2-Aminothiophene derivatives in a novel synthesis of phthalimidines

Article abstract of DOI:10.1007/s11172-011-0057-3

New aminophthalides were synthesized from o-formylbenzoic acid and substituted 2-aminothiophenes. Two of these compounds underwent recyclization in boiling Ac₂O to give the previously unknown 3-acetoxy-2-(3-cyano-4, 5-dimethylthiophen-2-yl)-1,3-dihydroisoindol-1-one and 3-acetoxy-2-(3-cyano-4,5- tetramethylenethiophen-2-yl)-1,3-dihydroisoindol-1-one. The possible reaction mechanism and factors preventing the recyclization, in particular, the formation of intramolecular hydrogen bonds in the starting phthalides, were discussed. Some reactions of the resulting compounds with C-nucleophiles in trifluoroacetic acid were investigated. Two derivatives containing 4-hydroxy-3,5-di-tert- butylphenyl substituents were studied by X-ray diffraction.

Full text of DOI:10.1007/s11172-011-0057-3

Russian Chemical Bulletin, International Edition, Vol. 60, No. 2, pp. 352—360, February, 2011
352
2ꢀAminothiophene derivatives in a novel synthesis of phthalimidines
L. Yu. Ukhin,a E. N. Shepelenko,b L. V. Belousova,a Zh. I. Orlova,a G. S. Borodkin,b and K. Yu. Suponitskyc
aInstitute 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
bSouthern Scientific Center, Russian Academy of Sciences,
41 prosp. Chekhova, 344006 RostovꢀonꢀDon, Russian Federation.
Fax: +7 (863) 243 4776. Eꢀmail: dubon@ipoc.rsu.ru
cA. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5085. Eꢀmail: kirshik@yahoo.com
New aminophthalides were synthesized from oꢀformylbenzoic acid and substituted 2ꢀamiꢀ
nothiophenes. Two of these compounds underwent recyclization in boiling Ac2O to give the
previously unknown 3ꢀacetoxyꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀdimethylthiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroisoindolꢀ
1ꢀone and 3ꢀacetoxyꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroisoindolꢀ1ꢀ
one. The possible reaction mechanism and factors preventing the recyclization, in particular,
the formation of intramolecular hydrogen bonds in the starting phthalides, were discussed.
Some reactions of the resulting compounds with Cꢀnucleophiles in trifluoroacetic acid were
investigated. Two derivatives containing 4ꢀhydroxyꢀ3,5ꢀdiꢀtertꢀbutylphenyl substituents were
studied by Xꢀray diffraction.
Key words: oꢀformylbenzoic acid, 2ꢀaminothiophenes, 3ꢀhetarylaminophthalides, azomeꢀ
thines of oꢀformylbenzoic acid, acetic anhydride, 2ꢀhetarylꢀ3ꢀacyloxyphthalimidines, 2,6ꢀdiꢀ
tertꢀbutylphenol, indole, Xꢀray diffraction study.
Scheme 1
Recently, we have reported on the new synthesis of
phthalimidines by the recyclization of arylaminophthalꢀ
ides or acyl hydrazones of oꢀformylbenzoic acid (1) in
acetic anhydride.1 The resulting phthalimidines were used
in the synthesis of potentially biologically active phthalꢀ
imidines attached via an amide bridged to quinoline deꢀ
rivatives.2
The aim of the present study was to extend the recyclꢀ
ization of arylaminophthalides of oꢀformylbenzoic acid to
the synthesis of phthalimidines containing thiophene subꢀ
stituents at position 2. It was found that tautomeric
oꢀformylbenzoic acid (1), which reacts with primary
aromatic amines to give 3ꢀarylaminophthalides,1,3 reacts
in a similar way with 2ꢀaminothiophene derivatives 2
(Scheme 1).
However, the resulting hetarylaminophthalides 3a—c
sharply differ in the chemical properties. Compounds conꢀ
taining the cyano group 3a,b easily undergo recyclization
in refluxing acetic anhydride to give the corresponding
phthalimidines 4a,b (see Scheme 1), as has been described
for arylaminophthalides,1 whereas compound 3c containꢀ
ing the ethoxycarbonyl group in the ortho position with
respect to the amino group is not involved in this reaction.
This behavior can be attributed to both the steric and elecꢀ
tronic factors. However, the experimental data obtained
R1 = CN, R2 = R3 = Me (a); R1 = CN, R2 + R3 = (CH2)4 (b); R1 = COOEt,
R2 = H, R3 = Et (c)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 345—352, February, 2011.
1066ꢀ5285/11/6002ꢀ352 © 2011 Springer Science+Business Media, Inc.

Phthalimidines from 2ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
353
in our studies do not allow unambiguous conclusions to be
drawn based only on these facts. For example, earlier1 we
have synthesized phthalides containing the 2ꢀcyanoaniline,
2ꢀchloroaniline, 2,4ꢀdichloroaniline, and 3ꢀnitroaniline
moieties, i.e., predominantly electronꢀwithdrawing subꢀ
stituents, and all these compounds were easily transformed
into phthalimidines in the reactions with Ac2O. Hence, it
is unlikely that the electronꢀwithdrawing properties of the
ethoxycarbonyl group hinder the reaction of 3c with acetic
anhydride. We confirmed this fact by comparing the beꢀ
havior of 3ꢀ(2ꢀmethoxycarbonylphenylamino)phthalide
(3d) and 3ꢀ(4ꢀethoxycarbonylphenyl)aminophthalide (3e)
in the reactions with Ac2O.
yl benzoate, readily undergoes recyclization in refluxing
Ac2O to the corresponding phthalimidine 4c (Scheme 2).
