Pyrazolo pyridines, synthesis from

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>. 

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

D. Synthesis of Reduced Pyrazolo[3,4-c]pyridines 1. From 3-Piperidones... 

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. 

Saleh et al. [102] developed novel, simple, and efficient methods for the synthesis of pyrimido[l,2-fl]benzimid-azoles and pyrazolo[3,4-b]pyridines (131) from amino azoles (128), aldehyde (129), and p-ketosulfone (130) under ultrasonic irradiation (Scheme 33). The reaction was proposed to proceed via utilization of p-ketosulfone as a main synthon. The ultrasound reaction in ethanol was inefficient at catalyst-free condition and produced only 29% of the product after 90 min. Yields were 87-92% in 10-15 min and 81-97% in 30-60min for pyrimido[l,2-a]benzimidazoles and pyrazolo[3,4-b]pyridines, respectively, xmder the optimized conditions. 

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. 

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. 

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>. 

The Skraup reaction has been applied to the synthesis of pyrazolo[4,3-h]-pyridines (cf. Section II,A,8) but is limited, because of the vigorous conditions involved, to the preparation of alkyl- or phenyl-substituted derivatives. Thus under Skraup conditions 185 (R2 = H) furnished a moderate yield of 1-phenyl products (186, R1 = H,Me),4,89 which were assigned, using UV spectroscopy.4 Attempts to form the 2-substituted isomer from the 5-sub-stituted 4-aminopyrazole 185 (R1 = H R2 = Me) were unsuccessful.4... 

Quiroga et al. [15] proposed a simple microwave-assisted, one-step, three-component methodology for the synthesis of pyrazolo [3,4-b]pyridine-spiro cycloalkanediones from 5-aminopyrazole derivatives (vi). 

Anthranil amide is also readily cychzed with carbon disulfide in pyridine to l,2,3,4-tetrahydroquinazolin-4-one-2-thione (XXXVII, m.p. 282° C) 159). Using a -amino thiocarbonamide instead of a -amino carbonamide yields condensed l,2,3,4-tetrahydropyrimidine-2,4-dithio-nes. An example is the synthesis of 4,5,6,7-tetrahydro-lH-pyrazolo-[3,4-d]pyrimidine-4,6-dithione (XXXVIII m.p. >26O°C) from 4-thio-carbamoyl-5-aminopyrazole 159). 

Pyrazole and fused heterocychc systems such as dipyrazolo[3,4-l> 3 4 -material chemistry. Sackus, Holzer, and coworkers have developed a new copper-free tandem cycHzation for the synthesis of pyrazolo[4, 3h3,4]pyr-ido[l,2-ii]perimidine 71 from 5-alkynylpyrazole-4-carbaldehydes 69 and 8-naphthalenediamine 70 (2015T(71)3385). They have found that conventional heating of the 5-aIkynylpyrazole-4-carbaldehydes 69 with... 

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