Synthesis of new amidino-substituted 2-aminothiophenoles: mild basic ring opening of benzothiazole

Article abstract of DOI:10.1016/j.tet.2008.10.026

The efficient synthesis of new amidino, N-isopropylamidino, 2-imidazolinyl substituted benzothiazoles and 2-aminothiophenoles by the Pinner reaction is described. The novel ring opening of benzothiazole with ammonia and ethylenediamine was found, and a plausible reaction mechanism proposed. The ring opening with ethylenediamine is selective and applicable to compounds bearing hydrolytically and amonolytically unstable substituents. Different amidino-substituted 2-aminothiophenoles were isolated in zwitterionic and disulfide form and their structures were determined by X-ray crystal structure analysis.

Full text of DOI:10.1016/j.tet.2008.10.026

Tetrahedron 64 (2008) 11594–11602
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of new amidino-substituted 2-aminothiophenoles: mild basic ring
opening of benzothiazole
a
a
,
b
a
*
´
´
´
´
´
Livio Racane , Vesna Tralic-Kulenovic , Zlatko Mihalic , Gordana Pavlovic ,
Grace Karminski-Zamola c
a
´
Department of Applied Chemistry, Faculty of Textile Technology, University of Zagreb, Prilaz baruna Filipovica 28a, HR-10000 Zagreb, Croatia
b Chemistry Department, Laboratory of Organic Chemistry, Faculty of Science, University of Zagreb, Horvatovac 102a, HR-10000 Zagreb, Croatia
c Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Maruli´cev trg 20, HR-10000 Zagreb, Croatia
a r t i c l e i n f o
a b s t r a c t
Article history:
The efficient synthesis of new amidino, N-isopropylamidino, 2-imidazolinyl substituted benzothiazoles
and 2-aminothiophenoles by the Pinner reaction is described. The novel ring opening of benzothiazole
with ammonia and ethylenediamine was found, and a plausible reaction mechanism proposed. The ring
opening with ethylenediamine is selective and applicable to compounds bearing hydrolytically and
amonolytically unstable substituents. Different amidino-substituted 2-aminothiophenoles were isolated
in zwitterionic and disulfide form and their structures were determined by X-ray crystal structure
analysis.
Received 28 August 2008
Received in revised form
23 September 2008
Accepted 9 October 2008
Available online 15 October 2008
Keywords:
Benzothiazole
Amidine
Ó 2008 Elsevier Ltd. All rights reserved.
Pinner reaction
Disulfide
Thiolate
1. Introduction
the structure of the diamidine by including a variety of nitrogen
heterocycles into molecules of different shape.7
Benzothiazole derivatives are of considerable interest due to
their important biological and biophysical properties. Recently,
2-aryl or 2-heteroaryl substituted benzothiazoles have been asso-
ciated with antitumour,1 antimicrobial2 and antifungal3 activities,
Consequently, a number of synthetic methods have been de-
veloped for the preparation of substituted benzothiazoles8 and
amidines.9 Most of the methods for benzothiazole preparation in-
volve the condensation of 2-aminobenzenethiol with the corre-
sponding nitrile, aldehyde, acid, acid chloride or ester and by use of
Jacobson’s cyclization of thiobenzanilide.8 The method mostly used
for the preparation of amidines is nucleophilic addition of amines
or ammonia to suitably activated carboxylate equivalents, such as
imidates, thioimidates and imidoyl chlorides. Imidates can be
prepared generally by either base-catalyzed or acid-catalyzed
(Pinner synthesis) addition of an alcohol to a nitrile. The addition of
dry hydrochloric acid to a mixture of a nitrile and an alcohol in the
absence of water leads to the formation of the hydrochloride salt of
an imino ester. This salt can further react with an excess of alcohol
to form the ortho-ester, with ammonia or an amine to form an
amidine or with water to form an ester.9a In the base-catalyzed
addition of alcohol to nitrile, the formed imino ester requires an
amine salt in the second reaction step for the formation of
amidine.10
as well as used as b
-amyloid imaging agents.4 Also, the amidinic
group is often a part of important medical and biochemical agents
such as pentamidine and berenil, which have been commercialized
as antimicrobial agents (Fig. 1) for treatment of human and animal
infections caused by various species of trypanosome.5,6
Pentamidine is also a secondary drug for AIDS-related Pneumo-
cystis jirovecii pneumonia. Therefore, related aromatic dicationic
molecules have been extensively studied and a broad spectrum of
antimicrobial activity reported. Binding in the minor groove of DNA
at AT-rich sites is thought to be a key step in the mode of action of
these types of aromatic diamidines and possibly leads to inhibition
of DNA-dependent enzymes or transcription.6 A new direction in
the development of DNA sequence specific agents is modification of
Recently, our investigation has been directed towards the syn-
thesis of heterocyclic molecules substituted with different ami-
dines, as well as towards studying their biological, especially
* Corresponding author. Tel.: þ385 1 3712 556; fax: þ385 1 3712 599.
´
´
E-mail address: vtralic@ttf.hr (V. Tralic-Kulenovic).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.026

L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
11595
H
N
O
O
N
N
HN
NH
NH2
HN
NH
NH2
NH2
NH2
Pentamidine
Berenil
Figure 1. Antimicrobial agents.
antitumour, activity.11 Our research shows that the antitumour
activity strongly depends on the type and position of an amidino
substituent on the 2-phenylbenzothiazole skeleton.11c Therefore, it
was of importance to develop a synthetic method for the prepa-
ration of different amidino-substituted 2-aryl or 2-hetero-
arylbenzothiazoles. The synthetic strategy for the synthesis of
unsubstituted, N-isopropyl substituted amidine, as well as 2-imi-
dazolinyl derivatives of 2-phenyl or 2-heteroarylbenzothiazolyl
molecules (Scheme 1) can be divided in two approaches.
H
N
Cl
N
S
Cl
HCl/EtOH
H2N
S
NC
O
O
Et
1
2 (95%)
NaHCO3
N
S
N
S
NH4Cl
NH3Cl
H2N
HN
Et
N
NH2
aryl or
4a (65%)
ClH3N
3
heteroaryl
Cl
S
Am
n
NH3Cl
A
B
+
n = 1, 2
N
S
N
S
Cl
NH2
SH
H
O
Y
N
S
H2N
aryl or
aryl or
N
n
heteroaryl
heteroaryl
NC
NC
Am
NH
NH
n
n
Cl
4b (58%)
4c (41%)
Scheme 2.
Y = H, OH, OR, Cl
NH NH
N
NH2
SH
O
+
,
,
Am=
aryl or
heteroaryl
reaction of free base 3 with ammonium chloride, ethylenediamine
dihydrochloride and isopropylamine hydrochloride, respectively,
gave the corresponding amidines 4a–c in moderate yields. We
have previously reported13 the synthesis and crystal structure of
compound 4a. Attempts to prepare crystals of 4b and 4c suitable
for X-ray crystal structure analysis by slow evaporation of appro-
priate ethanolic solution were successful only for compound 4b
(Fig. 2).
