Synthesis of phthalimidines linked to quinoline derivatives by an amide bridge

Article abstract of DOI:10.1007/s11172-010-0199-8

The reactions of 3-acetoxy-2-acetyl(cyanoacetyl)aminoisoindolin-1-one (1) with o-tosylaminobenzaldehyde and o-mesylaminobenzaldehyde morpholinals lead to a mixture of 2-(2-aminoquinoline-3-carboxamido)-3-morpholinoisoindolin-1-one (3) and 3-cyanoquinolin-2(1H)-one (4). The reaction of 1 with 5-nitro-2- tosylaminobenzaldehyde morpholinal yields a mixture of 2-(2-amino-6- nitroquinoline-carboxamido)-3-morpholinoisoindolin-1-one and 3-cyano-6-nitroquinolin-2(1H)-one. 3-Acetoxy-2-(quinolino[2,3-d]-2-methyl-4- oxopyrimidin-3-yl)isoindolin-1-one (20) was prepared by the condensation of o-formylbenzoic acid and 2-aminoquinoline-3-carbohydrazide in Ac₂O. The structures of compounds 3, 4, and 20 were established by X-ray analysis.

Full text of DOI:10.1007/s11172-010-0199-8

Russian Chemical Bulletin, International Edition, Vol. 59, No. 5, pp. 1023—1030, May, 2010
1023
Synthesis of phthalimidines linked
to quinoline derivatives by an amide bridge
L. Yu. Ukhin,a K. Yu. Suponitskii,b T. N. Gribanova,a L. V. Belousova,a and E. N. Shepelenkoc
aResearch Institute of Physical and Organic Chemistry, Southern Federal University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4776. Eꢀmail: may@ipoc.rsu.ru
bA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: kira@xrlab.ineos.ac.ru
cSouthern Scientific Center, Russian Academy of Sciences,
41 ul. Chekhova, 344006 RostovꢀonꢀDon, Russian Federation.
Eꢀmail: dubon@ipoc.rsu.ru
The reactions of 3ꢀacetoxyꢀ2ꢀacetyl(cyanoacetyl)aminoisoindolinꢀ1ꢀone (1) with
oꢀtosylaminobenzaldehyde and oꢀmesylaminobenzaldehyde morpholinals lead to a mixture of
2ꢀ(2ꢀaminoquinolineꢀ3ꢀcarboxamido)ꢀ3ꢀmorpholinoisoindolinꢀ1ꢀone (3) and 3ꢀcyanoꢀ
quinolinꢀ2(1H)ꢀone (4). The reaction of 1 with 5ꢀnitroꢀ2ꢀtosylaminobenzaldehyde morpholinal
yields a mixture of 2ꢀ(2ꢀaminoꢀ6ꢀnitroquinolineꢀcarboxamido)ꢀ3ꢀmorpholinoisoindolinꢀ1ꢀone
and 3ꢀcyanoꢀ6ꢀnitroquinolinꢀ2(1H)ꢀone. 3ꢀAcetoxyꢀ2ꢀ(quinolino[2,3ꢀd]ꢀ2ꢀmethylꢀ4ꢀoxoꢀ
pyrimidinꢀ3ꢀyl)isoindolinꢀ1ꢀone (20) was prepared by the condensation of oꢀformylbenzoic
acid and 2ꢀaminoquinolineꢀ3ꢀcarbohydrazide in Ac2O. The structures of compounds 3, 4, and
20 were established by Xꢀray analysis.
Key words: 3ꢀacetoxyꢀ2ꢀacetyl(cyanoacetyl)aminoisoindolinꢀ1ꢀone; morpholinals of
oꢀtosylaminobenzaldehyde, oꢀmesylaminobenzaldehyde, 5ꢀnitroꢀ2ꢀtosylaminobenzaldehyde;
2ꢀ(2ꢀaminoquinolineꢀ3ꢀcarboxamido)ꢀ3ꢀmorpholinoisoindolinꢀ1ꢀone; 3ꢀcyanoquinolinꢀ
2(1H)ꢀone; 3ꢀcyanoꢀ6ꢀnitroquinolinꢀ2(1H)ꢀone; 3ꢀacetoxyꢀ2ꢀ(quinolino[2,3ꢀd]ꢀ2ꢀmethylꢀ
4ꢀoxopyrimidinꢀ3ꢀyl)isoindolinꢀ1ꢀone; quantum chemical study, Xꢀray diffraction analysis.
