Synthesis of novel benzo-substituted macrocyclic ligands containing thienothiophene subunits

Article abstract of DOI:10.1002/jhet.2012

A facile synthetic approach was adopted toward the synthesis of benzo-fused macrocyclic ligands with thienothiophene group incorporated into the ring system. Thus, treatment of bis(bromomethyl) compound 2 with the K salt of the appropriate bis(phenol)s 3a, 3b, 3c, 3d in boiling DMF led to the formation of the novel macrocyclic diamides 4a, 4b, 4c, 4d in 39-58% yield. Reaction of 2 with the potassium salt (obtained upon treatment of salicylaldehyde 5 with ethanolic potassium hydroxide) in refluxing DMF afforded the novel bis(aldehyde) 6 in 73% yield. Cyclocondensation of 6 with the appropriate bis(N-substituted) cyanoacetamide derivatives 7a and 7b afforded the target macrocycles 8a and 8b in 48 and 55% yields, respectively. Reaction of the bis(aldehyde) 6 with 1,3- and 1,4-diaminopropane 9a and 9b in refluxing ethanol under high-dilution conditions afforded the corresponding macrocyclic Schiff bases 10a and 10b in 41 and 37% yields, respectively. Cyclocondensation of 6 with 1,3-bis(4-amino-5- phenyl-3-ylsulfanylmethyl)propane (15) in glacial acetic acid under high-dilution conditions gave the macrocyclic Schiff base 14 in 46% yield. On the other hand, cyclocondensation of bis(aldehydes) 17 and 20 with 3,4-bis(4-amino-5-phenyl-3-ylsulfanylmethyl)thienothiophene 16 in refluxing acetic acid under high-dilution conditions afforded unexpectedly the novel condensed heteromacrocycles 18 and 21 in 33 and 28%, respectively. The novel bis(amine) 16 was obtained in 50% yield upon treatment of 2 with 4-amino-1,2,4-triazol-3-thione 11 in ethanol/water mixture containing potassium hydroxide.

Full text of DOI:10.1002/jhet.2012

E34
Synthesis of Novel Benzo-substituted Macrocyclic Ligands Containing
Vol 51
Thienothiophene Subunits
Ahmed E. M. Mekky1,2 and Ahmed H. M. Elwahy
1
*
1Chemistry Department, Faculty of Science, Cairo University, Giza 12613, Egypt
2Chemistry Department, Faculty of Science, King Abdulaziz University, North Jeddah, P.O. Box 80203, Jeddah 21589,
Saudi Arabia
*
E-mail: aelwahy@hotmail.com
Received January 1, 2013
DOI 10.1002/jhet.2012
Published online 17 March 2014 in Wiley Online Library (wileyonlinelibrary.com).
This article is dedicated to Professor Klaus Hafner on the occasion of his 85th birthday.
S
S
EtOOC
S
S
S
COOEt
S
EtOOC
COOEt
EtOOC
COOEt
O
O
O
O
O
O
NH HN
X
NC
O
CN
N
N
O
O
NH HN
X
O
X
S
S
EtOOC
COOEt
S
S
COOEt
EtOOC
N
N
S
S
O
O
N
N
N
N
Ph
N
H
N
N
N
Ph
N
N
H
O
O
Ph
S
S
Ph
X
N N
N N
A facile synthetic approach was adopted toward the synthesis of benzo-fused macrocyclic ligands with
thienothiophene group incorporated into the ring system. Thus, treatment of bis(bromomethyl) compound
2 with the K salt of the appropriate bis(phenol)s 3a–d in boiling DMF led to the formation of the novel
macrocyclic diamides 4a–d in 39–58% yield. Reaction of 2 with the potassium salt (obtained upon treatment
of salicylaldehyde 5 with ethanolic potassium hydroxide) in refluxing DMF afforded the novel bis(aldehyde)
6 in 73% yield. Cyclocondensation of 6 with the appropriate bis(N-substituted) cyanoacetamide derivatives
7a and 7b afforded the target macrocycles 8a and 8b in 48 and 55% yields, respectively. Reaction of the bis
(aldehyde) 6 with 1,3- and 1,4-diaminopropane 9a and 9b in refluxing ethanol under high-dilution conditions
afforded the corresponding macrocyclic Schiff bases 10a and 10b in 41 and 37% yields, respectively.
Cyclocondensation of 6 with 1,3-bis(4-amino-5-phenyl-3-ylsulfanylmethyl)propane (15) in glacial acetic
acid under high-dilution conditions gave the macrocyclic Schiff base 14 in 46% yield. On the other hand,
cyclocondensation of bis(aldehydes) 17 and 20 with 3,4-bis(4-amino-5-phenyl-3-ylsulfanylmethyl)
thienothiophene 16 in refluxing acetic acid under high-dilution conditions afforded unexpectedly the novel
condensed heteromacrocycles 18 and 21 in 33 and 28%, respectively. The novel bis(amine) 16 was obtained
in 50% yield upon treatment of 2 with 4-amino-1,2,4-triazol-3-thione 11 in ethanol/water mixture containing
potassium hydroxide.
