An expeditious one-pot multicomponent synthesis of sterically hindered bis-1,2,4-triazolopyridazines under solvent-free conditions

Article abstract of DOI:10.24820/ark.5550190.p011.009

A simple and ecologically facile synthesis of sterically hindered 3,6-disubstituted-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazines was accomplished via a three-component reaction sequence between 3,6-dihydrazinopyridazine, an aromatic or heteroaromatic ald

Full text of DOI:10.24820/ark.5550190.p011.009

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Arkivoc 2019, part vi, 0-0
An expeditious one-pot multicomponent synthesis of sterically hindered
bis-1,2,4-triazolopyridazines under solvent-free conditions
Ranjana Aggarwal,a* Mamta,a and Garima Sumranb
a Department of Chemistry, Kurukshetra University, Kurukshetra, 136119, India
b Department of Chemistry, D. A. V. College (Lahore), Ambala City 134 003, Haryana, India
Email: ranjanaaggarwal67@gmail.com
Received 06-26-2019
Accepted 10-18-2019
Published on line 11-18-2019
Abstract
A simple and ecologically facile synthesis of sterically hindered 3,6-disubstituted-bis-1,2,4-triazolo-[4,3-b:3',4'-
f]pyridazines was accomplished via a three-component reaction sequence between 3,6-dihydrazinopyridazine,
an aromatic or heteroaromatic aldehyde and iodobenzene diacetate (IBD) on grinding at room temperature.
The 3,6-bis-arylidenehydrazinopyridazine intermediates, generated in situ, undergo oxidative cyclization to
afford the title compounds. The present protocol has excellent yields, short reaction times, broad substrate
scope, is a solvent-free greener synthesis, and has an easy purification of product.
Keywords: 3,6-Dihydrazinopyridazine, 3,6-bis-arylidenehydrazinopyridazine, 3,6-di-substituted-bis-1,2,4-
triazolo-[4,3-b:3',4'-f]pyridazines, iodobenzene diacetate, multicomponent synthesis, one-pot
DOI: https://doi.org/10.24820/ark.5550190.p011.009
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Introduction
The efficiency of a chemical synthesis can be measured not only by its selectivity, scalability and overall yield
but also by its feedstock, time consumption and energy requirements, as well as the toxicity and hazards of
the chemicals and the pathway involved. Multicomponent reactions (MCRs) have emerged as prominent
strategies for the efficient synthesis of various high merit chemical entities including natural products,
pharmaceuticals and poly-heterocyclic compounds which not only have molecular diversity but also
architectural complexity.1-3 Additionally, they involve several transformations in a single manipulation. Many
MCRs are superior to conventional methods owing to their enhanced selectivity, high atom-efficiency, cleaner
reaction profiles, minimum by-product formation, ease of manipulation, cost effectiveness and relatively
benign conditions.
Recently, a solvent-free strategy delineates further extremely powerful green chemical protocols from
both the economic and convenience perspective in terms of execution of complex reactions within limited
time with significant energy saving, avoidance of intermediates isolation, separation of side products at each
step and higher yields in target synthesis.
