Fisher cyclization

As shown in Scheme 4.3, the Fisher indolization was thought to involve (i) hydrolysis of diethyl dimethylamino acetal 11, (ii) formation ofhydrazone 22, (iii) isomerization ofhydrazone to me-hydrazine 23, and (iv) [3.3] sigmatropic rearrangement followed by ring closure to give indole 16b. Acetal 11 is stable in AcOH at room temperature, but can be readily hydrolyzed to aldehyde 19 at 100 °C, with subsequent cyclization to hemiaminal 20. Hemiaminal 20 was also formed readily... 

Similar to the Fisher indole synthesis, reductive cyclization of nitro aromatics offers a powerful means of forming indoles. Reductive cyclization of ortho, 2 -dinitrostyrenes has occurred in many ways, by TiCl3, NaBH4-Pd/C, H2-Pcl/C, and other reductive methods.89 Corey and coworkers have used the Borchardt modification (Fe-AcOFI, sihca gel, toluene at reflux for the reductive cyclization of o-ji-dinitrostyrenes) to prepare 6,7-dimethoxyindole (Eq. 10.65) in a total synthesis of aspidophytine (see Schemes 3.3 and 3.4 in Section 3.2.l).89d... 

One potential approach for the preparation of benzofuran derivatives involves the acid-catalyzed cyclization of O-aryl oximes 1193. 39 (equation 36). The transformation is analogous to well-known Fisher indole synthesis. The reaction proceeds through a [3,3]-sigmatropic rearrangement of enehydroxylamine 120 to compound 121 followed... 

A new synthetic method of benzofuran was reported (equation 39). The [3,31-sigma-tropic rearrangement of Af-trifluoroacetyl enehydroxylamines 136 obtained in situ by acylation of oxime ethers 135 in the presence of trifluoroacetic anhydride lead to the synthesis of cyclic or acyclic dihydrobenzofurans 138. The effects of base and temperature on the reaction products were studied. A similar pathway to that of Fisher indolization was proposed. The acylimine formed by the [3,3]-sigmatropic rearrangement of the V-trifluoroacetyl enehydroxylamine 136 gave the dihydrobenzofuran 137 by an intramolecular cyclization or the benzofuran 138 after elimination. 

The carboxylic acid family of substituents is most often introduced at the stage of ring synthesis for both pyrroles and indoles. Many of the cyclizative condensation routes to pyrroles in fact rely on the presence of ester substituents. Indoles with 2-carboxy substituents are easily available from the adaptation of the Fisher synthesis, which provides the arylhy-... 

Nature found a direct path to perform this tandem fragmentation cyclization reaction in a stereospecific manner and under neutral conditions. Human creativity and luck aimed to uncover synthetic variants, which can compete efficiently with it. With the advent of mild, metal mediated cyclization reactions, the early idea of Grosheinz and Fisher [19a], who converted 6-deoxy-6-nitrohexoses to nitroinositols in a single step, matured to a general strategy of broad interest. 

Cyclopropem synthesis. Fisher and ApplequisF treated metballyl chloride (1) with sodium amide in refluxing tetrahydrofurane and obtained 1-methylcyclopropene (2) in reasonable yield the reaction probably involves formation and cyclization of the vinylcarbene. Closs and Krantz found that cyclopropene (3) itself can be... 

Fisher synthesized a large group of l-aryIamino-2-arylnaphtho[l, 2-J]im-idazoles (60) by cyclization of l-benzeneazo-2-arylideneaminonaphtha-lenes under acidic conditions (22JPR102 24JPR16). It was shown later that this reaction can occur on heating 59 in pyridine (67AG(E)250). 3-Arylamino derivatives of naphtho[l, 2-[Pg.105]

Fisher and Overman used SnCU as catalyst when cyclizing the carbonate to the enol carbonate (64), a reaction which proceeded in 69% yield. 

The core skeleton of geissoschizine, an important biosynthetic precursor to numerous polycyclic indole scaffolds, was the target of a nickel-catalyzed alkylative coupling strategy. Cyclization precursor 13 was prepared by ozonolysis and double reductive amination of cyclopentene 12 (Scheme 8.13) [35]. Nickeldeprotection/oxidation sequence followed, and chromatography led to complete inversion of the C3 stereocenter. A Fisher indole synthesis followed to afford ( )-deformyl-isogeissoschizine, the core skeleton of geissoschizine. 

Another approach to N-heterocycles on the basis of nitroarenes is represented by cyclization of nitroaryl-substituted hydrazones of carbonyl compounds into indoles (Fisher indole synthesis) [141] (Scheme 92). 

Cyclic a-diazocarbonyl compounds (59) and enynones (61) have been used as Rh-and Zn-carbenoid precursors, respectively. Cyclic derivatives (59) have been found to favour intermolecular Rh-catalysed cyclopropanation reactions, relative to the formation of conjugated alkene (60) by intramolecular -hydride elimination as is usually observed in the case of a-alkyl-a-diazocarbonyl compounds this high level of chemoselectivity is reported for the first time. Rh-carbenoids derived from (59) have also promoted cyclo-propenation reactions as well as diverse X-H insertion reactions (i.e., X = C, N, O, S). In parallel, highly functionalized cyclopropylfiirans (62) have been successfiilly prepared from an alkene and an enynone (61) by a cyclization/cyclopropanation sequence conducted in the presence of catalytic amounts of ZnCl2, which is cheap and of low toxicity computations support the probable participation of intermediate Fisher-type Zn(II) carbene complexes (63). 

Fleming, M., Basta, R., Fisher, P.V., Mitchell, S., and West, F.G., Synthesis of bridged bicyclic ethers and fused oxetanes from pyran-4-ones via tandem solvent trapping and Norrish type II cyclization, /. Org. Chem., 64, 1626, 1999. 

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