Finally, phthalide 3f containing the oꢀanisidine moiety
(the electronꢀdonating substituent in the ortho position)
that is formed in quantitative yield also does not undergo
recyclization in refluxing Ac2O. We failed to prepare
phthalide and phthalimidine by the reactions with
2,6ꢀdichloroaniline. Taking into account that both reacꢀ
tions occur with 2,4ꢀdichloroaniline, the failure is most
likely attributed to the steric factor. By contrast, oꢀformylꢀ
benzoic acid (1) easily reacts with mesidine 5 to form
phthalide 3g, which is transformed into phthalimidine 4d
in high yield in refluxing Ac2O, i.e., two methyl groups in
the ortho position do not hinder the recyclization (see
Scheme 2).
Scheme 2
Compound
R1
COOMe
H
OMe
Me
R2
H
COOEt
H
Me
H
R3
H
H
H
Me
H
3d
3e
3f
3g
3h
CN
Phthalide 3d, which was synthesized from oꢀformylꢀ
benzoic acid and methyl anthranilate, does not undergo
recyclization in refluxing Ac2O; instead, the recrystallizaꢀ
tion of 3d was observed. Phthalide 3e, which was prepared
by the reaction of oꢀformylbenzoic acid with pꢀaminoethꢀ
All these facts can be explained by assuming that
azomethine rather than aminophthalide, which is in equiꢀ
librium with the former compound, reacts with acetic anꢀ
hydride. The possibility of this "electrophilic tautomerism"
was discussed in the review4 and in the study5 (Scheme 3).
Scheme 3
If, for one or other reason, aminophthalide cannot be
transformed into the tautomeric azomethine form, it does

354
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Ukhin et al.
Scheme 4
R1 = R2 = Me (a); R1 + R2 = (CH2)4 (b)
Scheme 5
not undergo recyclization to phthalimidine. In all the
aboveꢀmentioned cases, the tautomeric transformation
into azomethine can be hindered by the formation of an
intramolecular hydrogen bond between the proton at the
nitrogen atom and the oxygen atom of the ortho group
resulting in the formation of sixꢀ and fiveꢀmembered rings.
In the case of the oꢀcyano group, the formation of this
intramolecular hydrogen bond is impossible because of
the geometric factors, and aminophthalide 3h (see Ref. 1)
easily undergoes recyclization in Ac2O.
The proposed mechanism of the recyclization involves
the acylation of the C=N bond of the tautomeric azoꢀ
methine form and the phthalimidine ring closure accomꢀ
panied by elimination of acetic acid (Scheme 4).
intermolecular hydrogen bonds for 5ꢀ(3,5ꢀdiꢀtertꢀbutylꢀ
4ꢀhydroxyphenyl)ꢀ1,2,3,5ꢀtetrahydrophenazine.6 The
Xꢀray diffraction study of compounds 8a,b showed that
the anomalies in their IR spectra are also associated with
the formation of intermolecular hydrogen bonds. It should
be noted that the formation of such bonds has not been
observed in 2ꢀarylphthalimidines containing the 4ꢀhydrꢀ
oxyꢀ3,5ꢀdiꢀtertꢀbutylphenyl substituent at position 3,
which have been synthesized earlier.1
There is one molecule per asymmetric unit cell of comꢀ
pound 8a, whereas the asymmetric unit cell of compound
8b contains two independent molecules labeled with A
and B. Molecules 8a and 8b differ by the substituent at the
carbon atoms of the thiophene ring: two methyl groups in
8a and the cyclic moiety in 8b (Fig. 1). The structural
difference between molecules 8a, 8b(A), and 8b(B) is reꢀ
lated primarily to the mutual orientation of the cyclic
moieties and the different conformation of the cyclohexene
Other acylating agents, for example, acid chlorides,
can be used for the recyclization of aminophthalides
to phthalimidines. 3ꢀChloroꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀdimethylꢀ
thiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroisoindolꢀ1ꢀone (4e) and
3ꢀchloroꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀyl)ꢀ
1,3ꢀdihydroisoindolꢀ1ꢀone (4f) were synthesized by heatꢀ
ing phthalides 3a,b, respectively, with SOCl2 (Scheme 5).
In trifluoroacetic acid, compounds 4a,b react with
Cꢀnucleophiles like their analogs containing aryl substituꢀ
ents.1 As in the study,1 2,6ꢀdiꢀtertꢀbutylphenol (7) giving
compound 8 and indole (9) producing compounds 10
(Scheme 6) were used as Cꢀnucleophiles.
In the IR spectra of compounds 8a,b, the stretching
vibrations of the sterically hindered hydroxy group are obꢀ
served as strongly broadened absorption bands shifted to
lower frequencies (~3400 cm–1). Earlier, we have described
an analogous situation associated with the formation of

Phthalimidines from 2ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
355
Scheme 6
i. 72 °C, 1 min; ii. 20 °C, 3 h.
R1 = R2 = Me (a); R1 + R2 (CH2)4 (b)
moiety in 8b(A) and 8b(B), where it adopts a halfꢀchair
and envelop conformation, respectively. All aromatic moiꢀ
eties in all molecules are planar. The isoindolone and
3,5ꢀdiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl rings are almost perꢀ
pendicular to each other, like those in tetrahydrophenꢀ
azine studied earlier.6 The dihedral angle α and the
C(1)—N(1)—C(23)—S(1) torsion angle determining the
orientation of the thiophene moiety are given below.
hydrogen bonding with the O(1) atom (Table 1) to form
chains, like those in tetrahydrophenazine, where the nitroꢀ
gen atom of the pyrazine ring serves as the proton accepꢀ
tor. In the structures of 8a and 8b, the chains run along the
crystallographic axis a and the molecules are related by
the translation along this axis, the hydrogen bonds in 8b
being formed between the molecules of one type (A...A
and B...B) (Fig. 2).
