Facile synthesis and characterization of novel benzo-fused macrocyclic dicarbonitriles and pyrazolo-fused macrocycles containing thiazole subunits

Article abstract of DOI:10.1080/00397911.2019.1689269

Novel bis[2-(thiazol-2-yl)acetonitriles], linked to aliphatic cores via ethers, were prepared by the reaction of the appropriate bis(2-bromoethan-1-one) with 2-cyanothioacetamide in dioxane at reflux. Bis[2-(thiazol-2-yl)acetonitriles] were taken as key intermediates for the preparation of a new class of macrocyclic dicarbonitriles bearing two thiazole units and containing two O₂-donor sets and fused with two benzene units. The target macrocyclic dicarbonitriles were prepared by the cyclocondensation of bis[2-(thiazol-2-yl)acetonitriles] with the appropriate bis(aldehydes) in N,N-dimethylformamide in the presence of piperidine at reflux. Moreover, a new class of pyrazolo-fused macrocycles containing thiazole subunits were prepared by the reaction of macrocyclic dicarbonitriles with hydrazine hydrate in ethanol at reflux. The structures of the novel macrocycles bearing thiazole subunits were elucidated by considering their elemental analyses as well as their IR, mass, ¹H NMR and ¹³C NMR spectral data.

Full text of DOI:10.1080/00397911.2019.1689269

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Facile synthesis and characterization of novel
benzo-fused macrocyclic dicarbonitriles and
pyrazolo-fused macrocycles containing thiazole
subunits
Ahmed A. M. Ahmed, Ahmed E. M. Mekky, Ahmed H. M. Elwahy & Sherif M.
H. Sanad
To cite this article: Ahmed A. M. Ahmed, Ahmed E. M. Mekky, Ahmed H. M. Elwahy & Sherif
M. H. Sanad (2020): Facile synthesis and characterization of novel benzo-fused macrocyclic
dicarbonitriles and pyrazolo-fused macrocycles containing thiazole subunits, Synthetic
Communications, DOI: 10.1080/00397911.2019.1689269
To link to this article: https://doi.org/10.1080/00397911.2019.1689269
Published online: 09 Mar 2020.
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https://doi.org/10.1080/00397911.2019.1689269
Facile synthesis and characterization of novel benzo-fused
macrocyclic dicarbonitriles and pyrazolo-fused macrocycles
containing thiazole subunits
a,b
a
a
Ahmed A. M. Ahmed
Sherif M. H. Sanad
, Ahmed E. M. Mekky
, Ahmed H. M. Elwahy , and
a
a
b
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt; Preparatory Year Deanship,
Jouf University, Sakaka, Kingdom of Saudi Arabia
ABSTRACT
ARTICLE HISTORY
Novel bis[2-(thiazol-2-yl)acetonitriles], linked to aliphatic cores via
ethers, were prepared by the reaction of the appropriate bis(2-bro-
moethan-1-one) with 2-cyanothioacetamide in dioxane at reflux.
Bis[2-(thiazol-2-yl)acetonitriles] were taken as key intermediates for
the preparation of a new class of macrocyclic dicarbonitriles bearing
Received 20 September 2019
KEYWORDS
Benzo-fused macrocyclic
dicarbonitriles; pyrazolo-
fused macrocycles; bis[2-
2
two thiazole units and containing two O -donor sets and fused with
two benzene units. The target macrocyclic dicarbonitriles were pre-
pared by the cyclocondensation of bis[2-(thiazol-2-yl)acetonitriles]
with the appropriate bis(aldehydes) in N,N-dimethylformamide in the
presence of piperidine at reflux. Moreover, a new class of pyrazolo-
fused macrocycles containing thiazole subunits were prepared by the
reaction of macrocyclic dicarbonitriles with hydrazine hydrate in etha-
nol at reflux. The structures of the novel macrocycles bearing thiazole
subunits were elucidated by considering their elemental analyses as
(
thiazol-2-yl)acetonitriles];
bis(3-arylacrylonitriles);
bis(2H-chromen-2-imines)
1
13
well as their IR, mass, H NMR and C NMR spectral data.
GRAPHICAL ABSTRACT
CONTACT Sherif M. H. Sanad
sherif_hamed1980@yahoo.com
Chemistry Department, Faculty of Science,
Cairo University, Giza, Egypt.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

