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. 2024 May 6;9(19):20728–20752. doi: 10.1021/acsomega.4c02677

A Comprehensive Review on Benzofuran Synthesis Featuring Innovative and Catalytic Strategies

Aqsa Mushtaq †, Ameer Fawad Zahoor †,*, Sajjad Ahmad ‡, Muhammad Jawwad Saif §, Atta ul Haq †, Samreen Gul Khan †, Aamal A Al-Mutairi ∥, Ali Irfan †,*, Sami A Al-Hussain ∥, Magdi E A Zaki ∥,*
PMCID: PMC11097366  PMID: 38764672

Abstract

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Benzofurans have intrigued both pharmaceutical researchers and chemists owing to the medicinal usage of their derivatives against copious disease-causing agents (i.e., bacteria, viruses, and tumors). These heterocyclic scaffolds are pervasively encountered in a number of natural products and drugs. The ever-increasing utilization of benzofuran derivatives as pharmaceutical agents persuaded the chemists to devise novel and facile methodological approaches to assemble the biologically potent benzofuran nucleus. This review summarizes the current developments regarding the innovative synthetic routes and catalytic strategies to procure the synthesis of benzofuran heterocycles with their corresponding mechanistic details, reported by several research groups during 2021–2023.

1. Introduction

Heterocycles are the main components of most of the biologically active compounds.1 Benzofuran is one of the significant heterocyclic scaffolds, constituting the structural framework of medicinally important organic compounds. A fused benzene ring with a furan core is collectively named as “benzofuran”, which is also written as benzo(b)furan. In 1870, Perkin was the first chemist to synthesize the benzofuran ring.2 Since then, this heterocyclic ring has found numerous applications in the diverse fields of daily life. To date, various benzofuran derivatives have been synthesized which are known to play an efficacious role in medicinal, agricultural, and synthetic chemistry.3,4 The general structure of the benzofuran heterocycle is illustrated in Figure 1.

Figure 1.

Figure 1

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Structural framework of the benzofuran core.

Benzofuran derivatives have been found to be active against bacterial,5−9 viral,10,11 inflammatory,12 and protozoal diseases.13 For example, diabetes,14 HIV, tuberculosis,15 epilepsy,16 and Alzheimer’s disease17 are some of the most common and widely occurring diseases, against which benzofuran derivatives have been known to play a therapeutic role. In addition, these are effective against a variety of cancers18−21 and are also employed as efficient pain killers.22,23 They also act as efficient enzyme inhibitors, i.e., carbonic anhydrase,24,25 tyrosinase,26 topoisomerase I,27 farnesyl transferase,28 LSD1 (lysine specific demethylase 1),29 and histamine receptor inibitors.30 Furthermore, benzofuran derivatives are also widely harnessed in the preparation of different polymers, i.e., polyamides, polyarylates, polybenzimidazoles, and polyesters.31,32 They have also found applications in the synthesis of several dyes including dye-sensitized solar cells and industrial dyes.33,34

The synthesis of natural products has gained huge importance owing to its significant impact in medicinal chemistry.35 Most of the naturally occurring organic compounds are embodied with benzofuran heterocycles, particularly the Moraceae family36 and furocoumarins. For example, Mori cortex radicis (the root of a few Morus alba L.) is used against diabetes and to treat constipation as well.37−39 Similarly, the noteworthy members of the furocoumarin class, i.e., angelicin 2, psoralen 4, and 8-methoxypsoralen 3, are used in the treatment of skin diseases (psoriasis).40−43 Another benzofuran-based natural product, i.e., coumestrol 5, is responsible for estrogenic activity44 (Figure 2).

Figure 2.

Figure 2

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Structures of some biologically active naturally occurring organic compounds incorporated with a benzofuran nucleus.

Likewise, benzofuran-endowed clinically acknowledged drugs include dronedarone 6 and amiodarone 7, which inhibit the fast rhythm of the heart. Benzbromarone 8 is another benzofuran-based drug, used for the treatment of gout. Similarly, saprisartan 9 is used to control high blood pressure45 (Figure 3).

Figure 3.

Figure 3

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Structures of some clinically acknowledged drugs incorporated with a benzofuran nucleus.

Considering the medicinal applications of benzofuran derivatives, several methods are reported each year contributing toward their synthesis.46−54 Most common methods include the reaction of salicylaldehyde with ethylchloroacetate47/ethylbromoacetate48−50 or with α-haloketone51/acetone.52 Earlier methods also involved the treatment of hydroxy-substituted acetophenones/halogen-substituted acetophenones with ketones to attain the synthesis of benzofuran heterocycles.53,54

Many review articles covering the versatile synthetic approaches for benzofuran synthesis have been published by different research groups.55,56 Bhargava et al. in 2017 and later Miao et al. in 2019 presented reviews on the synthetic pathways toward the synthesis of medicinally important benzofurans and their derivatives.57,58 Recently, in mid-2022, another review reporting the biological applications and synthetic strategies to achieve benzofurans was published by Dwarakanath and Gaonkar.59 Since then, there has been a lot of advancement in the development of novel and efficient synthetic strategies to obtain benzofuran derivatives. This review provides an overview of all the novel and innovative protocols contributing toward the synthesis of a benzofuran nucleus along with their mechanistic details, reported during 2021–2023.

2. Precedented Approaches

2.1. Benzofuran Synthesis via Transition-Metal-Induced Catalysis

Transition metals are of irresistible significance, as they are used to catalyze a number of organic reactions, thus resulting in the synthesis of numerous organic compounds. They have also found considerable importance regarding the construction of a benzofuran nucleus. Isolated as well as bimetallic catalytic systems have been reported to construct a benzofuran core. This category involves the utilization of individual transition metals and their salts as catalytic systems for benzofuran synthesis.