J. Heterocyclic Chem., 51, E34 (2014).
INTRODUCTION
catalysis [4]. Of particular interest are macrocyclic ligands
incorporating amide groups, because such groups have
been reported to modify the binding properties and selec-
tivity of macrocyclic compounds with metal cation [5] as
well as organic molecules [6]. Moreover, a progressive
interest was directed in the last few years to the synthesis
of novel macrocyclic Schiff bases because they can be
obtained by simple self-condensation of suitable formyl-
or keto- and primary amine-precursors [7], and they can
be functionalized by inserting appropriate groups in the
aliphatic and/or aromatic chains of the precursors. They
The continued interest and quest in designing new
macrocyclic ligands stem mainly from their use as models
for protein–metal binding sites in a substantial array of
metalloproteins in biological systems [1], as synthetic
ionophores, as models to study the magnetic exchange
phenomena, as therapeutic reagents in chelate therapy for
the treatment of metal intoxication, as cyclic antibiotics
[2] that owe their antibiotic actions to specific metal com-
plexation, to study the host–guest interactions [3], and in
© 2014 HeteroCorporation

August 2014
Synthesis of Novel Benzo-Substituted Macrocyclic Ligands Containing
Thienothiophene Subunits
E35
generally can contain additional donor groups (O, S, P, etc.),
and this makes them good candidates for metal ion complex-
ation and for mimicking biological systems. Furthermore,
considerable attention has been focused on crown ethers
bearing heterocyclic groups in the macrocyclic ring [8]. Het-
erocyclic groups provide rigidity and are able to participate,
in some cases, in complexation through their soft donor
atoms. Modification of such molecules by heterocyclic frag-
ments also improves their use in biological environments
and for binding to biomolecules [9]. Although many macro-
cyclic compounds containing heterocycles such as pyridine,
bipyridine, pyrimidine, triazole, pyrazole, imidazole, and
thiophene have been synthesized and studied [10], very little
is known about using thienothiophene [11] as a subunit of
macrocyclic compounds. Thienothiophenes have been
developed for different purposes in the pharmaceutical
field and have been tested as potential antitumor, antiviral,
antibiotic, and antiglaucoma drugs or as inhibitors of
platelet aggregation [12]. In addition, thienothiophenes
find potential applications in a wide variety of optical
and electronic systems [13].
Recognition of the importance of macrocyclic ligands has
led to a considerable effort being invested in developing
reliable inexpensive synthetic routes for these compounds.
We are now engaged in a project aimed at the prepara-
tion of new macrocyclic ligands that incorporated a
thieno[2,3-b]thiophene unit within the cyclophane frame-
work via its 3,4-positions. Our objective in this project is to
study the effect of the rigidity provided by these groups on
the ability of the ligands to form stable complexes compared
with other macrocyclic analogues.
Treatment of 2 with the K salt of the appropriate bis
(phenol)s 3a–c (obtained upon treatment of 3a–c with
ethanolic KOH) [15] in boiling DMF led to the formation
of the novel macrocyclic diamides 4a–c in 51–58% yield
(Scheme 2).
The insertion of an additional 1,3-xyly unit into the
macrocyclic ring 4 instead of the alkylene moieties was
also investigated, aiming at studying the effect of rigidity
provided by these groups on the ability of the ligands to
form stable complexes compared with other macrocyclic
analogues. Thus, reaction of the dipotassium salts
[obtained from the corresponding bis(phenol) 3d upon
treatment with ethanolic KOH] [15] with 2 under similar
conditions gives the corresponding macrocyclic diamides
4d in 39% yield (Scheme 2).
We have also studied the synthesis of macrocycles
diamides 8 with a thienothiophene unit as a new class of
macrocyclic diamides by making structure variations
within the ligand 4 aiming at improving their selective
binding of charged or neutral species. To achieve this goal,
the novel bis(aldehyde) 6 was prepared as outlined in
Scheme 3. Thus, reaction of 2 with the potassium salt
(obtained upon treatment of salicylaldehyde 5 with ethanolic
potassium hydroxide) in refluxing DMF afforded the corre-
sponding bis(aldehyde) 6 in 73% yield. Cyclocondensation
of 6 with the appropriate bis(N-substituted) cyanoacetamide
derivatives 7a and 7b [16] afforded the target macrocycles
8a and 8b in 48 and 45% yields, respectively.
The structure of 8a,b was established through IR, 1H-NMR,
mass spectra, and elemental analysis data. Thus, their
1H-NMR spectra reveal the absence of the activated
methylene group and exhibit the presence of the ylidene
olefinic protons at (d) 8.33 and 8.36ppm, respectively. The
appearance of the olefinic proton signals at these chemical
shift values indicates that the methine protons are located
in a trans position to the nitrile group [17].