The term “twin drugs” accepted in modern medicinal
chemistry means physiologically active substances comꢀ
prising two pharmacophoric groups linked by a covalent
bridge.1 The activity of twin drugs can considerable
exceed that of their constituents. A typical example of the
“symmetrical twin drug” is the drug BDHP consisting of
two molecules of the calcium channel agonist nitrendipine
linked by a tetramethylene bridge. The hypotensive
activity of BDHP is about 10 times as high as that of
nitrendipine.1,2 Twin drugs can also be composed of two
different physiologically active substances. The examples
of such compounds comprising isoindoline derivatives and
3ꢀpiperazinoꢀ1,2ꢀbenzoisothiazole linked by different
bridges with activities of P2 dopamine and 5ꢀHT2 seroꢀ
tonin receptor antagonists are documented.3,4
of compound 1 with oꢀtosylaminobenzaldehyde morꢀ
pholinal7 (2) would result in 2ꢀaminoquinoline linked to
phthalimidine by the amide bridge. Recrystallization of
the reaction product from CH3CN gave a seemingly homoꢀ
geneous crystalline substance with a sharp melting point.
However, the Xꢀray diffraction study showed that it
was a mixture of two compounds, namely, the expected
2ꢀ(2ꢀaminoquinolineꢀ3ꢀcarboxamido)ꢀ3ꢀmorpholinoisoꢀ
indolinꢀ1ꢀone (3) and 3ꢀcyanoquinolinꢀ2(1H)ꢀone (4).
NꢀTosylmorpholine (5) that is formed in this variant of
the Friedlander synthesis6 was also isolated from the reacꢀ
tion mixture (Scheme 1).
Compounds 3 and 4 could easily be separated, beꢀ
cause the former is completely insoluble in acetone and
the latter is insoluble in CHCl3.
Recently,5 we have described the synthesis of phthalꢀ
imidines from oꢀformylbenzoic acid acylhydrazides,
including 3ꢀacetoxyꢀ2ꢀacetyl(cyanoacetyl)aminoisoꢀ
indolinꢀ2ꢀone (1). On the basis of a new modification of
the Friedlander synthesis,6 we expected that the reaction
Presumably, the first step of the reaction is the couꢀ
pling of 1 with 2 with elimination of two molecules of
morpholine and the formation of compound 6 (Scheme 2),
which may exist as two geometric isomers, Z and E, which
in turn may exist as several conformers.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 1000—1007, May, 2010.
1066ꢀ5285/10/5905ꢀ1023 © 2010 Springer Science+Business Media, Inc.

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Ukhin et al.
Scheme 1
Scheme 2

Synthesis of quinolinecarboxamidophthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1025
We performed a quantum chemical study of thermoꢀ
dynamical characteristics of the reaction of compound 1
with 2. The calculations (B3LYP/3ꢀ21G*) suggested8,9
the possibility of the formation of the respective conformꢀ
ers 6a (in Zꢀisomer) and 6b (in Eꢀisomer) (Fig. 1), which
are the most probable intermediates of compounds 3 and
4 whose putative mechanisms are outlined in Scheme 2.
In conformer 6a, the tosylamino fragment is oriented
relative to the C≡N bond in such a manner that the sysꢀ
tem becomes structurally prepared to further transformaꢀ
tion 6a→3 (proton transfer to the nitrogen center and
the formation of a new NC bond). In conformer 6b, the
tosylamino fragment is oriented relative to the C=O bond
in such a manner that the system is structurally prepared
to transformation 6b→4 (proton transfer to the oxygen
center and the formation of a new NC bond). The calculꢀ
C
O
C
C
C
O
C
C
C
...
