1.3.4.5- Tetrasubstituted pyrazoles

A rapid and efficient synthesis of 1,3,4,5-tetrasubstituted pyrazoles 21 and 23 was disclosed by applying the previously established protocol for the... 

A new synthesis of pyrroles generates a 1,3-diketone by reacting a lithium enolate of a ketone with an acid chloride in situ addition of a hydrazine yields, potentially, a tetrasubstituted pyrazole.297 Tolerant of a wide range of functional groups, it is also easily adapted to rapid preparation of fused bicyclic pyrazole systems. 

Stauffer SR, Katzenellenbogen JA, Solid-phase synthesis of tetrasubstituted pyrazoles, novel ligands for the estrogen receptor, J. Comb. Chem., 2 318-329, 2000. 

Tetrasubstituted pyrazoles 589 were synthesized regioselectively in good yields from the reaction of Baylis-Hillman adducts 588 with various hydrazine hydrochlorides in 1,2-dichloroethane (Equation 120) <2003TL6737>. Baylis-Hillman adducts 591, derived from aldehydes and 2-cyclohexen-l-one 590, reacted with hydrazines to give pyrazoles 592, which could be dehydrogenated to 277-indazoles 593 (Scheme 74) <2005TL5387>. 

Alkynyl ketones can be formed from addition of alkynyllithium or Grignard reagents to phthalimides and then the products converted into pyrazoles by reaction with hydrazines. For example, A -alkyl-substituted phthalimides 633 were easily transformed to mono-, di-, or trisubstituted pyrazoles 634 via a one-pot addition/decyclization/cyclocon-densation process (Equation 131) <2002J(P1)207>. A -Alkyl-substituted phthalimides 635 were easily converted into di-, tri-, and tetrasubstituted pyrazoles 636 via a one-pot addition-decyclization-cyclocondensation process (Equation 132) <2003H(60)2499>. 

Similarly, for the construction of a central imidazolinone core skeleton of rhopaladin D, a marine alkaloid, the PS-BEMP promoted aza-Wittig reaction followed by intramolecular cyclization was used [64], and a tetrasubstituted pyrazole ring of sildenafil... 

Tri- or tetrasubstituted pyrazole sulfonamides (e.g. 66) are most readily produced by condensation of a hydrazine derivative with an appropriately substituted ketene dithioacetal 65 (14). The ester may be further elaborated (e.g. 66... 

Pyrazoles and indazoles are important synthetic units in biologically active compounds and drugs. Glorius et al. reported a Cu(OAc)2 mediates regiospecific preparation of tetrasubstituted pyrazoles from enamines and nitriles. The C(sp )-H bond of imine was cleavaged via elimination of HOAc molecule. Cu(OAc)2 plays the role of the Lewis acid and oxidant. Moreover, an excess amount of nitrile was needed for this reaction [110]. To solve this problem, they report a modified synthetic approach using equivalent amounts of nitriles with an efficient Cu(OAc)2 catalyst system and molecular oxygen as the oxidant [111]. 

Scheme 8.65 Synthesis of tetrasubstituted pyrazoles from enamines and nitriles.

Although the mechanism of the transformation of single into double bonds has not been investigated in detail, a heteroatom attached to the single bond is necessary for an efficient introduction of the double bond. Trisubstituted pyrazo-lines 46 can be oxidized with (diacetoxyiodo)benzene 3 to the corresponding pyrazoles 47 in good yields [98]. Two double bonds can be introduced in easy accessible proline derivatives 48 [99] by an oxidative decarboxylation with [bis(trifluoroacetoxy)iodo]benzene 4 yielding tetrasubstituted pyrroles of type 49, Scheme 22 [100]. 

In the reaction of 179 with 3,5-dimethyl pyrazole anion, the hexasubstitution product is formed in 72%, with 8-9% of disubstitution and 18-22% of the tetrasubstitution product. With 3,5-dimethyl-4-nitropyrazole anion and imidazole anion, the hexasubstitution products are formed quantitatively228. 

With 3,5-disubstituted pyrazole the melt method is preferred, since tetrasubstitution does not take place, and high temperatures can be employed. It would be better to use a large excess of Hpzx (Hpzx MBH4 in 6 1 molar ratio) to prevent the precipitation of the less soluble potassium or sodium salt and decomposition. After completion of the reaction, the excess of Hpzx is sublimed out and the residue is converted to the Tl1 salt in the usual way. 

Mercapto pyrimidines 82 were synthesized from acetoacetanilide, dihydroxybenzaldehyde, and thiourea, which were readily alkylated with benzyl chloride to afford 2-benzylthio derivatives 83 (Scheme 32). 83 when reacted with different amines in acetic acid furnished 2-amino derivatives 84 (R = Ar), whereas upon reaction with hydrazine hydrate 83 afforded 2-hydrazinyl derivative 84 (R = NH2), which with different aldehydes gave hydrazones 85 (R = 2-furyl, 2-thienyl). Arylidene thiazolidinone 86 was obtained from 84 with carbon disulfide, monochloroacetic acid, and aryl aldehydes, while 84 with ethyl acetoacetate and different aromatic aldehydes provided pyrazoles 87 (Scheme 32) (10MI9). Such tetrasubstituted pyrimidines act as cyclin-dependent kinase (CDK2) inhibitors. 

Another area related to fluazolate (17) and pyraflufen-ethyl (18) chemistry is a series of 2,4,5,6-tetrasubstituted-phenyl pyrazoles 89 (Fig. 3.23) from Ishihara Sangyo Kaisha [96]. These compounds differ from previous phenyl pyrazoles in that they have substituents at the 6 position of the phenyl ring. Pre-emergence application of 89 provided 100% control at 63 g-a.i. ha of barnyardgrass, crab-grass, green foxtail, redroot pigweed, prickly sida, and velvetleaf Soybean was reported to have 20% injury for compound 89 at this rate of application. 

Multisubstituted pyrazoles commonly are difficult to prepare with conventional methods. The synthesis of a variety of high diversified tri- and tetrasubstituted... 

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