Synthesis of Tetrasubstituted Pyrazoles from Substituted Hydrazines and β‐Keto Esters

Abstract

Herein we report the synthesis of tetrasubstituted pyrazoles from simple hydrazines and β‐keto esters under mild, basic conditions. This reaction enables the selective synthesis of pyrazolones, alkoxypyrazoles, and tetrasubstituted pyrazoles for a large variety of aromatic hydrazines and substituted β‐keto esters with high yields and selectivities. This method permits access to highly complex pyrazole scaffolds with four orthogonal diversification groups.

Silica-zinc chloride (SiO2-ZnCl2) catalyzed Michael addition reaction of active methylene compounds to β-nitrostyrenes: Synthesis of functionalized pyrazole derivatives

“…The Michael addition reaction involving acetylacetone electrophile attack on the beta-position of nitroalkenes to yield addition product (or) Michael adduct and the progress of the reaction was monitored by TLC; the crude reaction mixture was purified by column chromatography to afford the expected product 3-(2-nitro-1-phenylethyl)pentane-2,4-dione (3a) in 89% isolated yield (Table 2). The product thus obtained was also confirmed by 1 H and 13 C NMR analysis. Excited with the preliminary result, we proceeded to explore the reactivity of other substrates in the current protocol.…”

“…The IR spectra were done on the Perkin-Elmer FT-IR instrument. The 1 H NMR and 13 C NMR spectra were taken in CDCl3 at 300 MHz/ 400MHz and 100 MHz respectively on Varian series (EM-360) NMR instruments. The mass spectra were done on an Agilent 1100 series instrument.…”

“…Pyrazole derivatives were found with wide range of biological activities including antimicrobial agent 4 , tyrosine kinase-2 inhibitors 5 , insulin-like growth factor−1 receptor (IGF-1R) 6 , ataxia telangiectasia mutated (ATM) kinase inhibitors 7 , T−type calcium channel blockers 8 , p21-activated kinase inhibitors 9 , etc. Biological properties of pyrazole derivatives have inspired chemists to develop various synthetic methods that have been reported for the synthesis of pyrazole derivatives [10][11][12][13][14][15] but still there is a requirement for the new derivatives of pyrazoles to address the new challenging tasks.…”

Facile One-Pot Preparation of 5-Substituted 4-Iodo-1-tosylpyrazoles from N-Propargyl-N′-tosylhydrazines through Iodocyclization

“…1 and 2). Recent examples of pyrazoles prepared in the absence of transition metals are as follows: 4 1-aryl-4-iodopyrazoles­ from the reaction of N -aryl- N ′-(α-alkynyl)­hydrazones with molecular iodine (I 2 ) and NaHCO 3 ; 4a 3-substituted pyrazoles from the reaction of propargylamines with m CPBA and then with hydrazines; 4b 3,5-disubstituted 1-arylpyrazoles from the reaction of α,β-unsaturated aldehydes with arylhydrazines and I 2 ; 4c 1-arylpyrazole-4-carboxylate esters from the reaction of α-[( tert -butoxycarbonyl)oxy]methylacrylate esters with N -arylazosulfones and Bu 3 P; 4d 5-amino-3-aryl-1-tosylpyrazoles from the reaction of N -tosylhydrazones with isocyanides, t BuOOH, and I 2 ; 4e ethyl 1-aryl-5-(acetylmethyl)pyrazole-4-carboxylates from the reaction of ethyl acetoacetate with arylhydrazines and NaOEt; 4f 1-aryl-5-hydroxy-4-thioarylpyrazoles from the reaction of arylhydrazines with ethyl acetoacetate, arenethiols, and I 2 ; 4g 1,5-diaryl-4-iodo-3-(trifluoromethyl)pyrazoles from the reaction of N -arylhydrazones of arylethynyl trifluoromethyl ketones with I 2 ; 4h 1,4-bis(arenesulfonyl)pyrazoles from the reaction of β-amino-α,β-unsaturated ketones­ with arenesulfonylhydrazines, t BuOOH, and I 2 ; 4i 5-amino-1-arylpyrazoles from the reaction of 3-aminocrotonitrile with arylhydrazine and 1 M HCl under microwave irradiation; 4j 1,3-diarylpyrazoles from the reaction of hydrazonyl chlorides with benzyl vinyl ether and Et 3 N; 4k 1,3-di­aryl-5-(bromomethyl)pyrazoles from the reaction of hydrazonyl chlorides with dimethyl propargylsulfonium and K 2 CO 3 ; 4l 1,4-bis(arenesulfonyl)pyrazoles from the reaction of 1,3-diketones with arenesulfonylhydrazines, arenesulfinate salts, and I 2 ; 4m and 1-aryl-4-selenoarylpyrazoles from the reaction of 1,3-diketones with arylhydrazines and diaryl diselenides by electrochemical method. 4n Examples of pyrazoles prepared in the presence of transition metals are as follows: 5 1-benzylpyrazole-4-carboxylates from the reaction of 2,3-allenoates with benzylamine in the presence of Cu(OAc) 2 ; 5a 1,4-diarylpyrazoles from the reaction of N -arylsydnone with terminal alkynes in the presence of silica-supported Cu(OAc) 2 ; 5b 1,5-diaryl-3-(trifluoromethyl)pyrazoles from the reaction of alkynyl trifluoromethyl ketones and arylhydrazines in the presence of AgOTf; 5c 1-aryl-3,5-dimethylpyrazoles from the reaction of arylhydrazines with Cu(acac) 2 under microwave irradiation; 5d 1,3,5-triaryl-4-selenophenylpyrazoles from the reaction of chalcones with arylhydrazines in the presence of CuBr; 5e 1-tosyl­pyrazole-4-boronate esters from the reaction of N -tosyl-(α-alkynyl)hydrazones with B -chlo...…”