We also aimed to introduce the thienothiophene unit into
macrocycles containing an O2N2-donor set and fused with
two benzene units. Lindoy and coworkers [18] pioneered
the synthesis of dibenzo O2N2 macrocycles and studied
the kinetic and thermodynamic stability of their complexes
with Ni(II) and Cu(II). The synthetic strategy depends on
the cyclocondensation between bis(amines) and the appro-
priate bis(aldehydes), either in the absence or in the
presence of metal ions. The latter can serve as a template to
direct the condensation preferentially to cyclic rather than
oligomeric/polymeric products and to stabilize the
RESULTS AND DISCUSSION
We initially aimed to introduce a thienothiophene unit
into macrocycles containing an O2-donor set and two
amide linkages and fused with two benzene units. For this
purpose, ethyl 3,4-bis(bromomethyl)-5-(propionyloxy)
thieno[2,3-b]thiophene-2-carboxylate 2 was chosen as a
key intermediate and could be readily obtained from
the corresponding 3,4-dimethylthieno[2,3-b]thiophene-2,
5-dicarboxylate [11b] 1 by radical bromination using
NBS/dibenzoyl peroxide (Scheme 1). Compound 1 was
obtained by the reaction of acetylacetone, CS2, and ethyl
bromoacetate in anhydrous DMF containing an excess of
anhydrous KF at room temperature for 8 h [14].
Scheme 1
S
S
CS2, BrCH2CO2Et
KF/DMF
S
S
NBS
CCl4
EtOOC
Br
COOEt
Br
EtOOC
COOEt
O
O
1
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E36
A. E. M. Mekky and A. H. M. Elwahy
Vol 51
Scheme 2
Scheme 3
S
S
EtOOC
COOEt
CHO
OH
KOH/DMF
73%
+
2
2
O
O
5
OHC
CHO
6
O
O
O
H
N
CN
NC
CN
N
H
NC
N
H
N
H
O
7a
7b
48%
S
DMF/pip.
45%
DMF/pip.
S
S
S
EtOOC
EtOOC
COOEt
COOEt
O
O
O
O
NC
O
CN
O
NC
O
CN
O
NH
HN
NH
HN
8a
8b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of Novel Benzo-Substituted Macrocyclic Ligands Containing
Thienothiophene Subunits
August 2014
E37
macrocycles once formed [19]. In the present work, we used
a nontemplate method for the formation of the novel
macrocycles 10a and 10b as outlined in Scheme 4. Thus,
reaction of bis(aldehyde) 6 with 1,3-diaminopropane 9a in
refluxing ethanol under high-dilution conditions afforded
the corresponding macrocyclic Schiff base 10a in 41% yield
as the only reaction product. Similarly, macrocyclic Schiff
base 10b was prepared in 37% yield by cyclocondensation
of 6 with 1,4-diaminobutane 9a.
Our study was extended to investigate the reactivity
of the, now available, bis(aldehyde) 6 toward the bis
(aminotriazole) 15 [20] in an attempt to obtain the corre-
sponding novel macrocycle Schiff base 14 upon which fused
triazole and thienothiophene units and contained N, O, and S
inside the macrocyclic ring as donor atoms. Thus,
cyclocondensation of 6 with 1,3-bis(4-amino-5-phenyl-
3-ylsulfanylmethyl)propane (15) in glacial acetic acid
under high-dilution conditions gave 14 in 46% yield
(Scheme 5). An alternative pathway to synthesize 14 from
3,4-bis[o-(N-methylidenamino-5-aryl-3-thiol-4H-1,2,4-triazole-
4-yl)phenoxymethyl]thienothiophene 12 by firstly treating with
hot ethanolic potassium hydroxide solution and subsequent
reaction with 1,3-dibromopropane 13 in refluxing DMF was
unsuccessful. Compound 12 was obtained in 32% yield by
the reaction of bis(aldehyde) 6 with 4-amino-5-phenyl-4H-
1,2,4-triazole-3-thiol 11 [21] in refluxing acetic acid.
On the other hand, an attempt to synthesize the macrocyclic
Schiff base 19 that is isomeric to 14 by cyclocondensation
of 1,3-bis(2-formylphenoxy)propane 17 [22] with 3,4-bis
(4-amino-5-phenyl-3-ylsulfanylmethyl)thienothiophene 16
in refluxing acetic acid under high-dilution conditions
was unsuccessful. Instead, the reaction gave 33% of
another product that could be characterized as the
condensed heteromacrocycle 18. The novel bis(amine)
16 was obtained in 50% yield upon treatment of 2 with
4-amino-1,2,4-triazol-3-thione 11 in ethanol/water mix-
ture containing potassium hydroxide (Scheme 6).
Similarly, the condensed heteromacrocycle 21 was
prepared in 28% yield by cyclocondensation of 1,3-bis
(2-formylphenoxy)propane 20 [22] with 3,4-bis(4-amino-
5-phenyl-3-ylsulfanylmethyl)thienothiophene 16 in refluxing
acetic acid under high-dilution conditions (Scheme 7).
