Pyrazolo pyridine from pyridines

A cycloaddition process involving dipole 22, readily prepared from thiazolidine 21, was reported to produce adducts such as 23 in the presence of sufficiently reactive dipolarophiles <2000T10011>. These adducts furnished substituted pyrazolo[l,5- ]pyridines 24 in fair yields upon further heating and extrusion of sulfur. However, diphe-nylacetylene did not react with dipole 22 (Scheme 10). 

While the alkynyl ketone route occurs under mild conditions, and can provide 4-substituted pyrimidines both substituted and unsubstituted at the 6-position, it cannot provide products substituted at the 5-position. However, this can be achieved by use of an oxidative enone cyclization, as demonstrated by the synthesis of the 3-(5-methylpyrimidinyl)pyrazolo[l,5- ]pyridine 1006 from 1002, where air oxidation of the initial adduct was catalyzed by the addition of palladium on carbon <2003T9001>. 

A range of trifluoromethyl-containing pyrazolo[3,4- ]pyridines have been prepared, in good yield, from the reaction of 4,4,4-trifluoro-3-oxobutanoates with electron-rich amino pyrazoles (Equation 53 Table 29) <2003S1531>. 

The formation of mixtures of pyrazolo[4,3-c]- and -[3,4-c]pyridines from 3,4-dibenzoylpyrazole has been discussed in Section II,C,5.117... 

The formation of pyrazolo[l,5-a]pyridines from diazocyclopentadienes was discussed in Section II,1,4,a The cyclopentanone 261 was converted to the corresponding reduced product 262 upon treatment with dipolarophiles, possibly involving [l,5]-sigmatropic rearrangement of the intermediate spiro adduct.212... 

Diels-Alder cyclizations are thermal reactions, and recent significant developments in the use of microwave irradiation to pyridine synthesis have been reported, including a series of pyrazolo[3,4- ]pyridines from nitroalkenes and pyrazolylimines with reaction times of 5-10min (Equation 115) <2000T1569>. This method appears to be general to this bicyclic class for example, replacement of the substituent on the imine allows for a C-2-unsubstituted pyridine. A range of cyclic and acyclic dienes have also been reported. 

Pyrazolo[l,5-a]pyridines from 1-ammopyridinium salts and carboxylic acid dilorides... 

Hydroxyindazoles. A soln. of 2-(4-methoxyphenyl)-4-phenyl-4-(2,4,6-trinitro-phenyl)-5(4//)-oxazolone in methanol refluxed for 3 h in the presence of a little /7-TsOH - 4,6-dinitro-3-phenyl-l//-indazol-l-ol. Y 78%. F.e. and 6-nitro-lff-pyrazolo 4,3- pyridin-l-ols from the corresponding dinitropyridyl analogs s. M. D Anello et al., Chem. Ber. 121, 67-73 (1988). 

Jiao et al. developed a Cul- and AgCOg-cocatalyzed synthesis of pyrazolo[l,5- ] pyridine derivatives via dehydrogenative annulations of pyridinium ylide and terminal alkynes (Scheme 8.68). Ag2C03 might assist the formation of copper acetylide from alkyne with Cu(I) catalyst. The C(sp)-H bond of alkyne... 

When the 1-position is substituted, 3- and 5-aminopyrazoles react at the C-4 carbon atom, the reactivity of which is enhanced by the amino group. Thus pyrazolo[3,4-Z ]pyridines (545) are obtained either by the Skraup synthesis or from 1,3-diifunctional compounds. Here also aminopyrazolinones have been used instead of aminopyrazoles to prepare (545 R = OH). If 1,4-ketoesters (succinic acid derivatives) are used instead of /3-ketoesters, pyrazolo[3,4-Z ]azepinones (546) are obtained. 

Pyrazolopyridines isomeric to those described previously have been obtained by other methods. Thus, the derivative (558) was formed by Raney nickel reduction of the 4-nitrosopyrazole (557) (7UHC1035), and the pyrazolo[3,4-c]pyridine derivative (560) was prepared from the azide (559) (79CC627). 

Conversions of diazonium salts into halogenated derivatives have been reported for compounds of type 128 and 129 [73JCS(P1)2901 80JCS(P 1)2398], Although some 7-substituted pyrazolo[ 1,5-u]pyridines have been made from the lithiated precursors, no halogeno products have been reported (92JOC5538). 

Diaz-Ortiz and co-workers carried out microwave cycloadditions to synthesize pyrazolo[3,4-A]pyridines, including tricyclic derivative 149 obtained from pyrrole 147 using A-methylmaleimide 148 as the dienophile (Equation 34)... 

An elegant strategy to pyrazolo[l,5-tf]pyridines derivatives in which the six-membered ring is partially or totally reduced relies on the cycloaddition of diazafulvenium methide 37, generated through S02 extrusion from pyrazolo sulfone 38 in refluxing 1,2,4-trichlorobenzene, with various dipolarophiles <2006TL791> (Scheme 14). 

The ring closure of ylides (1391) by heating in boiling xylene for 1.5 hr afforded pyrazolo[l,5-a]pyridine-3-carboxylates (1393) in 14-25% yields [73JCS(P1)2580]. The pyrazolo[l,5-a]pyridines (1393) were probably formed from the intermediate dihydropyrazolo[l,5-a]pyridines (1392) by the formal elimination of ethyl formate. 

As CH-acids in the MCRs with aldehydes and aminoazoles, other classes of organic compounds were used as well. Cyanoacetic acid derivatives, acetoyl(aroyl) acetonitriles, ketosulfones, acetophenones, and other reagents were successfully introduced into these three-component heterocyclizations. For example, synthesis of pyrazolo[3,4-b]pyridine-5-carbonitriles 40 was carried out as the multicomponent treatment of 5-aminopyrazole, aldehyde, and benzoylacetonitriles solvent-free by fusion either in ammonium acetate at 120°C or in boiling ethanol with EtsN (Scheme 17) [69]. The second approach gave the worst results from the viewpoint of yields and purity of the target compounds. 

Pyrazolo[l,5-fc]-l,2,4-triazole 154 " and l,2,4-triazolo[l,5-a]pyridine 156 ring systems were successfully obtained from the corresponding formamidoximes or related ami-doximes 153 and 155, respectively, and acylating agent (TsCl or TFAA) (equations 67 and 68). Similarly, l,2,4-triazolo[l,5-a]pyrimidines were obtained from pyrimidine formamidoximes . 

New pyrazolo[l,5-a]pyrimidine derivatives have been synthesized. These compounds are potent angiotensin-ll receptor antagonists <99CPB928>. Pyrazolot3,4-ri]dihydropyridazinone derivatives have been obtained by the reaction of 5-methyl-4-methoxycarbonyl-3-acetyl-1-phenylpyrazole with different hydrazines <99TL3891>. A direct synthesis of pyrazolo [3,4-b]pyridines 69 from pyrazole 67 and benzothiazole 68, through a Friendlander condensation, has been described <99SC655>. 

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