Pyrazoles, 4-halo

Several specialized cyclization strategies should not be dismissed. A novel rhodium acetate-mediated cyclization was employed for the first synthesis of 3-methyl-4,6-diphenylfuro[3,4-tf]is-oxazole (9) from the 5-(a-diazobenzyl)isoxazole (185) (Equation (56)). The reactive intermediate is believed to be a carbenoid species <9iCB248i>. Another strategy exploits the reactivity of 4-halo-pyrazol-5-ones (e.g., 186) with stabilized anions (e.g., cyanoacetate esters and nitriles) to afford the 4-cyanofuro[2,3-c]pyrazol-5-ones (187) and 5-aminofuro[2,3-c]pyrazoles (188) (Scheme 30) <84H(22)2523>. Also of interest is the trichloroacetonitrile cyclization of aminopyrazole ketones (189) to the pyrrolo[2,3-c]pyrazoles (190) (Equation (57)) <86S74>. The generality of this cyclization is not known. 

A consecutive three-component synthesis of pyrazoles [67] starting from (hetero)aroyl chlorides, terminal alkynes, and hydrazines represents an excellent entry to more sophisticated one-pot transformations on the regioselectively substituted heterocyclic core. For instance, the catenation of an electrophilic halogenation step led to a one-pot four-component synthesis of 4-halo pyrazoles 36 (halo = chloro or bromo) in good to excellent yield (Scheme 12.24) [68]. 

Indeed, by virtue of the in situ generated 4-halo pyrazole 36 and the presence of the catalytic metal complexes, a sequentially Pd-catalyzed Suzuki coupling was conceived. Upon addition of catalytic amounts of triphenylphosphane, the proper... 

Scheme 12.24 Four-component synthesis of 4-halo pyrazoles 36.

Pyrazole, C-formyl-conformation, 5, 209 Pyrazole, fluoro-reactions, 5, 263, 267 Pyrazole, 4-fluoro-5-hydroxy-tautomerism, 5, 214 Pyrazole, 1-germyl-synthesis, 5, 236 Pyrazole, halo-halogenation by, 5, 54 reactions, 5, 104, 105, 266 reduction, S, 105, 106, 266 Pyrazole, 3-halo-1-phenyl-quaternary salts... 

Propiolaldehyde diethyl acetal has found numerous synthetic applications in the literature which may be briefly summarized. The compound has been utilized in the synthesis of unsaturated and polyunsaturated acetals and aldehydes by alkylation of metal-lated derivatives, " by Cadiot-Chodkiewicz coupling with halo acetylenes, " and by reaction with organocuprates. Syntheses of heterocyclic compounds including pyrazoles, isoxazoles, triazoles, and pyrimidines have employed this three-carbon building block. Propiolaldehyde diethyl acetal has also been put to use in the synthesis of such natural products as polyacetylenes " and steroids. ... 

Merck has recently utilised a furo[2,3-b]pyridine core (554) as a bioisosteric replacement for the pyrazole scaffold of rimonabant (382) [328]. The same basic pharmacophore, that of two halo-substituted aryl groups and a third hydrophobic motif proximal to a hydrogen-bond acceptor, can be witnessed in the benzodioxole-based compounds, such as (555), disclosed by Roche [329]. 

Figure 2.8 Average radius Rav and effective or trispyrazole [22], oxygen atoms of the charge Zf resulting from the REC correction POM series LnW10 and LnW22, [23] and halo-of different homoleptic compounds nitro- genides F , Cl-, Br" anions [21]. genated ligands of the type bis-pyrazole...

A stepwise halogenation of pyrazole and substituted pyrazoles has been carried out via their silver salts. Thus silver pyrazolide yields 4-halopyrazoles and 5-methylpyrazole gave 4-halo-5-methylpyrazole (equation 5).60,61... 

The reaction of gcnt-dihalocyclopropyl acetates with hydrazine and substituted hydrazines provides a synthetic route to pyrazoles. It proceeds via aminolysis of the ester, followed by ring opening of the gcw-dihalocyclopropanoxide to give an a-halo-a,iS-unsaturated ketone. The latter condenses with the hydrazine to form the pyrazole (see Houben-Weyl, Vol. 4/3, p 656). " For example gew-dichlorocyclopropane 26 gave pyrazole 11 ... 

An interesting study reported in 2001, although it did not utilize any inverse-detected 2D NMR data, did report a wealth of useful chemical shift data for parent azoles and benzazoles. Solid-state chemical shift data were reported for several pyrazole analogues by Alvarez-Larena. Trofimenko et al reported a study of the buttressing effects of the A-tert-h xiy group of a series of pyrazoles in the solid state, followed by a study by Claramunt and co-workers of a series of halo triazoles. Martins and co-workers reported data for a series of 5-trichloromethyl-1,2-dimethyl-1/f-pyrazolium chlorides. Malpass and co-workers reported direct observe chemical shift data for a series of bicyclic amines and lactams. Recently, a large body of chemical shift data for a series of l,4-diazaspiro[4.5]decanes and l,4-oxazaspiro[4.5]-decanes using direct observe methods were reported by Ariza-Castolo and co-workers. " Readers with an interest in the chemical shift behavior of these systems are directed to these references as a source of data. 

Amino-1,2-azoles exist as the amino tautomers. Amino-pyrazoles and amino-isothiazoles are relatively well-behaved aromatic amines, for example 3(5)-aminopyrazole undergoes substituent-A-acetylation and easy electrophilic bromination at C-4. Diazotisation and a subsequent Sandmeyer reaction provides routes to halo-isothiazoles and azido-pyrazoles. ... 

On condensation of 4,4-dialkylthiosemicarbazides with a-halo ketones, ring-closure reactions only at Nl, N2, or S as well as subsequent reactions to pyrazoles are possible on account of the double substitution at the amino group.31,32,44 Thus, A, 7V-dialkyl-6//-1,3,4-thiadiazin-2-amines 4 are the exclusive products of these reactions and undergo interesting ring transformations to afford pyrazoles31,32,44 (see Houben-Weyl, Vol. E8b, p 562). 

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