Transformations of ortho-methoxyaryl(hetaryl)carboxamides into quinazolin-4-one and pyrido[2,3-d]pyrimidin-4-one derivatives

Article abstract of DOI:10.1007/s11172-006-0057-x

ortho-Chloroaryl(hetaryl)carboxamides containing one or two nitro groups at positions 3 and/or 5 of the ring undergo condensation accompanied by the pyrimidine ring closure on refluxing in an excess of sodium methoxide to form bicyclic products, viz., qui

Full text of DOI:10.1007/s11172-006-0057-x

Russian Chemical Bulletin, International Edition, Vol. 54, No. 8, pp. 1907—1914, August, 2005
1907
Transformations of orthoꢀmethoxyaryl(hetaryl)carboxamides into
quinazolinꢀ4ꢀone and pyrido[2,3ꢀd]pyrimidinꢀ4ꢀone derivatives
O. B. Ryabova,aꢀ V. A. Makarov,a L. M. Alekseeva,a A. S. Shashkov,b V. V. Chernyshev,c and V. G. Granika
aState Research Center of Antibiotics,
3a ul. Nagatinskaya, 117105 Moscow, Russian Federation.
Fax: +7 (495) 231 4284. Eꢀmail: makarꢀcl@ropnet.ruEꢀmail: vggranik@mail.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: vador@cacr.ioc.ac.ru
cDepartment of Chemistry, M. V. Lomonosov Moscow State University,
1 Leninskie Gory, 119992 Moscow, Russian Federation.
Fax: +7 (495) 939 3654. Eꢀmail: vladimir@struct.chem.msu.ru
orthoꢀChloroaryl(hetaryl)carboxamides containing one or two nitro groups at positions 3
and/or 5 of the ring undergo condensation accompanied by the pyrimidine ring closure on
refluxing in an excess of sodium methoxide to form bicyclic products, viz., quinazolinꢀ4ꢀone,
pyrido[2,3ꢀd]pyrimidinꢀ4ꢀone, and pyrido[4,3ꢀd]pyrimidinꢀ4ꢀone derivatives. The scheme of
cyclization processes was proposed. The structures of the reaction products were confirmed by
a number of physicochemical data, including Xꢀray diffraction analysis.
Key words: dinitrobenzamide, quinazolinꢀ4ꢀone, pyrido[2,3ꢀd]pyrimidinꢀ4ꢀone, 4ꢀchloroꢀ
5ꢀnitronicotinamide, pyrido[4,3ꢀd]pyrimidinꢀ4ꢀone, 4,6ꢀdichloroꢀ5ꢀpyrimidinocarboxamide,
Xꢀray diffraction analysis.
Earlier,1,2 we have synthesized a series of 3,5ꢀdinitroꢀ
benzenecarboxamide derivatives containing a dialkylꢀ
dithiocarbamoyl substituent at position 2 and found that
these compounds have high antituberculosis activity. As
part of our continuing studies, it was of interest to prepare
new 3,5ꢀdinitrobenzenecarboxamides containing no diꢀ
alkyldithiocarbamoyl fragments and investigate their bioꢀ
logical activities. It should be noted that the properties of
different diꢀ and trinitrobenzenecarboxamides have reꢀ
ceived considerable study, because some of them are
known to be energetic compounds3 and have found use in
industry. Most methods for the synthesis of nitrobenzꢀ
amides are based on nitration of the corresponding benꢀ
zoic acids followed by transformations to give acid chloꢀ
ride and amide.4,5 This approach was used to synthesize
2ꢀchloroꢀ3,5ꢀdinitrobenzenecarboxamide 1 starting from
salicylic acid.6
We prepared the corresponding 2ꢀmethoxy derivative
2 by the reaction of 2ꢀchlorobenzamide 1 with an equimoꢀ
lar amount of sodium methoxide in methanol (Scheme 1).
In addition to the target compound 2, we found an insigꢀ
nificant impurity of another compound with a molecular
weight of 432 among the reaction products. Based on the
results of different physicochemical methods, we assigned
the structure of 2ꢀ(2ꢀmethoxyꢀ3,5ꢀdinitrophenyl)ꢀ6,8ꢀ
dinitroquinazolinꢀ4ꢀone (3) to the latter product.
The 1H NMR spectra of compound 3 show four douꢀ
blets corresponding to H(5), H(7), H(4´), and H(6´) in
the aromatic proton region (see the Experimental secꢀ
tion). The 13C NMR spectrum (Table 1) has signals for
15 carbon atoms. Lowꢀfield signals were assigned to the
C(2), C(4), and C(2´) atoms (see Table 1). A group of
signals observed at higher field (at δ 141.5—146.8) correꢀ
sponds to the carbon atoms bound to the oxygen and
nitrogen atoms, viz., C(6), C(8), C(8a), C(3´), and C(5´).
