Synthesis of 6-substituted 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H) -2,4-diones using the Vilsmeier reaction

Article abstract of DOI:10.1016/j.tet.2004.09.075

The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50-80%. Functionalization of these dihydropyridopyrimidine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4- diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carboxaldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine derivatives. The reaction of 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones with phosphorous oxychloride and N,N-dimethylformamide affords either the shown 6-dimethylaminomethylidene substituted heterocycle or the corresponding pyridopyrimidine(1H,3H)-2,4-dione bearing a carboxaldehyde function. These compounds are suitable structures for further modifications by introducing pharmacologically relevant substituents.

Full text of DOI:10.1016/j.tet.2004.09.075

Tetrahedron 60 (2004) 11511–11517
Synthesis of 6-substituted
7-aryl-5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones
using the Vilsmeier reaction*
*
Ulrich Girreser, Dieter Heber and Martin Schu¨tt
Pharmazeutisches Institut, University of Kiel, Gutenbergstr. 76, 24118 Kiel, Germany
Received 22 March 2004; revised 6 September 2004; accepted 17 September 2004
Available online 12 October 2004
Abstract—The reaction of 6-amino-1,3-dimethyluracil with equimolar amounts of arylalkanone Mannich bases under optimized reaction
conditions leads to 7-aryl-5,6-dihydropyrido[2,3-d]pyrimidines in a yield of 50–80%. Functionalization of these dihydropyridopyrimi-
dine(1H,3H)-2,4-diones with the Vilsmeier reagent affords, depending on the reaction conditions, either 6-dimethylaminomethylidene
substituted 5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones or the corresponding pyridopyrimidine(1H,3H)-2,4-diones bearing a carbox-
aldehyde function in position 6 of the heterocycle. Some further transformations of the aldehyde function demonstrate the synthetic potential
of the synthesized structures, introducing pharmacologically relevant basic substituents into the side chain of these pyrido[2,3-d]pyrimidine
derivatives.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
biological activity of this class of compounds, that is, their
antitumor, antifolate and antibacterial properties are
referenced elsewhere.8 There are also only a few 6- or
7-substituted 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines
used as drugs described in the literature,9,10 for example,
the antineoplastic lometrexol sodium.10
Among the methods for the synthesis of 1,3-dimethyl-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones,2–8 the conden-
sation of 6-amino-1,3-dimethyluracil with suitable
electrophiles is a straightforward and often used approach.
The substitution pattern of the annelated pyridine ring
formed is determined in these reactions by the structure of
the biselectrophile. When an arylalkanone Mannich base is
employed, formation of mixtures of dihydropyridopyrimi-
dine(1H,3H)-2,4-dione 5 and pyridopyrimidine(1H,3H)-
2,4-dione 6 has been reported.3 However, the formation of
the regioisomeric 5-aryl substituted pyridopyrimidines is
not observed. The reaction mechanism is outlined in
Scheme 1, in cyclocondensations performed with
6-aminouracil analogs and Mannich bases the postulated
intermediates 3 und 4 could be isolated.8
2. Results and discussion
6-Amino-1,3-dimethyluracil (1) was reacted with an
equimolar amount of the Mannich bases 2a–c according
to the reported procedure.3 We performed this reaction
under an atmosphere of nitrogen in order to prevent
oxidation to 6, thus it was not necessary to purify the
reaction mixture by column chromatography. The pyrido-
pyrimidines 6 can be obtained directly, when the cyclo-
condensation is performed in acetic acid as the solvent.3 The
5,6-dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones 5
were then converted to the red colored dimethylamino-
methylidene derivatives 7 by treatment with the Vilsmeier
mixture of phosphorous oxychloride and N,N-dimethyl-
formamide at room temperature and subsequent hydrolysis
(Scheme 1). Crystals of 7 decolorized with formation of the
carbaldehyde 8, which was also the main product, when the
Vilsmeier reaction was performed at 80 8C followed by
hydrolysis. The position 6 of the carbaldehyde group is
evidenced by a H,H long-range coupling observed in the
two dimensional spectrum with the proton in position 5 and
We considered position 6 of the pyridopyrimidine 5 an
interesting target for further modifications and employed the
Vilsmeier reaction, as the structures obtainable are of
interest regarding their pharmacological properties. The
* See Ref. 1.
Keywords: Cyclization; Cyclocondensation; 6-Amino-1,3-dimethyluracil;
Mannich bases; Vilsmeier reaction; Pyrido[2,3-d]pyrimidines.
* Corresponding author. Fax: C49 431 8801352;
e-mail: girreser@pharmazie.uni-kiel.de
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.09.075

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U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
Scheme 2.
moiety connected via an aliphatic side chain to a basic
function.11 In order to modify the carbaldehydes 8, reactions
with a primary amine afforded the imines 11 and 12, the
reduction of which allowed access to the anilinomethyl
derivative 13, again without reduction of the pyridine
nucleus (Scheme 3).
Scheme 1.
also a weak cross peak in the NOESY spectrum which
showed additionally a strong cross peak with the protons in
ortho position of the phenyl group. Two dimensional C,H-
correlations aided also in the assignment of the 13C NMR
data of all the structures prepared.
Thus, oxidation of the dihydropyridine moiety is occurring
together with hydrolysis. The red dimethylaminomethyl-
idene derivatives 7, which are very sensitive towards air and
water, can be precipitated as yellow hydroperchlorates,
however, the salts do show only a slightly higher stability
towards hydrolysis and, for example, completely decom-
pose during the recording of the 13C NMR spectra under
routine conditions. The UV/vis spectra of the hydro-
perchlorates 7!HClO4 show an absorption band at about
465–470 nm with only a small bathochromic shift compared
with the bases 7 of about 5 nm. Upon reduction of the
carbaldehydes 8 with sodium borohydride, the expected
hydroxymethylderivatives 9 are obtained. However, when
performing the reduction of the hydroperchlorates 7 under
the same reaction conditions, a complex mixture was
obtained, the major product being the pyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-diones 10. The dimethylaminomethyl
derivative is not formed, instead cleavage of the amino
group and reduction to the methyl residue is observed, the
pyridine moiety being unaffected (Scheme 2).
Scheme 3.
Finally, under the reaction of the carbaldehydes 8 with
numerous C–H acidic compounds we describe here only the
one with ethyl cyano acetate under Knoevenagel conditions,
affording the expected acrylate derivatives in about 60–70%
yield.