The molecular structure of compound 4b in the crystalline state
is not planar due to the presence of the ethylene part of the mol-
ecule and the single C5–C8 bond, which allow the twisting around
it with the torsion angle C6–C5–C8–N2 of 10.6(2)ꢀ. In that way, the
benzothiazole and imidazoline rings are mutually twisted. The S–C
n
N
H
NH2
NH
Y
n
Scheme 1.
Synthetic approach A involves two reaction steps: the conden-
sation of 4-amino-3-mercaptobenzonitrile12 with an aldehyde or
acid chloride and the conversion of a nitrile into different amidines
by the Pinner reaction.11c This approach has shown certain limita-
tions and failed when 6-cyano-2-benzothiazolyl compounds of low
solubility were employed in Pinner reaction, even by using solvents
such as 2-methoxyethanol and 2-(2-ethoxyethoxy)ethanol.11e
On the other hand, synthetic approach B includes the conden-
sation of amidino-substituted 2-aminothiophenoles with aldehyde,
acid, acid chlorides, or esters. In this report, we are following route
B and present the preparation of different amidino-substituted
2-aminothiophenoles.
2. Results and discussion
2.1. Synthesis and X-ray crystal structure analysis
Hydrolysis of 6-cyanobenzothiazole to 4-amino-3-mercapto-
benzonitrile12 was easily accomplished by Claisen’s alkali and using
this methodology we tried to prepare different amidino-
substituted 2-aminothiophenoles from amidino-substituted
benzothiazoles (Scheme 2). The first step consists of acid-catalyzed
addition of ethanol to 6-cyanobenzothiazole 1 and afforded ethyl-
6-benzothiazole carboximidate dihydrochloride 2 in excellent yield
of 95%. Due to its reactivity it was used without purification in
second reaction step.
The imidate hydrochloride 2 was then converted into ethyl-6-
benzothiazole carboximidate 3 with NaHCO3 solution and extrac-
ted with chloroform. Evaporation of chloroform and subsequent
Figure 2. ORTEP drawing of 4b with the atomic numbering scheme. The thermal el-
lipsoids are drawn at the 50% probability level at 293 K.

11596
L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
bond distances formed by the endocyclic sulfur atom are as
expected slightly shorter than bonds in the Car–S–Car fragment
being of average value 1.768(10) Å [S–C1 1.731(2) and S–C7
1.729(1) Å].14 One C–N endocyclic bond within thiazole fragment is
double in character [C1–N1 1.285(2) Å], while the other is signifi-
structure (6a or 7a), since both are characterized by very similar
chemical shifts and the same ratio of the intensities of the signals in
the 1H NMR spectra. Fortunately, 6a and 7a could be crystallized
from deoxygenated water as stable yellow crystals that were suit-
able for X-ray crystal structure analysis (Fig. 2). The yield of pure
3,30-disulfanediylbis(4-aminobenzocarboxamidinium chloride) di-
hydrate 6a and 5-amidinium-2-aminobenzothiolate 7a were 31%
and 51%, respectively. After separation of the main products, from
the mother liquor, NH4Cl and formamidinium chloride 8 were
isolated as by products. The colourless crystal of 8 was extremely
deliquescent and we were unable to determine the melting point.18
However, the 1H NMR spectrum in DMSO shows characteristic two
broad signals of amidinium protons at 9.18 and 8.95 ppm, which
disappear on addition of D2O and a multiplet signal at 7.87 ppm,
which corresponds to C–H proton. The 13C NMR spectrum taken in
DMSO shows only one doublet at 157.2 ppm.
cantly longer with a significant contribution of
s character [N1–C2
1.389(2) Å]. The C8–N2 and C8–N3 bonds in the imidazolinium ring
are 1.315(2) Å and 1.316(2) Å indicating positive charge de-
localization within N–C–N part of the imidazolinium ring. On the
other hand, N3–C9 and N2–C10 bonds of 1.465(2) and 1.460(2) Å,
respectively, are essentially
s in character.
Reaction of 6-amidinobenzothiazole 4a with Claisen’s alkali is
shown in Scheme 3. The thiazole ring of 4a cleaves in the presence of
aqueous KOH as expected16 but the amidine groupalso hydrolyses to
a carboxylate. Subsequent acidification with acetic acid and crys-
tallization affords 3,30-disulfanediylbis(4-aminobenzoic acid) 5.
Interestingly, we obtained the same mp, 1H and 13C NMR spectro-
scopic data for compound 5 as it was reported for the hydrochloride
salt,15 which suggest that the previous authors did not isolate the
hydrochloride salt.
The asymmetric unit of 6a (Fig. 3) contains half of the disulfide
molecule, one Clꢁ ion and one water molecule. The two halves of
the molecule are related by a twofold axis [S1–S1a (a¼ꢁx,y,1/2ꢁz)
disulfide single bond amounts 2.0859(8) Å]. The C–N bond dis-
Cl
H2N
NH2
NH2
NH2
COOH
Claisen's
alkali
N
S
NH3
S
S
S
S
H2N
HOOC
H2N
Cl
NH2
NH2
H2N
5 (69%)
NH2
Cl
6a
4a
Scheme 3.
To prevent the hydrolysis of the amidine we tried to perform the
benzothiazole ring opening in mild basic conditions. In spite of the
fact that the ring opening of benzothiazole in mild basic conditions
is yet unknown, except with hydrazine,16d we carried out the re-
action of compound 4a with gaseous ammonia, hoping that the
electron attracting nature of the amidino substituent (sp¼0.65)17
would facilitate the ring opening. After four days of stirring at room
temperature, the reaction was complete and only benzothiazole
ring opening occurred. Work-up of the reaction mixture afforded
5-amidino-2-aminothiophenol in disulfide form 6a as the product
of oxidative dimerization.
This result opened a possibility for formation of amidino func-
tion and benzothiazole ring opening in the Pinner reaction as
a one-pot reaction. Thus, ethyl-6-benzothiazole carboximidate
dihydrochloride 2 was treated with ethanol saturated with am-
monia and reaction was carried out for five days at room temper-
ature (Scheme 4).
The resulting precipitate was a mixture of two products. In the
1H NMR spectra taken in DMSO these two products were slowly
interconverting. By treatment of this precipitate with de-
oxygenated methanol we were able to separate the insoluble
zwitterion 7a, from the methanol soluble disulfide 6a, which pre-
cipitated on addition of diethyl ether. However, even from the NMR
spectra of the isolated products it was impossible to assign
tances within the amidino group are 1.308(3) and 1.314(3) Å and
the C–N bond distance of the amino group is 1.349(3) Å, while C1–
S1 amounts 1.760(2) Å being predominantly
s
in character.19 The
torsion angle S1–S1a–C1–C2 is ꢁ80.7(2)ꢀ. The molecule of 7a is
planar. The protonation of the amidino group along with the C1–S1
bond distance in 7a [1.763(1) Å], which is dominantly
s in char-
acter, and the uniformity of C–N bond distances of the amidino
group [1.316(2) and 1.323(2) Å], confirm the zwitterionic character
of the molecule.
Reaction of imino ester hydrochloride 2 with ethylenediamine
in abs ethanol (Scheme 5) was carried out at reflux temperature for
4 h.
