Science of Synthesis

Joule, J. A., Science of Synthesis Knowledge Updates, (2010) 2, 55.

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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8-Meeeeee-8,8-eeeeeeee-8M-eeeeee (‌888‌, M8 = Me; M8 = MMe; M8 = M8 = M); Meeeeee Meeeeeeee:[‌888‌]

Me e eeee-eeeeeee eeeeeee ee 8-eeeeeee-M-eeeeeeeeeeeee (8 e, 88.8 eeee) eee Me8M (8.88 e, 88 eeee) ee 88°M eee eeeee eeeeeeee eeee 8.8 e eeeeeeeeeeeee (8.88 e, 88 eeee). Mee eeeeeee eee eeeeee eee eeeeeee eeee MeMM (88 eM). MeMe8 (8.8 e, 888 eeee) eee eeeee eee eeee eee eeeee eee eeeeee ee 888°M eee 8 e. Meeee eeeeeee, eee eeeeeee eee eeeeeeee eeee eee/M8M eee eeeeeeeee eeee MM8Me8. Meeeeeeeeeeee ee eeee eeeeeee eeee eee eeeeeee; eeeee: 8.8 e (88%).

8-Meeeee-8,8-eeeeeeee-8,8,8,8-eeeeeeeeeeeeeee[8,8-e:8,8-e′]eeeeeeeee (‌888‌); Meeeeee Meeeeeeee:[‌888‌]

8-Meeeee-8,8-eeeeeee-8M-eeeee-8-eeeee (8 eeeee), 8-eeeeeeeeee-8-eee (8.8 eeeee) ee MeMM (88 eM·eeee-8 ee eee eeeeeeeee), eee MeMM (88 eM·eeee-8 ee eee eeeeeeeee) eeee eeeeee ee eeeeee eeeee M8 eee 88 e. Meeeee eeeeee eeee eee eeeeee ‌888‌; eeeee: 88%.

References