Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic studies, and crystal structure determination

Article abstract of DOI:10.1007/s00706-016-1796-5

Abstract: New benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines are prepared in the reaction of o-phthalaldehyde and substituted 2-aminobenzothiazoles and 2-aminobenzimidazoles. The optimization of these reactions is discussed, and the reaction mechanisms are proposed based on the experimental findings. Isoindolines with other heterocyclic substituents are prepared as a confirmation of the proposed mechanisms. Molecular and crystal structures of several prepared compounds are determined by a single crystal X-ray diffraction. These structures are found to be in line with projections based on the chemical and spectroscopic properties, and thus offer an additional confirmation of the proposed reaction mechanisms. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1796-5

Monatsh Chem
DOI 10.1007/s00706-016-1796-5
ORIGINAL PAPER
Benzothiazolyl- and benzimidazolyl-substituted
1-iminoisoindolines: synthesis, mechanistic studies, and crystal
structure determination
1
2
3
•
Irena Sovic Iva Orehovec1 Vladimir Stilinovic Nikola Basaric
•
•
•
´
´
´
Grace Karminski-Zamola1
Received: 23 February 2016 / Accepted: 5 June 2016
Ó Springer-Verlag Wien 2016
Abstract New benzothiazolyl- and benzimidazolyl-substi-
Keywords Heterocycles Á Reaction mechanisms Á
Schiff bases Á X-ray structure determination
tuted 1-iminoisoindolines are prepared in the reaction of o-
phthalaldehyde and substituted 2-aminobenzothiazoles and
2-aminobenzimidazoles. The optimization of these reactions
is discussed, and the reaction mechanisms are proposed
based on the experimental findings. Isoindolines with other
heterocyclic substituents are prepared as a confirmation of
the proposed mechanisms. Molecular and crystal structures
of several prepared compounds are determined by a single
crystal X-ray diffraction. These structures are found to be in
line with projections based on the chemical and spectro-
scopic properties, and thus offer an additional confirmation
of the proposed reaction mechanisms.
Introduction
Derivatives of isoindoline have received great attention
from synthetic organic and medicinal chemists in recent
years due to their wide range of different biological activity,
as well as their application in herbicide and dye industries.
Natural derivatives of isoindolines that were first isolated in
the early 60s showed diverse biological activity [1, 2]; for
example, staurosporine isolated from the bacteria Strepto-
myces staurosporeus showed antimicrobial, hypotensive,
and cytotoxic activity and acts as a protein kinase C inhibitor
[3]. Recently prepared synthetic derivatives of isoindolines
exhibit a range of biological activities, such as anti-inflam-
matory [4], antipsychotic [5, 6], antihypertensive [7, 8], and
antitumor [9–11] activity. Moreover, they act as inhibitors of
dipeptidilpeptidase [12, 13] and protein kinase [14], in
addition to exhibiting a calatase-like activity [15]. Further-
more, derivatives of isoindoline serve as very convenient
ligands in coordination and organometallic chemistry
[16–18]. Most of the synthetic methods for the preparation
of isoindoline skeleton include o-phthalaldehyde and cor-
responding aliphatic and aromatic amines as a starting
material [19–21]. Synthetic methods starting from other
compounds include phthalonitrile, phthalanhydride, and
phthalaldehyde acid as well as multicomponent synthesis
[22–24]. It is worth mentioning several papers describing a
synthesis of N-substituted isoindolines by one-pot three-
component reaction of phthalaldehydic acid or phthaloni-
trile, primary amine and 2-mercaptobenzimidazole, 1H-
indole, TMSCN or alcohol [25–28]. These reactions were
Graphical abstract
´
& Irena Sovic
isovic@fkit.hr
& Grace Karminski-Zamola
gzamola@fkit.hr
1
Department of Organic Chemistry, Faculty of Chemical
Engineering and Technology, University of Zagreb,
Zagreb, Croatia
2
Department of Chemistry, Faculty of Science, University
of Zagreb, Zagreb, Croatia
3
Department of Organic Chemistry and Biochemistry, Ruder
¯
ˇ ´
Boskovic Institute, Zagreb, Croatia
123

´
I. Sovic et al.
found to be simple and environmentally benign. In the last
several years, new methods for the synthesis of 1- and 1,3-
substituted isoindolines are developed. For example,
1-isoindolecarboxylic acid esters and the corresponding
isoindolines have been selectively synthesized by efficient
palladium-catalyzed intramolecular a-arylation reactions of
a-amino acid esters, where a slight change of reaction con-
ditions leads to the desired product [29]. Also reported is a
synthesis of a series of 1-substituted isoindolines as well as
tetrahydro-b-carbolines and tetrahydroisoquinolines via
catalyst free [30] or palladium-catalyzed [31, 32] domino
Heck-aza-Michael reactions. A stereoselective synthesis of
1,3-disubstituted isoindolines with a wide range of sub-
stituents is described as well: a tandem reaction consisting of
a nucleophilic addition/intramolecular aza-Michael reaction
(IMAMR) on Ellman’s tert-butylsulfinyl imines, bearing a
Michael acceptor in the ortho position [33, 34]. Moreover, a
synthetic and structural study into bis-imino-substituted
diiminoisoindolines, which are synthesized either via CaCl2
mediated reaction of phthalonitrile with primary amines, or
via direct reaction of these amines with unsubstituted
diiminoisoindoline, was reported [35]. Facile access to
enantioenriched isoindolines bearing a quaternary stere-
ogenic centre and a tertiary stereogenic centre was
developed via one-pot sequential Cu(I)-catalyzed asym-
Results and discussion
Chemistry
For the synthesis of target compounds first were prepared
required precursors. 2-Amino-6-cyanobenzothiazole (2) was
prepared from 4-aminobenzonitrile in two-step reaction over
the corresponding thiocyanate according to the literature
[41]. 2-Amino-5-cyanobenzimidazole (7d) was prepared in
multistep synthesis starting from 4-aminobenzonitrile over
acetylamino, nitro compound, and 4-cyano-1,2-phenylene-
diamine, which was cyclised using BrCN into 7d according
to the literature [42]. 2-Amino-5-nitrobenzimidazole (7e)
and 2-amino-N-phenylbenzimidazole (10d) were prepared
by cyclisation from 4-nitro-1,2-phenylenediamine and N-
phenyl-1,2-phenylenediamine, respectively, following the
same procedure.
To optimize reaction conditions for the synthesis of
target compounds, we used test reaction of o-phthalalde-
hyde and 2-amino-6-cyanobenzothiazole (2) (Scheme 1).
In our previous report, we presented the synthesis of phe-
nyl- and pyridyl-substituted 1-iminoisoindolines, where
reactions were carried out in absolute ethanol in neutral or
acidic conditions [40]. The reaction of o-phthalaldehyde
with two equivalents of 2-amino-6-cyanobenzothiazole (2)
in absolute ethanol after 24 h of heating gave 2-(1-ethoxy-
3-hydroxyisoindolin-2-yl)benzothiazole-6-carbonitrile (3)
in 73 % yield. In acidic conditions, the reaction product
was the same. The structure of compound 3 was also
confirmed by X-ray diffraction. Next, we used dry toluene
as an aprotic solvent to avoid the reaction with solvent
molecule. After 8 h of heating, the product 2-(1,3-dihy-
droxyisoindolin-2-yl)benzothiazole-6-carbonitrile (4) was
obtained in 58 % yield. This type of compound was also
observed by Takahashi et al. [38]. Finally, when the
reaction was carried out in dry toluene in acidic conditions
(glacial acetic acid), the target compound 1-imino-substi-
tuted-2-N-substituted isoindoline 5 was obtained in the
mixture with N-substituted isoindolin-1-one 6. The com-
pounds were separated by column chromatography in 35
and 9 % yield, respectively. It seems that, because of lower
nucleophilicity of the amino group of 2-amino-6-
cyanobenzothiazole, the reaction was successful solely in
acidic conditions.
metric
1,3-dipolar
cycloaddition/aromatization
of
azomethine ylide with quinone derivatives [36]. Most of the
synthetic methods described are oriented towards the syn-
thesis of 1- and 1,3-substituted isoindolines and include use
of expensive starting material as well as catalysts and a
requirement for protection of nitrogen with Boc, Tc, etc.