The chemistry of pyridazine and its derivatives has sustained considerable interest owing to the presence
of two nitrogen atoms that present coordination sites to a variety of metal ions and their property of forming
and strengthening assembly of supramolecular and polymeric architectures.4 Other technological applications
involve the development of new π-conjugated organic materials for liquid crystals, electronic and
optoelectronic devices.5,6 The pyridazine ring appears in natural products such as antifungal antibiotic
pyridazomycin and meroterpenoid azamerone.7 The pyridazine scaffold as a privileged structure is present in a
large number of pharmacologically active drugs such as talazoparib (poly ADP ribose polymerase (PARP)
inhibitor with potential antineoplastic activity), minaprine (antidepressant), cilazapril (antihypertensive),
irdabisant (histamine H3 receptor antagonist), pipofezine (antidepressant), emorphazone (anti-inflammatory)
and LDN-212320 (excitatory amino acid transporter 2 (EAAT2) activator) (Figure 1).7-9 In addition, pyridazines
appear in plant growth regulators and crop protection agents such as chloridazon, norflurazon, pyridate and
pyridaben.10 Pyridazine-fused derivatives comprise a class of biologically active heterocyclic compounds having
potential in the field of drug design and development. Among fused pyridazine-containing heterocycles,
pyrrolo[1,2-b]pyridazines and imidazo[1,2-b]pyridazines exhibit anticancer11 and monopolar spindle 1 (Mps1)
inhibitory activities, respectively.12 Literature precedents indicate that 1,2,4-triazolo[4,3-b]pyridazine
derivatives, in particular, exhibit extensive pharmacological activities which encompass anticonvulsant,13
herbicidal,14 antitubulin,15
antimicrobial,16 anxiolytic activity,17 as well as tankyrase18 and pan-
phosphodiesterase (PDE) inhibitors.19 (S)-6-(1-(6-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-
yl)ethyl)quinoline (PF-04254644) was identified as a potent and exquisitely selective c-Met inhibitor but
development was terminated due to cardiotoxicity (Figure 1).9 SAR125844 is reported as a potent and
selective MET kinase inhibitor in MET-amplified and MET pathway-addicted tumors.20 Very recently our group
explored in vitro antiproliferative activity of a series of 6-chloro-3-substituted-[1,2,4]triazolo[4,3-b]pyridazines
against three human cancer cell lines namely SB-ALL, NALM-6 and MCF-7 using the MTT assay and the most
active compounds induced apoptosis in Nalm-6 cells via caspase 3/7 activation.21
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Figure 1. Structures of some clinical candidates and biologically active molecules containing a pyridazine ring.
Synthesis of bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines has been achieved by only two general methods.
The first consists in the construction of the second triazole ring by cyclization of 6-arylidenehydrazino-3-aryl-
1,2,4-triazolo[4,3-b]pyridazine to bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazine on treatment with an oxidant such
as Br2/AcOH or lead tetracetate,22 or Me4NBr/oxone®.23 Whereas, formation of 6-arylidenehydrazino-3-aryl-
1,2,4-triazolo[4,3-b]pyridazine involves three steps: i) conversion of 3,6-dichloropyridazine into 6-chloro-3-
hydrazinopyridazine, ii) condensation with an aldehyde, iii) oxidative cyclization of the resulting hydrazone to
triazole. The second method comprises simultaneous formation of both triazole rings by oxidative cyclization
of 3,6-bis-(arylidenehydrazino)pyridazines using Br2/AcOH or lead tetraacetate16 and by the reaction of 3,6-
dichloropyridazine with two equivalents of acid hydrazides.24 However, these methods suffer from several
limitations such as harsh reaction conditions, multistep synthesis, use of toxic reagents, high reaction
temperature, tedious work-up, extended reaction times and unsatisfactory yields.
In order to overcome these limitations, we have recently reported iodobenzene diacetate (IBD) mediated
stepwise synthesis of 3,6-disubstituted-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines in dichloromethane as
solvent via oxidative intramolecular cyclization of 6-arylidenehydrazino-3-aryl-1,2,4-triazolo[4,3-
b]pyridazines.25 Four synthesized compounds were evaluated for their in vitro cytotoxic activity against the
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human cervical carcinoma (HeLa) cell line using MTT assay, displaying low activity. X-ray crystallographic
studies of sterically strained 3,6-di-(2'-fluorophenyl)-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazine I and 3,6-di-(4'-
fluorophenyl)-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazine II revealed that the pyridazine ring has a twisted
conformation leading to nonplanar tricyclic core (Scheme 1). Thus, more efficient, economically viable and
expeditious methods for synthesis of the title compounds are of significant interest.
Scheme 1. (a) Recently reported synthesis of 3,6-disubstituted-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines.21,25
ORTEP plots of (b) I and (c) II with ellipsoids at 20% probability.
In view of these observations and as a part of our program on hypervalent iodine reagents in organic
transformations26-30and in continuance of our ongoing interest to develop solvent-free synthesis of
heterocyclic compounds,31,32 it was envisaged in the present study to synthesize 3,6-disubstituted-bis-1,2,4-
triazolo[4,3-b:3',4'-f]pyridazines through an efficient, concise and ecofriendly multicomponent solvent-free
protocol.
