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10.13.1.1.1.3.1.8 Method 8: From Arylamines and α-Halo Ketones; Bischler Synthesis

DOI: 10.1055/sos-SD-110-00001

Joule, J. A.Science of Synthesis Knowledge Updates, (2010255.

The Bischler synthesis consists of heating an arylamine 201 with an α-halo ketone 202 (or α-hydroxy ketone) usually at temperatures over 200°C to bring about N-alkylation and then electrophilic cyclization onto the aromatic ring. Moderate yields of 2-aryl-1H-indoles can be obtained using a microwave-assisted, solvent-free protocol.[‌221‌] Most examples involve aryl methyl ketones, or aryl benzyl ketones. An α-(arylamino) ketone 203 is certainly the first intermediate formed and the Bischler synthesis can be conducted by its prior preparation. Arylamines react with ketones having a 2-sulfonium substituent,[‌222‌,‌223‌] a 2-amino group,[‌224‌] a 2-pyridinium substituent,[‌225‌] and a 2-triphenylarsenium substituent,[‌226‌] generating intermediates for separate cyclization. Often, the electrophilic cyclization is achieved by heating with the hydrobromide of the aniline concerned.[‌227‌] Acceptable yields of 2,3-diarylindoles or 2,3-dialkylindoles[‌228‌,‌229‌] can be obtained provided the two substituent groups are identical. The main problem with this approach to indoles is the occurrence of isomerization,[‌230‌,‌231‌] for example aryl halomethyl ketones can give rise to 2-arylindoles 207 as well as 3-arylindoles 204 via a process which probably involves formation of the imine 205 of the α-arylamino ketone intermediate 203, tautomerization to 206, and then alternative ring closure to 207 (Scheme 65); indeed, the 2-arylindole 207 is the more usual product obtained.

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