Annelated Pyrazoles

Imidazoles activated by sulfur functional groups, reactivity of 87-YGK624. 

Synthesis of imidazoles from hydrogen cyanide derivatives 87-AHC(41)1. 

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This strategy is used mostly for the synthesis of annelated pyrazoles in which the second reactant has two electrophilic sites in a 1,3-juxtaposition. Under control conditions, the first synthesis of a 3-aminopyrrolo[2,3-d]pyrazole (129) was realized from ethyl(3-cyano-4,5-diphenyl-pyrrolylthio)acetate (128) (Scheme 18) <91T8243>. The synthesis of the benzothieno[3,2-c]pyrazole (131) occurred as a two-step process with initial SNAr addition of hydrazine to the chloro-benzothiophene 5,5-dioxide (130) (Equation (42)) <74LA1248>. 

For the synthesis of the sequiterpene (— )-cyclocopacamphene (6.112) an elegant application of an intramolecular cycloaddition, forming the annellated pyrazole derivative 6.111 followed by a photolytic azo-extrusion to the cyclopropane, was described by Piers et al. (1971). 

These methods are limited in scope. Direct thiation has been reported for the transformation of vicinal diketones to [3,4]-annelated thiophenes <1996CHEC-II(7)49>. Thionations and selenations of vicinal halomethyl ketones with thioacetamide or iV,iV-diethylselenopropionamide as sulfur and selenium donors, respectively, have also been reported <1996CHEC-II(7)49>. In a recent example, thieno[3,4-f]pyrazoles 160 were readily prepared from aryl 5-bromomethyl-l//-l-phenylpyrazole-4-yl ketones 159 by reaction with thioacetamide (Equation 35) <1998JHC71>. Additionally, an example of an amination cyclization by reaction of 161 with benzylamine to afford pyrrolo[3,4-i/ thiazole 162 has been described (Equation 36) <1998JHC71>. 

In the annelation of pyrazole-3 (or 5)-acetonitriles or -acetic acids, a cyano or carboxamido substituent in the 4-position is necessary to supply the nitrogen atom of the pyridine ring. The majority of reports concern the formation of 2-substituted products. Thus cyclization of the nitriles 142a... 

When n = 2 or 3, such structurally characterized ICC, in the majority of cases, have slightly tetrahedrizated c/.v-planar conformations [100]. The effect of the factor examined is so high that even zinc chelates 882 (M = Zn, R = Me, X = S, n — 2) show a considerably planar-distorted structure [209]. An analogous structural situation is observed for cobalt, nickel, and copper complexes containing R — cyclo-(C 12)3, annelated aromatic, and pyrazol fragments [100]. When n increases, for example n = 4 in the complexes capable of tetrahedrizating a structure, the influence of the examined factor decreases. This is observed in the ICC not only with X = S [100,210 212], but also for X = NH 222 [187]. 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

Cyclocondensation routes also provide access to pyrimidines. 2,3-Disubstituted pyrido[2,3-/i]-quinazolin-4(3//)-ones are obtained via cyclocondensation of 5-aminoquinoline-6-caiboxylic acid with acid chlorides <02SC235>. 5,6,8-Trialkyl-7-methoxy-2-aminoquinazolines are obtained from 1,3-dimethoxybenzenes via cyclocondensation of intermediate dihydrobenzenes with guanidine carbonate <02TL3295>. Diastereoselective intramolecular hetero Diels-Alder cyclization of a pyrazole carboxaldehyde condensed onto 1,3-dimethylbarbituric acid (101) gave polycyclic heterocycle 102 <02T531>. An efficient one-step synthesis of cyclobutene-annelated pyrimidinones 103 from methyl 2-chloro-2-cyclopropylideneacetate and amidines has been... 

We consider azoles as five-membered heteroaromatic compounds and their annelated derivatives containing at least two endocyclic heteroatoms, one of which is nitrogen (pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, selenazoles, tetrazole, indazole, benzimidazole, benzoxazole, benzothiazole, ben-zoselenazoles, benzotriazole, etc.). 

