Synthesis of 5‐Aryl‐3‐(methylsulfanyl)‐1H‐pyrazoles via Three‐Component Reaction of 1,1‐Bis(methylsulfanyl)‐2‐nitroethene,Aromatic Aldehydes,and Hydrazine

An efficient approach for the preparation of functionalized 5‐aryl‐3‐(methylsulfanyl)‐1H‐pyrazoles 2 is described. This three‐component reaction between benzaldehydes 1 , NH₂NH₂?H₂O, and 1,1‐bis(methylsulfanyl)‐2‐nitroethene proceeds in EtOH under reflux conditions in good‐to‐excellent yields. The structures of 2 were corroborated spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS). A plausible mechanism for this type of reaction is proposed (Scheme 2).     

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.     

Gold‐Catalyzed Synthesis of 1,3‐Diaminopyrazoles from 1‐Alkynyltriazenes and Imines

A new procedure for the synthesis of highly substituted 1,3‐diaminopyrazoles is described. As substrates, we have employed 1‐alkynyltriazenes and imines. The formation of pyrazoles was achieved by two‐fold C–N coupling reactions in the presence of (JohnPhos)AuCl and AgNT f₂ as catalyst precursors. The regioselectivity of the reaction was inferred from a crystallographic analysis of one reaction product.     

Ligand‐Promoted C(sp3)−H Olefination en Route to Multi‐functionalized Pyrazoles

A Pd‐catalyzed/N‐heterocycle‐directed C(sp³)?H olefination has been developed. The monoprotected amino acid ligand (MPAA) is found to significantly promote Pd‐catalyzed C(sp³)?H olefination for the first time. Cu(OAc)₂ instead of Ag⁺ salts are used as the terminal oxidant. This reaction provides a useful method for the synthesis of alkylated pyrazoles.     

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 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     

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.     

A Simple Efficient Procedure for the Synthesis of Benzopyrano[2,3‐c]pyrazoles

A one‐step procedure is proposed for synthesizing 2‐acyl benzopyrano[2,3‐c]pyrazoles and 2‐aryl benzopyrano[2,3‐c]pyrazoles. The method is based on the condensation of 2‐iminocoumarin‐3‐carbonitriles with hydrazides and hydrazines in acid as catalysts. A mechanism of reaction is proposed. All prepared compounds are identified by FTIR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis.     

Brominated Trihalomethylenones as Versatile Precursors to 3‐Ethoxy, ‐Formyl, ‐Azidomethyl, ‐Triazolyl,and 3‐Aminomethyl Pyrazoles

5‐Bromo[5,5‐dibromo]‐1,1,1‐trihalo‐4‐methoxy‐3‐penten[hexen]‐2‐ones are explored as precursors to the synthesis of 3‐ethoxymethyl‐5‐trifluoromethyl‐1H‐pyrazoles from a cyclocondensation reaction with hydrazine monohydrate in ethanol. 3‐Ethoxymethyl‐carboxyethyl ester pyrazoles were formed as a result of a substitution reaction of bromine and chlorine by ethanol. The dibrominated precursor furnished 3‐acetal‐pyrazole that was easily hydrolyzed to formyl group. In addition, brominated precursors were used in a nucleophilic substitution reaction with sodium azide to synthesize the 3‐azidomethyl‐5‐ethoxycarbonyl‐1H‐pyrazole from the reaction with hydrazine monohydrate. These products were submitted to a cycloaddition reaction with phenyl acetylene furnishing the 3‐[4(5)‐phenyl‐1,2,3‐triazolyl]5‐ ethoxycarbonyl‐1H‐pyrazoles and to reduction conditions resulting in 3‐aminomethyl‐1H‐pyrazole‐5‐carboxyethyl ester. The products were obtained by a simple methodology and in moderate to good yields.     

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.     

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.     

