Pyrazolo -7 , preparation

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. 

However, there are differences between o-phenylenediamine and 4,5-diaminopyrazoles in the synthesis of [5.5] systems. For example, the formation of pyrazolo[3,4-d]-[l,2,3]triazole (550) is similar to that of benzotriazole, but all attempts to extend the synthesis of benzimidazoles to the preparation of the imidazo[4,5-c]pyrazole system (551) have failed (78TH40400). 

Pyrazolo[3,4-d]pyridazines (555) can be prepared readily from hydrazines and pyrazoles substituted in positions 4 and 5 with an acyl and an ester group, or with two ester groups. 4,5-Pyrazolinediones have been used as starting materials for the synthesis of the quinoxaline derivatives (548) (see above) and of pyrazolo[3,4-e][l,2,4]triazines (556)... 

Pyrazolopyridines isomeric to those described previously have been obtained by other methods. Thus, the derivative (558) was formed by Raney nickel reduction of the 4-nitrosopyrazole (557) (7UHC1035), and the pyrazolo[3,4-c]pyridine derivative (560) was prepared from the azide (559) (79CC627). 

A heterocyclization involving the N-2 atom of indazole affords [l,2,4]triazino[4,5-h]-indazoles (561) from the 3-carbohydrazinoindazole (78JHC1159,79JHC53). The corresponding pyrazolo[l,5-tf][l,2,4]triazine (562) has been prepared by the same procedure (8UHC1319). 

Some tricyclic systems have been prepared by intramolecular cyclization from A-aryl-pyrazoles carrying substituents both in the pyrazole ring at C-5 and in the phenyl ring at the o-position. Thus pyrazolo[l,5-n]quinazolines (563) (69JHC947) and pyrazolo[l,5-n]-[l,4]benzodiazepines (564) (77JHC1163, 77JHC1171) can be prepared from suitable precursors. 

The Pschorr reaction has been employed successfully in the preparation of a pyrazolo[3,4-cjisoquinoline derivative (565) (78JHC1287). 

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). 

Pyrazolo[4,3-e][l, 2,4][triazines 365 were prepared (80JHC209) by treatment of 4-bromo-3-phenylpyrazol-5-ylhydrazonyl chlorides 364, obtained from 363, with hydrazine or phenylhydrazine. It should be noted that the reaction of 3-phenylpyrazol-5-ylhydrazonyl chloride gave (77JHC227) pyrazolo[l,5-c][l,2,4]triazine (Scheme 79). 

Pyrimido[5, 4 4,5]pyrazolo[3,2-c][l,2,4]triazine derivatives 1049and 1050 were prepared by treatment of diazo compound 1048, prepared from 1047, with pentane-2,4-dione and ethyl acetoacetate, respectively [92JCS(Pl)239]. 

The first microwave-assisted hetero-Diels-Alder cycloaddition reaction was described by Diaz-Ortiz and co-workers in 1998 between 2-azadiene 198 and the same electron-poor dienophiles as for the preparation of pyrazolo[3,4-b]pyridines 200 (Scheme 72) [127]. These dienes reacted with... 

Tricyclic pyrazolo-quinolines 239 were prepared from /1-chloro arylalde-hydes and hydrazine derivatives under microwave irradiation with an acid support [156]. The method, appHed to a series of tricyclic compounds (Scheme 89), can be used, in principle, also for the synthesis of bicycHc and even monocycHc pyrazoles. 

Novel thieno[2,3 3,4]pyrazolo[l,5-a]pyrimidines and triazines 58 can be prepared by reacting the thienopyrazoles 57 with 1,3-biselectrophiles <95MI02 96CA(124)176031>. 

Pyrazolo[l,2- ][l,2,4]triazolo[3,4-f][l,2,4]benzotriazines 485-487, containing the title substmcture, can be prepared by application of a well-known strategy using 1,3-dipolar cycloaddition to suitable azomethine imines... 

A library of fifteen 6,7,9,9a-tetrahydro-57/-pyrazolo[l,2-tf]pyrrolo[3,4-ir]pyrazole-l,3,5(2/7,3a7/)-triones 712 was prepared by combinatorial stereoselective cycloadditions of compounds 320 to A-substituted maleimides. 

Pyrazolo[4,3-e][l,2,4]triazine derivatives have been prepared from oximes of 5-aryl- and 5-formyl-l,2,4-triazines <06MI191 >. Novel pyrazolo[5,1 -c][ 1,2,4]triazines incorporating an Af-(2-oxoethyl)phthalimide moiety have been reported <06JCR(S)6>. 

A test library with three novel p38a inhibitory activity has been prepared, among them pyrazolo[3,4-c/]pyrimidine and pyrazolo[3,4-h]pyrazine with potent in vivo activity <06BMCL262>. A convenient route for the synthesis of pyrazolo[3,4-<7]pyrimidine involving Friedlander condensation of 5-aminopyrazole-4-carbaldehyde with formamide or benzamide has been reported <06JHC1169>. A facile synthesis of pyrazolo[3,4-<7]pyrimidines and pyrimido[4,5-<7]pyrimidin-4-one derivatives has been published <06SC2963>. 

Structurally related sets of triazinoquinoline, triazinoisoquinoline and pyridotriazine derivatives have been synthesized and their binding to benzodiazepine receptors studied <06EJM445>. Pyridazino[3 ,4 3,4]pyrazolo[5,l-c]-l,2,4-triazines have been prepared and their antimicrobial activity evaluated <06PS809> <06PS2505>. 

This is the first example of a [4+2] cydoaddition involving a pyrazole ring it is a new, interesting, and versatile approach to the preparation of pyrazolo-[3,4-fe]-pyri-dines. 

Pyrazolo[3,2-c]pyrido[4,3- ][l,2,4]triazine oxides704 were prepared by cyclization of the hydrazone derivatives 703 with ethanolic sodium hydroxide. Subsequent reduction of 704 gave 705 (76JPR835). Hydrazone 703 was prepared by condensation of 4-hydrazino-3-nitropyridine with 702. The mass spectral fragmentation patterns for 704 and 705 and their benzo analogues were studied (77ZC142). 

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-... 

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