Pyrazolo pyrazoles

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). 

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, 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)... 

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. 

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). 

Cyclopent-2-en-l-one, 2-hydroxy-3-methyl-synthesis, 3, 693 Cyclopentenone, 4-methoxy-formation, 1, 423 Cyclopenthiazide as diuretic, 1, 174 Cyclopent[2,3-d]isoxazol-4-one structure, 6, 975 Cyclophane conformation, 2, 115 photoelectron spectroscopy, 2, 140 [2,2]Cyclophane conformation, 2, 115 Cyclophanes nomenclature, 1, 27 Cyclophosphamide as pharmaceutical, 1, 157 reviews, 1, 496 Cyclopiloselloidin synthesis, 3, 743 Cyclopolymerization heterocycle-forming, 1, 292-293 6H-Cyclopropa[5a,6a]pyrazolo[l,5-a]pyrimidine pyrazoles from, 5, 285 Cydopropabenzopyran synthesis, 3, 700 Cyclopropachromenes synthesis, 3, 671 Cyclopropa[c]dnnolines synthesis, 7, 597 Cyclopropanation by carbenes... 

Pyrazolo[3,4-c]pyrazole, tetrahydro-rearrangement, 5, 250 Pyrazolo[4,3-c]pyrazole, tetraaryl-electrophilic substitution, 6, 1035 oxidation, 6, 1034-1035 reduction, 6, 1035 vacuum pyrolysis, 6, 1035 Pyrazolo[ 1,2-n]pyrazole-1,5-diones synthesis, 6, 991 Pyrazolo[ 1,2-n]pyrazoles reactions, 6, 1038 ring opening, 6, 983... 

Beeause of the mueh lower reaetivity of the diazonium salt with respeet to the Riehter eyelization, the same sequenee eould also be earried out starting with aminopyrazole 88 (R = Ph). The azodiazonium salt 89 (R = Ph) was thus obtained by sequential diazotization and neutralization of the resulting mixture at 5-10°C. The salt 89 (R = Ph) eould be smoothly eyelized in boiling ethanol in the presenee of triethylamine to afford the pyrazolo[4,3-c]pyrazole 90 (R = Ph) [96MC190 99JCS(P1)3721]. 

Cyclization of pyrazole 220 (R = NH2), obtained from the reaction of 2-nitophenylhydrazine with 219 and subsequent hydrogenation, gave (81USP4260751) pyrazolo[l,2-al[l,2,4]benzotriazines 221, a useful antiinflammatory agent (Scheme 49). 

Amino-4-arylazopyrazole 338 reacted with benzoyl isothiocyanate to give the expected pyrazol-5-ylthioureas 339, which on heating with acetic acid-hydrochloric acid afforded (76JOC3781) pyrazolo[3,4-e][l,2,41-... 

Pyrazolo[l,2-a]pyrazoles give 3-bromo products unless the 3-position is blocked by a methyl when bromomethyl products arise (80JA4983 81JOC1666, 87JOCI673). When all of the pyrazole ring positions are filled by phenyl groups, chlorination and bromination occur in thepara-positions (74BCJ946) (see also B, 1,2). 

Bromination of pyrazolo[2,3-c][l,2,4]triazines (179) occurred only in the pyrazole ring (83AP697). 

Scheme 12.28 Synthesis of pyrazolo[l, 2-a]pyrazoles from azomethine ylides.

Heteroaromatic diazonium salts can also be used for Gomberg-Bachmann aryla-tions. Fukata et al. (1973) refluxed 3,5-dimethyl-4-diazopyrazole (10.27) in benzene and obtained 3,5-dimethyl-4-phenylpyrazole (10.28, 36%), biphenyl (10.29, 17%), 3,5-dimethylpyrazole (10.30, 12%), and pyrazolo[4,3-c]pyrazole (10.31, 15%). In nitrobenzene the three isomeric 3,5-dimethyl-4-(nitrophenyl)-pyrazoles were formed in the ratio o m p = 10 3 3. In the opinion of Fukata et al. this ratio and the course of the reaction indicate a homolytic process. The present author thinks that the data do not exclude a competitive heterolytic reaction with the pyrazolyl cation, because equal amounts of substitution of nitrobenzene in the 3- and 4-positions are not typical for a homolytic aromatic substitution. 

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. 

---