e-2,4-dion e (6b)
an d 5,7-Diaryl-2-th ioxo-5,8-dih ydropyrido[2,3-d]pyrim idin -4-on es (7c–7e) by Oxidation .
Gen eral Procedure
A solution of 5,8-dih ydropyrido[2,3-d]pyrim idin e derivative (4b, 5c–5e; 0.005 m ol) an d NBS
(0.005 m ol) in dry DMF (3 m l) was refluxed for 2 h . Th en th e reaction m ixture was cooled
down an d diluted with m eth an ol. Th e precipitate form ed was filtered off an d crystallized
from eth an ol to give products iden tical with com poun ds prepared by m eth ods given above.
Th e yields are given in Table I.
Reaction of 6-Am in ouracil Derivatives with Arom atic Aldeh ydes an d Acetoph en on e.
Gen eral Procedure
A solution of 6-am in ouracil derivative (1, 2; 0.01 m ol), appropriate arom atic aldeh yde
(0.01 m ol) an d acetoph en on e (0.01 m ol) in glacial acetic acid (10 m l) (m eth od A) or in dry
DMF (5 m l) (m eth od B) was refluxed for 3 h . Th en th e reaction m ixture was cooled down
an d poured on crush ed ice (m eth od A) or diluted with m eth an ol (m eth od B). Th e precipi-
tate form ed was filtered off an d crystallized from eth an ol.
6,6′-Diamino-5,5′-[(4-methylphenyl)methylene]bispyrimidine-2,4-dione (13a). Yield 38%. M.p.
>300 °C. For
C16H16N6O4 (356.3) calculated: 53.93% C, 4.53% H, 23.58% N; foun d:
53.99% C, 4.49% H, 23.60% N. IR: 3363, 3156, 2776, 2325, 1708, 1662, 1622, 1598, 1515,
1448, 1402, 1282, 1168, 1088, 1022. 1H NMR: 1.89 s, 3 H (CH3); 5.25 s, 1 H (CH); 6.67 bs,
4 H (NH2-5,5′); 6.80–7.10 m , 4 H (Ar); 11.23 bs, 1 H (NH-1); 11.87 bs, 1 H (NH-3). 13C NMR:
22.4 (CH3); 30.1 (CH); 126.4 (C-5,5′); 154.5 (C-2); 160.1 (C-4); 163.3 (C-6,6′); 125.6, 132.6
(CHAr); 133.5, 145.2 (CAr).
6,6′-Diamino-2,2′-dithioxo-5,5′-[(4-chlorophenyl)methylene]bispyrimidin-4-ones (14b ). Yield
42%. M.p. >300 °C. For C15H13ClN6O2S2 (408.9) calculated: 44.06% C, 3.20% H, 8.67% Cl,
20.55% N, 15.68% S; foun d: 44.10% C, 3.15% H, 8.68% Cl, 20.57% N, 15.66% S. IR: 3336,
3156, 2849, 2304, 1705, 1665, 1640, 1599, 1535, 1435, 1242, 1202, 1175, 1008. 1H NMR:
5.30 s, 1 H (CH); 6.74 bs, 4 H (NH2-5,5′); 6.90–7.30 m , 4 H (Ar); 11.79 bs, 1 H (NH-1);
12.02 bs, 1 H (NH-3). 13C NMR: 32.3 (CH); 131.2 (C-5,5′); 158.1 (C-4); 163.8 (C-6,6′); 179.1
(C-2); 128.4, 129.3 (CHAr); 132.8, 148.5 (CAr).
6,6′-Diamino-2,2′-dithioxo-5,5′-[(4-fluorophenyl)methylene]bispyrimidin-4-ones (14c). Yield
45%. M.p. >300 °C. For C15H13FN6O2S2 (392.4) calculated: 45.91% C, 3.34% H, 21.42% N,
16.34% S; foun d: 45.86% C, 3.38% H, 21.44% N, 16.36% S. IR: 3370, 3145, 2766, 2315,
1701, 1665, 1609, 1595, 1432, 1400, 1177, 1065, 1002. 1H NMR: 5.26 s, 1 H (CH); 6.69 bs, 4 H
(NH2-5,5′); 6.90–7.20 m , 4 H (Ar); 10.29 bs, 1 H (NH-1); 12.50 bs, 1 H (NH-3). 13C NMR:
31.4 (CH); 131.3 (C-5,5′); 157.9 (C-4); 163.9 (C-6,6′); 179.0 (C-2); 121.2, 130.0 (CHAr); 146.7,
155.5 (CAr).
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Reaction of 6-Aminouracil and 6-Amino-2-Thiouracil
359
TABLE I
Syn th esis of pyrido[2,3-d]pyrim idin es
Startin g m aterials
Reaction products
Meth oda
Ch alcon es
Am in e
Com poun d
Yield, %
3b
3c
3d
3e
3a
3b
3a
3c
3d
3e
3f
1
2
2
2
1
1
2
2
2
2
2
2
2
2
2
4b
5c
A
78
A
58
5d
5e
A
52
A
67
6a
A
75
6b
7a
C
69
B/C
C
60b
7c
66
7d
7e
C
52
C
65
7f
B/C
B/C
B/C
A
40b
58b
52b
74
3g
3h
8a
8b
7g
7h
10a
10b
A
68
Aldeh ydes
11a
11b
11c
1
2
2
13a
14b
14c
A/B
A/B
A/B
38c
42c
45c
5,8-Dih ydropyrido[2,3-d]pyrim idin es
4b
5c
5d
5e
–
–
–
–
6b
7c
7d
7e
B
B
B
B
63
62
60
65
a
A, reflux in glacial acetic acid; B, reflux in DMF with NEt3; C, reflux in DMF with NBS.
Meth od C. Meth od B.
b
c
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360
Chebanov et al.:
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