Copper(II) Complexes of 3,4,5‐Trisubstituted Pyrazolates: In Situ Formation of Pyrazole Rings from Different Carbon Centers

The synthesis and characterization of two pyrazolate‐bridged dicopper(II) complexes, [Cu₂(L¹)₂(H₂O)₂](ClO₄)₂ ( 1 , HL¹=3,5‐dipyridyl‐4‐(2‐keto‐pyridyl)pyrazole) and [Cu₂(L²)₂(H₂O)₂](ClO₄)₂ ( 2 , HL²=3,5‐dipyridyl‐4‐benzoylpyrazole), are discussed. These copper(II) complexes are formed from the reactions between pyridine‐2‐aldehyde, 2‐acetylpyridine (for compound 1 ) or acetophenone (for compound 2 ), and hydrazine hydrate with copper(II) perchlorate hydrate under ambient conditions. The single‐crystal X‐ray structure of compound 1? 2 H₂O establishes the formation of a pyrazole ring from three different carbon centers through C? C bond‐forming reactions, mediated by copper(II) ions. The free pyrazoles (HL¹ and HL²) are isolated from their corresponding copper(II) complexes and are characterized by using various analytical and spectroscopic techniques. A mechanism for the pyrazole‐ring synthesis that proceeds through C? C bond‐forming reactions is proposed and supported by theoretical calculations.     

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 %).     

In Situ Scanning Tunneling Microscopy of Cobalt‐Phthalocyanine‐Catalyzed CO2 Reduction Reaction

We report a molecular investigation of a cobalt phthalocyanine (CoPc)‐catalyzed CO₂ reduction reaction by electrochemical scanning tunneling microscopy (ECSTM). An ordered adlayer of CoPc was prepared on Au(111). Approximately 14 % of the adsorbed species appeared with high contrast in a CO₂‐purged electrolyte environment. The ECSTM experiments indicate the proportion of high‐contrast species correlated with the reduction of Co^IIPc (?0.2 V vs. saturated calomel electrode (SCE)). The high‐contrast species is ascribed to the CoPc‐CO₂ complex, which is further confirmed by theoretical simulation. The sharp contrast change from CoPc‐CO₂ to CoPc is revealed by in situ ECSTM characterization of the reaction. Potential step experiments provide dynamic information for the initial stage of the reaction, which include the reduction of CoPc and the binding of CO₂, and the latter is the rate‐limiting step. The rate constant of the formation and dissociation of CoPc‐CO₂ is estimated on the basis of the in situ ECSTM experiment.     

Some new information on the formation of substituted 4‐amino‐1‐substituted phenyl‐1H‐pyrazoles from β‐enaminones and diazonium tetrafluoroborates

Upon reaction of 2‐methyl‐, 3‐ethoxycarbonyl, and 4‐ethoxycarbonylbenzenediazonium tetrafluoroborate with 1‐cyclopropyl‐3‐phenylaminohex‐2‐en‐1‐one 3‐cyclopropylcarbonyl‐1‐(substituted phenyl)‐5‐ethyl‐4‐phenylamino‐1H‐pyrazoles are formed. On the other hand, the reaction of 1‐cyclopropyl‐3‐phenylaminohex‐2‐en‐1‐one and 5‐methylaminohept‐4‐en‐3‐one with sterically more demanding 2‐ethoxycarbonylbenzenediazonium tetrafluoroborate does not give the corresponding pyrazoles but the probable intermediates on the route to the pyrazoles: 1‐cyclopropyl‐3‐phenyliminohexane‐1,2,4‐trione 2,4‐bis(2‐ethoxycarbonylphenylhydrazone) and 3‐methyliminoheptane‐2,4,5‐trione 2,4‐bis(2‐ethoxycarbonylphenylhydrazone), respectively. All the compounds were identified on the basis of ¹H‐ and ¹³C‐NMR spectra. The structure of 1‐cyclopropyl‐3‐phenyliminohexane‐1,2,4‐trione 2,4‐bis(2‐ethoxycarbonylphenylhydrazone) was confirmed by means of ¹⁵N‐NMR spectra and X‐ray. The bis(2‐ethoxycarbonylphenylhydrazones) were found to show atropoisomerism due to a hindered rotation around the bond between the carbons of imino group and the hydrazono group next to carbonyl. In the case of the crystalline cyclopropyl derivative, the unit cell was found out to contain two molecules of opposite chirality. J. Heterocyclic Chem., (2011).     

