Oxidative Aromatization of 1,3,5‐Trisubstituted 4,5‐Dihydro‐1H‐Pyrazoles Efficiently by Tetrabromine‐1,3,5,7‐Tetrazatricyclo[3.3.1.13,7]Decane Complex,Br4‐Tatcd,as a Novel Reagent both Under Microwave Irradiation and at Room Temperature

Oxidation of 1,3,5‐trisubstituted 4,5‐dihydro‐1H‐pyrazoles to the corresponding pyrazoles has been achieved by utilizing tetrabromine‐1,3,5,7‐tetrazatricyclo[3.3.1.1^3,7]decane complex, Br₄‐TATCD, in glacial acetic acid under microwave irradiation and conventional thermal condition at room temperature with excellent yields.     

Directing/Protecting‐Group‐Free Synthesis of Tetraaryl‐Substituted Pyrazoles through Four Direct Arylations on an Unsubstituted Pyrazole Scaffold

A directing/protecting‐group‐free synthesis of 1,3,4,5‐tetraaryl‐substituted pyrazoles was achieved through four transition metal‐catalyzed direct arylations. Various pyrazoles with four different aryl rings were obtained using readily available reagents from an unsubstituted pyrazole. Two aryl‐substituted pyrazoles showed intense violet fluorescence, high quantum yields (Φ_f=0.68, 0.64), and large Stokes shifts (19000, 15200 cm^?1).     

1,3‐Dipolar Cycloadditions of Ethyl 2‐Diazo‐3,3,3‐trifluoropropanoate to Alkynes and [1,5] Sigmatropic Rearrangements of the Resulting 3H‐Pyrazoles: Synthesis of Mono‐, Bis‐ and Tris(trifluoromethyl)‐Substituted Pyrazoles

The 1,3‐dipolar cycloadditions of ethyl 2‐diazo‐3,3,3‐trifluoropropanoate with electron‐rich and electron‐deficient alkynes, as well as the van Alphen? Hüttel rearrangements of the resulting 3H‐pyrazoles were investigated. These reactions led to a series of CF₃‐substituted pyrazoles in good overall yields. Phenyl‐ and diphenylacetylene proved to be unreactive, but, at high temperature, the diazoalkane and phenylacetylene furnished a cyclopropene derivative. As expected, the 1,3‐dipolar cycloaddition to the ynamine occurred much faster than those to electron‐deficient alkynes. With one exception, all cycloadditions proceeded with excellent regioselectivities. The [1,5] sigmatropic rearrangement of the primary 3H‐pyrazoles provided products with shifted acyl groups; products resulting from the migration of a CF₃ group were not detected. In agreement with literature reports, this rearrangement occurs faster with 3H‐pyrazoles bearing electron‐withdrawing substituents.     

One‐Pot Synthesis of Pyrazoles through a Four‐Step Cascade Sequence

A one‐pot synthesis of 3,4,5‐ and 1,3,5‐pyrazoles from tertiary propargylic alcohols and para‐tolylsulfonohydrazide has been accomplished. The pyrazoles are formed through a four‐step cascade sequence, including FeCl₃‐catalyzed propargylic substitution, aza‐Meyer–Schuster rearrangement, base‐mediated 6π electrocyclization, and thermal [1,5] sigmatropic shift. In this reaction, the 3,4,5‐ and 1,3,5‐pyrazoles are produced selectively according to different substituents in the starting alcohols.     

Asymmetric diels alder reaction using pyrazole derivatives as a chiral catalyst

N‐Acylpyrazoles ( 1 ) were promising as good dienophiles, which were easily converted into the desired carboxylic derivatives. Bis(pyrazolyl)methanes, which were derived from chiral pyrazoles, showed the activity of chiral catalyst. Particularly 10 mol% of bis(isomenthopyrazol‐1,1′‐yl)methane ( 8a ) catalyzed enantioselectively the Diels Alder reaction up to 40 % ee by the formation of complex with Mg(ClO₄)_2.     