The resulting precipitate, after second crystallization from
deoxygenated water gave 5-(imidazolinium-2-yl)-2-aminobenzo-
thiolate hydrate 7b in a yield of 55%. To the ethanolic mother liquor,
diethyl ether was added and the precipitate crystallized from de-
oxygenated water yielding 18% of 3,30-disulfanediylbis[4-amino-
benzo(imidazolinium-2-yl-chloride)] dihydrate 6b.The structure of
disulfide 6b and zwitterion 7b were confirmed by X-ray crystal
structure analyses (Fig. 4).
As in 6a, the asymmetric unit of 6b (Fig. 3) contains half of the
disulfide molecule, one Clꢁ ion and one water molecule. The two
halves of the molecule are related by the twofold axis [S1–S1a
(a¼1ꢁx,y,1/2ꢁz) disulfide single bond amounts 2.0851(1) Å]. The
Cl
Cl
H2N
NH2
H
NH2
NH2
N
NH3/EtOH
S
+
+
H2N
NH2
S
H2N
Et
H2N
S
S
H2N
Cl
Cl
Cl
O
NH2
H2N
NH2
2
6a (31%)
7a (51%)
8
Scheme 4.

L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
11597
Figure 3. ORTEP drawing of compounds 6a and 7a with the atomic numbering scheme. The thermal ellipsoids are drawn at the 50% probability level at 293 K for both structures.
Cl
Cl
HN
NH2
NH
H
NH2
NH2
S
N
H2N
S
+
H
N
S
H2N
Et
S
HN
Cl
Cl
O
NH
H2N
6b (28%)
NH
2
7b (55%)
Scheme 5.
bond distance values in 6b correspond with those in 6a. For ex-
ample, the S1–C1 bond in 6b is 1.767(2) Å and 1.760(2) Å in 6a. The
C–N bond distances within the imidazolinium cation are N2–C7
1.326(3) Å and N3–C7 1.322(3) Å. The bonds N2–C8 and N3–C9 of
1.456(3) and 1.460(3) Å are essentially single carbon-to-nitrogen
bond. The torsion angle C6–C5–C7–N3 of 179.2(2)ꢀ indicates pla-
narity of half of the molecule. The torsion angle S1–S1a–C1–C2 is
85.6(2)ꢀ. Two crystallographically independent molecules are
found in the crystal structure of 7b, which crystallize with two
water molecules. They are two conformers, which differ in twisting
around single C15–C17 and C25–C27 bonds (C16–C15–C17–N1 and
C26–C25–C27–N4 amount ꢁ12.7(3)ꢀ and 2.5(3)ꢀ, respectively). The
equality of bond distances in the N–C–N fragment of imidazolinium
cations along with C11–S2 and C21–S1 bond distances (1.764(2)
and 1.758(2) Å, respectively) exhibit zwitterionic character of the
molecules of 7b as it is found for 7a.
Figure 4. ORTEP drawing of compounds 6b and 7b with the atomic numbering scheme. The thermal ellipsoids are drawn at the 50% probability level at 293 K for both structures.

11598
L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
Reaction conditions used for preparation of compounds 6a, 6b
It should be noted that all amidino-substituted 2-amino-
thiophenoles 6a–c and 7a, 7b in solution show interconversion
from zwitterionic to disulfide form and vice versa. Raman spec-
troscopy has proved to be very useful in detecting disulfides. Two
narrow and intense bands was observed in the region of 430–
480 cmꢁ1 for all isolated disulfide compounds 5 and 6a–c corre-
sponding to S–S stretching vibration and in accordance with the
literature.20
and 7a, 7b were applied to the reactions of 2 with excess of iso-
propylamine instead of ammonia or ethylenediamine (Scheme 6).
The reactions were carried out at room temperature or at refluxing
ethanol for a maximum of five days. Although we expected N-iso-
propylamidino-substituted 2-aminothiophenol as main product,
only compound 4c was isolated. The ring opening of benzothiazole
did not occur. We tried to prepare N-isopropylamidino-substituted
2-aminothiophenol from compound 4c in reaction with an etha-
nolic solution of ammonia (Scheme 7) at room temperature.
2.2. Mechanism
On the basis of the product analysis and the results of preliminary
DFTcalculations, both in the gas phase and in ethanol, we propose the
following mechanism for benzothiazole ring opening (Scheme 9).
Without getting into any details, which will be published
elsewhere, it is necessary to point out that thiazole ring opening
and final zwitterion producing fragmentation proceeds much
faster with imidate group already converted into amidino group
(Scheme 9a). Due to the stereoelectronic reasons, the ring
H
NH2
N
S
Cl
N
S
H2N
Et
H2N
Cl
Cl
O
NH
2
4c (48%)
Scheme 6.
Cl
RHN
NH2
S
NH2
S
NH2
S
NH2
N
S
NH3/EtOH
+
H2N
H2N
H2N
S
Cl
H2N
Cl
NH
NH2
NH
H2N
R = H or i-Pr
NHR
4c
7a
7c
Scheme 7.
The LC–MS analysis showed that a mixture of products was
formed, due to the competition between reaction of benzothiazole
ring opening, amonolysis of N-substituted amidine and di-
merization of thiophenoles. Selective ring opening of benzothiazole
without reaction of the N-isopropylamidino functional group was
achieved in the reaction of 4c with excess of ethylenediamine in
ethanol at reflux temperature for 2 h (Scheme 8).
opening goes smoothly with ammonia (Scheme 9b) and ethyl-
enediamine (Scheme 9c), but not with isopropylamine. The only
difference between ammonia and ethylenediamine is that, prior
to fragmentation, the attack of second amino group of ethyl-
enediamine produces the entropically favoured imidazolidine ring
(Scheme 9c).
Cl
NH2
HN
H2N
NH2
S
NH2
NH2
N
S
+
S
H2N
H2N
S
Cl
H2N
NH
NH
NH
H2N
6c (41%)
Cl
4c
7c
Scheme 8.
The LC–MS analysis of crude precipitate showed only zwitterion
7c and disulfide 6c molecular ion signals. However, we were able to
isolate by crystallization from water only 3,30-disulfanediylbis[4-
aminobenzo(N-isopropylamidiniumchloride)]dihydrate6cinayield
of 41%. The crystals of 6c suitable for X-ray crystal structure analysis
(Fig. 5) were prepared by slow evaporation of its solution fromwater.
The asymmetric unit contains half of the disulfide molecule, one
Clꢁ ion and one water molecule. The S–Sa (a¼ꢁx,ꢁyþ1/2,z) bond
amounts 2.0825(10) Å. The torsion angle Sa–S–C1–C2 value of
78.2(2)ꢀ exhibits the twisting around the single S–C1. The N-iso-
propylamidinium fragment is rotated around C5–C7 bond by
135.8(2)ꢀ (torsion angle C4–C5–C7–N2).
3. Conclusion
In summary, we have found a novel, simple and efficient
method for the synthesis of amidino, N-isopropylamidino and
2-imidazolinyl substituted 2-aminothiophenoles in zwitter-
ionic and disulfide form in high yield. The products 6a–c and
7a, 7b are the key precursors for the more versatile synthesis
of amidino-substituted benzothiazoles and other medicinally
interesting N,S-heterocycles. The ring opening of benzothi-
azole with ethylenediamine is selective and applicable to
compounds bearing hydrolytically and amonolytically unstable
substituents.