3. Conclusions
Another approach to pharmacological relevant structures is
the introduction of a basic center into the side chain of the
heterocycle, presenting the characteristic string of aromatic
The synthetic approach to 6-substituted pyrido[2,3-d]-
pyrimidine(1H,3H)-2,4-diones presented here using the

U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
11513
Vilsmeier reaction of 5,6-dihydropyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-diones, allows access to a great number
of structures and introduction of functionalities via the
intermediate carboxaldehydes.
(C-20), 132.7 (C-40), 136.8 (C-10), 149.4 (C-8a), 152.1 (C-2),
163.0 (C-4), 174.6 (C-7).
4.2.2. 1,3-Dimethyl-7-(4-tolyl)-5,6-dihydropyrido[2,3-d]-
pyrimidine(1H,3H)-2,4-dione (5b). 690 mg (2.4 mmol,
61%), mp 181 8C. UV/vis l: 218 (4.2), 276 (4.2), 362
(3.9). IR n: 1692, 1660/1650. MS m/z: 283 (MC, 71), 282
(100), 281 (21), 192 (26), 81 (40). 1H NMR d: 2.44 (s, 3H,
40-CH3), 2.68/2.89 (2!t, JZ9.0 Hz, 2!2H, 5-H, 6-H),
3.42/3.56 (2!s, 2!3H, 1-CH3, 3-CH3), 7.30/7.98 (2!d,
JZ8.3 0Hz, 2!2H, 20-H, 30-H). 13C NMR d: 16.4 (C-5),
21.7 (4 -CH3), 24.1 (C-6), 28.2 (1-CH3), 30.0 (3-CH3), 94.4
(C-4a), 128.2 (C-20), 129.6 (C-30), 134.2 (C-10), 43.7 (C-40),
149.7 (C-8a), 152.2 (C-2), 163.1 (C-4), 174.5 (C-7). HRMS
Calcd for C15H12N3O2: 283.1321, found: 283.1319.
4. Experimental
4.1. General
Electron impact (EI) mass spectra were obtained with an
ionization energy of 70 eV using a HP 5989A mass
spectrometer and a direct inlet probe with a tungsten wire;
m/z values are reported followed by the relative intensity in
parentheses. APCI mass spectra were obtained on a Bruker
Esquire LC. Nuclear Magnetic Resonance (1H and 13C)
spectra were recorded on a Bruker instrument ARX300. In
all cases DMSO-d6 was used as the solvent. Chemical shifts
are reported in parts per million (d) downfield from an
internal TMS reference. Coupling constants (J) are reported
in Hertz (Hz), and spin multiplicities are indicated by the
following symbols s (singlet), d (doublet), t (triplet), q
(quartet), quint. (quintet), m (multiplet), br (broad signal).
Multiplets were analyzed according to first order coupling.
Elemental analyses were either performed by the Mikro-
analytisches Labor Beetz or at the Institute of Inorganic
Chemistry of the University of Kiel. High resolution mass
spectra were performed by the Institute or Organic
Chemistry at the University of Kiel. UV/vis spectra were
recorded with a HP 8542A spectrophotometer in MeOH as
the solvent. The wavelengths of the three or four strongest
absorption bands together with the logarithm of the
extinction coefficient 3 in l/(mol!cm) are given. IR spectra
were recorded as KBr pellets on a Perkin–Elmer 1600 PC
FT-IR machine. Melting points were recorded with a Thiele
(Bu¨chi SMP-20) melting point apparatus and are not
corrected. For preparative column chromatography silica
gel 60 (Merck) was used.
4.2.3. 7-(4-Bromophenyl)-1,3-dimethyl-5,6-dihydro-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (5c). 1.09 g
(3.1 mmol, 78%), mp 178–180 8C. UV/vis l: 218 220
(4.2), 284 (4.3), 370 (3.9). IR n: 1692, 1638 (br). MS m/z:
349 (MC, 81Br, 76), 348 (100), 347 (MC, 79Br, 88), 346
1
(85), 345 (23), 192 (59), 81 (64). H NMR d: 2.69/2.88
(2!t, JZ9 Hz, 2!2H, 5-H, 6-H), 3.41/3.64 (2!s, 2!03H,
1-CH3, 3-CH3), 7.64/7.95 (2!d, JZ8.7 Hz, 2!2H, 2 -H,
30-H). 13C NMR d: 16.3 (C-5), 24.0 (C-6), 28.3 (1-CH3),
30.0 (3-CH3), 94.5 (C-4a), 127.8 (C-10), 129.4 (C-20), 132.1
(C-30), 135.6 (C-40), 149.3 (C-8a), 152.0 (C-2), 163.0 (C-4),
173.5 (C-7).
4.2.4. 1,3-Dimethyl-7-phenylpyrido[2,3-d]pyrimidine-
(1H,3H)-2,4-dione (6a). 570 mg (2.2 mmol, 54%), mp
184 8C, mp3 156–157 8C. UV/vis l: 220 (4.5), 252 (4.1), 272
(4.0), 332 (4.2). IR n: 1706, 1658, 1602. MS m/z: 267 (MC,
100), 239 (47), 238 (42), 155 (44), 154 (19). 1H NMR data
in accordance with Ref. 3. 13C NMR d: 28.4 (1-CH3),
29.4 (3-CH3), 109.0 (C-4a), 115.0 (C-6), 127.5 (C-30),
128.9 (C-20), 130.7 (C-40), 137.4 (C-10), 138.3 (C-5), 150.7
(C-8a), 151.6 (C-2), 161.1 (C-7), 161.3 (C-4).