2.1.1. Benzofuran Synthesis via Copper-Based Catalyst

Benzofuran derivatives containing a thiophene ring, i.e., benzothieno[3,2-b]benzothiophene (BTBT), are known to play a crucial role in the buildout of highly efficient organic photovoltaics. They are efficiently utilized for the construction of field-effect transistors along with other photoelectronic devices.60 Based on the utilization of BTBT in the framework of these optical devices, various thiophene-substituted benzofuran derivatives have been synthesized by researchers, namely BTBF and BFBF.61,62 Being persuaded by the earlier reported work in this field, Ai et al.63 in 2021 carried out the O–H/C–H coupling reaction by intramolecular dehydrogenation that resulted in high yields of target molecules. For this purpose, benzothiophene derivative 10 was made to react with the copper catalyst in the presence of cesium carbonate (acting as base) and pyridine (as solvent) (Scheme 1). The reaction mechanism was proposed to initiate with the abstraction of a proton, followed by radical transfer between benzothiophene derivative 10 and a Cu catalyst to generate intermediate B. The resulting intermediate was then subjected to cyclization, oxidation (via copper acetate), and deprotonation (by using base) to synthesize benzofuran derivatives 11 (Figure 4). This established novel synthetic route was also employed toward the gram-scale synthesis of target molecules.

Scheme 1. Synthesis of Benzofuran Derivatives 11 by Using a Copper-Based Catalyst.

Scheme 1

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Figure 4.

Figure 4

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Proposed mechanism for the synthesis of benzofuran derivatives 11 by using a copper-based catalyst.

Owing to the significance of copper-based catalysts in several organic transformations,64,65 Weng et al. also proposed a novel copper-catalyzed methodology to obtain benzofuran derivatives with their gram-scale synthesis.66 They treated substituted salicylaldehyde-derived Schiff bases 12 and substituted alkenes 13 by utilizing copper chloride as a catalyst and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base in dimethylformamide solvent, thus attaining trifluoroethyl-substituted benzofuran derivatives 14 in efficient yields (45–93%) (Scheme 2). The reaction mechanism was presumed to proceed by the coupling of intermediate A (obtained by treating 12 with base) with copper acetylide (achieved by the treatment of substituted alkenes 13 with CuCl) to generate intermediate B. The intermediate B then underwent reductive elimination followed by acidification and rearrangement to prepare benzofuran derivatives 14 (Figure 5).

Scheme 2. Synthesis of Benzofuran Derivatives 14 by Using Copper-Based Catalyst.

Scheme 2

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Figure 5.

Figure 5

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Proposed mechanism for the synthesis of benzofuran derivatives 14 by using copper-based catalyst.

Contributing to the development of novel methods to obtain a benzofuran ring, Abtahi and Tavakol67 reported a green and environmentally benign approach. They carried out a one-pot synthesis by reacting different o-hydroxy aldehydes 15, amines 17, and diversely substituted alkynes 16 in the presence of copper iodide (acting as a catalyst). Moreover, they furnished the synthesis of benzofuran derivatives by availing the use of eco-friendly deep eutectic solvent (DES), i.e., choline chloride-ethylene glycol (ChCl.EG). DESs are known for their ability to stabilize the polar intermediates as well for speedy transformations. The chloride ion in DES also entails the ability to behave as a weak base. A number of different benzofuran derivatives were synthesized by using these catalyst and solvent conditions in good to excellent yields (70–91%). It was observed that high yields of target molecules were attained by employing electron-donating substituted salicylaldehydes as precursors. The reaction mechanism was proposed to proceed via iminium ion formation, followed by the attack of copper acetylide A on the iminium ion. The intermediate A was then transformed to generate benzofuran derivatives 18 as a result of intramolecular cyclization and isomerization (Scheme 3).

Scheme 3. Synthesis of Benzofuran Derivatives 18 by Using Copper-Based Catalyst.

Scheme 3

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In 2021, Ma et al.68 reported another efficient one-pot strategy yielding benzofuran derivatives 19 by treating substituted amines 17, salicylaldehydes 15, and calcium carbide (used to generate alkynes). The one-pot reaction involved the utilization of copper bromide, sodium carbonate, water, and dimethyl sulfoxide to afford amino-substituted benzofuran skeletons 19 in high yields (Scheme 4). This synthetic protocol is a potential gateway to achieve medicinally essential benzofuran derivatives. The plausible reaction pathway involved the formation of iminium ion B that proceeded by the attack of copper acetylide (which was obtained by the hydrolysis of calcium carbide followed by the utilization of cuprous bromide) to generate intermediate C. The intermediate C then afforded benzofuran derivatives 19 via intramolecular nucleophilic attack and isomerization (Figure 6).

Scheme 4. Synthesis of Benzofuran Derivatives 19 Using Copper-Based Catalyst.

Scheme 4

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Figure 6.

Figure 6

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Proposed mechanism for the synthesis of benzofuran derivatives 19 by using a copper-based catalyst.

2.1.2. Benzofuran Synthesis via Palladium-Based Catalyst

Palladium metal has been widely employed for the synthesis of various organic compounds69 as well as for benzofuran dervatives.70 Luo et al.71 carried out the synthesis of benzoyl-substituted benzofuran heterocycles 22 by treating aryl boronic acid 20 with 2-(2-formylphenoxy) acetonitriles 21 via palladium acetate-catalyzed reaction. A wide range of substituted reactants were employed in standard reaction conditions [(Pd(OAc)2 (30 mol %) as catalyst, bpy as ligand (30 mol %), toluene as solvent, and at 90 °C] to analyze the substrate scope of this novel synthetic methodology. As a result, a series of substituted benzofurans 22 was attained in moderate to excellent yields (58–94%). The reaction was proposed to move forward via transmetalation, which gave rise to intermediate A, followed by the coordination of the nitrile moiety and intramolecular insertion to afford intermediate C. The intermediate C then underwent subsequent hydrolysis and aldol condensation to yield benzofuran derivatives 22. Thus, the synthetic approach yielded target molecules by involving Pd-mediated sp–sp2 coupling with subsequent intramolecular annulation (Scheme 5).