One‐pot synthesis of aryl and heteroaroyl‐substituted hydroxypyrazolines from the reactions of β‐alkoxyvinyl trichloromethyl ketones with heteroarylhydrazides

The one‐step regiospecific synthesis of a novel series of 10 trichloromethyl‐, aryl‐, and heteroaroyl‐substituted 5‐hydroxy‐2‐pyrazolines affords 1‐(2‐thenoyl)‐, 1‐(2‐furoyl)‐, and 1‐(isonicotinoyl)‐3‐aryl‐5‐hydroxy‐5‐trichloromethyl‐4,5‐dihydro‐1H‐pyrazoles in 63–92% yields from the cyclocondensation reactions of 1,1,1‐trichloro‐4‐methoxy‐4‐aryl‐3‐buten‐2‐ones (where aryl substituents are –C₆H₅, 4‐CH₃C₆H₄, 4‐OCH₃C₆H₄, 4‐FC₆H₄, 4‐ClC₆H₄, 4‐BrC₆H₄) with 2‐thiophenecarboxylic hydrazide, furoic hydrazide, and isonicotinic acid hydrazide, respectively. Dehydration reaction of two 2‐pyrazolines with P₂O₅ furnished the corresponding 1H‐pyrazoles in low yields (21–29%). © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:685–691, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20261     

Regiospecific one‐pot synthesis of new trifluoromethyl substituted heteroaryl pyrazolyl ketones

A convenient and general method for the regiospecific synthesis of three novel series of 1‐(2‐thenoyl)‐, 1‐(2‐furoyl)‐ and 1‐(isonicotinoyl)‐3‐alkyl(aryl)‐5‐hydroxy‐5‐trifluoromethyl‐4,5‐dihydro‐1H‐pyrazoles, in good yields (53 – 91 %), from the cyclocondensation reactions of 1,1,1‐trifluoro‐4‐alkoxy‐4‐alkyl(aryl)‐but‐3‐en‐2‐ones, where alkyl = H and Me; aryl = ‐C₆H₅, 4‐CH₃C₆H₄, 4‐CH₃OC₆H₄, 4‐FC₆H₄, 4‐ClC₆H₄, 4‐BrC₆H₄, 4‐NO₂CgH₄ with 2‐thiophenecarboxylic hydrazide, furoic hydrazide and isonicotinic acid hydrazide, respectively, is reported. Subsequently dehydration reaction of phenyl substituted 2‐pyrazolines with P₂O₅ furnished the corresponding 1H‐pyrazoles as mixture of regioisomers and in low yields (35 – 36 %).     

Cu‐Promoted Sydnone Cycloadditions of Alkynes: Scope and Mechanism Studies

Cu salts have been found to promote the cycloaddition reaction of sydnones and terminal alkynes, providing significant reduction in reaction times. Specifically, the use of Cu(OTf)₂ is found to provide 1,3‐disubstituted pyrazoles, whereas simply switching the promoter system to Cu(OAc)₂ allows the corresponding 1,4‐isomers to be produced. The mechanism of the Cu‐effect in each case has been investigated by experimental and theoretical studies, and they suggest that Cu(OTf)₂ functions by Lewis acid activation of the sydnone, whereas Cu(OAc)₂ promotes formation of reactive Cu^I acetylides.     

Halogenation of Pyrazoles Using N‐Halosuccinimides in CCl4 and in Water

Reaction of pyrazoles with N‐halosuccinimides (NXS, X=Br, Cl) in either CCl₄ or water gave 4‐halopyrazoles in excellent yields. The reaction was carried out under mild conditions and did not require any catalysts or special precautions. The reaction provides an efficient method for 4‐C halogenation of pyrazoles.     

A general strategy for the synthesis of difluoromethyl-containing pyrazoles, pyridines and pyrimidines

Difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles are prepared by a two step method. The regioselective cyclizations of electron-excessive aminoheterocycles, hydrazines and amidines with CF₂Cl-substituted 1,3-dicarbonyl compounds provide the corresponding CF₂Cl-substituted heterocycles. Subsequent radical reactions with trimethylstannane or allyltrimethylstannane gave difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles, respectively.     

