Synthesis of novel scaffolds based on thiazole or triazolothiadiazine linked to benzofuran or benzo[d]thiazole moieties as new hybrid molecules

Article abstract of DOI:10.1080/00397911.2019.1694689

A synthesis of novel hybrid molecules containing thiazole or bis(thiazoles) each bearing benzofuran and/or benzo[d]thiazole moieties by the reaction of the appropriate thioamide derivatives with the corresponding bis-bromoacetyl derivatives is reported. M

Full text of DOI:10.1080/00397911.2019.1694689

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Synthesis of novel scaffolds based on thiazole
or triazolothiadiazine linked to benzofuran
or benzo[d]thiazole moieties as new hybrid
molecules
Mostafa E. Salem, Ahmed F. Darweesh & Ahmed H. M. Elwahy
To cite this article: Mostafa E. Salem, Ahmed F. Darweesh & Ahmed H. M. Elwahy (2019):
Synthesis of novel scaffolds based on thiazole or triazolothiadiazine linked to benzofuran
or benzo[d]thiazole moieties as new hybrid molecules, Synthetic Communications, DOI:
10.1080/00397911.2019.1694689
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https://doi.org/10.1080/00397911.2019.1694689
Synthesis of novel scaffolds based on thiazole or
triazolothiadiazine linked to benzofuran or
benzo[d]thiazole moieties as new hybrid molecules
Mostafa E. Salem, Ahmed F. Darweesh, and Ahmed H. M. Elwahy
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
ABSTRACT
ARTICLE HISTORY
Received 17 September 2019
A synthesis of novel hybrid molecules containing thiazole or bis(thia-
zoles) each bearing benzofuran and/or benzo[d]thiazole moieties by
the reaction of the appropriate thioamide derivatives with the corre-
sponding bis-bromoacetyl derivatives is reported. Mono- and bis(tria-
zolothiadiazine) derivatives based on benzofuran or benzo[d]thiazole
moieties were also synthesized in good yields by the reaction of
the appropriate bis(bromoacetyl) derivatives with each of 4-amino-5-
mercapto-1,2,4-triazoles and their corresponding bis-derivatives.
KEYWORDS
Bis(benzo[d]thiazol-2-yl)thia-
zol; bis(benzofuran-2-
yl)thiazol; bis(triazolothia-
diazine); molecular
hybridization;
triazolothiadiazine
GRAPHICAL ABSTRACT
CONTACT Ahmed F. Darweesh
darweesh@sci.cu.edu.eg; Ahmed H. M. Elwahy
aelwahy@hotmail.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 2019 Taylor & Francis Group, LLC

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M. E. SALEM ET AL.
Introduction
Thiazoles are promising scaffolds in the pharmaceutical chemistry and many of their
derivatives were reported to exhibit a wide variety of biological properties including
anti-HIV, anti-inflammatory, antimicrobial, antihypertensive, antifungal, anticonvulsant,
antiviral, anticancer, antimalarial, and anti-hypolipidemic activities.[1–11]
Moreover, 1,2,4-triazoles and their heterocyclic fused analogs especially, triazolothia-
diazines, have received considerable attention owing to their promising biological activ-
ities. They are reported to possess a widespread of medical applications such as
antimicrobial, anti-inflammatory, hypoglycemic, anticancer, anti-HIV, CNS-stimulant,
antifungal, antiviral, and analgesic properties.[12–20]
Furthermore, benzofuran constitutes one of the most important class of fused ring
heterocyclic due to their valuable biological activities including antifungal, antiprotozoal,
antitubercular, anti-inflammatory, anticonvulsant, anticancer, anti-HIV, analgesic, anti-
parasitic, antihyperlipidemic, antioxidant, antiplasmodial, and anti-Alzheimer’s.[21–31]
Likewise, benzothiazole is an important core of drug development. Their derivatives
demonstrated a wide spectrum of therapeutic functions including antitumor, antimicro-
bial, anti-tubercular, anti-HIV, anti-malarial, anti-convulsant, anthelmintic, antioxidant,
and analgesic properties.[32–44]
The incorporation of thiazole, 1,2,4-triazole, benzothiazole as well as benzofuran into
a wide variety of therapeutically interesting drugs are well established (Fig. 1).
Additionally, molecular hybridization concept has attracted much attention in the last
decades in the area of drug design. This tool involves the combination of two pharma-
cophoric moieties of different bioactive substances in new hybrid molecules aiming at
improving their biological efficacy and overcoming drug resistance.[14,44–49]
Motivated by these findings and in conjunction with our ongoing research work on
bis(heterocycles) as well as the new concept in drug design, we report herein on the
synthesis of novel hybrid molecules containing benzofuran and/or benzothiazole linked
to thiazole or triazolothiadiazine and their corresponding bis-derivatives.[50–78]
Results and discussion
The starting materials needed in the synthesis of our target compounds are prepared as
outlined in Scheme 1. Thus, bromoacetylbenzothiazole 2a and bromoacetylbenzofuran
2b were, respectively, obtained in good yields by the reaction of the corresponding
acetyl derivatives 1a and 1b with bromine in acetic acid.[70] 2-(1-(Benzo[d]thiazol-2-
yl)ethylidene)hydrazinecarbothioamide 4a and 2-(1-(benzofuran-2-yl)ethylidene)-hydra-
zinecarbothioamide 4b were prepared by condensation of thiosemicarbazide (3) with
the corresponding acetyl derivatives 1a and 1b, respectively, in acetic acid at reflux
(Scheme 1).
The novel 2-(2-(2-(1-(benzo[d]thiazol-2-yl)ethylidene)hydrazinyl)thiazol-4-yl)ben-
zo[d]thiazole (5) in which (ethylidenehydrazinyl)thiazole is located between two benzo-
thiazole rings were prepared in 76% yield by the reaction of 2a with 4a in refluxing
EtOH in the presence of TEA (Scheme 2). Similarly, 4-(benzofuran-2-yl)-2-(2-(1-(ben-
zofuran-2-yl)ethylidene)-hydrazinyl)thiazole (6) in which (ethylidenehydrazinyl)-thiazole

