RECENT ADVANCES IN THE SYNTHESIS OF PHARMACOLOGICALLY BENIGN COUMARIN AND INDOLE HETERO-STRUCTURED DERIVATIVES: A REVIEW

RECENT ADVANCES IN THE SYNTHESIS OF PHARMACOLOGICALLY BENIGN COUMARIN AND INDOLE HETERO-STRUCTURED DERIVATIVES: A REVIEW

Anil Kumar Bahe and Ratnesh Das ^*

Department of Chemistry, Dr. Harisingh Gour Vishwavidyalaya (A Central University), Sagar - 470003, Madhya Pradesh, India.

ABSTRACT: Indole and coumarin are the most versatile and cogent heterocyclic scaffolds which are not only decisively used in the synthesis of various organic compounds but also play a consequence role in natural product synthesis, modulation of biofilm formation, virulence and stress responses. In last few decades, an individual has witnessed considerable activity towards the synthesis of indole derivatives due to the possibilities for the design of polycyclic structures by the incorporation of multiple fused heterocyclic scaffolds in an attempt to achieve promising new heterocycles with chemical and biomedical relevance. Whereas, coumarin is a 2-oxo-2H-1-benzopyran and, also, have a wide range of application in the pharmaceutical field. In this review, we provide an overview of the synthesis of coumarin and indoles and their pharmacological evolution. The coumarin was synthesized using phenols, salicylaldehyde, benzaldehyde, phenylacetate, styrenes, and cinnamic acid with different catalyst and photocatalyst to give the best yield. Similarly, Indoles were synthesized iodobenzoic acid, alkynes, amines, alcohols, Nitrobenzaldehyde with the different catalyst under conventional and irradiation method. The effect of various catalytic medium, solvents and operational condition are discussed for obtaining the best yield. A comparative account of various reaction pathways like one-pot synthesis (Multicomponent reaction) and the multistep reaction of coumarin and indoles are discussed.

Coumarins, Indoles, Synthesis

INTRODUCTION: Coumarins belong to a large family of heterocyclic compounds with a benzo-a-pyrone moiety, of natural and synthetic origin. Coumarin is the most representative molecule are widely distributed in plants like tonka bean (Dipteryx odorata Wild). It has been extensively used in biochemical and pharmaceutical fields ¹.

Dicoumarol is a naturally occurring anticoagulant, was discovered in moldy, wet sweet-clover hay ². Osthole was found in Cnidium monnieri, and scoparone was found in Artemisia scoparia both have potential pharmacological properties including immune suppression and vasorelaxation ^{3, 4} Fig. 1.

Coumarins have attracted strong scientific interest over the past decades, stemming from their wide spectrum of pharmacological activities, such as antidepressants, ⁵ antimicrobials, ⁶ anti-oxidants, ⁷ anti-inflammatories, ⁸ antinociceptives, ⁹ anti-tumor agents, antiasthmatics, ¹⁰ antivirals (including anti-HIV) ¹¹ and anti-coagulants ¹².

Zacharski et al., demonstrated a beneficial effect of warfarin in cancer patients leading to prolonged survival ¹³. These derivatives have also been shown to be lipid-lowering agents that possess moderate triglyceride-lowering activity ¹⁴. Some reviews have recently summarized many important medicinal properties of coumarin and its derivatives ¹⁵. Furthermore, coumarins are used as lipid-lowering agents with moderate triglyceride lowering activity. The hydroxycoumarins are powerful chain-breaking antioxidants and prevent free radical injury by scavenging reactive oxygen species ¹⁶. Their capacities for inhibition of aromatase are useful in preventing the emergence of menopause-related diseases, i.e., osteoporosis, increased risk of cardiovascular events/heart disease and cognitive deficiencies ¹⁶.

Coumarins also show optical properties, including an extended spectral response, high quantum yields, and superior photostability. The optical applications of these compounds also been investigated, such as safer laser dyes, nonlinear optical chromophores, fluorescent whiteners, fluorescent probes, polymers, optical recording, and solar energy collectors ¹⁷. Moreover, these heterocyclic compounds containing coumarin moieties are widely found as additives in food, in cosmetic products, as pharmaceutical agents ¹⁸ and in luminescent materials ¹⁹.

FIG. 1: EXAMPLE OF BIOLOGICALLY ACTIVE COUMARIN BEARING COMPOUNDS

FIG. 2: EXAMPLE OF PHARMACOLOGICALLY ACTIVE COUMARIN BEARING COMPOUNDS

Compounds containing two or more heterocycles play a vital role in natural and synthetic bioactive compounds ²⁰. In this review, many examples of biologically active coumarins containing hetero-cycles have been cited. The incorporation of another heterocyclic moiety, either as a substituent group or as a fused component into coumarin, creates a change in the properties of the parent material. The resulting compounds may generally demonstrate promising or even unprecedented properties.