The stoichiometry of compounds 10a and 10b was conꢀ
firmed by mass spectrometry and elemental analysis. Howꢀ
ever, the H NMR spectra of these compounds are more
similar to the spectra of mixtures of isomers (Table 2). In
compound 10a, the methyl groups give two multiplets,
and the CH2 groups of the cyclohexane moiety of comꢀ
pound 10b appear as two broadened singlets. The region of
aromatic protons is particularly complicated, the signals
Comꢀ
pound
8a
8b(A)
8b(B)
Angle/deg
C(1)—N(1)—C(23)—S(1)
–24.3(3)
α
1
83.38(6)
85.13(7)
77.40(7)
–33.5(4)
–44.3(3)
In spite of the presence of the tertꢀbutyl substituents,
the hydroxy groups in both structures are involved in the
C(21)
a
b
O(2)
C(18)
O(2)
C(17)
C(17)
C(18)
C(22)
C(20)
C(21)
C(15)
C(12)
C(19)
C(12)
C(16)
C(6)
C(7)
C(19)
C(13)
C(14)
C(15)
C(11)
C(10)
C(13)
C(14)
C(11)
C(10)
C(5)
C(20)
C(22)
C(27)
C(16)
C(6)
C(9)
C(8)
C(4)
C(3)
C(9)
C(8)
N(1)
C(2)
C(1)
C(31)
N(2)
C(23)
C(24)
N(2)
C(26)
C(27)
C(5)
C(4)
C(24)
C(28)
C(7)
N(1)
C(1)
O(1)
C(23)
C(25)
O(1)
S(1)
C(25)
C(30)
C(29)
C(2)
C(3)
S(1)
C(26)
C(29)
C(28)
Fig. 1. Molecular structures of 8a (a) (the second position of the disordered tertꢀbutyl group is not shown) and 8b(A) (b) with
displacement ellipsoids drawn at the 50% probability level.

356
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Ukhin et al.
a
b
b
b
a
0
c
c
a
0
b
Fig. 2. Fragments of the crystal structures of 8a (a) and 8b (b); hydrogenꢀbonded ribbons running along the crystallographic direction a
are shown. The central chain in the structure of 8b consists of molecules A; two terminal chains consist of molecules B.
in this region being doubled and broadened. The absence
of signals at δ 6.0—6.3 in the spectra of both compounds
suggests that indole is attached at position 3, although
other directions of the amidomethylation of indoles in
strongly acidic media were also described in the literaꢀ
Experimental
The IR spectra were recorded on a Varian Excalibur 3100
FIꢀIR instrument using the attenuated total internal reflection
(ATR) technique. The 1H NMR spectra were measured on
a Varian UNITYꢀ300 spectrometer. The mass spectra were obꢀ
tained on a Finnigan MAT INCOS 50 GCꢀmass spectrometer
using a direct inlet probe (EI, ionization energy was 70 eV).
2ꢀAminoꢀ3ꢀcyanoꢀ4,5ꢀdimethylthiophene (2a), 2ꢀaminoꢀ3ꢀ
cyanoꢀ4,5ꢀtetramethylenethiophene (2b), and 2ꢀaminoꢀ3ꢀethoxyꢀ
carbonylꢀ5ꢀethylthiophene (2c) were synthesized according to
the Gewald method9 by the condensation of carbonyl compounds
with malonodinitrile (2a,b) or ethyl cyanoacetate (2c) and sulfur
in the presence of bases.
1
ture.7 Apparently, this character of the H NMR spectra
of compounds 10a,b is associated with the formation of
rotational isomers. This phenomenon has recently been
described in detail in the study8 on the new catalytic methꢀ
od for the synthesis of phthalimidines containing the inꢀ
dole substituents at position 3 from the corresponding
hydroxy derivatives.
The 1H NMR spectra of the compounds synthesized are
given in Table 2.
Table 1. Geometric parameters of hydrogen bonds in the strucꢀ
tures of 8a and 8b
3ꢀ(3ꢀCyanoꢀ4,5ꢀdimethylthiophenꢀ2ꢀylamino)phthalide (3a).
A hot solution of oꢀformylbenzoic acid 1 (1.5 g, 10 mmol) in
PriOH (5 mL) was added to a hot solution of 2ꢀaminoꢀ3ꢀcyanoꢀ
4,5ꢀdimethylthiophene (2a) (1.52 g, 10 mmol) in PriOH (10 mL).
The reaction mixture was refluxed for 2 min, cooled, and kept
on ice for 1 h. The precipitate that formed was filtered off, washed
with cold PriOH and petroleum ether, and dried. A colorless
compound was obtained in a yield of 1.3 g, m.p. 170—175 °C.
Water (5 mL) was added to the filtrate, and the mixture was kept
on ice for 2 h. An additional amount (0.82 g) of the colorless
Comꢀ
pound
D—H...A
D—H H...A D...A D—H...A
/deg
Å
8a
O(2)—H(2)...O(1)i
0.85 1.99 2.799
0.85 1.99 2.820
158
166
144
8b(A) O(2)—H(2)...O(1)ii
8b(B) O(2´)—H(2´)...O(1´)ii 0.85 2.20 2.929
Symmetry codes: (i) –1 + x, y, z; (ii) 1 + x, y, z.