Asymmetric borane reduction of ketones catalyzed by N‐hydroxyalkyl‐l‐menthopyrazoles

The equimolar mixture of N‐(hydroxyalkyl)pyrazoles and borane formed boric ester complex, in which the remaining borane was stabilized by the adjacent nitrogen of thr pyrazole ring. The borane complex derived from the chiral pyrazoles such as 3‐phenyl‐l‐menthopyrazole reduced p‐methylacetophenone ( 21 ) enantioselectively. When (2′S)‐2‐(2′‐phenyl‐2′‐hydroxyethyl)‐3‐phenyl‐l‐menthopyrazole ((2′S)‐ 10b ) was used, 21 was reduced into (S)‐p‐methylphenyl‐1‐ethanol ( 22 ) in moderate chemical and optical yields. Due to the inconvenience of the preparation and the lower optical yield, the use of N‐(α‐hydroxyalkyl)pyrazoles was unpromising for the enantioselective reduction of ketones by borane.     

Facile synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles via Sonogashira and Suzuki–Miyaura approaches

A concise and efficient synthesis of densely substituted novel pyrazoles with alkynyl, aryl and ferrocenyl functionalities is reported, providing a platform for biological studies. The general strategy involves Sonogashira and Suzuki–Miyaura cross‐coupling reactions of easily obtainable 5‐ferrocenyl/phenyl‐4‐iodo‐1‐phenylpyrazoles with terminal alkynes and boronic acids, respectively. The starting 4‐iodopyrazoles were synthesized by electrophilic cyclization of α,β‐alkynic hydrazones with molecular iodine. Sonogashira reactions have been achieved by employing 5 mol% PdCl₂(PPh₃)₂, 5 mol% CuI, excess Et₃N and 1.2 equiv. of terminal alkyne, relative to 4‐iodopyrazole, in tetrahydrofuran at 65 °C, while Suzuki–Miyaura reactions have been accomplished using 5 mol% PdCl₂(PPh₃)₂ and 1.4 equiv. of both boronic acid/ester and KHCO₃, with respect to 4‐iodopyrazole, in 4:1 dimethylformamide–H₂O solution at 110 °C. Both Sonogashira and Suzuki–Miyaura coupling reactions have proven effective for the synthesis of alkynyl‐, aryl‐ and ferrocenyl‐substituted pyrazoles and demonstrated good tolerance to a diverse range of substituents, including electron‐donating and electron‐withdrawing groups. These coupling approaches could allow for the rapid construction of a library of functionalized pyrazoles of pharmacological interest. Copyright © 2016 John Wiley & Sons, Ltd.     

The reaction of aryl and heteroarylhydrazines with aryl‐trifluoromethyl β‐diketones

We report the results obtained when five aromatic or heteroaromatic hydrazines react with six β‐diketones bearing trifluoromethyl and aryl substituents. Forty‐two compounds have been isolated corresponding to two isomeric trifluoromethyl pyrazoles and the intermediate 5‐CF₃, 5‐OH pyrazolines. The results have provided useful information for establishing the mechanism of the synthesis of pyrazoles.     

Photoinduced Electron Transfer Reactions of 3,3‐Dialkylated 4,5‐Diphenyl‐3H‐Pyrazoles: A New Route to the Formation of the Solvent Adducts

3,3‐Dialkyl‐4,5‐diphenyl‐3H‐pyrazoles undergo readily photoinduced electron transfer (PET) reaction with 2,4,6‐triphenylpyrylium tetrafluoroborate (TPP⁺) in acetonitrile to produce cyclopropenes and 2H‐pyrroles. During prolonged irradiation, the new ring‐closure products derived from 2H‐pyrroles as the secondary photoproducts are also produced. However, the corresponding ester analog exhibits different behavior to obtain the cyclopropene as the primary photoproduct and a [2+2] dimer of the cyclopropene as the secondary photoproduct. A rationale for the different behavior is offered.     