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Figure 1. Some therapeutically interesting drugs incorporated thiazole, 1,2,4-triazole, benzothiazole as
well as benzofuran.
Scheme 1. Synthesis of bromoacetyl derivatives 2a,b and thiosemicarbazone derivatives 4a,b.
is located between two benzofuran rings was obtained in 71% yield by the reaction of
2b with 4b under the same reaction conditions.
Our study also included the synthesis of the new isomeric compounds, 2-(2-(2-
(1-(benzofuran-2-yl)ethylidene)hydrazinyl)thiazol-4-yl)benzo[d]thiazole (7) and 2-(1-
(2-(4-(benzofuran-2-yl)thiazol-2-yl)hydrazono)ethyl)benzo[d]thiazole (8) in which

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M. E. SALEM ET AL.
Scheme 2. Reaction of the appropriate bromoacetyl derivatives 2a,b with the corresponding thiose-
micarbazone derivatives 4a and 4b, respectively.
Scheme 3. Reaction of the appropriate bromoacetyl derivatives 2a,b with the corresponding thiose-
micarbazone derivatives 4b and 4a, respectively.
(ethylidene-hydrazinyl)thiazole is located between benzothiazole and benzofuran
rings. These isomers were prepared in 70 and 73% yields by the reaction of 2a
and 2b, respectively, with 4b and 4a in refluxing EtOH in the presence of TEA
(Scheme 3).
Compounds 5–8 were characterized by elemental analyses, as well as their spectral
data which agree with the proposed structures. The structure of Compound 5 as a rep-
1
resentative example was confirmed by IR, H NMR, and mass spectra. Thus, Mass spec-
trum of compound 5 showed an intense molecular ion peak at m/z 407 in agreement
with its respective molecular formula. IR spectrum of 5 showed absorption bands at
3525 cmꢀ1 because of NH group. Moreover, the 1H NMR spectra of compound 5
showed a D2O-exchangeable signal at d 12.26 because of NH proton, a sharp singlet sig-
nal at 2.48 attributed to methyl group, and a characteristic singlet signal at d 7.91 attrib-
uted to C-5 proton of the thiazole ring. All other protons appeared at the expected
chemical shifts and integral values.
Our study was extended to include the synthesis of novel bis(benzofuran-2-ylethylide-
nehydrazinylthiazoles) and bis(benzo[d]thiazol-2-ylethylidene-hydrazinylthiazoles) 11a–f,
which are linked to aliphatic spacer via phenoxy groups (Scheme 4). Thus, the reaction

