1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 z Organic & Supramolecular Chemistry An Unexplored Lewis Acidic Catalytic System for Synthesis of Pyrazole and its Biaryls Derivatives with Antimicrobial Activities through Cycloaddition-Iodination-Suzuki Reaction Manashjyoti Konwar, [a] Parmita Phukan, [a] Amrita K. Chaliha, [b] Alak K. Buragohain, [b] Krishnaiah Damarla, [c] Dipshikha Gogoi, [d] Arvind Kumar, [c] and Diganta Sarma* [a] Here an environmentally friendly process has been developed for the synthesis of pyrazole and its derivatives through cycloaddition-iodination-Suzuki type reaction by the use of lithium perchlorate as a Lewis acid catalyst. The synthetic pathway involves the synthesis of pyrazoles with various electron donating and electron withdrawing functional groups containing hydrazines and 1,3-diketones (70-95% yields); then one step formation of 4-iodo-pyrazoles (59% yield) followed by modification via palladium catalyzed Suzuki-Miyaura cross coupling reaction to obtain the desired biaryls substituted pyrazoles under mild reaction conditions with high efficiency and product purity (53-70% yields). The biological activity was evaluated through in vitro analysis towards the antimicrobial activities against the growth of Staphylococcus Aureus (for Gram positive) and Pseudomonas Aeruginosa (for Gram neg- ative) with minimum inhibitory concentration (MIC) values ranging from 225 to 850 μg/ml. Molecular docking studies of the compounds into the active site of thymidylate kinase receptor of Pseudomonas Aeruginosa PAO1 revealed notable information on the probable binding interaction. Pyrazole, a five membered aromatic heterocyclic compound with six delocalized π-electrons and a planar conjugated ring structure with two adjacent nitrogen atoms, is available in many drugs having antibacterial, antifungal, antiviral, anti- inflammatory and anticoagulant activities. [1–4] It is also used as ligand in catalysis due to the presence of nitrogen lone pair. [5] Halogenated and other derivatives of pyrazole are equally important either as potent biological scaffold or they take part in different types of cross-coupling reactions to functionalize the parent heterocycles due to the greater flexibility of the C À X bond. [6–7] To functionalize a molecule as its halogenated derivative, many well known organic catalysts such as N- halosuccinimide (NXS), [8] 1,3-diiodo-5,5-dimethylhydantoin (DIH) [9] etc. are generally applied, but these processes are associated with several drawbacks such as formation of unwanted by products, high cost of the chemicals etc. making the process as incompetent one. To overcome these problems, several inorganic catalysts such as I 2 , [10] KI, [11] etc are successfully used for the formation of C À X bond; by-products of these methods are simple water soluble salts. Once the C À X bond is formed in efficient manner, different cross coupling reactions can easily be performed through the C À X bond and it was well established by different known reactions. [12] To synthesize the pyrazole core moiety, various Lewis acidic metal catalyzed methodologies such as [Ce(L-Pro) 2 ] 2 (Oxa), [13a] Sc(OTf) 3 , [13b] Bis- muth(III)trifluoroacetate, [13c] CeCl 3 .7H 2 O, [13d] nano-TiO 2 , [13e] Zn[(L) proline] 2 , [13f] 12-Tungstophosphoric acid, [13g] Layered Zirconium Sulfophenyl Phosphonate [13h] are well reported in literature but they are associated with various drawbacks such as high cost, complex catalyst preparation, harsh reaction conditions, ele- vated temperature etc. Therefore we tried to find out the milder way to synthesize pyrazole moiety with low cost, easily available Lewis acid metal catalyst. LPDE (Lithium Perchlorate Diethyl Ether) is very well known as catalyst and it finds applications towards the activation of nitrogenous compounds. [14] Lewis acid catalysts often get decomposed or deactivated after the reaction and more than stoichiometric amount of the catalyst is required to complete the reaction. On the other hand, LPDE does not get decom- posed or deactivated even after the reaction with basic amino compounds and effectively proceeds towards the completion of the reaction. [15–17] As compared to other common Lewis acid catalysts based on main group metals (such as aluminium, boron, tin, titanium, iron etc.) lithium atom also forms an adduct with a lone-pair bearing electronegative atom in the [a] M. Konwar, P. Phukan, Dr. D. Sarma Department of Chemistry Dibrugarh University Dibrugarh-786004, Assam, India E-mail: dsarma22@gmail.com dsarma22@dibru.ac.in [b] Dr. A. K. Chaliha, Prof. A. K. Buragohain Centre for Biotechnology and Bioinformatics Dibrugarh University Dibrugarh-786004, Assam, India [c] K. Damarla, Dr. A. Kumar Academy of Scientific and Innovative Research (AcSIR) Central Salt and Marine Chemicals Research Institute G. B. Marg, Bhavnagar 364002 Gujarat, India [d] D. Gogoi DBT-Bioinformatics Infrastructure Facility, Centre for Biotechnology and Bioinformatics Dibrugarh University Dibrugarh-786004, Assam, India Supporting information for this article is available on the WWW under https://doi.org/10.1002/slct.201902266 Communications DOI: 10.1002/slct.201902266 10236 ChemistrySelect 2019, 4, 10236–10245 © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim