3/f-indazoles

Aminoindazole (340) with EP gave a compound having either structure 341 or 342.205 The work of Plescia122 with tetrahydrobenz-pyrazoles (described in Section IV,B,2) indicates that 342 is correct. 3 Diazo-3/f-indazole (343) with DMAD regenerated indazole.206... 

In some cases the indazole and spiroindazole route did not lead to isolable cycloproparenes. Thus, the attempted synthesis of a 1,1-diphenylbenzocyclopropene or 1-phenylbenzocyclo-propene-l-carbonitrile by this route resulted instead in isolation of fluorene derivatives. The photolysis or pyrolysis of spiro[fluorene-9,3 -3//-indazole] gave fluoradene (4b//-indeno-[l,2,3-y, ]fluorene) as the major product (80%). The cycloproparene, spiro[17/-bcnzocyclo-propene-l,9 -fluorene], although formed as a reaction intermediate, was not isolable. Similarly, the thermolysis and photolysis of 9,10-dihydrospiro[anthracene-9,3 -3 /f-indazole]-10-one gave spirocycloproparenes as (non-isolable) reactive intermediates. ... 

Free Electron Molecular Orbital method colour and constitution, 1, 342 Freelingyne occurrence, 4, 706 Free radical processes in photography, 1, 387-389 Friedlander synthesis quinolines, 2, 443 thioindigo dyes, 4, 910 Fries rearrangement chroman-4-one synthesis from, 3, 850 Fructose, 1-deoxy- C NMR, 4, 575 Frusemide as diuretic, 1, 174 metabolism, 1, 245 FS-32 — see 1/f-Indazole, l-[3-... 

Few heteroaryl-substituted 37/-azepines are known however, photolysis of 2-(2-azidophenyl)-pyridine (80) in diethylamine provides Ar,Ar-diethyl-3-(2-pyridyl)-3/f-azepin-2-amine(81), along with minor amounts of pyrido[3,2-6]indole (82) and the mesoionic pyridofl, 2-7>]indazole (83).191... 

Indazolinone exists as such (227) in the solid state but only as a minor isomer (15%) in DMSO solution, where the 3-hydroxy-17/-indazole tautomer (228) predominates (85%) (86JCS(P2)1677). No evidence for the existence of 3-hydroxy-2 f-indazole (229) has been found. 

Pyrazin 3-Amino-2-cyan-5-(2-furyi)-E9b/2, 31 If. (N-Oxid-Red.) lH-Pyrazol 4-Diazo-5-oxo-3-phenyl-4,5-dihydro- X/4, 525/ El4b, 1114 (Amin 4- NaN02) lH-(Pyrimido 5,4-f]indazol) 5(bzw. 9)-Hydroxy- E8b, 849 (Pyrimidin-Ringschl.)... 

Amino-3-methoxy-2-(3-pyridyl-methylen-amino)-E15/2, 1809 [(NC)2CH-NH2 + R-CHO] Azetidin 3-Azido-4-(4-methyl-phenyl)-2-oxo- E16b, 371 (Nj-C-CO-Cl + Imin) Furazan 4-(Anilinomethylen-amino)-3-methyl- E8c, 673 (NH2 -> N=CH —NH —Ar) Hydrazin l,2-Bis-[2-pyrrylme-thylen]- -1-oxid X/2, 121 1 H-(Imidazo 1,2-a]-l,3,5-benzotriaze-pin), 10-Hydroxy-2,3-dihydro E9d, 476 [1 -(2-NH2 — Ar) — 2-imino — imidazolidin/COCl2) Imidazo[4,5-f indazol 5,6-Dimethyl-... 

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-f>]indazoles (539). 

Oxo-2,3-dihydro-1//-indazol-2-yl)niethylene](triphenyl)phosphoranes 9 undergo thermal and/or acid-catalyzed rearrangement to yield quinazolin-4(l//)-ones which more likely exist as 4(3/f)-tautomers 10 and triphenylphosphane. Compounds 9 are, in some cases, isolated as intermediates in a thermal rearrangement of [(aryldiazenyl)methylene](triphenyl)phosphoranes (cf. p72). 