However, there are several papers that describe the synthesis
of 1-imino-substituted isoindolines. For example, Takahashi
et al. reported a condensation reaction of o-phthalaldehyde
and substituted aniline to afford 1-imino-substituted isoin-
dolines, but other products were isolated depending on the
amine structures [37, 38].
Because of the interesting and diverse biological activity
of isoindoline derivatives, we prepared novel benzothia-
zolyl- and benzimidazolyl-substituted 1-iminoisoindolines
starting from o-phthalaldehyde and corresponding hetero-
cyclic amines, as a part of our ongoing research to develop
novel compounds with potential antitumor activity. We
previously reported the condensation reaction of o-phtha-
laldehyde and substituted anilines and aminopyridines,
where the isolated products were the expected 2-aryl-1-(N-
arylimino)isoindolines [39, 40]. The reactions were carried
out in absolute ethanol in neutral or acidic reaction condi-
tions. However, in the reaction with bicyclic heteroaromatic
amines, such as 2-aminobenzothiazole and 2-aminobenz-
imidazole derivatives, different products were obtained
depending on the solvent and other reaction conditions.
Using the optimized reaction conditions, other target
compounds were prepared (Scheme 2). Unsubstituted
2-aminobenzothiazole
7a,
and
nitro-substituted
2-aminobenzothiazole 7b and 2-aminobenzimidazole 7e in
the reaction with o-phthalaldehyde gave corresponding
1-imino-substituted-2-N-substituted isoindolines 8a in the
yield of 41 %, 8b in the yield of 28 %, and 8e (12 %).
Unsubstituted 2-aminobenzimidazole 7c gave mixture of
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
CHO
N
S
Scheme 1
+
H N
2
2
CN
CHO
2
1
Toluene
Toluene
EtOH
glac. acetic acid
Δ
Δ
Δ
CN
S
OH
N
N
N
N
N
H5
N
OC2
N
S
5
CN
N
OH
4
S
+
S
CN
OH
3
N
NC
N
S
CN
O
6
cyano-substituted 2-aminobenzimidazole 7d gave 1-imino-
substituted-2-N-substituted isoindoline 8d (6 %) and N-
substituted isoindolin-1-one 9 (58 %), the same as cyano-
substituted 2-aminobenzothiazole 2.
Scheme 2
CHO
R
X
N
+
2H2N
7a
7b
7c
7d
7e
X = S, R = H
CHO
X = S, R = NO2
X = NH, R = H
X = NH, R = CN
X = NH, R = NO2
1
7a-7e
Toluene
glac. acetic acid
All compound structures were confirmed by the analysis
1
of H and 13C NMR spectra except nitro-substituted com-
Δ
pounds 8b and 8e and cyano-substituted compound 8d,
where 13C NMR analysis failed due to their very low sol-
ubility in DMSO. Characteristic chemical shifts for
N
N
CN
N
X
R
+
N
N
1
8a-8e
isoindoline ring were found at 5.55–4.93 ppm in H NMR
X
N
H
spectra as well as at 54.12–50.22 ppm in 13C NMR spectra
which matches CH2 group of isoindoline (5, 6, 8a–8e, 9).
The presence of imino group was confirmed by the
chemical shift at 157.33–155.36 ppm (5, 8a, 8c) in 13C
NMR spectra characteristic for quaternary carbon atom of
imino group. In 13C NMR spectra of isoindolinone 6 and 9
chemical shifts at 167.07 and 167.02 ppm, respectively,
support the presence of carbonyl group. Compound struc-
tures were also confirmed by the analysis of IR spectra. The
main attributes of IR spectra are C=N stretching band of
imino group at 1667–1617 cm-1 for isoindolines 6 and 8a–
8e and C=O stretching band of carbonyl group at 1696 and
1689 cm-1 for isoindolinones 6 and 9. Other bands that are
characteristic for different substituents on benzothiazole
and benzimidazole ring are C:N stretching band of cyano
group at 2222–2219 cm-1 (5, 6, 8d, 9), NO2 asymmetric
stretching band of nitro group at 1503 and 1518 cm-1, and
NO2 symmetric stretching bands of nitro group at
1324–1277 cm-1 (8b, 8e).
N
O
8a
8b
8c
8d
8e
X = S, R = H
9
R
X = S, R = NO2
X = NH, R = H
X = NH, R = CN
X = NH, R = NO2
stereoisomers 8c which were separated based on the dif-
ference in solubility. Less soluble Z stereoisomer was
isolated from the hot DMF solution in the 42 % yield, and
E stereoisomer was obtained by slow cooling of the solu-
1
tion in the 6 % yield. Z and E isomers differ in the H
NMR spectra by the position of NH protons, which are for
Z isomer 12.48 and 12.15 ppm and for E isomer 12.71 and
10.82 ppm. In addition, proton chemical shifts character-
istic for aromatic protons were found in the narrow area at
7.80–7.10 ppm for Z isomer, while for E isomer, two
separate signals at lower magnetic field were observed
which indicates difference in the surroundings of the aro-
matic protons. The structure of E isomer was also
confirmed by X-ray diffraction. In the reactions with
unsubstituted and nitro-substituted amines 7a, 7b, 7c, and
7e, monosubstituted isoindolinone was not detected, while
Based on the isolated products 3–9 and our previous
results [39, 40], mechanisms for the formation of isoin-
doline derivatives can be proposed. As we have reported,
the reaction of o-phthalaldehyde with anilines and
aminopyridines is unambiguous giving expected
123

´
I. Sovic et al.
Schiff base, where the substituent is sterically hindered
highly bulky 2,6-diisopropylaniline.
Scheme 3
O
C
HO
C
HO
H
H
NHR
H
H+
To confirm the proposed mechanistic scenarios, we
conducted reactions with some other amino-substituted
heterocycles, i.e., thiazole, pyrimidine, and triazole, as well
as N-substituted benzimidazoles. Isolated products are
given in Fig. 1.
H+
C
H
R
H
N
H2N
R
H
C
O
C
O
C
O
H
A
HO
HO
HO
H
H
H
-OH-
C
EtOH
Amino-substituted thiazole gave in the same reaction
conditions expected iminoisoindoline 11a and isoin-
dolinone 11b, while amino-substituted pyrimidine gave
only isoindolinone 11c. When 4-amino-1,2,4-triazole was
introduced, di-Schiff base 11d was isolated as terminal
compound which could be in favour of the assumption that
the o-disubstituted Schiff base is the intermediate in the
formation of isoindoline ring. Nitrogen atom of the imino
group in 11d is probably less nucleophilic and does not
react further to give isoindoline ring. Substitution on the
nitrogen atom of the benzimidazole ring changes reaction
pathway, probably due to a steric hindrance. Reactions
were successful only in toluene in neutral conditions. In the
case of N-phenyl-substituted 2-aminobenzimidazole, the
isolated product 11e is similar to compound 3, where one
OH group is substituted with one molecule of amine and in
the case of N-methyl-substituted 2-aminobenzimidazole,
bicyclic product 11f was isolated. It is assumed that 10e is
more nucleophilic but sterically hindered and thus isoin-
doline ring is not formed. Instead, intermediate Schiff base
could react in intramolecular cyclization reaction to give
11f (Scheme 5). All compound structures were confirmed
by use of 1H and 13C NMR spectra as well as analysis of IR
spectra. Values are given in Experimental part and are in
accordance with previously explained findings. Additional
confirmation of the structure of compounds 11e and 11f
was given by X-ray diffraction.