Scheme 5. Synthesis of Benzofuran Derivatives 22 by Using Palladium-Based Catalyst.

Scheme 5

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Another example of palladium-mediated synthesis of benzofuran heterocycles 25 was reported in the same year by Qi et al.72 They accomplished the ligand-free synthesis of benzofuran derivatives 25 by treating 2-(phenylethynyl)phenol 24 and N-(2-iodophenyl)-N-methylmethacrylamides 23 utilizing a palladium-tetrakis(triphenylphosphine) catalyst in the presence of lithium tert-butoxide base and acetonitrile solvent. In this way, alkenes were subjected to aryl furanylation to synthesize numerous benzofuran derivatives, 25 (Scheme 6). Their synthetic route involved the oxidative addition followed by the cyclization process via an intramolecular Heck reaction to give intermediate B. The intermediate B then coordinated with 24, thereby giving intermediate C. In the next step, intermediate C underwent lithium tert-butoxide-base-mediated cyclization followed by reductive elimination to construct the benzofuran scaffolds 25 (Figure 7).

Scheme 6. Synthesis of Benzofuran Derivatives 28 by Using Palladium-Based Catalyst.

Scheme 6

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Figure 7.

Figure 7

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Proposed mechanism for the synthesis of benzofuran derivatives 25 by using a palladium-based catalyst.

In the same year, Semwal et al.73 proposed the palladium-promoted synthesis of benzofuran derivatives via ring formation reaction between imidazo[1,2-a]pyridines 26 and coumarins 27. They treated coumarins and imidazo[1,2-a]pyridines by employing palladium acetate as a catalyst, Cu(OTf)2·H2O as an oxidant, dimethylformamide as solvent, and 1,10-phenanthroline (as an excellent additive and catalyst) to procure benzofuran derivatives (by the removal of CO) in efficient yields (Scheme 7). The reaction mechanism was proposed to proceed via generation of a metal complex as a result of oxidative addition of imidazo-pyridines 26 and coumarins 27. This step was followed by the reductive elimination, insertion of palladium, and removal of carbonyl to generate intermediate D. Later, the oxidation of palladium was carried out by using copper triflate (oxidant), followed by subsequent electrophilic C–H palladation, which ultimately resulted in benzofuran-based fused products 28 by undergoing reductive elimination (Figure 8). The synthesized benzofuran derivatives were found to manifest the fluorescence in the visible light range.

Scheme 7. Synthesis of Benzofuran Derivatives 28 by Using Palladium-Based Catalyst.

Scheme 7

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Figure 8.

Figure 8

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Proposed mechanism for the synthesis of benzofuran derivatives 28 by using a palladium-based catalyst.

Activated carbon fibers are widely exploited in organic reactions due to their efficient resistance against severe chemicals and high temperature. Considering the significance of activated carbon fibers in catalytic systems, Wang et al.74 reported the use of palladium-linked activated carbon fibers as catalyst to furnish benzofuran derivatives 31. In this regard, nitroarenes 29 were made to react with o-alkynylphenols 30 over a heterogeneous catalytic system (activated carbon fibers sustained palladium) involving triphenylphosphine as an oxidant, molybdenum hexacarbonyl as a carbonyl group substitute and reductant, potassium carbonate as a base, and iodine as an additive in water and acetonitrile. Electron-withdrawing substituents on the phenyl ring diminished the yield of benzofuran derivatives and vice versa (Scheme 8). The reaction strategy involved the preparation of iodonium salt by using iodine followed by (triphenylphosphine-mediated) oxidative addition to generate intermediate C. In the next step, insertion of a carbonyl group transformed intermediate C to intermediate D. The intermediate D further carried out the reduction of nitroarenes 29 by using water to generate targeted derivatives 31 via intramolecular nucleophilic reaction (Figure 9).

Scheme 8. Synthesis of Benzofuran Derivatives 31 by Using Palladium-Based Catalyst.

Scheme 8

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Figure 9.

Figure 9

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Proposed mechanism for the synthesis of benzofuran derivatives 31 by using a palladium-based catalyst.

Another example of palladium-catalyzed synthesis of benzofuran derivatives was reported by Sun’s75 group in 2023. In this regard, they treated N-tosylhydrazones 32 (obtained from cyclobutane) and iodobenzene-joined alkynes 33 using bis(triphenylphosphine)palladium(II) dichloride catalyst, PCy3 (tricyclohexylphosphine), as a ligand in the presence of cesium carbonate base and toluene (as solvent) (Scheme 9). The reaction was initiated with the oxidative addition proceeded by carbopalladation with iodobenzenes 33 to generate intermediate B. The intermediate B was then made to react with diazocompounds (obtained by cesium carbonate promoted decomposition of N-tosylhydrazones 32) to attain intermediate C. The obtained intermediate C further underwent migratory insertion of Pd-carbene, followed by γ-hydride elimination and cycloaddition reactions to afford dihydrobenzofurans 34 (Figure 10).

Scheme 9. Synthesis of Benzofuran Derivatives 34 by Using Palladium-Based Catalyst.

Scheme 9

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Figure 10.

Figure 10

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Proposed mechanism for the synthesis of benzofuran derivatives 34 by using a palladium-based catalyst.