For example, neo-anshinlactone, a component isolated from an ethanolic extract of Salviamiltiorrhiza, was 10-fold more potent and 20-fold more selective against breast cancer cells than tamoxifen ²¹. SP500263, a coumarin derivative with piperidine-ethoxy-benzyl side-chain at C-4, bound with high affinity to both estrogen receptor a and b, and functions as a potent antiestrogen in in-vitro and in-vivo models of breast cancer ²². Ensaculin, a coumarin with a piperazine moiety was identified as a unique compound profile of pharmacodynamics effects on the central nervous system and has been tagged as potential support in the treatment of dementia Fig. 2. ²³

The synthesis of 3-benzyl substituted 4-hydroxycoumarins got much attention in recent years, owing to their tremendous application in various research fields including biological sciences and medicinal chemistry. 3-benzyl substituted 4-hydroxycoumarin derivatives are a component of numerous natural products like warfarin, phenprocoumon, coumatetralyl, carbochromen, bromadiolone, Fig. 3 are also shows a widespread biological activities ²⁴.

FIG. 3: BIOLOGICALLY ACTIVE 3- SUBSTITUTED COUMARINS

Methods for Synthesis of Coumarin Derivatives: A variety of methods have been developed for the construction of coumarin and indole framework in which inter or intramolecular C-O and C-C bond are formed for engagement of different group in these heterocycles.

Synthesis of Coumarin using Phenol: A mixture or Ethyl acetoacetate & bismuth chloride as catalyst and ethanol as a solvent were taken in an iodine flask and stirred for 12 h on the Magnetic stirrer. The reaction mixture was poured into crushed ice precipitate separated which is then filtered, dried and recrystallized by ethanol. The reaction was monitored by TLC, and the melting point of the recrystallized sample was determined ²⁵.

FIG. 4: REACTION REPRESENTING SYNTHESIS OF COUMARIN USING PHENOL

TABLE 1: SYNTHESIS OF COUMARIN VIA VON-PACHMANN CONDENSATION OF PHENOL WITH β– KETOESTERS INDUCED BY BICL3 CATALYST AND SOLVENT

S. no.	Substrate	Time (h)	a product	m.p.	% yield
1		12		78 ºC	86
2		12		145-149 ºC	71.57

Synthesis of Coumarin from Salicylaldehyde: The knoevenagel condensation can be successfully used for the synthesis of coumarin by a solvent free reaction under microwave irradiation.

The coumarins were synthesized by the condensation of salicylaldehyde or its derivative with various derivatives of ethyl acetate in the presence of piperidine ^{26, 27}.

FIG. 5: SYNTHESIS SCHEME OF COUMARINS VIA CONDENSATION OF SALICYLALDEHYDE OR ITS DERIVATIVE WITH VARIOUS DERIVATIVE OF ETHYL ACETATE IN THE PRESENCE OF PIPERIDINE

TABLE 2: RESULT OF THE COUMARINS SYNTHESIS BY KNOEVENAGEL REACTION UNDER MICROWAVE IRRADIATION

The solvent-free condition under microwave irradiation offers advantages over expensive, toxic, difficult to remove in the case of aprotic dipolar solvent with high boiling point Solvent are often environment polluting agent. The resulted compound is shown in Table 2 produced with good yield under room temperature reaction condition. All compounds were identified by GC/MS, IR, NMR, and gave satisfactory result in comparison with authentic samples. Melting points are in good agreement with literature data.

Synthesis of Substituted Coumarins by Knoevenagel Condensation of 2-hydroxybenzaldehydes:

FIG. 6: SYNTHESIS SCHEME OF SUBSTITUTED COUMARINS DEVELOPED BY KNOEVENAGEL CONDENSATION OF 2-HYDROXYBENZALDEHYDES REACTS WITH KETONES OR ALDEHYDE

The basic ionic liquid 1-butyl-3-methyl-imidazolium hydroxide, [bmim]OH, efficiently catalyzes the knoevenagel condensation of different aliphatic and aromatic aldehydes and ketones with active methylenes group at room temperature without the requirement of any organic solvent in THF reflux ²⁸.

The ionic liquid, 1-butyl-3-methylimidazolium tetrafluoroborate has also been used for knoevena-gel condensation of aldehydes or ketones with active methylene compound catalyzed by ethylene-diammonium diacetate (EDDA). The catalyst and solvent can be recycled ²⁹.

