Indazoles intermediates

Indazole -> benzimidazole photoisomerization involves a singlet state and has been determined to be monomolecular and monophotonic. The UV spectrum of an intermediate with a lifetime of the order of seconds was recorded. Irradiation of the indazole (526) resulted in a 96% yield of the 1-methylbenzimidazole (528) probably via the intermediate (527)... 

In different seetions of this ehapter, pyrazoles and indazoles C-linked to a metal or a metalloid have been deseribed or they will be deseribed in the preparative seetions, ineluding lithio derivatives (Seetion 4.04.2.1.7), pyrazolylmagnesium reagents (Seetion 4.04.2.3.7(iii)), ehloromereury derivatives (Seetion 4.04.2.1.4(vii)) and silylpyrazoles (Section 4.04.3.1.2(ii)). All these compounds are useful intermediates and some of their most characteristic reactions will be dijcussed here. 

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). 

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. 

Clear evidence in favor of 6.75 being an intermediate came, however, from stereochemistry. If the indazole cyclization takes place at a chiral carbon atom in the exposition of the alkyl group in 6.78, the stereochemistry of the 3-i/-indazole 6.79 can indicate whether the 5-diazo-6-methylene-l,3-cyclohexadiene 6.75 is an intermediate or whether, on the other hand, deprotonation and cyclization are synchronous. In the first case a racemic indazole 6.79 is expected. In the case of a synchronous reaction, however, a stereospecific product, probably with retention of the chirality at Ca, should be observed. 

The experiment was carried out with (i )-(-)-2[l-(methoxycarbonyl)ethyl]benzene-diazonium chloride (6.80). The product, methyl 3-methyl-3-//-indazole-3-carboxylate (6.81), was racemic. With regard to the inconclusive H/D exchange experiments one therefore has to conclude that the cyclization of the diazo-methylene intermediate 6.75 is faster than the rate of deuterium incorporation. 

The photocyclization of cis-diaminomaleonitrile (372) to 4-amino-5-cyanoimidazole (373) has been shown to proceed via the trans isomer 374.308 4-Amino-3-cyanopyrazole does not seem to be an intermediate in this transformation.309 Analogous cyclizations have been reported in the imidazole 373 which undergoes further photoreaction to yield the bicycle 375, and in o-aminobenzonitrile which is converted into indazole.310 This photocyclization has been extended to include enaminonitriles 376 spectroscopic evidence for the intermediacy of iminoketenimes 377 in this311 and other similar transformations312 have been reported. 

Numerous reports of the photoelimination of nitrogen from spiro-3//-pyrazoles have been published.348 The diaza[2,2]spirenes 420 were converted into the benzocyclopropenes 421 by a pathway which has been shown not to involve intermediate indazoles.349 3f/-Indazoles undergo analogous photoreactions.350... 

Cycloproparenes may be prepared by formation of one of the lateral cyclopropane o-bonds either via biradical closing, or via 1/3/elimination. The first reported synthesis of a benzocyclopropene derivative (see Section 1)" is an application of the former of these approaches. Upon irradiation, 3//-pyrazoles 70 loose Nj, and the intermediate biradical 71 cyclizes to 72. There is evidence that the intermediate biradical is in the triplet state, but an alternative interpretation in favor of an excited singlet state has also been presented. A variety of 1,1-disub-stituted benzocyclopropenes has been synthesized by the 3ff-indazole route, which is however limited. Cycloproparenes lacking substituents at Cl are not accessible in this way, because the required indazoles occur in the IH tautomeric form 73. 

Only one heterocyclic cycloproparene having the heteroatom in the ring adjacent to the cyclopropene has been isolated, namely the l,l-dimethylcyclopropa[c]pyri-dine derivative 170 which is available in moderate yield upon photochemical extrusion of Nj from the 3Ff-indazole 169. In contrast, irradiation of 171 produces no cycloproparene 173, but other products derived from the intermediate biradical 172. Apparently, the radical centers in 172 are too far apart to allow ring-closure. ... 