2.1.3. Benzofuran Synthesis via Palladium–Copper-Based Catalyst

Considering the utility of Pd- and Cu-catalyzed synthesis of benzofuran heterocycles, the Reddy group76 in 2022 availed the used of both palladium and copper by employing them as catalysts in Sonogashira coupling reaction between terminal alkynes 36/37 and iodophenols 35, which upon intramolecular cyclization resulted in the synthesis of benzofuran derivatives. In the developed approach, copper iodide was employed as a cocatalyst with the (PPh3)PdCl2 catalyst in triethyl amine (base and solvent). It was observed that target molecules were not attained by proceeding the reaction without the addition of cocatalyst, i.e., CuI. This methodology resulted in high yields of target molecules (84–91%). The synthesized benzofuran derivatives were then assessed for their activity as antitubercular agents, i.e., chorismate mutase inhibitors (which inhibits the activity of chorismate mutase enzyme in bacterial action). Among the synthesized compounds, benzofuran derivatives 39(a–c) were found to be active against chorismate muatse with 64–65% in vitro inhibition at 30 mM. Thus, these active compounds can be further utilized to develop efficient antitubercular agents (Scheme 10).

Scheme 10. Synthesis of Benzofuran Derivatives 38 and 39 by Using Pd–Cu-Based Catalyst.

Scheme 10

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2.1.4. Benzofuran Synthesis via Nickel-Based Catalyst

In recent times, the catalytic role of nickel has been utilized by some research groups, thus expanding the transition metal induced synthesis of benzofuran heterocycles.77 In 2021, Zhu78 reported a novel and efficient synthetic methodology toward their synthesis. For this purpose, they utilized the nickel catalyst to provide activation energy for the nucleophilic addition reaction within the molecule, thereby furnishing benzofuran derivatives in noteworthy yields. The results indicated that the use of Ni(OTf)2 as catalyst, 1,10-phenanthroline as ligand, and acetonitrile as solvent led to the high yields of benzofuran derivatives. The reaction pathway involved the combination of nickle salts with the ligand (1,10-Phen), followed by reduction via zinc powder and oxidative addition to generate nickle intermediate A. The generated intermediate A further underwent nucleophilic addition, transmetalation, and finally subsequent removal of metal and water to furnish target molecules 41 in efficient yields (23–89%) (Scheme 11).

Scheme 11. Synthesis of Benzofuran Derivatives 41 by Using Ni-Based Catalyst.

Scheme 11

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2.1.5. Benzofuran Synthesis via Rhodium-Based Catalyst

Among transition-metal-catalyzed organic syntheses, rhodium-based catalysts have acquired considerable weightage.81 Recently, the rhodium-catalyzed multicomponent synthesis of optically active organic compounds has been achieved by Glorius et al.79 In 2022, Kitano et al.80 brought out the synthesis of (C4) substituted benzofurans by rhodium-mediated transfer of vinylene between vinyl carbonate 42 and meta-salicylic acid derivative 43. They treated substituted benzamides 43 with vinylene carbonate 42 in the presence of cyclopentadienyl-based rhodium complex CpRh (as ligand) in a catalytic amount by using tetrachloroethane as a solvent to obtain widely substituted benzofuran heterocycles 44 in low to good yields (30–80%) (Scheme 12). The synthetic pathway was accomplished with four main steps, i.e., C–H activation, migratory insertion, nucleophilic substitution, and β-oxygen elimination, to achieve desired benzofuran derivatives 44 (Figure 11).

Scheme 12. Synthesis of Benzofuran Derivatives 47 by Using Rh-Based Catalyst.

Scheme 12

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Figure 11.

Figure 11

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Proposed mechanism for the synthesis of benzofuran derivatives 44 by using Rh-based catalyst.

In 2022, Zhu et al.82 carried out the arylation and subsequent cyclization between propargyl alcohols 46 and substituted aryl boronic acids 45 via relay rhodium-mediated catalysis to attain chemodivergent generation of benzofuran skeletons. Their synthetic route was processed by involving toluene sulfonic acid and tetrahydrofuran/water within the reaction medium. Substrates with electron-donating substituents have been observed to provide high yields of target molecules 47. The synthetic route involved the β-specified carborhodation, followed by hydrolysis and Bronsted-acid-mediated cyclization to furnish target molecules 47 (Scheme 13).

Scheme 13. Synthesis of Benzofuran Derivatives 47 by Using Rh-Based Catalyst.

Scheme 13

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Facile and direct formation of C–H and C–X bonds is highly attributed to transition-metal-mediated and directing-group-accompanied bond formation.82 There is very limited reported work concerning the C–H alkenylation or (DG migration) with 1,3-diynes due to arduous attainment of stereo- and regioselectivity. In 2023, Gong et al.83 reported the rhodium-catalyzed novel synthesis of a benzofuran ring by C–H directing group migration between 1,3-diynes 49 and N-benzoxyacetamide 48. It was inferred that rhodium-catalyzed annulation in the presence of NaOPiv·H2O (additive) and dichloromethane (solvent) gave higher yields of target molecules 50. The benzofuran derivatives 50 were achieved by undergoing C–H activation, migratory insertion, protonation, and intramolecular substitution (Scheme 14).

Scheme 14. Synthesis of Benzofuran Derivatives 53 by Using Rh-Based Catalyst.