The signals for the quaternary C(4a), C(1´), C(5), C(7),
C(4´), and C(6´) atoms appear at high field (the assignꢀ
ment of the latter atoms was made based on the HSQC
spectrum). The detailed assignment of the 13C signals in
the spectrum of compound 3 was made by comparing the
chemical shifts in the spectra of 3 and its Nꢀmethylꢀsubꢀ
stituted derivative 4.
The structure of quinazolinone 3 was unambiguously
established by Xꢀray diffraction (Fig. 1). Selected interꢀ
atomic distances and bond angles in the structure of comꢀ
pound 3 are given in Table 2. Further investigation demꢀ
onstrated that the reaction of amide 1 with a threefold
excess of sodium methoxide afforded exclusively quinazoꢀ
linone 3. This compound was prepared in higher yield by
refluxing methoxy derivative 2 with one mole of sodium
methoxide in methanol. Methylation of quinazolinone 3
with diiodomethane in the presence of potassium carꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1851—1858, August, 2005.
1066ꢀ5285/05/5408ꢀ1907 © 2005 Springer Science+Business Media, Inc.

1908
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Ryabova et al.
Scheme 1
bonate was demonstrated to occur selectively at NH to
give 3ꢀmethylquinazolinone 4. The HMBC spectrum of
this compound (see Table 1) shows correlation peaks at
δ 3.39/156.1 (N(3)Me/C(2)), 3.39/159.4 (N(3)Me/C(4)),
and 9.04/159.4 (H(5)/C(4)). The replacement at the niꢀ
trogen atom in position 1 would give rise to a correlation
peak of N(1)Me with C(8a), but the spectrum shows corꢀ
relation peaks only with H(5) and H(7). The use of the
HMBC spectrum enabled us to assign all 13C signals in
the spectra of compounds 4 and 3 (see Table 1), because
it is evident that methylation should not be accompanied
by a substantial change in the chemical shifts.
To confirm the proposed scheme of condensation,
it was necessary to elucidate whether other aromatic
compounds containing the methoxy substituent in the
ortho position with respect to the amide group can unꢀ
3, 4: X = Y = C—NO2; 10, 11: X = C—NO2, Y = N
Table 1. 13C NMR spectroscopic data for compounds 3, 4, 10, and 11
a
Atom
δ
3
4
10
11
2
4
4а
5
6
7
8
8а
155.4
159.5
123.5
124.4
146.6
156.1 (N(3)Me)
159.4 (N(3)Me, Н(5))
122.4
122.8
146.2 (H(7))
122.5
142.2 (H(7))
144.4 (H(5), H(7))
130.7
155.5 (Н(6´))
161.2
116.6 (116.0)
131.4
141.8 (H(5), H(7))
150.6
157.1 (N(3)Me, H(6´))
161.0 (N(3)Me)
117.9
132.0
142.1 (H(5), H(7))
150.7
—
122.8
b
—
144.2
128.7
161.2 (H(5), H(7))
116.0 (116.6)
159.4 (H(5), H(7))
114.7
1´
2´
3´
4´
5´
154.7
154.5 (C(2´)OMe, Н(6´))
142.0 (142.6)
122.6
142.6 (142.0)
129.4
163.6 (C(2´)OMe, Н(6´), Н(4´))
—
146.8
139.1 (Н(6´))
135.6
162.5 (C(2´)OMe, Н(6´), Н(4´))
—
146.3
139.3 (Н(4´), Н(6´))
135.0
32.7
55.6
b
123.4
b
6´
130.2
—
N(3)Me
C(2´)ОMe 64.0
33.6
63.5
—
55.6
a The protons, which show correlation peaks with the indicated atoms in the HMBC spectrum, are given in parentheses.
b
δ 141.4, 143.0, and 144.0.

Aryl(hetaryl)carboxamides transformation
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
1909
O(25)
Scheme 2
O(26)
O(23)
N(24)
O(22)
C(8)
C(15)
N(21)
C(9)
C(16)
N(1)
C(2)
C(11)
O(19)
C(14)
C(13)
N(27)
C(7)
C(6)
C(12)
N(18)
O(20)
N(3)
C(5)
C(10)
O(28)
C(4)
O(29)
O(30)
C(31)
O(17)
Fig. 1. Molecular structure of compound 3 (Xꢀray diffraction
data) with displacement ellipsoids drawn at the 40% probability
level.
