1. Umesh N. Bhisea and Dhananjay V. Mane *
FACILE SYNTHESIS OF 3-METHYL-1-PHENYL-1H PYRAZOLE SUBSTITUTED AMINE DERIVATIVES USING LAWESSSONS REAGENT
Umesh N. Bhisea and Dhananjay V. Mane *
aP.G. Department of Chemistry & Research Center, S.C.S. College, Omerga &
*Deputy Director, UGC- Academic Staff College,
Dr. Babasaheb Ambedkar Marathwada University, Aurangabad (MS)
Abstract : Pyrazoles are very important heterocyclic compounds which are widely present in the medicinal, pesticide type of molecules. Wide literature for the preparation of pyrazole is present till date. We have synthesized pyrazole using uncommon reagent i.e. Lawesson’s Reagent (LR) with excellent yield and minimum reaction time at room temperature. The role of LR here is for cyclization. We have reported 11 examples (4a-4k) of amino pyrazole using symmetrical and unsymmetrical 2°amine.
All the aminopyrazoles synthesized are fully characterized using H1NMR and mass spectroscopy.
Keywords : Lawesson’s Reagent, Cyclization, Aminopyrazole, Excellent yield.
Introduction:
Highly substituted heterocyclic compounds, pyrazole are interesting scaffolds for medicinal and pharmaceutical applications. Among this wide range of compounds, phenyl pyrazole scaffold and related substituted analogue have previously found broad application in pharmaceutical and medicinal chemistry programs as antibacterial, antimicrobial, anti HIV and anti allergic agents. 3-Methyl-1-phenyl-1H-pyrazole substituted amine derivatives are rather rare in literature. Reported methods involve like Knorr pyrazole synthesis in which phenyl hydrazine is treated with 1,3-dicarbonyl compound using acid as catalyst, Monosubstituted hydrazine gives functionalized pyrazoles, alkynyl ketones and alkynyl imines on reaction with hydrazines gives substituted pyrazoles.
Lawesson’s reagent (LR) is a chemical compound having dimeric structure with two sulfur and one phospurous atom. Lawesson’s reagent is also used for the preparation of pyrazole, but the conditions used are very hash and the yields also very less. Generally the application of LR is to introduce sulfur atom (S) in the molecules having carbonyl functionality. (CO), where carbonyl group is replaced by the thiocarbonyl group. Thianation reaction required heating or reflux in a non polar solvents like toluene, xylene etc.
Reaction Scheme:
EXPERIMENTAL :
Conclusions :
We have prepared pyrazole using uncommon reagent i.e. Lawesson’s Reagent (LR) with excellent yield and minimum reaction time at room temperature. We have developed convenient synthetic route for the Synthesis of 3-METHYL-1-PHENYL-1H PYRAZOLE SUBSTITUTED AMINE DERIVATIVES USING LAWESSSONS REAGENT using environmental benign and ecosustainable protocol. The starting materials required for the synthesis are easily available. Some of these synthesized derivatives were found to be potent Antimicrobial agent.
All the reagents and solvents were used as obtained from the supplier or recrystallized /redistilled as necessary. The moiety tert-Butyl acetoacetate and all the 2° amine used commercially available and is also in Sigma Aldrich. Melting points were recorded on open capillary melting point apparatus and are uncorrected. Mass spectra were recorded on ‘LCMS-QP2010s’ instrument by direct injection method. Nuclear Magnetic Resonance spectra (1H NMR) and (13C NMR) were recorded in DMSO-d6 & CDCl3 using Tetramethylsilane (TMS) as internal standard on Varian advance spectrometer at 400MHz. The chemical shifts (δ) are reported in parts per million (ppm). The reaction monitoring and purity of the synthesized compounds was checked by Thin Layer Chromatography (TLC) technique by Merck pre-coated plates (silica gel 60 F254) were visualized with UV light and Ninhydrin spray reagent.
General procedure : Synthesis of N,N-Disubstituted-3-oxo-butyramide (2a-2k) :
The compound 1 (6.329 mmol) and 2°Amine (6.329 mmol) was heated together at ° C for 2-4 h without solvent. The completion of reaction was monitored by TLC. The by-product forming during the reaction was distilled off. The corresponding compounds
(3a-3k) were isolated and used for next step. (Yield : 99 %)
General procedure :
Synthesis of N,N-Disubstituted-5-methyl-2-phenyl-2H-pyrazole-3-yl)-amine (4a-4k) :
To the solution of 3a-3k (1.0 mmol) in THF 10 mL, was added Lawesson’s reagent (LR)
(0.5 mmol) and stirred the reaction mass for 2 to 5 mins at 25-30°C. Reaction progress was monitored by TLC. After completion of reaction added saturated solution of NaHCO3 (25 mL) and extracted ethyl acetate (2X50 mL). Ethyl acetate layer was then washed with brine solution (25 mL). Ethyl acetate layer was concentrated to get N,N-Disubstituted-5-methyl-2-phenyl-2H-pyrazole-3-yl)-amine (4a-4k) as pale yellow to off white solids. The purification wherever required was done by column chromatography. (Yield : %).
REFERENCES
1. Heterocyclic Chemistry – J. A. Joule, K. Mills and G. F. Smith
2. Hamama, W. S.; Zoorob, H. H. Tetrahedron 2002, 58, 6143.
3. Vaquero, J. J.; Alvarez-Builla, J. In Modern Heterocyclic Chemistry; J. Alvarez-Builla J Vaquero, and J. Barluenga (Eds.); Wiley-VCH: Weinheim, 2011; vol. 4, pp. 1989–2070.
4. Katritzky, R.; Rees, C.; Scriven, E. F. V. In Comprehensive Heterocyclic Chemistry II; G Jones (Ed.); Elsevier Science: Oxford, 1996; vol. 8.
5. Elsner, J.; Boeckler, F.; Davidson, K.; Sugden, D.; Gmeiner, P. Bioorg. Med. Chem ,14, 1949.
6. Amir, M.; Kumar, H.; Javed, S. A. Eur. J. Med. Chem. 2008, 43, 2056.