Only three systems belong to this group pyrazole (3), 1/f-indazole (4) and 2//-indazole (isoindazole 5). The fused carbon atoms in indazoles are numbered 3a and 7a. When R = H, annular tautomerism (76AHC(Sl)l) makes the 3- and 5-positions of pyrazoles equivalent and thus the name 3(5)-R-pyrazole means that the compound is a mixture of tautomers with the substituent R in position 3 and in position 5. The same applies to iV-unsubstituted indazoles however, the numbering is identical in both tautomers and thus 3-R-indazole means either (4) or (5) (R or R = H). Since the indazole tautomer is largely predominant (Section 4.04.1.5.1), indazoles are usually represented by the formula (4). 

A heterocyclization involving the N-2 atom of indazole affords [l,2,4]triazino[4,5-f)]-indazoles (561) from the 3-carbohydrazinoindazole (78JHC11S9,79JHC53). The corresponding pyrazolo[l,5-fi(][l,2,4]triazine (562) has been prepared by the same procedure (81JHC1319). 

Photophysical experiments and theoretical calculations have been used to determine the tautomeric equilibrium between IH- and 2/f-indazoles (15a) and (15b) both in the ground (So) and in the excited state (S,) <94JPC10606>. The measurement of sublimation and solution enthalpies in water at 25°C, basicities in the excited state of 1-methylindazole (pAa = 1.61) and 2-methylindazole (pA a = 3.00), and MP2//6-31G //6-31G calculations of the difference in energy between their conjugated acids in the ground state allows the complete thermodynamic cycle to be established. Indazole in the excited state is 3.0 pA a units more acid (pA a = 1108) and 1.8 pK units more basic... 

The structure of indazolinone and some of its derivatives was determined by the combined used of crystallography, C CPMAS NMR, and N NMR <86JCS(P2)1677>. It was concluded that indazolinone exists as such (67a) in the solid state but only as a minor isomer (15%) in DMSO solution, where the 3-hydroxy-l//-indazole tautomer (67b) predominates (85%). The 3-hydroxy-2//-indazole tautomer (67c) has never been observed. The equilibrium between 2-hydroxy-3-methyl-indazole and 1/f-3-methylindazole-2-oxide has been studied in DMSO, methanol, and trifluoro-methanol by C and N NMR spectroscopy <87MRC721>. The position of the equilibrium was found to be dependent on the acidity of the solvent, the hydroxy form being predominant in weakly acidic media. 

Lithiation of 2-alkyl-2/f-indazoles proceeds straightforwardly and thus 3-substituted 2/f-indazoles can be obtained and comparable lithiations of 2-trimethylsilyl-indazoles, followed by removal of the silicon substituent, produce 3-substituted indazoles. 

Die Bildung eines isomeren 1,3-Oxazolo[4,5-f]indazols konntc nicht beobachtet werden. Auch die Umsetzung des 6-Azido-indazols fuhrt ausschlieBlich zur Bildung von 2-Methyl-8 H-(l,3-... 

The 3-(A -acyl-JV-benzylamino-2-(triphenylphosphoranylidene)-amino-2/f-indazoles (228) on treatment with concentrated hydrochloric acid cyclize to 2-alkyl-1-benzyl-l/f-[l,2,4]triazolo-[l,5-h]indazoles (229) (Equation (61)) <90JOC4724>. 

A number of reports detailing the preparation of novel fused thiophenes have appeared including tetrahydrobenzothieno[2,3- /]imidazole 226 , dihydrothieno[3,2-g]indazole 227 and dihydrothieno[3,2-AJquinazoline 228 , benzothieno[2,3-Z7]pyridine 229 , thieno[2,3-f ]thiadiazine 230 , thieno[5,6-fc]thiazin-4-one 231 , tetrahydrothieno[3,4-c]pyrid-4-one 232 , and dihydrothieno[4,3,2- /][1.4]benzoxazepine 233 . 