Phthalimidines from 2ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
357
Table 2. 1H NMR spectra (CDCl3) of compounds 3a—g, 4a—f, 8a,b, and 10a,b
Comꢀ
pound
δ, J/Hz
3а
3b
3c
2.09 (d, 3 Н, Me, J = 0.9); 2.19 (d, 3 Н, Me, J = 0.6); 5.39 (d, 1 H, NH, J = 9.75); 6.56 (d, 1 H, CH, J = 9.75);
7.50—7.80 (m, 3 H, CHarom); 7.93 (d, 1 H, C(7)H, J = 6.9)
1.80 (m, 4 H, CH2); 2.55 (m, 4 H, CH2); 5.44 (d, 1 H, NH, J = 9.8); 6.59 (d, 1 H, CH, J = 9.8); 7.50—7.85
(m, 3 H, CHarom); 7.95 (d, 1 H, C(7)H, J = 6.7)
1.23 (t, 3 H, Me, J = 7.5); 1.29 (t, 3 H, Me, J = 7.0); 2.65 (q, 2 H, CH2, J = 7.5); 4.20 (q, 2 H, CH2, J = 7.0);
6.62 (d, 1 H, CH, J = 10.0); 6.73 (t, 1 H, C(4´)H, J = 1.2); 7.50—7.80 (m, 3 H, CHarom); 7.93 (m, 1 H, CHarom);
8.12 (d, 1 H, NH, J = 10.0)
3d
3e
3f
3.82 (s, 3 H, Me); 6.83 (d, 1 H, CH, J = 9.0); 6.91 (m, 1 H, CHarom); 7.28 (d, 1 H, CHarom, J = 8.4); 7.50
(m, 1 H, CHarom); 7.55—7.85 (m, 3 H, CHarom); 7.90—8.10 (m, 2 H, CHароm); 8.65 (d, 1 H, NH, J = 9.0)
1.37 (t, 3 H, Me, J = 7.0); 4.33 (q, 2 H, CH2, J = 7.0); 5.02 (d, 1 H, NH, J = 10.5); 6.83 (d, 1 H, CH, J = 10.5);
6.93 (m, 2 H, CHarom); 7.40—7.80 (m, 3 H, CHarom); 7.90—8.20 (m, 3 H, CHarom
)
3.80 (s, 3 H, Me); 5.23 (d, 1 H, NH, J =10.8); 6.70—7.00 (m, 4 H, CH, CHarom); 7.13 (m, 1 H, CHarom);
7.50—7.80 (m, 3 H, CHarom); 7.93 (d, 1 H, C(7)H, J = 7.5)
3g
2.25 (s, 3 H, Me); 2.36 (s, 6 H, Me); 3.70 (d, 1 H, NH, J =12.0); 6.38 (d, 1 H, CH, J =12.0); 6.89 (s, 2 H,
C(3´)H, C(5´)H); 7.60 (m, 1 H, CHarom); 7.75 (m, 2 H, CHarom); 7.91 (d, 1 H, C(7)H, J = 7.5)
2.18 (s, 3 H, Me); 2.25 (d, 3 H, Me, J = 0.5); 2.35 (d, 3 H, Me, J = 0.5); 7.56 (s, 1 H, CH); 7.65 (m, 2 H,
CHarom); 7.77 (d, 1 H, CHarom, J = 7.3); 7.92 (d, 1 H, CHarom, J = 6.9)
1.87 (m, 4 H, CH2); 2.18 (s, 3 H, Me); 2.69 (m, 4 H, CH2); 7.55 (s, 1 H, CH); 7.57—7.80 (m, 3 H, CHarom);
7.92 (d, 1 H, C(7)H, J = 7.0)
4a
4b
4c
4d
1.38 (t, 3 H, Me, J = 7.1); 2.06 (s, 3 H, Me); 4.36 (q, 2 H, CH2, J = 7.1); 7.50—7.80 (m, 6 H, CH, CHarom);
7.90 (m, 1 H, CHarom); 8.10 (m, 2 H, CHarom
)
1.98 (s, 3 H, COMe); 2.14, 2.23, 2.28 (all s, 9 H, Me); 6.94 (d, 2 H, C(3´)H, C(5´)H, J = 2.4); 7.21 (s, 1 H,
CH); 7.60 (m, 3 H, CHarom); 7.91 (m, 1 H, C(7)H)
4e
4f
8a
2.25, 2.35 (both s, 6 H, Me); 7.27 (s, 1 H, CH); 7.40—7.80 (m, 3 H, CHароm); 7.93 (d, 1 H, C(7)H, J = 7.5)
1.87 (m, 4 H, CH2); 2.69 (m, 4 H, CH2); 7.26 (s, 1 H, CH); 7.40—7.80 (m, 3 H, CHarom); 7.93 (d, 1 H, C(7)H, J = 7.5)
1.34 (s, 18 H, But); 2.11, 2.25 (both s, 6 H, Me); 5.22 (s, 1 H, OH); 6.44 (s, 1 H, CH); 6.96 (s, 2 H, C(2´)H,
C(5´)H); 7.29 (m, 1 H, CHarom); 7.53 (m, 2 H, CHarom); 7.98 (d, 1 H, C(7)H, J = 7.2)
8b
1.35 (s, 18 H, But); 1.78 (m, 4 H, CH2); 2.30—2.90 (m, 4 H, CH2); 5.23 (s, 1 H, OH); 6.42 (s, 1 H, CH);
6.96 (s, 2 H, C(2´)H, C(6´)H); 7.29 (m, 1 H, CHarom); 7.53 (m, 2 H, CHarom); 7.98 (d, 1 H, C(7)H, J = 7.5)
2.03 (m, 3 H, Me); 2.15 (m, 3 H, Me); 6.30—8.10 (m, 10 H, CH, CHarom); 8.30 (m, 1 H, NH)
1.73 (br.s, 4 H, CH2); 2.52 (br.s, 4 H, CH2); 6.35—8.20 (m, 10 H, CH, CHarom); 8.35 (m, 1 H, NH)
10a
10b
compound characterized by the identical IR spectrum was obꢀ
tained, m.p. 170—173 °C. The total yield of phthalide 3a
was 2.12 g (75%). Found (%): C, 63.43; H, 4.55; S, 11.65.
