Synthesis of 6-acylpyrido[2,3-d]pyrimidine derivatives from 5-acetyl-4-aminopyrimidine hydrochlorides

Article abstract of DOI:10.1007/s11172-007-0362-z

Reaction of 2,6-disubstituted 5-acetyl-4-aminopyrimidine hydrochlorides with acetylacetone or benzoylacetone afforded new substituted 6-acylpyrido[2,3-d]pyrimidines. The reaction of these hydrochlorides with ethyl acetoacetate also proceeds according to t

Full text of DOI:10.1007/s11172-007-0362-z

Russian Chemical Bulletin, International Edition, Vol. 56, No. 11, pp. 2293—2297, November, 2007
2293
Synthesis of 6ꢀacylpyrido[2,3ꢀd]pyrimidine derivatives
from 5ꢀacetylꢀ4ꢀaminopyrimidine hydrochlorides
A. V. Komkov and V. A. Dorokhovꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: vador@ioc.ac.ru
Reaction of 2,6ꢀdisubstituted 5ꢀacetylꢀ4ꢀaminopyrimidine hydrochlorides with acetylꢀ
acetone or benzoylacetone afforded new substituted 6ꢀacylpyrido[2,3ꢀd]pyrimidines. The reꢀ
action of these hydrochlorides with ethyl acetоacetate also proceeds according to the classical
version of the Friedländer condensation to form the corresponding pyrido[2,3ꢀd]pyrimidineꢀ6ꢀ
carboxylic acid esters.
Key words: 2,6ꢀdisubstituted 5ꢀacetylꢀ4ꢀaminopyrimidine hydrochlorides, acetylacetone,
benzoylacetone, ethyl acetоacetate, the Friedländer reaction, 6ꢀacylpyrido[2,3ꢀd]pyrimidines,
ethyl pyrido[2,3ꢀd]pyrimidineꢀ6ꢀcarboxylates.
Earlier, in a series of papers,1—5 we proposed various
pathways for the synthesis of pyrido[2,3ꢀd]pyrimidine
derivatives from 2,6ꢀdisubstituted 5ꢀacetylꢀ4ꢀaminoꢀ
pyrimidines (AAP), easily obtained from acetylacetone or
benzoylacetone and Nꢀcyanoamidines in the presence of
Ni acetate.1,3,6 In particular,4 it was found that the heatꢀ
ing (180—190 °С) of AAP with excess acetоacetic or
benzoylacetic ester in the absence of a catalyst leads to
the corresponding 6ꢀacylpyrido[2,3ꢀd]pyrimidinꢀ7(8Н )ꢀ
ones (structure А), i.e., the heterocyclization proceeds
with elimination of EtOH from βꢀketoester, rather than
follows the classical version of the Friedländer condensaꢀ
tion, which should lead to pyrido[2,3ꢀd]pyrimidineꢀ6ꢀ
carboxylic acid esters (structure B).
6ꢀAcylpyrido[2,3ꢀd]pyrimidines, obviously, can be
transformed to the corresponding azomethines, oximes,
and hydrazones, as well as they can be used in other
schemes for the modification of pyrido[2,3ꢀd]pyrimidine
derivatives. In continuation of the preceding research, it
was logically to try βꢀdiketones in the reactions with AAP
to obtain 6ꢀacylpyrido[2,3ꢀd]pyrimidines. However, the
reflux of AAP with acetylacetone in the absence of cataꢀ
lysts leaves the starting compounds unchanged. It is pertiꢀ
nent to mention the data in Ref. 7 which reported unsucꢀ
cessful efforts to obtain the condensation products of
acetylacetone with 4ꢀaminoꢀ2ꢀmethoxyꢀ5ꢀformylpyriꢀ
midine both in the presence of bases and under acidꢀ
catalyzed conditions. It should be also taken into account
that the use of bases as the catalysts in the transformations
of compounds of the AAP type is not advisable, since the
latter can undergo the Friedländer selfꢀcondensation unꢀ
der such conditions.3
Scheme 1
For the problem formulated to be solved, a version of
the Friedländer reaction (the Kempter modification, for
a review see Ref. 8), based on the use of AAP in form of
hydrochloride, turned out to be suitable. In fact, the solꢀ
ventꢀfree heating of hydrochlorides 1а,b with excess
acetylacetone or benzoylacetone to 140—150 °С afforded
the corresponding 6ꢀacylpyrido[2,3ꢀd]pyrimidines 2a,b
(Scheme 2). It is noteworthy that, in case of unsymmetriꢀ
cal diketone, benzoylacetone, the condensation proceeds
selectively with participation of the acetyl fragment to
form 6ꢀbenzoylpyridopyrimidine 2с only.
