A new synthesis of phthalimidines

Article abstract of DOI:10.1007/s11172-009-0347-1

A new synthesis of phthalimidines is described. 3-Acyloxy-2-aryl- and 2-acylamino-3-acyloxyphthalimidines were prepared by the reaction of 3-arylaminophthalides or o-formylbenzoic acid acylhydrazones with acetic or propionic anhydrides. Their reactions wi

Full text of DOI:10.1007/s11172-009-0347-1

Russian Chemical Bulletin, International Edition, Vol. 58, No. 12, pp. 2478—2487, December, 2009
2478
A new synthesis of phthalimidines
L. Yu. Ukhin,a K. Yu. Suponitsky,b L. V. Belousova,a and Zh. I. Orlovaa
aResearch Institute of Physical and Organic Chemistry,
Southern Federal University,
194/2 prosp. Stachki, 344090 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4776. Еꢀmail: 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. Еꢀmail: kira@xrlab.ineos.ac.ru
A new synthesis of phthalimidines is described. 3ꢀAcyloxyꢀ2ꢀarylꢀ and 2ꢀacylaminoꢀ
3ꢀacyloxyphthalimidines were prepared by the reaction of 3ꢀarylaminophthalides or
oꢀformylbenzoic acid acylhydrazones with acetic or propionic anhydrides. Their reactions with
Oꢀ, Nꢀ, Sꢀ, and Cꢀnucleophiles were studied. The structure of 2ꢀacetyl(cyanoacetyl)aminoꢀ
3ꢀacetoxyindolinꢀ1ꢀone was confirmed by Xꢀray diffraction analysis.
Key words: оꢀformylbenzoic acid, 3ꢀarylaminophthalides, oꢀformylbenzoic acid acylꢀ
hydrazones, acetic and propionic anhydrides, 3ꢀacyloxyꢀ2ꢀarylꢀphthalimidines, 2ꢀacylꢀ
aminoꢀ3ꢀacyloxyphthalimidines, Xꢀray diffraction analysis.
Phthalimidines descibed for the fist time in 1884 (see
(1050—1096 cm–1) and symmetric (847—900 cm–1
С—О—С vibrations in the IR spectra.6
)
Ref. 1) have recently attracted increasing attention of
investigators. The essential role in revival of interest in
these compounds is the fact that compounds that possess
various kinds of biological activity2—4 are found among
them. One of the first method of the synthesis of phthalꢀ
imidines was the reaction of phthalide (3Hꢀ1,3ꢀdihydroꢀ
isobenzofuranꢀ1ꢀone) with ammonia or primary amines
that led to replacement of the phthalide oxygen atom by
the nitrogen one.1,5
The hydroxy analog of phthalide, i.e., oꢀformylꢀ
benzoic acid, which undergoes ringꢀchain tautomerism,
reacts with amines quite differently. It exists as cyclic
3ꢀhydroxyphthalide form 1b in the solid state, in aqueous6
and DMSO7 solutions (Scheme 1). It affords 3ꢀarylaminoꢀ
phthalides 2 as a result of reactions with primary amines,
i.e., the hydroxyl group is replaced by the amino group,
the initial phthalide structure being retained.6,8 Phthalides
are easily identified due to intense absorption bands of
the carbonyl groups (1715—1750 cm–1), antisymmetric
At the same time, reaction of оꢀformylbenzoic acid
with of anthranilohydrazide affords normal hydrazone,
i.e., derivative of the open tautomeric form 1а (see Ref. 9).
In the present study, we report a new synthesis of
phthalimidines from aminophthalides and hydrazones.
It was found that heating of 3ꢀarylaminophthalides 2
in acetic or propionic anhydrides (3а,b) leads to recycliꢀ
zation with formation of 3ꢀacyloxyꢀ2ꢀarylꢀphthalimidines
6 or 7. A putative mechanism is given in Scheme 2. It
includes Nꢀacylation (structure 4), addition of a carbꢀ
oxylic acid to the С—О bond followed by phthalide ring
opening (5) and recyclization followed by elimination
of the acid to afford phthalimidines 6.
The reaction proceeds smoothly only if the anhydride
contains some acid, which agrees with the scheme.
It was noted6 that the reactivity of the cyclic form
of oꢀformylbenzoic acid is comparable to that of acid
chlorides and anhydrides. 3ꢀAcyloxyphthalimidines 6
are also highly reactive in the reactions with Оꢀ, Nꢀ and
Sꢀnucleophiles. They can be hydrolyzed upon heating in
aqueous acid media, therefore, dry and aprotic, where
possible, solvents should be used for recrystallization. Our
attempt of recrystallization of phthalimidine 6f from
aqueous НОАс led to the corresponding hydroxy derivaꢀ
tive 7 (Scheme 3). Compound 6а was converted into
hydroxy derivative 9 under shortꢀterm heating in conꢀ
centrated HCl. Obviously, the reaction proceeds via
Scheme 1
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 12, pp. 2399—2407, December, 2009.
1066ꢀ5285/09/5812ꢀ2478 © 2009 Springer Science+Business Media, Inc.

A new synthesis of phthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2479
Scheme 2
2, 6: R = Ph (2a, 6a,i), 2ꢀClC6H4 (b), 2,4ꢀCl C6H3 (c), 3ꢀO2NC6H4 (d), 2ꢀNCC6H4 (e), 4ꢀCO2HC6H4 (f),
(g),
2
N
(h). 3, 6: R´ = Me (3a, 6a—g), Et (3b, 6h,i)
hydrolytically unstable intermediate chlorolactam 8
(see Ref 10). Hydroxy derivative 9 was also obtained in
the reaction of 6а with hydrazine hydrate. Refluxing for
1 h of compound 6а with propargyl alcohol affords
propargyl derivative 10 in almost quantitative yield. With
boiling morpholine compound 6а reacts smoothly as well
with formation of morpholine derivative 11а. The reacꢀ
tion of 6а with 2ꢀsulfanylbenzoxazole 12 proceeds almost
instantly when the mixture was heated to 150 °С (see
Scheme 3).
It would be logical to use in such reactions acylꢀ
immonium salts as electrophiles, which could be proꢀ
duced upon reaction of hydroxy lactams (in our case, 7 or
9) with strong protic acids or Lewis acids,11 such as SbCl5,
HClO4, BF3•OEt2, hexachlorophosphoric acid, and trityl
perchlorate. Of these salts, only perchlorates were found
to be almost insensitive to hydrolysis. Only two such
compounds could be isolated in the crystalline form.10
It turned out that antimony pentachloride was the most
convenient reagent for the synthesis of acylimmonium
salt. However, toxicity and hydrolytic unstability of both
the reagent and acylimmonium hexachloroantimonates
However, it was of interest to carry out such a reacꢀ
tions with Сꢀnucleophiles.
