1.3.5- Trisubstituted 2-pyrazolines

Synthesis and Anticancer Activity of Some Novel 1,3,5-Trisubstituted pyrazolines using MDA-MB-231 and Hep-G2 cancer cell lines... 

Many pyrazole-type compounds have been elaborated further. Zirconium(IV) nitrate was found to be a versatile oxidizing agent for the aromatization of 1,3,5-trisubstituted pyrazolines 30 to the corresponding pyrtizoles 31 in acetic acid at ambient temperature <03S1267>. 4-... 

Trisubstituted pyrazolines were converted to the corresponding pyrazoles efficiently by the treatment of a catalytic amount of HIO, or in water <06TL9283>. 1,3>5-Trisubstituted pyrazolones were oxidized to the corresponding pyrazoles in high yields by molecular oxygen in the presence of catalytic amount of A-hydroxyphthalimide and Co(OAc)j in acetonitrile at room temperature <06T2492>. 

Trisubstituted pyrazolines were readily oxidized to the corresponding pyrazoles by l,3-dibromo-5,5-dimethylhydantoin (DBH) which reduces the time and enhances the yield [161]. 

TCCA was used also as an effective oxidizing agent for the oxidation of 1,3,5-trisubstituted pyrazoline 331 to the corresponding pyrazole 332 under both heterogeneous and solvent-free conditions (Equation 68). The 1,3,5-trisubstituted pyrazole was obtained by simple filtration and evaporation of the solvent <2004TL2181>. 

In the case of 3,5-disubstituted and 3,4,5-trisubstituted pyrazolines, electrophilic attack is directed to position 1 of the heterocycle (NH group). 

Pyrazolidinediones 52 were oxidized with manganese(III) acetate in the presence of alkenes 53 at elevated temperatures to produce 4,4-bis(alkenyl)pyrazolidinediones 54 in good yields <03T8383>. Photolysis of chiral trisubstituted pyrazolines 55 afforded cyclopropanes 56, in which the mechanism and stereospecificity were studied in detail <03JOC4906>. 

Solid-phase synthesis of substituted pyrazolones 550 from polymer-bound /3-keto esters 549 has been described (Scheme 68) <2001EJ01631>. Trisubstituted pyrazole carboxylic acids were prepared by reaction of polymer-bound arylidene- or alkylidene-/3-oxo esters with phenylhydrazines <1999S1961>. 2-(Pyrazol-l-yl)pyrimi-dine derivatives were prepared by cyclocondensation of ethyl acetoacetate and (6-methyl-4-oxo-3,4-dihydropyrimi-din-2-yl)hydrazine with aromatic aldehydes <2004RJC423>. Reactions of acylated diethyl malonates with hydrazine monohydrochloride in ethanol afforded 3,4-disubstituted-pyrazolin-5-ones <2002T3639>. Reactions of hydrazines with A -acetoacetyl derivatives of (45 )-4-benzyloxazolidin-2-one (Evans oxazolidinone) and (2R)-bornane-10,2-sultam (Oppolzer sultam) in very acidic media gave pyrazoles retaining the 3(5)-chiral moiety <1999S157>. 

Dihydropyrazoles can be prepared under microwave irradiation conditions. /3-Alkyl chalcones 649 reacted with hydrazines under microwave conditions followed by addition of acid chlorides to yield 1-acyl-3,5-diaryl-5-alkyl-4,5-dihydropyrazoles 650 (Scheme 82) <2004TL1489>. l,3,5-Trisubstituted-2-pyrazolines 652 were obtained from chalcones 651 and phenylhydrazine on silica gel and with microwave irradiation (Equation 135) <2005JHC157>. 

Palladium-based catalysts also bring about cyclopropanations in high-yield. With palladium acetate/CHjNj, styrene , unactivated terminal olefins strained olefins , 1,3-dienesan enamine , as well as a,3-unsaturated carbonyl compounds have been cyclopropanated (Table 1). Contrary to an earlier report, the reaction also works well with cyclohexene if the conditions are chosen appropriately it seems that the notniyst is rapidly deactivated in the presence of this olefin >. Trisubstituted a,p-unsaturated carbonyl compounds were found to be unreactive, and the same is true for the double bonds in diethyl fumarate, maleic anhydride, coumarin and 1,3-dimethyluracil. Whereas the latter two were totally unreactive, [3-1-2] cycloaddition of diazomethane gave pyrazolines in the former two cases. The last entry of Table 1 shows that an allyl alcohol function can still be cyclopropanated, but methylene insertion into the O—H bond is a competing process. 

Trisubstituted-2-pyrazolines 4 were obtained from chalcones 3 and phenylhydrazine under silica gel and microwave irradiation conditions <05JHC157>. An efficient and convenient synthesis of... 

Several interesting reactions of pyrazole or pyrazolines have been noted in the literature. Efficient aromatization of l,3,5-trisubstituted-2-pyrazolines 49 to pyrazoles 50 was achieved under microwave irradiation with silica-gel supported jV-bromosuccinimide and solvent-free conditions or with bismuth(iii) nitrate pentahydrate in acetic acid <0513(65)865, 05SC2581>. 

Cyclopropanation (5, 496). Vorbriiggen et al. have extended the cyclo-propanation procedure of styrene by Paulissen et al. to a, -unsaturated ketones and esters. The reaction proceeds stereospecifically cis to a,a- or a, 3-disub-stituted ketones and esters in excellent yield, but fails with trisubstituted carbonyl compounds. The reaction evidently Involves a carbenoid, since there is no evidence for formation of pyrazolines. 

Cycloaddition approaches to pyrazole derivatives were employed extensively in 1997. Thus, aldhydrazones combine with mercuric acetate to form nitrileimines which react in situ with olefins to give 1,3,5-trisubstituted 2-pyrazolines <97SC3737>. Oxidation of the latter to pyrazoles with iodobenzene diacetate was reported <97SC2683>. The most common cycloaddition pathway, however, is from the reaction of alkenes or alkynes with diazo compounds. The facial selectivity of the regiospecific reactions of diazomethane (and other... 

G.G. Mandawad, B.S. Dawane, S.D. Beedkar, C.N. Khobragade, O.S. Yemul, Trisubstituted thiophene analogues of l-thiazolyl-2-pyrazoline, superoxidase inhibitors and free radical scavengers, Bioorg. Med. Chem. 21 (2013) 365-372. 

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