N
R
N
R
N R
C
H
H
HO
H
H
3CH2CO
3
4
N
S
=
R
CN
1-iminoisoindoline. However, when the amino group is less
nucleophilic, as in the case of aminobenzothiazole and
aminobenzimidazole, and the reaction is performed in
neutral conditions, products 3 and 4 were formed. The
mechanism for their formation is presented in Scheme 3.
Our assumption is that the cyclization to isoindoline ring
takes place after the formation of geminal amino alcohol
A. That is, the elimination of water to give imine cannot
take place in the absence of acid. Alcohol 3 is then con-
verted to ether 4 in the presence of ethanol.
When the condensation reaction is carried out under
acidic conditions, the elimination of water from the gem-
inal amino alcohol to give imine is possible. The proposed
mechanism of the reaction under acidic conditions is
shown in Scheme 4.
Probably, the first step is the same as in the neutral
conditions; the carbaldehyde reacts with an amine to give
the geminal amino alcohol A, which could then under acid
catalyzed conditions react in two ways, to form 1-imi-
noisoindoline E or isoindolinone D. It is presumed that
there is a competition between the formation of isoindoline
ring by intramolecular reaction and elimination of water to
form o-formyl-Schiff base. When the isoindoline ring is
formed before the elimination of water, the resulting
intermediate ultimately gives compound D via water
elimination and keto-enol tautomerism, as described by
Takahashi et al. [38]. If the water molecule is eliminated
first, the o-formyl-Schiff base B is formed which then
probably cyclizes to the iminium ion (route a). The imi-
nium is prone to a nucleophilic attack of second amine
giving imino-substituted isoindoline E via imine-enamine
tautomerism. However, the possibility that E is formed via
intermediate o-disubstituted Schiff base C (route b) cannot
be disregarded, as it has been demonstrated by Chitanda
et al. [16]. They described the isolation of o-disubstituted
Crystal structure determination
The crystal and molecular structures of 3, 8a, 8c, 11e, and
11f were determined by single crystal X-ray diffraction. In
all five structures, the bond lengths and angles are normal
[43, 44]. Compound 3 crystallises in the orthorhombic P
nma space group with eight molecules per-unit cell. The
dihedral angle between the two ring systems is somewhat
larger than in 8a and 8c (7.1°), which is in accordance with
the fact that the two rings cannot share p electron density as
is the case in the other two molecules. The molecule is
chiral with two asymmetrically substituted carbon atoms
(C1 and C8; Fig. 2), but it crystallises as a racemate in a
centrosymmetric space group. Two chiral centres are of
opposite absolute configurations, so that the crystal is
comprised of equal amounts of (R, S) and (S,
R) stereoisomers.
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
Scheme 4
O
H2N R
H
H
O
H+
HO
H
H
H
N R
H
N
H+
-H
R
N
R
1)H2N R
H
N
H
a
2O
O
O
2) H+, -H2O
A
B
H
b
C
H+
OH
R
H+
OH
H
H
H
H
N R
N R
N R
OH
H+
1) NH2-R
2) H+
N R
E
-H
2O
OH
N R
keto-enol
tautomerism
O
OH
H
N R
NHR
H
H+
H+
-H
2O
H
H
imine-enamine
tautomerism
H
N R
H
N R
NHR
N R
H
N R
D
E
˚
˚
The molecules are interconnected into the crystal
structure via O–HÁÁÁN hydrogen bonds between the
hydroxyl group of one molecule and the cyano group of its
H21ÁÁÁC21 of 3.75 A and C8—H8bÁÁÁC6 of 3.58 A) which
interconnect molecules into double chains along the crys-
tallographic c axis (Fig. 5).
˚
neighbour (O1—H1oÁÁÁN3 of 2.94 A) into chains along the
Compound 8c (Fig. 6) crystallises as a N,N-dimethyl-
ꢀ
formamide solvate in the triclinic P 1 space group with two
crystallographic a axis (Fig. 3). These chains are com-
prised of homochiral molecules and form elongated helices
about the screw axes. Each chain is further connected to
two neighbouring chains of opposite chirality via (C15—
molecules of 8c and two of N,N-dimethylformamide per-
unit cell. The benzimidazole system bonded to the isoin-
doline nitrogen is almost coplanar with the isoindoline
system (dihedral angle of 2.9°), and the benzimidazole
system bonded to the imino group is at a dihedral angle of
ca. 77.3° to the isoindoline system. The imine group is of E
configuration. The molecular geometry is stabilised by an
˚
H15ÁÁÁO2 of 3.25 A) into layers perpendicular to the
crystallographic c axis.
Compound 8a was found to crystallise in the monoclinic
P 21 space group with two molecules per-unit cell. The
molecular geometry is very similar to that of 8c, with the
benzothiazole system bonded to the isoindoline nitrogen
almost coplanar with the isoindoline system (dihedral angle
of 1.4°), and the benzothiazole system bonded to the imino
group is at a dihedral angle of ca. 66.9° to the isoindoline
system (Fig. 4). As there are no strong hydrogen donors or
acceptors present in the molecule, the crystal packing is
governed only by weak C—HÁÁÁp interactions (C21—
˚
intramolecular hydrogen bond N4—H1nÁÁÁN2 of 2.70 A
between the imino nitrogen atom and a nitrogen atom of
the benzimidazole bonded to the isoindoline nitrogen. This
hydrogen bond, however, is bifurcated, and the same
hydrogen atom is also in contact with the N,N-dimethyl-
˚
formamide oxygen atom (N4—H1nÁÁÁO1 of 3.01 A). The
NH group of the other benzimidazole ring forms a hydro-
gen bond with an isoindoline bound benzimidazole system
123

´
I. Sovic et al.
Amine
Product
and
S
N
N
N
S
NH2
N
N
S
N
N
10a
O
11a
11b
S
N
N
N
NH2
N
N
10b
O
11c
N
N
Fig. 2 Molecular structure of 3 with the atom-labelling scheme.
Thermal ellipsoids are drawn at the 50 % probability level, and
hydrogen atoms are presented as spheres of arbitrary small radii
N
N
N
N
N
N
N
N NH2
10c
N
11d
OH
N
N
N
NH2
N
N
NH
N
11e
10d
N
CH3
N
N
N
N
NH2
N
N
Fig. 3 Hydrogen-bonded chains connected in the crystal structure of
3
CH3
N
N
10e
11f
CH3
molecules of 8c and two N,N-dimethylformamide mole-
cules (Fig. 7a), which are further connected into chains
along the crystallographic axis c via weak hydrogen bonds
Fig. 1 Amino-substituted heterocycles and corresponding products
in the reaction with o-phthalaldehyde
˚
(C23—H23ÁÁÁN5 of 3.55 A; Fig. 7b). The hydrogen bond-
˚
of a neighbouring molecule (N6—H2nÁÁÁN3 of 2.95 A),
ing of the solvent molecule to the 8c molecule also
accounts for the observed stability of the crystals (no sol-
vent loss was noticed), similarly as in other Schiff base—
N,N-dimethylformamide solvates [45].
forming a centrosymmetric dimer via a R22(16) hydrogen-
bonding motif. The crystal structure, therefore, comprises
centrosymmetric hydrogen-bonded complexes of two
Scheme 5
CH3
N
N
N
N
N
N
N
H
3C
N
3C
CH3
H
3C
CH3
N
N
N
N
N
N
N
H
N
N
N
11f
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
The molecule is chiral with two asymmetrically substituted
carbon atoms (C1 and C8; Fig. 8). While the compound
crystallises in a centrosymmetric space group with equiv-
alent amounts of two enantiomers, the stereoisomers
present [(R, R) and (S, S)] correspond to those found in 3,
with hydrogen atoms on the one side of the isoindoline ring
plane, and the hydroxyl group and the other substituent
(ethoxy group in 3, 2-amino-N-phenylbenzimidazole in
11e) on the other. This seems to imply that the hydroxyl
group bonded on the atom C1 of the isoindoline controls
the chirality on the C8 atom, probably by hydrogen
bonding with the incoming nucleophile and thus directing
it to the same side of the ring plane. As both the strong
hydrogen bond donors of the molecule are employed in
intramolecular bonding, the crystal packing is governed
only by weak interactions, most notably C—HÁÁÁN (C34—
Fig. 4 Molecular structure of 8a with the atom-labelling scheme.