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Scheme 4. Reaction of the appropriate bis(a-bromoketones) 10a–c with the corresponding thiosemi-
carbazone derivatives 4a,b.
of bis(a-bromoketones) 10a–c with each of 2-(1-(benzo[d]thiazol-2-yl)ethylidene)hydra-
zinecarbothioamide (4a) and 2-(1-(benzofuran-2-yl)ethylidene)hydrazinecarbothioamide
(4b) in refluxing EtOH in the presence of TEA afforded 11a–f respectively, in 72–86%
yields (Scheme 4).
Compounds 10a–c were obtained from the corresponding bis(acetophenones) 9a–c
upon treatment with N-bromosuccinimide (NBS) in the presence of p-toluenesulfonic
acid (p-TsOH).[53]
The novel isomeric bis(4-(2-(4-(benzo[d]thiazol-2-yl)thiazol-2-yl)hydrazono)-ethyl)-
phenoxy)alkanes and bis(4-(2-(4-(benzofuran-2-yl)thiazol-2-yl)hydrazono)ethyl)-phenox-
y)alkanes 13a–f could also prepared using a similar approach. Thus, reaction of
bis(thiosemicarbazones) 12a–c with each of 1-(benzo[d]thiazol-2-yl)-2-bromoethanone

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M. E. SALEM ET AL.
Scheme 5. Reaction of the appropriate bis(thiosemicarbazones) 12a–c with the corresponding bro-
moacetyl derivatives 2a,b.
(2a) and 1-(benzofuran-2-yl)-2-bromoethanone (2 b) in refluxing ethanol in the pres-
ence of TEA afforded 13a–f in 69–83% yields, respectively (Scheme 5). Compounds
12a–c were obtained by the reaction of the appropriate bis(ketones) 9a–c with thiosemi-
carbazide (3) in refluxing EtOH containing few drops of AcOH.[62]
All of the isolated bis(compounds) 11a–f and 13a–f were characterized by elemental
analyses, as well as their spectral data, which agree with the proposed structures. Thus,
the IR spectrum of 11a, as a representative example, showed absorption bands at
1
3425 cmꢀ1 due to (NH) stretching frequency. The H NMR spectra of compound 11a
showed a D2O-exchangeable signal at d 11.99 due to NH protons and a characteristic
singlet signal at d 7.44 attributed to C-5 proton of the thiazole ring. Moreover, they also
featured the methylene ether linkage OCH2 as a singlet signal at d 4.36 ppm. All other
protons were seen at the expected chemical shifts and integral values. Mass spectrum of
compound 11a showed the correct molecular ion peak at m/z 758.
The utility of 1-(benzo[d]thiazol-2-yl)-2-bromoethanone (2a) and 1-(benzofuran-2-
yl)-2-bromoethanone (2b) as building units for novel mono- and bis-(triazolothiadia-
zine) derivatives, each bearing benzo[d]thiazolyl or benzofuranyl moieties, were also
investigated. Thus, reaction of 2a and 2b with 4-amino-3-mercapto-1,2,4-triazole deriva-
tives[79,80] 14a and 14b in refluxing ethanol in the presence of triethylamine as a
catalyst, afforded the novel 6-(benzo[d]thiazol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazines 15a and 15b as well as 6-(benzofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thia-
diazines 15c and 15d in 76–79 and 74–76% yields, respectively (Scheme 6).
We also explored the reactivity of 2a and 2b towards bis(4-amino-5-mercapto-1,2,4-
triazoles) 16a–d.[81] Thus, the reaction of two equivalents of each of 2a and 2b with
16a–d in ethanol at reflux in the presence of trimethylamine as a catalyst afforded the
corresponding bis(6-(benzo[d]thiazol-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-

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Scheme 6. Reaction of bromoacetyl derivatives 2a and 2b with 4-amino-3-mercapto-1,2,4-triazole
derivatives 14a and 14b.
Scheme 7. Reaction of bromoacetyl derivatives 2a and 2b with bis(4-amino-5-mercapto-1,2,4-tria-
zoles) 16a–d.
yl)alkanes 17a–d and bis(6-(benzofuran-2-yl)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-
3-yl)alkanes 17e–h in 69–77% and 69–76% yields, respectively (Scheme 7).
The structures of triazolothiadiazine compounds 15a–d and their corresponding bis
derivatives 17a–h were characterized by elemental analysis and spectral data. Thus, the
absence of NH2 stretching bands in the IR spectra of triazolothiadiazines 15 together
with the disappearance of the characteristic signals belonging to primary amine in their
1H NMR spectra are evidences for the cyclocondensation reaction. In addition, the pres-
ence of SCH2 protons, resonated at d 4.48–4.71 as singlet signals integrating two pro-
tons, clearly indicated that ring closure reaction occurred. The aromatic and the