Scheme 3
X = H (a), NO2 (b)

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009
Ukhin et al.
Scheme 5
make these compounds inconvenient for carrying out the
reactions.
We supposed that trifluoroacetoxyphthalimidine deꢀ
rivatives can be used for this purpose (even if these
compounds are not acylimmonium salts but rather highly
polarized trifluoroacetates).
It was found that compounds obtained from acetoxyꢀ
phthalimidines 6 in the presence of CF3COOH are reacꢀ
tive electrophilic agents. We chose 2,6ꢀdiꢀtertꢀbutylphenol
as a Cꢀnucleophile. Heterocycles containing 3,5ꢀdiꢀ
tertꢀbutylꢀ4ꢀhydroxyphenyl substituents are potential
bioantioxidants. Such derivatives of isoquinoline12—14 and
indazole15, which turned out to be low toxic and more
effective inhibitors of lipid peroxidation than ionol and
natural αꢀtocopherols, were described by us earlier.
Phthalimidines containing 3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyꢀ
phenyl substituents 15a,b,c were obtained by heating of
compounds 6a,d,f, respectively, with 2,6ꢀdiꢀtertꢀbutylꢀ
phenol 14 in the presence of CF3COOH (Scheme 4).
The possible pathways of their reaction with Ac2O are
presented in Scheme 6. The formation of mixed anhyꢀ
dride 20 (path a)16а followed by its intramolecular addiꢀ
tion to the С=N bond could be the first step of the reacꢀ
tion. An alternative possibility (path b) supposes the addiꢀ
tion of Ac2O to the C=N bond to produce compound 21
(see Ref. 16b) followed by cyclization with elimination of
HOAc. In the course of reaction, the exocyclic NH group
can also undergo acylation.
The structure of compound 22a,b was unambiguously
established by IR and Н NMR spectroscopy and mass
Scheme 4
1
spectrometry. The situation with compound 22с was far
more complicated. The total number of protons in the
1Н NMR spectrum corresponded to the formula 22с, howꢀ
ever, doubling of signals, which could be considered as a
result of the presence of a mixture of two isomers, was
observed. Four signals, viz., at δ 2.21, 2.24, 2.33, and
2.66, corresponded to six protons of two methyl groups,
and the pattern typical of the AB system (doublets at
δ 3.77 and 4.00, J = 19.5 Hz (~40%) and a singlet at δ 4.23
(~60%)) corresponded to two protons of the methylene
group (Table 1).
The molecular weight of compound 22с is 315, howꢀ
ever, its mass spectrum contains a peak with a maximum
m/z of 273. It should also be noted that we faced a
rare case where elemental analysis cannot help with soluꢀ
tion of the problem. The percentage of С and Н in the
compound containing an acetyl group or a hydrogen atom
at the nitrogen atom coincided to within one tenth of
percent, and the difference in the percentage of N was
only 2% (13.33 and 15.38, respectively). Although the
results of the analysis (percentage of nitrogen) were in
favor of the structure 22с, this structure was unambiguꢀ
ously established by Xꢀray diffraction analysis. The
abnormal character of the mass spectrum of compound
22с can be explained by the electronꢀimpactꢀinduced
elimination of the acetyl group. The mass spectrum shows
a peak with m/z 43 with 100% intensity, which correꢀ
sponds to the mass of the acetyl group.
i. CF3COOH, Δ
The feasibility of using hetrocyclic nucleophiles in
this reaction was shown by the example of indole 16
(Scheme 5).
Starting from oꢀformylbenzoic acid and acylhydrazines
18а—с, acylhydrazones 19а—с were obtained in high
yields upon mixing equimolar amounts of the reactants
in hot PriOH (Scheme 6). They react with Ac2O similarly
to arylaminophthalides 2. In contrast to the IR spectra of
phthalides, the absorption bands of the carbonyl groups in
The overall view of molecule 22с is presented in
Figure 1. The fiveꢀmembered ring has a flattened enveꢀ
lope conformation with the deviation of N(1) by 0.162(2) Å.
The acetyl(cyanoacetyl)amine substituent is orthogonal
to the plane of the bicycle (interplane angle is 87.05(2)°),
their IR spectra are always below 1700 cm–1
.

A new synthesis of phthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2481
Scheme 6
19a–c
18—22: R = 4ꢀMeOC6H4 (a), PhOCH2 (b), CH2CN (c); 22: R´ = H (a, b), MeCO (c)
C(4)
C(3)
C(5)
C(6)
C(2)
C(1)
C(8)
O(1)
O(3)
C(10)
C(9)
O(2)
C(7)
N(1)
N(2)
C(15)
O(4)
C(14)
C(16)
N(3)
C(11)
Conformers of compound 22c
A
B
C
O(5)
–1
Total energy*/kcal•mol
0
0
3.5
2.8
7.4
10.4
C(12)
Contribution of energy of conjugation
of acetyl(cyanoacetyl)amine
substituent and energy of nonvalence
intraatomic contacts
Fig. 1. Overall view of molecule 22с (atoms are represented as
–1
thermal ellipsoids at the 50% probability level).
to the total energy*/kcal•mol
which could obviously be explained by steric repulsion
from the substituent at the С(7) and С(8) atoms, and the
perpendicular orientation is apparently stabilized by
anomeric interaction of a lone electron pair of the N(1) atom
and the antibonding orbitals of the N(2)—C(11) and
N(2)—C(14) bonds. The acetyl(cyanoaceyl)amine subꢀ
stituent is planar, which suggests the conjugation of the
C=O groups and the lone electron pair of the N(2) atom.
In order to investigate the possibility of existence
of compound 22с in another conformations and to find
out if the conformation observed in the crystal meets the
energy minimum in the isolated molecule, we carried out
quantum chemical calculations (in a PBE0/6ꢀ311G(d,p)
approximation using the Gaussian0317 program) of tree
* The energy of the most favorable conformer A set to be zero.

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Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009
Ukhin et al.
