Heterocycle synthesis Fischer indole

N. Campbell, B. M. Barclay, Chem. Rev. 40, 361 (1947) W. Freudenberg, Heterocyclic Compounds 3, 298 (1952) P. Bruck, J. Org. Chem. 35,2222 (1970). Cf. Bucherer Carbazole Synthesis Fischer Indole Synthesis Pilotv-Robinson Synthesis. 

Intramolecular cyclization in perfluoroaromanc systems proves useful for the synthesis of heterocyclic compounds [72] For example, the Fischer indole synthesis, which normally requires the presence of an ortho proton, occurs satisfactonly with an ortho fluonne in theperfluoronaphthalene senes [73] (equation 37)... 

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. ... 

Wherever the heterocyclic ring is fused to an aromatic system the starting material must always be a preformed aromatic derivative. In this context the Fischer indole synthesis (Scheme 6.12) provides a good example ... 

Similar enamine cyclization processes occur in several other successful heterocycle syntheses, e.g. in the Fischer indole synthesis. In this case, however, a labile N—N bond of a l-aryl-2-vinylhydrazine is cleaved in a [3,3]-sigmatropic rearrangement, followed by cyclization and elimination of ammonia to yield the indole (B. Robinson, 1963, 1969 R. J. Sundberg, 1970). Regioselectivity is only observed if R2 contains no enolizable hydrogen, otherwise two structurally isomeric indoles are obtained. Other related cyclization reactions are found in the Pechmann synthesis of triazoles (T.L. Gilchrist, 1974) and in G. Bredereck s (1939) imidazole synthesis (M.R. Grimmett, 1970). 

The most important of the heterocycles fused to benzene rings are the indoles 75. The obvious enamine disconnection gives 76 which would certainly cyclise to the indole, but how are we to make 76 As a result of this difficulty, many special reactions have been invented to make indoles and the most important is the Fischer indole synthesis.12 A phenylhydrazone 77 of a ketone or aldehyde is treated with acid or Lewis acid and the product is an indole. 

Azoles can be produced from the products of palladium-catalyzed hydrazone arylation and can themselves serve as substrates for arylation reactions to produce N-aryl azoles by the Fischer indole synthesis. N-Aryl pyrazoles and related heterocycles can also be prepared after obtaining N-aryl hydrazines by palladium-catalyzed procedures. Benzophenone hydrazone was first found by both the Yale and MIT groups to be a particularly effective substrate for palladium-catalyzed reactions, as summarized in Eq. (25) [183, 184]. Reactions of benzophenone hydrazone with either aryl bromides or iodides occur in high yields in the presence of either DPPF- or BINAP-ligated palladium. These reactions are general and proceed with electron-rich, electron-poor, hindered, or unhindered aryl halides. The products of these re-... 

In the same domain of heterocyclic synthesis, much effort has been devoted to understanding the selectivities in the synthesis of indoles starting from phenylhydrazine and ketones, i.e. the Fischer indole synthesis. With phenyl-hydrazine, l-phenyl-2-butanone and zeolite H-Beta, the slimmer product 2-phenyl-3-methylindole dominates over the more bulky isomer (13) ... 

R. A. Heacock, Advan. Heterocyclic Chem. 5, 205-290 (1965). Fischer indole synthesis ... 

Zimmermann, T. Afacile synthesis of 3H-indolium perchlorates by one-pot hydrazone formation/Fischer indolization. J. Heterocycl. Chem. 2000, 37, 1571-1574. 

Rosas-Garcia, V. M., Quintanilla-Licea, R., Longoria R, F. E. The Fischer indole synthesis a semiempirical study. ECHET98 Electronic Conference on Heterocyclic Chemistry, June 29-July 24, 1998 1998, 237-243. 

Fujii, H., Mizusuna, A., Tanimura, R., Nagase, H. A novel abnormal rearrangement in the Fischer indole synthesis. Heterocycles 1997,45, 2109-2112. 

Heterocycle formation (Hantzsch condensation, Pictet-Spengler, Fischer synthesis of indoles, Pd-heteroannulation)... 

There has probably been more work carried out on the synthesis of indoles than on any other single heterocyclic system and consequently many routes are available ring syntheses of benzo[Z ]furans and benzo[fc]thiophenes have been much less studied. The Fischer indole synthesis, now more than 100 years old, is still widely used - an arylhydrazone is heated with an acid, a multi-step sequence ensues, ammonia is lost and an indole is formed. 

There are general reviews on heterocyclic syntheses by cycloaddition reactions of isocyanates and on the use of heterocyclic cations in preparative organic chemistry. More specific topics are 5-hydroxymethylfuran-2-carb-aldehyde, isobenzofurans and related ort/io-quinonoid systems, the conversion of 2//-cyclohepta[Zj] furan-2-one (1) into derivatives of azulene, the synthesis of indoles from o-alkylphenyl isocyanides, and abnormal Fischer indolization reactions of o-methoxyphenylhydrazones. Two reviews on isoindoles have appeared and a lecture on highly conducting charge-transfer complexes that are based on heterocyclic selenium and tellurium donors has been reprinted.Recent advances in the chemistry of imidazole and in the use of nitro-imidazoles as radiosensitizers have been summarized. There have been reviews on benzimidazole A -oxides and on dihydrobenzimidazoles, benzimidazolones, benzimidazolethiones, and related compounds. Other topics are synthetic applications of 1,3-dithiolium and 1,3-oxathiolium salts and of isoxazoles, the chemistry of benzisoxazoles, 2-amino-oxazoles, 5-oxazolones (2), furoxans, benzofuroxans, and related systems, the synthesis of five-membered meso-ionic compounds, and tetrazoles. ... 

Zeolites are known to catalyze the formation of various nitrogen-containing aromatic ring systems. Examples include the synthesis of pyridines by dehydrogenation / condensation / cyclization of C -Cg precursors [1], the formation of methylpyridines by high-temperature isomerization of anilines [2], the amination of oxygen-containing heterocyclic compounds [3] and the Fischer indole synthesis [4,5]. The latter synthesis consists (see Scheme 1) of a condensation towards a phenylhydrazone followed by an acid-catalyzed cyclization with elimination of ammonia. The two reaction steps are usually combined in a one-pot procedure. 

Reactions of heterocycles ch29 How to make pyridazines and pyrazoles How to make pyrimidines from 1,3-dicarbonyl compounds and amidines How to make thiazoles How to make isoxazoles and tetrazoles by 1,3-dipolar cycloadditions The Fischer indole synthesis Making drugs Viagra, sumatriptan, ondansetron, indomethacin How to make quinolines and isoquinolines ... 

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