The present review is comprehensive Chemical Abstracts has been searched by indexes up to mid 1981 and by a computer on-line substructure search up to Issue 26 of Volume 96. A few more recent references are included directly from the commoner international journals. This review covers 3//-pyrazoles that have been isolated or characterized spectroscopically, although some examples that are only transient intermediates in rearrangement reactions are also mentioned. Compounds having exocyclic double bonds and the benz-fused derivatives, the 3//-indazoles, are considered to be outside its scope. 

What has now become clear with this synthetic methodology is that the substrate may not be a spiro-3//-pyrazole but a 3//-indazole. However, this is of little consequence to the final outcome as the latter is a proposed intermediate in the photorearrangement of the former. 

Similar redox-combined processes have been reported. For example, it has been clarified by control experiments using a photoirradiated semiconductor electrode that the photocatalytic production of indazoles from substituted azobenzenes is based on the condensation of two intermediates formed through oxidation and reduction.38 40) In the case of oxidation of substituted olefins a similar redox combined mechanism is assumed cation and anion radicals are formed by the reaction of olefin with positive hole and of 02 with excited electron, respectively, and they react to produce a 4-membered ring intermediate, a dioxethane, to undergo bond cleavages into the desired products.4l) In the photocatalytic reactions, a positive hole and excited electron must react at the neighboring surface sites of a small semiconductor particle, enabling the combination of reduction and oxidation without the addition of an electrolyte, which is an indispensable component in electrolysis. However, in the particulate system the recombination of positive hole and electron is also likely, as well as... 

The pyrolysis of indazoles 113-115 with bulky substituents R has also given some interesting results. For R = Ph3C, FVP of 113 at 400 °C leads to partial conversion into 114, while at 300 °C 114 gives 113. The less stable isomer 115 is converted at 300 °C into a mixture of 113 and 11465. For R = 1-adamantyl, 113 and 114 are again interconverted at 600 °C, while at 700 °C the new product 117 is formed from either by way of the azirine intermediate 11666. 

The reaction of l-aryl-4,6,6-trimethyl-3-phenyl-l,6-dihydropyrano[2,3-cjpyrazoles 88a-d with DMAD in dimethylformamide (DMF) at reflux is the first example of a Diels-Alder reaction involving the pyrazole ring. The reaction afforded an indazole 89 by elimination of a molecule of acetone from the intermediate cycloadduct (83S852). The s-cis conformation of the reactive diene fixed by the dihydropyran and the aromatization process to afford the indazole by elimination of acetone could be the driving force for this reaction. 

Carbethoxypyrazol-5-yl-, indazol-3-yl- and indazol-5-yl-2-iodobenzamides have been synthesized from the corresponding 1,2,3-benzotriazinones <02FES183>. The reduction of benzo-l,2,3,4-tetrazine 1,3 dioxides 72 afforded benzotriazoles 74 via intermediates 73 <02OL3227>. 

The unstable fused 1,2,6-oxadiazepine intermediate 299 has been reported as resulting from 1,7-electrocyclisation of the non-stabilised azomethine ylide 298 on to the nitro group subsequent ring contraction afforded the indazole-JV-oxide 300 [01TL5081]. 

A versatile and efficient synthesis of 3-substituted-l//-indazoles 199 is based on the generation and subsequent cyclization of the intermediate hydrazones from aryl mesylates 198 and hydrazines (Scheme 119) <1999S588, CHEC-111(4.01.9.1.2)94>. 

Intramolecular carbenoid and nitrenoid insertions are also quite effective for the preparation of peri-condensed heterocycles. Thus, photolysis of 1-naphthyl-1,2,3-triazoles 113 leads to bcnzo[d,e quinolines 115, possibly via carbene intermediate 114 (Scheme 55) <1987J(P1)413>. Similarly, on photolysis or thermolysis of 8-azido-l-arylazonaphtha-lenes 116 naphtho[l,8-<7, ]triazine derivatives 117 are formed along with A-aryhminobenzo[/y/]indazoles 118 (Scheme 56) <1978JOC2508, 1982JOC1996>. 

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