Acylation of Indole under Friedel−Crafts ConditionsAn Improved Method To Obtain 3-Acylindoles Regioselectively

Abstract

The reaction of unsubstituted indole with different acylating agents such as acid chlorides, anhydrides, nitriles, and amino acid derivatives in the presence of Lewis acid is reported.The synthesis of 3-acylindoles has been the subject of considerable interest not only because they are used as synthetic intermediates in alkaloid synthesis but also because they have biological activities. 1 Three major synthetic methods have been employed to prepare this class of compounds using indole as the starting material: (1) acylation of indole Grignard reagents, [2][3][4] (2) acylation of N-protected indoles, 5 and (3) the Vilsmeier-Haack reaction. 2 There are also other methods based on acyl cation equivalents such as nitrilium salts 6 and dialkyl carbenium ions. 7,8 Another method, using N-(R-haloacyl)pyridinium salts, gives predominantly 3-acylindoles under controlled conditions, but it seems to be restricted to some very reactive R-haloacyl halides. 9 Each of these methodologies has merits and shortcomings that limit their scope and yield.

Metal-organic framework MIL-53(Al): synthesis, catalytic performance for the Friedel-Crafts acylation, and reaction mechanism

“…This result might be due to an effective absorptive properties effect of MIL-53(Al) [30] in which the excess of catalyst content contributes to the absorption of reactants and thus decelerates the speed of the reaction. In comparison with [26], which reported the use SnCl 4 as catalyst for Friedel-Crafts acylation reaction of indole, our yield was 95.0% when catalyst content was 1.20 mmol (1:1.2). However, we used only 0.06 mmol (1:0.06) MIL-53(Al) to catalyze the reaction but obtained a yield of 93.9%, which showed that MIL-53(Al) has higher catalytic activity than traditional Lewis acid catalysts.…”

“…Wynne et al [25] found the same trends of the conversion of indole and the selectivity of 3-acylindole. The reason for these results might be that the active Al 3+ sites of MIL-53(Al) were more conducive to reacting with electrophile benzoyl chloride and forming acylium ion at low temperature, which could further induce electrophilic substitution [26].…”

Catalytic enantioselective addition of indoles to arylnitroalkenes: An effective route to enantiomerically enriched tryptamine precursors

“…26 The activating role of Lewis acids in Friedel-Crafts reactions has been deeply investigated and the interaction between the metal center and the electrophile is accepted to be involved in the rate-determining step of the transformations. 27 However, recent computational 28 as well as experimental evidence 29 suggests that, particularly when electron-rich aromatic compounds are involved, possible interactions between the Lewis acid and the aromatic system cannot be ruled out. Moreover, transition metals were also found to react with indoles under mild conditions to afford the corresponding N-1 indole -metal bond containing complexes.…”

General Aspects and Historical Background

“…Here, for the first time, a tight Al-C contact (2.35 A ) was found with consequent marked pyramidalization of AlCl 3 (Cl-Al Á Á Á Cl % 98 ) and loss of the benzene nodal plane. Such an interaction should be even more pronounced with electron-rich arenes or with late-transition metal-based catalysts in which the back-donation of charge should strengthen the interaction [12].…”