ated noncovalent distances N C in conformers 6a and
C
O
C
N
O
6b (3.24 and 3.38 Å respectively) are close to the sum of
the van der Waals atomic radii of carbon and nitrogen
(3.31 Å),10 therefore the attractive interaction between
the oppositely charged atoms is possible. At the same
time, the Bader topological analysis of distribution of
total electron density (AIMꢀanalysis11) in conformer 6a
allows us to conclude the bonding between an oxygen
atom of the tosyl group and the sp2ꢀhybridized carbon
atom of the C=C bond bearing two electronꢀwithdrawing
substituents (Fig. 1). Thus, the approaching of C and N
atoms can be regarded as compulsive. Conformation 6b
is additionally stabilized by the intramolecular hydrogen
bond between the amino group and the carbonyl fragꢀ
ment. According to the calculations conformer 6b is only
by 1.8 kcal mol–1 energetically more stable then conformer
6a. Both processes are exothermic: the energetic effect of
the reaction resulting in compound 3 is 63.9 kcal mol–1,
the energetic effect of the second reaction is almost twice
as low (34.5 kcal mol–1). However, the yield of cyanoꢀ
quinolinone 4 appeared to be considerably higher than
the yield of compound 3, which suggests importance of
other factors in addition to the energetic one.
C
N
C
C
C
C
N
O
C
C
C
C
3.243
C
C
C
C
2.782
O
C
N
C
C
C
C
C
S
C
O
6a
C
C
C
O
C
O
C
C
C
C
N
O
We also performed the analogous reaction with
oꢀmesylaminobenzaldehyde morpholinal (11). Compound
3 was the major product with quinolinone 4 as the minor
byꢀproduct (Scheme 3). Starting from phthalimidine 1
and 5ꢀnitroꢀ2ꢀtosylaminobenzaldehyde morpholinal 12
(Refs. 12, 13) we obtained 2ꢀ(2ꢀaminoꢀ6ꢀnitroquinolineꢀ
3ꢀcarboxamido)ꢀ3ꢀmorpholinoisoindolinꢀ1ꢀone (13) and
3ꢀcyanoꢀ6ꢀnitroquinolinꢀ2(1H)ꢀone (14) (Scheme 3).
The calculations for the reaction with the mesyl
derivative also indicate the possibility of the formation
of conformers 15a (in Zꢀisomer) and 15b (in Eꢀisomer)
N
C
C
O
C
N
C
C
O
C
3.377
C
1.810
C
C
C
C
N
C
O
C
S
...
characterized by shortened distance N C (Fig. 2). In
C
C
conformer 15a, the mesylamino fragment is oriented relaꢀ
tive to the C≡N bond in such a manner that the system
becomes structurally prepared to further transformation
15a→3, while in conformer 15b the mesylamino fragment
is oriented relative to the C=O in such a manner that the
system is structurally prepared to transformation 15b→4.
C
O
C
C
C
C
...
6b
The calculated noncovalent distances N C in conformers
Fig. 1. The structures of conformers 6a and 6b as calculated by
B3LYP/3ꢀ21G* method. The bond lengths are given in Å.
15a and 15b (2.847 and 2.940 Å, respectively) are considꢀ
erably shortened than those in the tosyl derivative and are

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Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Ukhin et al.
considerably smaller than the sum of the van der Waals
atomic radii of carbon and nitrogen. Both conformers are
additionally stabilized by a hydrogen bond, which deterꢀ
mines the direction of the further proton migration. The
hydrogen bond is rather strong (1.76 Å) in compound 15b
and considerably weaker (2.24 Å) in compound 15a. Conꢀ
former 15a is by 15.3 kcal mol–1 more energetically favorꢀ
able than conformer 15b. According to our calculations,
both processes are exothermic. The energetic effect of the
reaction resulting in compound 3 is 56.8 kcal mol–1, the
energetic effect of the second reaction is 40.1 kcal mol–1.
Theoretically, an alternative synthesis of a derivative
of compound 3 was possible, viz., by cyclization of hydraꢀ
zone 18 prepared from oꢀformylbenzoic acid 16 and
2ꢀaminoquinolinꢀ3ꢀcarbohydrazide 17 (see Ref. 6) in
acetic anhydride (Scheme 4). However, in this reaction
instead of the expected compound 19 the product of furꢀ
ther condensation 20 was isolated (Scheme 4), whose
structure was established by Xꢀray analysis.
