Design and synthesis of diaziridinyl quinone thiadiazole hybrids via nitrile sulfide cycloaddition reaction as a key step

Article abstract of DOI:10.1016/j.tetlet.2016.02.082

A series of novel diaziridinyl quinone thiadiazole hybrids (9a-9j) were synthesized starting from 2-hydroxy-5-methoxybenzoic acid 1 in a 7 step synthetic sequence. The key step in the scheme involves the nitrile sulfide cycloaddition reaction of oxathiazo

Full text of DOI:10.1016/j.tetlet.2016.02.082

Accepted Manuscript
Design and Synthesis of Diaziridinyl Quinone Thiadiazole Hybrids via Nitrile
Sulfide Cycloaddition Reaction as a Key Step
Anjaiah Aitha, Satyanarayana Yennam, Manoranjan Behera, Jaya Shree
Anireddy
PII:
S0040-4039(16)30191-5
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.082
TETL 47357
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
13 January 2016
19 February 2016
20 February 2016
Please cite this article as: Aitha, A., Yennam, S., Behera, M., Anireddy, J.S., Design and Synthesis of Diaziridinyl
Quinone Thiadiazole Hybrids via Nitrile Sulfide Cycloaddition Reaction as a Key Step, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.082
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Design and Synthesis of Diaziridinyl Quinone Thiadiazole
Hybrids via Nitrile Sulfide Cycloaddition Reaction as a
Key Step
Anjaiah Aithaa,b, Satyanarayana Yennam*a, Manoranjan Beheraa, Jaya Shree Anireddyb,

Tetrahedron Letters
1
TETRAHEDRON
LETTERS
Pergamon
Design and Synthesis of Diaziridinyl Quinone Thiadiazole Hybrids
via Nitrile Sulfide Cycloaddition Reaction as a Key Step
Anjaiah Aithaa,b, Satyanarayana Yennam*a, Manoranjan Beheraa, Jaya Shree Anireddyb,
a Chemistry Services, GVK Biosciences Pvt. Ltd., Survey Nos:125 (part) & 126, IDA Mallapur, Hyderabad-500076, Telangana State, India
b Centre for Chemical Sciences & Technology, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072,
Telangana, India
Abstract: A series of novel diaziridinyl quinone thiadiazole hybrids (9a-9j) were synthesized starting from 2-hydroxy-5-
methoxybenzoic acid 1 in a 7 steps synthetic sequence. The key step in the scheme involves the nitrile sulfide cycloaddition reaction of
oxathiazolone 4 with p-tosylcyanide to obtain 1,2,4-thiadiazole derivative 5. We have demonstrated that p-tosyl group of thiadiazole 5 can
be displaced with various nitrogen heterocycles to generate unknown 3,5-disubstituted thiadiazole derivatives.
The quinone containing compounds have been widely
used for their antitumor and anticancer activities. But the
problems associated with these compounds such as
toxicity and drug resistance has stimulated an increasing
demand for the discovery of new and novel anti-tumor
agents.1 In the last few decades, a significant progress has
been made towards the screening of quinone containing
compounds for antitumor activity2. Mitomycin C,
drugs containing aziridinyl quinones from the clinical
perspective. Essentially, these drugs has three potential
active constituent’s viz. quinone, an unusual aziridine, and
a C-10 carbamate groups3. Several studies have shown
that all three constituents are essential and play a
functional role in the cytotoxic action of these quinones.
Reduction oxidation reactions of the quinone group may
lead to the formation of oxygen free radicals which can
induce DNA damage4, and this has been observed with
Mitomycin C5 and Diaziquone (AZQ)6. Several aziridinyl
Triaziquone, Carboquone, Diaziquone (AZQ), 2,5-bis(2’-
hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone
(BZQ) and 2,5-diaziridinyl-3-(hydroxymethyl)-6-methyl-
1,4-benzoquinone (RH-1) (Figure 1) are the best known
Key words: Nitrile sulfide, Cycloaddition, Quinone, Thiadiazole,
Diaziridine quinone
Corresponding author:Satyanarayana Yennam
Email: satya@gvkbio.com