FIG. 7: SYNTHESIS SCHEME OF COUMARINS USING HYDROXYL BENZALDEHYDE AND KETONES CATALYSED BY EDDA

The synthesis of 4- carboxyalkyl- 8- formyl coumarins have also been developed with the reaction of 2-hydroxybenzaldehydes and triphenylphosphine and dialkyl acetylene dicarboxylate ³⁰.

FIG. 8: SYNTHESIS SCHEME OF 4-CORBOXYALKYL-8-FORMYL COUMARINS

Synthesis of Coumarins Derivatives using Different Solvents:

FIG. 9: SYNTHESIS SCHEME OF COUMARINS

The sodium and lithium telluride-triggered cyclization of bromoacetate of salicylaldehyde to coumarin. The change of the telluride counter ion from sodium to lithium reduced reaction times and increases the yield of coumarin to 75%. ^{31, 32}

TABLE 3: SOLVENT EFFECTS ON YIELD OF COUMARINS 3A (FIG. 9) VIA SODIUM OR LITHIUM TELLURIDE

One-Pot Synthesis of Coumarin:

FIG. 10: REACTION SCHEME FOR ONE-POT SYNTHESIS OF COUMARIN USING BENZALDEHYDE

The use of cyanuric chloride (TCT) [2, 4, 6-trichloro-1, 3, 5-triazine] and N-methyl morpholine (NMM) enables an efficient and general protocol for rapid synthesis of substituted 3-aryl coumarins. A series of substituted phenylacetic acids have been successfully reacted with substituted 2-hydroxybenzaldehydes to give an excellent yield of 3-aryl coumarins ³³.

FIG. 11: SYNTHESIS SCHEME OF COUMARINS VIA REACTION OF PHENYLACETIC ACIDS AND SUBSTITUTED SALICYLALDEHYDE

Synthesis of 4-Hydroxycoumarins: Ring-closing metathesis and one-pot synthesis of coumarins from the corresponding o-carbonylphenols ^{34, 35}

FIG. 12: REACTION SCHEME OF 4-HYDROXYCOUMARINS

 Synthesis of Coumarins from Cinnamic Acid:

FIG. 13: REACTION SCHEME FOR SYNTHESIS OF COUMARINS FROM CINNAMIC ACID USING PHOTOCATALYST

The one-pot synthesis of coumarin using two photochemical and photocatalyst activation modes of (-) –riboflavin sequentially include isomerization and cyclization by energy transfer (ET) and single-electron transfer (SET) activation pathways in an emulation of coumarin biosynthesis pathway via a key photochemical E-Z isomerization step I this reaction the substituted propyl group and low time product will be highest ³⁶.

TABLE 4: SUBSTITUTION, PRODUCT, AND YIELD OF COUMARINS FROM CINNAMIC ACID

R1	R	Product	Time (h)	% Yield
H	H		13.5	79
F	H		48	77
Et	OMe		10	81
CF3	CH3		48	48
Pr	H		13.5	91

Synthesis of Coumarins from Phenyl Acetate: An efficient annulations of phenolic acetates with acrylates, in the presence of [Rh₂(OAc)₄] as a catalyst and formic acid as reducing agent provides a high yield of coumarin derivatives via C-H bond activation. The yield of the product was increased by the addition of NaOAc as a base. The reaction is instantly successful for both electron-rich, and electron-deficient phenolic acetate gives coumarins with excellent regioselectivity ³⁷.

FIG. 14A: SYNTHESIS SCHEME OF COUMARIN FROM PHENOLIC ACETATES REACTION WITH ACRYLATES IN EXISTENCE OF CATALYST

Synthesis of Coumarins from 2-hydroxy-styrenes: In this one-pot synthesis reaction, a direct carboxylation of alkenyl C-H bond of 2-hydroxystyrenes in the presence of catalyst Pd(OAc)₂ and Cs₂Co₃ under atmospheric pressure of CO₂ gives coumarins in excellent yield. The reaction undergoes a reversible nucleophilic addition of the alkenyl palladium intermediate to CO₂. ³⁸

FIG. 14B: SYNTHESIS SCHEME OF COUMARINS FROM 2-HYDROXYSTYRENES TAKING Pd AS CATALYST

The direct synthesis of various coumarin derivatives via palladium-catalyzed oxidative cyclocabonylation of 2-vinylphenols in the presence of low pressures of CO, and air or 1, 4-benzoquinone as the oxidant gives a good yield. The reaction is environmentally benign in terms of condensations and operational simplicity ³⁹.