The structures proposed for the new compounds 18 and
21 were confirmed by the presence of the correct molecular
ion peak in their mass spectra. On the basis of the lack of
characteristic proton resonance for the aldimine H-atom
(CHN) at d = 8–9 ppm, the expected macrocyclic Schiff
base structure was completely ruled out [20].
Scheme 4
Scheme 5
N
N
N N
N
N
6
Ph
Ph
2
Ph
S
S
SH
11
N
N
N
NH2
NH2
NH2
15
AcOH/
32%
S
46%
S
AcOH/
S
S
EtOOC
COOEt
EtOOC
COOEt
O
O
O
O
Br
Br
13
N
N
N
N
N
N
N
N
KOH/DMF
Ph
S
SH
S
Ph
Ph
HS
Ph
N
N
N
N
N
N
N
N
12
14
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E38
A. E. M. Mekky and A. H. M. Elwahy
Vol 51
Scheme 6
S
S
EtOOC
COOEt
N N
N
N
Ph
Ph
S
S
N
N
N
N
O
O
19
CHO
O
OHC
S
S
EtOOC
N
COOEt
N
O
N
N
2 equiv. 11
KOH/DMF
17
2
Ph
Ph
S
S
N
N
AcOH/
NH2
NH2
16
33%
S
50%
S
COOEt
EtOOC
S
N
N
S
N
N
N
N
Ph
N
H
N
Ph
H
O
O
18
Scheme 7
membered ring is the driving force for the formation of
18 and 21. We also expect that the restricted rotational
freedom in the cyclic precursor 19, caused by the rigidity
provided by the heterocyclic as well as the aromatic moie-
ties, together with the presence of the two reacting species
in close proximity in the same molecule may assist the
intramolecular ring closure.
S
S
O
O
EtOOC
S
COOEt
S
N
N
N
CHO OHC
20
N
N
N
Ph
16
N
H
N
H
Ph
O
O
AcOH/
28%
21
In conclusion, we have incorporated a thienothiophene
ring within a cyclophane framework via its 3,4-positions.
Ethyl 3,4-bis(bromomethyl)-5-(propionyloxy)thieno[2,3-b]
thiophene-2-carboxylate 2 was chosen as a key inter-
mediate and was allowed to react with the appropriate
bis(phenol)s leading to the synthesis of a new series
of amide-crownophanes. Moreover, new bis(4-amino-
1,2,4-triazol-3-ylsulfanylmethyl)thienothiophene and a
bis(2-formyl-phenoxymethyl)-thienothiophene were prepared
and utilized successfully as key intermediates for the
synthesis of novel macrocyclic Schiff bases upon which
fused triazole and thienothiophene units and contained N,
O, and S inside the macrocyclic ring as donor atoms.
Another type of amide-crownophanes was prepared by
cyclocondensation of the novel bis(aldehyde) with the
appropriate bis(N-substituted) cyanoacetamide derivatives.
Some derivatives of the new dilactams and the new Schiff
bases showed promising cation binding properties in a
preliminary spectrophotometric study. These data will be
published separately because of the large quantity of analy-
tical data accumulated.
The reaction can proceed via the initial formation of the
corresponding macrocyclic Schiff bases. Under the reac-
tion conditions, the acid catalyst affords a small amount
of the tautomeric methylene form A that could then react
with benzylideneamino carbon that acts as an electrophile
followed by aromatization under reaction conditions to
give 18 and 21. In both cases, the formation of the six-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of Novel Benzo-Substituted Macrocyclic Ligands Containing
Thienothiophene Subunits
August 2014
E39
Macrocycle 4d.
With the use of the general procedure,
EXPERIMENTAL
the potassium salt of 3d and 2 gave 4d as colorless crystals
(2.7 g, 39%); mp 214–216ꢀC; IR (KBr) n/cmꢁ1
: 3368
General. All melting points are uncorrected. IR spectra were
recorded in KBr using Pye Unicam SP-1000 spectrophotometer
(Pye Unicam Ltd., Cambridge, UK). 1H NMR spectra were
recorded in CDCl3 or DMSO-d6 using a Varian Em-200MHz
spectrometer (Varian, Santa Clara, CA) and TMS as internal
reference. Mass spectra were recorded on AEI MS 30 mass
spectrometer operating at 70 eV (Shimadzu Scientific Intruments,
Tokyo, Japan). Elemental analyses were carried out at the
Microanalytical Centre of Cairo University.
Synthesis of the dipotassium salt of 3a–d. A solution of
each of compounds 3a–d (10mmol) and KOH (1.14 g, 20mmol)
in ethanol (10mL) was stirred at room temperature for 10min.
The solvent was removed in vacuo, and the remaining solvent
was triturated with dry ether, collected, and dried. It was then
used in the next steps without further purification.
