Indazole, acidity

H-4,7 - Indazoledione, 4,7-dihydro-3-vinyl-synthesis, 1, 279 Indazole-l-lsN synthesis, 5, 291 Indazole-2-lsN synthesis, 5, 291 Indazoles acidity, 5, 224 N-l -alkylated ring opening, 5, 219 alkylation, S, 228, 230 amination, S, 55, 234 anions... 

Amination at an azole ring nitrogen is known for Af-unsubstituted azoles. Thus 4,5-diphenyl-1,2,3-triazole with hydroxylamine-O-sulfonic acid gives approximately equal amounts of the 1- (104) and 2-amino derivatives (105) (74AHC(16)33). Pyrazole affords (106) and indazole gives comparable amounts of the 1- and 2-amino derivatives. 

Aromatic pyrazoles and indazoles, in the broad sense defined in Sections 4.04.1.1.1 and 4.04.1.1.2, will be discussed here. Tautomerism has already been discussed (Section 4.04.1.5) and acid-base equilibria will be considered in Section 4.04.2.1.3. These two topics are closely related (Scheme 10) as a common anion (156a) or a common cation (156b) is generally involved in the mechanism of proton transfer (e.g. 78T2259). For aromatic pyrazoles with exocyclic conjugation there is also a common anion (157) for the three tautomeric forms... 

N-Amination of indazole affords a mixture of 60% (271) and 40% (272), which compares with the 55 45 ratio obtained in methylation (Section 4.04.2.1.3(viii)). A camphopyrazole derivative (a mixture of tautomers 275 and 276) when treated with hydroxylamine O-sulfonic acid yields exclusively the (4S,7i )-4,7-methano-2-amino-7,8,8-trimethyl-4,5,6,7-tetrahydro-2H-indazole (277) (79YZ699). 

With mixed acid 1-methylpyrazole 2-oxide (268) gives high yields of l-methyl-5-nitropyrazole 2-oxide (269) (B-76MI40402). The form undergoing the reaction is the base, for which first-order kinetics are observed in the Hq range from -5 to -6.5 a dinitro derivative is also formed under slightly different conditions. The reaction of indazole with fuming nitric acid affords a nearly quantitative yield of 5-nitroindazole (Section 4.04.2.3.2(i)). 

In the indazole series an example of a type (c) reaction (Figure 25) has been described utilizing a 1,3-dipole instead of a diene (Scheme 32) (76H(4)1655). The cycloadduct (351) is transformed into the triazole (352) on reaction with hydrochloric acid. 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

Substituents in the indazole ring may direct a given reaction towards another position either by their R and I electronic properties or simply by protecting the most reactive position. Examples of both types are found in sulfonation studies (67HC(22)l). As indicated before (Section 4.04.2.3.2(i)), sulfonation takes place at position 7. However, the presence of an amino group at positions 5 or 7 directs the attack towards the 4-position (Scheme 40). To obtain the indazole-5-sulfonic acid a more complicated procedure has been used but it is still based on the same ideas. 

The Frasca method for obtaining 1-arylindazoles also involves a C(3)—C(3a) ring closure (67CJC697). It consists in the cyclization of p-nitrophenylhydrazones of ketones and aldehydes with polyphosphoric acid. The Barone computer-assisted synthetic design program has found several new methods for preparing indazoles (79MI40409). The selected method involves the transformation of jV, jV -diphenylhydrazides (596) into 1-phenylindazoles (597) by means of trifluoromethanesulfonic anhydride. The yields vary from 2% (R = H) to 50% (R = Ph). 

Most of the pharmacologically active indazole derivatives are useful as antiinflammatory drugs, e.g. bendazac or [(1-benzyl-l J/-indazol-3-yl)oxy]acetic acid (LDso in mice and rats of 355 and 388mgkg i.p., respectively) and benzydamine or l-benzyl-3-[3-(dimethyl-amino)propoxy]-l//-indazole (LDso in mice and rats of 110 and lOOmgkg" i.p., respectively). The last cited compound also has analgesic and antipyretic properties (B-76MI40404). 