C15H12N2O2S. Calculated (%): C, 63.36; H, 4.25; S, 11.27. IR,
ν/cm–1: 3253 (NH), 2214 (CN), 1774 (CO), 1560 (arom.), 1058,
901 (C—O—C). MS, m/z: 284 [M]+.
3ꢀ(3ꢀCyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀylamino)phthalide
(3b) was synthesized analogously to 3a from a solution of 1 (0.75 g,
5 mmol) in PriOH (10 mL) and a solution of 2ꢀaminoꢀ3ꢀcyanoꢀ
4,5ꢀtetramethylenethiophene (2b) (0.9 g) in PriOH (15 mL).
After cooling, an emulsion was precipitated with water, and the
mixture was kept for 1 day. The precipitate that formed was
filtered off, washed with H2O, and dried. The yield was 1.2 g
(77%). Analytically pure compound 3b was obtained by recrystalꢀ
lization from PriOH. A colorless compound, m.p. 155—157 °C
(from PriOH). Found (%): C, 65.53; H, 4.62; S, 10.60.
C17H14N2O2S. Calculated (%): C, 65.79; H, 4.55; S, 10.33. IR,
ν/cm–1: 3267 (NH), 2210 (CN), 1756 (CO), 1559 (arom.), 1067,
877 (C—O—C). MS, m/z: 310 [M]+.
oxyꢀ5ꢀethylthiophene (2c) (3.5 g, 17 mmol) in EtOH (5 mL).
The reaction mixture was cooled with ice and triturated. Then
EtOH (10 mL) was added to the solidified mixture. The crystals
that formed were filtered off, washed with EtOH, and dried.
A colorless compound was obtained in a yield of 3.75 g, m.p.
115 °C. After 1 day, an addition amount (0.93 g) of the product,
which was characterized by the identical IR spectrum, was isoꢀ
lated from the filtrate, m.p. 110—113 °C. The total yield was
4.68 g (80%). Found (%): C, 61.57; H, 5.32; S, 9.90.
C17H17NO4S. Calculated (%): C, 61.62; H, 5.17; S, 9.68. IR,
ν/cm–1: 3263 (NH), 1770, 1665 (CO), 1567, 1551 (arom.), 1052,
893 (C—O—C). MS, m/z: 331 [M]+.
3ꢀ(2ꢀMethoxycarbonylphenylamino)phthalide (3d). A. A mixꢀ
ture of compound 1 (0.5 g, 3.3 mmol) and methyl anthranilate
(0.6 mL) was heated over a stove. The solidification of the mixꢀ
ture accompanied by elimination of water was observed. Then
PriOH (3 mL) was added, the mixture was refluxed, the precipiꢀ
tate was triturated, and the mixture was cooled. The precipitate
that formed was filtered off, washed with PriOH, and dried.
A colorless compound. The yield was 0.87 g (92%). Found (%):
C, 67.92; H, 4.83; N, 4.76. C16H13NO4. Calculated (%):
C, 67.84; H, 4.63; N, 4.94. IR, ν/cm–1: 3322 (NH); 1764,
3ꢀ(3ꢀEthoxycarbonylꢀ5ꢀethylthiophenꢀ2ꢀylamino)phthalide
(3c) was synthesized analogously to 3a from a solution of 1 (3 g,
20 mmol) in EtOH (5 mL) and a solution of 2ꢀaminoꢀ3ꢀcarbethꢀ

358
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Ukhin et al.
1682 (CO); 1587, 1518 (arom.); 1063, 886 (C—O—C). MS, m/z:
283 [M]+.
3ꢀAcetoxyꢀ2ꢀ(4ꢀethoxycarbonylphenyl)ꢀ1,3ꢀdihydroisoindolꢀ
1ꢀone (4c). A mixture of phthalide 3e (0.6 g, 2 mmol) and Ac2O
(1.5 mL) was heated until dissolution, refluxed for 2 min, and
cooled. Then BuiOH (5 mL) was added, and the reaction mixꢀ
ture was cooled. The precipitate that formed was filtered off,
washed with cold BuiOH and petroleum ether, and dried. The
yield was 0.5 g (74%). To prepare the chemically pure product,
the compound was recrystallized from isooctane. Colorless crysꢀ
tals, m.p. 122—123 °C. Found (%): C, 67.03; H, 5.27; N, 4.25.
B. Methyl anthranilate (0.6 mL) was added to a boiling soluꢀ
tion of oꢀformylbenzoic acid (0.5 g, 3.3. mol) in PriOH (5 mL).
After a short period of time, almost immediate crystallization
occurred. The reaction mixture was cooled. The precipitate that
formed was filtered off, washed with cold PriOH and petroleum
ether, and dried. A colorless compound, m.p. 202—204 °C (from
PriOH). The yield was 0.9 g (95%).