Three-Components Synthesis of Coumarin Derivatives:

FIG. 15: SYNTHESIS SCHEME OF 3-(5^’-SUBSTITUTED-2^’-BENZOXAZOLYL)-7-DIETHYLAMINOCOUMARINS FROM 4-DIETHYLAMINOSALICYLALDEHYDE, ETHYL CYNOACETATE, AND 4-SUBSTITUTED-2-AMINOPHENOL WITH PENTANOL CONTAINING BENZOIC ACID, REFLUXED FOR 10-12h

These multicomponent reaction (MCR) was conducted with equimolar amounts of starting compounds taking benzoic acid as catalyst and n-pentanol as a solvent with the oil bath temperature at 138 °C for 12 h. The isolated yield is represented in Table 5. The purity is obtained from HPLC analysis after recrystallization. The UV-Vis spectra were observed in methanol ⁴⁰.

TABLE 5: R SUBSTITUTION AND THEIR RESPECTIVE YIELD WITH λ_max (UV-VIS)

Methods for Synthesis of Indole Derivatives:

Synthesis of Indoles from 2-iodobenzoic Acid and Alkynes: These reactions are based on a multi-component process that follows the transformation of readily available one-pot curtius rearrangement palladium-catalyzed indolization process Fig. 16. In this reaction, the 2-iodoaniline intermediate is not isolated and produces a by-product via curtius rearrangement. The formation of 2, 3-dipropyl-1H-indole using a one-pot curtius-indolization process starting from 2-iodobenzoic acid. This substrate was treated under the standard Curtius reaction conditions, which allows the direct conversion of aromatic carboxylic acids into carbamates and ureas _.⁴¹ The CBz protected aniline intermediate was not isolated, but directly reacted with the palladium-catalyzed indolization reaction condition. But a disappointing 29% low yield of the desired indole derivative was obtained when the standard reaction conditions for indolization (including one equivalent of LiCl) were used (Table 6, entry 1). Formerly it has been shown that an excess of a chloride salt in the reaction is detrimental for palladium-catalyzed hetero-annulations ⁴² After optimization conditions, three equivalents of sodium carbonate proved to be the best base and gives 84 % excellent yield (compare Table 6, entries 2–4 and 5-6) ⁴³.

FIG. 16: ONE-POT MULTICOMPONENT SYNTHESIS SCHEME OF INDOLES FROM 2-IODOBENZOIC ACID

TABLE 6: ONE-POT CURTIUS REARRANGEMENT- PALLADIUM-CATALYZED INDOLIZATION STARTING FROM 2-IODOBENZOIC ACID AND 4-OCTYNE

One-Pot Three-Component Synthesis of Indoles:

FIG. 17: ONE-POT REACTION SCHEME OF INDOLES FROM 2-ISOCYANOBENZYL TRIPHENYL-PHOSPHONIUM BROMIDES, ALDEHYDES AND AMINES

In such reactions, where p-toluene sulfonic acid was utilized, the yields of entries 6 and 7 Table 7 was obtained low to 40-50%. When catalyst was used up to 10% resulted in a rather lower yield (44%, entry5). While for entry 4 Table 7 the yield was increased by 72%. When an aromatic aldehyde or amine (R2 or R3=aryl) was used, a good yield of the products was obtained ⁴⁴.

A green multicomponent one-pot synthesis of 2-(1H-indol-3-ylmethyl)-5, 5-dimethyl-cyclohexane-1,3-diones was conveniently carried out in an aqueous medium at room temperature over heterogeneous catalyst as mpCuO, produces excellent yields.

TABLE 7: OPTIMIZATION OF THE REACTION CONDITIONS

Entry	Catalyst (%)	Yield (%)
1	-	0
2	FeCl3 (20)	0
3	(20)	0
4	H3PO4 (20)	72
5	H3PO4 (10)	44
6	TsOH (20)	57
7	TsOH (20)	40

The highly catalytic, maximum surface area and recyclability features make mpCuO a suitable catalyst. The in-vitro antitubercular examination has verified that these compounds are used to generate reliable antitubercular analogs with better selectivity. The porous nano-catalyst has been recycled five times without a significant drop in product yield ^45-47.