1
Table 1. Н NMR spectra of phthalimidines obtained
Compound Solvent
1Н NMR spectra, δ, (J/Hz)
6a
6b
6c
6d
CDCl3
CDCl3
CDCl3
CDCl3
2.07 (s, 3 H, Me); 7.27 (m, 1 H, CHarom); 7.45 (m, 2 Н, СН, СНarom); 7.55—7.70 (m, 6 Н, СНarom);
7.92 (m, 1 Н, С(7)Н)
2.04 (s, 3 Н, Me); 7.30—7.45 (m, 4 Н, СН, СНarom); 7.50—7.75 (m, 4 Н, СНarom);
7.94 (m, 1 Н, С(7)Н)
2.07 (s, 3 Н, Me); 7.30—7.55 (m, 4 Н, СН, СНarom); 7.55—7.75 (m, 3 Н, СНarom);
7.93 (m, 1 Н, С(7)Н)
2.11 (s, 3 Н, Me); 5.16 (s, 1 Н, СН); 7.50—7.80 (m, 4 Н, СНarom); 7.94 (m, 1 Н, С(7)Н);
3
8.01 (dd, 1 Н, С(6´)Н, J = 8.2, 4J = 2.2); 8.11 (dd, 1 Н, С(4´)Н, 3J = 8.2, 4J = 2.2);
8.57 (two d, 1 Н, С(2´)Н, J = 2.2)
6e
CDCl3
2.04 (s, 3 H, Me); 7.40—7.56 (m, 3 H, СН, СНarom); 7.56—7.76 (m, 4 H, СНarom); 7.80 (dd, 1 H,
СНarom, 3J = 7.7, 4J = 1.1); 7.95 (m, 1 H, С(7)Н)
6f
6g
DMSOꢀd6
DMSOꢀd6
2.05 (s, 3 H, Me); 7.80—8.10 (m, 9 H, СН, СНarom); 12.60 (br.s, 1 H, ОН)
2.05 (s, 3 H, Me); 3.77, 3.81 (both s, 6 H, ОMe); 5.94 (s, 1 H, СНpyrimid); 7.50—8.20
(m, 9 H, СН, СНarom); 11.30 (br.s, 1 H, NН)
6h
6i
DMSOꢀd6
CDCl3
1.06 (t, 3 H, Me, J = 7.6); 2.33 (m, 2 H, СН2); 7.20 (s, 2 H, NH2); 7.50—8.00 (m, 9 H, СН, СНarom
1.07 (t, 3 H, Me, J = 7.5); 2.32 (q, 2 H, СН2, J =7.5); 7.28 (m, 1 H, СНarom); 7.44 (m, 2 H, СНarom);
7.60 (m, 6 H, СН, СНarom); 7.92 (m, 1 H, С(7)Н)
)
7
DMSOꢀd6
DMSOꢀd6
CDCl3
6.47 (br.d, 1 H, СН); 6.82 (br.d, 1 H, ОН); 7.40—7.85 (m, 4 H, СНarom); 7.99 (m, 4 H, СНarom);
11.00—13.60 (br.s, 1 H, ОН)
6.37 (d, 1 H, ОН, J = 10.0); 6.71 (d, 1 H, СН, J = 10.0); 7.15 (m, 1 H, СНarom);
9
7.39 (m, 2 H, СНarom); 7.45—7.90 (m, 6 H, СНarom
)
10
2.34 (t, 1 H, ≡СН, J = 2.4); 3.77, 3.90 (both dd, 2 H, СН2, 2J = 15.0, 4J = 2.4); 6.56 (s, 1 H, СН);
7.26 (m, 1 H, СНarom); 7.40—7.75 (m, 5 H, СНarom); 7.80 (d, 2 H, СНarom, J = 7.8);
7.92 (d, 1 H, С(7)Н, J = 7.2)
11a
11b
CDCl3
CDCl3
2.36 (m, 2 H, NCH2); 2.66 (m, 2 H, NCH2); 3.53 (m, 4 H, ОСН2); 7.28 (m, 1 H, СНarom);
7.45 (m, 2 H, СНarom); 7.50—7.70 (m, 5 H, СНarom); 7.91 (d, 1 H, С(7)Н, J = 7.5)
2.48 (m, 2 H, NCH2); 2.71 (m, 2 H, NCH2); 3.57 (t, 4 H, ОСН2, J = 4.7); 5.95 (s, 1 H, СН);
7.45—7.80 (m, 4 H, СНarom); 7.94 (d, 1 H, С(7)Н, J = 7.95); 8.10 (m, 1 H, СНarom);
4
8.22 (m, 1 H, СНarom); 8.53 (t, 1 H, С(2´)Н, J = 2.1)
13
CDCl3
6.52 (d, 1 H, СНarom, J = 8.1); 6.85—7.80 (m, 11 H, СНarom); 8.10 (dd, 1 H, С(7)Н,
3J = 6.0, 4J = 2.4); 8.19 (s, 1 H, СН)
15a
15b
DMSOꢀd6
CDCl3
1.28 (s, 18 H, But); 6.26 (s, 1 H, СН); 6.57 (s, 1 H, ОН); 6.90 (s, 2 H, СНarom); 7.06 (m, 1 H,
СНarom); 7.30 (m, 3 H, СНarom); 7.40—7.70 (m, 4 H, СНarom); 7.80 (d, 1 H, С(7)Н, J = 7.9)
1.32 (s, 18 H, But); 5.20 (s, 1 H, СН); 6.7 (s, 1 H, ОН); 6.95 (s, 2 H, СНarom); 7.31 (br.d, 1 H,
СНarom); 7.40—7.70 (m, 3 H, СНarom); 7.34 (br.d, 1 H, СНarom); 7.98 (br.d, 1 H, СНarom);
8.32 (two d, 1 H, СНarom, J = 2.1)
1.29 (s, 18 H, But); 6.38 (s, 1 H, СН); 6.62 (s, 1 H, ОН); 6.94 (s, 2 H, СНarom); 7.00—8.00
(m, 8 H, СНarom); 12.5 (br.s, 1 H, ОН)
15c
DMSOꢀd6
17
22a
CDCl3
CDCl3
6.40 (s, 1 H, СН); 6.85—7.70 (m, 13 H, СНarom); 8.03 (m, 1 H, С(7)Н); 8.12 (br.s, 1 H, NH)
2.17 (s, 3 H, Me); 3.84 (s, 3 H, ОMe); 6.88 (d, 2 H, СНarom, J = 8.6); 7.18 (s, 1 H, СН);
7.45—7.55 (m, 3 H, СНarom); 7.82 (d, 2 H, СНarom, J = 8.6); 7.87 (d, 1 H, СНarom, J = 7.15);
8.62 (s, 1 H, NH)
22b
22c
CDCl3
CDCl3
2.14 (s, 2 H, Me); 4.71 (s, 2 H, СН2); 6.98 (d, СНarom, J = 7.8); 7.07 (t, 1 H, СНarom, J = 7.4);
7.15 (s, 1 H, СН); 7.36 (m, 2 H, СНarom); 7.50—7.80 (m, 3 H, СНarom); 7.88 (d, 1 H, СНarom
J = 7.4); 8.51 (s, 1 H, NH)
,
2.21, 2.24, 2.33, 2.66 (all s, 6 H, Me); 3.77 (d, 0.5 H, СН2, J = 19.5); 4.00 (d, 0.5 H, СН2,
J = 19.5); 4.23 (s, 1 H, СН2); 7.01, 7.04 (both s, 1 H, СН); 7.50—7.85 (m, 3 H, СНarom);
7.93 (m, 1 H, С(7)Н)
conformations that differ from one other in the turn of the
С(12)—С(11)—O(4) and O(5)—C(14)—C(15)—C(16)—N(3)
fragments relative to the N(2)—C(11) and N(2)—C(14)
bonds (of the four possible conformations A—D, conforꢀ
mation D should be the least stable due to repulsion of
hydrogen atoms at the C(12) and C(15) atoms; this conꢀ
formation was not considered).