4.2. 5,6-Dihydropyrido[2,3-d]pyrimidine(1H,3H)-2,4-
diones 5a–c and pyrido[2,3-d]pyrimidine(1H,3H)-2,4-
diones 6a–c
4.2.5. 1,3-Dimethyl-7-(4-tolyl)-pyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-dione (6b). 550 mg (2.0 mmol, 49%),
mp 183 8C, mp3 173–174 8C. UV/vis l: 220 (4.6), 254
(4.1), 336 (4.1), 336 (4.4). IR n: 1704, 1660, 1596. MS m/z:
1
281 (MC, 100),0 253 (46), 252 (43), 169 (34). H NMR d:
A solution of 620 mg (4 mmol) of 4-amino-1,3-dimethyl-
uracil (1) (Merck, Darmstadt, Germany) and 4 mmol of the
corresponding arylalkanone Mannich bases 2a–c was
heated to reflux in 20 mL of deoxygenated water for
90 min under an atmosphere of nitrogen. After cooling to rt
the yellow crystals were filtered and recrystallized from
ethanol. In order to obtain pyrido[2,3-d]pyrimidine(1H,3H)-
2,4-diones 6a–c, the reaction was performed on the same
scale as described above for 5, acetic acid was employed as
the solvent and air was not excluded. After cooling to rt the
slightly yellow crystals were filtered and recrystallized from
ethanol.
2.44 (s, 3H, 4 -CH3), 3.50/3.82 (2!s, 2!3H, 1-CH3,
3-CH3), 7.31/8.02 (2!d, JZ8.0 Hz, 2!2H, 20-H, 30-H),
7.62/8.46 (2!d, JZ8.2 Hz, 2!1H, 6-H, 5-H). 13C NMR d:
21.4 (40-CH3), 28.4 (1-CH3), 29.3 (3-CH3), 108.7 (C-4a),
114.7 (C-6), 127.4 (C-20), 129.6 (C-30), 134.6 (C-10), 138.1
(C-5), 141.4 (C-40), 150.6 (C-8a), 151.6 (C-2), 161.1 (C-7),
161.3 (C-4).
4.2.6. 7-(4-Bromophenyl)-1,3-dimethylpyrido[2,3-d]-
pyrimidine(1H,3H)-2,4-dione (6c). 910 mg (2.6 mmol,
66%), mp 216 8C. UV/vis l: 222 (4.5), 256 (4.2), 276
(4.2), 336 (4.3). IR n: 1704, 1656, 1598. MS m/z: 347 (MC,
81Br, 100), 319 (36), 318 (35), 317 (36), 316 (29), 235 (35),
233 (36). 1H NMR d: 3.51/3.81 (2!s, 2!3H, 1-CH3,
3-CH3), 7.60/8.47 (2!d, JZ8.1 Hz, 2!1H, 6-H, 5-H),
7.63/7.97 (2!d, JZ8 Hz, 2!2H, 20-H, 30-H). 13C NMR d:
28.5 (1-CH3), 29.4 (3-CH3), 109.3 (C-4a), 114.8 (C-6),
125.4 (C-10), 129.0 (C-30), 132.2 (C-20), 136.3 (C-40), 138.6
(C-5), 150.8 (C-8a), 151.6 (C-2), 160.0 (C-7), 161.2 (C-4).
4.2.1. 1,3-Dimethyl-7-phenyl-5,6-dihydropyrido[2,3-
d]pyrimidine(1H,3H)-2,4-dione (5a). 540 mg (2.0 mmol,
50%), mp 180 8C, mp3 180 8C. UV/vis l: 218 (4.1), 276
(4.2), 368 (3.8). IR n: 1688, 1644/1640. MS m/z: 269 (MC,
84), 268 (100), 192 (38), 154 (19), 81 (40). 1H NMR data in
accordance with Ref. 5. 13C NMR d: 16.3 (C-5), 24.2 (C-6),
28.2 (1-CH3), 29.9 (3-CH3), 94.2 (C-4a), 128.0 (C-30), 128.8

11514
U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
HRMS Calcd for C15H12N3O729Br 345.0113, found:
345.0113.
2,4-dione (7c). 250 mg (0.63 mmol, 63%), mp 143 8C,
decomposition upon recrystallization. UV/vis l: 218 (4.4),
276 (4.3), 368 (4.1), 466 (3.8). IR n: 1686, 1640 (s). MS m/z:
402 (MC, 79Br, 8), 387 (21), 279 (55), 58 (100). 1H NMR d:
3.17 (s, 6H, N(CH3)2), 3.37/3.54 (2!s, 2!3H, 1-CH3,
3-CH3), 3.86 (br s, 2H, 5-H), 6.64 (br s, 1H, 6]CH), 7.42/
7.54 (2!d, JZ8.4 Hz, 2!2H, 20-H, 30-H). 13C NMR d:
22.9 (C-5), 27.9 (1-CH3), 29.4 (3-CH3), 43.9 (N-CH3), 90.0
(C-6), 100.1 (C-4a), 124.8 (C-10), 131.6 (C-30), 131.9 (C-20),
139.2 (C-40), 151.3 (C-2), 152.4 (C-8a), 155.0 (6]CH),
162.9 (C-4), 175.6 (C-7).
4.3. 6-(Dimethylaminomethylidene)-5H-pyrido[2,3-
d]pyrimidine(1H,3H)-2,4-diones 7a–c, hydroperchlor-
ates 7a–c!HClO4, and 1,3-dimethyl-2,4-dioxo-(1H,3H)-
pyrido[2,3-d]pyrimidine-6-carbaldehydes 8a–c
To a suspension of 1.0 mmol of 5 in 2 mL of DMF was
added dropwise 200 ml (0.33 g, 2.1 mmol) of POCl3 while
cooling with an ice/water bath. The reaction mixture was
stirred for 15 min at rt, followed by the addition of 10 mL of
cold water. Solid sodium bicarbonate was added to the
yellow solution until alkaline. The red solution was
extracted with three 10 mL portions of dichloromethane,
the combined organic layers were washed with water, dried
over anhydrous sodium sulfate, filtered, and evaporated.
The remainder was treated with diethyl ether and the solids
of 7a–c obtained were filtered and dried in vacuo. The
corresponding hydroperchlorates were obtained by dis-
solving 1 mmol of 7 in 25 mL of methanol and 0.2 mL of
HClO4 (70%) was added while cooling with an ice/water
bath. After about 15 min a precipitate was formed, which
was filtered off and dried in vacuo. In all cases the yield was
quantitative. The carbaldehydes 8a–c were obtained when
performing the reaction on the same scale as described
above for 7a–c, after stirring the reaction mixture for 30 min
at rt, then the reaction mixture was heated to 80 8C for 3 h.
After cooling 15 g of ice was added and the mixture was
stirred vigorously. The yellow precipitate was filtered,
dried, and recrystallized.