Usually (see, for example, Ref. 9). the Friedländer
condensation is considered as the twoꢀstep process,
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2215—2219, November, 2007.
1066ꢀ5285/07/5611ꢀ2293 © 2007 Springer Science+Business Media, Inc.

2294
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007
Komkov and Dorokhov
Scheme 2
reflux in benzene in the presence of catalytic amount of
1,8ꢀdiazabicyclo[5.4.0]undecꢀ7ꢀene (DBU).
If enamine 3d is treated with MeONa in MeOH even
under mild conditions (~20 °С), the cyclization to a conꢀ
siderable extent is accompanied by deacetylation to form
pyrido[2,3ꢀd]pyrimidine 4 (according to the NMR spectra,
compounds 2d and 4 were obtained in the ratio ~1 : 6).
However, it should be noted that enamines 3a—c are
presented as the small admixtures in the reaction mixꢀ
tures, obtained by the reaction of diketones with salts 1a,b.
The main products, pyrido[2,3ꢀd]pyrimidines 2а—с, can
be easily enough purified from these admixtures by colꢀ
umn chromatography, the intermediate enamine 3a being
successfully isolated in pure form in 8% yield when comꢀ
pound 2а has been synthesized.
The synthesized crystalline compounds 2a—d, 3d,
and 4 are readily soluble in organic solvents, excluding
light petroleum. Their structures were confirmed by
spectroscopy methods. In the mass spectra of pyriꢀ
do[2,3ꢀd]pyrimidines 2a—d and 4, intensive peaks of the
molecular ions are observed (Table 1). The 1Н NMR
spectra of compounds 2a—b,d in CDCl3, containing acetyl
group, are characterized by the presence of singlets in the
region 2.53—2.62 ppm, the spectrum of heterocycle 2с
contains sets of signals from the two phenyl groups (COPh
and 2ꢀPh), while in the spectrum of compound 4, a charꢀ
acteristic singlet at 7.12 ppm (Н(6)) is observed (Table 2).
An absorption of the carbonyl group of the acetyl fragꢀ
ment with ν 1708 cm–1 (compounds 2а,b,d) or the benꢀ
zoyl fragment with ν 1672 cm–1 (compound 2с) is charꢀ
acteristic of the IR spectra of the pyridopyrimidines in
CHCl3 (see Table 2). In contrast to pyridopyrimidines 2,
a very weak peak of the molecular ion is observed in
the mass spectrum of enamine 3d, while the ion
Compound
R1
R2
Compound
R3
1a, 2a
1b, 2b
2c
Ph
4ꢀClC6H4
Ph
Me
Me
Me
2a
2b
2c
Me
Me
Ph
including formation of enamines of the type 3 (see
Scheme 2) and their cyclization. It is interesting that
hydrochloride 1с upon reflux in excess acetylacetone gives
the enamine 3d (Scheme 3), whereas the corresponding
pyrido[2,3ꢀd]pyrimidine is not formed under these conꢀ
ditions. Apparently, the electrophilicity of the carbonyl
group of the acetyl fragment in this case is weakened
by the influence of the phenyl group in the adjacent posiꢀ
tion of the pyrimidine ring, that is why no pyridine
ring closure takes place. Nevertheless, enamine 3d can be
converted to 6ꢀacetylpyrido[2,3ꢀd]pyrimidine 2d upon
1
[M – COMe]+ is the most intensive. In Н NMR specꢀ
trum of this compound in CDCl3, characteristic singlets
are presented at 5.4 ppm (СН=) and 12.9 ppm (NH),
while the IR spectra in CHCl3 show the presence of two
carbonyl groups (absorption bands with ν 1684 and
Scheme 3
i. DBU, C6H6, ∆. ii. MeONa, MeOH, 20 °C.