The estimation of the energy of intramolecular interꢀ
actions was carried out in the framework of natural analyꢀ
sis of populations, which is included in the Gaussian proꢀ
gram, and of the R. Bader theory «Atoms in molecules».18—20
The calculations carried out has shown that all three conꢀ
formations correspond to minimas on the potential energy
surface, conformer A observed in the crystal being the

A new synthesis of phthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2483
3.8 mmol) was heated to fusion, which followed by instant
solidification. The reaction product was recrystallized from
PriOH, cooled on ice, the precipitate was filtered off, washed
with PriOH and petroleum ether and dried. A colorless substance
was obtained, m.p. 170 °C (cf. Ref. 6: m.p. 170—171 °C). The
yield was 0.59 g (68%). IR, ν/сm–1: 3327 (NH), 1747, 1727
(СО), 1595 (arom.), 1060, 855 (С—О—С).
3ꢀ(2,4ꢀDichloroanilino)phthalide (2с). A hot solution of
2,4ꢀdichloroaniline (0.9 g, 5.5 mmol) in МеОН (10 mL) was
added to a hot solution of oꢀformylbenzoic acid (0.75 g, 5 mmol)
in МеOH (10 mL). The reaction mixture was refluxed for
2—3 min and cooled in ice water triturating with a glass rod. The
precipitate that formed was filtered off, washed with cold МеOH
and dried. A colorless substance was obtained, m.p. 160—165 °C
(BuOH). The yield was 1 g (68%). Found (%): С, 57.11;
Н, 3.23; N, 4.82. С14H9NO2Cl2. Calculated (%): С, 57.17;
Н, 3.08; N, 4.76. IR, ν/сm–1: 3395 (NH), 1759 (СО), 1063, 888
(С—О—С).
most favorable. For the explanation of obtained energy
values of conformers, we used a relatively simple scheme
that takes into account the energy of conjugation of the
acetyl(cyanoacetyl)amino fragment and the energy of
nonvalence intraatomic contacts appeared as a result
of the turn relative to the N(2)—C(11) and N(2)—C(14)
bonds. The scheme proposed explains the difference in
the energy at a semiquantitative level. The acetyl(cyanoꢀ
acetyl)amine substituent is planar in conformers A and B.
The О(2) atom participates in С(15)—H(15A)...O(2)
nonvalence contact in conformer A and in O(2)...O(5)
nonvalence contact in conformer B, both of the contacts
being similar in energy, and the difference is caused by
slightly greater conjugation in conformer A. Probably, the
anomaly in the 1Н NMR spectrum of compound 22с can
be explained by the presence in the solution of these
similar in energy conformers with different orientation
of the СН2 group regarding the chiral center of the molꢀ
ecule. The acetyl(cyanoacetyl)amine substituent in
conformer C is deviates to some extent from the plane
(the conjugation energy is 16 kcal•mol–1 smaller). Howꢀ
ever, this structure is favorable for the interaction
between oxygen atoms О(4) and О(5): the lone electron
pair of the О(4) atom is directed to the area of local
vacuum of the electron density of the О(5) atom, which
leads to the appearance of the critical point (3, –1)
between these atoms. Two additional weak contacts
С(15)—H(15A)...O(2) and С(15)—H(15B)...O(1) also
are realized in conformer С.
3ꢀ(3ꢀNitroanilino)phthalide (2d).
A hot solution of
mꢀnitroaniline (1.4 g, 10 mmol) in МеОН (10 mL) was added
to a hot solution of oꢀformylbenzoic acid (1.5 g, 10 mmol)
in МеOH (20 mL). The precipitate that formed after short
induction period was cooled in ice water, filtered off, washed
with МеOH, and dried. A light yellow substance was obtained,
m.p. 228 °C. The yield was 2.55 g (94%). Found (%): C, 61.97;
H, 3.92; N, 10.18. C14H10N2O4. Calculated (%): C, 62.22;
H, 3.73; N, 10.37. IR, ν/сm–1: 3379 (NH), 1738 (СО), 1530,
1352 (NO2), 1080, 867 (С—О—С).
3ꢀ(2ꢀCyanoanilino)phthalide (2е) was prepared analogously
to 2d from oꢀformylbenzoic acid (0.75 g, 5 mmol) in PriOH
(5 mL) and anthranilonitrile (0.65 g, 5.5 mmol) in PriOH (5 mL).
A colorless substance was obtained, m.p. 188—190 °C. The yield
was 0.4 g (32%). An additional amount (0.13 g) of this substance
with the same melting point was precipitated with petroleum
ether from the mother liquor. Total yield was 0.53 g (42%).
Found (%): С, 72.12; Н, 4.21; N, 11.03. С15H10N2O2. Calculꢀ
ated (%): С, 71.99; Н, 4.03; N, 11.19. IR, ν/сm–1: 3355 (NH),
2220 (CN), 1763, 1740 (СО), 1073, 888 (С—О—С).
In the crystal structure, molecules are linked by the
van der Waals interactions and weak C—H...O contacts
(commensurable in energy with the van der Waals
contacts).
Experimental
3ꢀ(4ꢀCarboxyanilino)phthalide (2f) was prepared analogously
to 2d from pꢀaminobenzoic acid (1.4 g, 10 mmol) in EtOH
(10 mL) and oꢀformylbenzoic acid (1.5 g, 10 mmol) in EtOH
(5 mL). This reaction was exothermic. After cooling, the
precipitate was filtered off and dried. A colorless substance
was obtained, m.p. 280—282 °C. The yield was 2.45 g (91%).
Found (%): С, 66.57; Н, 4.43; N, 4.97. С15H11NO4. Calculꢀ
ated (%): С, 66.91; Н, 4.12; N, 5.20. IR, ν/сm–1: 3321 (NH),
1752, 1663 (СО), 1070, 881 (С—О—С).
