Pyrazolo pyrimidine ring

Move 3] This work surveys complementary routes for the synthesis of pyrazolo[f,5-a] pyrimidine-7-ones 1 and pyrazolo[l,5-a]pyrimidin-5-ones 2. The use of 1,3-dimeth-yluracil 3 as an electrophile for pyrimidine ring construction affords pyrazolo[f,5-a] pyrimidin-5-ones 2, contrary to literature reports. Novel use of trans-3-ethoxyacrylate 4 as an electrophile also afforded 2, and the isolated intermediates from this reaction support our proposed mechanism. (55 words)... 

Cyclization of a 1-substituted 3-amino-5-pyrazolone or its 5-amino isomer produces 2- or 1-substituted pyrazolo[3,4-b]pyridones, respectively. Alternative reaction at N-2 to form a pyrimidine ring has not been reported. 

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]. 

A halogen substituent at C-4 of the pyrazolo[3,4-c ]pyrimidine ring system is readily replaced by active methylene reagents (76S824, 76YZ1352). For example, treatment of the derivatives (207) with active methylene reagents in the presence of sodium hydride results in the formation of derivatives (208) in 70-80% yield (Equation (21)). The methylsulfonyl derivative (209) is converted into the carboxamide (211) when treated with cyanide ion intermediacy of the nitrile (210) seems most likely (Scheme 16) <82JMC1334>. 

The synthetic potential of a novel precursor of 2,6-diaminopurine CDK inhibitors, 2-(benzylsulfanyl)-6-chloro-9-isopropylpurine, has been described <05EJO939>. Novel highly potent adenosine deaminase inhibitors containing the pyrazolo[3,4-c/]pyrimidine ring system have been reported <05JMC5162>. The synthesis of substituted 6-phenylpyrazolo[3,4-c/]pyrimidines as potential adenosine A(A2) receptor antagonists has been published... 

The pyrimidine rings of the pyrazolo[4,3-d]pyrimidin-5-yl C-nucleosides 485 and 486 were formed as a result of cyclocondensation of the P-d-ribofuranosylthioformimidate 230 with 4-amino-3-cyanopyrazole and 4-amino-3-carbamoylpyrazole, respectively. The products were obtained as a mixture of the a- and jS-anomers (75JOC2825 78NJC357) (Scheme 132). Proton spin-lattice relaxation, particularly that of the anomeric proton (HT), proved very valuable for characterizing the two anomers of each of 485 and 486 (77JA3267). 

Intramolecular ring-closure of 6-(thiosemicarbazido)uracils (368) to pyrimido-thiadiazines (369) is achieved in 32—75% yield by oxidation with Af-chloro- or N-bromo-succinimide. On heating the thiadiazines, sulphur is extruded and pyrazolo-pyrimidines (370) are formed (Scheme 142). ... 

The pyrimidine ring was fused to a number of heterocycles with a bridge-head nitrogen when mixtures of enaminones 613 and heterocyclic amines 614, 615, or 616 were subjected to MWI for 10-20min. Thus, pyrazolo[l,5-u]pyrimidines 617, triazolo[l,5-a]pyrimidines 618, or pyrimido[l,2-u]benzimidazole 619 were obtained in 88-95% yields (Scheme 121). Those products required 0.5-6 h heating at reflux in absolute ethanol to give 70-80% yields (04JCR(S)174). 

Holla et al. [13] reported the synthesis of some new pyrazolo[3,4]pyrimidine derivatives and its antimicrobial studies. Replacement of IH of pyrazole of pyrazolo[3,4]pyrimidine ring system by some other bioactive moiety drastically alters its pharmacological properties. Introduction of a fluorine atom as the CF3 group provides a more lipophilically and pharmacologically interesting compound compared to their non-fluorinated analogues. 

The palladium-catalysed reaction of the pyrazolo-pyrimidine derivative (141) with 3-bromotoluene may result in arylation at the 3-position in the pyrazole ring or at an sp hybridized site in the 7-methyl side-chain depending on the base and ligands used. After initial insertion of the palladium catalyst into the aryl halide bond, palladation of (141) occurs by a concerted metalation-deprotonation pathway and is followed by reductive elimination. Concerted metalation-deprotonation is also likely in the palladium-acetate-catalysed reaction of imidazo[l,2-a]pyridines with aryl bromides to give 3-substituted derivatives such as (142). A careful mechanistic study of the arylation of pyridine A-oxide by bromotoluene, catalysed by palladium acetate and t-butylphosphine, has shown that direct reactions of an aryl palladium complex with... 

The 3- or 5-aminopyrazoles are the synthons used most frequently. The second heterocyclic ring is created between the amino group and the 1-position (if unsubstituted) or between the amino group and the 4-position. Thus 3-substituted 5-aminopyrazoles react with 1,3-difunctional compounds to afford pyrazolo[l,5-a]pyrimidine derivatives (538) (Table 34). Aminopyrazolinones (R = OH) can be used instead of aminopyrazoles. Similarly 3-aminoin-dazole yields pyrimido[l,2-h]indazoles (539). 

Pyrazoles can be prepared by ring opening reactions of fused systems already containing the pyrazole nucleus. Thus several [5.5], [5.6] and [5.7] fused heterocycles have been opened to substituted pyrazoles, usually in basic medium. In general, the method has little preparative interest since another pyrazole derivative has usually been used to build the ring-fused system. However, due to the unexpected structures obtained, two publications are worthy of notice. 6//-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine (638) was readily obtained from the corresponding pyrazolopyrimidine by the action of diazomethane at room temperature (Scheme 59) (81H(15)265). When (638) was treated with potassium hydroxide, the pyrazole (640) was formed, probably via the diazepine (639). 

Imidazolopyrimidine 212, formed by reaction of 210 with bromoacetaldehyde 211, undergoes cyclization catalyzed by sulfuric acid to form the five-membered ring of l-phenyl-lH-pyrazolo[3,4-<7]thiazolo[3,2-tf]pyrimidin-4-one 213 in virtually quantitative yield (Scheme 14) <1996BML59>. 

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