2
Tetrahedron Letters
benzoquinone drugs have undergone clinical trials as
potential antitumor drugs. These bioreductive compounds
are designed to kill cells preferentially within the hypoxia
tumor microenvironment7. The strain and reactivity of the
aziridine ring possessed molecules has interesting
biological activity and the efforts in this area has been
summarised8. Most of the interest in biological activity of
aziridine has focused on those chemically modified DNA.
product formation. We did not observe any isomer
formation in the reaction. The key step nitrile sulfide
cycloaddition reaction40 of 1,3,4-oxathiazol-2-one 4 with p-
toluenesulfonylcyanide
was
performed
in
1,2-
dichlorobenzene at 165 oC for 2 h to obtain p-tosyl
substituted thiadiazole derivative 5. The nitrile sulfides
generated in situ by thermal decomposition of 1,3,4-
oxathiazol-2-one 4 reacted with dipolarphile tosyl cyanide
in a 1,3-dipolar cyclization reaction to provide the
Thiadiazoles represent an important class of
heterocyclic compounds that exhibit different types of
biological activity.9 In the past decade, a number of potent
compounds based on thiadiazoles have been discovered.10
Indeed, compounds containing a 1,2,4-thiadiazole fragment
thiadiazole
intermediate containing a labile 5-tosyl
substituents. No side product was observed during the
cycloaddition reaction as determined by LC-MS analysis.
The compound 5 was characterized by spectroscopic
analysis. 1H NMR shows peak at 2.4 δ corresponds to
methyl proton and two singlets at 3.8 δ correspond two
methoxy groups. MS analysis shows M+1 peak at 377
which confirmed the formation of compound 5.
have
anti-inflammatory,11,12
antihypertensive,13
antibacterial,14,15 and anticonvulsant properties.16,17
Furthermore, it has been confirmed that many thiadiazole-
related compounds are potential drugs in the treatment of
disorders of the central nervous system such as Alzheimer’s
disease due to the antioxidant properties, influence on
muscarinic acetylcholine receptors,18 and inhibition of
acetylcholinesterase activity.19 Compounds containing a
1,2,4- thiadiazole fragment also display high inhibitory
activity against glycogen synthase kinase-3β and, therefore,
can be used for treatment of neuropathology, disordered
motor function, chronic inflammatory process, cancer, and
diabetes of type-II.20 Recently, 2,5-disubstituted-1,2,4-
thiadiazole derivatives are shown to be selective S1P1
agonists.21
Our approach to develop new chemotherapeutic
agents involves the conjugation of two biologically active
compounds viz. diaziridinylquinone and thiadiazole to
prepare a single hybrid molecule. Based on this hypothesis,
we previously synthesized quinone isoxazole (QI) hybrid
molecules in this laboratory22. There are few quinone
natural product hybrid molecules has been reported in
literature.23-32 But there are no reports of diaziridinyl
quinone five membered heterocyclic hybrids, as per the
literature search. The promising biological results of
After obtaining the key intermediate 5, we want to explore
the displacement reaction with various nitrogen
nucleophiles. Thus, treatment of compound 5 with pyrazole
6a in presence of K2CO3/DMF at room temperature gave
the 5-pyrazolyl-3-phenyl thiadiazole derivative 7a in good
yield (Scheme 2). The compound 7a on oxidation using
cerium ammonium nitrate in acetonitrile/water (1:1) at
room temperature for 1 h gave quinone thiadiazole hybrid
derivatives 8a in very good yield. The compound 8a was
characterized by 1H NMR, 13C NMR, and HRMS data. The
diaziridinylquinone33-39
and thiadiazole derivatives
motivated us to synthesize new diaziridinylquinone
heterocyclic hybrids. We herein, report the synthesis of
novel diaziridinylquinone thiadiazole (DAQT) derivatives
as new hybrid molecules to identify more potent biologically
active compounds.
The synthesis starts with the commercially available 2-
hydroxy-5-methoxybenzoic acid 1 (Scheme 1) which was
1
characteristic quinone proton at 6.9 δ in H NMR spectrum
converted to methyl 2,5-dimethoxybenzoate
2 using
confirms the oxidation of compound 7a to generate
compound 8a. IR spectrum of the compound 8a shows the
carbonyl peaks at 1655 cm-1. The two carbonyl peaks at
187.3 and 183.8 δ in 13C NMR spectrum validate the
benzoquinone moiety. All the benzoquinones are
characteristic yellowish solid. Finally the aziridine moiety
was introduced into the quinone ring system by reaction of
compound 8a with freshly prepared aziridine41 in the
presence of Cu(OAc)2 in MeOH at room temperature to
MeI/K2CO3/DMF condition. Compound 2 was treated with
aqueous ammonia in sealed tube at 80 C for 6 h to obtain
o
2,5-dimethoxybenzamide 3 in very good yields. The
1
compound 3 was characterized by H NMR and MS data.
The compound 3 on reaction with chlorocarbonyl sulfenyl
o
chloride in toluene at 80 C for 6 h gave 2,5-dimethoxy
substituted 1,3,4-oxathiazol-2-one 4. The compound 4 was
characterized by 1H NMR and MS data. M+1 peak at 240 in
the MS spectra along with 1H NMR data indicate the