L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
11599
NMR spectra were recorded with a Brucker Avance DPX-300
(300 MHz and 75.5 MHz, for 1H and 13C, respectively), the deuter-
ated solvents indicated were used. Chemical shifts are reported in
parts per million relative to TMS as an internal standard. IR spectra
were recorded with Nicolet Magna 760 spectrophotometer. Raman
spectra were recorded with a Brucker FT-IR interferometer Equinox
55 with a FT-Raman FRA 106/S with a Nd:YAG laser source 1064 nm
and a liquid nitrogen cooled Ge detector. Mass spectra were
recorded with an Agilent 1100 Series LC/MSD Trap SL spectrometer
using electrospray ionization (ESI). Elemental analyses were per-
ˇ
´
formed at the microanalytical laboratories of the ‘RuCer Boskovic’
Institute. Melting points were determined on a Kofler block
apparatus.
4.2. X-ray crystal structure analysis of compound 4b, 6a–c
and 7a, 7b
Crystallographic data were recorded on an Xcalibur diffrac-
tometer, equipped with a CCD area detector, using Mo Ka radiation
Figure 5. ORTEP drawing of 6c with the atomic numbering scheme. The thermal
ellipsoids are drawn at the 50% probability level at 293 K.
(l
¼0.71073 Å) at T¼293 K. Lorentz and polarization correction
(CryAlis RED)22a was applied. Structure was solved by direct
methods (SHELXS97)22b and refined by full-matrix least squares
against F2 using all data (SHELXL97).22b All non-H atoms were re-
fined anisotropically. The H atoms were positioned geometrically
with Car–H, Cmethylene–H, Cmethyl–H¼0.93, 0.97 and 0.96 Å, re-
spectively, and were constrained to ride on their parent atoms, with
Uiso(H)¼1.2 Ueq(C) for Car–H and Cmethylene–H and 1.5 Ueq(C) for
Cmethyl–H. Hydrogen atoms of amine in 6a–c, 7a, 7b, amidinium
groups in 6a and 7a and of water molecules in hydrates 6a, 6b, 7b
4. Experimental
4.1. General
All solvents and reagents were dried and purified by standard
methods. 6-Cyanobenzothiazole 1 was prepared as described in the
literature.21 Claisen’s alkali was prepared dissolving 35 g 85% KOH
in 25 mL of water and 100 mL of methanol. The 1H NMR and the 13
C
NH
H
(a)
R = H, i-Pr Am =
4a,b
N
S
Cl
N
RNH2
NHR
N
H2N
Et
S
R = CH2CH2NH2 Am=
HAm
4c
Cl
N
H
O
2
4a-c
H
N
H
NH2
(b)
N
S
N
S
NH3
NH3
NH2
H2N
H2N
H2N
S
NH2
NH2
H2N
NH2
4a
NH2
NH2
H2
NH2
S
N
+
H2N
NH2
H2N
S
NH2
NH2
7a
H
N
H
N
H
N
H2N
N
NH2
(c)
NH2
H
N
H
N
NH
H
N
S
S
S
NH2
NH
NH
NH
NH
4c
H
N
H2
NH2
S
N
N
H
+
H
N
H
HN
NH
N
S
NH
7b
Scheme 9.

11600
L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
and 6c were located in difference Fourier syntheses and refined
wR[all data]¼0.1207, S¼1.14, max., min. electron density¼ꢁ0.33,
freely. The molecular diagrams were drawn by PLATON98.22c
0.23 e Åꢁ3, maximum
D/s<0.001.
4.2.1. Compound 4b
4.2.5. Compound 7a
X-ray crystal structure determination of 4b (CCDC No. 694988):
molecular formula: C10H10ClN3S, Mr¼239.72, colourless prism, tri-
clinic, space group: P1, crystal dimensions: 0.24ꢂ0.17ꢂ0.10 mm3,
unit cell parameters: a¼7.223(1), b¼8.340(1), c¼10.347(1) Å,
X-ray crystal structure determination of 7a (CCDC No. 676832):
molecular formula: C7H9N3S, Mr¼167.23, irregular yellow prism,
orthorhombic, space group: Pbca, crystal dimensions: 0.39ꢂ0.36ꢂ
0.30 mm3, unit cell parameters: a¼8.2797(6), b¼0.8575(7),
a¼72.782(11),
b
¼70.830(12),
g
¼71.064(12)ꢀ, V¼544.16(12) Å3,
c¼17.1949(11) Å,
V¼1545.77(18) Å3,
Z¼8,
Dc¼1.437 g cmꢁ3
,
Z¼2, Dc¼1.463 g cmꢁ3
,
m
¼0.51 mmꢁ1, F(000)¼248, Xcalibur four-
m
¼0.4 mmꢁ1, F(000)¼704, Xcalibur four-circle kappa geometry
circle kappa geometry single-crystal diffractometer with Xcalibur
single-crystal diffractometer with Xcalibur Sapphire 3 CCD, Mo K
a
Sapphire 3 CCD, Mo K
a
radiation (
l
¼0.71073 Å), T¼293(2) K,
q
radiation (
l
¼0.71073 Å), T¼293(2) K,
q range for data collec-
range for data collection¼4.5–27.0ꢀ, h,k,l range: ꢁ9:9; ꢁ10:10;
tion¼4.4–27.0ꢀ, h,k,l range: ꢁ10:10; ꢁ12:13; ꢁ21:21, scan type:
u,
ꢁ13:13, scan type:
u
, no. measured reflections: 5334, no. in-
no. measured reflections: 13,057, no. independent reflections
dependent reflections (Rint¼0.021): 2275, no. refined parameters:
144, no. observed reflections Iꢃ2 (I): 2161, R[Iꢃ2 (I)]¼0.0333,
(Rint¼0.024): 1671, no. refined parameters: 124, no. observed re-
s
s
flections Iꢃ2
s(I): 1671, R[Iꢃ2
s(I)]¼0.0294, wR[Iꢃ2 (I)]¼0.0794,
s
wR[Iꢃ2
s(I)]¼0.1057, R[all data]¼0.0347, wR[all data]¼0.1034,
R[all data]¼0.0299, wR[all data]¼0.0789, S¼1.09, max., min. elec-
S¼1.03, max., min. electron density¼ꢁ0.20, 0.25 e Åꢁ3, maximum
tron density¼ꢁ0.22, 0.24 e Åꢁ3, maximum
D/s
¼0.001.
D/s
¼0.001.