Scheme 3
The general view of molecule 4 is shown in Fig. 3.
Molecule 4 is planar (the rootꢀmeanꢀsquare deviation is
0.015 Å). In the crystal structure, the molecules form the
centrosymmetric dimers owing to the rather strong Hꢀbond
N(1)—H(1N)...O(1) (H...O 1.92 Å, N...O 2.799(3) Å,
N—H...N 165°).
Molecule 3 is outlined in Fig. 4. The quinoline and
phthalimidine fragments are planar (the rootꢀmeanꢀsquare
deviations are 0.037 and 0.023 Å, respectively). The cenꢀ
tral amide fragment NHCO is rotated relative to both the
quinoline (40.57(9)°) and the phthalimidine (77.5(2)°)
rings. In the former case, it is connected with the steric
repulsion of the hydrogen atoms at N(3) and N(15) along
with the presence of a weak intramolecular hydrogen bond
between the carbonyl group C(13)=O(3) and the amino
group N(5)—H(5)N(2)...O(3) (H...O 2.12 Å, N...O
C
O
C
C
C
C
O
O
C
C
C
N
C
O
N
C
C
C
C
C
O
C
N
C
C
C
C
C
C
N
C
N
O
C
N
O
O
C
C
C
O
2.236
C
C
C
C
C
C
O
2.847
N
C
C
C
C
O
O
C
C
2.940
C
C
1.757
S
C
S
C
C
O
C
C
N
C
O
15b
Fig. 2. The structures of conformers 15a and 15b as calculated by B3LYP/3ꢀ21G* method. The bond lengths are given in Å.
15a

Synthesis of quinolinecarboxamidophthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1027
Scheme 4
characterized by the flattened envelope conformation, the
nitrogen atom N(4) deviates from the ring plane (includꢀ
ing the benzene ring atoms) by 0.148(2) Å. The mutual
orientation of the cyclic fragments is close to perpendicuꢀ
lar (the interplanar angle is 79.48(2)°), it is caused, as in
molecule 4, by the steric repulsion of the orthoꢀsubstituꢀ
2.808(4) Å, N—H...N 132°). The structure of the fragꢀ
ment phthalimidine—NHCO can be explained by the
steric repulsion of the substituents at N(1) and N(8) from
the nearest atoms of the central fragment NHCO and,
probably, by the anomeric interaction between of the loneꢀ
electron pair of the N(2) atom and the N(3)—C(13) bond
antibonding orbital.
In the crystal, the carbonyl group C(8)=O(2) takes
part in the intermolecular hydrogen bonding with the
hydrogen atom of the amide group N(3)—H(3)N...O(2)
(H...O 1.97 Å, N...O 2.869(3) Å, N—H...N 174°) along
with the formation of the centrosymmetric dimers that link
in the ribbons by a weaker Hꢀbond N(5)—H(5)N(1)...N(4)
(H...N 2.15 Å, N...N 3.052(4) Å, N—H...N 177°), located
along the crystallographic axis c (Fig. 2, b).
The general view of molecule 20 is shown in Fig. 5.
The tricyclic quinolineꢀoxopyrimidine fragment has a plaꢀ
nar structure (the rootꢀmeanꢀsquare is 0.061 Å), while
the fiveꢀmembered ring of the phthalimidine fragment is
a
O(1)
C(10)
C(11)
C(12)
N(1)
C(9)
C(1)
C(2)
C(17)
C(16)
C(3)
C(4)
C(18)
N(3)
C(15)
C(13)
C(19)
N(2)
C(8)
C(5)
C(6)
C(7)
C(14)
C(20)
C(21)
N(4)
O(2)
C(22)
O(3)
N(5)
b
C(10)
N(2)
a
C(3)
c
C(5)
0
C(2)
C(6)
C(4)
N(1)
C(1)
O(1)
C(8)
C(7)
C(9)
b
Fig. 4. The molecular (a) and crystal (b) structure of compound 3
with displacement of atoms by ellipsoids drawn at the 50% probꢀ
ability level.