Thermal ellipsoids are drawn at the 50 % probability level, and
hydrogen atoms are presented as spheres of arbitrary small radii
˚
Compound 11e (Fig. 8) crystallises in the monoclinic
P 21/c space group with four molecules per-unit cell. The
molecule comprises two N-phenylbenzimidazole systems
of which one is bonded to the isoindoline nitrogen and the
other through an amine group. The dihedral angle between
the benzimidazole system bonded to the isoindoline nitro-
gen and the isoindoline system is larger than in 3 (14.82°),
and the benzimidazole system bonded to the amino group
is at a dihedral angle of ca. 76.64° to the isoindoline sys-
tem. The molecular geometry is stabilised by an
H34ÁÁÁN6 of 3.53 A) and C—HÁÁÁp interactions (C8—
˚
˚
H8ÁÁÁC24 of 3.60 A, C17—H17ÁÁÁC15 of 3.42 A, and
˚
C19—H19ÁÁÁC23 of 3.55 A) which interconnect the mole-
cules into undulating layers perpendicular to the
crystallographic a axis. The layers are further connected
into a 3D structure by C—HÁÁÁO interactions (C11—
˚
H11ÁÁÁO1 of 3.35 A).
Compound 11f (Fig. 9) crystallises in the triclinic C 2/
c space group with four molecules per-unit cell. The
molecule possesses C2 symmetry that is positioned on the
crystallographic twofold axis. Two benzimidazole systems
have bonded to the central ring derived from o-phtha-
laldehyde forming a central bicyclic system with C9 carbon
atoms bonded to the o-phthalaldehyde phenylene (C10),
and also bind to a benzimidazole nitrogen (N3) of one
benzimidazole system and an imine nitrogen (N1) which
connects it to the other benzimidazole system. This renders
˚
intramolecular hydrogen bond O1—H1oÁÁÁN3 of 2.80 A
between the hydroxyl group and a nitrogen atom of the
benzimidazole bonded to the isoindoline through the amine
group. There is also another intramolecular hydrogen bond,
˚
N2—H1nÁÁÁN6 of 2.94 A between the amine group and a
nitrogen atom of the other benzimidazole; however, it is
sterically unfavourable with the N–H–N angle of ca. 105°.
Fig. 5 Double chains
connected by C—HÁÁÁp
interactions in the crystal
structure of 8a
123

´
I. Sovic et al.
isoindolines 8c–8e, 9, 11e, and 11f in the reaction of o-
phthalaldehyde and substituted 2-aminobenzothiazoles and
2-aminobenzimidazoles. To obtain 1-imino-substituted
isoindoline derivatives, reaction conditions were optimized
in the test reaction of o-phthalaldehyde with 2-amino-6-
cyanobenzothiazole in different solvents (ethanol or
toluene, and neutral or acidic conditions). The proposed
reaction mechanisms in ethanol and toluene in neutral
conditions include the attack of one molecule of amine on
aldehyde group of o-phthalaldehyde to give geminal amino
alcohol followed by cyclization to form isoindoline ring
(compounds 3 and 4). In acidic conditions, the elimination
of water from the geminal amino alcohol is possible which
leads to the attack of second molecule of amine followed
by intramolecular reaction to form 1-imino-substituted-2-
N-substituted isoindoline (5, 8a–8e, 11a) or intramolecular
reaction followed by the elimination of water to form 2-N-
substituted-isoindolin-1-one (6, 9, 11b, 11c). Thiazole,
pyrimidine, and triazole heterocycles were also introduced
to support proposed mechanisms (11a–11c). The proposed
structures of 3, 8a, 8c, 11e, and 11f were also confirmed by
single crystal X-ray diffraction. The molecular structures of
8a and 8c are very similar with an approximately coplanar
isoindoline-benzothiazole (i.e., isoindoline-benzimidazole)
system with an E-imino-benzothiazole (i.e., E-imino-ben-
zimidazole) substituent. Chiral molecules 3, 11e, and 11f
were found to crystallise as racemic mixture of (R, S) and
(S, R) stereoisomers for 3 and (R, R) and (S, S) stereoiso-
mers for 11e and 11f.
Fig. 6 Molecular structure of 8c - N,N-dimethylformamide solvate
with the atom-labelling scheme. Thermal ellipsoids are drawn at the
50 % probability level, and hydrogen atoms are presented as spheres
of arbitrary small radii
C9 unsymmetrical with both C9 atoms in the molecule of
the same chirality, and 11f crystallises as a racemic mixture
of (R, R) and (S, S) stereoisomers. The general shape of the
molecule is a threefoil with two planar benzimidazole
blades and the third phthalaldehyde one. The mean planes
of the benzimidazole systems are at a dihedral angle of ca.
66.4° to one another and 57.4° to the mean plane of the o-
phthalaldehyde phenylene ring. In lieu of strong hydrogen
bond donors or acceptors, the crystal packing is governed
only by weak C—HÁÁÁp interactions between the o-phtha-
laldehyde phenylene hydrogen and the imine groups of the
˚
neighbouring molecule (C12—H12ÁÁÁN3 of 3.59 A and
˚
C12—H12ÁÁÁN3 of 3.58 A) which interconnect molecules
into chains along the crystallographic b axis.
Experimental
Melting points were determined on a Kofler hot stage
microscope. IR spectra were recorded on a Bruker Vertex
Conclusion
1
70 spectrophotometer with diamond crystal. H and 13C
In this paper, we presented synthesis and mechanistic
studies of new benzothiazolyl-substituted isoidolines 3, 4,
5, 6, 8a, and 8b and benzimidazolyl-substituted
NMR spectra were recorded on Bruker AV300 or Bruker
AV600 spectrophotometers at 300 or 600 MHz (1H NMR
spectra) and 75 or 150 MHz (13C NMR spectra). All NMR
Fig. 7 Crystal structure of 8c—N,N-dimethylformamide solvate: a a hydrogen-bonded centrosymmetric complex; b chain formed from
centrosymmetric complex by C—HÁÁÁN hydrogen bonding
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
50 cm3 absolute ethanol was refluxed for 24 h. After
cooling, the resulting product was filtered off and dried
under vacuum to obtain 1.231 g (73 %) of yellow
crystalline product. m.p.: 188–190 °C; 1H NMR
(300 MHz, DMSO-d6, 25 °C): d = 8.45 (s, 1H, Harom),
7.74 (s, 2H, Harom), 7.55 (s, 1H, Harom), 7.52 (s, 3H, Harom),
7.13 (s, 1H, Hisoind), 6.39 (s, 1H, Hisoind), 6.35 (s, 1H, OH),
3.53 (q, J = 7.1 Hz, 1H, CH2), 3.26 (q, J = 7.1 Hz, 1H,
CH2), 1.08 (t, J = 7.0 Hz, 3H, CH3) ppm; 13C NMR
(75 MHz, DMSO-d6, 25 °C): d = 167.88, 155.26, 140.41,
136.12, 132.09, 130.26, 130.23, 129.91, 126.59, 124.45,
124.14, 120.14, 119.91, 103.83, 90.94, 85.25, 59.31,
ꢀ
15.69 ppm; IR (diamond): m = 3415 (O–H st), 2231
(C:N), 1607, 1552, 1515 cm-1; MS (ESI): m/z = 328.1
([M ? 1]?).