Table 2. Selected bond lengths and bond angles in molecule 3
followed by treatment with thionyl chloride. The reaction
of this acid chloride with 25% aqueous ammonia at –20 °C
produced 2ꢀchloroꢀ5ꢀnitropyridineꢀ3ꢀcarboxamide (8) in
86% yield. The reaction of the latter with an equimoꢀ
lar amount of sodium methoxide gave the target
2ꢀmethoxyꢀ5ꢀnitropyridineꢀ3ꢀcarboxamide 9 in high
yield8 (Scheme 3). It was found that refluxing of comꢀ
pound 9 in methanol in the presence of sodium methoxide
afforded 2ꢀ(2ꢀmethoxyꢀ5ꢀnitropyridinꢀ3ꢀyl)ꢀ6ꢀnitropyriꢀ
do[2,3ꢀd]pyrimidinꢀ4ꢀone (10) in 22% yield.
With the aim of establishing the structure of comꢀ
pound 10, we methylated the latter with diiodomethane
in the presence of potassium carbonate. This reaction was
demonstrated to give exclusively methyl derivative 11.
The 13C NMR, HSQC, and HMBC spectra of compounds
10 and 11 were compared with the corresponding spectra
of 3 and 4 (see Table 1). The similarity of the chemical
shifts of particular signals (for example, for C(2) and C(4))
and the changes in the shifts of other signals (for C(7),
C(4´), and C(8a)) upon the replacement of the benzene
ring with the pyridine moiety in the series of the aboveꢀ
mentioned four compounds, as well as the presence of
identical correlation peaks in the HMBC spectra, conꢀ
firm the structures of 10 and 11.
Our experiments showed that the presence of a strong
electronꢀwithdrawing substituent at position 3 (which
needs not be the second nitro group) is a necessary condiꢀ
tion for the cyclization reaction under consideration. To
elucidate the role of the nitro group at position 5 of the
ring, we examined the possibility of condensation of two
4ꢀmethoxyꢀ5ꢀnitronicotinamide molecules (12). Comꢀ
pound 12 was synthesized starting from 4ꢀhydroxyꢀ
nicotinic acid 13.9 Nitration of acid 13 was carried out
with the use of fuming nitric acid and sulfuric acid. Howꢀ
ever, refluxing for 10 h was required to complete the
reaction. It should be noted that nitration of salicylic acid
with a nitrating mixture was completed within 30 min,
whereas nitration of 2ꢀhydroxynicotinic acid required 1 h
for completion (both reactions proceeded at room temꢀ
Bond
d/Å
Angle
ω/deg
N(1)—C(2) 1.298(2)
N(1)—C(9) 1.373(2)
C(2)—N(3) 1.366(2)
C(2)—C(11) 1.491(2)
C(4)—O17) 1.218(2)
C(4)—C(10) 1.464(3)
C(5)—C(6) 1.369(3)
C(5)—C(10) 1.389(2)
C(6)—C(7) 1.390(3)
C(6)—N(18) 1.469(2)
C(7)—C(8) 1.365(3)
C(8)—C(9) 1.409(3)
C(8)—N(21) 1.468(2)
C(9)—C(10) 1.405(2)
C(2)—N(1)—C(9) 116.93(15)
N(1)—C(2)—N(3) 124.58(16)
C(2)—N(3)—C(4) 122.82(16)
N(3)—C(4)—C(10) 114.07(15)
C(6)—C(5)—C(10) 118.96(17)
C(5)—C(6)—C(7) 122.58(17)
C(8)—C(7)—C(6) 117.45(17)
C(7)—C(8)—C(9) 123.03(17)
N(1)—C(9)—C(10) 123.08(17)
N(1)—C(9)—C(8) 119.96(16)
C(10)—C(9)—C(8) 116.89(16)
C(5)—C(10)—C(9) 120.99(17)
C(5)—C(10)—C(4) 120.54(16)
C(9)—C(10)—C(4) 118.45(16)
dergo analogous cyclization and whether the presence of
two nitro groups is a necessary condition.
For this purpose, we synthesized 2ꢀchloroꢀ5ꢀnitroꢀ
benzenecarboxamide 5 according to a known procedure4
and transformed this compound into methoxy derivative 6
(Scheme 2). Refluxing of the latter with different amounts
of sodium methoxide in methanol as well as an attempt to
perform this process in an autoclave at 150 °C with a
twofold excess of sodium methoxide did not lead to the
pyrimidine ring closure and the formation of quinazoꢀ
linone 7. In all cases, the starting compound 6 was reꢀ
covered.