Fig. 3. The general view of molecule 4 with displacement of
atoms by ellipsoids drawn at the 50% probability level.

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Ukhin et al.
compound 3 as a yellow substance, m.p. 245—247 °C. Found:
N, 17.62%. C22H21N5O3. Calculated: N, 17.36%.
C(23)
C(22)
The acetonitrile filtrate was concentrated, the residue
was extracted with boiling isooctane to give Nꢀtosylmorpholine
(5) (Ref. 6) as a colorless substance, m.p. 147—148 °C (Ref. 6:
m.p. 147—150 °C).
O(4)
O(3)
N(2)
C(11)
C(12)
C(20)
C(19)
N(1)
IR of compound 4, ν/cm–1: 3456 (NH), 2229 (C≡N), 1662
(CO), 1620, 1564, 1490 (arom.).
C(18)
C(2)
C(1)
C(9)
C(17)
C(3)
C(4)
N(3)
N(4)
C(8)
C(7)
IR of compound 3, ν/cm–1: 3489, 3375, 3166 (NH), 1722,
1666 (NH), 1615, 1584, 1565 (arom.). 1H NMR (DMSOꢀd6) of
compound 3, δ: 2.69 (m, 2 H, NCH2); 2.83 (m, 2 H, NCH2);
3.59 (m, 4 H, OCH2); 5.61 (s, 1 H, NH); 6.92 (s, 2 H, NH2);
7.20 (t, 1 H, NHarom, J = 7.2 Hz); 7.40—7.80 (m, 7 H, NHarom);
8.59 (s, 1 H, N(4)Hquinoline).
C(6)
C(5)
C(13)
C(10)
C(16)
C(14)
C(15)
O(1)
O(2)
Fig. 5. The general view of molecule 20 with displacement of
atoms by ellipsoids drawn at the 50% probability level.
A. A mixture of compound 1 (0.32 g, 1 mmol) and
oꢀmesylaminobenzaldehyde morpholinal (11) (see Ref. 16)
(0.36 g, 1 mmol) in 5 mL of MeCN was refluxed for 25 min.
During this time the red solution became almost colorless and a
precipitate formed. The reaction mixture was cooled with ice,
the precipitate was filtered off, washed with cold MeCN, and
dried. The precipitate (132 mg) was refluxed with 5 mL of
acetone, cooled with ice, filtered off, washed with acetone, and
dried to obtain 90 mg (22 %) of compound 3, which was identified
based on the IRꢀspecrtum, melting point and the absence of a
decrease in the melting point when mixed with the authentic
sample.
The acetone filtrate was concentrated, the residue was
triturated with 3 mL of CHCl3, filtered off, washed with CHCl3,
and dried to obtain 5 mg (3%) of compound 4, which was
identified based on the IRꢀspecrtum, melting point and the
absence of a decrease in the melting point when mixed with
the authentic sample.
2ꢀ(2ꢀAminoꢀ6ꢀnitroquinolineꢀ3ꢀcarboxamido)ꢀ3ꢀmorpholinoꢀ
isoindolinꢀ1ꢀone (13) and 3ꢀcyanoꢀ6ꢀnitroquinolinꢀ2(1H)ꢀone
(14). A mixture of compound 1 (0.32 g, 1 mmol) and the complex
of 5ꢀnitroꢀ2ꢀtosylaminobenzaldehyde morpholinal (12) (see
Refs 12, 13) with CCl4 (0.65 g, 1.03 mmol) in 6 mL of MeCN
was refluxed for 1 hour, cooled with ice, with trituration by a
glass rod. The precipitate was filtered off, washed with cold
MeCN, and dried to obtain 0.185 g (41%) of almost pure
compound 13 as colorless crystals, m.p. 235—240 °C (from
MeCN).
ents of the rings. It should be mentioned that the structure
of the fragment phthalimidine—NRCO appeared to be
almost the same in molecules 3, 20, and in 1, which was
described by us earlier.5 The N—N bonds lengths are also
identical (in 3, N(2)—N(3) 1.387(3) Å; in 20, N(3)—N(4)
1.389(2) Å; in 1 (see. Ref. 5), N(1)—N(2) 1.390(3) Å)
and close to the average value of the single N—N bond
1.401 Å (see Ref. 14). A slight difference in the structure
of the fiveꢀmember ring and the rotation of the NRCO
group could be influenced by the crystal packing effect.