(NH), 1709, 1650 (CO); 1H-NMR (DMSO-d6): d 1.21 (t, 6H,
CH3, J = 7.2 Hz), 4.28 (q, 4H, CH2, J = 7.2 Hz), 4.33 (s, 4H,
CH2NH), 5.87 (s, 4H, OCH2), 6.95–7.61 (m, 12H, ArH0s), 8.19
(s, 2H, NH, D2O-exchangeable); MS: m/z 684 (M+, 10.6%);
Anal. Calcd for C36H32N2O8S2 (684.78): 63.14; H, 4.71; N,
4.09; S, 9.37. Found C, 63.12; H, 4.66; N, 4.05; S, 9.31%.
Diethyl 3,4-bis((2-formylphenoxy)methyl)thieno[2,3-b]
thiophene-2,5-dicarboxylate (6).
Salicylaldehyde (20mmol)
was dissolved in hot ethanolic KOH [prepared by dissolving
1.12 g (20 mmol) of KOH in absolute ethanol (20 mL)]. The
solvent was then removed in vacuo, and the remaining solid
was dissolved in DMF (15 mL). Dibromo compound
2
(10 mmol) was added, and the reaction mixture was refluxed
for 10 min. During which time, KBr was separated. The solvent
was then removed in vacuo, and the remaining material was
washed with water and purified by crystallization from dioxane
to give 6 as colorless crystals (4 g, 73%); mp 224–226ꢀC; IR
Synthesis of macrocycles 4a–d. General procedure. A
solution of the appropriate potassium salt of 3a–d (10 mmol)
and the dibromo compound 2 (10 mmol) in DMF (20 mL) was
heated under reflux for 10 min. During which time, KBr
precipitated. The solvent was then removed in vacuo, and the
remaining material was washed with water (50 mL) and purified
by crystallization from acetic acid.
(KBr) n/cmꢁ1
:
2850, 2726 (CHO),1698 (CO); 1H-NMR
(CDCl3): d 1.38 (t, 6H, CH3, J = 7.2 Hz), 4.39 (q, 4H, CH2,
J = 7.2 Hz), 5.82 (s, 4H, OCH2), 6.86 (d, 2H, ArH0s,
J = 8.4 Hz), 6.97 (t, 2H, ArH0s, J = 7.8 Hz), 7.31 (t, 2H,
ArH0s, J = 7.8 Hz), 7.77 (d, 2H, ArH0s, J = 8.4 Hz) 10.31
(s, 2H, CHO); 13C-NMR (CDCl3): d 14.18, 61.66, 61.98,
112.81, 121.20, 124.89, 126.03, 128.78, 135.27, 136.00,
145.51, 146.88, 160.25, 161.44, 189.19; MS: m/z 552
(M+, 0.43%); Anal. Calcd for C28H24O8S2 (552.62): 60.86; H,
4.38; S, 11.60. Found C, 60.80; H, 4.33; S, 11.58%.
Synthesis of macrocycles 8a and 8b. General procedure. To
a solution of the bis(aldehyde) 6 (10 mmol) in DMF (50 mL) was
added a solution of the appropriate bis(amides) 7a,b (10 mmol) in
DMF (50 mL), in the presence of catalytic amount of piperidine.
The reaction mixture was then heated under reflux for 8 h. The
solution was concentrated to a small volume (~2 mL), and then,
cold water (~15 mL) was added. The precipitate obtained was
Macrocycle 4a.
With the use of the general procedure, the
potassium salt of 3a and 2 gave 4a as colorless crystals (3.5 g,
58%); mp 220–222ꢀC; IR (KBr) n/cmꢁ1: 3383 (NH), 1707, 1651
(CO); 1H-NMR (CDCl3): d 1.32 (t, 6H, CH3, J = 7.2 Hz),
3.68 (s, 4H, NCH2CH2N), 4.34 (q, 4H, CH2, J = 7.2 Hz), 5.95
(s, 4H, OCH2), 6.98 (d, 2H, ArH0s, J = 8.4 Hz), 7.06 (t, 2H,
ArH0s, J = 7.8 Hz), 7.27 (t, 2H, ArH0s, J = 7.8 Hz), 7.61
(s, 2H, NH, D2O-exchangeable), 7.95 (d, 2H, ArH0s,
J = 8.4 Hz); 13C-NMR (CDCl3): d 14.16, 39.35, 62.14, 64.86,
116.03, 122.73, 124.31, 131.34, 132.36, 134.11, 137.80,
145.80, 146.31, 156.68, 161.47, 166.13; MS: m/z 608 (M+,
22%); Anal. Calcd for C30H28N2O8S2 (608.68): 59.20; H, 4.64;
N, 4.60; S, 10.54. Found C, 59.16; H, 4.62; N, 4.55; S, 10.53%.
Macrocycle 4b.