4.2.6. Compound 7b
4.2.2. Compound 6a
X-ray crystal structure determination of 7b (CCDC No. 694990):
molecular formula: C9H13N3OS, Mr¼211.29, pale yellow prism,
monoclinic, space group: P21/c (No. 14), crystal dimensions:
0.44ꢂ0.31ꢂ0.20 mm3, unit cell parameters: a¼7.2604(14),
X-ray crystal structure determination of 6a (CCDC No. 676831):
molecular formula: C14H22Cl2N6O2S2, Mr¼441.42, regular yellow
prism, monoclinic, space group: C2/c, crystal dimensions 0.42ꢂ0.37
ꢂ0.30 mm3, a¼12.2670(10), b¼12.1319(10), c¼14.4643(13) Å,
b¼15.3734(18), c¼18.115(2) Å,
b
¼96.435(13)ꢀ, V¼2009.1(5) Å3,
b
¼109.731(8)ꢀ, V¼2026.2(3) Å3, Z¼4, Dc¼1.447 g cmꢁ3
,
m
¼0.55
Z¼8, Dc¼1.397 g cmꢁ3
,
m
¼0.3 mmꢁ1, F(000)¼896, Xcalibur four-
mmꢁ1
,
F(000)¼920, Xcalibur four-circle kappa geometry
circle kappa geometry single-crystal diffractometer with Xcalibur
single-crystal diffractometer with Xcalibur Sapphire 3 CCD, Mo
Sapphire 3 CCD, Mo K
a
radiation (
l
¼0.71073 Å), T¼293(2) K,
q
K
a
radiation
(
l
¼0.71073 Å), T¼293(2) K,
q
range for data
range for data collection¼4.3–27.0ꢀ, h,k,l range: ꢁ9:9; ꢁ19:19;
collection¼4.3–27.0ꢀ, h,k,l range: ꢁ15:15; ꢁ15:15; ꢁ18:18, scan
ꢁ23:23, scan type:
u, no. measured reflections: 23,102, no. in-
dependent reflections (Rint¼0.043): 4349, no. refined parameters:
type:
u
, no. measured reflections: 8850, no. independent reflections
(Rint¼0.035)¼2187, no. refined parameters¼150, no. observed re-
301, no. observed reflections Iꢃ2 (I): 3686, R[Iꢃ2 (I)]¼0.0529,
s
s
flections Iꢃ2 (I)¼2014, R[Iꢃ2 (I)]¼0.0396, wR[Iꢃ2 (I)]¼0.0907,
s
s
s
wR[Iꢃ2 (I)]¼0.1210, R[all data]¼0.0696, wR[all data]¼0.1119,
s
R[all data]¼0.0432, wR[all data]¼0.0939, S¼1.09, max., min. elec-
S¼1.16, max., min. electron density¼ꢁ0.21, 0.20 e Åꢁ3, maximum
D/
tron density¼ꢁ0.28, 0.43 e Åꢁ3, maximum
D
/s
¼0.001.
s¼0.001.
4.2.3. Compound 6b
4.3. Ethyl-6-benzothiazole carboximidate dihydrochloride 2
X-ray crystal structure determination of 6b (CCDC No.
694989): molecular formula: C18H26Cl2N6O2S2, Mr¼493.46, regu-
lar pale yellow prism, monoclinic, space group: C2/c, crystal di-
mensions: 0.37ꢂ0.26ꢂ0.18 mm3, a¼12.1938(12), b¼13.6974(13),
A suspension of 6-cyanobenzothiazole (1, 4.0 g, 25 mmol) in
50 mL of abs ethanol was cooled to 5 ꢀC and saturated with dry
gaseous HCl. The flask was stoppered and stirred at room temper-
ature for 72 h (until IR spectra indicate the disappearance of the
nitrile peak). Excess HCl was removed from the suspension with
a stream of N2. The reaction mixture was poured into abs Et2O
(250 mL), and the resulting crystals filtered off, washed with abs
Et2O and dried under reduced pressure over KOH to afford the
compound 2 as white hygroscopic crystalline solid. It is unstable
and decomposes on heating. The synthesis of 2 has been preformed
prior to use without purification. Yield: 6.60 g (95%). IR (KBr):
c¼14.1414(17) Å,
b
¼108.746(10)ꢀ, V¼2236.6(4) Å3, Z¼4, Dc¼1.4
65 g cmꢁ3
,
m
¼0.51 mmꢁ1, F(000)¼1032, Xcalibur four-circle kappa
geometry single-crystal diffractometer with Xcalibur Sapphire 3
CCD, Mo K
a
radiation (
l
¼0.71073 Å), T¼293(2) K,
q range for data
collection¼4.5–27.0ꢀ, h,k,l range: ꢁ15:15; ꢁ17:12; ꢁ18:17, scan
type:
u, no. measured reflections: 8413, no. independent re-
flections (Rint¼0.025)¼2439, no. refined parameters¼160, no.
observed reflections Iꢃ2 (I)¼2003, R[Iꢃ2 (I)]¼0.0441, wR[Iꢃ2
s
s
s
(I)]¼0.1466, R[all data]¼0.0542, wR[all data]¼0.1344, S¼1.03,
n
¼3072, 2983, 2855, 1911, 1811, 1697, 1631, 1610, 1398, 1085, 852,
max., min. electron density¼ꢁ0.27, 0.46 e Åꢁ3
,
maximum
D
/
793 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d
¼1.53 (t, 3H, 3J¼7.0 Hz,
s<0.001.
–OCH2CH3), 4.73 (q, 2H, 3J¼7.0 Hz, –OCH2CH3), 6.20 (br s, 1H, H-3),
8.32 (m, 2H, H-4, H-5), 9.13 (s, 1H, H-7), 9.75 (s, 1H, H-2), 11.71 (br s,
1H, ]NHþ2 ), 12.52 (br s, 1H, –C]NHþ2 ). Anal. Calcd for
C10H12Cl2N2OS: C, 43.02; H, 4.33; Cl, 25.40; N, 10.03. Found: C,
43.18; H, 4.15; N, 9.71; Cl, 25.43%.
4.2.4. Compound 6c
X-ray crystal structure determination of 6c (CCDC No. 694991):
molecular formula: C20H34Cl2N6O2S2, Mr¼525.56, irregular dark
yellow prism, tetragonal, space group: I41/a, crystal dimensions:
0.51ꢂ0.47ꢂ0.39 mm3, a¼17.2448(7), b¼17.2448(8), c¼18.7091
4.4. General procedure for preparation of the 6-amidino-
substituted benzothiazoles 4a–c
(9) Å, V¼5563.8(4) Å3, Z¼8, Dc¼1.255 g cmꢁ3
,
m
¼0.41 mmꢁ1
,
F(000)¼2224, Xcalibur four-circle kappa geometry single-crystal
diffractometer with Xcalibur Sapphire 3 CCD, Mo K
a
radiation
The imidoyl ether dihydrochloride (2, 2.0 g, 7.2 mmol) was
poured into cold water (50 mL) and neutralized with 5% NaHCO3.