4.3.4. 1,3-Dimethyl-6-(dimethylaminomethylidene)-7-
phenyl-5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione
hydroperchlorate (7a!HClO4). Mp 206–208 8C,
decomposition upon recrystallization. UV/vis l: 204 (4.4),
268 (4.2), 316 (4.1), 456 (3.9). IR n: 3200 (br), 1690, 1664,
1090 (s). MS m/z: 325 [MCHC] in MeOH/10 mM
1
NH4OAc by APCI. H NMR d: 3.20/3.47 (2!s, 2!3H,
1-CH3, 3-CH3), 3.50 (br s, 6H, N(CH3)2), 3.73 (br s, 2H,
5-H), 7.55–7.75 (m, 6H, phenyl-H, 6]CH), 10.31 (br s,
1H, NH). 13C NMR d: 22.2 (C-5), 27.8 (1-CH3), 30.3
(3-CH3), 43–49 (very br, N-CH3), 86.9 (C-6), 102.6 (C-4a),
128.9 (C-30), 131.3 (C-20), 132.4 (C-10), 132.8 (C-40), 143.0
(C-8a), 150.5 (C-2), 160.7 (C-4), 160.8 (C-7), 166.4
(6]CH).
4.3.5. 1,3-Dimethyl-6-(dimethylaminomethylidene)-7-(4-
tolyl)-5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione
hydroperchlorate (7b!HClO4). Mp 192–194 8C,
decomposition upon recrystallization. UV/vis l: 278 (4.2),
322 (4.1), 462 (4.0). IR n: 3200–2800 (w), 1694, 1664, 1092
(br, s). MS m/z: 339 [MCHC] in MeOH/10 mM NH4OAc
by APCI. 1H NMR d: 2.43 (s, 3H, 40-CH3), 3.19/3.47 (2!s,
2!3H, 1-CH3, 3-CH3), 3.49 (br s, 6H, N(CH3)2), 3.70 (br s,
2H, 5-H), 7.52 (m, 5H, phenyl-H, 6]CH), 10.26 (br s, 1H,
NH). 13C NMR d: 21.1 (40-CH3), 22.2 (C-5), 27.8 (1-CH3),
30.2 (3-CH3), 43-47 (very br, N-CH3), 87.0 (C-6), 102.1
(C-4a), 129.4 (C-20), 129.7 (C-10), 131.3 (C-30), 143.3
(C-8a), 143.9 (C-40), 150.6 (C-2), 160.7 (C-4), 161.0 (C-7),
166.2 (6]CH).
4.3.1. 1,3-Dimethyl-6-(dimethylaminomethylidene)-7-
phenyl-5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione
(7a). 165 mg (0.51 mmol, 51%), mp 141 8C, decomposition
upon recrystallization. UV/vis l: 260 (3.9), 324 (3.8), 464
(3.6). IR n: 2910 (w), 1662, 1636 (w). MS m/z: 324 (MC,
1
21), 323 (17), 309 (53), 280 (38), 166 (35), 58 (100). H
NMR d: 3.16 (s, 6H, N(CH3)2), 3.38/3.56 (2!s, 2!3H,
1-CH3, 3-CH3), 3.87 (br s, 2H, 5-H), 6.69 (t, JZ1 Hz, 1H,
6]CH), 7.30–7.60 (m, 5H, phenyl-H). 13C NMR d: 22.9
(C-5), 27.9 (1-CH3), 29.4 (3-CH3), 43.9 (N-CH3), 89.9
(C-6), 100.02 (C-4a), 128.1 (C-30), 130.1 (C-20), 130.3 (C-40),
140.3 (C-1 ), 151.5 (C-2), 152.5 (C-8a), 155 (6]CH), 162.9
(C-4), 176.9 (C-7).
4.3.6. 7-(4-Bromophenyl)-1,3-dimethyl-6-(dimethyl-
aminomethylidene)-5H-pyrido[2,3-d]pyrimidine(1H,3H)-
2,4-dione hydroperchlorate (7c!HClO4). Mp 195–197 8C,
decomposition upon recrystallization. UV/vis l: 220 (4.3),
274 (4.3), 326 (4.1), 470 (4.0). IR n: 3400–2900 (w), 1694,
1666, 1090 (br, s). MS m/z: 404/406 [MCHC] in MeOH/
10 mM NH4OAc by APCI. 1H NMR d: 3.19/3.45 (2!s, 2!
3H, 1-CH3, 3-CH3), 3.50 (br s, 6H, N(CH3)2), 3.72 (br s, 2H,
5-H), 7.60-7.80 (m, 5H, phenyl-H, 6]CH), 10.25 (br s, 1H,
NH). 13C NMR d: 22.2 (C-5), 27.8 (1-CH3), 30.2 (3-CH3),
43-50 (very br, N-CH3), 86.8 (C-6), 103.0 (C-4a), 126.6
(C-10), 131.6 (C-40), 131.8 (C-30), 132.1 (C-20), 143.9
(C-8a), 150.5 (C-2), 159.7 (C-7), 160.7 (C-4), 166.2
(6]CH).
4.3.2. 1,3-Dimethyl-6-(dimethylaminomethylidene)-7-(4-
tolyl)-5H-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione
(7b). 210 mg (0.61 mmol, 61%), mp 166 8C, decomposition
upon recrystallization. UV/vis l: 276 (4.1), 326 (4.1), 466
(3.9). IR n: 1684, 1644 (s), 1610. MS m/z: 338 (MC, 54),
337 (51), 323 (94), 294 (82), 180 (48), 58 (100). 1H NMR d:
2.38 (s, 3H, 40-CH3), 3.16 (s, 6H, N(CH3)2), 3.38/3.57
(2!s, 2!3H, 1-CH3, 3-CH3), 3.83 (br s, 2H, 5-H), 6.72
(t, JZ1 Hz, 1H, 6]CH), 7.21/7.46 (2!d, JZ8.1 Hz,
13
2!2H, 20-H, 30-H). C NMR d: 21.4 (40-CH3), 22.9
(C-5), 27.9 (1-CH3), 29.4 (3-CH3), 43.8 (N-CH3), 89.9
(C-6), 100.1 (C-4a), 128.9 (C-20), 130.2 (C-30), 137.4
(C-10), 140.8 (C-40), 151.6 (C-2), 152.5 (C-8a), 155.2
(6]CH), 163.0 (C-4), 176.9 (C-7).