3ꢀ[4ꢀ(Nꢀ(2,6ꢀDimethoxypyrimidineꢀ4ꢀyl)sulfamoyl)anilino]ꢀ
phthalide (2g). A hot solution of oꢀformylbenzoic acid (0.25 g,
1.65 mmol) was added to a hot solution of Sulfadimethoxine
(0.5 g, 1.6 mmol) in PriOH (10 mL). The reaction mixture was
refluxed for 1—2 min, cooled, the oil that formed was triturated
with a glass rod with cooling in ice water. The precipitate was
filtered off, washed with cold PriOH and petroleum ether and
dried. A colorless substance was obtained, m.p. 198—200 °C. An
additional amount of this substance with the same melting point
was precipitated with petroleum ether from the filtrate. Total
yield was 0.45 g (63%). Found (%): С, 54.03; Н, 4.37; N, 12.41.
С20H18N4O6S. Calculated (%): С, 54.29; Н, 4.10; N, 12.66.
IR, ν/сm–1: 3340, 3307 (NH), 1748 (СО), 1590 (arom.), 1064,
868 (С—О—С).
The IR spectra were recorded on a Specord IRꢀ75 instrument
in Nujol mulls for compounds 2a,b, 6a,b,c,f—i, 9, and 22a,c
and in CHCl3 for compound 15а. The IR spectra of compounds
2c—h; 6d,e; 7; 10; 11a,b; 13; 15b,c; 17; 19a—с; 22b were
recorded on a Varian Excalibur 3100 FTꢀIR instrument by the
method of frustrated total internal reflection. The 1Н NMR
spectra were recorded on a Varian UNITYꢀ300 spectrometer.
Mass spectra were obtained on a Finnigan MAT INCOS 50
spectrometer with direct sample inlet into the ion source, and
mass spectra of compound 11b was obtained on an Agilrut 1200
Bruker Daltonius mir OTOFQ spectrometer.
3ꢀAnilinophthalide (2а). Aniline (1 mL, 10.5 mmol) was added
to a hot solution of oꢀformylbenzoic acid (1.5 g, 10 mmol) in
PriOH (15 mL), the reaction mixture was heated to boiling
and cooled with ice. The precipitate that formed was filtered
off, washed with PriOH and petroleum ether and dried. A colorꢀ
less substance was obtained, m.p. 182—185 °С (cf. Ref. 6:
m.p. 180—181 °С). The yield was 2.15 g (95%). IR, ν/сm–1
3327 (NH), 1727, 1715 (СО), 1600 (arom.), 1060, 855 (С—О—С).
3ꢀ(2ꢀChloroanilino)phthalide (2b). A mixture of oꢀformylꢀ
benzoic acid (0.5 g, 3.3 mmol) and oꢀchloroaniline (0.4 mL,
:

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Ukhin et al.
3ꢀ(4ꢀSulfamoylanilino)phthalide (2h). oꢀFormylbenzoic acid
(0.45 g, 3 mmol) in EtOH (5 mL) was added to a hot solution of
Streptocide White (0.55 g, 3 mmol) in EtOH (10 mL). The
reaction mixture was heated to boiling and cooled to room
temperature. The precipitate was filtered off, washed with EtOH,
and dried. A colorless substance was obtained, m.p. 256—260 °C.
The yield was 2.1 g (67%). Found (%): С, 55.11; Н, 4.27;
N, 9.00. С14H12N2O4S. Calculated (%):С, 55.26; Н, 3.97;
N, 9.21. IR, ν/сm–1: 3340, 3242 (NH), 1729 (СО), 1325, 1150
(SO2), 1094, 868 (С—О—С).
and Ac2O (3.5 mL). The reaction mixture was refluxed (~10 min)
until complete homogenization, cooled, and quenched with a
mixture of MeOH (5 mL) and H2O (25 mL). The oil that formed
was cooled on ice and triturated with a glass rod until complete
solidification. The preciritate was filtered off, washed with H2O
and 50% EtOH and dried. A colorless substance was obtained,
m.p. 193—195 °C. The yield was 1 g (91%). Found (%):
С, 65.24; Н, 4.43; N, 4.35. С17H13NO5. Calculated (%):
С, 65.59; Н, 4.21; N, 4.50. IR, ν/сm–1: 1735, 1715, 1680 (СО),
1595, 1500 (arom.). M+ = 311.
3ꢀAcetoxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (6а). A mixture of
phthalide 2а (0.95 g, 4.2 mmol) and Ac2O (2.5 mL) was heated
up to dissolution, refluxed for 3 min, cooled, and quenched with
a mixture of MeOH (5 mL) and H2O (15 mL). The oily
precipitate that formed was cooled on ice, triturated using a
glass rod until solidification, filtered off, washed with H2O, and
dried. A colorless substance was obtained. The yield was 1.05 g
(93%). After recrystallization from isooctane (30 mL), compound
6a was obtained in a yield of 0.85 g (75 %), m.p. 97—99 °C.
Found (%): С, 71.76; Н, 5.11; N, 5.32. С16H13NO3. Calculꢀ
ated (%):С, 71.90; Н, 4.90; N, 5.24. IR, ν/сm–1: 1735, 1714
(СО), 1595, 1495 (arom.). M+ = 276.
3ꢀAcetoxyꢀ2ꢀ[4ꢀ(Nꢀ(2,6ꢀdimethoxypyrimidinꢀ4ꢀyl)ꢀ
sulfamoyl)phenyl]isoindolinꢀ1ꢀone (6g) was prepared analogously
to 6а from phthalide 2g (0.45 g, 1 mmol) and Ac2O (1.5 mL).
After cooling, EtOH (3 mL) was added, and the oil was
precipitated with water, which was separated and triturated with
small amount of PriOH with ice cooling. The crystalls that
formed were filtered off, washed with cold PriOH and dried.
A colorless substance was obtained, m.p. 150—154 °C. The yield
was 0.07 g (14%). Found (%): С, 54.25; Н, 4.30; N, 11.42.
С22H20N4SO7. Calculated (%): С, 54.54; Н, 4.16; N, 11.56.
IR, ν/сm–1: 3365, 3170 (NH), 1740, 1715 (СО), 1600, 1580
(arom.), 1155, 1355 (SO2). MS (EI): 64 (SO2, 100%), М+ = 484
(weak signal).
3ꢀAcetoxyꢀ2ꢀ(2ꢀchlorophenyl)isoindolinꢀ1ꢀone (6b) was preꢀ
pared analogously to 6а from phthalide 2b (0.55 g, 2.1 mmol)
and Ac2O (1 mL). It was precipitated with a mixture of HOAc
(3 mL) and H2O (20 mL). The emulsion that formed was cooled
on ice and triturated with a glass rod until solidification.
A colorless substance was obtained, m.p. 99—102 °C. The yield
was 0.64 g (~100%). Found (%): С, 63.42; Н, 4.27; N, 4.72.
С16H12NClO3. Calculated (%): С, 63.69; Н, 4.01; N, 4.64.
IR, ν/сm–1: 1727, 1700 пл. (СО), 1607, 1580 (arom.). M+ = 301.5.