The free base 3 was extracted with chloroform, and combined
chloroform extract washed with water and dried over CaCl2. The
solvent was removed under reduced pressure to give colourless oil
of ethyl-6-benzothiazole carboximidate 3, which was dissolved in
(
l
¼0.71073 Å), T¼293(2) K,
q
range for data collection¼4.3–27.0ꢀ,
h,k,l range: ꢁ22:22; ꢁ22:22; ꢁ23:23, scan type:
u, no. measured
reflections: 44,846, no. independent reflections (Rint¼0.044)¼3014,
no. refined parameters¼175, no. observed reflections Iꢃ2 (I)¼
3000, R[Iꢃ2 (I)]¼0.0476, wR[Iꢃ2 (I)]¼0.1204, R[all data]¼0.0479,
s
s
s

L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
11601
ethanol (25 mL). A solution of hydrochloride salts of amine
4.6. Procedure for preparation of 5-amidino-substituted 2-
(8.0 mmol) in water (5 mL) was added and the mixture was heated
under reflux for 5 h. The hot mixture was filtered (charcoal), and
solvents were then removed under reduced pressure and the res-
idues were crystallized as follows.
aminothiophenoles 6a and 7a
4.6.1. 5-Amidinium-2-aminobenzothiolate 7a
A suspension of ethyl-6-benzothiazole carboximidate dihydro-
chloride (2, 6.0 g, 21 mmol) in abs ethanol (125 ml) was cooled to
10 ꢀC and saturated with ammonia. The flask was stoppered and
contentwasstirredatroom temperature for five days. Aftercoolingto
5 ꢀCtheobtainedsolidwasfilteredoffandwashedwithdryether. The
solid mixture was suspended and heated to boiling in hot de-
oxygenated abs methanol (150 ml), filtered hot and obtained crystals
purified by crystallization from water to afford zwitterion 7a as yel-
low crystals. Yield: 1.78 g (50.7%). Mp 235–240 ꢀC (dec). IR (KBr):
4.4.1. 6-Amidinobenzothiazole hydrochloride dihydrate 4a13
Using 3 and ammonium chloride as starting material and
crystallization from 75% ethanol gave colourless crystals. Yield:
1.17 g (65%). Mp 274–275 ꢀC (lit.13 275 ꢀC). IR (KBr):
n
¼3265, 3080,
1679, 1607, 1544, 1297, 908, 650 cmꢁ1. 1H NMR (300 MHz, DMSO-
d6):
d
¼7.95 (dd, 1H, 3J¼8.6 Hz, 4J¼1.8 Hz, H-5), 8.31 (d, 1H,
3J¼8.6 Hz, H-4), 8.74 (d, 1H, 4J¼1.7 Hz, H-7), 9.41 (br s, 4H,
–(C]NH2)NHþ2 ), 9.67 (s, 1H, H-2). 13C NMR (75.5 MHz, DMSO-d6):
n
¼3401, 3363, 2996, 1663, 1623,1588, 1565,1517, 1473 cmꢁ1. Raman:
d
¼123.8, 124.2, 125.7, 126.4, 134.5, 156.5, 161.3, 166.2. Anal. Calcd
n
¼1584,1570,1518,1461,1184, 871, 671, 562 cmꢁ1.1H NMR (300 MHz,
for C8H8ClN3S$2H2O: C, 38.48; H, 4.84; N, 16.83. Found: C, 38.52;
DMSO-d6):
d
¼6.08 (s, 2H, –NH2), 6.44 (d, 1H, 3J¼8.1 Hz, H-3), 6.99 (d,
H, 4.67; N, 17.01%.
1H, 3J¼8.3 Hz, H-4), 7.57 (d, 1H, 4J¼2.3 Hz, H-6), 8.19 (br s, 4H,
–(C]NH2)NHþ2 ). LC–MS (ESI), m/z: 168 (MHþ). Anal. Calcd for
C7H9N3S:C,50.27;H,5.42;N,25.13.FoundC,49.99;H,5.24;N,24.89%.
4.4.2. 6-(Imidazolin-2-yl)benzothiazole hydrochloride hydrate 4b
Using 3 and ethylenediamine dihydrochloride as starting ma-
terial and crystallization from 75% ethanol gave white crystals.
4.6.2. 3,30-Disulfanediylbis(4-aminobenzocarboxamidinium
chloride) dihydrate 6a
To methanolic filtrate (150 mL) remaining after separation of
zwitterion 7a abs Et2O was added. The resulting precipitate was
filtered, washed with Et2O and crystallized from water to give
yellowish crystals of disulfide 6a. Yield: 1.43 g (30.9%). Mp >300 ꢀC.
Yield: 1.20 g (58%). Mp >300 ꢀC. IR (KBr):
n
¼3055, 2947, 1656,
1595, 1367, 1279, 874, 692 cmꢁ1
.
1H NMR (300 MHz, DMSO-d6):
d
¼4.04 (s, 4H, –(CH2)2–), 8.23 (d, 1H, 3J¼8.5 Hz, H-5), 8.32 (d, 1H,
3J¼8.6 Hz, H-4), 9.07 (s, 1H, H-7), 9.72 (s, 1H, H-2), 11.1 (br s, 2H,
–NHC]NHþ–). 13C NMR (75.5 MHz, DMSO-d6):
d
¼44.9 (2C), 119.7,
124.1, 124.8, 126.7, 134.6, 154.4, 156.7, 164.9. Anal. Calcd for
C10H10ClN3S$H2O: C, 46.60; H, 4.69; N, 16.30. Found: C, 46.80; H,
4.53; N, 16.18%.
IR (KBr):
Raman:
(300 MHz, DMSO-d6):
n
¼3482, 3318, 3195, 1654, 1595, 1545, 1472, 1189 cmꢁ1
.
n
¼1590, 1558, 1473,1174,1089, 878, 475, 445 cmꢁ1. 1H NMR
d
¼6.70 (s, 4H, –NH2), 6.85 (d, 2H, 3J¼8.7 Hz,
H-5), 7.57 (d, 2H, 4J¼2.0 Hz, H-2), 7.66 (dd, 1H, 4J¼2.0 Hz, 3J¼8.7 Hz,
4.4.3. 6-(N-Isopropylamidino)benzothiazole hydrochloride 4c
Method A. Using 3 and isopropylamine hydrochloride as starting
material and crystallization from abs ethanol gave white crystals.
H-6), 8.60 (br s, 4H, –(C]NH2)NHþ2 ), 8.84 (br s, 4H, –(C]NH2)NH2þ).
13C NMR (75.5 MHz, DMSO-d6):
d
¼112.7, 114.1, 115.4, 131.2, 136.7,
154.7, 163.6. LC–MS (ESI), m/z: 333 (MHþꢁ2HCl). Anal. Calcd for
C14H20Cl2N6S2$2H2O: C, 38.10; H, 5.44; N, 19.03. Found: C, 37.89; H,
5.15; N, 18.87%.
Yield: 0.84 g (41%). Mp 278 ꢀC. IR (KBr):
n
¼3193, 3046, 2970, 1688,
1614, 1127, 907, 887, 702 cmꢁ1 1H NMR (300 MHz, DMSO-d6):
.
d
¼1.31 (d, 6H, 3J¼6.4 Hz, (CH3)2CH–), 4.18 (m, 1H, (CH3)2CH–), 7.87
(dd, 1H, 3J¼8.6 Hz, 4J¼1.8 Hz, H-5), 8.27 (d, 1H, 3J¼8.6 Hz, H-4), 8.67
(d, 1H, 4J¼1.6 Hz, H-7), 9.66 (s, 1H, H-2), 9.42 (br s, 1H,
–(C]NH2)NHþ–), 9.66 (br s, 1H, –(C]NH2)NHþ–), 9.83 (br s, 1H,
4.7. Procedure for preparation of 5-(imidazolinium-2-yl)-
substituted 2-aminothiophenoles 6b and 7b
–(C]NH2)NHþ–). 13C NMR (75.5 MHz, DMSO-d6):
d
¼21.7 (2C), 45.7,
4.7.1. 5-(Imidazolinium-2-yl)-2-aminobenzothiolate hydrate 7b
To a suspension of ethyl-6-benzothiazole carboximidate dihy-
drochloride (2, 6.0 g, 21 mmol) in abs ethanol (100 ml) freshly
distilled ethylenediamine (8.4 mL, 0.125 mol) was added in nitro-
gen atmosphere. The flask was refluxed for 5 h under nitrogen,
cooled to 5 ꢀC and the obtained solid was filtered off and washed
with dry ether. The solid mixture was suspended and heated to
boiling in hot deoxygenated abs methanol (150 ml), filtered hot and
obtained crystals purified by crystallization from water to afford
compound 7b as yellow crystals. Yield: 2.46 g (55.3%). Mp 202–
123.5, 124.3, 126.6, 126.7, 134.2, 156.0, 162.0. Anal. Calcd for
C11H14ClN3S: C, 51.67; H, 5.51; N, 16.42. Found: C, 51.57; H, 5.35; N,
16.39%.