With the use of the general procedure, the
collected and recrystallized from DMF/ethanol.
potassium salt of 3b and 2 gave 4b as colorless crystals (3.4 g,
55%); mp 230–232ꢀC; IR (KBr) n/cmꢁ1: 3400 (NH), 1712, 1649
(CO); 1H-NMR (CDCl3): d 1.29 (t, 6H, CH3, J = 7.2 Hz), 1.91
(brs, 2H, NCH2CH2CH2N), 3.46 (brs, 4H, NCH2CH2CH2N), 4.35
(q, 4H, CH2, J = 7.2 Hz), 5.79 (s, 4H, OCH2), 6.84–6.92 (m, 4H,
ArH0s), 7.23 (t, 2H, ArH0s, J = 7.8 Hz), 7.52 (s, 2H, NH, D2O-
exchangeable), 7.85 (d, 2H, ArH’s, J = 8.4 Hz); 13C-NMR
(CDCl3): d 14.08, 28.13, 38.59, 62.12, 62.29, 112.16, 121.68,
122.71, 131.52, 132.04, 135.75, 136.14, 145.23, 145.75, 156.28,
161.29, 165.30; MS: m/z 622 (M+, 25.6%); Anal. Calcd for
C31H30N2O8S2 (622.7): 59.79; H, 4.86; N, 4.50; S, 10.30. Found
C, 59.75; H, 4.83; N, 4.45; S, 10.27%.
Macrocycle 8a. With the use of the general procedure, the
bis(amide) 7a and 6 gave 8a as colorless crystals (3.5 g, 48%);
mp 180–182ꢀC; IR (KBr) n/cmꢁ1: 3386 (NH), 2210 (CN), 1700
(CO); 1H-NMR (DMSO-d6): d 1.28 (t, 6H, CH3, J = 7.2 Hz), 1.92
(brs, 2H, NCH2CH2CH2N), 3.45 (brs, 4H, NCH2CH2CH2N), 4.35
(q, 4H, CH2, J = 7.2 Hz), 5.80 (s, 4H, OCH2), 7.02–7.09 (m,
4H, ArH0s), 7.40 (t, 2H, ArH0s, J = 7.8 Hz), 7.69 (d, 2H,
ArH0s, J = 8.4 Hz), 8.03 (s, 2H, NH, D2O-exchangeable), 8.36
(s, 2H, CH); MS: m/z 724 (M+, 9.6%); Anal. Calcd for 61.31; H,
4.45; N, 7.73; S, 8.85. Found C, 61.25; H, 4.38; N, 7.69; S, 8.82%.
Macrocycle 8b. With the use of the general procedure, the bis
(amide) 7b and 6 gave 8b as colorless crystals (3.3 g, 45%); mp 188–
1
190ꢀC; IR (KBr) n/cmꢁ1: 3398 (NH), 2212 (CN), 1678 (CO); H-
Macrocycle 4c.
With the use of the general procedure,
the potassium salt of 3c and 2 gave 4c as colorless crystals
NMR (DMSO-d6): d 1.29 (t, 6H, CH3, J= 7.2 Hz), 1.52 (brs, 4H,
NCH2CH2CH2CH2N), 3.24 (brs, 4H, NCH2CH2 CH2CH2N), 4.29
(q, 4H, CH2, J= 7.2 Hz), 5.78 (s, 4H, OCH2), 7.11 (t, J = 7.8 Hz,
2H, ArH0s), 7.21 (d, J = 8.4 Hz, 2H, ArH0s), 7.56 (t, J = 7.8 Hz,
2H, ArH0s), 7.98 (d, J = 7.8 Hz, 2H, ArH0s), 8.33 (s, 2H, CH),
8.42 (s, 2H, NH, D2O-exchangeable); 13C-NMR (DMSO-d6): d
14.09, 25.63, 39.31, 60.85, 66.78, 107.18, 112.72, 116.37,
120.93, 121.04, 128.43, 129.21, 133.86, 140.43, 144.54,
146.20, 146.51, 156.87, 161.45, 161.79; MS: m/z 738 (M+,
5.2%); Anal. Calcd for C38H34N4O8S2 (738.83): 61.77; H, 4.64;
N, 7.58; S, 8.68. Found C, 61.69; H, 4.60; N, 7.53; S, 8.65%.
(3.2 g, 51%); mp 174–176ꢀC; IR (KBr) n/cmꢁ1: 3396 (NH),
1708, 1648 (CO); 1H-NMR (CDCl3):
d 1.28 (t, 6H,
CH3, J = 7.2 Hz), 1.77 (brs, 4H, NCH2CH2CH2CH2N), 3.33
(brs, 4H, NCH2CH2 CH2CH2N), 4.32 (q, 4H, CH2, J = 7.2 Hz),
5.93 (s, 4H, OCH2), 6.88 (d, 2H, ArH0s, J = 8.4 Hz), 7.00
(t, 2H, ArH0s, J = 7.8 Hz), 7.27 (t, 2H, ArH0s, J = 7.8 Hz), 7.36
(s, 2H, NH, D2O-exchangeable), 7.88 (d, 2H, ArH0s,
J = 8.4 Hz); MS: m/z 636 (M+, 21.9%); Anal. Calcd for
C32H32N2O8S2 (636.74): 60.36; H, 5.07; N, 4.40; S, 10.07.
