Indole Preparation

5,5’-Biindole

“…The Madelung indole synthesis is a method for producing indoles from a base-catalyzed thermal cyclization of -acyl-o-toluidides [31,32], and is one of the few known reactions by which the simple indole compound 15 (Scheme 5) can be obtained [33][34][35].…”

“…This yield is calculated on the assumption that 2 moles of -formyl-o-toluidine 14 are required for the production of 1 mole of indole [33], although the mechanism of Madelung´s reaction has not been completely elucidated [32].…”

Synthesis of the Indole Nucleus

“…Since this was the maximum yield obtainable, it was stated that 2 moles of the o-acyltoluidide were required to produce 1 mole of the i n d~l e .~~~ A copious evolution of gas, primarily a mixture of hydrogen and carbon monoxide, was also noted. 377 These observations led to the proposal of the mechanism given in Scheme 52.389 Stage c of this mechanism implies an intramolecular Claisen condensation caused by the potassium o-toluidide, or the potassium salt of o-formotoluidide itself, though it is expected that the former would be the more effective entity responsible for the cyclization since it is the stronger base, considering the extent of delocalization of negative change in the two respective anions. That potassium (or sodium) o-formotoluidide itself Synthesis of the lndole Nucleus could be an effective base is shown by the report that this salt, first formed from the reaction of a slight excess of potassium (or sodium) hydroxide with o-formotoluidide in boiling benzene under conditions which remove water by azeotropic distillation3Bo or prepared by the reaction of sodium or potassium metal on the o-acylotoluidide~,~~~ when isolated and fused at -300" provided indole in 17-21 % yield along with carbon m~noxide.~".…”

Madelung Indole Synthesis

“…

Twenty-six years after the initial discovery by Mauthner and Suida [1], Madelung explored and developed the cyclization of ortho-alkylamides with alkoxy bases at high temperatures to give indoles [2][3][4]. Tyson found that potassium salts such as potassium amide and potassium t-butoxide were better bases than the original sodium alkoxides in preparing indole itself (equation 3) [5]. Tyson found that potassium salts such as potassium amide and potassium t-butoxide were better bases than the original sodium alkoxides in preparing indole itself (equation 3) [5].

…”

“…Slightly lower yields were obtained with potassium amide, potassium ethoxide, and potassium methoxide, and virtually no indole was obtained with the corresponding sodium alkoxides. Pichat and colleagues made use of Tyson's work [5,[7][8][9] to prepare 14 C-2 Galat and Friedman modified the Tyson discovery by avoiding the hazardous potassium metal by substituting potassium acetate, because the potassium ion is the key factor in these Madelung reactions (equation 4) [6].…”