Scheme 14

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2.1.6. Benzofuran Synthesis via Gold- and Silver-Based Catalysts

In 2022, Li et al.84 described a novel approach toward the formation of a benzofuran nucleus by treating alkynyl esters 51 and quinols 52 via gold-promoted catalysis. The use of a JohnPhosAuCl/AgNTf2 catalyst and Ph2SiF2 additive in the presence of dichloroethane gave moderate to good yields. Then, the scope of various electron-donating and -withdrawing group substituted substrates was assessed by applying high yielding reaction conditions (Scheme 15). Their proposed mechanism was initiated by the formation of intermediate A as a result of a combination of a gold catalyst with alkynyl esters 51. The intermediate A then underwent nucleophilic attack by quinols 52 to generate intermediate B, which was further subjected to sigmatropic rearrangement (Claisen), aromatization, and condensation to yield benzofuran heterocycles 53 (Figure 12).

Scheme 15. Synthesis of Benzofuran Derivatives 53 by Using Au- and Ag-Based Catalysts.

Scheme 15

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Figure 12.

Figure 12

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Proposed mechanism for the synthesis of benzofuran derivatives 53 by using Au- and Ag-based catalysts.

The benzofuran-based heterocycle 53a (obtained by applying standard reaction conditions) was further subjected to reduction followed by hydrolysis to attain compound 54. The acid 54 was later transformed to benzofuran derivatives 55 which exhibit high potency against various microbes. Thus, gold-promoted cyclization between alkynyl esters and quinols paved the pathway toward the generation of medicinally active benzofuran derivatives 55 (Scheme 16).

Scheme 16. Synthesis of Biologically Active Benzofuran Derivatives 55.

Scheme 16

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Taking into account the unparalleled contribution of benzofuran-substituted heterocycles in pharmaceutical chemistry, Hu et al.85 in 2022 utilized silver-based catalyst, i.e., AgNTf2, for Friedel-Crafts propargylation, Michael addition, and hydride shift between phenol 56 and CF3-substituted propynols 57 to yield benzofuran derivatives 58 in excellent yields. Similarly, Hashmi’s group86 employed a bimetallic catalytic system, i.e., gold–silver (Ph3PAuCl/AgNTf2/Phen), to contribute toward the synthesis of heterocyclic organic compounds. They utilized the oxidation–reduction characteristics of gold with its ability to activate the carbophilic (π) acidity. They reported the synthesis of benzofuran heterocycles 60 by treating readily accessible substituted phenols 56 with alkynylbenziodoxoles 59 over a Au–Ag bimetallic catalyst. The reaction proceeded via alkynylation and oxyalkynylation to give alkyne-substituted benzofurans 60 regioselectively (Scheme 17).

Scheme 17. Synthesis of Benzofuran Derivatives 58 and 60 by Using Au- and Ag-Based Catalysts.

Scheme 17

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2.1.7. Benzofuran Synthesis via Ruthenium-Based Catalyst

In 2021, Zheng and co-workers87 reported the synthesis of benzofuran derivatives 64 by ruthenium-catalyzed reaction between alkynes 62 and m-hydroxybenzoic acids 61. The reaction proceeded via C–H alkenylation of m-hydroxybenzoic acids followed by oxygen-induced annulation by employing magnesium acetate as a base and γ-valerolactone (GVL) as a solvent to carry out facile aerobic oxidation. It was interpreted that benzoic acids substituted with electron-withdrawing groups, i.e., Cl, Br, CF3, and OH, resulted in lower yields of target molecules as compared to those with electron-donating groups, i.e., CH3 and OCH3 (−ve inductive and +ve resonance effect) (Scheme 18).

Scheme 18. Synthesis of Benzofuran Derivatives 64 by Using Ru-Based Catalyst.

Scheme 18

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Substituted alkyne 65 and methoxy-substituted hydroxy-benzoic acid 66 were treated under standard conditions to synthesize benzofuran derivatives 67 and 67′. These derivatives were subjected to reaction in the presence of trifluoroacetic acid followed by demethylation via BBr3 to achieve a naturally occurring biologically active benzofuran-constituting organic compound, i.e., diptoindonesin G 68(88) (Scheme 19).

Scheme 19. Synthesis of Diptoindonesin G 68 by Using Ru-Based Catalyst.

Scheme 19

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Similarly, Kotha et al.89 treated substituted phenols 56 with allyl bromide in the presence of acetone and potassium carbonate to obtain diallyl compound 69. The diallyl compound 69 was further reacted in the presence of a ruthenium-based catalyst and toluene, followed by subsequent treatment using a Grubbs II generation catalyst to obtain benzofuran derivatives 70 (Scheme 20).

Scheme 20. Synthesis of Benzofuran Derivatives 70 by Using Ru-Based Catalyst.

Scheme 20

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The benzannulation strategy was further extended to achieve the total synthesis of biologically potent phenylpropanoids. Compound 71 was subjected to olefin migration by using potassium tert-butoxide followed by DDQ-mediated oxidation to obtain the aldehyde derivative in 77% yield. The aldehyde moiety was then subjected to ring conversion metathesis under standard conditions to obtain 7-methoxywutaifuranal 72. The naturally occurring 7-methoxywutaifuranal 72 afforded 7-methoxywutaifuranol 73 in 96% yield upon reduction. On the other side, an esterification reaction was carried out to convert 7-methoxywutaifuranal 72 to 7-methoxywutaifuranate 74 in 90% yield. These naturally occurring phenylpropanoids act as anticancer and antidiabetic agents. Moreover, they have also been found to be effective against inflammatory, bacterial, and heart diseases90 (Scheme 21).

Scheme 21. Synthesis of Phenylpropanoids 72–74 by Using Ru-Based Catalyst.

