Fisher indolization

The uncatalyzed thermolysis of hydrazone (24) gave, among other products, an indole by loss of the ortho F in a mirror image of the usual Fisher indole synthesis [83JCS(P1)821]. 

The key Fisher indole synthesis using diethyl 4-chlorobutanal (8) suffered from poor yield to make the primary tryptamine 10, which then calls for reductive amination to complete the synthesis. 

We envisioned that improvement of the key Fisher indole reaction using diethyl 4-(N,N-dimethylamino)butanal (11) instead of diethyl 4-chlorobutanal (8) would lead to formation of the desired product directly. The approach would circumvent... 

Scheme 4.2 Fisher indole synthesis of N,N-dimethyl tryptamines.

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... 

Scheme 4.3 Mechanism of the improved Fisher indole synthesis using N, N-dimethylaminobutanal.

Scheme 4.15 Fisher indole and oxidation approach to indole acetic acid 2.

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... 

The 2-propanone 1,2,4-thiadiazole derivative 44 undergoes the Fisher indole synthesis to give a range of indoles 45 substituted with a 1,2,4-thiadiazole at the 3-position (Equation 12) <2000CPB160>. 

Tetrahydrocarbazole synthesis from cyclohexanone phenylhydrazone. Cf. Fisher indole synthesis. 

Robinson, B. The Fisher Indole Synthesis, John Wiley Sons, New York, NY, 1982. 

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. 

Fisher indole synthesis.1 2,3-Disubstituted indoles are formed in 70-90% yield when a ketone phenylhydrazone is treated in benzene with PC13 at 25°. The same indoles are formed when the ketone and phenylhydrazine are treated with PC13. PC15 is less satisfactory than PC13. The method is not applicable to aldehydes. 

Hydrazones of thiochroman-4-ones are converted into thiochromans under Wolff-Kishner-Huang conditions65 and into the azo dimers by silver oxide.66 Fisher indolization of the phenylhydrazones (33) gives 6,ll-dihydrobenz[6]indolo[2,3-d]thiopyrans (34), which by hydride loss form the thiopyrylium salts (35), or on dehydrogenation produce the pseudoazulenes (36) (heterocyclic analogs of the carcinogen, benz[a]-carbazole), as shown in Scheme 6.87-73... 

Indolo[2,3-6][ 1,5]benzothiazepines (130 and 132) were prepared by Fisher indolization of phenylhydrazone derivatives 129 and 131, respec-... 

The synthesis of substituted indolo[3,2-ib]carbazoles is presented in Scheme 4.4. Parent indolo[3,2-jb]carbazole can be first prepared by double Fisher indolization to... 

Introduction of 14/ -ethoxy and 5/ -methyl groups into the NTI molecule resulted in the pure opioid antagonist (121) with somewhat lower S potency but much higher 5 selectivity in the MVD due to very low fi and k affinities (Table 3.11) [191]. Indole (121) was prepared by reacting the fi receptor-preferring opioid antagonist 14-O-ethyl-5-methyl naltrexone [192] with phenyl-hydrazine under conditions used for the Fisher indole synthesis. 

When the objective is either to make a carful screening for finding a good candidate for future development, or to study whether a gradual change in the performance of the reaction could be traced to the properties of the reaction system, a design which affords a selection of test items which are uniformly spread in the score plot should be employed. An example of this principle is given in the study of the Fisher indole reaction below. 

To avoid the expense of keto ketal 295, Bisagni et al. (116) devised an alternative synthesis that began with 4-methoxycyclohexanone 302 (Scheme 48). The usual Fisher indolization, dehydrogenation, and chlorination gave methoxy derivative 303. A sequence of demethylation and/or methylation provided the target 8-methoxy- and 8-hydroxy-y-carbolines, which were transformed into the amine derivatives (e.g., 304, 305). By the same route (Scheme 48), Bisagni and team (116) converted hydrazine 306 to the 4-demethyl-y-carbolines (307-310). 

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