3ꢀAcetoxyꢀ2ꢀ(2,4ꢀdichlorophenyl)isoindolinꢀ1ꢀone (6с) was
prepared analogously to 6а from phthalide 2с (0.5 g, 1.7 mmol)
and Ac2O (1 mL). It was precipitated with a mixture of MeOH
(5 mL) and H2O (25 mL). The oil that formed gradually hardened
with cooling on ice and trituration with a glass rod. The yield
was ~0.6 g (~100%). A colorless substance was obtained,
m.p. 95—97 °C. Found (%): С, 56.93; Н, 3.57; N, 4.28.
С16H11NCl2O3. Calculated (%):С, 57.17; Н, 3.30; N, 4.17.
IR, ν/сm–1: 1760, 1735, 1725 (СО), 1607, 1595, 1580 (arom.).
3ꢀAcetoxyꢀ2ꢀ(3ꢀnitrophenyl)isoindolinꢀ1ꢀone (6d) was preꢀ
pared analogously to 6а from phthalide 2d (2.55 g, 9.4 mmol)
and Ac2O (2.5 mL). 50% MeOH (15 mL) was added to the
reaction mixture hardened after cooling, the precipitate was
filtered off, washed with 50% MeOH and dried. A colorless
substance was obtained, m.p. 160 °C (from toluene). The yield
was 2.65 g (98%). Found (%): С, 61.56; Н, 3.92; N, 8.80.
С16H12N2O5. Calculated (%): С, 61.54; Н, 3.87; N, 8.97.
IR, ν/сm–1: 1729 (СО), 1522, 1355 (NO2).
3ꢀPropionyloxyꢀ2ꢀ(4ꢀsulfamoylphenyl)isoindolinꢀ1ꢀone (6h).
A mixture of phthalide 2h (0.3 g, 1 mmol) and propionic
anhydride (1 mL) was refluxed for 4 min. A mixture of MeOH
(2 mL) and H2O (8 mL) was added, the mixture obtained was
heated to boiling and cooled. A part of the oily precipitate that
formed was triturated with MeOH, and solidified substance was
added to the remaining mass with cooling on ice and trituration
with a glass rod. The solid was filtered off, washed with cold
MeOH and dried. A colorless crystalline substance was obtained
in a yield of 2 g (55%), m.p. 198—200 °C. Found (%): С, 56.27;
Н, 4.72; N, 7.63. С17H16N2SO5. Calculated (%): С, 56.66;
Н, 4.47; N, 7.77. IR, ν/сm–1: 3300, 3220 (NH2), 1727, 1707 (СО),
1595, 1495 (arom.), 1340, 1155 (SO2).
3ꢀPropionyloxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (6i). A mixture of
phthalide 2а (0.41 g, 1.8 mmol) and propionic anhydride (1 mL)
was refluxed until complete dissolution (3 min), cooled, and
quenched with a mixture of MeOH (2 mL) and H2O (8 mL).
The mixture obtained was kept on ice and triturated with a glass
rod for 30 min. The precipitate that formed was filtered off,
washed with 50% EtOH and dried. A colorless substance was
obtained, m.p. 93—96 °C. The yield was 0.42 g (80%). Found (%):
С, 72.49; Н, 5.43; N, 5.11. С17H15NO3. Calculated (%):
С, 72.58; Н, 5.37; N, 4.98. IR, ν/сm–1: 1740, 1700 (СО), 1595,
1495 (arom.).
3ꢀHydroxyꢀ2ꢀ(4ꢀcarboxyphenyl)isoindolinꢀ1ꢀone
(7).
A suspension of phthalimidine 6f (0.31 g, 1 mmol) in 12 mL of a
mixture of AcOH and H2O (1 : 1) was refluxed for 30 min, then
cooled. H2O (10 mL) was added to the reaction mixture, the
precipitate was filtered off, washed with H2O and dried.
A colorless substance was obtained, m.p. 244—247 °C. The yield
was 0.19 g (70%). Found (%): С, 66.82; Н, 4.37; N, 5.24.
С15H11NO4. Calculated (%): С, 66.91; Н, 4.12; N, 5.20.
IR, ν/сm–1: 3223 (ОН), 1677 (СО), 1604, 1573, 1513 (arom.).
3ꢀAcetoxyꢀ2ꢀ(4ꢀcyanophenyl)isoindolinꢀ1ꢀone (6e) was preꢀ
pared analogously to 6а from phthalide 2e (0.24 g, 1 mmol)
and Ac2O (1 mL). The reaction mixture was refluxed for 5 min,
MeOH (3 mL) and H2O (10 mL) were added to a cooled solution,
the oil that formed hardened with cooling on ice (~1 h) and
triturating with a glass rod. A colorless substance was obtained,
m.p. 130—132 °C (fromisooctane). The yield was 0.27 g (93%).
Found (%): С, 70.21; Н, 4.47; N, 9.32. С17H12N2O3. Calculꢀ
ated (%): С, 69.86; Н, 4.14; N, 9.58. IR, ν/сm–1: 2227 (CN),
1753, 1721 (СО).
M
+ = 269.
3ꢀHydroxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (9). А. Isoindolinone 6а
(0.2 g, 0.75 mmol) was dissolved in EtOH (3 mL) with heating.
This solution was cooled to room temperature, hydrazine hydrate
(0.1 g) was added and the mixture obtained was refluxed for
3ꢀAcetoxyꢀ2ꢀ(4ꢀcarboxyphenyl)isoindolinꢀ1ꢀone (6f) was
prepared analogously to 6а from phthalide 2f (0.95 g, 3.5 mmol)

A new synthesis of phthalimidines
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 12, December, 2009 2485
1 min and then cooled on ice. A few drops of the solution was
triturated with water until formation of hard flakes, and H2O
(6 mL) was added. The suspension obtained was added to a
cooled solution with trituration with a glass rod. The precipitate
that formed was filtered off, washed with 50% EtOH and dried.
A colorless substance was obtained, m.p.160—162 °C. The yield
was 0.1 g (59%).
B. The analogous transformation of 6а occured on heating
with concentrated HCl to boiling. At first the substance melted
and then hardened. The yield of crude product was quantitative.
The IR spectra of this product coincides with that obtained from
the reaction with hydrazine hydrate, and the melting point
of the mixed sample does not display depression. Found (%):
С, 74.53 Н, 5.13; N, 6.37. С14H11NO2. Calculated (%): С, 74.65;
Н, 4.92; N, 6.22. IR, ν/сm–1: 3380 (ОН), 1695 (СО), 1595,
1500 (arom.).