Scheme 21

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2.2. Benzofuran Synthesis via Lewis-Acid-Based Catalysis

Lewis acids are among the most widely used catalysts that usually decrease the activation energy by harmonizing the reactant’s lone pair with the lowest unoccupied orbital (LUMO). The potential of Lewis acids to assimilate the electron pairs actually governs the productivity of the reaction.91 In 2021, Reddy et al.92 executed Lewis-acid-catalyzed reaction (Domino reaction) toward the synthesis of benzofuran derivatives. They employed a boron trifluoride diethyl etherate promoted Domino reaction between 2,4-diyn-1-ols 75 and dicarbonyl compounds 76 in the presence of base. This novel synthetic route proceeded through Lewis-acid-promoted propargylation, followed by potassium carbonate-mediated intramolecular cyclization, isomerization, and finally benzannulation to procure benzofuran derivatives 77 in efficient yields (75–91%). The synthetic strategy was also applied to generate the three naturally occurring eustifoline D analogues 77(g–i), obtained by treating 75g as a precursor, which are of great pharmaceutical significance owing to the presence of a biologically active carbazole scaffold93 (Scheme 22).

Scheme 22. Synthesis of Benzofuran Derivatives 77 by Using Lewis Acid As a Catalyst.

Scheme 22

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In 2021, Liu et al.94 reported the iron-chloride-catalyzed ring-closing reaction between trifluoromethylselenolating reagent 78 and substituted alkynyl benzenes 79 utilizing toluene as solvent to furnish substituted benzofuran derivatives 80. The reaction was proposed to be accomplished via Lewis-acid-promoted intramolecular cyclization (Scheme 23).

Scheme 23. Synthesis of Benzofuran Derivatives 80 by Using Lewis Acid As a Catalyst.

Scheme 23

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Similarly, recently in this year, the Yang group95 also reported a novel and facile Lewis acid (scandium triflate) promoted synthetic route toward the construction of benzofuran scaffolds. They demonstrated scandium triflate-mediated [4 + 1] cycloaddition of isocyanide and o-quinone methides (prepared within the reaction from o-hydroxybenzhydryl alcohol 81) employing toluene as solvent to acquire substituted aminobenzofurans 82 in eco-friendly conditions. Similarly, the synthesis of amino-substituted benzofurans 84 was reported by Lin et al.96 in 2022, via scandium-triflate-catalyzed [4 + 1] cycloaddition between isocyanide 83 and ortho-quinone methides. This novel synthetic methodology is highly efficient and high yielding with moderate reaction conditions involving nucleophilic addition, cyclization, and isomerization (Scheme 24).

Scheme 24. Synthesis of Benzofuran Derivatives 82 and 84 by Using Lewis Acid As Catalyst.

Scheme 24

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2.3. Benzofuran Synthesis via Bronsted-Acid-Mediated Catalysis

For the construction of carbon–carbon bonds, Bronsted-acid-mediated reactions have gained substantial significance in organic synthesis.97 Taking into account the efficiency of Bronsted-acid-catalyzed reactions, Chen et al.98 in 2022 proposed the triflic-acid-mediated reaction of substituted quinone imine ketals (QIK) 86 with substituted dicarbonyl compounds 85 involving water and HFIP (hexafluoroisopropanaol) medium to achieve substituted benzofuran cores 87 in high yields (Scheme 25).

Scheme 25. Synthesis of Benzofuran Derivatives 87 by Using Bronsted Acid As Catalyst.

Scheme 25

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Another example of triflic-acid-mediated synthesis of benzofuran derivatives was presented by Mandal and Balamurugan99 by using o-alkynylphenols. This novel synthetic approach proceeded by the protonation of vinylogous esters 88 (obtained via o-alkynyl phenols) by TfOH to obtain oxocarbenium ion A, which was then followed by the addition of alkyne to release vinyl triflate B. This vinyl triflate B was then subjected to the oxa-Michael reaction, finally leading to the synthesis of substituted benzofuran derivatives 89. HFIP was selected as solvent for the developed synthetic route owing to its ability to stabilize the charged intermediates (Scheme 26 and Figure 13).

Scheme 26. Synthesis of Benzofuran Derivatives 89 by Using Bronsted Acid As Catalyst.

Scheme 26

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Figure 13.

Figure 13

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Proposed mechanism for the synthesis of benzofuran derivatives 89 by using Bronsted acid as catalyst.

In 2021, Pirouz et al.100 proposed the heterocyclic ring formation by treating benzoquinones 91 and compound 90 via a one-pot synthetic protocol. This novel methodology proceeded via an acetic acid catalyst, employing toluene as solvent to yield benzofuran derivatives. Acetic acid protonated the benzoquinone to generate intermediate A, which resulted in the synthesis of benzofuran derivative 92 by undergoing ring opening, addition of water, oxidation, and lactonization (Scheme 27).

Scheme 27. Synthesis of Benzofuran Nucleus 92 by Employing Bronsted Acid As Catalyst.

Scheme 27

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2.4. Benzofuran Synthesis via Visible-Light-Mediated Catalysis

Considering the wide utilization of visible-light-promoted organic reactions,101 in 2022, Li et al.102 carried out the novel synthetic route to synthesize benzofuran heterocycles 94 between disulfides and enynes 93 to afford high yields of benzofuran heterocycles. Their synthetic route began with the generation of an enyene peroxo radical, followed by the formation of peroxoenynthio intermediate A, which further underwent a 1,5-proton transfer reaction in N-methyl pyrrolidone (NMP) solvent to yield benzofuran derivatives 94 by the removal of the hydroxyl group. The reaction pathway was also utilized to carry out the gram-scale synthesis of target molecules. In the same year, Liu et al.103 also employed visible-light-mediated cyclization to achieve carbonyl and hydroxyl group substituted benzofuran heterocycles 96. They treated 1,6-enynes 93 and bromomalonates 95 via visible-light-promoted cyclization without employing any photocatalyst, oxidant, transition metal, and additive, thereby reporting an atom-economic synthetic protocol. This reaction route involved the radical-mediated pathway involving 5-exo-dig cyclization, nucleophilic substitution, and aromatization to afford target molecules 96 (Scheme 28).