FIG. 18: ONE-POT THREE COMPONENT REACTION SCHEME OF INDOLE DERIVATIVES FROM INDOLE, ALDEHYDE AND DIMEDONE CATALYSED WITH GREEN MESOPOROUS CuO

TABLE 8: REACTION CONDITION FOR WATER MEDIATED ONE-POT SYNTHESIS OF 2-1H-(INDOLE-3-YLMETHYL)-5, 5-DIMETHYL-CYCLOHEXANE-1, 3-DIONES

^rtRoom temperature

Synthesis of Substituted Indoles: These reactions were based on N-methyl indole, a substituted benzaldehyde, and N-methylaniline. The reaction conditions were optimized by monitoring a model reaction between substituted indole, 4-chloro-benzaldehyde or 4-methoxy benzaldehyde and N-methylaniline. The acetonitrile solvent was found to be more efficient reaction media and using Yb(OTf)₃-SiO₂ as a catalyst, gives good yield (88%) while the reaction yield investigated in other solvents and other catalyst was very poor ⁴⁸.

FIG. 19: ONE-POT THREE COMPONENT COUPLING REACTION SCHEME OF 3-SUBSTITUTED INDOLES

The 3-substituted indoles are structural units of many natural and biologically interesting compounds, which possess various pharmaco-logically activities. The indole-based derivatives have been investigated for anticancer activities ⁴⁹.

FIG 20: SYNTHESIS SCHEME OF BIS (INDOLYL) METHANE DERIVATIVES CATALYSED BY BENZENESULFONIC ACID AND ACETONITRILE UNDER CONVENTIONAL AND IRRADIATION METHOD

TABLE 9: THE REACTION OF INDOLE WITH 4-NITROBENZALDEHYDE IN THE PRESENCE OF DIFFERENT CATALYST AND EFFECT OF SOLVENTS IN THIS REACTION CATALYZED BY BENZENESULFONIC ACID

The reaction of indole with the 4-Nitrobenzaldehyde compound in the presence of 5-mol% benzene-sulfonic acid in acetonitrile solvent performed to synthesize  3,3’’-((4-Nitrophenyl) methylene) bis (1H-indole) compound is observed that the reaction proceeded in shorter reaction times and times and in high yield in the ultrasonic method than compare to the conventional method. Its synthesized compound was tested for antioxidant activity. Synthesized compound characterized by ¹H NMR, ¹³C NMR, and Mass spectroscopy.

TABLE 10: EFFECT OF CONCENTRATION OF BENZENESULFONIC ACID ON REACTION OF INDOLE WITH 4-NITROBENZALDEHYDE

Synthesis of Indole 2-(2-aminophenyl) Ethanol:

The using Pt/Nb₂O₅ and Pt/HBEA as two of the effective catalysts for this reaction, we carried out detailed catalytic studies. For Pt/Nb₂O₅.

The yield of indole increased with time and reached 93% after 7 h. For Pt/HBEA, the yield of indole reached 95% after 12 h. ⁵⁰

FIG. 21: SYNTHESIS SCHEME OF INDOLE FORM 2(2-AMINOPHENYL) ETHANOL

TABLE 11: HETEROGENEOUS Pt CATALYSTS, GC YIELD, AND TURNOVER NUMBER (TON)

The reactions with 0.2 mol% of Pt/Nb₂O₅ and Pt/HBEA as two of the effective catalysts for this reaction, we carried out 52 h. A green and environmentally benign protocol for electrophilic substitution reaction of indole derivatives with various aldehydes in the water taking squaric acid catalyst provides good yield ^{51, 52}.

FIG. 22: SYNTHESIS SCHEME OF BIS (INDOLYL) METHANE IN WATER FOR GREEN PROCEDURE

TABLE 12: COMPARISON OF THE CATALYTIC EFFICIENCY OF VARIOUS CATALYSTS REPORTED

CONCLUSION: This review summarizes recent advances in the synthesis of pharmacologically important coumarin and indole heterocyclic derivatives. Over past decades, synthesis of coumarins and indoles fused or linked with different heterocycle derivatives has been gaining importance because of their medical chemical and biological applications. The present review is emphasized on the innovative synthesis scheme of substituted coumarin and indoles via green techniques and harmless chemical. Although, this review describes the interesting, green and efficient syntheses strategy of coumarin and indole derivatives to obtaining good yield in less time. But shortly new eco-compatible protocols are strongly expected.

ACKNOWLEDGEMENT: Authors are thankful to Department of chemistry Dr. Harisingh Gour Vishwavidyalaya (A Central University) Sagar, for providing lab facilities and UGC, not NET fellowship assistance. Also, we would like to acknowledge Mr. Amit K. Harit and Dr. Imran Khan for their valuable discussion.

CONFLICT OF INTEREST: The authors declare no conflict of interest.

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    How to cite this article:

    Bahe AK and Das R: Recent advances in the synthesis of pharmacologically benign coumarin and indole hetero-structured derivatives: a review. Int J Pharm Sci & Res 2019; 10(5): 2119-32. doi: 10.13040/IJPSR.0975-8232.10(5).2119-32.

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