Indoles Fisher indole synthesis

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). 

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. 

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

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

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... 

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. 

With conventional methods, the formation of indole derivatives proceeds at the expense of both unsubstituted otho positions in the phenyl ring. This leads to undesirable by-products. In particular, the formation of the by-products takes place during Fisher s synthesis of benzoheterocycles. In the previously described ion radical variant of the synthesis, only one indole isomer is formed, the isomer that corresponds strictly to the structure of the starting haloaniline. 

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. 

Running the Fisher indole synthesis on an unsymmetrical phenyl hydrazone gives a mixture of 2,3-disubstituted indoles. For example, reaction of the phenyl hydrazone, 34, with acid can give both 35 and 36 (Eqn. 22.26). Soluble acids and Amberlyst-15 give these two products in a 75 25 ratio at 100% conversion. With an H-M catalyst they are formed in a 65 35 ratio but over a dealuminated H-beta zeolite, the selectivity is reversed and 36 is produced in an 82% yield at 100% conversion.62 n was proposed that the preferential formation of 36 over the H-beta catalyst was the result of a restricted transition state selectivity. ... 

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