This experiment provided evidence that the electronꢀ
withdrawing properties of one nitro group are insufficient
for the nucleophilic substitution of the methoxy group in
compound 6. This fact has been studied in detail for other
compounds.7 Then we examined the possibility of the
pyrimidine ring closure for a compound containing not
only the nitro group at position 5 but also an electronꢀ
withdrawing group at position 3. For this purpose, we
synthesized 2ꢀchloroꢀ5ꢀnitronicotinoyl chloride by nitraꢀ
tion of 2ꢀhydroxynicotinic acid with fuming nitric acid

1910
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Ryabova et al.
Scheme 3
perature). Treatment of the resulting nitro acid 14 with
thionyl chloride smoothly afforded the corresponding acid
chloride 15, which was used in the reaction with 12%
aqueous ammonia at –20 °C. We isolated a mixture of
compounds consisting of the target 4ꢀchloroꢀ5ꢀnitroꢀ
nicotinamide 16 (80%) and the corresponding 4ꢀamino
derivative 17 (20%). The reaction of 4ꢀchloropyrimidine
16 with an equimolar amount of sodium methoxide proꢀ
duced methoxy derivative 12 in high yield.
Study of the behavior of the resulting compound 12 in
a refluxing methanolic solution of sodium methoxide
showed that this reaction also produced 2ꢀ(4ꢀmethoxyꢀ
5ꢀnitropyridinꢀ3ꢀyl)ꢀ8ꢀnitropyrido[4,3ꢀd]pyrimidinꢀ4ꢀ
one (18). It should be noted that we succeeded in isolatꢀ
ing only the hydrolysis product of methoxypyridine 18,
viz., 2ꢀ(4ꢀhydroxyꢀ5ꢀnitropyridinꢀ3ꢀyl)ꢀ8ꢀnitropyriꢀ
do[4,3ꢀd]pyrimidinꢀ4ꢀone (19), in low yield after diluꢀ
tion of the reaction mixture with water and its acidificaꢀ
tion with aqueous hydrochloric acid. This product was
characterized by various physicochemical methods (see
the Experimental section). Therefore, the formation of
the pyridopyrimidine system cannot be excluded by using
mononitro derivatives of pyridine instead of bisꢀnitroꢀ
substituted benzene, although the pyridyl group is known7
to have a lower electronꢀwithdrawing ability than the
nitrophenyl group.
Scheme 4

Aryl(hetaryl)carboxamides transformation
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
1911
Scheme 5
It is also of interest to find out whether compounds
devoid of nitro groups can be involved in the condensaꢀ
tion under study. Hence, it was worthwhile to study this
reaction with 5ꢀcarbamoylꢀ4ꢀmethoxypyrimidine (20)
containing two "pyridine" nitrogen atoms instead of the
nitro groups. This compound was synthesized based
on 4,6ꢀdichloroꢀ5ꢀformylpyrimidine (21),10 which was
treated with sulfuryl chloride in the presence of AIBN
Scheme 6

1912
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Ryabova et al.
eluent; visualization with UV light). The melting points were
determined on an Electrothermal 9100 instrument (UK).
The 13C NMR spectra of compounds 3, 4, 10, and 11 are
given in Table 1. The physicochemical characteristics, elemenꢀ
tal analysis data, and yields of the reaction products are given in
Table 3.
2ꢀMethoxyꢀ3,5ꢀdinitrobenzamide (2), 2ꢀmethoxyꢀ5ꢀnitroꢀ
benzamide (6), and 5ꢀcarbamoylꢀ6ꢀchloroꢀ4ꢀmethoxypyrimidine
(24) (general procedure). A freshly prepared solution (10 mL) of
sodium methoxide (0.35 g of sodium (15 mmol) in 10 mL of
methanol) was added to a solution of chloroamide 1, 5, or 23
(15 mmol) in methanol (50 mL) at a temperature lower than
<3 °C. The reaction mixture was allowed to stand at room temꢀ
perature for 3 h and diluted with cold water (100 mL). The white
precipitate that formed was filtered off. Methoxy derivatives 2,
6, or 24 were recrystallized from methanol, acetic acid, or waꢀ
ter, respectively.
