Grinding induced catalyst free, multicomponent synthesis of Indoloindole pyrimidine

Highlight

• Liquid assisted hand grinding.

• Pure product without column chromatography.

• High yield.

• Metal free synthesis.

Abstract

A simple, efficient, environmentally friendly, and ethanol assisted mechanochemical approach for the synthesis of Indoloindole pyrimidine has been developed through a simple mortar and pestle under catalyst-free grinding method. The present protocol is green and associated with easy workup step, high yield of product, short reaction time, and bear an extensive range of functional groups.

Introduction

Multicomponent reactions have risen as a successful and incredible tool in current synthetic organic chemistry, because of their esteemed properties. Multicomponent reactions, which give rise to fascinating heterocyclic scaffolds, are exclusively advantageous for the development of several “drug-like” molecules [1], [2].

Indole is one of the most essential and abundant nitrogen-containing heterocycles present in natural products and medicinal products [3]. Compounds having an indole unit show a wide range of biological activities, including antiviral [4], antitumor [5], anticonvulsant [6], anti-inflammatory [7], anti-bacterial [8], and cardiovascular activities [9].

Pyrimidine and its derivatives play a significant role in numerous pharmacological and biological activities, such as antibacterial, anticonvulsant, antiviral, antifungal, and anticancer properties [10], [11]. They are also a fundamental part of nucleic acid RNA and DNA [12]. Derivatives of pyrimidine have been utilized to produce metal-cage complexes, in coordination chemistry, and furthermore function as CDK 4 inhibitors [13]. Substituted pyrimidines are usually found in naturally occurring and biologically active compounds like avitriptan and voriconazole [14]. Furthermore, the substitution of the indole with an extra heterocyclic ring like pyrimidine [15], imidazole [16], oxadiazine pyridine [17], oxazole [18], pyrazole [19] and dihydroimidazole, produced a variety of biologically active compounds. Considering resourceful pharmaceutical properties of indole and pyrimidine moieties and to enhance the biological and pharmacological activity of indole, we synthetically attached the pyrimidine moiety to obtain potent molecules with better biological activity. Some example containing indole moieties are given below (Fig. 1).

Due to the fascinating biological properties, several methodologies have been developed for the construction of indoloindolpyrimidine derivatives [20]. Nevertheless, many of these approaches have shortcomings, such as harsh reaction conditions, restricted accessibility of starting materials, and the uses of costly metal catalysts. Therefore, developing effective and new methods for the synthesis of indoloindolpyrimidine derivatives by easily accessible starting materials is of great significance. Enaminones are versatile and powerful building blocks that have been extensively used in the synthesis of a variety of biologically active heterocycles [21].

Simple grinding methods by using mortar and pestle have taken a central place as a highly valuable approach with the advantages of simple experimental setup, energy efficient, economical and ecologically favorable procedure, and the accessible complexity of the very large number of compounds [22], [23], [24].

In view of the above and as a part of our ongoing research on the synthesis of biologically active heterocyclic compounds [25], [26], we report herein an efficient and new protocol for the synthesis of indoloindolpyrimidine derivatives through a one-pot, multicomponent reaction of isatin derivatives (1), 1,3 diketones (2) and enaminones (3) under the grinding condition for 2 h with excellent yield (86–93% yields, Scheme 1).