Multicomponent Approach to the Synthesis of 4-(1 H -indol-3-yl)-5-(4-methoxyphenyl)furan-2(5 H )-one

: A simple one-pot approach was developed for the synthesis of furan-2(5 H )-one derivative containing indole fragments. This method includes the telescoped multicomponent reaction of indole, 4-methoxyphenylglyoxal, and Meldrum’s acid. The synthetic utility of the prepared furan-2(5 H )-one was demonstrated by condensation with 4-methoxybenzaldehyde. The advantages of this method include the employment of readily accessible starting materials, atom economy, process simplicity, and the easy isolation of the target products. The structure of the synthesized furanones was conﬁrmed by 1 H and 13 C-NMR spectroscopy and high-resolution mass spectrometry with electrospray ionization (ESI-HRMS).

Various methods for the synthesis of the butenolide core are described in the literature. Most often, gamma-keto acids and their derivatives are used as starting compounds [11,12], the intramolecular cyclization of which leads to furan-2-ones. Another common approach is the use of transition-metal-catalyzed coupling reactions [13,14]. Although many methods are known regarding the synthesis of furan-2(5H)-one moiety [15][16][17][18], some examples of multicomponent reactions (MCRs) used for the preparation of γ-butenolides are presented in the literature [19][20][21][22][23].
It should be noted the indole is one of the most widespread classes of heterocyclic compounds presented in the variety of natural products and synthetic biologically active substances [24][25][26][27][28]. In this regard, the introduction of an indole substituent into the structure of furan-2(5H)-one can led to the essential modification of the pharmacological properties. Thus, the elaboration of a novel multicomponent approach to the synthesis of furan-2(5H)-ones containing indole substituents is of great interest.

Results and Discussion
Herein, we disclosed a highly efficient approach to 4-(1H-indol-3-yl)-5-(4-methoxyphenyl) furan-2(5H)-one 1 on the basis of the MCR of indole 2, 4-methoxyphenylglyoxal 3, and Meldrum's acid 4 (Scheme 1). Previously, we have shown that the analogous synthesis of substituted furan-2(5H)-ones containing 4H-chromen-4-one fragment is a two-stage telescoped process [26,29]. Wherein, the starting step includes the interaction of components in acetonitrile (MeCN) to form unstable intermediates, which under the action of acidic reagents are transformed into the final products. In the present communication, it was demonstrated that for the synthesis of target compound 1, the optimal conditions are the reflux in MeCN for 1 h with the use of triethylamine as the basic reagent. Further reflux in acetic acid (AcOH) for 30 min allows to synthesizing furanone 1 with a 74% yield. The synthetic utility of the synthesized 4-(1H-indol-3-yl)-5-(4-methoxyphenyl)furan-2(5H)-one 1 is shown by reaction with 4-methoxybenzaldehyde 5. As a result of the interaction, a previously unknown 4-(1H-indol-3-yl)-3-(4-methoxybenzylidene)-5-(4-methoxyphenyl) furan-2(3H)-one 6 was obtained with a 84% yield. The use of an equivalent amount of piperidine in the refluxing ethanol for 1 hour is the optimal conditions for the considered condensation (Scheme 3).

Materials and Methods
All starting chemicals and solvents were commercially available and were used as received. NMR spectra were recorded with a Bruker AM 300 (300 MHz) spectrometer in DMSO-d 6 . Chemical shifts (ppm) were given relative to solvent signals (DMSO-d 6 : 2.50 ppm ( 1 H NMR) and 39.52 ppm ( 13 C NMR)). High-resolution mass spectra (HRMS) were obtained on a Bruker micrOTOF II instrument using electrospray ionization (ESI). The melting points were determined on a Kofler hot stage.
Author Contributions: A.N.K., conceptualization, synthesis, spectroscopic analysis, and writing of the manuscript; B.V.L., conceptualization, synthesis, spectroscopic analysis, and writing of the manuscript; V.G.M., conceptualization, synthesis, spectroscopic analysis, and writing of the manuscript. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data for the compounds presented in this study are available in the Supplementary Materials of this paper.

Conflicts of Interest:
The authors declare no conflict of interest.