3ꢀ(4ꢀEthoxycarbonylphenylamino)phthalide (3e). A hot soluꢀ
tion of compound 1 (0.5 g, 3.3 mmol) in PriOH (3 mL) was
added to a hot solution of 4ꢀaminoethyl benzoate (0.55 g,
3.3 mmol) in PriOH (5 mL). The reaction mixture was heated to
reflux, cooled, and triturated. The precipitate that formed was
filtered off, washed with cold PriOH and petroleum ether, and
dried. A colorless compound, m.p. 190—192 °C. The yield was
0.86 g (87%). Found (%): C, 68.43; H, 5.32; N, 4.59. C17H15NO4.
C19H17NO5. Calculated (%): C, 67.25; H, 5.05; N, 4.13. IR, ν/cm–1
1731, 1703 (CO); 1606, 1514 (arom.). MS, m/z: 339 [M]+.
:
3ꢀAcetoxyꢀ1,3ꢀdihydroꢀ2ꢀ(2,4,6ꢀtrimethylphenyl)isoindolꢀ1ꢀ
one (4d). A mixture of phthalide 3g (0.53 g, 2 mmol) and Ac2O
(1 mL) was refluxed for 1 min and cooled. Then MeOH (5 mL)
and water (25 mL) were added. The oil that formed was trituratꢀ
ed with ice cooling until the mixture completely solidified (~3 h).
The precipitate was filtered off, washed with water, and dried.
A colorless compound, m.p. 100—101 °C. The yield was 0.54 g
(87%). After recrystallization from isooctane (20 mL), compound
4d was obtained in a yield of 0.4 g (64%). Found (%): C, 73.44;
H, 6.27; N, 4.82. C19H19NO3. Calculated (%): C, 73.77; H, 6.19;
N, 4.53. IR, ν/cm–1: 1746, 1712 (CO); 1611, 1486, 1466 (arom.).
MS, m/z: 309 [M]+.
Synthesis of compounds 4e,f (general procedure). Thionyl
chloride (0.25 mL) was added to phthalide 3a or 3b (1 mmol).
After the cessation of gas evolution and the formation of a homoꢀ
geneous mixture, an excess of SOCl2 was removed in vacuo. The
residue was recrystallized from isooctane (60—80 mL).
3ꢀChloroꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀdimethylthiophenꢀ2ꢀyl)ꢀ1,3ꢀdiꢀ
hydroisoindolꢀ1ꢀone (4e). A paleꢀyellow crystalline compound,
m.p. 143—144 °C (from isooctane). The yield was 0.41 g
(68%). Found (%): C, 59.90; H, 3.93; Cl, 11.40; S, 10.23.
C15H11ClN2OS. Calculated (%): C, 59.50; H, 3.66; Cl, 11.71;
S, 10.59. IR, ν/cm–1: 2213 (CN); 1727 (CO); 1615, 1573, 1504
(arom.). MS, m/z: 302 [M]+.
Calculated (%): C, 68.68; H, 5.09; N, 4.71. IR, ν/cm–1
:
3314 (NH); 1732, 1692 (CO); 1604, 1524 (arom.); 1078, 873
(C—O—C). MS, m/z: 297 [M]+.
3ꢀ(2ꢀMethoxyphenylamino)phthalide (3f) was synthesized
analogously to 3e from a solution of compound 1 (0.5 g,
3.3 mmol) in PriOH (5 mL) and oꢀanisidine (0.5 mL, 4.5 mmol).
A colorless compound, m.p. 161—162 °C. The yield was 0.82 g
(96%). Found (%): C, 70.39; H, 5.24; N, 5.52. C15H13NO3.
Calculated (%): C, 70.58; H, 5.13; N, 5.49. IR, ν/cm–1: 3373
(NH); 1747 (CO); 1600, 1505 (arom.); 1020, 855 (C—O—C).
MS, m/z: 255 [M]+.
3ꢀ(2,4,6ꢀTrimethylphenylamino)phthalide (3g). 2,4,6ꢀTriꢀ
methylaniline (5) (0.5 mL) was added to a hot solution of comꢀ
pound 1 (0.5 g, 3.3 mmol) in PriOH (3 mL). The reaction mixꢀ
ture was heated to reflux, cooled with ice water, and triturated.
An equal volume of petroleum ether was added to the voluminous
crystalline precipitate. Then the precipitate was filtered off,
washed with petroleum ether, and dried. A colorless compound,
m.p. 130 °C. The yield was 0.65 g (quantitative). Found (%):
C, 76.19; H, 6.70; N, 5.56. C17H17NO2. Calculated (%):
C, 76.38; H, 6.41; N, 5.24. IR, ν/cm–1: 3357 (NH); 1757 (CO);
1615, 1486 (arom.); 1065, 867 (C—O—C). MS, m/z: 267 [M]+.
3ꢀAcetoxyꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀdimethylthiophenꢀ2ꢀyl)ꢀ1,3ꢀdiꢀ
hydroisoindolꢀ1ꢀone (4a). A mixture of phthalide 3a (0.85 g,
3 mmol) and Ac2O (2.5 mL) was heated until dissolution, reꢀ
fluxed for 2 min, cooled with ice, and triturated. Then PriOH
(3 mL) was added, and the mixture was kept on ice for 10 min.
The precipitate that formed was filtered off, washed with cold
PriOH and petroleum ether, and dried. A yellowish compound,
m.p. 155—160 °C. The yield was 0.88 g (90%). Found (%):
C, 62.86; H, 4.11; N, 8.69; S, 9.43. C17H14N2O3S. Calculatꢀ
ed (%): C, 62.56; H, 4.32; N, 8.58; S, 9.82. IR, ν/cm–1: 2217
(CN); 1748, 1726 (CO); 1578, 1504. MS, m/z: 326 [M]+.
3ꢀAcetoxyꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀyl)ꢀ
1,3ꢀdihydroisoindolꢀ1ꢀone (4b). A mixture of phthalide 3b (0.62 g,
2 mmol) and Ac2O (1.5 mL) was heated until dissolution, reꢀ
fluxed for 1 min, and cooled. Then PriOH (20 mL) was added,
and the mixture was cooled with ice. The precipitate that formed
was filtered off, washed with cold PriOH and petroleum ether,
and dried. A yellowish compound, m.p. 155—160 °C. The yield
was 0.55 g (78%). Found (%): C, 64.90; H, 4.12; N, 8.13; S, 8.75.
C19H16N2O3S. Calculated (%): C, 64.76; H, 4.58; N, 7.95;
S, 9.10. IR, ν/cm–1: 2214 (CN); 1753, 1723 (CO); 1583,
1508 (arom.). MS, m/z: 352 [M]+.
3ꢀChloroꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀyl)ꢀ1,3ꢀ
dihydroisoindolꢀ1ꢀone (4f). A paleꢀyellow crystalline compound,
m.p. 161—163 °C (from isooctane). The yield was 0.2 g (61%).
Found (%): C, 61.73; H, 4.11; Cl, 10.41; S, 9.30. C17H13ClN2OS.
Calculated (%): C, 62.10; H, 3.99; Cl, 10.78; S, 9.75. IR, ν/cm–1
:
2210 (CN); 1726 (CO); 1613, 1574, 1505 (arom.). MS, m/z:
328 [M]+.
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀdiꢀ
methylthiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroisoindolꢀ1ꢀone (8a). A mixture
of phthalimidine 5a (0.33 g, 1 mmol), 2,6ꢀdiꢀtertꢀbutylphenol
(7) (0.3 g, 1.4 mmol), and CF3COOH (0.2 mL) was refluxed for
1 min and cooled. Then PriOH (5 mL) was added, and the
mixture was heated until homogenezation, after which colorless
crystals formed. The reaction mixture was cooled with ice. The
precipitate that formed was filtered off, washed with cold EtOH
and petroleum ether, and dried. A colorless compound, m.p.
200—203 °C. The yield was 0.39 g (82%). Found (%): C, 74.03;
H, 7.01; N, 6.18; S, 6.95. C29H32N2O2S. Calculated (%):
C, 73.70; H, 6.82; N, 5.93; S, 6.78. IR, ν/cm–1: 3475 br. (OH);
2205 (CN); 1695 (CO); 1600, 1595, 1567 (arom.). MS, m/z:
472 [M]+.
3ꢀ(3,5ꢀDiꢀtertꢀbutylꢀ4ꢀhydroxyphenyl)ꢀ2ꢀ(3ꢀcyanoꢀ4,5ꢀtetraꢀ
methylenethiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroisoindolꢀ1ꢀone (8b). A mixꢀ
ture of phthalimidine 5b (0.35 g, 1 mmol), 2,6ꢀdiꢀtertꢀbutylꢀ
phenol (7) (0.3 g, 1.4 mmol), and CF3COOH (0.2 mL) was
refluxed for 1 min and cooled. Then PriOH (5 mL) was added

Phthalimidines from 2ꢀaminothiophenes
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
359
and the mixture was kept on ice for 1 h. The precipitate that
formed was filtered off, washed with cold EtOH and petroleum
ether, and dried. A colorless compound, m.p. 210—213 °C. The
yield was 0.3 g (60%). Found (%): C, 74.33; H, 7.01; N, 5.83;
S, 6.51. C31H34N2O2S. Calculated (%): C, 74.66; H, 6.87; N, 5.62;
S, 6.43. IR, ν/cm–1: 3420 br. (OH); 2205 (CN); 1695 (CO);
1615, 1600, 1567 (arom.). MS, m/z: 498 [M]+.
2ꢀ(3ꢀCyanoꢀ4,5ꢀdimethylthiophenꢀ2ꢀyl)ꢀ1,3ꢀdihydroꢀ3ꢀ(3ꢀ
indolyl)isoindolꢀ1ꢀone (10a). A mixture of phthalimidine 5a (0.33 g,
1 mmol), indole (9) (0.12 g, 1 mmol), and CF3COOH (1 mL)
was kept at room temperature for 3 h, EtOH (5 mL) was added,
and the reaction mixture was cooled with ice. The precipitate
that formed was filtered off, washed with cold EtOH and petroꢀ
leum ether, and dried. Analytically pure paleꢀyellow compound
10a was obtained in a yield of 0.06 g, m.p. 200—201 °C (from
PriOH). Water (20 mL) was added to the filtrate, and an addiꢀ
tional amount (0.25 g) of compound 10a was isolated. The total
yield was 0.31 g (81%). Found (%): C, 71.90; H, 4.40; N, 10.73;
S, 8.81. C23H17N3OS. Calculated (%): C, 72.04; H, 4.47;
N, 10.96; S, 8.36. IR, ν/cm–1: 3300 br. (NH); 2215 (CN); 1705
(CO); 1614, 1568, 1503 (arom.). MS, m/z: 383 [M]+.