Found C, 60.29; H, 5.03; N, 4.36; S, 10.05%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E40
A. E. M. Mekky and A. H. M. Elwahy
Vol 51
Synthesis of macrocyclic Schiff bases 10a,b. General
4.28; N, 11.91; S, 13.63. Found C, 59.92; H, 4.20; N,
11.88; S, 13.61%.
procedure. To a solution of the bis(aldehyde) 6 (10 mmol) in
absolute ethanol (50 mL) was added a solution of the appropriate
bis(amines) 9a,b (10 mmol) in absolute ethanol (50 mL), in the
presence of catalytic amount of glacial acetic acid. The reaction
mixture was then heated under reflux for 6 h. The solution was
concentrated to small volume (~2 mL), and then, cold water
(~15 mL) was added. The precipitate obtained was collected and
recrystallized from acetic acid.
Diethyl 3,4-bis((4-amino-5-phenyl-4H-1,2,4-triazol-3-ylthio)
methyl)thieno[2,3-b]-thiophene-2,5-dicarboxylate (16). To a
solution of 11 (50 mmol) in aqueous ethanol (50 mL, 50%)
containing KOH (50 mmol) was added the dibromo
compound 2 (25 mmol). The reaction mixture was heated
under reflux for 1 h. The solvent was then removed in
vacuo, and the remaining solid was collected and crystallized
from acetic acid to give 16 as colorless crystals (8.6 g,
Macrocycle 10a. With the use of the general procedure, the
bis(amine) 9a and 6 gave 10a as colorless crystals (2.4 g, 41%);
mp 126–128ꢀC; IR (KBr) n/cmꢁ1: 1709 (CO); 1H-NMR
50%); mp 128–130ꢀC; IR (KBr) n/cmꢁ1
: 3557, 3339
(NH2), 1707 (CO); 1H-NMR (DMSO-d6): d 1.25 (t, 6H,
CH3, J = 7.2 Hz), 4.25 (q, 4H, CH2, J = 7.2 Hz), 5.11 (s,
4H, SCH2), 6.11 (s, 4H, NH2), 7.49–8.00 (m, 10H, ArH0s);
(DMSO-d6):
d 1.26 (t, 6H, CH3, J = 7.2 Hz), 2.03 (brs,
2H, NCH2CH2CH2N), 3.62 (brs, 4H, NCH2CH2CH2N), 4.25
(q, 4H, CH2, J = 7.2 Hz), 5.51 (s, 4H, OCH2), 6.67 (t, 2H,
ArH0s, J = 7.8 Hz), 6.90 (d, 2H, ArH0s, J = 8.4 Hz), 7.14
(t, 2H, ArH0s, J = 7.8 Hz), 7.49 (d, 2H, ArH0s, J = 8.4 Hz), 8.31
(s, 2H, CHN); MS: m/z 590 (M+, 26.2%); Anal. Calcd for
C31H30N2O6S2 (590.71): 63.03; H, 5.12; N, 4.74; S, 10.86.
Found C, 62.98; H, 5.06; N, 4.70; S, 10.81%.
Macrocycle 10b. With the use of the general procedure, the
bis(amine) 9b and 6 gave 10b as colorless crystals (2.2 g, 37%);
mp 210–212ꢀC; IR (KBr) n/cmꢁ1: 1692 (CO); 1H-NMR
(DMSO-d6): d 1.24 (t, 6H, CH3, J = 7.2 Hz), 1.51 (brs, 4H,
NCH2CH2CH2CH2N), 3.46 (brs, 4H, NCH2CH2 CH2CH2N),
4.31 (q, 4H, CH2, J = 7.2 Hz), 5.71 (s, 4H, OCH2), 6.90
(t, J = 7.8 Hz, 2H, ArH0s), 7.18 (d, J = 8.4 Hz, 2H, ArH0s), 7.27
(t, J = 7.8 Hz, 2H, ArH0s), 7.67 (d, J = 7.8 Hz, 2H, ArH0s),
8.39 (s, 2H, CHN); MS: m/z 604 (M+, 1.8%); Anal. Calcd for
C32H32N2O6S2 (604.74): 63.56; H, 5.33; N, 4.63; S, 10.60.
13C-NMR (DMSO-d6):
d 13.95, 27.82, 61.41, 126.80,
127.78, 128.42, 130.36, 133.01, 137.18, 143.49, 145.83, 151.49,
154.16, 161.13; MS: m/z 692 (M+, 11.18%); Anal. Calcd for
C30H28N8O4S4 (692.85): 52.01; H, 4.07; N, 16.17; S, 18.51.
Found C, 51.97; H, 4.01; N, 16.14; S, 18.49%.
Synthesis of fused heteromacrocycles 18 and 21.