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M. E. SALEM ET AL.
heteroaromatic protons appear as multiplets at d 7.59–9.32. All other protons were seen
at the expected chemical shifts and integral values.
Conclusions
We developed a simple approach for the synthesis of novel hybrid molecules containing
thiazole or bis(thiazoles) each bearing benzofuran and/or benzothiazole moieties. Our
study included also the synthesis of mono- and bis(triazolothiadiazine) derivatives based
on benzofuran or benzo[d]thiazole moieties. The newly synthesized compounds are
interesting as promising pharmacological molecules. The simple approach used in the
synthesis of the target compounds from inexpensive starting materials is the main
advantage of this strategy. Our current studies are directed to examine the biological
activities of the new compounds and to extend the scope of the described tool to cover
additional hybrid molecules with effective biological potency.
Experimental
Materials and methods
Melting points were determined in open glass capillaries with a Gallenkamp apparatus.
Elemental analyses were carried out at the Microanalytical Center of Cairo University,
Giza, Egypt. The infrared spectra were recorded as potassium bromide disks on a Pye
Unicam SP 3-300 and Shimaduz FTIR 8101 PC infrared spectrophotometer. NMR spec-
tra were recorded with a Varian Mercury VXR-300 NMR spectrometer operating at
300 MHz (1H NMR) and 75 MHz (13C NMR), a Varian VXR spectrometer operating at
400 MHz (1H NMR) and 101 MHz (13C NMR) and a Varian VXR spectrometer operat-
ing at 500 MHz (1H NMR) and 126 MHz (13C NMR). Mass spectra (EI) were obtained
at 70 eV with a type Shimadzu GCMQP 1000 EX spectrometer. Analytical thin-layer
chromatography was performed using pre-coated silica gel 60,778 plates (Fluka), and
the spots were visualized with UV light at 254 nm. Acetyl derivatives 1a,b,[70] bromoa-
cetyl derivatives 2a,b,[70] bis(acetophenones) 9a–c,[53] bis(a-bromoketones) 10a–c,[53]
bis(thiosemicarbazones) 12a–c,[62] 4-amino-3-mercapto-1,2,4-triazole 14a,b[79,80] and
bis(4-amino-5-mercapto-1,2,4-triazoles) 16a–d[81] were prepared according to the litera-
ture procedures.
Synthesis and characterization data for selected compounds
Synthesis of 2-(2-(2-(1-(benzo[d]thiazol-2-yl)ethylidene)hydrazinyl)thiazol-4-yl)ben-
zo[d]thiazole (5)
A mixture of 1-(benzo[d]thiazol-2-yl)-2-bromoethanone (2a) (1 mmol) and 2-(1-(ben-
zo[d]thiazol-2-yl)ethylidene)hydrazinecarbothioamide (4a) (1 mmol) was dissolved in
ethanol (20 mL) containing TEA (1 mL). The reaction mixture was heated at reflux for
3 h. The solid obtained upon cooling was filtered off and recrystallized from DMF/
EtOH to afford the title compounds 5 as green powder (76% yield), mp. 268–270 ꢁC;
1
IR: (potassium bromide) 3525 (NH), 1566 (C¼N) cmꢀ1; H NMR (300 MHz, DMSO) d