3ꢀPropargyloxyꢀ2ꢀphenylisoindolinꢀ1ꢀone (10). A mixture of
phthalimidine 6а (0.53 g, 2 mmol) and propargyl alcohol (1 mL)
was refluxed for 30 min, then cooled, and H2O (10 mL) was
added. The oily precipitate that formed was cooled on ice and
triturated with a glass rod until complete solidification. The
precipitate was filtered off, washed with H2O and dried. The yield
of the crude product was 0.496 g (94%). After recrystallization
from petroleun ether, a colorless substance was obtained in a
yield of 0.325 g (62%), m.p. 122—124 °С. Found (%): С, 77.62;
Н, 5.11; N, 5.43. С17H13NO2. Calculated (%): С, 77.55; Н, 4.98;
N, 5.32. IR, ν/сm–1: 3265 (≡СН), 2127 (С≡С), 1705 (СО),
1596, 1501 (arom.).
3ꢀMorpholinoꢀ2ꢀphenylisoindolinꢀ1ꢀone (11а). A mixture of
phthalimidine 6а (0.27 g, 1 mmol) and morpholine (0.5 mL)
was refluxed for 7 min, then cooled, and EtOH (3 mL) was
added. The solution was triturated under cooling on ice until
complete solidification. The precipitate was filtered off, washed
with cold EtOH and dried. The yield was 0.173 g (59%).
Analytically pure product was obtained after recrystallization
from PriOH (5 mL), the yield of colorless crystals was 80 mg,
m.p. 177—178 °C. Found (%): С, 73.12; Н, 6.42; N, 9.24.
С18H18N2O2. Calculated (%): С, 73.45; Н, 6.16; N, 9.52.
IR, ν/сm–1: 1680 (СО), 1595, 1498 (arom.).
3ꢀMorpholinoꢀ2ꢀ(3ꢀnitrophenyl)isoindolinꢀ1ꢀone (11b).
A mixture of phthalimidine 6d (0.31 g, 1 mmol) and morpholine
(0.5 mL) was refluxed for 10 min, then cooled and dissolved in
PriOH (5 mL), a precipitate and resin were precipitated with
water. The resin was separated, triturated with MeOH, and the
solid together with MeOH was poured into the remaining mass.
The suspension was cooled on ice and triturated with a glass rod,
the precipitate was filtered off, washed with H2O and dried.
A colorless substance that easily crystallized from PriOH was
obtained in a yield of 0.29 g (85%), m.p. 130—132 °C (PriOH).
Found (%): С, 63.52; Н, 5.12; N, 12.54. С18H17N3O4. Calculꢀ
ated (%): С, 63.71; Н, 5.05; N, 12.38. IR, ν/сm–1: 1709 (СО),
1611 (arom.), 1520, 1363 (NO2). [M + H]+ = 340.139;
M = 339.131.
3ꢀ(Benzoxazolꢀ2ꢀylsulfanyl)ꢀ2ꢀphenylisoindolinꢀ1ꢀone (13).
A mixture of phthalimidine 6а (0.27 g, 1 mmol) and 2ꢀmercaptoꢀ
benzoxazole (0.16 g, 1 mmol) was ground in a mortar and fused
at 150 °C. The solid foam was cooled, dissolved under reflux in
CH3CN (8 mL), filtered while hot and cooled on ice. The
precipitate that formed was filtered off, washed with cold CH3CN
and dried. A colorless substance was obtained, m.p 240 °C
(petroleum ether). The yield was 0.166 g (46.5%). It was
recrystallized from toluene (3 mL), washed with cold toluene
and petroleum ether, and analytically pure compound 13 was
obtained in a yield of 0.054 g, m.p. 243—250 °C. Found (%):
С, 70.22; Н, 4.17; N, 8.00. С21H14N2SO2. Calculated (%):
С, 70.37; Н, 3.94; N, 7.82. IR, ν/сm–1: 1713 (СО), 1595, 1500,
1476 (arom.).
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ2ꢀphenylisoindolinꢀ
1ꢀone (15а). A mixture of phthalimidine 6а (0.27 g, 1 mmol),
CF3COOH (0.2 mL) and 2,6ꢀdiꢀtertꢀbutylphenol (0.25 g,
1.2 mmol) was heated until boiling and refluxed for 1 min,
then cooled, and PriOH (3 mL) was added. The solution was
cooled on ice and triturated with a glass rod. The crystalline
precipitate that formed was filtered off, washed with PriOH and
petroleun ether and dried. A colorless substance was obtained,
m.p 229—230 °C (isooctane—toluene, 1 : 1). The yield was
0.32 g (77%). Found (%): С, 81.28; Н, 7.84; N, 3.67. С28H31NO2.
Calculated (%): С, 81.32; Н, 7.55; N, 3.39. IR, (CHCl3), ν/сm–1
:
3635 (OH), 2960, 2905, 2865 (But), 1687 (СО). M+ = 413.
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ2ꢀ(3ꢀnitrophenyl)ꢀ
isoindolinꢀ1ꢀone (15b). A mixture of phthalimidine 6d (0.312 g,
1 mmol) and 2,6ꢀdiꢀtertꢀbutylphenol (0.3 g, 1.5 mmol) was fused,
CF3COOH (0.2 mL) was added, the mixture obtained was
refluxed for 1 min, cooled, PriOH (7 mL) was added, and the
mixture was cooled on ice. The precipitate that formed was
filtered off, washed with PriOH and petroleun ether and dried.
A colorless substance was obtained, m.p 183—185 °C. The yield
was 0.421 g (92%). Found (%): С, 73.42; Н, 6.80; N, 6.44.
С28H30N2O4. Calculated (%): С, 73.34; Н, 6.59; N, 6.11. IR,
ν/сm–1: 3568 (ОН), 2959, 2915, 2874 (tꢀBu), 1691 (СО), 1525,
1349 (NO2).
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ2ꢀ(4ꢀcarboxyphenyl)ꢀ
isoindolinꢀ1ꢀone (15с). A mixture of phthalimidine 6с (0.31 g,
1 mmol) and CF3COOH (0.3 mL) was heated until boiling.
After complete homogenization, 2,6ꢀdiꢀtertꢀbutylphenol (0.3 g,
1.5 mmol) was added. PriOH (10 mL) was added to almost
instantaneously solidified reaction mixture, it was refluxed and
triturated with a glass rod until complete dissolution. Clear
solution was cooled on ice, triturated with a glass rod until
complete precipitation. The precipitate was filtered off, washed
with PriOH and petroleum ether and dried. A colorless substance
was obtained, m.p 290—295 °C (CH3CN). The yield was 0.28 g
(61%). Found (%): С, 75.93; Н, 6.98; N, 3.27. С29H31NO4.
Calculated (%): С, 76.12; Н, 6.83; N, 3.06. IR, ν/сm–1: 3623
(ОН), 2954, 2909, 2870 (But), 1711, 1673 (СО).
