Pyrazolo pyridine ring

No halogenations of the pyrazolo[4,3-c]pyridine ring system have been reported. 

Substitution of two carbons in position 2,3 of the pentadienyl anion (see Section 6.1) creates a type 2,3 system. Such molecules are the dihydropyrazolo-pyridines (DHPP) 42.50 51 The 1,3 dipolar cycloaddition reaction, which is so effective as a method for synthesizing five-membered rings, can also be used to prepare spiroheterocyclic compounds of the 2,3 type. If a suitable bromo-substituted dibenzopentafulvene is reacted with pyridine the pyrazolo-pyridine 42 is formed in 30-90% yields (Scheme 18). 

The structures of several compounds containing the pyrazolo[l,5-a]pyridine ring system have been established by x-ray crystallography <90CPB2667,91TL4977,94AJC99l>. 

The reaction of 1-aminopyridinium iodide (429) with dimethyl chlorofumarate in ethanol/K2C03 to form, ultimately, a pyrazolo[l,5-n]pyridine also occurs via a 1,5-dipolar mechanism. The initially formed 1 1 adduct (430), stabilized by delocalization of the negative charge, underwent disrotatory ring closure as shown to give (431) in which the 3... 

Ring-methylated 1-ethynylpyrazoles were similarly obtained as minor produets in the pyrolysis of 3,5-dimethyl- and a mixture of 3- and 5-methyl- 1-propynoylpyrazoles. Pyrolysis of the 3-methyl derivative gave only pyrazolo[l,5-a]pyridin-5-ol... 

Pyrazole derivatives are very reluctant to participate as dienes in Diels-Alder cycloadditions that involve the pyrazole ring, because of the loss of aromatic character during the process [79]. Microwave irradiation under solvent-free conditions, however, induces pyrazolyl 2-azadienes 96 to undergo Diels-Alder cycloadditions with ni-troalkenes 97 and 98 in 5-10 min to give good yields of pyrazolo-[3,4-b]-pyridines (Scheme 9.29) [80], Under the action of classical heating only traces of the corresponding cycloadducts were detected. 

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 7V-(5-unsubstituted pyrazol-4-yl)aminomethylenema-lonates (898) in boiling Dowtherm A for 15 min gave l//-pyrazolo[4,3-b]pyridine-6-carboxylates (899) in 56-88% yields [76JCS(P1)507 77JAP(K)77086], but N-( 1,5-dimethylpyrazol-4-yl)aminomethylenemalo-nate (900) afforded 2//-pyrazolo[4,3-/j]pyridine-6-carboxylate (901) in 65% yield under similar conditions [76JCS(P1)507]. 

The ring closure of N-(pyrazolo[3,4-/>]pyridin-5-yl)- and N-(pyra-zolo[4,3-h]pyridin-6-yl)aminomethylenemalonates (997and 999) in boiling Gilotherm for 10 min gave the angular tricycles (998 and 1000) in 75% and 54% yields, respectively (81 Mil). 

The ring closure of (V-(l-substituted 3-pyrazolyl)aminomethylenemalo-nates (1104, R = Me, Et, R1 = H) by heating in diphenyl ether at 220°C for 30 min afforded 2-substituted pyrazolo[3,4-b]pyridine-5-carboxylates (1105) in 67-71% yields (76GEP2617157 77GEP2646670, 77USP-4038281, 77USP4038283). 

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. 

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 . 

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>. 

The acylation of a series of pyrazolo[3,4-c]pyridines has been studied.110 Acetic anhydride in refluxing benzene converted S-substituted derivatives to 1-acyl compounds (101 R2 = H), whereas the 7-methoxy derivative afforded the 2-substituted product 102 (R1 = H, R2 = OMe), attributed to peri interaction. In the absence of solvent, however, the latter reaction gave the 1-acyl isomer as the major product. Furthermore, benzoylation of the 5-chloro bicycle furnished a mixture of 101 and 102 (R1 = Cl, R2 = H). However, products benzoylated mainly at N-6 were obtained following introduction of a nitro group into the pyrazole ring. 

In addition to ring syntheses, amines have also been obtained by hydrogenation of a 3-nitro substituent in 5-methylpyrazolo [4,3-h]- (92%)1U and -[3,4-c]pyridines.110 In the pyrazolo [3,4-h]pyridine series, decarbonylation of a carboxamido232 group (Br2-NaOH) or hydrolysis of an acid azide74 gave 5- and 4-amino derivatives, respectively. 

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