Scheme 28. Visible-Light-Mediated Synthesis of Benzofuran Derivatives 94 and 96.

Scheme 28

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2.5. Base-Catalyzed Benzofuran Synthesis

Among the recently employed synthetic pathways toward the synthesis of benzofuran derivatives, various bases have been utilized as catalysts for the construction of these heterocyclic scaffolds. In 2022, Koca et al.104 reported the use of triethylamine as a basic catalyst in the Rap–Stoermer reaction to obtain benzofuran derivatives 99 (Scheme 29). In their synthetic methodology, α-haloketones 98 were treated with diversely substituted salicylaldehydes 97 via triethylamine-catalyzed Dieckmann-like aldol condensation in neat conditions that resulted in remarkable yields (81–97%) of benzofuran derivatives 99 (Figure 14).

Scheme 29. Synthesis of Benzofuran Derivatives 99 by Using Triethylamine As a Catalyst.

Scheme 29

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Figure 14.

Figure 14

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Proposed mechanism for the synthesis of benzofuran derivatives 99 by using triethylamine as a catalyst.

In the same year, the Zhang group105 devised another novel base-mediated synthesis of benzofuran heterocyclic cores. They carried out the transition-metal-free, potassium tert-butoxide-catalyzed synthesis of benzofuran derivatives 101 by treating substituted o-bromobenzylvinyl ketones 100 through intramolecular cyclization, using dimethylformamide as solvent. This novel synthetic approach encompasses a broad range of substituents and has also been applied toward the synthesis of a medicinally significant natural product, i.e., coumestrol 5 (Scheme 30).

Scheme 30. Synthesis of Benzofuran Derivatives 101 and 5 by Using Potassium tert-Butoxide As a Catalyst.

Scheme 30

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In 2023, tert-butoxide was employed as a catalyst toward the synthesis of benzofuran heterocycles 103 in the presence of dimethyl sulfoxide solvent by Wang’s group106 (Scheme 31).

Scheme 31. Synthesis of Benzofuran Derivatives 103 by Using tert-Butoxide As a Catalyst.

Scheme 31

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The Reddy group107 proposed a novel methodology by employing nonaromatic precursors to obtain benzofuran derivatives 105. They employed DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) promoted cyclization (5-exo-dig cyclization) of 2-propargyl cyclohexenone 104 followed by oxidation-induced formation of a benzene ring utilizing oxone as an oxidant. The direct approach toward the procurement of target molecules and mild and atom-economic reaction conditions are some of the essential features of this developed protocol (Scheme 32).

Scheme 32. Synthesis of Benzofuran Derivatives 105 by Using DBU As a Catalyst.

Scheme 32

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2.6. Catalyst-Free Benzofurans Synthesis

Catalyst-free synthesis has gained a valuable place in novel methodologies regarding the synthesis of benzofuran derivatives. Yu et al.108 reported the catalyst-free synthesis of benzofuran heterocycles 108 by successive reactions of hydroxyl-substituted aryl alkynes 106 and sulfur ylides 107 which included the formation of isomers followed by the addition of nucleophile to generate intermediate B. The subsequent cyclization of intermediate B then led to the formation of an aromatic ring. The successive reactions between the substrates were carried out in acetonitrile in the absence of any catalyst to afford tricyclic benzofuran derivatives 108 via a facile manner (Scheme 33 and Figure 15).

Scheme 33. Catalyst-Free Synthesis of Benzofuran Derivatives 108.

Scheme 33

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Figure 15.

Figure 15

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Proposed mechanism for the catalyst-free synthesis of benzofuran derivatives 108.

To further investigate the catalyst-free synthetic pathways, Ranjbari and Tavakol109 treated substituted salicylaldehydes 15 with diversely substituted nitro epoxides 109 in the absence of catalyst using potassium carbonate and dimethylformamide. As a result, substituted benzofuran derivatives 110 were obtained in efficient yields (33–84%) (Scheme 34). The reaction mechanism was proposed to move forward by deprotonation, followed by epoxide ring opening to generate intermediate B. The intermediate B further underwent intramolecular cyclization followed by the elimination of water to yield benzofuran derivatives 110 (Figure 16).

Scheme 34. Catalyst-Free Synthesis of Benzofuran Heterocycles 110.

Scheme 34

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Figure 16.

Figure 16

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Proposed mechanism for the catalyst-free synthesis of benzofuran derivatives 110.

Another catalyst-free, one-pot approach toward the synthesis of benzofuran derivatives was described by Mundhe et al.110 recently. They carried out the condensation reaction between aryl ketones 111 and substituted benzaldehydes 112 to attain α,β-unsaturated ketones 113. These ketones were treated with phenacyl bromides 114 via potassium-carbonate-mediated alkylation followed by subsequent condensation to furnish required benzofuran derivatives 115 in a facile manner (Scheme 35).

Scheme 35. Catalyst-Free Synthesis of Benzofuran Derivatives 115.

Scheme 35

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2.7. Benzofuran Synthesis by Employing Miscellaneous Synthetic Strategies

2.7.1. Benzofuran Synthesis via an Electrochemical Approach

The Doerner group111 reported the synthesis of benzofuran derivatives by employing electrochemical conditions. They carried out the cyclization of 2-alkynylphenols 117 and various diselenides 116 in the presence of platinum electrodes using acetonitrile as the solvent, thereby providing substituted benzofuran heterocycles 118 in high yields. The synthetic pathway involved the formation of seleniranium intermediate A, which further underwent nucleophilic cyclization to furnish benzofuran derivatives 118 (Scheme 36).