2ꢀ(2ꢀMethoxyꢀ3,5ꢀdinitrophenyl)ꢀ6,8ꢀdinitroquinazolinꢀ4ꢀ
one (3). A suspension of benzamide 2 (1.0 g, 4 mmol) and
sodium methoxide (0.22 g, 4 mmol) in methanol (30 mL) was
refluxed for 24 h. Then the reaction mixture was cooled and
filtered. The residue was washed with methanol (30 mL). The
filtrate was acidified with 35% aqueous HCl to pH ~3. The
precipitate of quinazolinone 3 that formed was filtered off and
recrystallized from methanol. Single crystals of the solvate
3•MeOH were obtained. 1H NMR (DMSOꢀd6), δ: 3.91 (s, 3 H,
C(2´)OMe); 8.80 (d, 1 H, H(6´), J = 2.7 Hz); 8.99 (d, 1 H,
H(5), J = 2.3 Hz); 9.00 (d, 1 H, H(4´), J = 2.7 Hz); 9.24 (d, 1 H,
H(7), J = 2.3 Hz); 13.70 (br.s, 1 H, N(3)H).
Pale yellow single crystals of the solvate of quinazoline 3
with methanol were prepared by slow evaporation of a methanoꢀ
lic solution of 3. Xꢀray diffraction data were collected on an
automated fourꢀcircle CADꢀ4 diffractometer (CuꢀKα radiation,
graphite monochromator, ω scanning technique). The unit cell
parameters were determined using 25 reflections in the θ angle
range of 23—32° by autoindexing and refined to a = 8.2558(11) Å,
(2,2´ꢀazobis(isobutyronitrile)) to prepare acid chloride 22
(Scheme 5) in high yield. Interestingly, the latter is a
quite stable compound and can be purified by both reꢀ
crystallization from petroleum ether and, which is very
unusual for acid chlorides, by column chromatography
(silica gel, dichloromethane as the eluent). Apparently,
this is associated with steric shielding of the acid chloride
fragment by two adjacent bulky chlorine atoms. The reacꢀ
tion of acid chloride 22 with aqueous ammonia at 0 °C
smoothly afforded the corresponding amide 23, which, in
turn, reacted with an equimolar amount of sodium
methoxide in methanol to give 4ꢀmethoxy derivative 24.
The chlorine atom was eliminated according to a known
procedure11,12 involving hydrogenation of chlorinated aroꢀ
matic derivatives with hydrogen in the presence of pallaꢀ
dium on carbon and potassium hydroxide (0.5 mol). The
yield of pyrimidine 20 was 75%. We also demonstrated
that refluxing of this compound with sodium methoxide
in a methanolic solution, including refluxing over a long
period of time (72 h), did not afford pyrimidopyrimiꢀ
dine 25, the starting pyrimidine 20 being isolated from the
reaction mixture in all cases. Apparently, the aboveꢀmenꢀ
tioned weaker electronꢀwithdrawing effect of the "pyriꢀ
dine" nitrogen atoms compared to the nitro groups plays a
critical role.
Taking into account all results of our investigaꢀ
tion, the most probable pathways of condensation of
orthoꢀmethoxyaryl(hetaryl)carboxamides in the presence
of sodium methoxide are presented in Scheme 6.
The transformation of the starting compound into the
Nꢀanion (A1) is the key step of the scheme of the selfꢀ
condensation under consideration (see Scheme 6). The
possibility of the formation of this anion is determined by
the presence of powerful electronꢀwithdrawing substituꢀ
ents in the aromatic ring and the presence of an efficient
base, such as the methoxide anion, in the system. The
addition of this anion to dinitroamide 2 gives rise to a
σ complex (which is, apparently, preceded by the formaꢀ
tion of a π complex) structurally similar to Meisenheimer
salts. Here, the most probable mechanism is analogous to
the usual nucleophilic bimolecular aromatic substitution.13
The subsequent synthesis of quinazoline derivatives or
their heteroanalogs also most likely includes the intermeꢀ
diate formation of the Nꢀanion (A2).
b = 8.4096(11) Å, c = 13.9019(15) Å, α = 99.486(12)°, β =
–
90.308(15)°, γ = 94.85(2)°, V = 948.4(12) Å3, space group P1,
Z = 2. A total of 3475 reflections were measured in the θ angle
range of 3—70°. The absorption correction was applied based on
the ψ scan of six reflections.
The structure was solved by direct methods using the
SHELXSꢀ97 program package.14 The positional and therꢀ
mal parameters of the nonhydrogen atoms were refined anisoꢀ
tropically by the fullꢀmatrix leastꢀsquares method using the
SHELXLꢀ97 program package.14 The coordinates of the hydroꢀ
gen atoms were determined from difference Fourier syntheses or
calculated geometrically. The refinement converged to the
R factor of 0.042 using 2619 reflections with I > 2σ(I ).