A new efficient procedure has been proposed for the synthesis of 3-aryl-5-amino-l//-pyrazoles by reaction of a-chloro-/ -arylacrylonitriles with hydrazine hydrate <2004RJ01518>. Reaction of 2-(3,3-dicyano-2-propenylidene)-4,4,5,5-tetra-methyl-l,3-dioxolane 641 with hydrazine afforded 3-(2-hydroxy-l,l,2-trimethylpropoxy)pyrazole 642 (Equation 134) <2003RJ01016>. Treatment of ethyl 3,3-dicyano-2-methoxyacrylate with alkyl, aryl, heterocyclic, and sulfonyl hydrazines led to the synthesis of N-l-substituted 3-acyM-cyano-5-aminopyrazoles, which are versatile intermediates for the synthesis of many biologically active scaffolds <2006TL5797>. 2-Hydrazinothiazol-4(5//)-one reacted with a variety of cinnamonitrile derivatives and activated acrylonitriles to yield annelated pyrazolopyrano[2,3-rf thiazole <1998JCM730>. 

Double bonds of benzene and related aromatic compounds do not react with diazoalkanes in 1,3-cycloadditions. The corresponding benzo-annellated dihydro-pyrazoles such as (1 a,6a)-6,9,9-trimethyl-7,8-diazabicyclo[4.3.0]nona-2,5,7-triene (6.98, R = H) can be synthesized, however, from methyl cyclohexa-l,4-dienecarboxy-late (6.97, R = H), as shown by Klarner et al. (1990). The reduction of the ester group to a methyl group was carried out with di-isobutylaluminum hydride (DIBAL-H), esterification of the OH group with methanesulfonyl chloride and reduction with lithium triethyl borohydride. The second double bond was introduced by bromina-tion with Br2 on a polymeric carrier after Bongini et al. (1980). Cycloaddition with 2-diazopropane in ether at -- 5 °C and the following steps gave 6.98 in a yield of 58%. 

New methods or variations of existing methods for pyrazole synthesis continued to be reported. Notable are several hydrazine-based annelations which afford highly substituted pyrazoles for example, the perfluorinated silyl alcohol (7) with hydrazines affords the tluorinated pyrazoles (8) [94TL(35)409]. In contrast, the ketene dithioacetal... 

Intramolecular (4+2 cycloaddition reactions of pyridazino(4,S-with acetylenic side-chain dienophiles were found to provide convenient access to /-annelated phthalazine derivatives 94JHC(31)3571. Base-catalysed cycli-sation of pyrazoles (11) followed by oxidation was shown to yield cinnoline-4-carboxylic acid l-A/-oxides (13) (93CC1756). 

A great deal of early work on the acidities of the azoles was performed by Catalan, Abboud, and Elguero [348]. They found, for instance, that annelation increases the gas-phase acidity by 5.9-8.2 kcal/mol [349], and carried out early DFT (B3LYP/6-31G ) calculations of the gas-phase acidities [350]. Lopez et al. [351] found that the pK values of pyrazoles and benzazoles display two straight lines when plotted against the oxidation potentials of pentacyanoferrate(II) complexes of these compounds allowing estimates for missing pK, values. 

The synthesis of l-methyl-l,4-dihydro-9H-pyrazolo[4,3-(i]quinoline-9-one 72, inhibitor of protein kinase C, has been performed by means of cyclization of 4-[(4-fluorophenyl)amino]-l-methyl-lH-pyrazole-5-carboxylic acid (Scheme 33) [227]. The main trends in development of research studies in the field of [b]-annelated fluoroquinolones are dealt with use of these compounds for the synthesis of novel [ij]-annelated systems, a varying of substituents at C-7, and also with obtaining of new 2-substituted fluoroquinolones. 

Further annelation to pyrimidine ring based on substitution of fluorine at 5-position was used in patent literature. Alantos Pharmaceuticals in a course of matrix metaUoprotease inhibitors development described an efficient pyrazole annelation to pyrimidine. The synthesis of key intermediate - pyrimidine dicarbox-ylic acid 188 was accomplished in 3 step bromination - carbonylation - oxidation sequence from pyrimidinone 185. The acid was converted to the corresponding... 

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