6ꢀAcylpyrido[2,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2295
Table 1. Yield, melting points, elemental analysis data, and mass spectra of compounds 2a—d, 4, and 5a,b
Comꢀ Yield
M.p.
/°С
Found
Calculated
Molecular
formula
MS,
m/z (Irel (%))
(%)
N
poꢀ
(%)
und
C
H
2a
55
37
22
210—211
164—165
200—201
73.97 6.15 14.13 C18H17N3O
74.20 5.88 14.42
291 [M]+ (49), 276 [M – Me]+(100), 207 [M – MeCN –
COMe]+ (77), 166 [M – 2 MeCN – COMe]+ (34)
2b*
2c
66.54 5.18 12.74 C18H16ClN3O 325 [M]+ (63), 310 [M – Me]+ (100), 241 [M – MeCN –
66.36 4.95 12.90
77.87 5.36 11.54 C23H19N3O
78.16 5.42 11.89
COMe]+ (93), 200 [M – 2 MeCN – COMe]+ (43)
353 [M]+ (100), 352 [M – H]+ (83), 337 [M – H – Me]+
(27), 311 [M – H – MeCN]+ (19), 276 [M – Ph]+ (19),
207 [M – MeCN – COPh]+ (18), 166 [M – 2 MeCN –
COPh]+ (16), 105 [COPh]+ (34)
2d
53
128—129
73.85 6.18 13.92 C18H17N3O
74.20 5.88 14.42
291 [M]+ (100), 276 [M – Me]+ (94), 248 [M – COMe]+
(60), 207 [M – MeCN – COMe]+ (26), 166 [M –
2 MeCN – COMe]+ (33)
4
48
33
27
147—148
144—145
91—92
76.73 5.92 16.85 C16H15N3
77.08 6.06 16.86
70.93 6.21 12.78 C19H19N3O2
71.01 5.96 13.08
70.62 6.09 12.59 C19H19N3O2
71.01 5.96 13.08
249 [M]+ (44), 248 [M – H]+ (100), 234 [M – Me]+ (10),
233 [M – H – Me]+(15)
5a
5b
321 [M]+ (100), 306 [M – Me]+ (39), 276 [M – OEt]+ (37)
321 [M]+ (74), 320 [M – H]+ (52), 292 [M – Et]+ (25),
276 [M – OEt]+ (32), 274 [M – H – EtOH]+ (100),
248 [M – Et – CO2]+(39)
* Found/calculated (%): Cl, 10.83/10.88.