The crystal structure of compound 20 is stabilized by
the van der Waals and the weak C—H...O interactions,
and also by the weak stacking interaction between the
tricyclic fragments (the interplanar spacing is 3.325(2) Å,
the shortest interaction N(1)...N(5) is 3.406(2) Å), which
leads to formation of centrosymmetric dimers.
Experimental
The IR spectra were recorded on a Varian Excalibur 3100
FTꢀIR spectrometer using an attenuated total internal reflectꢀ
ance. The 1H NMR spectra were recorded on a Varian UNITYꢀ300
spectrometer. The mass spectra were obtained on an Agilrut 1200
Bruker Daltonic NicrOTOFꢀQ instrument with the direct inlet
in the negative/positive ions mode that permits detecting of the
molecular weight from the peak with m/z of the quasiꢀmolecular
ion [M – H]–/[M + H]+.
Compound 13. Found (%): C, 58.72; H, 4.65; N, 18.87.
C22H20N6O5. Calculated (%): C, 58.93; H, 4.50; N, 18.74.
IR, ν/cm–1: 3414, 3294, 3152 (NH), 1718, 1672 (CO), 1645,
1
1615, 1573 (arom.), 1521, 1334 (NO2). H NMR (DMSOꢀd6),
δ: 2.70 (m, 2 H, NCH2); 2.84 (m, 2 H, NCH2); 3.60 (m, 4 H,
OCH2); 5.60 (s, 1 H, CH); 7.40—7.62 (m, 5 H, NH2, NHarom);
2ꢀ(2ꢀAminoquinolineꢀ3ꢀcarboxamido)ꢀ3ꢀmorpholinoꢀ
isoindolinꢀ1ꢀone (3) and 3ꢀcyanoquinolinꢀ2(1H)ꢀone (4). A.
A mixture of 3ꢀacetoxyꢀ2ꢀacetyl(cyanoacetyl)aminoisoindolinꢀ
1ꢀone (1) (Ref. 5) (0.32 g, 1 mmol) and oꢀtosylaminobenzꢀ
aldehyde morpholinal 2 (Ref. 7) (0.43 g, 1 mmol) in 6 mL of
MeCN was refluxed for 1 h, cooled with ice, the precipitate that
formed was filtered off, washed with a small amount of cold
MeCN and dried. The obtained crystalline product (90 mg)
represented a mixture of compounds 3 and 4. It was refluxed
with 2 mL of CHCl3, cooled, the precipitate was filtered off,
washed with 1 mL of CHCl3, and petroleum ether and dried to
obtain 44 mg (26 %) of quinolone 4 as a colorless substance,
m.p. 305 °C (Ref. 15: m.p. >300 °C). The chloroform filtrate
was concentrated, the residue was triturated with acetone, filtered
off, washed with acetone and dried to obtain 30 mg (7.5%) of
7.69 (t, 1 H, NHarom, J = 7.5 Hz); 7.77 (d, 1 H, NHarom
,
J = 7.5 Hz); 8.28 (dd, 1 H, C(7)H, J = 9.3, 4J = 2.4 Hz); 8.75
(d, 1 H, C(5')H, J = 2.4 Hz); 8.78 (s, 1 H, C(4')H); 11.27 (s,
1 H, NH). MS, m/z: found 447.1103 [M – H]–; C22H20N6O5;
calculated: [M – H]– = 447.429.
3
The acetonitrile filtrate of compound 13 was concentrated,
the residue was triturated with CHCl3, the precipitate was filꢀ
tered off, washed with CHCl3 and petroleum ether, and dried to
obtain 44 mg (20%) of quinolone 14 as a colorless substance,
sublimation temperature was >270 °C.
Compound 14. Found (%): C, 56.52; H, 2.49; N, 19.78.
C10H5N3O3. Calculated (%): C, 56.61; H, 2.38; N, 19.81.