4.3.7. 1,3-Dimethyl-2,4-dioxo-7-phenyl-(1H,3H)-pyr-
ido[2,3-d]pyrimidine-6-carbaldehyde (8a). 210 mg
(0.71 mmol, 71%), mp 189 8C (ethyl acetate). UV/vis l:
222 (4.4), 256 (4.0), 276 (4.1), 336 (4.2). IR n: 1718, 1680,
1658. MS m/z: 295 (MC, 95), 294 (100), 267 (17), 239 (27),
238 (24). 1H NMR d: 3.52/3.81 (2!s, 2!3H, 1-CH3,
4.3.3. 7-(4-Bromophenyl)-1,3-dimethyl-6-(dimethyl-
aminomethylidene)-5H-pyrido[2,3-d]pyrimidine(1H,3H)-

U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
11515
3-CH3), 7.50–7.80 (m, 5H, phenyl-H), 9.06 (s, 1H, 5-H),
10.05 (s, 1H, CHO). 13C NMR d: 28.6 (1-CH3), 30.0
(3-CH3), 109.6 (C-4a), 125.5 (C-6), 128.8 (C-30), 130.5
(C-20), 130.8 (C-40), 136.1 (C-10), 139.3 (C-5), 151.3
(C-2), 152.3 (C-8a), 160.5 (C-4), 166.2 (C-7), 189.2
(6-CHO). Anal. Calcd: C: 65.08, H: 4.44, N: 14.23, found:
C: 65.40, H: 4.48, N: 14.12.
1-CH3, 3-CH3), 4.76 (s, 2H, 6-CH2), 7.50/7.69 (2!m, 5H,
phenyl-H), 8.66 (s, 1H, 5-H). 13C NMR d: 28.5 (1-CH3),
29.5 (3-CH3), 61.7 (6-CH2), 109.1 (C-4a), 128.4 (C-30),
129.3 (C-20), 129.6 (two overlapping signals, C-6, C-40),
138.3 (C-10), 138.8 (C-5), 149.5 (C-8a), 151.6 (C-2), 161.4
(C-4), 162.5 (C-7). HRMS Calcd for C16H15N3O3 297.1133,
found: 297.1114.
4.3.8. 1,3-Dimethyl-2,4-dioxo-7-(4-tolyl)-(1H,3H)-pyr-
ido[2,3-d]pyrimidine-6-carbaldehyde (8b). 220 mg
(0.70 mmol, 70%), mp 194 8C (ethyl acetate). UV/vis l:
220 (4.4), 274 (4.3), 326 (4.2). IR n: 1718, 1686, 1662. MS
m/z: 309 (MC, 100), 308 (82), 294 (61), 253 (33), 252 (31),
169 (34). 1H NMR d: 2.49 (s, 3H, 40-CH3), 3.51/3.80 (2!s,
2!3H, 1-CH3, 3-CH3), 7.38/7.57 (2!d, JZ7.9 Hz, 2!2H,
20-H, 30-H), 9.05 (s, 1H, 5-H), 10.06 (s, 1H, CHO). 13C
NMR d: 21.5 (40-CH3), 28.6 (1-CH3), 29.9 (3-CH3), 109.4
(C-4a), 125.4 (C-6), 129.6 (C-20), 130.6 (C-30), 133.3 (C-10),
139.3 (C-5), 141.3 (C-40), 151.4 (C-2), 152.2 (C-8a), 160.6
(C-4), 166.2 (C-7), 189.4 (6-CHO). Anal. Calcd: C: 66.01,
H: 4.89, N: 13.58, found: C: 65.82, H: 5.14, N: 13.41.
4.4.2. 6-Hydroxymethyl-1,3-dimethyl-7-(4-tolyl)-pyr-
ido[2,3-d]pyrimidine(1H,3H)-2,4-dione (9b). 140 mg
(0.45 mmol, 90%), mp 198 8C. UV/vis l: 220 (4.6), 254
(4.2), 328 (4.2). IR n: 3400 (br), 1700, 1640, 1605. MS m/z:
1
311 (MC, 100), 310 (76), 296 (17), 282 (16). H NMR d:
2.44 (s, 3H, 40-CH3), 2.61 (br s, 1H, OH), 3.46/3.71 (2!s,
2!3H, 1-CH3, 3-CH3), 4.76 (s, 2H, 6-CH2), 7.31/7.59 (2!
d, JZ8.0 Hz, 2!2H, 20-H, 30-H), 8.47 (s, 1H, 5-H). 13C
NMR d: 21.4 (40-CH3), 28.5 (1-CH3), 29.5 (3-CH3), 61.8
(6-CH2), 108.8 (C-4a), 129.2 (two overlapping signals
C-20, C-300), 129.5 (C-6), 135.5 (C-10), 138.7 (C-5),
139.9 (C-4 ), 149.5 (C-8a), 151.7 (C-2), 161.4 (C-4), 162.5
(C-7). Anal. Calcd: C: 65.58, H: 5.50, N: 13.50, found: C:
65.46, H: 5.42, N: 13.55.
4.3.9.
7-(4-Bromophenyl)-1,3-dimethyl-2,4-dioxo-
(1H,3H)-pyrido[2,3-d]pyrimidine-6-carbaldehyde (8c).
250 mg (0.67 mmol, 67%), mp 203 8C (toluene). UV/vis
l: 220 (4.4), 258 (4.3), 324 (4.1). IR n: 1720, 1684, 1660.
MS m/z: 375 (MC, 81Br, 96), 374 (71), 373 (MC, 79Br, 100),
4.4.3. 1,3,6-Trimethyl-7-phenylpyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-dione (10a). 56 mg (0.20 mmol, 20%),
mp 165 8C, mp3 162–163 8C. UV/vis l: 218 (4.5), 248 (4.2),
330 (4.1). IR n: 1706, 1670, 1606. MS m/z: 281 (MC, 98),
280 (100), 253 (23), 252 (32), 169 (37). 1H NMR d: 2.45 (s,
3H, 6-CH3), 3.50/3.73 (2!s, 2!3H, 1-CH3, 3-CH3), 7.49/
7.62 (2!m, 3H/2H, phenyl-H), 8.33 (s, 1H, 5-H). 13C NMR
d: 19.2 (6-CH3), 27.3 (1-CH3), 28.9 (3-CH3), 108.5 (C-4a),
125.8 (C-6), 127.8 (C-30), 128.6 (two overlapping signals
C-20,C-40), 138.8 (C-10), 139.1 (C-5), 148.2 (C-8a), 151.2
(C-2), 161.0 (C-4), 162.3 (C-7). HRMS Calcd for
C16H15N3O2 281.1164, found: 281.1164.