Tetrahedron Letters
3
afford novel diaziridinyl benzoquinone thiadiazole
distance couplings over
2
to
3
bonds. HMBC
derivatives 9a as orange solid with good yield (Scheme 2).
spectroscopy of 9a where the delay in pulse sequence was
optimized for 8 Hz shows both two and three bond
coupling cross peaks. Absence of correlation of proton
(H7, 6.055 ppm) to the C-2 (114.824 ppm) confirmed the
structure of 9a with aziridine moiety at 3-position and 6-
position respectively. NOESY data also supported the
structure by showing special correlation of H7 (6.055
ppm) proton with one of the aziridine moiety C8 and C8a.
Once the reaction condition was standardized,
various highly substituted nitrogen heterocycles were
subjected to displacement reaction to give the compounds
7a-7j (Table 1). We followed the same two step synthetic
protocol to obtain diaziridinyl benzoquinone thiadiazole
derivatives 9a-9j. All the compounds 9a-9j was well
1
characterized by H NMR, IR, MS and 13C NMR. The
purity of the diaziridinyl benzoquinone thiadiazole
derivatives was obtained by HPLC analysis. It is
noteworthy to mention here that previously inaccessible
triazole, 5-phenyl-pyrazole and azaindole analogues were
synthesized in moderate yield (entries 9, 6 and 10). As
indicated in Table 1, triazole substituted quinone gave the
aziridine product in very low yield. Although, 5-
pyrazolyl-3-phenyl thiadiazole derivatives having both
alkyl as well aryl substituted pyrazole are undergoing the
two step reaction protocol smoothly to generate
diaziridinyl benzoquinone thiadiazole derivatives, it was
observed that aryl substitution gave better yield compared
to alkyl group.
In order to confirm the positions of aziridine moiety in
compound 9a, NMR studies were conducted (Fig 2). The
NOESY spectra explain the substitution regioselectivity in
compound 9a. We utilized Heteronuclear Multiple Bond
Correlation (HMBC) to obtain proton-carbon long

4
Tetrahedron Letters
Table 1: Synthesis of 2, 5-diaziridinyl-quinone-1,2,4-thiadiazole derivatives
Conclusion:
Acknowledgements:
Authors are grateful to GVK Biosciences Pvt. Ltd., for the
financial support and encouragement. Help from the
analytical department for the analytical data is appreciated.
We thank Dr. Sudhir Kumar Singh for his invaluable
support and motivation.
In conclusion, we developed an efficient and simple method
to synthesize the diaziridinyl benzoquinone thiadiazole
derivatives using nitrile sulfide cycloaddition and oxidation
reactions as key steps in good yields. We believe that this
methodology will find a wide spread application for synthesis
of aziridine quinone and its derivatives. The biological
activities of these synthesized compounds for potential
antitumor application is undergoing in our group.

Tetrahedron Letters
5
Supplementary Material
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1
The spectroscopic data (experimental procedure, H NMR,
13C NMR, IR and HRMS) associated with this article can be
found in the online version
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*Highlights
Highlights
 Synthesis of novel diaziridinyl quinone thiadiazole hybrids.
 1,2,4-Thiadiazole derivatives by nitrile sulfide cycloaddition reaction.
 Preparation of a large set of 3,5-disubstituted thiadiazole derivatives.