IR, ν/cm–1: 2235 (CN), 1660 (CO), 1625, 1568 (arom.), 1531,

Synthesis of quinolinecarboxamidophthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
1029
1
1343 (NO2). H NMR (DMSOꢀd6), δ: 7.48 (d, 1 H, N(8)H,
latter was dissolved in a small amount of MeOH and added to
the iceꢀcooled supernatant liquid with trituration by a glass rod.
When the solidification was complete, the solid was filtered off,
washed with 50% EtOH, and dried to obtain 0.26 g (65%) of
compound 20 as a colorless substance, m.p. 202—205 °C (from
a mixture of toluene—isooctane). The analytically pure product
was prepared by recrystallization from a mixture of toluene
(7.5 mL) and isooctane (2.5 mL). The structure of the product
was established by Xꢀray diffraction analysis. Found: N, 14.28%.
C22H16N4O4. Calculated: N, 13.99%. IR, ν/cm–1: 1739, 1689
J = 9.3 Hz); 8.35 (br d, 1 H, N(7)H); 8.78 (s, 1 H, N(5)H); 8.89
(s, 1 H, N(4)H); 12.97 (s, 1 H, NH). MS, m/z: found 214.0163
[M – H]–; C10H5N3O3; calculated: [M – H]– = 214.159.
oꢀFormylbenzoic acid 2ꢀaminoquinolineꢀ3ꢀcarbonylhydrazone
(18) and 3ꢀacetoxyꢀ2ꢀ(quinolino[2,3ꢀd]ꢀ2ꢀmethylꢀ4ꢀoxopyriꢀ
midinꢀ3ꢀyl)isoindolinꢀ1ꢀone (20). A. Hydrazone 18 was prepared
according to the general method described earlier,5 viz., by
mixing hot solutions of oꢀformylbenzoic acid 16 (0.3 g, 2 mmol)
in 5 mL of PriOH and hydrazide 17 (see Ref. 6) (0.404 g,
2 mmol) in 12 mL of PriOH. The yellow precipitate of compound
18 separated after a short induction period was cooled to room
temperature, filtered off, washed with PriOH and petroleum
ether, dried, and used in the synthesis of compound 20 without
further purification. The yield of compound 20 was 0.66 g
(quantitative), m.p. >240 °C (decomp.). Found: N, 16.41%.
C18H14N4O3. Calculated: N, 16.76%. IR, ν/cm–1: 3230 br (NH,
OH), 1697, 1659 (CO), 1563, 1535, 1504 (arom.).
1
(NH), 1605, 1597, 1562, 1492 (arom.). H NMR (CDCl3), δ:
2.19 (s, 3 H, NHMe); 2.70 (s, 3 H, Me); 7.40 (s, 1 H, NH);
7.45—8.10 (m, 7 H, NHarom); 8.24 (d, 1 H, N(7)H, J = 8.6 Hz);
9.17 (s, 1 H, C(5')H).
XꢀRay diffraction study of compounds 4, 3 and 20. The single
crystals of compounds 4, 3, and 20 suitable for Xꢀray diffraction
study were grown by slow concentration of their solutions
in MeCN. The experimental intensities of reflections were
measured using a SMART 1000 CCD and a SMART APEX2
CCD diffractometers (λ(MoꢀKα) = 0.71073 Å, graphite monoꢀ
chromator, ωꢀscanning technique). The initial arrays of measured
intensities were processed using the SAINT Plus,17 SADABS,18
A. Compound 18 (0.33 g, 1 mmol) was heated with Ac2O
(2 mL) until dissolution and the solution was refluxed for 3 min,
and cooled. Then MeOH (3 mL) and H2O (20 mL) were added.