Fig. 8 Molecular structure of 11e with the atom-labelling scheme.
Thermal ellipsoids are drawn at the 50 % probability level, and
hydrogen atoms are presented as spheres of arbitrary small radii
2-(1,3-Dihydroxyisoindolin-2-yl)benzothiazole-6-
carbonitrile (4, C16H11N3O2S)
A solution of 0.175 g o-phthalaldehyde (1, 1.3 mmol) and
0.456 g 2-amino-6-cyanobenzothiazole (2, 2.6 mmol) in
30 cm3 absolute toluene was refluxed for 8 h. After
cooling, the resulting product was filtered off and recrys-
tallised from methanol to obtain 0.235 g (58 %) of yellow
1
powder. m.p.: 151–153 °C; H NMR (300 MHz, DMSO-
d6, 25 °C): d = 8.44 (s, 1H, Harom), 8.18 (d, J = 1.4 Hz,
1H, Harom), 8.02 (s, 1H, Harom), 7.73 (s, 1H, Harom), 7.61
(dd, J1 = 8.3 Hz, J2 = 1.6 Hz, 1H, Hisoind), 7.52 (s, 1H,
H
arom), 7.51 (s, 2H, Harom), 7.42 (d, J = 8.4 Hz, 1H,
H
isoind), 6.69 (d, J = 8.9 Hz, 1H, OH), 6.29 (d,
J = 8.9 Hz, 1H, OH) ppm; 13C NMR (150 MHz,
DMSO-d6, 25 °C): d = 170.51, 156.95, 139.70, 132.24,
130.10, 129.77, 126.44, 125.71, 124.18, 124.15, 120.10,
119.87, 118.34, 102.55, 85.56, 85.53 ppm; IR (diamond):
Fig. 9 Molecular structure of 11f with the atom-labelling scheme.
Thermal ellipsoids are drawn at the 50 % probability level, and
hydrogen atoms are presented as spheres of arbitrary small radii
ꢀ
m = 3353 (O–H st), 3305, 3059, 2222 (C:N), 1647, 1605,
1512 cm-1; MS (ESI): m/z = 310.1 ([M ? 1]?).
2-[1-[(6-Cyanobenzothiazol-2-yl)imino]isoindolin-2-
yl]benzothiazole-6-carbonitrile (5, C24H12N6S2) and 2-
(1-oxoisoindolin-2-yl)benzothiazole-6-carbonitrile
(6, C16H9N3OS)
spectra were measured in DMSO-d6 solutions using TMS
as an internal standard. Chemical shifts are reported in ppm
(d) relative to TMS. Mass spectra were recorded on an
Agilent 1200 series LC/6410 QQQ instrument. Elemental
analysis for carbon, hydrogen, and nitrogen was performed
on a Perkin-Elmer 2400 Series II CHNS analyzer, and their
results were found to be in good agreement with the cal-
culated values. All compounds were routinely checked by
thin layer chromatography (TLC) using precoated Merck
silica gel 60F-254 plates, and the spots were detected under
UV light (254 nm). Column chromatography (CC) was
performed using silica gel (0.063–0.2 mm) Fluka; glass
column was slurry-packed under gravity.
To a solution of 0.123 g o-phthalaldehyde (1, 0.9 mmol)
and 0.320 g 2-amino-6-cyanobenzothiazole (2, 1.8 mmol)
in 20 cm3, absolute toluene glacial acetic acid was added
and the reaction mixture was refluxed for 8 h. After
cooling, the reaction mixture was evaporated to dryness
and resulting mixture was purified by column chromatog-
raphy using dichloromethane/methanol as eluent (gradient
elution from 50:1 to 10:1).
5: 0.139 g (35 %) of yellow powder; m.p.:[300 °C; 1H
NMR (600 MHz, DMSO-d6, 25 °C): d = 8.66 (s, 1H,
2-(1-Ethoxy-3-hydroxyisoindolin-2-yl)benzothiazole-6-
carbonitrile (3, C18H15N3O2S)
H
arom), 8.62 (s, 1H, Harom), 8.02 (d, J = 8.5 Hz, 1H,
H
arom), 7.99 (d, J = 8.0 Hz, 1H, Harom), 7.90 (d,
A solution of 0.670 g o-phthalaldehyde (1, 5.0 mmol) and
1.750 g 2-amino-6-cyanobenzothiazole (2, 10.0 mmol) in
J = 8.0 Hz, 2H, Harom), 7.82 (s, 1H, Harom), 7.79 (s, 1H,
H
arom), 7.53 (d, J = 7.7 Hz, 1H, Harom), 7.43 (s, 1H,
123

´
I. Sovic et al.
Harom), 5.54 (s, 2H, Hisoind) ppm; 13C NMR (75 MHz,
DMSO-d6, 25 °C): d = 169.71, 160.18, 155.36, 151.51,
142.29, 141.30, 135.18, 133.70, 133.40, 128.37, 127.71,
127.10, 126.82, 126.00 (2C), 124.18 (2C), 122.10, 121.58,
118.95, 118.86, 106.18, 105.77, 53.91 ppm; IR (diamond):
(300 MHz,
DMSO-d6,
25 °C):
d = 9.12
(dd,
J1 = 8.7 Hz, J2 = 2.4 Hz, 2H, Harom), 8.35 (t,
J = 2.7 Hz, 1H, Harom), 8.32 (t, J = 2.7 Hz, 1H, Harom),
8.04 (d, J = 5.6 Hz, 1H, Harom), 8.01 (d, J = 5.6 Hz, 1H,
H
arom), 7.83 (d, J = 7.5 Hz, 1H, Harom), 7.76 (t,
m = 2221 (C:N), 1667 (C=N), 1605, 1505 cm-1; MS
J = 7.4 Hz, 1H, Harom), 7.55 (d, J = 8.0 Hz, 1H, Harom),
7.43 (t, J = 7.3 Hz, 1H, Harom), 5.55 (s, 2H, Hisoind) ppm;
13C NMR (75 MHz, DMSO-d6, 80 °C): not soluble
ꢀ
(ESI): m/z = 449.1 ([M ? 1]?).
6: 0.023 g (9 %) of pale yellow powder; m.p.:[300 °C;
1H NMR (600 MHz, DMSO-d6, 25 °C): d = 8.63 (s, 1H,
enough; IR (diamond): m = 1659 (C=N), 1503 (NO2 st
ꢀ
H
arom), 7.98 (d, J = 8.4 Hz, 1H, Harom), 7.95 (d,
as), 1323 (NO2 st sy), 1283 (NO2 st sy) cm-1; MS (ESI):
J = 7.6 Hz, 1H, Harom), 7.88 (dd, J1 = 8.4 Hz,
m/z = 489.1 ([M ? 1]?).
J2 = 1.4 Hz, 1H, Harom), 7.83-7.78 (m, 2H, Harom), 7.63
(t, J = 7.2 Hz, 1H, Harom), 5.31 (s, 2H, Hisoind) ppm; 13C
NMR (150 MHz, DMSO-d6, 25 °C): d = 167.07, 160.29,
151.61, 142.31, 134.15, 132.52, 129.84, 129.58, 128.56,
127.18, 124.15, 124.07, 121.50, 119.08, 105.64,
N-[2-(1H-Benzimidazol-2-yl)isoindolin-1-ylidene]-1H-
benzimidazol-2-amine (8c, C22H16N6)
From 0.50 g o-phthalaldehyde (1, 3.7 mmol) and 1.00 g
2-aminobenzimidazole (7c, 7.5 mmol) after recrystallisa-
tion from toluene two isomers were isolated. From the hot
solution, less soluble isomer Z was obtained, and after
cooling, isomer E was obtained.
