Microwave-Assisted, Solvent-Free Bischler Indole Synthesis

Abstract

The solid-state reaction between anilines and phenacyl bromides in the presence of an equimolecular amount of sodium bicarbonate gives N-phenacylanilines. Microwave irradiation of mixtures of these compounds with anilinium bromides at 540 W for 45-60 s provides a mild, general, and environmentally friendly method for the synthesis of 2-arylindoles in 50-56% overall yields. A onepot variation of the method, involving irradiation of 2:1 mixtures of anilines and phenacyl bromides, was also developed, allowing a simplified experimental procedure and leading to improved yields (52-75%).

Comprehensive Analysis on the Synthesis Methods of 2-Phenylindole Derivatives with Pharmacological Importance for Green Synthesis

“…However, compared with other indole synthesis methods, the reaction conditions are more stringent, with a reaction temperature at 170 °C for over 10 h, resulting in poor regioselectivity and yielding two different compounds (see Scheme and Figure ). − In 2006, Sridharan et al improved the method by irradiating a mixture of aniline and phenyl bromide at 2:1 with 540 W microwave radiation for 45–60 s. This modification resulted in the synthesis of 2-phenylindole derivatives in yields ranging from 52% to 75%, offering a mild, general, and environmentally friendly approach. In 2013, Bunescu et al synthesized N -aryl-2,3-disubstituted indoles under the catalysis of CsF and Cs 2 CO 3 at room temperature, achieving complete control over the regioselectivity.…”

Rh(III)-Catalyzed C–H Bond Activation for the Construction of Heterocycles with sp3-Carbon Centers

“…Nitrogen-containing heterocycles, especially indoles, are the most important chemical substances, which play an important role in a variety of biologically active natural and unnatural compounds [50], and also act as a versatile synthon in organic synthetic science, so it is referred as the "privileged structure". Therefore, the synthesis and further functionalization of indoles have been a long-standing goal of research for over 100 years, and a vast number of well-established methods are available [51], many of them have been incorporated into undergraduate textbooks in the form of named reactions, for example, Bartoli indole synthesis [52], Fischer indole synthesis [53], Gassman oxindole synthesis [54], and Bischler-Moehlau indole synthesis [55]. However, compared to the synthetic strategies for aromatic indole derivatives, the synthesis for indole scaffolds with sp 3 carbon centers, such as indolines, 1H-isoindoles, oxindoles, and isoindolin-1-ones, have emerged more recently, and mainly focus on translation-metal-mediated aromatic (sp 2 ) C-H bond cleavage and subsequent intermolecular or intermolecular annulation cascade transformations with various π-component partners.…”

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

“…For a long time this procedure has received little attention due to the requirement for rather extreme reaction conditions. However, the use of microwave radiation in combination with Lewis acid catalysis allows the reaction to be conducted much more efficiently [32]. This gives mid range yields (50–70%) of the 2-arylindoles over the two step sequence and tolerates a selection of functional groups on the aniline ring.…”