1
372 (53), 294 (47), 293 (35). H NMR d: 3.52/3.79 (2!s,
2!3H, 1-CH3, 3-CH3), 7.54/7.72 (2!d, JZ8.6 Hz, 2!2H,
20-H, 30-H), 9.05 (s, 1H, 5-H), 10.04 (s, 1H, CHO). 13C
NMR d: 28.7 (1-CH3), 30.0 (3-CH3), 109.9 (C-4a), 125.4
(C-6), 125.7 (C-10), 131.9 (C-30), 132.1 (C-20), 135.0 (C-40),
139.6 (C-5), 151.3 (C-2), 152.4 (C-8a), 160.4 (C-4), 164.9
(C-7), 188.7 (6-CHO). Anal. Calcd: C: 51.36, H: 3.23, N:
11.23, found: C: 51.07, H: 3.13, N: 11.56.
4.4. 6-Hydroxymethyl-1,3-dimethylpyrido[2,3-d]pyri-
midine(1H,3H)-2,4-diones 9a–b and 1,3,6-trimethyl-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-diones 10a–b
4.4.4. 1,3,6-Trimethyl-7-(4-tolyl)-pyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-dione (10b). 44 mg (0.15 mmol, 15%),
mp 166 8C. UV/vis l: 220 (4.6), 252 (4.1), 332 (4.1). IR n:
1702, 1654 (s), 1604. MS m/z: 295 (MC, 92), 294 (100), 267
(16), 266 (22), 183 (18). 1H NMR d: 2.44 (s, 6H, 6-CH3, 40-
CH3), 3.49/3.71 (2!s, 2!3H, 1-CH3, 3-CH3), 4.76 (s, 2H,
6-CH2), 7.30/7.59 (2!d, JZ8.0 Hz, 2!2H, 20-H, 30-H),
8.29 (s, 1H, 5-H). 13C NMR d: 19.6 (6-CH3), 21.3 (40-CH3),
28.3 (1-CH3), 29.3 (3-CH3), 108.6 (C-4a), 126.2 (C-6),
128.9 (C-20), 129.0 (C-30), 136.4 (C-10), 139.1 (C-40), 139.4
(C-5), 148.6 (C-8a), 151.6 (C-2), 161.4 (C-4), 162.7 (C-7).
HRMS Calcd for C17H17N3O2 295.1321, found: 295.1320.
0.5 mmol of 8 and 100 mg (2.65 mmol) of sodium
borohydride were suspended in 10 mL of ethanol and
stirred for 45 min at rt. The mixture was concentrated in
vacuo and vigorously stirred with 20 mL of cold water.
Then the mixture was acidified by addition of diluted HCl,
the precipitate was filtered, washed with water, and
recrystallized from ethanol. The trimethyl derivatives
10a–b were obtained by heating 1 mmol of 7!HClO4 and
100 mg (2.65 mmol) of sodium borohydride in 25 mL of
ethanol to 50 8C for 90 min. After cooling the reaction
mixture was concentrated in vacuum and 20 mL of cold
water was added to the remainder. The mixture was stirred
vigorously and the precipitate was filtered off, dried in
vacuum and subjected to column chromatography on silica
gel (cyclohexane/ethyl acetate 6/4) to afford the colorless
derivatives 10.
4.5. Substituted 6-iminomethylpyrido[2,3-d]pyrimi-
dine(1H,3H)-2,4-diones 11a–b, 12a–b, and substituted
6-aminomethylpyrido[2,3-d]pyrimidine(1H,3H)-2,4-
diones 13a–b
2 mmol of 8 and 4 mmol of aniline or the corresponding
amount of a solution of methyl amine in ethanol were
suspended in 20 mL of ethanol and heated to reflux for
30 min. The solids 11a–b, 12a–b formed upon cooling of
the mixture were filtered off, dried in vacuo, and used as
such for further reactions. 13a–b was obtained by reaction
of 0.5 mmol of 12 and 100 mg (2.65 mmol) of sodium
borohydride in 25 mL of ethanol, the mixture was stirred
overnight at rt. The solvent was evaporated in vacuum,
4.4.1. 6-Hydroxymethyl-1,3-dimethyl-7-phenylpyrido-
[2,3-d]pyrimidine(1H,3H)-2,4-dione (9a). 120 mg
(0.41 mmol, 81%), mp 193 8C. UV/vis l: 220 (4.5), 250
(4.3), 326 (4.1). IR n: 3438 (br), 1714, 1670, 1608. MS m/z:
297 (MC, 100), 296 (77), 268 (19), 239 (16), 220 (15). H
1
NMR d: 2.57 (br s, 1H, OH), 3.47/3.72 (2!s, 2!3H,

11516
U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
25 mL of cold water was added and the mixture was stirred
vigorously. The precipitate which formed was filtered off,
dried, and subjected to column chromatography on silica gel
(ethyl acetate/cyclohexane, 3:7).
Calcd: C: 71.86, H: 5.24, N: 14.57, found: C: 71.78, H: 5.24,
N: 14.58.
4.5.5. 1,3-Dimethyl-7-phenyl-6-(N-phenylaminomethyl)-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (13a). 37 mg
(0.10 mmol, 20%), mp 131 8C (ethyl acetate). UV/vis l: 218
(4.6), 248 (4.4), 328 (4.0). IR n: 3350 (m), 1708, 1652, 1640
(s). MS m/z: 372 (MC, 19), 281 (25), 280 (100), 223 (51). 1H
NMR d: 2.44 (s, 1H, NH), 3.48/3.73 (2!s, 2!3H, 1-CH3,
3-CH3), 4.39 (s, 2H, 6-CH2), 6.48 (d, JZ7.7 Hz, 2H,
aniline-2H), 6.71 (t, JZ7.3 Hz, 1H, aniline-4H), 7.12 (br t,
JZ7.8 Hz, 2H, aniline-3H), 7.50/7.63 (2!m, 5H, phenyl-H),
8.60 (s, 1H, 5-H). 13C NMR d: 28.5 (1-CH3), 29.5 (3-CH3),
45.3(6-CH2),109.3(C-4a), 113.2(aniline-C2), 118.3(aniline-
C4), 128.2 (C-6), 128.5 (C-30), 129.0 (C-200), 129.3 (aniline-
C3), 129.5 (C-40), 138.6 (C-5), 139.6 (C-1 ), 146.9 (aniline-
C1), 149.4 (C-8a), 151.6 (C-2), 161.3 (C-7), 162.8 (C-4).