2
A. A. M. AHMED ET AL.
Introduction
The synthesis and study of macrocycles have gained much attention over the past few
[
1]
years. In general, macrocycles can contain several donor atoms such as oxygen, nitro-
gen, sulfur, etc and so they play an important role in the field of complexation of metal
ions, ammonium and primary alkylammonium salts, selective ion separation and detec-
[
2–5]
tion.
Functionalized chelators bearing macrocycles can form highly stable complexes
[
6]
and, afford the opportunity to adjust the environment of coordination.
Macrocycles exhibit many medical applications. About one hundred drugs and clin-
ical candidates containing macrocycles are commercially marketed nowadays or in proj-
ects of drug discovery. This could be attributed to their capability to dynamically
modify their conformation and so macrocycles have enhanced physicochemical and
pharmacokinetic features than expected. Moreover, macrocycles can mimic some struc-
[
7–12]
tural properties of protein interfaces.
Macrocycles exhibit significant applications as promising catalysts. Supramolecular
compounds with hydrophobic cavities such as calixarenes and cyclodextrins were inves-
tigated as catalysts due to their ability to host selectively the substrates and isolate them
from the reaction environment. These compounds were able to act in water as a green
[
13]
solvent.
Macrocyclic ligands, bearing heteroarenes such as pyridine nucleus, have
been used in the study of catalytic oxidation reactions as well as stereoselective C–C
[
2]
and C–O bond-forming reactions. Moreover, metal complexes bearing Schiff base
[
14]
macrocycles were used to catalyze the ring-opening polymerization of cyclic esters.
The incorporation of arenes and/or heteroarenes into the macrocycles afford both the
rigidity and the possibility to contribute in complexation via their soft donor atoms (O,
[
15]
N, S, etc.).
via their modification by heteroarene fragments.
Several macrocycles bearing heterocycles as triazole, pyridine, quinoxaline, and thie-
Moreover, the binding of macrocycles to biological molecules is improved
[
16]
[
17–21]
nothiophene have been studied
macrocyclic subunit.
activities such as antimicrobial, anticancer and antidiabetic agents.
but very little is known about using thiazole as a
[
22]
[23,24]
Derivatives bearing thiazole moiety
exhibit significant bio-
[
25–28]
This study was aimed at the synthesis of new macrocyclic ligands 1 and 2 that incor-
porated two thiazole subunits within the cyclophane framework via their 2,4-positions
and to study the effect of their rigidity in the formation of stable complexes compared
with other macrocyclic analogs (see Figure 1).
Results and discussion
In this study, we aimed to design a facile and efficient synthetic route for the prepar-
ation of macrocyclic dicarbonitriles 1 bearing two thiazole units and containing two O2-
donor sets and fused with two benzene units as a new class of macrocycles aiming to
improve their selective binding of neutral or charged species.
For this purpose, the novel bis[2-(thiazol-2-yl)acetonitriles] 6, linked to aliphatic cores
via ethers, were chosen as key synthons. Compounds 6 could be readily obtained from
the bromination of bis(ethan-1-one) derivatives 3a,b with N-bromosuccinimide (NBS)
[
29]
to give the corresponding bis(2-bromoethan-1-one) 4a,b
which then reacted with 2-
cyanothioacetamide 5 in dioxane at reflux to give 6a and 6b in 86 and 82% yield,

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Figure 1. The structure of the target macrocyclic dicarbonitriles 1 and pyrazolo-fused macrocycles 2
containing thiazole subunits.
Scheme 1. Synthesis of bis[2-(thiazol-2-yl)acetonitriles] 6.
[
30]
respectively
(Scheme 1). The structure of compounds 6 was confirmed by their elem-
ental analyses and spectral data. The IR spectrum of 6a, as a representative example,
ꢀ
1
showed the presence of nitrile function at 2215 cm . Its mass spectrum gave a molecu-
1
lar ion peak at m/z ¼ 472. Its H-NMR exhibited two singlet signals at d 4.58 and
7
.94 ppm corresponding to CH CN groups and thiazole H-5 protons (see
2
Experimental).
Two synthetic routes were designed for the formation of macrocyclic dicarbonitriles
1
. The first route came from the cyclocondensation of bis[2-(thiazol-2-yl)acetonitriles] 6
[
31]
with the appropriate bis(aldehydes).
Initially, the reactivity of compounds 6
towards aromatic aldehydes 7 was investigated. The reaction was carried out in N,N-
dimethylformamide (DMF) in the presence of piperidine to give the corresponding
bis(3-arylacrylonitriles) 8 in 90–93% yield (Scheme 2).
The IR spectrum of 8d, as a representative example, showed the presence of nitrile
ꢀ
1
1
function at 2212 cm . Its H-NMR exhibited two quintet and one triplet signals at d
.61, 1.81 and 4.06 ppm, respectively, corresponding to three sets of methylene protons
1
at pentane linker and two singlet signals at d 3.85 and 8.24 ppm corresponding to
OCH and methine-H protons, respectively. It also revealed the presence of signals cor-
3
responding to 16 aromatic protons and two thiazole-H5 protons at d 7.01–8.06 ppm. Its
1
3
C-NMR exhibited three signals at 22.8, 28.9 and 68.0 ppm corresponding to three sets
of methylene carbons at pentane linker. It also revealed four signals at 55.8, 109.7, 114.7
and 145.2 ppm, respectively, corresponding to OCH , C–CN, CN and methine–CH car-
3
bons. In addition, it showed 11 signals corresponding to aromatic and thiazole carbons
(see Experimental). With regards to bis(3-arylacrylonitriles) 8a–d, it is noteworthy to
mention that the presence of methine H group at d 8.24–8.30 ppm indicated that both
[
18]
methine H and cyano groups are in trans position to each other.