3ꢀ(Indolꢀ3ꢀyl)ꢀ2ꢀphenylisoindolinꢀ1ꢀone (17). Phthalimidine
6а (0.27 g, 1 mmol) and indole (0.13 g, 1.1 mmol) were mixed
and CF3COOH (0.1 mL) was added. The mixture obtained was
heated until boiling, cooled, dissolved in EtOH (5 mL) with
heating, cooled, the oil precipitated with water. This gradually
solidified upon cooling on ice and trituration. The precipitate
was filtered off and recrystallized from toluene (15 mL). A whiteꢀ
pink substance was obtained in a yield of 0.18 g (56%). After
recrystallization from a toluene—isooctane mixture, colorless
crystals were obtained, m.p. 230—235 °C. Found (%): С, 81.32;
Н, 5.11; N, 8.56. С22H16N2O. Calculated (%): С, 81.46;
Н, 4.97; N, 8.64. IR, ν/сm–1: 3188 (NН), 1663 (СО). M+ = 324.
oꢀFormylbenzoic acid anisoylhydrazone (19а). A hot solution
of anisohydrazide (0.55 g, 3.3 mmol) in PriOH (5 mL) was
added to a hot solution of oꢀformylbenzoic acid (0.5 g, 3.3 mmol)
in PriOH (5 mL). PriOH (5 mL) was added to a thick mass
formed as a result of the exothermic reaction. The mixture was

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Ukhin et al.
filtered while hot, washed with PriOH and petroleun ether and
dried. A colorless substance 19а was obtained in a yield of 0.83 g
(84%), m.p. 200—202 °C. Found (%): С, 64.32; Н, 4.68;
N, 9.27. С16H13N2O4. Calculated (%): С, 64.64; Н, 4.41; N,
9.42. IR, ν/сm–1: 3251—3005 (NН), 1681 (СО), 1624, 1603,
1570 (arom.).
with H2O and 50% MeOH and dried. The yield was 0.22 g
(69%). After twofold recrystallization from PriOH, a colorless
substance was obtained, m.p. 145 °C. Its structure was established
by Xꢀray diffraction analysis. IR, ν/сm–1: 2256 (С≡N), 1755 pl.,
1730, 1715 (СО), 1620 (arom.). MS (EI): 273, 43 (about 100%,
CH3CO).
oꢀFormylbenzoic acid phenoxyacetylhydrazone (19b) was
prepared analogously to 19а by mixing hot solutions of
oꢀformylbenzoic acid (0.5 g) and phenylacetohydrazide (0.55 g)
in PriOH (5 mL each). The mixture was heated until boiling.
After cooling to room temperature, the precipitate was filtered
off, washed with PriOH and petroleum ether and dried.
A colorless substance (19b) was obtained in a yield of 0.95 g
(96%), m.p. 192—194 °C. Found (%): С, 64.17; Н, 5.02;
N, 9.28. С16H14N2O4. Calculated (%): С, 64.43; Н, 4.73; N, 9.39.
IR, ν/сm–1: 3028 (NН), 1684 (СО), 1599, 1559, 1495 (arom.).
oꢀFormylbenzoic acid cyanoacetylhydrazone (19с) was preꢀ
pared analogously to 19а by mixing hot solutions of oꢀformylꢀ
benzoic acid (1.5 g) in PriOH (10 mL) and cyanoacetohydrazide
(1 g) in PriOH (15 mL). After completion of exothermic reaction,
PriOH (10 mL) was added to the solid mass, then the mixture
was cooled to room temperature, the precipitate was filtered off,
washed with PriOH and petroleum ether and dried. Compound
19с was obtained in a yield of 2.1 g (91%), m.p. 186—188 °C.
Found (%): С, 56.93; Н, 4.15; N, 18.32. С11H9N3O3. Calculated
(%): С, 57.14; Н, 3.92; N, 18.17. IR, ν/сm–1: 3171—3078 (NН),
2260 (C≡ N),1674, 1649 (СО), 1606, 1566 (arom.). M+ = 231.
3ꢀAcetoxyꢀ2ꢀ(pꢀmethoxybenzoylamino)isoindolinꢀ1ꢀone
(22а). A mixture of hydrazone 19а (0.3 g, 1 mmol) and Ac2O
(2 mL) was heated until dissolution and refluxed for 5 min,
cooled, and quenched with MeOH (3 mL) and H2O (10 mL).
The mixture was cooled on ice and triturated with a glass rod.
The crystalline precipitate that formed was filtered off, washed
with H2O and 50% EtOH and dried. A colorless substance was
obtained in a yield of 0.28 g (81%), m.p. 159—161 °C. The
analytically pure product was obtained by recrystallization from
PriOH or toluene. Found (%): С, 63.42; Н, 7.85; N, 8.27.
С18H16N2O5. Calculated (%): С, 63.53; Н, 4.74; N, 8.23.
IR, ν/сm–1: 3113 (NН), 1755, 1730, 1675 (СО), 1615, 1500
(arom.). M+ = 340.
Xꢀray diffraction analysis. Crystals of 22с (C15H13N3O5)
at 100 K are monoclinic, a = 8.6329(4) Å, b = 17.4658(9) Å,
c = 9.6957(5) Å, V = 1457.05(13) Å3, Z = 4, space group P21/с,
μ = 0.11 mm–1, dcalc = 1.437 g•cm–3. Intensities of 16383
reflections were measured on a SMART APEX2 CCD diffracꢀ
tometer (λ(MoꢀKα) = 0.71073 Å, graphite monochromator,
ω scanning technique, scan step was 0.5°, 2θ < 58°). The initial
array of measured intensities were processed using the SAINT21
,
SADABS22 programs. The structure was solved by the direct
method and refined by the fullꢀmatrix leastꢀsquares method in
the anisotropic approximation for nonhydrogen atoms against
F2hkl. Hydrogen atoms were placed at the calculated positions
and refined using the riding model (Uiso(H) = nUeq(C), where
n = 1.5 for C atoms of the methyl groups, n = 1.2 for the
remaining C atoms). 3858 independent reflections were included
in the refinement (Rint = 0.0274, the number of refined paramꢀ
eters was 210). The accuracy of the refinement on all independent
reflections (wR2) was 0.0840 (R1 = 0.0357 on 3192 reflections with
I > 2σ(I)). All calculations were carried out on an IBM PC AT
using the SHELXTL23 complex program. The atomic coorꢀ
dinates and thermal parameters were deposited with the Cambridge
Crystallographic Data Centre (CCDC 753793).*
This study was financially supported by the Council on
Grants at the President of the Russian Federation (Proꢀ
gram for State Support of Leading Scientific Schools,
Grants NShꢀ363.2008.3 and NShꢀ3019.2008.3).
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* http://www.ccdc.cam.ac.uk/products/csd/request/.

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Received March 10, 2009;
in revised form October 6, 2009