Table 2. 1Н NMR spectra in CDCl3 and IR spectra in CHCl3 of compounds 2a—d, 4, and 5a,b
Comꢀ
poꢀ
und
1H NMR, δ (J/Hz)
IR,
ν/cm–1
2ꢀМе
(s, 3 H)
4ꢀМе
(s, 3 H)
5ꢀМе
(s, 3 H)
7ꢀМе
СОМе
CO2Et
Ar
(s, 3 H)
(s, 3 H)
2a
2b
2c
—
—
—
3.12
3.14
3.18
2.69
2.69
2.58
2.74
2.61
2.62
—
—
—
—
7.52 (m, 3 H);
8.71 (m, 2 H)
1708 (СО),
1584, 1556
1708 (СО),
1580, 1560
1672 (СО),
1600, 1584,
1556
2.77
2.69
7.48 (d, 2 H, J = 7.5);
8.67 (d, 2 H, J = 7.5)
7.45—7.60 (m, 5 H);
7.68 (t, 1 H, J = 7.8);
7.85 (d, 2 H, J = 7.8);
8.76 (m, 2 H)
2d
2.93
—
1.95
2.70
2.53
—
7.40—7.60 (m, 5 H)
1708 (СО),
1580, 1548
1600, 1556
1724 (СО),
1588, 1556
4*
5a
2.93
—
—
3.14
2.03
2.74
2.74
2.82
—
—
—
7.40—7.60 (m, 5 H)
7.51 (m, 3 H);
8.72 (m, 2 H)
1.45 (t, 3 H,
Me, J = 6.8);
4.50 (q, 2 H,
CH2, J = 6.8)
1.38 (t, 3 H,
Me, J = 6.8);
4.42 (q, 2 H,
CH2, J = 6.8)
5b
2.94
—
2.02
2.75
—
7.40—7.60 (m, 5 H)
1724 (СО),
1588, 1552
* 7.12 (s, 1 Н, Н(6)).
1640 cm–1), one of which is involved into the intramoꢀ
lecular hydrogen bonding.
As it was mentioned above, the reaction of AAP with
ketoesters does not follow the classical version of the
Friedländer condensation. That is why it would have been
interesting to study the reaction of acetоacetic ester with
hydrochlorides of AAP. It turned out that the heating
of hydrochloride 1а with excess acetоacetic ester to
130—135 °С afforded pyrido[2,3ꢀd]pyrimidineꢀ6ꢀcarboxyꢀ
lic acid ester 5а in 33% isolated yield (Scheme 4). Ester 5b,

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Komkov and Dorokhov
6ꢀAcylꢀ2ꢀarylꢀ4,5,7ꢀtrimethylpyrido[2,3ꢀd]pyrimidines
(2а—с) (general procedure). A mixture of hydrochloride 1а or 1b
(1 mmol) and acetylacetone (120 mmol) was refluxed for 2—3 h
or a mixture of hydrochloride 1а (1 mmol) and benzoylacetone
(25 mmol) was heated for 4 h at 145—150 °С. The residue was
subjected to column chromatography on SiO2 (eluent: С6Н6,
then, С6Н6—СНСl3 1 : 1, and СНСl3), the fraction composiꢀ
tions were monitored by TLC (in the preparation of comꢀ
pounds 2a,b, with prior evaporation of excess acetylacetone).
The solvent was evaporated in vacuo from the latter fractions,
the residue was recrystallized from light petroleum — benzene,
4 : 1 (in case of 2a,b) and from МеСN (in case of 2с) to obtain
pyridopyrimidines 2а—c (see Tables 1 and 2).
similar to compound 5а, was obtained from salt 1с, howꢀ
ever, the more drastic conditions were required (the reacꢀ
tion was carried out at the temperature of 160—165 °С).
Scheme 4
In the synthesis of compounds 2а, after evaporation of the
solvent from the medium fractions and crystallization of the
residue from light petroleum, 5ꢀacetylꢀ6ꢀmethylꢀ4ꢀ(2ꢀoxopentꢀ
3ꢀenꢀ4ꢀyl)aminoꢀ2ꢀphenylpyrimidine (3a) was isolated, the yield
was 8%, m.p. 110—111 °С. Found (%): С, 69.96; Н, 6.35;
N, 13.19. С18H19N3O2. Calculated (%): С, 69.88; Н, 6.19; N,
13.58. MS, m/z (Irel (%)): 309 [М]+ (2), 266 [M – MeCO]+
(100), 249 [M – COCH2 – H2O]+ (82). IR (CHCl3), ν/cm–1
:
1696 (СО); 1636 (СО); 1544. 1H NMR (CDCl3), δ: 2.14 (s,
3 Н, СОМе); 2.52 (s, 3 Н, СОМе); 2.68 (s, 3 Н, Ме); 2.70 (s,
3 Н, Ме); 5.43 (s, 1 Н, СН=); 7.49 (m, 3 Н, Ph); 8.48 (m, 2 Н,
Ph); 12.89 (br.s, 1 H, NH).
