3- -pyrazolo

Pyrazolo(7,4 4,qpyiMdo 2,1-t4tMnzolhiazoM-[Pg.260]

Bielectrophiles have found appreciable applications in the synthesis of ring-fused systems, especially those involving [5,6] fused systems. The following serve to illustrate these applications. Reaction of pyrazole with (chlorocarbonyl)phenyl ketene (214) (Type 1, Scheme 6) readily formed the zwitterionic pyrazolo[l,2-a]pyrazole derivative (215) (80JA3971). With l-methylimidazole-2-thione (216), anhydro-2-hydroxy-8-methyl-4-oxo-3-phenyl-4//-imidazo[2,l-6][l,3]thiazinium hydroxide (217) was obtained (80JOC2474). 

Oxidation of the hydrazone of 2-hydrazinopyrazole (226) with Pb(OAc)4 in CH2CI2 is a two-step reaction. The azine (227) was formed as an intermediate and this underwent ring closure to the 3H-pyrazolo[5,l-c][l,2,4]triazole (228) (79TL1567). A similar reaction applied to the benzal derivative of 2-hydrazinobenzothiazole (229) gave 3-phenyl-[l,2,4]triazolo[3,4-6]benzothiazole (230) together with a by-product (231) (72JCS(P1)1519). 

The 2-thienylthiourea (245) on oxidation with bromine in acetic acid gave the thieno[3,2-djthiazole (247). It has been suggested that the intermediate electrophilic sulfenyl bromide adds to the 2,3-bond of the thiophene ring to form (246) when then loses HBr to give (247) (71AJC1229, 78JHC81). Pyrazolo(3,4- /]thiazoles are formed in a similar fashion (76GEP2429195). 

The reaction of 1-aminopyridinium iodide (429) with dimethyl chlorofumarate in ethanol/K2C03 to form, ultimately, a pyrazolo[l,5-n]pyridine also occurs via a 1,5-dipolar mechanism. The initially formed 1 1 adduct (430), stabilized by delocalization of the negative charge, underwent disrotatory ring closure as shown to give (431) in which the 3... 

Oxidative cyclization of the fully methylated 6-(benzylidenehydrazino)uracils (536) provides a 90% yield of the pyrazolo[3,4-J]pyrimidines (537) (75BCJ1484). 

An interesting application of a phosphorus ylide in heterocyclic synthesis is in a ring annulation. The diazopyrazole (592) when treated with various phosphorus ylides gave the 3//-pyrazolo[5,l-c][l,2,4]triazole derivatives (593) with elimination of triphenylphosphine (79TL1567). 

Dimers of 3-alkoxycarbonyI-5-formyl-5-methyI-A -pyrazoIine 9-Oxo-2a,3,5,6,7,8,8a,9-octahydroindoIizino[l, 2 5,4]pyrazolo- 75AX(B)548, 76AX(B)2216... 

Another possibility is that both nitrogen atoms react with a double alkylating agent. In this way fused pyrazole derivatives (pyrazolo[l,2-a]pyrazoles) like (237) can be obtained by reaction of 3,5-dimethylpyrazole with 1,3-dichloropropane or l-chloro-3-propanol (69BSF2064). More surprising is the reaction with a-chlorocarbonylphenylketene which yields the paraionic compound (238) (80JA3971) which can also be obtained from 3,5-dihydroxy-4-phenylpyrazole and /3-dicarbonyl compounds (82JOC295). 

However, when the molecules are converted into their anions, the cyclic pyrazolo[l,5- fjtetrazole (471) form predominates. It is possible to trap the cyclized anions such as (471) by methylation and to obtain stable azapentalenes (472) and (473). 

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). 

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. 

Pyrazolo[l,5-a]pyrimidine (538) 67CB2577, 70BCJ849, 70JHC247, 74JHC423, 77JHC155,... 

Pyrazolo[3,4-6]pyridine (545) 68AHC(6)347, 67AG981, 68CB3265, 70JHC247,... 

Pyrazolo[3,4-4]pyrimidine (552) 70TL4611, 73JCS(P1)1903, 75JHC1199, 79AP610 76JOC3781,... 

Pyrazolo[3,4-4]pyridazine (555) 69BSF2061, 69JPR1058, 70TL4611, 77JHC375, 77T45, 78JHC813 ... 

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). 

The pyrazole analogues of anthranilic acids or anthranilonitriles are a convenient source of [5.6] fused systems (for a general review see (80T2359)). Thus 5-amino-4-cyanopyrazoles (in some examples an ester or a hydrazido group replaced the cyano group) have been transformed into pyrazolo[3,4-d]pyrimidines (552) and into pyrazolo[2,3-e]diazepinones (553), and 4-amino-5-methoxycarbonylpyrazoles have been converted into pyrazolo[4,3-d]pyrimidines (554). 

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). 

Finally, some results obtained from indazoles substituted in the carbocycle are of interest, even though in these cases the reaction does not involve the heterocyclic moiety (Section 4.04.2.3.2(ii)). For example, pyrazolo[3,4-/]- (566) and pyrazolo[4,3-/]-quinolines (567) have been obtained from aminoindazoles by the Skraup synthesis (76JHC899). Diethylethoxy-methylenemalonate can also be used to give (566 R = C02Et, R = OH) (77JHC1175). Pyrazolo-[4,3-/]- and -[4,3-g]-quinazolones (568) and (569) have been obtained from the reaction of formamide with 5-amino-4-methoxycarbonyl- and 6-amino-5-carboxyindazole, respectively (81CB1624). 

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[ 1,5-n]pyridine electron density, 5, 306 (71JA1887, 72CB388, 74JHC223, 65JHC410)... 

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