ꢀ
51.01 ppm; IR (diamond): m = 2222 (C:N), 1696
; MS (ESI): m/z = 292.1
(C=O), 1660, 1508 cm-1
([M ? 1]?).
(Z)-Isomer: 0.571 g (42 %) of yellow-green powder;
m.p.: 244–247 °C; 1H NMR (300 MHz, DMSO-d6, 25 °C):
d = 12.48 (bs, 1H, NH), 12.16 (bs, 1H, NH), 7.75 (d,
J = 7.6 Hz, 1H, Harom), 7.65 (t, J = 7.3 Hz, 1H, Harom),
7.58 (s, 2H, Harom), 7.48 (s, 2H, Harom), 7.39–7.31 (m, 2H,
General method for the synthesis of compounds
8a–8e, 9, and 11a–11d
A solution of o-phthalaldehyde (1) and corresponding
amines in molar ration 1:2 in absolute toluene was pre-
pared, and glacial acetic acid was added. After refluxing for
24 h, the resulting product was filtered off and recrys-
tallised from the corresponding solvent or purified by
column chromatography using dichloromethane/methanol
as eluent (gradient elution from 50:1 to 10:1).
H
arom), 7.18–7.11 (m, 4H, Harom) 5.35 (s, 2H, Hisoind) ppm;
13C NMR (75 MHz, DMSO-d6, 25 °C): d = 157.33,
154.23, 147.31, 142.19 (2C), 141.18, 133.50, 133.02,
129.48 (2C), 128.40, 126.04, 124.39, 121.99, 121.60,
121.42 (4C), 117.59, 112.23, 52.45 ppm; IR (diamond):
m = 3432, 1646 (C=N), 1589 cm-1; MS (ESI): m/
ꢀ
z = 365.2 ([M ? 1]?).
N-[2-(Benzothiazol-2-yl)isoindolin-1-ylidene]benzothiazol-
2-amine (8a, C22H14N4S2)
(E)-Isomer: 0.084 g (6 %) of orange crystalline product;
m.p.: 229–231 °C; 1H NMR (300 MHz, DMSO-d6, 25 °C):
d = 12.71 (s, 1H, NH), 10.82 (s, 1H, NH), 8.47 (t,
J = 4.6 Hz, 1H, Harom), 8.33 (d, J = 7.2 Hz, 1H, Harom),
7.80 (s, 1H, Harom), 7.72 (dd, J1 = 7.7 Hz, J2 = 1.9 Hz,
2H, Harom), 7.67 (dd, J1 = 4.1 Hz, J2 = 1.5 Hz, 1H,
From 0.45 g o-phthalaldehyde (1, 3.3 mmol) and 1.00 g
2-aminobenzothiazole (7a, 6.6 mmol), after recrystallisa-
tion from ethanol/toluene 0.545 g (41 %) of yellow
crystalline product was obtained. m.p.: 257–259 °C; 1H
NMR (300 MHz, DMSO-d6, 25 °C): d = 8.07 (d,
J = 7.7 Hz, 1H, Harom), 8.03 (d, J = 7.8 Hz, 1H, Harom),
7.91–7.79 (m, 3H, Harom), 7.72 (t, J = 7.2 Hz, 1H, Harom),
7.54–7.47 (m, 2H, Harom), 7.45–7.33 (m, 4H, Harom), 5.51
(s, 2H, Hisoind) ppm; 13C NMR (75 MHz, DMSO-d6,
25 °C): d = 167.65, 157.18, 155.28, 151.95, 148.93,
142.56, 134.83, 133.71, 133.00, 128.67, 128.53, 126.86,
126.74, 126.10, 124.71, 124.53, 124.24, 122.47, 122.43,
H
arom), 7.63 (dd, J1 = 5.9 Hz, J2 = 1.9 Hz, 1H, Harom),
7.60 (d, J = 4.8 Hz, 1H, Harom), 7.33–7.24 (m, 4H, Harom),
4.93 (s, 2H, Hisoind) ppm; 13C NMR (75 MHz, DMSO-d6,
25 °C): d = 163.65, 156.23, 145.12, 143.84, 141.92,
141.49, 134.38, 132.86, 132.19, 131.70, 128.38, 124.31,
123.84, 123.77, 122.65, 122.48, 122.21, 118.60, 117.51,
ꢀ
114.15, 112.49, 51.05 ppm; IR (diamond): m = 3418,
3356, 1617 (C=N), 1547 cm-1; MS (ESI): m/z = 365.2
([M ? 1]?).
ꢀ
121.91, 121.29, 54.12 ppm; IR (diamond): m = 3054, 1665
(C=N), 1591 cm-1; MS (ESI): m/z = 399.2 ([M ? 1]?).
2-[1-[(6-Cyano-1H-benzimidazol-2-yl)imino]isoindolin-2-
yl]-1H-benzimidazole-6-carbonitrile (8d, C24H14N8) and
2-(1-oxoisoindolin-2-yl)-1H-benzimidazole-6-carbonitrile
(9, C16H10N4O)
6-Nitro-N-[2-(6-nitrobenzothiazol-2-yl)isoindolin-1-yli-
dene]benzothiazol-2-amine (8b, C22H12N6O4S2)
From 0.67 g o-phthalaldehyde (1, 5.0 mmol) and 1.95 g
2-amino-6-nitrobenzothiazole (7b, 10.0 mmol) after
recrystallisation from DMF 0.680 g (28 %) of green
powder was obtained. m.p.: [300 °C; 1H NMR
From 0.123 g o-phthalaldehyde (1, 0.9 mmol) and 0.320 g
2-amino-5-cyanobenzimidazole (7d, 1.8 mmol) after col-
umn chromatography two compounds were obtained.
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
8d: 0.022 g (6 %) of yellow powder; m.p.: 266–269 °C;
1H NMR (300 MHz, DMSO-d6, 25 °C): d = 13.08 (s, 1H,
NH), 13.01 (s, 1H, NH), 8.56 (s, 1H, Harom), 8.41–8.34 (m,
1H, Harom), 8.28–8.25 (m, 1H, Harom), 7.95 (s, 1H, Harom),
7.91 (s, 1H, Harom), 7.75 (s, 1H, Harom), 7.73–7.71 (m, 1H,
117.04, 114.95, 53.03 ppm; IR (diamond): mꢀ = 1643 (C=N),
1498, 1472 cm-1; MS (ESI): m/z = 299.1 ([M ? 1]?).
11b: 0.170 g (31 %) of pink powder; m.p.: 190–193 °C;
1H NMR (300 MHz, DMSO-d6, 25 °C): d = 7.88 (d,
J = 7.6 Hz, 1H, Harom), 7.77-7.73 (m, 2H, Harom),
7.64–7.55 (m, 2H, Harom), 7.39 (d, J = 3.5 Hz, 1H,
H
arom), 7.69 (s, 1H, Harom), 7.67–7.65 (m, 2H, Harom), 4.93
(s, 2H, Hisoind) ppm; 13C NMR (75 MHz, DMSO-d6,
H
arom), 5.18 (s, 2H, Hisoind) ppm; 13C NMR (75 MHz,
ꢀ
80 °C): not soluble enough; IR (diamond): m = 2924,
DMSO-d6, 25 °C): d = 166.27, 157.46, 142.29, 138.31,
133.78, 130.81, 128.99, 124.49, 124.08, 114.79,
2851, 2222 (C:N), 1659 (C=N), 1582 cm-1; MS (ESI):
m/z = 415.1 ([M ? 1]?).
ꢀ
51.07 ppm; IR (diamond): m = 3106, 1705 (C=O),
1
9: 0.143 g (58 %) of ivory powder; m.p.: [300 °C; H
1506 cm-1; MS (ESI): m/z = 217.1 ([M ? 1]?).