4
A. A. M. AHMED ET AL.
Scheme 2. Synthesis of macrocyclic dicarbonitriles 1 and bis(3-arylacrylonitriles) 8.
Similarly, bis[2-(thiazol-2-yl)acetonitrile] derivative 6a reacted with bis(aldehyde) 9a
in DMF in the presence of piperidine to give the target macrocyclic dicarbonitrile 1a in
5
5% yield (Scheme 2). The mass spectrum of 1a gave a molecular ion peak at
1
m/z ¼ 720. The H-NMR spectrum of 1a exhibited two quintet signals at d 2.20,
2.33 ppm and two triplet signals at d 4.19 and 4.35 ppm, respectively, corresponding to
two propane linker protons and two singlet signals at d 7.98 and 8.43 ppm correspond-
ing to two thiazole-H5 and methine–H protons, respectively. Moreover, it showed the
13
presence of signals corresponding to 16 aromatic protons at d 7.03–7.94 ppm. Its C-
NMR exhibited four signals at 28.1, 28.2, 66.0 and 66.2 ppm corresponding to four sets
of methylene carbons at two propane linkers. It also revealed three signals at 107.9,
114.7 and 144.6 ppm, respectively, corresponding to C–CN, CN and methine–CH car-
bons. In addition, it showed 13 signals corresponding to aromatic and thiazole carbons
(see Experimental).
In the same reaction conditions, the target macrocyclic dicarbonitriles 1b–f were pre-
pared in 52–63% yield by the cyclocondensation of the appropriate bis[2-(thiazol-2-yl)a-
cetonitriles] 6a,b with the bis(aldehydes) 9a–c (Scheme 2). The structure of macrocyclic
dicarbonitriles 1b–f was elucidated by their elemental analyses and spectral data (see
Experimental).
The second route came from the reaction of bis[2-(thiazol-2-yl)acetonitriles] 6 with
the appropriate salicylaldehydes 10 in DMF in the presence of piperidine to give the
corresponding bis[3-(2-hydroxyphenyl)acrylonitriles] 11 followed by its reaction with
1,x-dibromoalkanes 12 in basic medium to afford the target macrocyclic dicarbonitriles
1. Sadly, the bis[3-(2-hydroxyphenyl)acrylonitriles] 11 could not be isolated and this

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Scheme 3. Synthesis of bis(2H-chromen-2-imines) 13.
Scheme 4. Synthesis of pyrazolo-fused macrocycles 2.
route was failed. Compounds 6 reacted with salicylaldehydes 10 to give 11 as non-isol-
able intermediates and the reaction continued by the intramolecular addition of nucleo-
philic oxygen atom in hydroxy groups to the electrophilic carbon atom in nitrile
functions to give the final isolable bis(2H-chromen-2-imines) 13 in 82–88% yield
(
Scheme 2 and 3). The IR spectrum of 13a, as a representative example, showed the
ꢀ
1
1
absence of nitrile functions and the presence of NH groups at 3314 cm . Its H-NMR
exhibited three singlet signals at d 8.01, 8.11 and 9.09 ppm corresponding to thiazole-
H5, chromene-H4 and imino protons, respectively (see Experimental section). The for-
mation of bis(2H-chromen-2-imine) 13 as a final isolable product from the above reac-
0
tion confirms the presence of the intermediate 11 as an (2E,2 E) isomer, in which both
methine H and cyano groups are trans to each other and so undergo easily intramolecu-
[
18,24]
lar cyclization.
Finally, we investigate the synthetic potential of macrocyclic dicarbonitriles 1 as precur-
sors for novel macrocycles containing two fused pyrazole units 2. Therefore, each of 1a and
[
32]
1d reacted with hydrazine hydrate (14) in ethanol at reflux
(Schemes 3 and 4). The reac-
tion proceeds by the initial hetero-Michael addition of NH group in hydrazine to
2
[
sbond]CH[dbond]CH[sbond] in acrylonitrile units followed by ring closure via addition of
the other hydrazine NH group to nitrile function in acrylonitrile units and subsequent
2