R1 = Ph, R2 = Me (1a, 5a); R1= Me, R2 = Ph (1c, 5b)
Esters 5a,b are readily soluble in organic solvents. Their
structures were confirmed by spectroscopy methods. Their
mass spectra contain intensive peaks of the molecular
5ꢀAcetylꢀ2ꢀmethylꢀ4ꢀ(2ꢀoxopentꢀ3ꢀenꢀ4ꢀyl)aminoꢀ6ꢀphenylꢀ
pyrimidine (3d). A mixture of hydrochloride 1с (0.264 g, 1 mmol)
and acetylacetone (12 mL, 116 mmol) was refluxed for 2 h,
acetylacetone was evaporated in vacuo, the residue was subꢀ
jected to column chromatography on SiO2 (eluent: С6Н6, then,
С6Н6—СНСl3, 4 : 1). After the solvent was evaporated from the
corresponding fraction, the residue was recrystallized from light
petroleum (3 mL) to obtain enamine 3d (0.124 g, 40%),
m.p. 111—112 °С. Found (%): С, 69.74; Н, 6.43; N, 13.22.
1
ions (see Table 1), in the Н NMR spectra, signals of the
ethyl group from ethoxycarbonyl fragment are observed,
while in the IR spectrum there is an absorption with
ν 1724 cm–1 characteristic of the fragment.
In conclusion, it was found that the use of AAP hydroꢀ
chlorides instead of free bases in the transformations with
βꢀdiketones allows one to accomplish the Friedländer
reaction with the construction of pyrido[2,3ꢀd]pyrimidine
system and, in case of ketoesters, also gives a possibility to
conduct the Friedländer condensation in its classical
version.
С18H19N3O2. Calculated (%): С, 69.88; Н, 6.19; N, 13.58. MS,
m/z (Irel (%)): 309 [М]+ (1), 266 [M – MeCO]+ (100), 183 (24).
IR (CHCl3), ν/cm–1: 1684 (СО); 1640 (СО); 1600, 1584, 1544.
1H NMR (CDCl3), δ: 1.98 (s, 3 Н, СОМе); 2.17 (s, 3 Н,
СОМе); 2.58 (s, 3 Н, Ме); 2.68 (s, 3 Н, Ме); 5.43 (s, 1 Н, СН=);
7.50 (m, 3 Н, Ph); 7.62 (m, 2 Н, Ph); 12.88 (br.s, 1 H, NH).
6ꢀAcetylꢀ2,5,7ꢀtrimethylꢀ4ꢀphenylpyrido[2,3ꢀd]pyrimidine
(2d). 1,8ꢀDiazabicyclo[5.4.0]undecene (3 drops) was added to
enamine 3 (0.155 g, 0.5 mmol) in benzene (10 mL), the mixture
was refluxed for 1 h, then, benzene was evaporated in vacuo and
the residue was subjected to column chromatography on SiO2
(eluent: СНСl3). The solvent was evaporated, the residue was
recrystallized from light petroleum to obtain pyridopyrimidine 2d
(0.077 g, 53%) (see Tables 1 and 2).
Experimental
1
Н NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer, IR spectra were recorded on a SpecordꢀM80 specꢀ
trometer, mass spectra were recorded on a Kratos MSꢀ30 instruꢀ
ment (EI, 70 eV; the ionizing chamber temperature, 250 °С;
direct inlet of a substance). 2,6ꢀDisubstituted 5ꢀacetylꢀ4ꢀ
aminopyrimidines were synthesized according to the known proꢀ
cedures.1,3,6 Their hydrochlorides were obtained by treatment
with concentrated НСl in МеОН. After МеОН was evaporated
in vacuo, benzene was added to the residue, this was refluxed
with a Dean—Stark trap, and salts 1а—с were filtered off.*
2,5,7ꢀTrimethylꢀ4ꢀphenylpyrido[2,3ꢀd]pyrimidine (4). A mixꢀ
ture of enamine 3 (0.155 g, 0.5 mmol) and MeONa (0.5 mmol)
in МеОН (10 mL) was stirred for 30 min. The solvent was
evaporated in vacuo, the residue was subjected to column chroꢀ
matography on SiO2 (eluent: С6Н6—СНСl3, 1 : 1). The solvent
was evaporated in vacuo from the corresponding fractions
(TLC monitoring) and the residue was recrystallized from light
petroleum to obtain pyridopyrimidine 4 (0.059 g, 48%) (see
Tables 1 and 2).