Recently, Picciola et al. (81FES1037) prepared some 2iT-indazole derivatives containing a phenylalkanoic acid residue with potential antiinflammatory activity (693). M.G. 18755 (R = CHMeC02H, R = R = R = H) and its lysine salt, M.G. 18334, showed greater activity than ibuprofen, and the homologous butyric acid derivative M.G. 18860 showed good activity as a platelet aggregation inhibitor. 

Antiarthritic effects on primary or secondary arthritis have been shown by the ethyl ester of l-(p-chlorobenzoyl)-5-methyl-liT-indazole-3-carboxylic acid (694) (81FES315). 

Finally, a new class of antispermatogenic agents containing the same fundamental structure cited above has been described (76JMC778). 1-Halobenzyl-l J/-indazole-3-carboxylic acids are potentially useful for birth control, and because they act after a single administration they are of interest for the physiological study of the male reproductive system. 

Indazole-3-carboxylic acid, 1-aryl-ring cleavage, 5, 246... 

Support for this suggestion comes from many quarters. Reduction of the jS-carboline anhydro-bases with sodium and alcohol or with tin and hydrochloric acid gives the 1,2,3,4-tetrahydro derivatives, as does catalytic reduction over platinum oxide in an alkaline medium. On the other hand, catalytic reduction with platinum oxide in acetic acid results in the formation of the 5,6,7,8-tetrahydro-j3-carbolinium derivatives (see Section III,A,2,a). It should be noted, however, that reduction of pyrido[l,2-6]indazole, in which the dipolar structure 211 is the main contributor to the resonance hybrid, could not be effected with hydrogen in the presence of Adams catalyst. 

Another example of this rearrangement has been used to prepare 1,2,3-triazole 146 from furazanic phenylhydrazone 147 (Scheme 84) [93JCS(P1)2491]. Interestingly, furoxanic Z-phenylhydrazones 150 underwent thermal recyclization to 1,2,3-triazole A-oxides 152, evidently through intermediate 151. Treatment of the hydrazone 150 with rerr-BuOK leads to the nitromethyl derivative 149 [OOOMIl] (Scheme 84). Lead tetraacetate oxidation of 147 with subsequent Lewis acid treatment of the initially formed intermediate afforded indazole 148 (Scheme 84) (85JHC29). 

An attempt to cyclize the corresponding fully aromatic system (16) gave instead the indazole (17), Eq. (24), probably because the acidity of the bridging methylene group in (16) enables cyclization to occur on the diazonium ion through the carbanion. ... 

Indazoles can be considered as either azaindoles or azaisoindoles depending on the reader s prejudice. Benzydamine (54) represents a drug with this heterocyclic nucleus. Alkylation of the amine of anthranilic acid methyl ester with benzyl chloride in the presence of sodium acetate gives 52. Treatment with nitrous acid leads to the nitrosoamine, which cyclizes spontaneously to the 3-ketoindazole system, 53. This intermediate forms an ether of its enol form on heating the sodium salt with 3-dimethylaminopropyl chloride. There is thus obtained benzydamine (54), a fairly potent nonsteroidal antiinflammatory agent with significant antipyretic and analgesic properties. 

Chemical Name 21-ester of 1(1-benzyl-1 H-indazol-3-yl-oxy]-acetic acid with 11/3,17a, tri-hydroxy-pregn-4-ene 3 0-dione... 

Chemical Name [(1-benzyl-1 H-indazol-3-yl)oxy]acetic acid... 

The 1//-l,2,4-benzotriazepines are stable to aqueous alkali acidic hydrolysis results in ring opening and subsequent ring closure to yield indazoles, e.g. formation of 1,3-diphenyl-l//-indazole.345... 

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