HRMS Calcd for C22H20N4O2 372.1586, found: 372.1584.
4.5.1. 1,3-Dimethyl-6-(N-methyliminomethyl)-7-phenyl-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (11a). 350 mg
(1.1 mmol, 57%), mp 208 8C (ethanol). UV/vis l: 206 (4.4),
228 (4.6), 332 (4.3). IR n: 1712, 1676, 1600.MS m/z: 308
(MC, 20), 307 (100), 250 (11), 193 (8). 1H NMR d: 3.50 (br
s, 6H, 1-CH3, N-CH3), 3.76 (s, 3H, 3-CH3), 7.52/7.62 (2!
m, 5H, phenyl-H), 8.31 (q, JZ1.6 Hz, 1H, 6-CH), 9.08 (s,
1H, 5-H). 13C NMR d: 28.5 (1-CH3), 29.6 (C-3-CH3), 48.4
(N-CH3), 109.7 (C-4a), 125.7 (C-6), 128.5 (C-30), 129.8
(C-40), 130.2 (C-20), 137.5 (C-10), 138.0 (C-5), 150.6
(C-8a), 151.5 (C-2), 158.7 (C-6-CH), 160.9 (C-4), 162.7
(C-7). Anal. Calcd: C: 66.22, H: 5.23, N: 18.17, found: C:
65.97, H: 5.11, N: 18.05.
4.5.6. 1,3-Dimethyl-6-(N-phenylaminomethyl)-7-(4-
tolyl)-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (13b).
60 mg (0.16 mmol, 32%), mp 195 8C (ethanol). UV/vis l:
220 (4.6), 250 (4.4), 328 (4.1). IR n: 3408, 1702, 1666, 1602.
4.5.2. 1,3-Dimethyl-6-(N-methyliminomethyl)-7-(4-
tolyl)-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (11b).
390 mg (1.2 mmol, 60%), mp 190 8C (ethanol). UV/vis l:
228 (4.5), 268 (4.4), 334 (4.1). IR n: 1710, 1684, 1600. MS
m/z: 322 (MC, 22), 321 (100), 264 (7), 132 (7). 1H NMR d:
2.46 (s, 3H, 40-CH3), 3.49 (s, 3H, N-CH3) 3.51/3.76 (2!s,
2!3H, 1-CH3, 3-CH3), 7.33/7.52 (2!d, JZ8.0 Hz, 2!2H,
phenyl-H), 8.32 (q, JZ1.6 Hz, 1H, 6-CH), 9.06 (s, 1H, 5-H).
13C NMR d: 21.4 (40-CH3), 28.5 (1-CH3), 29.6 (3-CH3),
48.3 (N-CH3), 109.4 (C-4a), 125.6 (C-6), 129.2 (C-20),
130.0 (C-30), 134.7 (C-10), 137.9 (C-5), 140.1 (C-40), 150.5
(C-8a), 151.5 (C-2), 158.9 (6-CH), 160.9 (C-4), 162.8 (C-7).
Anal. Calcd: C: 67.07, H: 5.63, N: 17.38, found: C: 66.93,
H: 5.39, N: 17.13.
1
MS m/z: 384 (MC, 22), 295 (20), 294 (100), 237 (36). H
NMR d: 2.46 (s, 3H, 40-CH3), 3.47/3.72 (2!s, 2!3H, 1-CH3,
3-CH3), 4.07 (br s, 1H, NH), 4.38 (br s, 2H, 6-CH2), 6.48 (d,
JZ7.9 Hz, 2H, aniline-2H), 6.68 (t, JZ7.3 Hz, 1H, aniline-
4H), 7.12 (t, JZ7.8 Hz, 2H, aniline-3H), 7.31/7.59 (2!d, 2!
2H, 4H, phenyl-H), 8.56 (s, 1H, 5-H). 13C NMR d: 21.8 (40-
CH3),28.4(1-CH3), 29.4(3-CH3),45.2(6-CH2), 109.0(C-4a),
113.0 (aniline-C2), 118.1 (aniline-C4), 128.0 (C-6), 129.0
(C-200), 129.2 (C-30), 129.2 (aniline-C3), 135.7 (C-10), 138.6
(C-4 ), 139.8 (C-5), 147.1 (aniline-C1), 149.4 (C-8a), 151.6
(C-2), 161.3 (C-7), 162.9 (C-4), Anal. Calcd: C: 71.48, H:
5.74, N: 14.50, found: C: 71.41, H: 5.81, N: 14.43.
4.5.3. 1,3-Dimethyl-7-phenyl-6-(N-phenyliminomethyl)-
pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (12a). 460 mg
(1.26 mmol, 63%), mp 210 8C (ethanol). UV/vis l: 232
(4.3), 254 (4.2), 300 (4.1), 334 (4.2). IR n: 1718, 1670 (s),
1605. MS m/z: 370 (MC, 30), 369 (100), 312 (4), 278 (8),
255 (5). 1H NMR d: 3.51/3.79 (2!s, 2!3H, 1-CH3,
3-CH3), 7.10–7.70 (m, 10H, phenyl-H, aniline-H), 8.52 (s,
1H, 5-H), 9.33 (s, 1H, 6-CH). 13C NMR d: 28.6 (1-CH3),
29.7 (3-CH3), 109.8 (C-4a), 121.1 (aniline-C2), 125.7 (C-6),
128.6 (aniline-C3), 129.2 (C-30), 130.1 (C-40), 130.2 (C-20),
137.4 (C-10), 138.4 (C-5), 138.4 (aniline-C4), 151.0 (C-8a),
151.2 (aniline-C 1), 151.5 (C-2), 156.0 (6-CH), 160.9 (C-4),
163.7 (C-7). HRMS Calcd for C23H17N4O2 (M-H)C
369.1352, found: 369.1351.