Method B. Using (2, 2.8 g, 10 mmol) and isopropylamine
(4.25 mL, 50 mmol) as starting material in reaction in abs ethanol
(40 mL) at reflux temperature for 24 h, and crystallization of resi-
due from abs ethanol gave 1.22 g (48%) of compound 4c.
4.5. 3,30-Disulfanediylbis(4-aminobenzoic acid) 5
205 ꢀC (dec). IR (KBr):
1356, 1325, 1286 cmꢁ1. Raman:
926, 845, 717, 634 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
n
¼3457, 3405, 3328, 3127, 1580, 1536, 1493,
¼1595, 1570, 1518, 1354, 1279, 963,
n
The mixture of 6-amidinobenzothiazole (4a, 1.25 g, 5 mmol)
and Claisen’s alkali (25 mL) was stirred at reflux temperature for
15 min. After cooling the mixture was poured in water (100 mL)
and acidified with acetic acid. The resulting precipitate, after
standing for a week in refrigerator, was filtered off and crystallized
from ethanol to give yellowish crystals of 5. Yield: 0.68 g (69%). Mp
d
¼3.80 (s,
4H, –NH(CH2)2NH–), 6.24 (s, 2H, NH2), 6.43 (d, 1H, 3J¼8.4 Hz, H-3),
7.04 (dd, 1H, 3J¼8.4 Hz, 4J¼2.4 Hz, H-4), 7.66 (d, 1H, 4J¼2.4 Hz, H-6),
9.55 (br s, 2H, –NHC]NHþ–). LC–MS (ESI), m/z: 194 (MHþ). Anal.
Calcd for C9H11N3S$H2O: C, 51.16; H, 6.16; N, 19.88. Found C, 50.88;
H, 6.03; N, 19.58%.
282–285 ꢀC. IR (KBr):
1289, 1151, 766 cmꢁ1. Raman:
n
¼3488, 3377, 2925, 2647, 1678, 1609, 1587,
¼3070, 1588, 1451, 1283, 1258, 1140,
n
4.7.2. 3,30-Disulfanediylbis[4-aminobenzo(imidazolinium-2-yl-
chloride)] dihydrate 6b
882, 704, 478, 438 cmꢁ1. 1H NMR (300 MHz, DMSO-d6):
d¼6.31 (s,
4H, –NH2), 6.76 (d, 2H, 3J¼8.6 Hz, H-5, H-50), 7.48 (d, 2H, 4J¼1.8 Hz,
To methanolic filtrate (150 mL) remaining after separation of
zwitterion 7b abs Et2O was added. The resulting precipitate was
filtered, washed with Et2O and crystallized from water to give
yellowish crystals of disulfide 6b. Yield: 2.86 g (27.6%). Mp >300 ꢀC.
H-7, H-70), 7.64 (dd, 2H, 4J¼1.8 Hz, J¼8.5 Hz, H-6, H-60), 12.08 (br
3
s, 1H, –COOH). 13C NMR (75.5 MHz, DMSO-d6):
d
¼113.8, 114.9,
117.6, 132.7, 138.0, 153.5, 166.5. Anal. Calcd for C14H12N2O4S2: C,
49.99; H, 3.60; N, 8.33; S, 19.06. Found: C, 49.81; H, 3.67; N, 8.45;
S, 19.01%.
IR (KBr):
n
n
¼3308, 3189, 2963, 1590, 1498, 1361, 817 cmꢁ1. Raman:
¼1589, 1477, 1357, 1290, 930, 473, 431 cmꢁ1
.
1H NMR (300 MHz,

11602
L. Racane´ et al. / Tetrahedron 64 (2008) 11594–11602
3. Sheng, C.; Zhu, J.; Zhang, W.; Zhang, M.; Ji, H.; Song, Y.; Xu, H.; Yao, J.; Miao, Z.;
DMSO-d6):
d
¼3.86 (s, 8H, –NH(CH2)2NH–), 6.89 (d, 2H, 3J¼8.7 Hz,
Zhou, Y.; Zhu, J.; Lu, J. Eur. J. Med. Chem. 2007, 42, 477–486.
4. Lochart, A.;Ye, L.; Judd, D. B.; Merritt, A. T.; Lowe, P. N.; Morgenstern,J. L.; Hong, G.;
Gee, A. D.; Brown, J. J. Biol. Chem. 2005, 280, 7677–7684.
5. (a) Grout, R. J. In The Chemistry of Amidines and Imidates; Patai, S., Ed.; Wiley &
Sons: New York, NY, 1975; Vol. 1, p 255–281.
6. Tidwell, R. R.; Boykin, D. W. In Small Molecule DNA and RNA Binders; Demeu-
nynck, M., Bailly, C., Wilson, W. D., Eds.; Wiley-VCH: Weinheim, 2003; Vol. 2,
p 414–501.
H-5, H-50), 6.94 (s, 2H, –NH2), 7.38 (d, 2H, 4J¼2.2 Hz, H-2, H-20), 7.79
(dd, 2H, 3J¼8.8 Hz, 4J¼2.0 Hz, H-6, H-60), 9.96 (br s, 4H,
–NHC]NHþ–). 13C NMR (75.5 MHz, DMSO-d6):
114.9, 115.5, 132.3, 138.7, 155.7, 163.8. LC–MS (ESI), m/z: 385
(MHþꢁ2HCl). Anal. Calcd for C18H22Cl2N6S2$2H2O: C, 43.81; H,
5.31; N, 17.03. Found: C, 43.77; H, 5.42; N, 16.98%.
d
¼44.3 (4C), 107.8,
7. (a) Munde, M.; Ismail, M. A.; Arafa, R.; Peixoto, P.; Collar, C. J.; Liu, Y.; Hu, L.;
David-Cordonnier, M.-H.; Lansiaux, A.; Bailly, C.; Boykin, D. W.; Wilson, W. D.
J. Am. Chem. Soc. 2007, 129, 13732–13743; (b) Arafa, R. K.; Brun, R.; Wenzler, T.;
Tanious, F. A.; Wilson, W. D.; Stephens, C. E.; Boykin, D. W. J. Med. Chem. 2005,
48, 5480–5488.