6
A. A. M. AHMED ET AL.
auto-oxidation to give 2a and 2b as final reaction products in 66 and 70% yield, respectively.
The IR spectrum of compound 2a, as a representative example, showed the absence of nitrile
functions and the presence of absorption bands corresponding to NH and NH groups at
2
ꢀ1
1
3
353, 3242, 3189cm . Its H-NMR exhibited two quintet signals at d 2.20, 2.32ppm and
two triplet signals at d 4.15 and 4.31ppm corresponding to two propane linker protons and
two singlet signals at d 6.42 and 8.90ppm corresponding to two NH and two NH protons,
2
respectively. In addition, it showed the presence of signals corresponding to 16 aromatic
protons and two thiazole-H5 protons at d 6.87–7.94ppm (see Experimental).
Conclusion
A new class of macrocyclic dicarbonitriles bearing two thiazole units and containing
two O -donor sets and fused with two benzene units was prepared by the cycloconden-
2
sation of novel bis(acetonitriles), bearing thiazole moiety, with the appropriate bis(alde-
hydes). On the other hand, the macrocyclic dicarbonitriles reacted with hydrazine
hydrate to afford the novel pyrazolo-fused macrocycles. The new macrocycles contain-
ing thiazole subunits were prepared in an efficient and facile procedures aiming to
improve their selective binding of neutral or charged species.
Experimental
All organic solvents used in this study were commercial. All other chemicals were
acquired from Merck or Aldrich and not subjected for further purification. The melting
points are uncorrected and measured on a Stuart melting point device. IR spectra were
recorded on a Smart iTR, which is an ultra-high-performance, versatile Attenuated
Total Reflectance (ATR) sampling accessory on the Nicolet iS10 FT-IR spectrometer.
1
NMR spectra were recorded on Varian Mercury spectrophotometer (300 MHz for H
and 75 MHz for 13C) using TMS as an internal standard and DMSO-d as solvent and
6
chemical shifts were expressed as d ppm units. Mass spectra were recorded on a GC-
MS-QP1000EX spectrometer using inlet type at 70 eV. Elemental analyses were per-
formed using a EuroVector instrument C, H, N, S analyzer EA3000 Series. Compounds
[
29]
[31]
4
and 9
were prepared according to the literature procedure.
General procedure for the synthesis of macrocyclic dicarbonitriles 1a–f
To a solution of the appropriate bis[2-(thiazol-2-yl)acetonitriles] 6a,b (5 mmol) in DMF
(
(
100 mL) was added a solution of the appropriate bis-aldehyde 9a–c (5 mmol) in DMF
100 mL) in the presence of piperidine (1.0 mL). The mixture was boiled at reflux for
5
h. The solvent was evaporated and the remaining solid recrystallized from glacial
acetic acid.
Macrocycle 1a
ꢁ
ꢀ1
1
Yellow crystals (55%); m.p. 188–190 C; IR (t cm ): 2216 (CN); H-NMR (DMSO-d ):
6
d 2.20 (quint, 2H, OCH CH CH O), 2.33 (quint, 2H, OCH CH CH O), 4.19 (t, 4H,
2
2
2
2
2
2

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7
OCH CH CH O), 4.35 (t, 4H, OCH CH CH O), 7.03 (d, 4H, Ar–H’s), 7.15 (t, 2H,
2
2
2
2
2
2
Ar–H’s), 7.23 (d, 2H, Ar–H’s), 7.53 (t, 2H, Ar–H’s), 7.88–7.94 (m, 6H, Ar–H’s), 7.98 (s,
13
2
H, 2 thiazole H-5), 8.43 (s, 2H, 2 methine H); C-NMR (DMSO-d ): d 28.1, 28.2 (2
6
OCH CH ), 66.0, 66.2 (2 OCH ), 107.9 (C–CN), 114.7 (CN), 115.2, 116.3 (Ar–C’s),
2
2
2
1
20.5 (thiazole-C5), 121.2, 121.8, 128.4, 128.7, 130.5, 133.8 (Ar–C’s), 144.6 (methine-
þ
CH), 145.8, 157.4 (thiazole-C4, C2), 158.2, 162.0 (Ar–C’s); MS m/z (%): 720 (M , 60.2);
Anal. for C H N O S : C, 69.98; H, 4.47; N, 7.77; S, 8.89. Found: C, 69.75; H, 4.56; N,
4
2
32 4 4 2
7.58; S, 8.97%.
ORCID
Ahmed A. M. Ahmed
Ahmed E. M. Mekky
Sherif M. H. Sanad
http://orcid.org/0000-0002-4855-8850
http://orcid.org/0000-0002-8226-010X
http://orcid.org/0000-0002-0186-6418
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[
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