Ethyl (2E)-3-(dimethylamino)-2-(5-ethoxy-l-phenyl-lH-pyrazol-3-yl) propenoate (36) was prepared in two steps from ethyl (5-oxo-l-phenyl-4,5-dihydro-lH-pyrazol-3-yl)acetate (12) by treatment with ethyl bromide in ethanol under reflux to give ethyl (5-ethoxy-l-phenyl-lH-phenyl-3-yl) acetate (35), followed by treatment with DMFDM A in toluene under reflux. Compound 36 reacted with anilines, methyl glycinate hydrochloride, 3-amino-lf-f-indazole and 3-amino-5-methylisoxazol in ethanol in the... 

Terzidis MA, Tsoleridis CA et al (2008) Synthesis of chromeno[2,3-b]carbazole and chro-meno[3,2-f]indazole derivatives. A new class of indole- and pyrazole-fused polycyclic compounds using o-quinodimethane chemistry. A reactivity and regioselectivity computational study. ARKIVOC 132-157... 

Methyl 3-azido-2-naphthoate refluxed 1 hr. with hydrazine hydrate in abs. ethanol lH-benz[f]indazol-3(2H)-one. Y 44%. M. E. Peek, C. W. Rees, and R. C. Storr, Soc. Perkin I 1974, 1260. 

Also in this field, Larock et al. have described that sydnones 29 undergo [3+2] dipolar cycloadditions with arynes affording 2//-indazoles 30 nndo" mUd reaction conditions. These heterocyclic derivatives are formed by a spontaneons extmsion of CO from the initial cycloadduct (Scheme 12.19) [30]. The same authors have developed a simple route to pyrido[l,2-f>]indazoles 31 via an aryne [3+2] cycloaddition with A(-tosylpyridininm imides and subsequent flnoride-induced elimination of the tosylate anion (Scheme 12.19) [31]. 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

Wang et al. [49] developed a highly regioselective Povarov reaction of an aromatic aldehyde, l//-indazol-5-amine, and methyl 3-oxobutanoate catalyzed by iodine. This novel reaction selectively gave 3/f-pyrazolo[4,3-y]quinolin-9-yl acetates 20, rather than 3//-pyrazolo[4,3-/jquinoline-8-carboxylate derivatives. Further, they [50] also extended the reaction using tetrahydropy ran-4-one instead of methyl-3 -oxobutanoate for the synthesis of 7-aiylpyrano[3,4-c]pyrazolo[3,4-/]quinoline derivatives 21 (Scheme 10.16). 

Baiocchi L, Corsi G, Palazzo G (1978) Synthesis, properties, and reactions of l/f-indazol-3-ols and 1,2-dihydro-3/7-indazol-3-ones. Synthesis 9 633-648. doi 10.1055/s-1978-24840... 

A multitude of similar routes have been reported employing such intramolecular C—N bond formation. A-Tosyl hydrazones have also been established as effective indazole precursors [78] and were utilized in the synthesis of the natural product nigel-licine [79]. 3-Amino- l/f-indazoles were also prepared by similar palladium-catalyzed cyclizations [80]. Generating the appropriate halo-substituted arylhydrazone or aryl-hydrazine in situ has proved a popular tactic and has led to the development of effective one-pot processes [81-85]. 

A (1/7-imidazol-l-yl) silver species (55) has been postulated as the key intermediate in the 3-l-2-cycloaddition reaction of diazoalkanes (54) with benzynes yielding 2-aryl-2H-indazoles (56) (Scheme 18). The 3-I-2-cycloaddition reaction of 3-trifluoromethyl-4-diazopyrazolinones with dialkyl acetylene dicarboxylates, in refluxing toluene, produced spiro 3/f-pyrazole adducts that rearranged to the trifluoromethyl-substituted pyrazolo[l,5-fi(][l,2,4]triazin-7-ones. ° The 1,3-dipolar cycloaddition reaction of aromatic thioketones (58) with 2-aza-1,3-dicarbonyl compounds (57), at 20-50 C, yielded thiadiazoline adducts (59) that readily eliminate nitrogen to produce oxathioles (60) in moderate yields (up to 70%) (Scheme 19). ... 

A soln. of 3-acetyl-2-naphthol in diethylene glycol refluxed 3 hrs. under Ng with excess hydrazine hydrate not exceeding a concentration of 5% 3-methyl-lH-benz[f]indazole. Y 85%. F. e. s. H. Duewell and T. J. Haig, Soc. (C) 1968, 169. 

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