Pyrazolo pyrimidines reactions

Chloro, 3-bromo, 3-iodo, and 3-nitro derivatives of 5,7-dimethyl-pyrazolo[l,5-a]pyrimidine derivatives were prepared by chlorination, bromination, iodination, and nitration of 3-unsubstituted 5,7-dimethyl-pyrazolo[l,5-a]pyrimidines. Reaction with bromine and potassium thiocyanate gave a 3-thiocyanato derivative, which was converted into the mercapto derivative upon saponification. Nitrosation gives the 3-nitroso derivative and acylation with trifluoroacetic anhydride affords the trifluoroacetyl derivative (74JMC645 77JMC386). 

One final interesting preparation of pyrimido[5,4-ring transformation of pyrazolo[4,3-d]pyrimidines. Reaction of the A-oxides (272) with sodium ethoxide in.refluxing ethanol leads to the isolation of l,3-dimethyl-6-substituted pyrimido[5,4-[Pg.365]

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... 

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). 

A series of interesting pyrazolo[3,4-(f pyrimidine derivatives was obtained by a thermal denitrocyclization reaction of hydrazones, e.g. 164 or 166, easily formed from the corresponding aldehyde or ketone hydrazones with halo-nitrouracil derivatives, e.g. 163 (71CC1442, 72CC298). Intermediates 164 or 166 can be isolated and their cyclization in suitable solvents (methanol, DMF, DMSO) provided high yields of the products. Aldehyde hydrazones yielded the corresponding l,7-dihydropyrazolo[3,4-J]pyrimidines, e.g. 165, whereas ketone hydrazones gave l,5-dihydropyrazolo[3,4-pyrimidine derivatives, e.g. spirocyclic compound 167 (Scheme 26). 

The pyrimidines 62 undergo cyclisation on refluxing in dioxane to yield not only the pyrazolopyrimidines 63, but the novel pyrazolo[3, 4 4,5]pyrido[2,3-rflpyrimidines 64 by an intramolecular 1,3-dipolar cycloaddition reaction (Scheme 9)<96JCS(P1)1999>. 

The inverse electron demand reactions of 2,4,6-tris(ethoxycarbonyl)-1,3,5-triazine and 5-aminopyrazoles to provide a one-step synthesis of pyrazolo[3,4-. 

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>. 

Microwave-assisted regiospecific shyntesis of 2-trifluoromethyl-7-trihalomethylated pyrazolo[l,5-a]pyrimidines has been reported <06MI358>. A one-step synthesis of pyrazolo[ 1,5-a]pyrimidine via an intermolecular aza-Witting reaction has been achieved <06JHC523>. 

Pyrazolo[5, l 3,4][l,2,4]triazino[5,6-d]pyrimidine 720 was prepared (89JHC853) by reaction of 716 with formamide. Treatment of 716 with aromatic amines gave 717, whose cyclization with triethyl ortho-... 

An efficient one-pot synthesis of some novel azolo[l,5-a]pyrimidines, via enaminonitriles, has been described <00SC1985>. The utility of 3-aminocinnamonitrile in the synthesis of new pyrazolo[l,5-a]pyrimidines has been reported <00ZN(B)321>. The synthesis of novel arylaminopyrazolo[3,4-d]pyrimidin-4-ones has been described <99IJC(B)1075>. The synthesis and properties of a-Thiagra, a substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra, have been described <00H(53)2643>. Imidazo[4,5-b]pyrazines are obtained by the reaction of 4-amino- 5-imino-imidazole derivatives with acetophenone dimethylacetal . 

Both amino groups of 3,5-diamino-4-phenylpyrazole reacted with EMME during 2 min. at reflux [83JCS(P1)11], The amino group at position 3 underwent a cyclocondensation reaction to form the bicyclic pyraz-olo[l,5-a]pyrimidine, while the amino group at position 5 participated in an addition reaction to give a (2,2-diethoxycarbonyl-l-ethoxyethyl)amino side-chain. Pyrazolo[l,5-a]pyridine (25) was obtained in 27% yield. 

Pyrazolo[l,5-a]pyrimidine-6-carboxylates (1402) were prepared in 70% yields in the reaction of 3-aminopyrazoles and diethyl amino(trichloro-methyl)methylenemalonate in boiling ethanol in the presence of sodium ethoxide for 6 hr (78JPR533). 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

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)... 

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 reactivity of amino functions on diazotization and condensation with dimethylformamide dimethyl acetal has been discussed in CHEC-II <1996CHEC-II(7)431>. The diamine 220 is readily converted into a variety of tricyclic pyrazolo[3,4-r/ pyrimidines under a variety of conditions <2004T5093>. Thus with chloroacetyl chloride the chlor-oacetyl derivative 221 was formed. This could not be further cyclized into 222. Refluxing 220 with diethyl oxalate afforded 223 while 224 was formed when the reaction was conducted at 40 °C. Treatment of 224 with POCI3 afforded 223. Reacting 220 with carbon disulfide afforded 225 (Scheme 14) <2004T5093>. 

Ready formation of pyrazolo[3,4-4 pyrimidines from reaction of 5-aminopyrazole -carboxylic acid derivatives is a well-established route to derivatives of this ring system. A recent application is the conversion of 286 into 288 by reaction with formamide and NIS 287 (Equation 40) <2002BML1687>. 

Several pyrazolo[3,4-rf pyrimidine derivatives were prepared via reaction of 289 with reagents that can furnish an N-C fragment, for example, urea, thiourea, and formamide <2002BML1687>. 

Reaction of 5-amino-l-phenyl-177-pyrazole-l-carboxamide with aromatic aldehydes in the presence of heteropolyacid Hi4[NaP5W3oMoOio] gave derivatives of 6-aryl-l-pyrazolo[3,4-t/]pyrimidin-4-[5//]ones <2006MI1>. 

Ethyl 5-aminopyrazole -carboxylates are converted into pyrazolo[3,4- / pyrimidines via condensation with Ph3P/Bt2 subsequent reaction with an arylazocyanate and further reacting two carbodiimide with amines. Yields ranged from 13 to 65% dependant on the substituent <2006MI1584, 2007BMCL2203>. A similar approach was used for synthesis of triazolo[4,5- / pyrimidine-7(6)ones from ethyl 4-aminothiazolo-5-carboxylates <2007MIxx>. 

Reaction of 12 (R = OH, R = H) with j -keto esters also depends on the reaction conditions. Generally acid media favor the formation of pyrazolo-[1,5-fl]pyrimidines 34, whereas pyrazolo[3,4-h]pyrimidines 33 are formed in basic media (56USP2735769 61G973 79MI2 81MI3). 

The enaminonitriles 55a and c react with 12 in refluxing pyridine to give 59a and b. In contrast, 12 and 55b react in acetic acid to give the oxa-zinopyrazolo[l,5-a]pyrimidines 60. It is assumed that the amino function in 12 adds to the activated double bond in 55 to yield the intermediate adduct 56, which loses chloroform to yield 57. This cyclizes under basic conditions to yield 59a and b. In acetic acid, the 58 that is formed is converted under the reaction conditions to the oxazino[4,5 5,6 ]pyrazolo[I,5-a]pyrimidine derivative 60 (77ZN(B)I478). 

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