Results and Discussion
In an endeavour to synthesize the title compounds, a mixture of 3,6-dihydrazinopyridazine 1 and two
equivalents of benzaldehyde (2a) was ground in a pestle and mortar at room temperature. The reaction was
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regularly monitored at short intervals by TLC which indicated completion of reaction in 20 minutes by
consumption of reactants and appearnce of a new spot. Work-up afforded a solid product corresponding to
3,6-bis-benzylidenehydrazinopyridazine (3a) which was confirmed by comparing its melting point with the
literature value.22 Subsequently 3a on grinding with 2.2 equivalents of IBD for one hour underwent oxidative
cyclization to afford 3,6-diphenyl-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazine 4a in 85% yield. Formation of 4a
was confirmed on the basis of co-TLC and mixed mp with a sample prepared via the sequential route.25 With
optimized reaction conditions in hand, reaction of 1 with benzaldehyde (2a) was repeated under same
condition but without isolation of 3a. Compound 3a generated in situ undergoes oxidative cyclization upon
addition of 2.2 equivalents of IBD under grinding for another one hour to give 4a (Scheme 2).
Scheme 2. Multicomponent one-pot solvent-free synthesis of 3,6-diphenyl-bis-1,2,4-triazolo[4,3-b:3',4'-
f]pyridazine (4a).
Encouraged by this success, and to examine the substrate scope of the method, a series of bis-1,2,4-
triazolo[4,3-b:3',4'-f]pyridazine derivatives 4b-l were envisaged having mono, di-substituted aryl and
heteroaryl ring at positions 3 and 6 of the triazole ring. We explored the substrate scope by grinding various
aldehydes (2b-l) with 3,6-dihydrazinopyridazine 1 followed by addition of IBD, which provided 3,6-
di(aryl/heteroaryl)-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines 4b-l in uniformly high yields in just one hour and
twenty mintues following a simple work-up (Scheme 3). A series of mono and di-substituted benzaldehydes
bearing electron-donating groups (CH3, OCH3) as well as electron-withdrawing groups (F, Cl, Br) at ortho-,
meta- or para-positions and heteroaryl aldehydes (furfuraldehyde and thiophene-2-carbaldehyde) reacted
efficiently to give desired products. The results presented in Scheme 3 clearly indicate that the new one-pot
multicomponent synthesis affords improved overall yields (54-68%) for the title compounds, as compared to
the reported procedure (20-29%) that involves five steps starting from 6-chloro-3-hydrazinopyridazine
(Scheme 1).21,25 The same conversion took longer times for completion when carried out by conventional
stepwise method.21,25 Compound 3a was isolated only in the case of benzaldehyde. Other hydrazones were
not isolated. All the synthesized compounds 4 were identified on the basis of their mp, mixed mp and co-TLC
with same samples synthesized by the conventional method.25
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Scheme 3. Substrate scope and isolated yields of bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines (4a-l) obtained
from 3,6-dihydrazinopyridazine 1. Yields in parenthesis correspond to isolated yield for product 4 obtained
from the sequential procedure starting from 6-chloro-3-hydrazinopyridazine.21,25
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Conclusions
Summarising, we have demonstrated an efficient, economical, and versatile protocol to synthesize valuable
bis-triazolo[4,3-b:3',4'-f]pyridazines 4 via one-pot solvent-free multicomponent syntheses using IBD as
environmentally benign non-metallic oxidant. The superiority of the MCR route over the conventional
approach is due to its two-step sequential synthesis, atom-economy, short reaction times, improved yields, no
isolation of intermediates and operational simplicity. Whereas conventional synthesis of target compounds 4,
starting from 6-chloro-3-hydrazinopyridazine as presursor, involves a five-step sequence, long reaction times,
low overall yields due to multisteps, isolation and purification of intermediates at each steps and high energy
consumption. Moreover, conventional synthesis using lead tetraacetate as oxidant is ecologically unfriendly.
Experimental Section
General. Melting points were determined in digital melting point apparatus MEPA and are uncorrected.
Analytical thin layer chromatography (TLC) was performed using Merck Kieselgel 60 F254 silica gel plates.
Visualisation was performed under UV light using Ultra Violet Fluorescence Inspection Cabinet (Perfit, India).
