Highly Chemoselective Synthesis of Indole Derivatives

Abstract

A facile and efficient synthesis of polysubstituted indoles from α-arylamino-β-hydroxy-2-enamides, α-arylamino-β-oxo-amides, or their tautomeric mixture via electrophilic activation strategy is described. The salient feature of this methodology is the use of either combined Hendrickson reagent and triflic anhydride (Tf 2 O) or triflic acid (TfOH) to control the chemoselectivity in the intramolecular cyclo-dehydration to provide a predictable approach to these valuable indoles with flexible substituent patterns. Moreover, the mild reaction conditions, simple execution, high chemoselectivity, excellent yields, and wide range of synthetic potential of products make this protocol much attractive for academic research and practical applications.

Triflic Acid-Promoted 1,2-Amino Migration Reactions in α-Arylaminoacrylamides: Access to Substituted β-Aminoamides

“…It should be mentioned that in our previous work, ( E )-enol triflate 2a was obtained in excellent yield when 1a was subjected to Tf 2 O (2.0 equiv) and triethylamine (Et 3 N, 2.0 equiv) in dichloromethane (DCM) at room temperature, whereas an intramolecular cyclization of 1a occurred in the presence of triflic acid (TfOH, 2.0 equiv) in isobutanol ( i -BuOH) at reflux temperature to afford 2-carbamoyl-1 H -indole 3a (Scheme ). Encouraged by these results, we conducted the reaction of 2a with TfOH (2.0 equiv) in methanol (MeOH) under reflux in the present work. As indicated by TLC results, the reaction proceeded smoothly to form a new product instead of 3a .…”

“…In the first step of the entire transformation process, substrate 1/1′ reacts with Tf 2 O in the presence of Et 3 N in a chemoselective manner to generate a relatively stable intermediate, (E)-enol triflate 2. 17,20,21 In the second step, 2 is instantaneously protonated by the added TfOH to afford carboxonium cationic intermediate A (2• TfOH). 17,22,23 Most probably, the adjacent carboxonium cationic group enhances the electrophilic reactivity of the vinyl group in intermediate A, 23 which enables A to undergo an intramolecular nucleophilic vinylic substitution (S N V) reaction to form dicationic 1H-azirinium intermediate B.…”

“…17,20,21 In the second step, 2 is instantaneously protonated by the added TfOH to afford carboxonium cationic intermediate A (2• TfOH). 17,22,23 Most probably, the adjacent carboxonium cationic group enhances the electrophilic reactivity of the vinyl group in intermediate A, 23 which enables A to undergo an intramolecular nucleophilic vinylic substitution (S N V) reaction to form dicationic 1H-azirinium intermediate B. 24 The overwhelming importance of 1H-azirine derivatives in organic synthesis has been recognized for their significant "ring strain" character, which can lead to a variety of ring-opening reactions under the influence of a wide range of chemical and physical conditions.…”

“…They were prepared and characterized, and their analytical data are in good agreement with those reported in the literature. 17,18 Procedure for the Preparation of (E)-3-Hydroxy-N-phenyl-2…”

“…16 Most recently, we achieved highly chemoselective synthesis of indoles from α-arylaminoacrylamides (Scheme 1f). 17 In connection with our previous work, we investigated the reaction behaviors of α-arylaminoacrylamides toward Tf 2 O under different conditions. As a result of these studies, we developed an efficient synthesis of polysubstituted β-arylaminoamides, and this protocol was successfully expanded to other precursors, such as αarylamino-β-oxoamides and their enol−keto tautomeric mixtures (Scheme 1f).…”