Pyrazolo pyridines, formation

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... 

Deprotonation readily occurs at C-7, and the resulting anion can further react with various electrophiles. Thus, treatment with BuLi at — 78 °C followed by reaction with diiodoethane was used to prepare the 7-iodo derivatives depicted in Table 2, while the 7-chloro derivatives were prepared by lithiation with lithium diisopropylamide (LDA), followed by reaction with CCI4. The 7-formyl derivative of the parent pyrazolo[l,5- ]pyridine has been prepared in 82% yield by reaction of the BuLi-generated anion with ethyl formate <2001JME2691>. 

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. 

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>. 

Table 32 Formation of trifluoromethylated pyrazolo[4,3-c]-pyridines 152-154 (Scheme 10) <200172051 >...

Nitropyridines containing an adjacent bromomethyl substituent react with aromatic primary amines to give pyrazolo[3,4-c]- and -[4,3-6]pyridines. The intermediate secondary amines 98b undergo further reaction at elevated temperatures to afford arylamino derivatives 99 in good yield.108 A mechanism has been proposed for the analogous formation of pyrazolo[4,3-h]-pyridines (Section II,G,1).109... 

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... 

Addition of triethylamine to a stirred suspension of the salt 1 and potassium carbonate in toluene at room temperature resulted in formation of a yellow colour. Addition of 2.5 equivalents of DMAD produced a red colour, and the pyrazolo[l,5-u]pyridine 2 was obtained in 82% yield. 

Chebanov et al. [202] noted that condensation of the unsaturated acids 236 with 5-aminopyrazoles 220-222 never yielded isomers with opposite location of the aryl and carboxyl groups on the pyridine or pyrimidine rings, respectively. In the case of the multicomponent reaction of aminopyrazoles 220-222 with pyruvic acid 239 and aromatic aldehydes a different direction was observed. Refluxing of the starting materials in acetic acid led exclusively to pyrazolo[3,4-Z ]pyridine-4-carboxylic acids 249-251 instead of the anticipated carboxylic acids 243-248 (Scheme 3.69). The three-component procedures led only to the formation of heteroaromatized compounds even under a nitrogen atmosphere [202]. 

In an interesting reaction, the oxazolo[3,4-6]pyridine (598) was converted to the pyrazolo[3,4-6]pyridine (599) (70%) by heating at reflux in a mixture of aniline, ammonium acetate, and glacial acetic acid for 2 h <9lPS(63)ll9>. The authors propose that the reaction proceeds by ring opening of the isoxazole ring by aniline with the formation of a phenylhydrazino intermediate which then cyclizes (Equation (61)). 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

A limited number of examples of C-alkylations of aminopyridines have been reported. With 1-hydroxymethylbenzotriazole (29.3) in the presence of acid, 2-aminopyridine reacts at C-5. 4-Dimethylaminopyridine is trifluoroacetylated at C-3 with trifluoroacetic anhydride the example shows the subsequent intramolecular nucleophilic displacement of the dimethylamino group and thence formation of a pyrazolo[4,3-c]pyridine. °... 

Condensed and other multimembered heterocycles Benzoylacetonitrilehydrazones reacted with TCNE to yield pyrazolo[3,4-Z7]pyridines Pyrazolopyrimidines 403 have been obtained from arylazoaminopyrazoles and TCNE. The first step of the reaction is the formation of a charge-transfer complex". ... 

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