Arylhydrazones synthesis

Substituted indoles can be prepared using the Buchwald-Hartwig N-arylhydrazone synthesis provided that a functionalization of the intermediate A -arylhydrazone is carried out before the Fisher indole synthesis synthesis step. Both A -alkyl and A -aryl indoles may be prepared in this manner. For instance, an A -methylindole was prepared as a mixture of regioisomers by first methylating an arylhydrazone. 

Retrosynthesis a in Scheme 7,1 corresponds to the Fischer indole synthesis which is the most widely used of all indole syntheses. The Fischer cyclization converts arylhydrazones of aldehydes or ketones into indoles by a process which involves orf/io-substitution via a sigmatropic rearrangement. The rearrangement generates an imine of an o-aminobenzyl ketone which cyclizes and aromatizes by loss of ammonia. 

Jacobson-Hugershofi synthesis benzothiazoles, 5, 135 Japp-KJingemann reaction JV-arylhydrazones from, 4, 337 1,2,4-triazole synthesis by, 5, 768 Jasmine lactone synthesis, 3, 847 Jasminine occurrence, 2, 626 y-Jasmolactone synthesis, 4, 674 cis-Jasmone synthesis, 1, 422, 427 Jatropham synthesis, 1, 426 Josephson junctions, 1, 359 Juliprospine... 

The Fischer indole synthesis can be regarded as the cyclization of an arylhydrazone 1 of an aldehyde or ketone by treatment with acid catalyst or effected thermally to form the indole nucleus 2. ... 

A large number of Brpnsted and Lewis acid catalysts have been employed in the Fischer indole synthesis. Only a few have been found to be sufficiently useful for general use. It is worth noting that some Fischer indolizations are unsuccessful simply due to the sensitivity of the reaction intermediates or products under acidic conditions. In many such cases the thermal indolization process may be of use if the reaction intermediates or products are thermally stable (vide infra). If the products (intermediates) are labile to either thermal or acidic conditions, the use of pyridine chloride in pyridine or biphasic conditions are employed. The general mechanism for the acid catalyzed reaction is believed to be facilitated by the equilibrium between the aryl-hydrazone 13 (R = FF or Lewis acid) and the ene-hydrazine tautomer 14, presumably stabilizing the latter intermediate 14 by either protonation or complex formation (i.e. Lewis acid) at the more basic nitrogen atom (i.e. the 2-nitrogen atom in the arylhydrazone) is important. 

In addition to /3-diketones, /3-ketoacids and /3-ketoesters, cyanoacetic ester and related compounds are suitable starting materials. The arylhydrazones 4 thus obtained are of great importance as starting materials for the Fischer indole synthesis, as well as for the preparation of other iV-heterocycles. ... 

When arylhydrazones of aldehydes or ketones are treated with a catalyst, elimination of ammonia takes place and an indole is formed, in the Fischer indole synthesis,Zinc chloride is the catalyst most frequently employed, but dozens of others, including other metal halides, proton and Lewis acids, and certain transition metals have also been used. Microwave irradiation has been used to facilitate this reaction. Aniline derivatives react with a-diazoketones, in the presence of a... 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

Construction of the indole ring via Fischer synthesis. Starting from a variety of 3,4-dihydro-lH-benzo[l ]azepine-2,5-diones 40 and arylhydrazines Fischer syntheses of indolo benzazepinones 41 have been reported (Scheme 8 (1999JMC2909)). Usually, the reaction comprises a two-step one-pot procedure with the formation of intermediate arylhydrazones in warm acetic acid followed... 

The synthesis of cyclic ethers 137 was achieved by a Fischer indole synthesis starting from cyclic keto arylhydrazones generated in situ from 4-(hydroxy-methylene)-3,4-dihydrobenzo[ 7]oxepin-5(2H)-one 136 and the corresponding diazonium salt (Equation (20), 1993JHC1481). 

The Fischer method (497) of indole synthesis by the indolization of an arylhydrazone by treatment with an acid catalyst was applied to the synthesis of tetrahydrocarba-zoles by Borsche (498). 

A highly efficient one-pot, two-step microwave procedure has been developed for the synthesis of l-aryl-l/7-indazoles. Microwave heating of 2-halobenzaldehydes or 2-haloacetophenones with phenylhydrazines at 160°C for 10 min quantitatively yielded the arylhydrazones, which were further cyclized to give l-aryl-17/-indazoles via Cul/diamine-catalyzed... 

Fischer indole synthesis Cyclization of arylhydrazones by heating with an acid or Lewis acid catalyst yields an indole system. The most commonly used catalyst is ZnCl2- The disadvantage of this reaction is that unsymmetrical ketones give mixtures of indoles if R also has an a-methylene group. 

N—N Bond Cleavage and Rearrangements of Arylhydrazones and Arylhydrazides — Recent Developments R. Fusco and F. Sannicolo, Tetrahedron, 1980, 36, 161-170. An Application of Beta-Lactam to the Synthesis of Heterocyclic Compounds S. Kano, Yuki Gosei Kagaku Kyokaishi, 1978, 36, 581-594. 

Ilac Fischer indole synthesis from /V-arylhydrazones 3.06.3.4.2... 

The Fischer indole synthesis is the conversion of an Af-arylhydrazone to an indole with elimination of ammonia (equation 88). This method is of very broad scope, and is able to accomodate a wide variety of functionalized and unfunctionalized 2- and 3-side chains as well as substituents in the carbocyclic ring (B-70MI30605,72HQ25-D232). Ironically, the parent 2,3-unsubstituted indoles are difficult to obtain via the Fischer method. Indole itself was not successfully made by the Fischer method until 1976, and then only using a high temperature (290-300 °C) procedure (76JOC1877). 

Processes include the Fischer indole synthesis from arylhydrazones and related sigmatropic syntheses, reductive evclizations of nitni compounds, the Madelung synthesis from anilides and related base-cululyxed condensations. and transition-metal catalyzed cyclizations,... 

The Fischer Indole Synthesis and Related Sigmatropic Syntheses. In the Fischer indole synthesis (26) an N-arylhydrazone is cyclized, usually under acidic conditions, to an indole. The key step is a [3,3]sigmatropic rearrangement of an enehydrazone tautomer of the hydrazone. 

This chapter covers the literature from mid-1995 to mid-2007. Recent advances include the preparation of the first A2-l,2,3,4-oxatriazolines 7 by intramolecular [3+2] cycloaddition (Section 6.08.9), synthesis of mesoionic derivatives 4 using bromonitroformaldehyde iV-arylhydrazones as the starting materials (Section 6.08.9), and detailed studies of the biologically active mesoionic oxatriazoles in the context of their nitric oxide donating capabilities (Section... 

Complex compounds with halide bridges are prepared by immediate interaction of unsaturated hydrocarbons with metal salts (Sec. 2.2.4.1). Their examples are classic 7i-complexes of the type 123 which are characteristic for fi 8-metals [75]. Such complexes are also formed by the method of ligand exchange. The bridges of this type are widespread in products of cyclometallation reactions with the use of metal halides (Sec. 2.2.5.1) 371-374, 381, 382 [41,46,48]. An example of such a synthesis is the reaction of arylhydrazones of 2-oxopropionic aldehyde and benzoylformalde-hyde, as well as butadiene-2,3-dione 635, with palladium dichloride, leading (3.71) to dipalladium complexes 636 [88] ... 

The use of arylhydrazones for the synthesis of indoles has been widely discussed in the literature [1,2, 169], One of the most useable methods is the Fischer reaction [169, 170, 171], modified by Arbuzov [172],... 

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