To a
solution of the appropriate bis(aldehyde) 17 or 20 (10 mmol) in
glacial acetic acid (50 mL) was added a solution of the bis
(amine) 16 (10 mmol) in glacial acetic acid (50 mL). The
reaction mixture was then heated under reflux for 4 h. The
solution was concentrated to a small volume (~2 mL), and then,
cold water (~15 mL) was added. The precipitate obtained was
collected and recrystallized from acetic acid.
Macrocycle 18.
With the use of the general procedure,
the bis(amine) 16 and bis(aldehyde) 17 gave 18 as colorless
crystals (3.1 g, 33%); mp 252–254ꢀC; IR (KBr) n/cmꢁ1: 3416
(NH), 1702 (CO); 1H-NMR (DMSO-d6): d 1.07 (t, 6H,
CH3, J = 7.2 Hz), 1.28 (brs, 2H, OCH2CH2CH2O), 3.90 (q, 4H,
CH2, J = 7.2 Hz), 4.34 (brs, 4H, OCH2CH2CH2O), 7.00–7.88
(m, 18H, ArH0s), 9.32 (s, 2H, NH); MS: m/z 936 (M+, 4.13%);
Anal. Calcd for C47H36N8O6S4 (936.16): 60.24; H, 3.87; N,
11.96; S, 13.69. Found C, 60.21; H, 3.82; N, 11.90; S, 13.65%.
Macrocycle 21. With the use of the general procedure, the
bis(amine) 16 and bis(aldehyde) 20 gave 21 as colorless crystals
Found C, 63.49; H, 5.29; N, 4.58; S, 10.57%.
Diethyl 3,4-bis(2-(3-mercapto-5-phenyl-4H-1,2,4-triazol-
4-ylimino)methyl)phenoxy)-methyl)thieno[2,3-b]thiophene-
2,5-dicarboxylate (12). To
a solution of each of bis
(aldehydes) 6 (10 mmol) in glacial acetic acid (10 mL) was
added a solution of 4-aminotriazole-3-thiol derivative 11
(20 mmol) in glacial acetic acid (10 mL). The reaction
mixture was heated under reflux for 3 h, and the solvent was
then removed in vacuo. The remaining solid was collected
and purified by crystallization from acetic acid to give 12ꢁa1s
(2.6 g, 28%); mp 264–266ꢀC; IR (KBr) n/cmꢁ1
: 3407
(NH), 1701 (CO); 1H-NMR (DMSO-d6): d 1.04 (t, 6H, CH3,
J = 7.2 Hz), 3.88 (q, 4H, CH2, J = 7.2 Hz), 4.33 (s, 4H,
OCH2CH2O), 6.99–7.87 (m, 18H, ArH0s), 9.31 (s, 2H, NH);
MS: m/z 923 (M+, 16.84%); Anal. Calcd for C46H34N8O6S4
(923.07): 59.85; H, 3.71; N, 12.14; S, 13.89. Found C, 59.79;
H, 3.67; N, 12.11; S, 13.87%.
colorless crystals (2.9 g, 32%); mp 120–122ꢀC; IR (KBr) n/cm
:
1706 (CO); 1H-NMR (DMSO-d6): d 1.26 (t, 6H, CH3, J = 7.2 Hz),
4.32 (q, 4H, CH2, J = 7.2 Hz), 5.77 (s, 4H, OCH2), 6.91–7.90 (m,
18H, ArH0s), 9.79 (s, 2H, CHN), 14.04 (s, 2H, SH); MS: m/z 900
(M+, 5.77%); Anal. Calcd for C, C44H36N8O6S4 (900.16): 58.65;
H, 4.03; N, 12.44; S, 14.23. Found C, 58.59; H, 3.96; N, 12.40;
S, 14.20%.
Synthesis of macrocyclic bis(Schiff base) (14). To a
Acknowledgment. Dr. A. H. M. Elwahy thanks the Alexander
solution of the appropriate bis(aldehyde) 6 (10 mmol) in
glacial acetic acid (50 mL) was added a solution of the bis
(amine) 15 (10 mmol) in glacial acetic acid (50 mL). The
reaction mixture was then heated under reflux for 4 h. The
solution was concentrated to a small volume (~2 mL), and
then, cold water (~15 mL) was added. The precipitate
obtained was collected and recrystallized from acetic acid to
give 14 as colorless crystals (4.3 g, 46%); mp 200–202ꢀC;
IR (KBr) n/cmꢁ1: 1707 (CO); 1H-NMR (DMSO-d6): d 1.18
(t, 6H, CH3, J = 7.2 Hz), 1.90 (brs, 2H, SCH2CH2CH2S),
2.78 (brs, 4H, SCH2CH2CH2S), 4.24 (q, 4H, CH2,
J = 7.2 Hz), 5.67 (s, 4H, OCH2), 6.76–7.68 (m, 18H, ArH0s),
8.52 (s, 2H, CHN), 14.04 (s, 2H, SH); MS: m/z 940 (M+,
6.16%); Anal. Calcd for C47H40N8O6S4 (940.20): 59.98; H,
von Humboldt Foundation for a research fellowship.
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August 2014
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