NMR (300 MHz, DMSO-d6, 25 °C): d = 12.80 (d, 1H,
J = 15.2 Hz, NH), 8.02 (s, 1H, Harom), 7.92 (d, J = 6.5 Hz,
1H, Harom), 7.77 (s, 2H, Harom), 7.75–7.66 (m, 1H, Harom),
7.64–7.58 (m, 1H, Harom), 7.55 (d, J = 8.2 Hz, 1H, Harom),
5.18 (s, 2H, Hisoind) ppm; 13C NMR (75 MHz, DMSO-d6,
25 °C): d = 167.42, 149.13, 148.43, 142.76, 140.88,
137.28, 134.10, 129.06, 125.94, 124.53, 122.09, 120.66,
2-(Pyrimidin-2-yl)-isoindolin-1-one (11c, C12H9N3O)
From 0.200 g o-phthalaldehyde (1, 1.6 mmol) and 0.300 g
2-aminopyrimidine (10b, 3.2 mmol) after column chro-
matography 0.060 g (18 %) of white powder was obtained.
m.p.: 180–185 °C; 1H NMR (300 MHz, DMSO-d6, 25 °C):
d = 8.79 (d, J = 4.8 Hz, 2H, Harom), 7.83 (d, J = 7.6 Hz,
1H, Harom), 7.75–7.68 (m, 2H, Harom), 7.58–7.53 (m, 1H,
118.70, 113.41, 104.05, 50.22 ppm; IR (diamond):
-1
H
arom), 7.29 (t, J = 4.8 Hz, 1H, Harom), 5.11 (s, 2H, Hisoind)
ꢀ
m = 3300, 2219 (C:N), 1689 (C=O), 1626, 1538 cm
;
ppm; 13C NMR (75 MHz, DMSO-d6, 25 °C): d = 165.90,
158.88 (2C), 157.83, 141.82, 133.46, 132.52, 128.73,
124.22, 124.18, 117.53, 50.66 ppm; IR (diamond):
MS (ESI): m/z = 275.1 ([M ? 1]?).
6-Nitro-N-[2-(6-nitro-1H-benzimidazol-2-yl)isoindolin-1-
m = 3040, 2942, 1714 (C=O), 1564 cm-1; MS (ESI): m/
ꢀ
ylidene]-1H-benzimidazol-2-amine (8e, C22H14N8O4)
From 0.14 g o-phthalaldehyde (1, 1.0 mmol) and 0.35 g
2-amino-5-nitrobenzimidazole (7e, 2.0 mmol) after column
chromatography 0.236 g (52 %) of yellow powder was
z = 212.1 ([M ? 1]?).
N,N’-Bis(1,2,4-triazol-4-yl)-phthalimine
(11d, C12H10N8)
1
obtained. m.p.: [300 °C; H NMR (600 MHz, DMSO-d6,
From 0.400 g o-phthalaldehyde (1, 3.0 mmol) and 0.500 g
4-amino-1,2,4-triazole (10c, 6.0 mmol) after recrystallisa-
tion from ethanol 0.560 g (71 %) of green powder was
25 °C): d = 13.17 (bs, 2H, NH), 8.64 (d, J = 16.7 Hz, 1H,
H
arom), 8.35 (d, J = 1.9 Hz, 1H, Harom), 8.25 (t,
J = 9.4 Hz, 1H, Harom), 8.20 (bs, 1H, Harom), 7.95 (s,
1H, Harom), 7.83 (s, 1H, Harom), 7.78–7.74 (m, 2H, Harom),
7.73–7.68 (m, 2H, Harom), 4.97 (s, 2H, Hisoind) ppm; 13C
NMR (75 MHz, DMSO-d6, 80 °C): not soluble enough; IR
1
obtained. m.p.: 252–255 °C; H NMR (300 MHz, DMSO-
d6, 25 °C): d = 9.57 (s, 2H, CH), 9.24 (s, 4H, Harom),
8.12–8.07 (m, 2H, Harom), 7.79–7.73 (m, 2H, Harom) ppm;
13C NMR (150 MHz, DMSO-d6, 25 °C): d = 155.65,
139.20, 132.14, 131.96, 128.13 ppm; IR (diamond):
ꢀ
(diamond): m = 3199, 2896, 1633 (C=N), 1570, 1518 (NO2
st as), 1324 (NO2 st sy), 1277 (NO2 st sy) cm-1; MS (ESI):
ꢀ
m = 3444, 3121, 3115, 3072, 1611 (C=N), 1584,
m/z = 455.2 ([M ? 1]?).
1503 cm-1; MS (ESI): m/z = 267.2 ([M ? 1]?).
N-[2-(Thiazol-2-yl)isoindolin-1-ylidene]thiazol-2-amine
(11a, C14H10N4S2) and 2-(thiazol-2-yl)isoindolin-1-one
(11b, C11H8N2OS)
2-(N-Phenyl-1H-benzimidazol-2-yl)-3-[(N-phenyl-1H-
benzimidazol-2-yl)amino]isoindolin-1-ol
(11e, C34H26N6O)
From 0.4 g o-phthalaldehyde (1, 3.0 mmol) and 0.5 g
2-aminothiazole (10a, 6.0 mmol) after column chromatog-
raphy two compounds were obtained.
A solution of 0.092 g o-phthalaldehyde (1, 0.7 mmol) and
0.300 g 2-amino-N-phenylbenzimidazole (10d, 1.4 mmol)
in 20 cm3 absolute toluene was refluxed for 6 h. After
cooling, the resulting product was filtered off and dried
under vacuum to obtain 0.273 g (73 %) of white powder.
White crystals were obtained by slow evaporation of
dichloromethane solution. m.p.: 175–176 °C; 1H NMR
(300 MHz, CDCl3, 25 °C): d = 8.46 (d, J = 10.8 Hz, 1H,
NH), 7.66 (d, J = 7.8 Hz, 2H, Harom), 7.60–7.50 (m, 8H,
11a: 0.370 g (50 %) of yellow powder; m.p.:
205–208 °C; 1H NMR (600 MHz, DMSO-d6, 25 °C):
d = 7.75 (d, J = 7.7 Hz, 1H,
Harom), 7.66 (td,
J1 = 7.6 Hz, J2 = 0.9 Hz, 1H, Harom), 7.62 (d,
J = 3.5 Hz, 1H, Harom), 7.58 (d, J = 3.7 Hz, 1H, Harom),
7.48 (d, J = 3.7 Hz, 1H, Harom), 7.39 (t, J = 7.5 Hz, 1H,
H
arom), 7.37 (d, J = 3.5 Hz, 1H, Harom), 7.33 (d, J = 8.0 Hz,
H
H
H
arom), 7.47–7.41 (m, 2H, Harom), 7.38–7.33 (m, 3H,
arom), 7.20–7.13 (m, 2H, Harom), 7.03–6.90 (m, 3H,
arom), 6.86 (d, J = 7.1 Hz, 1H, Harom), 6.77 (d,
1H, Harom), 5.34 (s, 2H, Hisoind) ppm; 13C NMR (150 MHz,
DMSO-d6, 25 °C): d = 168.77, 157.06, 153.93, 141.61,
140.05, 137.94, 132.55, 128.29, 127.81, 125.46, 124.05,
123

