Pyrazolo pyridines, synthesis

Scheme 72 Solvent-free synthesis of pyrazolo-pyridines...

Reproduoed with permission A Novei Method for the Synthesis of Isoxazolo and Pyrazolo Pyridines Using Hypervaient iodine Reagent A. C. S. Reddy ef al. 1997 Tayior Francis Ltd. 

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. 

Formation of Complex Heterocycles. The C—H activation of pyridine (generally used in excess amount) has enabled the synthesis of more complex heterocycles such as imidazo and pyrazolo pyridines as well as indolizines. Copper metal salt... 

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. 

Pyrazolo[ 1,5-n Jpyridine, 2-hydroxy-tautomerism, 5, 309 Pyrazolo[3,4-6]pyridine, 3-bromo-synthesis, 5, 315... 

Pyrazolo[4,3-6]pyridine, 1-acetyl-synthesis, 5, 339 Pyrazolo[4,3-6]pyridine, 3-nitro-alkylation, 5, 310 Pyrazolo[4,3-c]pyridine, 1-alkyl- H NMR, 5, 308 Pyrazolo[4,3-c]pyridine, 2-alkyl- H NMR, 5, 308... 

Pyrazolo[l,5-a]pyridine-2,3-dicarboxylic acid dimethyl ester synthesis, 5, 153 Pyrazolopyridines acylation, 5, 311 6-fused... 

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. 

In order to introduce substituent variation on the amino group at the pyrazolo[l,5- 7]pyridine 7-position, a modified procedure was investigated where a 7-chloro substituent was carried through the synthesis. However, this procedure was compromised by the fact that dimethylamine displacement of the chlorine also occurred during formation of the enamino ketone 1000, giving the dimethylamino compound 1001 as a major by-product <2003X9001, 2005BMC5346>. 

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>. 

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>. 

The synthesis of pyrazolo[3,4-. ]pyridines can be achieved by reaction of 2,6-dichloro-3-lithiopyridine with 5-bromo-2-methoxybenzaldehyde 138 to provide the alcohol, which after Jones oxidation gave ketone 139. Treatment of the ketone with hydrazine furnished the desired pyrazolo[3,4-3]pyridine 140 (Scheme 8) <2006BML262>. 

A one-pot, two-step synthesis of a wide variety of pyrazolo[3,4-3]pyridines has been reported by Zheng in situ diazo transfer followed by Friedlander cyclization affords good yields of the desired products (Equation 54 Table 30) <2006SC1549>. 

The pyrazolo[3,4-c]pyridine 157 was a key intermediate in the synthesis of 4-deazaformycin A 158 (Equation 57) <2003JOC6466>. Compound 157 was synthesized in good yield by cyclization of the intermediate nitroso compound derived from 159 on treatment with potassium acetate, acetic anhydride, and isoamyl nitrite. This methodology was also applied to the synthesis of deazaformycin B 160 <2002SL1479>. 

Using the same method as for the synthesis of the pyrazolo[4,3-dpyridine 181, Ponticelli and co-workers also prepared the corresponding pyrazolo[3,4-/ ]pyridine 182 (Equation 76) <2003S2518>. 

Synthesis from Acyclic Precursors 10.08.11.1 Pyrazolo[4,3-c]pyridines... 

A new synthesis of the pyrazolo[4,3-r ]pyridine core based on an unusual one-step tandem ring closure and rearrangement of bisacetylenic N-acylated hydrazones using aqueous ammonia has been reported (Equation 81 Table 34) <2004T933>. 

Table 34 Synthesis of pyrazolo[4,3-c]pyridines (Equation 81) <2004T933>...

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