New Route for the Synthesis of Pyrazole,Triazole, Triazine,and Triazepine Derivatives

N,N′‐Diphenylpiperidine‐1‐carbohydrazonamide 1 was prepared and treated with halo compounds, active nitriles, diethylhy malonate, ketones, CS₂, phenylisocyanate, phenylisothiocyanate, LR, ethyl 2‐cyano‐3,13‐dithiomethylacetate, and benzylidenenitriles to give the corresponding triazines 2–4, pyrazoles 5 and 6, triazoles 7, 8, and 10, triazaphosphole 11, and triazepines 12 – 14, respectively.     

Convenient one‐pot syntheses of pyrazoles from imines,a vilsmeier type reagent and hydrazine

A simple one‐pot procedure for the regioselective synthesis of pyrazoles from readily available starting materials is described. Vilsmeier type reagent 1 reacts with imines 10 (via the corresponding tautomeric secondary enamines) in tetrahydrofuran to give enaminoimine hydrochlorides 11 . Nonsymmetrical imines generally react preferentially with 1 at the sterically less hindered α‐position. The enaminoimine hydrochlorides 11 are transformed in situ to the corresponding pyrazoles 12 in moderate to high yields by the addition of hydrazine.     

In Situ Generation of Difluoromethyl Diazomethane for [3+2] Cycloadditions with Alkynes

A novel approach to agrochemically important difluoromethyl‐substituted pyrazoles has been developed based on the elusive reagent CF₂HCHN₂, which was synthesized (generated in situ) for the first time and employed in [3+2] cycloaddition reactions with alkynes. The reaction is extremely practical as it is a one‐pot process, does not require a catalyst or the isolation of the potentially toxic and explosive gaseous intermediate, and proceeds in a common solvent, namely chloroform, in air. The reaction is also scalable and allows for the preparation of the target pyrazoles on gram scale.     

Sequential SNAr Reaction/Suzuki–Miyaura Coupling/C−H Direct Arylations Approach for the Rapid Synthesis of Tetraaryl‐Substituted Pyrazoles

A rapid synthesis of 1,3,4,5‐tetraaryl‐substituted pyrazoles has been achieved through a sequence of S_NAr reaction/Suzuki–Miyaura coupling/Pd‐catalyzed direct arylations that used 3‐iodo‐1H‐pyrazole as a scaffold. Pyrazoles with four different aryl groups were synthesized in a straightforward manner with no extra synthetic steps, such as protection/deprotection or the introduction of activating/directing groups, using readily available substrates and reagents. The developed synthetic approach enabled the structurally diverse synthesis of multiaryl‐substituted pyrazoles without using a glovebox technique.     

One‐Pot Synthesis of Functionalized 3‐Aryl‐1‐phenyl‐1H‐pyrazoles from Hydrazonoyl Chlorides and Acetylenic Esters in the Presence of Ph3P

The zwitterionic 1 : 1 intermediates generated by addition of Ph₃P to acetylenic esters is trapped by 1‐[(aryl)chloromethylene]‐2‐phenylhydrazines (=N‐phenylarenecarbohydrazonoyl chlorides) to yield functionalized 3‐aryl‐1‐phenyl‐1H‐pyrazoles in good yields.     

Synthesis of Molecular Frameworks Containing Two Distinct Heterocycles Connected in a Single Molecule with Enhanced Three‐Dimensional Shape Diversity

Herein, we report the synthesis of fused‐triazole scaffolds that are connected by pyrimidines, pyrazoles, or pyrazolopyrimidines through carbohydrate‐derived stereodivergent linkers. Pyrimidine‐, pyrazole‐, or pyrazolopyrimidine‐based carbohybrids were constructed through condensations of the key intermediates, 2‐C‐formyl glycals, with various dinucleophiles. Fused‐triazole scaffolds were obtained through intramolecular 1,3‐dipolar cycloadditions after selective functionalization of the carbohybrid polyol moieties with azide and alkyne functionalities using S_N2‐type alkylations or Mitsunobu reactions. Overall, this synthetic method affords two distinct privileged substructures in a single molecule, connected by stereodivergent diol linkers derived from abundant natural chiral sources, namely, carbohydrates. The resulting vicinal diols in the linker were further modified to achieve unique connectivities between the two privileged structures for maximized three‐dimensional shape diversity, which we called the linker diversification strategy.