The detailed characteristics of Xꢀray diffraction data collecꢀ
tion, parameters of the solution and refinement of the molecular
and crystal structure of 3, and the atomic coordinates of 3
were deposited with the Cambridge Structural Database
(CCDC 274255).
2ꢀ(2ꢀMethoxyꢀ3,5ꢀdinitrophenyl)ꢀ3ꢀmethylꢀ6,8ꢀdinitroꢀ
quinazolinꢀ4ꢀone (4). A suspension of quinazolinone 3 (0.18 g,
0.42 mmol), diiodomethane (1.0 mL, 1.6 mmol), and potassium
carbonate (0.086 g, 0.62 mmol) in acetone (15 mL) was kept for
1 h and filtered. The residue was washed with acetone, the
filtrate was concentrated, and the oily residue was treated with
water. Quinazolinone 4 (a yellow compound) was filtered off
Experimental
The IR spectra were recorded on a Perkin—Elmer 457 inꢀ
strument in Nujol mulls. The mass spectra (EI) were obtained
on a Finnigan SSQꢀ710 mass spectrometer with direct inlet of
the sample into the ion source. The NMR spectra were recorded
on Bruker ACꢀ200 and Bruker DRXꢀ500 spectrometers in
DMSOꢀd6. The purity of the products was checked and the
course of the reactions was monitored by TLC on Merck
TLCꢀ254 Silicagel 60 plates (hexane—acetone, 3 : 1, as the

Aryl(hetaryl)carboxamides transformation
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
1913
Table 3. Physicochemical characteristics, elemental analysis data, and yields of the reaction products
Comꢀ
pound
Yield
(%)
M.p.
/°С
Found
Calculated
Molecular
formula
MS,
m/z (Irel (%))
(%)
С
H
N
2
74 166—167
33 203—205
19 186—187
78 212—213
64 181—183
83 228—230
22 174—176
18 159—161
51 172—174
62 217—219
55 189—190
10 179—181
39.71
39.84
41.38
41.68
42.97
43.06
48.93
48.98
35.73
35.75
42.69
42.65
45.27
45.36
46.92
46.93
42.73
42.65
39.23
39.14
35.81
35.75
39.76
39.57
43.47
43.65
47.12
47.06
28.39
28.40
31.21
31.28
38.49
38.42
2.87
2.93
1.79
1.87
2.02
2.26
4.20
4.11
2.09
2.00
3.76
3.58
2.52
2.34
3.89
2.81
3.65
3.58
2.14
2.19
2.07
2.00
3.45
3.32
2.03
1.83
4.65
4.61
0.47
0.48
1.46
1.57
3.30
3.22
17.54
17.42
19.56
19.44
18.81
18.83
14.39
14.28
21.01
20.85
21.28
21.31
24.53
24.41
23.43
23.46
21.34
21.31
15.29
15.22
20.89
20.85
30.78
30.76
25.58
25.45
27.42
27.44
13.24
13.25
22.05
21.89
22.47
22.40
C8H7N3O6
C15H8N6O10
C16H10N6O10
C8H8N2O4
C6H4ClN3O3
C7H7N3O4
C13H8N6O6
C14H10N6O6
C7H7N3O4
C6H4N2O5
C6H4ClN3O3
C6H6N4O3
241 [M]+ (7)
432 [M]+ (8)
446 [M]+ (8)
196 [M]+ (6)
201 [M]+ (29)
197 [M]+ (32)
344 [M]+ (4)
358 [M]+ (25)
197 [M]+ (27)
184 [M]+ (8)
201 [M]+ (17)
182 [M]+ (12)
330 [M]+ (36)
153 [M]+ (7)
211 [M]+ (18)
192 [M]+ (2)
187 [M]+ (4)
3
4
6
8
9
10
11
12
14
16
17
19
20
22
23
24
7
234—236
82 181—182
76 30—32
53 202—204
75
C12H6N6O6
C6H7N3O2
C5HCl3N2O
C5H3Cl2N3O
C6H6ClN3O2
—
and purified by column chromatography (silica gel 60, chloroꢀ
form—methanol, 10 : 1, as the eluent).
temperature lower than 3 °C. Then the reaction mixture was
allowed to stand at room temperature for 3 h, diluted with cold
water (100 mL), and acidified with concentrated HCl to pH ~7.
The white precipitate of nicotinamide 9 that formed was filtered
off and recrystallized from a methanol—DMF mixture.