2ꢀ[2ꢀ(3ꢀCyanoꢀ4,5ꢀtetramethylenethiophenꢀ2ꢀyl)]ꢀ1,3ꢀdiꢀ
hydroꢀ3ꢀ(3ꢀindolyl)isoindolꢀ1ꢀone (10b). A mixture of compound
5b (0.35 g, 1 mmol), indole (9) (0.12 g, 1 mmol), and CF3COOH
(1 mL) was kept at room temperature for 3 h, EtOH (7 mL) was
added, and the reaction mixture was cooled with ice. The crysꢀ
talline precipitate that formed was filtered off, washed with cold
EtOH and petroleum ether, and dried. A yellow compound was
obtained in a yield of 0.14 g, m.p. 210—211 °C (from PriOH). An
additional amount (0.14 g) of compound 10b was precipitated
from the filtrate. The total yield was 0.28 g (68%). Found (%):
C, 73.40; H, 4.59; N, 10.34; S, 7.65. C25H19N3OS. Calculatꢀ
ed (%): C, 73.33; H, 4.68; N, 10.26; S, 7.83. IR, ν/cm–1: 3328
br. (NH); 2217 (CN); 1709 (CO); 1613, 1568, 1502 (arom.).
MS, m/z: 409 [M]+.
Xꢀray diffraction study. Single crystals of compounds 8a and
8b were grown by slow evaporation of their solutions in PriOH.
The experimental intensities were measured on a SMART
APEX2 CCD diffractometer (λ(MoꢀKα) = 0.71073 Å, graphite
monochromator, ωꢀscanning technique). The measured intenꢀ
sities were processed using the SAINT Plus,10 SADABS,11 and
APEX2 programs.12 The structures of the complexes were solved
Table 3. Crystallographic data and the Xꢀray data collection and structure refinement statistics for compounds
8a and 8b
Parameter
8а
8b
Molecular formula
Molecular weight
C29H32N2O2S
472.63
C31H34N2O2S
498.66
Crystal color
Crystal shape
Colorless
Prism
Colorless
Plate
Crystal dimensions/mm
T/К
0.21×0.18×0.12
100(2)
0.32×0.26×0.16
100(2)
Crystal system
Space group
Monoclinic
P21/c
Triclinic
P–1
a/Å
b/Å
c/Å
α/deg
9.9095(16)
17.281(3)
15.463(3)
90
90.572(3)
90
2647.8(7)
4
1.186
9.944(2)
15.097(4)
18.067(4)
96.141(5)
92.267(5)
93.588(5)
2688.6(11)
4
β/deg
γ/deg
V/Å3
Z
dcalc/g cm–3
1.232
0.151
μ/mm–1
0.150
F(000)
1008
1064
θꢀScan range/deg
1.77—28.00
28662
6380
0.0508
1.13—28.00
29921
12911
0.0863
Number of measured reflections
Number of independent reflections
Rint
Number of refined parameters
Number of reflections with I > 2σ(I)
Completeness of the data set (%)
GOOF
315
5370
99.7
1.120
661
6966
99.6
0.983
R1(F)a (I > 2σ(I)
0.0689
0.1649
0.578/–0.462
0.0647
0.1479
0.473/–0.455
wR2(F2)b (based on all reflections)
Residual electron density (min/max)/e•Å–3
a R1 = Σ|F0 – |Fc||/Σ(F0).
2
2 2
2 2 1/2
b wR2 = (Σ[w(F0 – Fc ) ]/Σ[w(F0 ) ]
.

360
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 2, February, 2011
Ukhin et al.
by direct methods and refined by the fullꢀmatrix leastꢀsquares
method with anisotropic displacement parameters for all nonhyꢀ
drogen atoms based on F2hkl. In compound 8a, the C(16) and
C(17) atoms of the tertꢀbutyl group are disordered over two sites
with equal occupancies and were refined isotropically. The hyꢀ
drogen atoms, except for the hydrogen atoms at the oxygens,
were positioned geometrically. The hydrogen atoms at the oxyꢀ
gens were located in difference electron density maps and
then normalized to the distance of 0.85 Å. The positions of all
hydrogen atoms were refined using a riding model (Uiso(H) =
= nUeq(C,O), where n = 1.5 for the carbon atoms of the methyl
groups and the oxygen atoms, n = 1.2 for the other C atoms).
The structure solution and refinement was performed with the
use of the SHELXTL program package.13 Crystallographic data
and the Xꢀray data collection and structure refinement statistics
are given in Table 3.
5. R. E. Valter, V. P. Tsiekure, Khim. Geterotsikl. Soedin., 1975,
1258 [Chem. Heterocycl. Compd. (Engl. Transl.), 1975,
11, 1476].
6. L. Yu. Ukhin, K. Yu. Suponitskii, L. V. Belousova, T. N.
Gribanova, Izv. Akad. Nauk, Ser. Khim., 2009, 919 [Russ.
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7. A. Muminov, L. G. Yudin, E. Ya. Zinchenko, N. N. Romaꢀ
nova, A. N. Kost, Khim. Geterotsikl. Soedin., 1985, 1218
[Chem. Heterocycl. Compd. (Engl. Transl.), 1985, 21, 1012].
8. N. P. Andryukhova, O. A. Pozharskaya, G. A. Golubeva,
L. A. Sviridova, A. V. Sadovoi, Khim. Geterotsikl. Soedin.,
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99, 94.
10. SMART and SAINT, Release 5.0, Area Detector control and
Integration Software, Bruker AXS, Inc., Analytical XꢀRay
Instruments, Madison (WI), USA, 1998.
11. G. M. Sheldrick, SADABS: A Program for Exploiting the
Redundancy of Areaꢀdetector XꢀRay Data, University of Götꢀ
tingen, Göttingen, Germany, 1999.
12. APEX2 and SAINT, Bruker AXS, Inc., Madison (WI),
USA, 2005.
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in revised form November 23, 2010