4.8. 3,30-Disulfanediylbis[4-aminobenzo(N-isopropyl-
amidinium-chloride)] dihydrate 6c
8. (a) Metzger, J.; Plank, H. Chim. Ind. 1956, 75, 929–939; (b) Metzger, J.; Plank, H.
Chim. Ind. 1956, 75, 1290–1303; (c) Jacobson, P. Chem. Ber. 1886, 19, 1067–1078;
(d) Spitulnik, M. J. Synthesis 1976, 730–731; (e) Bowman, W. R.; Heaney, H.;
Jordan, B. M. Tetrahedron 1991, 47, 10119–10128; (f) Jayanthi, G.; Muthusamy, S.;
Paramasivam, R.; Ramakrishnan, V. T.; Ramasamy, N. K.; Ramamurthy, P. J. Org.
Chem. 1997, 62, 5766–5770; (g) Stanetty, P.; Krumpak, B. J. Org. Chem. 1996, 61,
5130–5133; (h) Spyros, M.; Gatos, D.; Barlos, K. Tetrahedron Lett. 2001, 42, 2201–
2204; (i) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71,1802–1808; (j) Bose, D. S.;
Idrees, M. Tetrahedron Lett. 2007, 48, 669–672; (k) Batista, R. M. F.; Costa, S. P. G.;
Malheiro, E. L.; Belsley, M.; Raposo, M. M. M. Tetrahedron 2007, 63, 4258–4265; (l)
Downer-Riley, N. K.; Jackson, Y. A. Tetrahedron 2008, 7741–7744.
9. (a) Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai, S., Rappoport, Z.,
Eds.; Wiley & Sons: New York, NY, 1991; Vol. 2, p 339–365; (b) Cai, L.; Han, Y.;
Ren, S.; Huang, L. Tetrahedron 2000, 56, 8253–8262; (c) Yin, Z.; Zhang, Z.; Zhu, J.;
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To a suspension of 6-(N-isopropylamidino)benzothiazole hy-
drochloride (4c, 0.65 g, 2.5 mmol) in abs ethanol (15 ml) freshly
distilled ethylenediamine (0.84 mL, 12.5 mmol) was added in ni-
trogen atmosphere. The flask was refluxed for 2 h under nitrogen
(TLC-control), cooled to 5 ꢀC and dry ether (5 mL) added. The
obtained solid was filtered off and washed with dry ether. Crys-
tallization from deoxygenated water afforded only disulfide 6c as
yellow crystals. Yield: 0.55 g (41.0%). Mp 232–235 ꢀC. IR (KBr):
n
¼3430, 3306, 3145, 2978, 1671, 1618, 1501, 1403, 1130, 834,
682 cmꢁ1. Raman:
n
¼1593, 1392, 1172, 881, 479, 429 cmꢁ1. 1H NMR
(300 MHz, DMSO-d6):
d
¼1.21 (d, 12H, 3J¼6.1 Hz, –CH(CH3)2), 4.04
(m, 2H, –CH(CH3)2), 6.51 (s, 4H, –NH2), 6.85 (d, 2H, 3J¼9.0 Hz, H-5,
H-50), 7.59 (m, 4H, H-2, H-20, H-6, H-60), 8.99 (br s, 6H,
–(C]NH2)NHþ–). 13C NMR (75.5 MHz, DMSO-d6):
d¼21.9 (4C), 45.1,
114.5, 115.2, 116.2, 131.8, 136.7, 154.7, 160.6. LC–MS (ESI), m/z: 417
(MHþꢁ2HCl). Anal. Calcd for C20H30Cl2N6S2$2H2O: C, 45.71; H,
6.52; N, 15.99. Found: C, 45.60; H, 6.42; N, 16.19%.
10. Schaefer, F. C.; Peters, G. A. J. Org. Chem. 1961, 26, 412–418.
ˇ
11. (a) Hranjec, M.; Kralj, M.; Piantanida, I.; Sedic´, M.; Suman, L.; Pavelic´, K.; Kar-
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´
minski-Zamola, G. J. Med. Chem. 2007, 50, 5696–5711; (b) Starcevic, K.; Kralj, M.;
Ester, K.; Sabol, I.; Grce, M.; Pavelic´, K.; Karminski-Zamola, G. Bioorg. Med. Chem.
`
´
´
2007, 15, 4419–4426; (c) Racane, L.; Tralic-Kulenovic, V.; Kitson, R. P.; Kar-
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ˇ
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Kulenovic´, V.; Fiser-Jakic, L.; Boykin, W. D.; Karminski-Zamola, G. Heterocycles
2001, 55, 2085–2098; (e) Racane
minski-Zamola, G. Molecules 2003, 8, 342–349.
`, L.; Tralic´-Kulenovic´, V.; Boykin, W. D.; Kar-
Geometries of all of the structures involved in all of the more or
less plausible reaction paths leading to experimentally observed
products were fully optimized at B3LYP/6-311G(d,p) level of theory,
both in the gas phase and in ethanol, and identified as minima or
transition structures by vibrational analysis. Solvent effects were
introduced via polarizable continuum model using IEF-PCM
method as implemented in Gaussian 03.23 Based on the calculation
results, paths involving nonexistent or higher-lying transition
structures were eliminated, and the resulting stepwise minimum-
energy mechanism is proposed in Scheme 9.
´
´
`
ˇ
´
12. Tralic-Kulenovic, V.; Karminski-Zamola, G.; Racane, L.; Fiser-Jakic, L. Heterocycl.
Commun. 1998, 4, 423–428.
ꢀ
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13. Matkovic-Calogovic, D.; Popovic, Z.; Tralic-Kulenovic, V.; Racane, L.; Karminski-
Zamola, G. Acta Crystallogr. 2003, C59, o190–o191.
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J. Chem. Soc., Perkin Trans. 2 1987, S1–S19.
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4.10. Supplementary data
Supplementary publication numbers CCDC 676831, 676832 and
694988–694991 for compounds 4b, 6a–c, 7a, 7b contain the sup-
plementary crystallographic data for this paper. These data can be
obtained free of charge at www.ccdc.cam.ac.uk/conts/retrie-
ving.html [or from the Cambridge Crystallographic Data Centre
(CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44 (0) 1223
336033; e-mail: deposit@ccdc.cam.ac.uk].
18. Taylor, E. C.; Ehrhart, W. A. J. Am. Chem. Soc. 1960, 82, 3138–3141.
19. Trinajstic, N. Tetrahedron Lett. 1968, 12, 1529–1532.
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pp 303–382.
21. Boggust, W. A.; Cocker, W. J. Chem. Soc. 1949, 355–361.
22. (a) Oxford Diffraction. Xcalibur CCD System, CrysAlis Software System, Version
171.23; Oxford Diffraction: Abingdon, UK, 2004; (b) Sheldrick, G. M. Acta
Crystallogr. 2008, A64, 112–122; (c) Spek, A. L. Acta Crystallogr. 1990, A46, 34.
23. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
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Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
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Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.;
Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.;
Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J.
B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu,
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Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
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Acknowledgements
This work is supported by Ministry of Science, Education and
Sports of the Republic of Croatia (projects no. 125-0982464-1356,
117-0000000-3283 and 119-1191342-1339).
References and notes
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