5- Substituted pyrazolo pyrimidine

At the same time, the cyclization of N-( 1 -substituted 3-pyrazolyl)amino-methylenemalonates (1104) by refluxing in a 1 4.4 mixture of polyphos-phoric acid and phosphoryl chloride for 30 min gave 1-substituted pyrazolo[l,5-u]pyrimidine-6-carboxylates (1105) in good yields (83GEP-3309432). 

Plenty of biological activities have been attributed to derivatives of ring systems 1-50 in the patent and published literature. New substituted pyrazolo[4,3- pyrimidines have been synthesized and claimed to be useful for treatment of male erectile dysfunction due to the inhibitory action they exerted on phosphodiesterase enzymes <1998EPP995750, 2000USP6066722>. Diverse biological activities have been attributed to pyrazolo[3,4-, pyrimidines... 

JHC247 75CJC119). This approach was used to synthesize several substituted pyrazolo[l,5-a]pyrimidines (35) (63YZ745 73GEP2257547). 

Several other syntheses of differently substituted pyrazolo[3,4-r/]-pyrimidines from 5-aminopyrazoles have been reported (83CB1547 83JPR41). The most interesting are summarized in Scheme 2 (74ZOR1088 76IJC(B)688 82OPP403). 

Similar to haloazoles and haloazines, 7-halo-substituted pyrazolo[l,5-a]-pyrimidine underwent nucleophilic substitution with a variety of nucleophilic reagents to yield substituted pyrazolo[l,5-a]pyrimidines (74GEP2343702 76JAP761789 83AP697). Thus, 7-chloropyrazolo[l,5-a]pyrimidines 228, generally prepared from the 7-oxo derivatives 227 and phosphorus oxychloride, are converted into the 7-thioxo derivative 229 by the action of thio-... 

Similarly N-1 glycosylation of a variety of substituted pyrazolo[3,4-d]-pyrimidines was reported (74JHC1033 82JMC1040 83MI1). Unexpectedly, glycosylation of 253 affords the N-2 glycosyl derivative as a major reaction product (83M11). 

Substituted pyrazolo[l,5-a]pyrimidines are selective inhibitors of adenosine 3, 5 -Cyclic monophosphate (CAMP) phosphodiesterases in vitro (74JMC645 75JMC460). 

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. 

This high-pressure methodology was later used by several groups, e.g., for the preparation of 4-(dimethylamino)pyridine (DMAP) derivatives [91] and oligoanilines [92]. More intriguingly, the synthesis of enantiomerically pure C-6 substituted pyrazolo[3,4-d]pyrimidines 147 has been performed by SNAr reaction of 4-amino-6-chloro-l-phenylpyrazolo[3,4-d]pyrimidine (145) under high-pressure conditions at ambient temperature. Conventional synthetic conditions (reflux at 0.1 MPa) were unsuccessful. The S enantiomer displayed higher affinity and selectivity for the adenosine Al receptor than the R enantiomer (Scheme 40) [93]. 

H, C, and NMR chemical shifts of 10 substituted pyrazolo[l,5- ]pyrimidines 40 were assigned based on double quantum filtering (DQF) H, H correlation spectroscopy (COSY), pulsed field gradient (PFG) H, C... 

Aldehydes, arylideneanilines, carboxylic acids and orthoesters have been used as one-oarbon units for binding the two amino functions of 4-amino-l-alkyl-3-propylpyrazole-5-oarboxamide to give l,6-dihydro-pyrazolo[4,3-<7]pyrimidin-7-ones <05MC619 05JHC751>. A modified efficient synthesis of variably substituted pyrazolo[4,3-<7]pyrimidm-7-ones has been described using a pyrazole-5-carboxylic acid, which was selectively brominated at position 4 and then converted into the carboxamide. Microwave irradiation gave better yields in the conversion of the carboxamides to pyrazolo[4,3-J]pyrimidinones <05JHC1085>. 

Standard procedures have been used to synthesize 1-deazaguanosine and 1 -deaza-6-thioguanosine. The latter compound and its 6-methylthio-analogue have also been synthesized by another group. The ribonucleosides of 7-substituted pyrazolo [4,3-f/]pyrimidines, (20) and (21), have been prepared by... 

Frizzo CP, Martins MAP, Marzari MRB, Campos PT, Claramunt RM, Garcia MA, Sanz D, Alkorta I, Elguero J (2010) Structural studies of 2-methyl-7-substituted pyrazolo[l,5-a] pyrimidines. J Heterocycl Chem 47 1259-1268... 

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). 

Bromo-4-chloro-lH-pyrazolo[3,4-d]pyrimidine could be easily fimc-tionalized at C-3 and C-4 in a one-pot two-step microwave-assisted process (Scheme 34) [55]. Ding and Schultz reported that nucleophilic substitution of the addition-elimination type at the C-4 position with amines and anilines smoothly occurred under acidic conditions in dioxane upon irradiation... 

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