Ethyl 4,5,7ꢀtrimethylꢀ2ꢀphenylꢀ and 2,5,7ꢀtrimethylꢀ4ꢀpheꢀ
nylpyrido[2,3ꢀd]pyrimidineꢀ6ꢀcarboxylates (5a,b). A mixture of
hydrochloride 1а or 1с (1 mmol) and ethyl acetоacetate
(120 mmol) was heated for 2—3 h to 130—135 °С and
*
1Н NMR spectrum of hydrochloride 1а (DMSOꢀd6), δ: 2.59
(s, 3 Н, Ме); 2.64 (s, 3 Н, Ме); 7.61 (t, 2 Н, Ph, J = 7.8 Hz);
7.68 (t, 1 Н, Ph, J = 7.8 Hz); 8.31 (d, 2 Н, Ph, J = 7.8 Hz); 8.71
(br.s, 2 Н, NH2); signals of the salt's NН and Н2О in DMSOꢀd6
are broadened to a large extent due to the exchange and, thereꢀ
fore, are not visible. For a comparison, the spectrum of the
starting base is given (DMSOꢀd6), δ: 2.50 (s, 3 Н, Ме); 2.55 (s,
3 Н, Ме); 7.38 (br.s, 2 Н, NH2); 7.49 (m, 3 Н, Ph); 8.33
(m, 2 Н, Ph).

6ꢀAcylpyrido[2,3ꢀd]pyrimidines
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 11, November, 2007 2297
165—170 °С, respectively, the excess ethyl acetоacetate was
evaporated in vacuo, and the residue was subjected to column
chromatography on SiO2 (eluent: С6Н6, then, С6Н6—СНСl3,
2 : 1). After the solvent was evaporated from the corresponding
fractions (TLC monitoring), the oily residue was recrystallized
from light petroleum to obtain esters 5а,b (Tables 1 and 2).
3. A. V. Komkov and V. A. Dorokhov, Izv. Akad. Nauk, Ser.
Khim., 2002, 1726 [Russ. Chem. Bull., Int. Ed., 2002, 51, 1875].
4. A. V. Komkov, I. P. Yakovlev, and V. A. Dorokhov, Izv.
Akad. Nauk, Ser. Khim., 2005, 770 [Russ. Chem. Bull., Int.
Ed., 2005, 54, 784].
5. A. V. Komkov, M. A. Prezent, A. V. Ignatenko, I. P. Yakovlev,
and V. A. Dorokhov, Izv. Akad. Nauk, Ser. Khim., 2006, 2006
[Russ. Chem. Bull., Int. Ed., 2006, 55, 2085].
6. V. A. Dorokhov, M. F. Gordeev, A. V. Komkov, and V. S.
Bogdanov, Izv. Akad. Nauk SSSR, Ser. Khim., 1990, 145
[Bull. Acad. Sci. USSR, Div. Chem. Sci., 1990, 39, 130
(Engl.Transl.)].
7. F. Perandones and J. L. Soto, J. Heterocycl. Chem., 1998,
35, 413.
This work was financially supported by the Russian
Academy of Sciences (the Presidium of RAS Program for
Basic Research "Development of Methodology of Orꢀ
ganic Synthesis and Creation of Compounds with Valuꢀ
able Applied Properties").
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Received September 27, 2007;
in revised form October 17, 2007