´
I. Sovic et al.
Table 1 Crystallographic data for compounds 3, 8a, 8c, 11e, and 11f
3
8a
8c
11e
11f
Formula
Mr
C18H15N3O2S
337.39
C22H14N4S2
398.49
C22H16N6 Á C3H7NO
437.5
C34H26N6O
534.61
C24H20N6
392.46
T/K
295 (2)
Orthorhombic
P nma
295 (2)
Monoclinic
P 21
295 (2)
295 (2)
Monoclinic
P 21/c
295 (2)
Monoclinic
C 2/c
Crystal system
Space group
Triclinic
ꢀ
P 1
˚
a/A
9.3795 (3)
14.4178 (8)
24.6086 (13)
90
11.8505 (7)
4.3945 (4)
17.8941 (10)
90
8.301 (3)
10.966 (4)
12.561 (5)
96.85 (3)
100.58 (3)
99.06(3)
1097.0 (7)
2
15.0779 (9)
19.8773 (10)
9.7120 (6)
90
15.915 (3)
7.8946 (6)
16.973 (3)
90
˚
b/A
˚
c/A
a/°
b/°
c/°
90
99.931 (6)
90
107.622 (7)
90
116.93 (3)
90
90
3
˚
V/A
3327.9 (3)
8
917.91 (11)
2
2774.2 (3)
4
1901.2 (7)
4
Z
q
calc/g cm-3
1.347
1.442
1.324
1.28
1.371
Radiation
l/mm-1
MoKa
MoKa
MoKa
MoKa
MoKa
0.21
0.306
0.086
0.08
0.085
h, k, l range
-11 \ h \ 11
-18 \ k \ 18
-31 \ l \ 31
26,914
-14 \ h \ 15
-4 \ k \ 5
-22 \ l \ 22
7148
-9 \ h \ 9
-13 \ k \ 13
-14 \ l \ 14
9882
-19 \ h \ 17
-24 \ k \ 24
-12 \ l \ 12
12,082
-20 \ h \ 20
-10 \ k \ 9
-21 \ l \ 21
7703
Reflections collected
Reflections unique
Reflections observed (I [ 2 r(I))
R1 (obs)
3595
3210
3826
5956
2064
2220
2406
2561
2719
1306
0.0401
0.0546
0.1081
0.0385
0.036
wR2 (obs)
0.1251
0.1341
0.2534
0.1016
0.089
GooF
0.971
1.029
1.14
0.868
0.88
J = 7.9 Hz, 1H, Harom), 6.51 (d, J = 5.7 Hz, 1H, OH),
6.43 (d, J = 5.7 Hz, 1H, CH), 5.81 (d, J = 10.8 Hz, 1H,
CH) ppm; 13C NMR (75 MHz, CDCl3, 25 °C):
d = 151.09, 150.78, 141.70, 141.28, 140.78, 137.49,
136.58, 136.27, 134.40, 134.20, 131.11, 130.39, 130.38,
129.38, 129.21, 129.09, 128.90, 127.52, 127.05, 126.66,
123.32, 122.46, 122.20, 121.99, 121.76, 120.66, 120.22,
116.57, 115.70, 109.11, 108.44, 108.19, 83.60, 72.36 ppm;
(600 MHz, CDCl3, 25 °C): d = 7.42–7.40 (m, 1H, Harom),
7.38–7.35 (m, 4H, arom), 7.07 (td, J1 = 7.7 Hz,
H
J2 = 1.0 Hz, 2H, Harom), 7.02 (td, J1 = 7.6 Hz,
J2 = 0.9 Hz, 2H, Harom), 6.82 (d, J = 7.3 Hz, 2H, Harom),
6.54 (s, 2H, CH), 3.31 (s, 6H, CH3) ppm; 13C NMR
(150 MHz, CDCl3, 25 °C): d = 150.89, 134.09, 132.09,
130.61, 128.51, 125.45, 120.76, 119.86, 106.39, 105.93,
ꢀ
69.22, 27.52 ppm; IR (diamond): m = 3435, 2934, 1629,
IR (diamond): m = 3389, 3058, 2912, 1597, 1555 cm
;
1602, 1494 cm-1; MS (ESI): m/z = 393.1 ([M ? 1]?).
-1
ꢀ
MS (ESI): m/z = 535.1 ([M ? 1]?).
X-ray structure determination
Bis-N,N0-3,30-dimethyl-[1,2-a:10,20-e]-N(H)benzimidazolyl-
9,10-phenylene-1,3,5,7-tetraazabicyclo[2,3]-1,5-octadiene
(11f, C24H20N6)
The crystal and molecular structures of 3, 8a, 8c, 11e, and
11f were determined by single crystal X-ray diffraction.
The diffraction data were collected at 295 K for all five
crystals. Diffraction measurements were made on an
Oxford Diffraction Xcalibur Kappa CCD X-ray diffrac-
A solution of 0.092 g o-phthalaldehyde (1, 0.7 mmol) and
0.20 g 2-amino-N-methylbenzimidazole (10e, 1.4 mmol)
in 20 cm3 absolute toluene was refluxed for 6 h. After
cooling, the resulting product was filtered off and dried
under vacuum to obtain 0.190 g (69 %) of yellow powder.
Yellow crystals were obtained by slow evaporation of
dichloromethane solution. m.p.: 195–196 °C; 1H NMR
tometer
with
graphite-monochromated
MoKa
˚
(k = 0.71073 A) radiation [46]. The data sets were col-
lected using the x scan mode over the 2h range up to 54°.
The structures were solved by the direct methods and
123

Benzothiazolyl- and benzimidazolyl-substituted 1-iminoisoindolines: synthesis, mechanistic…
16. Chitanda JM, Prokopchuk DE, Quail JW, Foley SR (2008)
Organometallics 27:2337
refined using SHELXS and SHELXL programs [47]. The
structural refinement was performed on F2 using all data.
The hydrogen atoms were placed in calculated positions
˚
and treated as riding on their parent atoms [C–H = 0.93 A
˚
and Uiso(H) = 1.2 Ueq(C); C–H = 0.97 A and Uiso(-
17. Broering M, Kleeberg C, Koehler S (2008) Inorg Chem 47:6404
18. Broering M, Kleeberg C (2009) Inogr Chim Acta 362:1065
19. Takahashi I, Hatanaka M (1997) Heterocycles 45:2475
20. Wan J, Wu B, Pan Y (2007) Tetrahedron 63:9338
21. Wan J-P, Zhou J, Mao H, Pan Y-J, Wu A-X (2008) Tetrahedron
64:11115
22. Cul A, Daich A, Decroix B, Sanz G, Van Hijfte L (2004)
Tetrahedron 60:11029
23. Souvie J-C, Fugire C, Lecouve J-P (2001) Process for the
preparation of isoindoline. U.S. Patent 6320058 B2. Chem Abstr
135:195499
H) = 1.2 Ueq(C)]. All calculations were performed, and the
drawings were prepared using WINGX crystallographic
suite of programs [48]. The crystal data are listed in
Table 1. Supplementary crystallographic data for this paper
can be obtained from the Cambridge Crystallographic Data
Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
?44 1223 336033; or deposit@ccdc.cam.ac.uk. CCDC
1412953–1412954 contain the supplementary crystallo-
graphic data for this paper.
24. Yoshida H, Fukushima H, Ohshita J, Kunai A (2004) Tetrahedron
Lett 45:8659
25. Shen S, Xu X, Lei M, Hu L (2012) Synthesis 44:3543
26. Hu L-J, Zhan Z-J, Lei M, Hu L-H (2013) Arkivoc 2013:189
27. You H, Chen F, Lei M, Hu L (2013) Tetrahedron Lett 54:2972
28. Chen F, Lei M, Hu L (2014) Green Chem 16:2472
29. Sole D, Serrano O (2010) J Org Chem 75:6267
30. Zang Q, Javed S, Porubsky P, Ullah F, Neuenswander B, Lush-
ington GH, Basha FZ, Organ MG, Hanson PR (2012) ACS Comb
Sci 14:211
Acknowledgments This work was financially supported by Croatian
Science Foundation (project No. 5596).
31. Priebbenow DL, Stewart SG, Pfeffer FM (2011) Org Biomol
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