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2.48 (s, 3H, CH3), 7.43–7.55 (m, 4H, ArH), 7.91 (s, 1H, thiazole-5-H), 8.00–8.13 (m,
4H, ArH), 12.26 (s, 1H, NH); 13C NMR (101 MHz, DMSO) d 13.85, 111.57, 122.62,
122.79, 123.06, 123.50, 125.70, 126.49, 126.77, 127.00, 135.00, 135.35, 143.73, 145.48,
153.56, 154.00, 162.83, 168.03, 169.53; ms: m/z (%) 407 (Mþ). Anal. Calcd. for
C19H13N5S3: C, 56.00; H, 3.22; N, 17.18; S, 23.60. Found: C, 55.76; H, 3.14; N, 17.09;
S, 23.70%.
Synthesis of 4-(benzofuran-2-yl)-2-(2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl)-thia-
zole (6)
A mixture of 1-(benzofuran-2-yl)-2-bromoethanone (2b) (1 mmol) and 2-(1-(benzo-
furan-2-yl)ethylidene)hydrazinecarbothioamide (4b) (1 mmol) was dissolved in ethanol
(20 mL) containing TEA (1 mL). The reaction mixture was heated at reflux for 3 h. The
obtained solid product was filtered off and recrystallized from DMF/EtOH to afford the
title compounds 6 as brown powder (71% yield), mp. 249–251 ꢁC; IR: (potassium brom-
1
ide) 3325 (NH), 1543 (C¼N) cmꢀ1; H NMR (300 MHz, DMSO) d 2.34 (s, 3H, CH3),
7.07 (s, 2H, benzofuran-3-H), 7.26 (s, 1H, thiazole-5-H), 7.43–7.49 (m, 4H, ArH),
7.57–7.88 (m, 4H, ArH),11.70 (s, 1H, NH); 13C NMR (126 MHz, DMSO) d 14.21,
102.22, 105.80, 108.62, 113.44, 113.72, 115.96, 116.01, 124.22, 124.28, 127.57, 128.33,
130.88, 131.27, 153.37, 153.77, 155.33, 170.22; ms: m/z (%) 373 (Mþ). Anal. Calcd. for
C21H15N3O2S: C, 67.54; H, 4.05; N, 11.25; S, 8.59. Found: C, 67.27; H, 3.89; N, 11.06;
S, 8.33%.
Synthesis of 2-(2-(2-(1-(benzofuran-2-yl)ethylidene)hydrazinyl)thiazol-4-yl)benzo-
[d]thiazole (7)
A mixture of 1-(benzo[d]thiazol-2-yl)-2-bromoethanone (2a) (1 mmol) and 2-(1-(benzo-
furan-2-yl)ethylidene)hydrazinecarbothioamide (4b) (1 mmol) was dissolved in ethanol
(20 mL) containing TEA (1 mL). The reaction mixture was heated at refluxed for 3 h.
The solid product which formed was filtered off and recrystallized from DMF/EtOH to
afford the title compounds 7 as dark Green powder (73% yield), mp. 228–230 ꢁC; IR:
1
(potassium bromide) 3433 (NH), 1558 (C¼N) cmꢀ1; H NMR (300 MHz, DMSO) d
2.36 (s, 3H, CH3), 7.27 (s, 1H, thiazole-5-H), 7.45–7.62 (m, 5 H, ArH & benzofuran-3-
H), 7.84 (d, 2H, ArH, J ¼ 7.5), 8.01 (d, 1H, ArH, J ¼ 8.1), 8.10 (d, 1H, ArH, J ¼ 7.8),
11.79 (s, 1H, NH); 13C NMR (101 MHz, DMSO) d 14.30, 105.96, 110.92, 113.73,
116.03, 122.77, 123.03, 124.30, 125.65, 126.97, 128.38, 130.85, 135.00, 139.15, 145.32,
153.79, 154.02, 155.24, 163.00, 170.06; ms: m/z (%) 390 (Mþ). Anal. Calcd. for
C20H14N4OS2: C, 61.52; H, 3.61; N, 14.35; S, 16.42. Found: C, 61.25; H, 3.53; N, 13.76;
S, 16.30%.
Synthesis of 2-(1-(2-(4-(benzofuran-2-yl)thiazol-2-yl)hydrazono)ethyl)benzo[d]-thia-
zole (8)
A mixture of 1-(benzofuran-2-yl)-2-bromoethanone (2b) (1 mmol) and 2-(1-(benzo[d]-
thiazol-2-yl)ethylidene)hydrazinecarbothioamide (4a) (1 mmol) was dissolved in ethanol

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M. E. SALEM ET AL.
(20 mL), containing TEA (1 mL). The reaction mixture was heated at reflux for 3 h. The
solid product which formed was filtered off and recrystallized from DMF/EtOH to
afford the title compounds 8 as brown powder (70% yield), mp. 248–250 ꢁC; IR: (potas-
1
sium bromide) 3425 (NH), 1558 (C¼N) cmꢀ1; H NMR (300 MHz, DMSO) d 2.45 (s,
3H, CH3), 7.10 (s, 1H, benzofuran-3-H), 7.45–7.61 (m, 5 H, ArH & thiazole-5-H),
7.89–8.09 (m, 4H, ArH), 12.20 (s, 1H, NH); ms: m/z (%) 390 (Mþ). Anal. Calcd. for
C20H14N4OS2: C, 61.52; H, 3.61; N, 14.35; S, 16.42. Found: C, 60.98; H, 3.41; N, 14.29;
S, 16.33%.
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