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.     

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).     

Reactions of Methyl Diazoacetate with (E)‐ and (Z)‐1,2‐Bis(trifluoromethyl)ethene‐1,2‐dicarbonitrile: Novel and Unanticipated Pathways

The cycloadditions of methyl diazoacetate to 2,3‐bis(trifluoromethyl)fumaronitrile ((E)‐ BTE ) and 2,3‐bis(trifluoromethyl)maleonitrile ((Z)‐ BTE ) furnish the 4,5‐dihydro‐1H‐pyrazoles 13 . The retention of dipolarophile configuration proceeds for (E)‐ BTE with > 99.93% and for (Z)‐ BTE with > 99.8% (CDCl₃, 25°), suggesting concertedness. Base catalysis (1,4‐diazabicyclo[2.2.2]octane (DABCO), proton sponge) converts the cycloadducts, trans‐ 13 and cis‐ 13 , to a 94 : 6 equilibrium mixture (CDCl₃, r.t.); the first step is N‐deprotonation, since reaction with methyl fluorosulfonate affords the 4,5‐dihydro‐1‐methyl‐1H‐pyrazoles. Competing with the cis/trans isomerization of 13 is the formation of a bis(dehydrofluoro) dimer (two diastereoisomers), the structure of which was elucidated by IR, ¹⁹F‐NMR, and ¹³C‐NMR spectroscopy. The reaction slows when DABCO is bound by HF, but F^? as base keeps the conversion to 22 going and binds HF. The diazo group in 22 suggests a common intermediate for cis/trans isomerization of 13 and conversion to 22 : reversible ring opening of N‐deprotonated 13 provides 18 , a derivative of methyl diazoacetate with a carbanionic substituent. Mechanistic comparison with the reaction of diazomethane and dimethyl 2,3‐dicyanofumarate, a related tetra‐acceptor‐ethylene, brings to light unanticipated divergencies.     

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.     

Siamese‐Twin Porphyrin: A Pyrazole‐Based Expanded Porphyrin of Persistent Helical Conformation

The 3+3‐type synthesis of a pyrazole‐based expanded porphyrin 22 H₄ , a hexaphyrin analogue named Siamese‐twin porphyrin, and its homobimetallic diamagnetic nickel(II) and paramagnetic copper(II) complexes, 22 Ni₂ and 22 Cu₂ , are described. The structure of the macrocycle composed of four pyrroles and two pyrazoles all linked by single carbon atoms, can be interpreted as two conjoined porphyrin‐like subunits, with the two opposing pyrazoles acting as the fusion points. Variable‐temperature 1D and 2D NMR spectroscopic analyses suggested a conformationally flexible structure for 22 H₄ . NMR and UV/Vis spectroscopic evidence as well as structural parameters proved the macrocycle to be non‐aromatic, though each half of the molecule is fully conjugated. UV/Vis and NMR spectroscopic titrations of the free base macrocycle with acid showed it to be dibasic. In the complexes, each metal ion is coordinated in a square‐planar fashion by a dianionic, porphyrin‐like {N₄} binding pocket. The solid‐state structures of the dication and both metal complexes were elucidated by single‐crystal diffractometry. The conformations of the three structures are all similar to each other and strongly twisted, rendering the molecules chiral. The persistent helical twist in the protonated form of the free base and in both metal complexes permitted resolution of these enantiomeric helimers by HPLC on a chiral phase. The absolute stereostructures of 22 H₆ ²⁺, 22 Ni₂ , and 22 Cu₂ were assigned by a combination of experimental electronic circular dichroism (ECD) investigations and quantum‐chemical ECD calculations. The synthesis of the first member of this long‐sought class of expanded porphyrin‐like macrocycles lays the foundation for the study of the interactions of the metal centers within their bimetallic complexes.