2ꢀ(2ꢀMethoxyꢀ5ꢀnitropyridinꢀ3ꢀyl)ꢀ6ꢀnitropyrido[2,3ꢀd]pyꢀ
rimidinꢀ4ꢀone (10). A solution of nicotinamide 9 (0.8 g,
4.1 mmol) and sodium methoxide (0.22 g, 4.1 mmol) in methaꢀ
nol (15 mL) was heated to 100 °C for 30 min. The reaction
mixture was cooled, diluted with water (80 mL), and acidified
with 35% HCl to pH ~3. The precipitate of pyridopyrimidinone
10 that formed was filtered off and purified by column chromaꢀ
tography (silica gel 60, chloroform—methanol, 15 : 1, as the
eluent). 1H NMR (DMSOꢀd6), δ: 4.10 (s, 3 H, C(2´)OMe);
8.87 (d, 1 H, H(6´), J = 2.6 Hz); 9.06 (d, 1 H, H(5), J = 2.7 Hz);
9.29 (d, 1 H, H(4´), J = 2.6 Hz); 9.66 (d, 1 H, H(7), J = 2.7 Hz);
13.65 (br.s, 1 H, N(3)H).
2ꢀChloroꢀ5ꢀnitronicotinamide (8). A solution of 2ꢀchloroꢀ5ꢀ
nitronicotinoyl chloride (5.0 g, 23 mmol) in acetonitrile (20 mL)
was slowly added dropwise with vigorous stirring to 25% aqueꢀ
ous ammonia (200 mL) at –20 °C. The reaction mixture was
allowed to stand until it warmed up to 0 °C (15 min) and immeꢀ
diately extracted with ethyl acetate (3×50 mL). The ethyl acꢀ
etate extracts were combined, treated with activated carbon,
dried with sodium sulfate, and concentrated in vacuo. The reꢀ
sulting pale yellow precipitate as large crystals was recrystallized
1
from ethanol. H NMR (DMSOꢀd6), δ: 3.39 (s, 3 H, N(3)Me);
3.90 (s, 3 H, C(2´)OMe); 8.82 (d, 1 H, H(6´), J = 2.7 Hz); 8.99
(d, 1 H, H(4´), J = 2.7 Hz); 9.04 (d, 1 H, H(5), J = 2.3 Hz); 9.24
(d, 1 H, H(7), J = 2.3 Hz).
2ꢀMethoxyꢀ5ꢀnitronicotinamide (9). A freshly prepared soꢀ
lution (10 mL) of sodium methoxide (0.12 g of sodium (5 mmol)
in 10 mL of methanol) was added to a solution of chloroꢀ
nicotinamide 8 (0.5 g, 2.5 mmol) in methanol (50 mL) at a
2ꢀ(2ꢀMethoxyꢀ5ꢀnitropyridinꢀ3ꢀyl)ꢀ3ꢀmethylꢀ6ꢀnitropyriꢀ
do[2,3ꢀd]pyrimidinꢀ4ꢀone (11). A suspension of pyridopyriꢀ

1914
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 8, August, 2005
Ryabova et al.
midinone 10 (0.11 g, 0.32 mmol), diiodomethane (0.08 mL,
1.28 mmol), and potassium carbonate (0.066 g, 0.48 mmol) in a
mixture of acetone (3 mL) and Nꢀmethylpyrrolidone (1 mL)
was kept for 24 h. Then the reaction mixture was filtered off,
concentrated to 2 mL, and diluted with water (15 mL). Pyridoꢀ
pyrimidinone 11 was filtered off and purified by column chroꢀ
matography (silica gel 60, hexane—acetone, 20 : 1, as the eluꢀ
4,6ꢀDichloropyrimidineꢀ5ꢀcarboxylic acid chloride15 (22).
Sulfuryl chloride (1.5 mL) and 2,2´ꢀazobis(2ꢀmethylpropioꢀ
nitrile) (Aldrich, USA) (100 mg) were added to a solution of
pyrimidine 21 (2.0 g, 11 mmol) in carbon tetrachloride (20 mL).
The reaction mixture was refluxed for 7 h and concentrated.
Acid chloride 22 was purified by column chromatography (silica
gel 60, dichloromethane as the eluent). After recrystallization
from petroleum ether (70/100), a white crystalline product was
obtained in a yield of 1.8 g. 1H NMR (DMSOꢀd6), δ: 8.92.
13C NMR (DMSOꢀd6), δ: 131.5 (C(5)); 156.5 (C(4) and C(6));
158.7 and 162.6 (C(2) and COCl).