4.6. Ethyl 2-cyano-3-(pyrido[2,3-d]pyrimidin-6-yl)acryl-
ates 14a–b
2 mmol of 8 was dissolved together with 2.5 mmol of ethyl
cyano acetate in 20 mL of toluene, three drops of piperidine
and eight drops of acetic acid were added and the reaction
mixture was heated to reflux until no more water condensed.
After cooling the mixture was washed with brine, dried, and
concentrated in vacuo. The precipitate was treated with
diethyl ether, filtered, and recrystallized from ethyl acetate
to afford yellow crystals of 14.
4.6.1. Ethyl 2-cyano-3-(1,3-dimethyl-2,4-dioxo-7-phenyl-
(1H,3H)-pyrido[2,3-d]pyrimidine-6-yl)acrylate (14a).
490 mg (1.26 mmol, 63%), mp 171 8C (ethyl acetate). UV/
vis l: 262 (4.3), 338 (4.3). IR n: 2210, 1720, 1680, 1600. MS
m/z: 390 (MC, 21), 361 (8), 318 (26), 317 (100). 1H NMR d:
1.28 (t, JZ7.1 Hz, 3H, OCH2CH3), 3.51/3.79 (2!s, 2!3H,
1-CH3, 3-CH3), 4.37 (q, JZ7.1 Hz, 2H, OCH2CH3), 7.56
(m, 5H, phenyl-H), 8.27 (d, JZ0.6 Hz, 1H, 5-H), 9.28 (d,
JZ0.6 Hz, 1H, 6-CH). 13C NMR d: 14.1 (CH3), 28.6
(1-CH3), 29.8 (3-CH3), 62.9 (CH2), 105.8 (C^N), 109.3
(C-4a), 114.6 (C]C), 121.0 (C-6), 128.8 (C-30), 130.4
(C-20), 130.9 (C-40), 137.1 (C-10), 139.0 (C-5), 151.3
(C-2), 151.6 (C-8a), 151.8 (C]CH), 160.2 (C-7), 161.7
(C-4), 164.5 (C]O). Anal. Calcd: C: 64.61, H: 4.65, N:
14.35, found: C: 64.76, H: 4.65, N: 14.04.
4.5.4. 1,3-Dimethyl-6-(N-phenyliminomethyl)-7-(4-
tolyl)-pyrido[2,3-d]pyrimidine(1H,3H)-2,4-dione (12b).
445 mg (1.16 mmol, 58%), mp 209 8C (ethanol). UV/vis
l: 232 (4.6), 270 (4.6), 336 (4.5). IR n: 1712, 1664, 1600.
MS m/z: 384 (MC, 30), 383 (100), 326 (3), 292 (7). 1H NMR
d: 2.45 (s, 3H, 40-CH3), 3.51/3.78 (2!s, 2!3H, 1-CH3,
3-CH3), 7.18-7.57 (m, 9H, phenyl-H, aniline-H), 8.53 (s,
13
1H, 5-H), 9.30 (s, 1H, 6-CH). C NMR d: 21.4 (40-CH3),
28.5 (1-CH3), 29.6 (3-CH3), 109.5 (C-4a), 121.0, (aniline-
C2), 0125.5 (C-6), 129.1 (aniline-C3), 129.3 (C-20), 130.1
(C-3 ), 1340.5 (C-10), 138.3 (C-5), 138.4 (aniline-C4),
140.4 (C-4 ), 150.9 (C-8a), 151.2 (aniline-C1), 151.7
(C-2), 156.2 (6-CH), 161.0 (C-4), 163.7 (C-7). Anal.

U. Girreser et al. / Tetrahedron 60 (2004) 11511–11517
11517
Electronic Symposium on Organic Synthesis (ECSOC 5),
2001, A0008.
4.6.2. Ethyl 2-cyano-3-(1,3-dimethyl-2,4-dioxo7-(4-
tolyl)-(1H,3H)-pyrido[2,3-d]pyrimidine-6-yl)acrylate
(14b). 525 mg (1.30 mmol, 65%), mp 188 8C (ethyl
acetate). UV/vis l: 284 (4.3), 342 (4.4). IR n: 2239, 1718,
1714, 1670, 1590. MS m/z: 404 (MC, 6), 332 (14), 331 (53),
2. Warner, J. C. In Miscellaneous Fused Pyrimidines; Delia, T.,
Ed.; Wiley: New York, 1992; Vol. 99, pp 17–117; Part IV.
3. Troschutz, R.; Roth, H. J. Arch. Pharm. 1978, 311, 406–414.
4. Kiesel, M.; Haug, E.; Kantlehner, W. J. Prakt. Chem. 1997,
339, 159–170.
¨
1
45 (100). H NMR d: 1.39 (t, JZ7.1 Hz, 3H, OCH2CH3),
2.46 (s, 3H, 40-CH3), 3.52/3.79 (2!s, 2!3H, 1-CH3,
3-CH3), 4.37 (q, JZ7.1 Hz, 2H, OCH2CH3), 7.34/7.49 (2!
d, JZ8.0 Hz, 2!2H, phenyl-H), 8.28 (s, 1H, 5-H), 9.26 (s,
¨
5. Gorlitzer, K.; Diers, K. Pharmazie 1997, 52, 97–100.
6. Hirota, K.; Kubo, K.; Sajiki, H.; Kitade, Y.; Sako, M.; Maki,
Y. J. Org. Chem. 1997, 62, 2999–3001.
13
1H, 6-CH). C NMR d: 14.1 (CH3), 21.4 (40-CH3), 28.6
(1-CH3), 29.7 (3-CH3), 62.9 (CH2), 105.4 (C^N), 109.0
(C-4a), 114.6 (C]C), 120.9 (C-6), 129.5 (C-200), 130.4
(C-30), 134.3 (C-10), 139.0 (C-5), 141.5 (C-4 ), 151.3
(C-2), 151.6 (C-8a), 152.0 (C]CH), 160.2 (C-7), 161.8
(C-4), 164.5 (C]O). HRMS Calcd for C22H20N4O4,
404.1485, found: 404.1483.
7. Singh, K.; Singh, J.; Singh, H. Tetrahedron 1998, 54,
935–942.
8. Quiroga, J.; Insuasty, H.; Insuasty, B.; Abonia, R.; Cobo, A. S.;
Nogueras, M. Tetrahedron 2002, 58, 4873–4877.
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