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

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.


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.2][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.

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 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. 22Subsequently 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. 25With 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).Encouraged by this success, and to examine the substrate scope of the method, a series of bis-1,2,4triazolo[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 3,6di(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 (CH 3 , OCH 3 ) 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). 21,25The same conversion took longer times for completion when carried out by conventional stepwise method. 21,25Compound 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. 25cheme 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. 21,25RKAT USA, Inc

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. 336-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-benzylidenehydrazinopyridazine (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 (4al).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- Compounds 4a-l were identified on the basis of their mp, mixed mp and co-TLC with conventionally synthesized 4a-l. 25

Figure 1 .
Figure 1.Structures of some clinical candidates and biologically active molecules containing a pyridazine ring.