1
ent). H NMR (DMSOꢀd6), δ: 3.38 (s, 3 H, N(3)Me); 4.10 (s,
3 H, C(2´)OMe); 8.83 (d, 1 H, H(6´), J = 2.6 Hz); 9.14 (d, 1 H,
H(5), J = 2.7 Hz); 9.33 (d, 1 H, H(4´), J = 2.6 Hz); 9.70 (d, 1 H,
H(7), J = 2.7 Hz).
4ꢀMethoxyꢀ5ꢀnitronicotinamide (12). A freshly prepared soꢀ
lution (10 mL) of sodium methoxide (sodium (0.11 g, 5 mmol)
in 10 mL of methanol) was added to a solution of nicotinamide
16 (1.0 g, 5 mmol) in methanol (50 mL) at room temperature.
The reaction mixture was allowed to stand for 3 h, diluted with
cold water (100 mL), and filtered. Methoxy derivative 12 was
obtained in a yield of 0.48 g. The filtrate was extracted with ethyl
acetate (3×30 mL), and the organic phase was dried with soꢀ
dium sulfate and concentrated to obtain an additional amount
of pyridine 12 (0.28 g). The products were combined and recrysꢀ
tallized from water.
4ꢀHydroxyꢀ5ꢀnitronicotinic acid (14). A solution of 4ꢀhydrꢀ
oxynicotinic acid (8.0 g, 58 mmol) in a mixture of concentrated
sulfuric acid (70 mL) and fuming nitric acid (16 mL) was kept at
100 °C for 10 h. Then the reaction mixture was cooled and
poured into crushed ice (400 g). The white precipitate of pyridine
14 that formed was filtered off and recrystallized from ethanol.
4ꢀChloroꢀ5ꢀnitronicotinoyl chloride (15). A suspension of pyꢀ
ridine 14 (5.7 g, 31 mmol) in a mixture of carbon tetrachloride
(70 mL), thionyl chloride (15 mL), and DMF (0.5 mL) was
heated to reflux for 9 h. The resulting solution was concentrated
and oily acid chloride 15 was used in the further synthesis withꢀ
out additional purification. MS, m/z (Irel (%)): 220 [M]+ (20).
C6H2Cl2N2O3.
4ꢀChloroꢀ5ꢀnitronicotinamide (16) and 4ꢀaminoꢀ5ꢀnitroꢀ
nicotinamide (17). A solution of acid chloride 15 (7.0 g, 32 mmol)
in acetonitrile (20 mL) was slowly added dropwise with vigorous
stirring to 25% aqueous ammonia (200 mL) at 0 °C. The reacꢀ
tion mixture was allowed to stand for 15 min and extracted with
ethyl acetate (5×50 mL). The ethyl acetate fractions were comꢀ
bined, treated with activated carbon, dried with sodium sulfate,
and concentrated in vacuo. The bright yellow solid residue was
crystallized from water, while nicotinamide 16 (3.8 g) was colꢀ
lected on a filter (the latter was then recrystallized from ethaꢀ
nol), and nicotinamide 17 precipitated from the aqueous filtrate
(0.9 g) as yellowꢀgreen needleꢀlike crystals.
4,6ꢀDichloropyrimidineꢀ5ꢀcarboxamide (23) was prepared
analogously to 4ꢀchloroꢀ5ꢀnitronicotinamide (16) and recrysꢀ
tallized from PriOH.
This study was financially supported by the Federal
Agency for Science and Innovations of the Russian Fedꢀ
eration (Contract No. 1/05) and the US Civilian Reꢀ
search and Development Foundation (CRDF, Grant
RUB2ꢀ2704ꢀMOꢀ05).
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2ꢀ(4ꢀHydroxyꢀ5ꢀnitropyridinꢀ3ꢀyl)ꢀ8ꢀnitropyrido[4,3ꢀd]pyriꢀ
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1
5 : 1, as the eluent). H NMR (DMSOꢀd6), δ: 15.70 (br.s, 1 H,
OH); 8.67, 9.13, 9.23, and 9.34 (all br.s, 1 H each, H(7), H(5),
H(6´), H(4´)).
4ꢀChloropyrimidineꢀ5ꢀcarboxamide (20). A solution of 5ꢀcarꢀ
bamoylꢀ4ꢀchloroꢀ6ꢀmethoxypyrimidine (24) (0.6 g, 3.2 mmol)
in ethanol (25 mL) was reduced with hydrogen in the presence
of palladium on carbon (10%, 0.03 g) and potassium hydroxide
(0.12 g, 1.6 mmol). After 3 h, the reaction mixture was filtered,
the filtrate was concentrated, and the residue was recrystallized
from a methanol—DMF mixture.
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Received June 15, 2005;
in revised form July 15, 2005