3,6-Dihydrazinopyridazine (1) was prepared from 3,6-dichloropyridazine according to the literature
procedure.33
3,6-bis-Benzylidenehydrazinopyridazine (3a). A mixture of 3,6-dihydrazinopyridazine (1) (280 mg, 2.0 mmol)
and 2 equivalents of benzaldehyde (2a) (424 mg, 4.0 mmol) was ground in a porcelain pestle and mortar. The
TLC of the reaction mixture evinced the completion of reaction in 20 min as there were no spots
corresponding to the reactants on TLC. On completion of reaction, EtOH (3 mL) was added to the reaction
mixture. A solid separated out which was filtered off and recrystallized from EtOH. Yield 75%; mp 260.5 °C; Lit
mp 261-262 °C.22
3,6-Diphenyl-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazine (4a). A mixture of 3,6-bis-benzylidenehydrazino-
pyridazine (3a) (316 mg, 1.0 mmol) and 2.2 equivalents of IBD (708 mg, 2.2 mmol) was ground in a pocelain
pestle and mortar at rt. TLC of the reaction mixture was executed at regular intervals which evinced the
completion of reaction in 1 h. The crude product was triturated with petroleum ether ether in order to remove
iodobenzene and then the residue recrystallized using EtOH to afford 4a as single product. The product was
characterized on the basis of its mp, mixed mp and co-TLC with a sample synthesized through the
conventional route. Yield 85%; mp 274 °C; Lit mp 277-278 °C.22,25
General procedure for one-pot synthesis of 3,6-disubstituted-bis-1,2,4-triazolo[4,3-b:3',4'-f]pyridazines (4a-
l). A mixture of 3,6-dihydrazinopyridazine (1) (280 mg, 2.0 mmol) and 2 equivalents of the appropriate
aldehyde (2) (4.0 mmol) was ground in a pestle and mortar for 20 min which resulted in the formation of
corresponding 3,6-bis-arylidenehydrazinopyridazine (3). After complete consumption of aldehyde, 2.2
equivalents of IBD (2.2 mmol) was added and the reaction mixture was ground for another 1 h. TLC of the
reaction mixture was overseen at regular intervals. Solid separated out after triturating with petroleum ether
was filtered off and recrystallized with EtOH to afford the corresponding bis-1,2,4-triazolo[4,3-b][3',4'-
f]pyridazine (4a-l).
Compounds 4a-l were identified on the basis of their mp, mixed mp and co-TLC with conventionally
synthesized 4a-l.25 NMR spectra of known compounds are reported.25
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3,6-Diphenyl-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4a). mp 274 °C; Lit mp 274 °C.25
3,6-Di-(2-chlorophenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4b). mp 201.5 °C; Lit mp 201.5 °C.25
3,6-Di-(4-chlorophenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4c). mp 244 °C; Lit mp 244.5 °C.25
3,6-Di-(3-bromophenyl)-bis-1,2,4-triazolo-[4,3-b:3’,4’-f]pyridazine (4d). mp 190 °C; Lit mp 190 °C.25
3,6-Di-(4-bromophenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4e). mp 197 °C; Lit mp 197 °C.25
3,6-Di-(2-fluorophenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4f). mp 257.5 °C; Lit mp 257.5 °C.25
3,6-Di-(4-fluorophenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4g). mp 292.5 °C; Lit mp 292.5 °C.25
3,6-Di-(4-methoxyphenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4h). mp 224 °C; Lit mp 225 °C.25
3,6-Di-(2,5-dimethoxyphenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4i). mp >315 °C; Lit mp >315 °C.25
3,6-Di-(3,4-dimethoxyphenyl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4j). mp 226 °C; Lit mp 226 °C.25
3,6-Di-(thien-2-yl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4k). mp 232 °C; Lit mp 231 °C.25
3,6-Di-(furan-2-yl)-bis-1,2,4-triazolo-[4,3-b:3',4'-f]pyridazine (4l). mp 225 °C; Lit mp 225 °C.25
Acknowledgements
We are grateful to the Haryana State Council for Science and Technology (HSCST), Haryana for providing
financial assistance to Mamta.
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