The aqueous layer was decanted from the sedimented oil, the
Table 1. The crystal data and the parameters Xꢀray study for compounds 4, 3 and 20
Parameter
4
3
20
Molecular formula
Molecular weight
Crystal color
Crystal shape
Crystal dimensions, mm
T/К
Crystal system
Space group
a/Å
b/Å
c/Å
α/deg
C10H6N2O
170.17
C22H21N5O3
403.44
C22H16N4O4
400.39
Yellow
Prisms
0.20×0.15×0.15
120(2)
Triclinic
P1
Light yellow
Plates
0.25×0.10×0.02
0.20×0.10×0.02
296(2)
120(2)
Monoclinic
P21/c
3.900(2)
11.553(6)
17.841(10)
90
91.036(13)
90
803.8(8)
4
P21/n
8.969(2)
19.817(4)
12.015(3)
90
109.804(4)
90
2009.3(8)
4
6.8709(7)
8.4846(9)
16.157(2)
94.491(2)
94.512(2)
99.064(2)
923.3(2)
2
β/deg
γ/deg
V/Å3
Z
dcalc/g cm–3
1.406
0.095
352
1.334
0.092
848
1.440
0.102
416
Absorption coefficient μ/mm–1
F(000)
Scaning interval by θ/deg
Number of measured reflections
Number of independent reflections
Rint
Number of refined parameters
Number of reflections with I ≥ 2σ(I)
Fullness of reflections array (%)
GOOF
2.10—29.00
9548
2129
0.0973
118
2.06—27.00
18464
4342
0.0986
271
2.44—28.00
9563
4427
0.0218
273
993
99.3
0.978
2219
98.9
1.029
3426
99.4
1.012
Convergence of refinement(R1(F))a
of reflections with I ≥ 2σ(I)
Convergence of refinement
of all reflections (wR2(F2)b
Residual electron density (min/max), e/A3
0.0529
0.0586
0.0555
0.1196
0.1819
0.1127
0.154/–0.174
0.282/–0.283
0.362/–0.252
2 2
a R1 = ∑|Fo – |Fc||/∑(Fo); b wR2 = (∑[w(Fo2 – Fc ) ]/∑[w(Fo2)2]1/2
.

1030
Russ.Chem.Bull., Int.Ed., Vol. 59, No. 5, May, 2010
Ukhin et al.
APEX219 programs. The structures was solved by the direct
method and refined by the fullꢀmatrix leastꢀsquares method with
anisotropic displacement parameters for nonhydrogen atoms
Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox,
H. P. Hratchian, J. B. Cross, C. Adamo, J. Jaramillo,
R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin,
R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko,
P. Piskorz, I. Komaromi, R. L. Martin, D. J. Fox, T. Keith,
M. A. AlꢀLaham, C. Y. Peng, A. Nanayakkara, M. Challacombe,
P. M. W. Gill, B. Johnson, W. Chen, M. W. Wong, C. Gonzalez,
J. A. Pople, Gaussian 03, Revision B.03, Pittsburgh PA,
Gaussian Inc., 2003.
based on F2 . The hydrogen atoms were positioned at geoꢀ
hkl
metrically calculated positions, except for the hydrogen atoms
at the nitrogen atoms, whose position was located in the
difference electron density synthesis and then normalized to
the distance of 0.90 Å. All hydrogen atoms were refined using a
riding model (Uiso(H) = nUeq(C,N), where n = 1.5 for the carbon
atoms of the methyl groups, n = 1.2 for the other C and N atoms).
The processing and the refinement of the structures was perꢀ
formed using the SHELXTL program.20 The crystallographic data
and parameters of Xꢀray diffraction study are given in Table 1.
The authors are grateful to O. V. Filonova for recording
the mass spectra of compounds 13 and 14.
9. J. B. Foresman, E. Frisch, Exploring Chemistry with Elecꢀ
tronic Structure Methods (2nd ed.), Gaussian Inc., Pittsburg,
1996.
This study was financially supported by the Council
for Grants at the President of the Russian Federation (the
Program for the State Support of Leading Scientific
Schools, Grants NShꢀ363.2008.3 and NShꢀ3019.2008.3).
10. R. S. Royland, R. Taylor, J. Phys. Chem., 1996, 100, 7384.
11. R. F. W. Bader, Atoms in Molecules. A Quantum Theory,
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12. L. Yu. Ukhin, Zh. I. Orlova, Mendeleev Commun., 1995,
234.
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Orlova, T. N. Gribanova, O. V. Shishkin, Z. Kristallogr.,
1998, 213, 296.
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Received October 15, 2009;
in revised form February 11, 2010