Scheme 36. Electrochemical Induced Synthesis of Benzofuran Heterocycles 118.

Scheme 36

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2.7.2. Benzofuran Synthesis via Interrupted Pummerer Reaction

In 2022, Kobayashi et al.112 envisioned the synthesis of benzofuran derivatives by treating phenol 119 and alkynyl sulfoxide 120 via interrupted Pummerer reaction. Numerous derivatives of benzofuran heterocycles 121 have been prepared by this novel methodology considering the facile accessibility of alkynyl sulfoxides (Scheme 37). The synthetic pathway was proposed to be accomplished by involving electrophilic activation of alkynyl sulfoxides 120 with trifluoroacetic acid anhydride proceeded by nucleophilic substitution with phenol 119 to generate intermediate B via an interrupted Pummerer reaction. The intermediate B then underwent sigmatropic rearrangement and deprotonation to yield target molecules 121 (Figure 17).

Scheme 37. Synthesis of Benzofuran Nucleus 121 by Employing an Interrupted Pummerer Reaction.

Scheme 37

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Figure 17.

Figure 17

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Proposed mechanism for the synthesis of benzofuran heterocycles 121 by employing an interrupted Pummerer reaction.

2.7.3. Benzofuran Synthesis by Employing Wittig Reaction

Liou et al.113 demonstrated the synthesis of alkenyl-substituted benzofuran derivatives 124 by phosphine-catalyzed Wittig reaction. At first, o-acylated nitrostyrenes A were obtained by treating nitrostyrenes 122 with substituted acyl chlorides 123 using triethylamine. o-Acylated nitrostyrenes A were then subjected to reaction with phosphine [which was obtained within the reaction mixture from the reduction of phosphine oxide (OPR3) and PhSiH3] via Phospha–Michael addition. The resulting phosphonium ylide C on release of nitrous acid underwent Wittig reaction to result in benzofuran derivatives 124 in a one-pot synthesis (Scheme 38 and Figure 18).

Scheme 38. Synthesis of Benzofuran Nucleus 123 by Employing Wittig Reaction.

Scheme 38

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Figure 18.

Figure 18

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Proposed mechanism for the synthesis of benzofuran nucleus 124 by employing the Wittig reaction.

2.7.4. Benzofuran Synthesis by Employing PIDA As an Oxidant

In 2022, Lin et al.114 proposed the synthesis of benzofuran derivatives by utilizing PIDA (phenyliodonium diacetate) as an oxidant in oxidative coupling reaction of hydroquinone 125 and dicarbonyl compounds 76 followed by cyclization. The reaction was carried out in the presence of zinc iodide and phenyl chloride, thereby leading to the efficient synthesis of target molecules 126 (Scheme 39).

Scheme 39. PIDA-Mediated Synthesis of Benzofuran Nucleus 125.

Scheme 39

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2.7.5. Benzofuran Synthesis by Using C-Glycosyltransferase-Based Coumarins As Precursors

Besides the discovery of plant-based C-glycosyltransferase, recently coumarin-based C-glycosyltransferases have also been found. These coumarin C-glycosyltransferases 127 have been employed for the synthesis of benzofuran derivatives by Chen et al. in 2021.115 First, they carried out the total synthesis of coumarin C-glycosyltransferase by adding d-glucose and utilizing MACGT as a (whole cell) biocatalyst. Then, the synthesized coumarin C-glycosidase was cyclized in the presence of sodium hydroxide followed by subsequent acidification to achieve two novel carboxylic acid substituted benzofuran derivatives 128 and 129 (Scheme 40).

Scheme 40. Synthesis of Benzofuran Nucleus 128 and 129 by Using C-Glycosyltransferase-Based Coumarins.

Scheme 40

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2.7.6. Benzofuran Synthesis by Employing HNTf2/TMSOTf

A triflimide/trimethylsilyl trifluoromethanesulfonate-catalyzed, transition-metal-free synthesis of benzofuran heterocycles 131 has been recently proposed by the Tan group.116 They reported the synthesis of a series of substituted benzofuran derivatives 131 by treating substituted aldehydes 112 with substituted o-alkenyl phenols 130 by employing triflimide as a catalyst and trimethylsilyl trifluoromethanesulfonate as an additive in dichloromethane (Scheme 41). The reaction mechanism was proposed to move forward by the TMSNTf2-mediated (obtained by HNTf2 and TMSOTf) generation of intermediate B. The intermediate B was further subjected to a triflic-acid-mediated nucleophilic substitution reaction, followed by the removal of TfOH to furnish benzofuran derivatives 131 (Figure 19).

Scheme 41. Synthesis of 2,3-Disubstituted Benzofurans 131 by Using Triflimide As a Catalyst.

Scheme 41

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Figure 19.

Figure 19

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Proposed mechanism for the synthesis of benzofuran derivatives 131 by using triflimide as a catalyst.

3. Conclusion

This review provides a detailed outlook of all novel and facile synthetic routes to yield benzofuran heterocycles, reported in 2021–2023. Most of the reported methodologies mainly involved the synthesis of benzofuran heterocycles by employing various types of cyclization processes (intramolecular, radical induced, benzannulation, etc.) under various reaction conditions, i.e., Lewis/Bronsted acids, bases, photochemical, as well as catalyst-free conditions. Some protocols also involved cycloaddition reactions, condensation reactions, coupling reactions involving nucleophilic addition, or nucleophilic substitution processes to yield the target molecules. For this purpose, various transition metals, i.e., copper, palladium, nickel, gold, silver, rhodium, ruthenium, etc., have been employed to avail their catalytic usage, thereby furnishing the benzofuran nucleus in high yields. Almost all the recently developed protocols entailed the high yielding and broad substrate scope featuring reaction conditions by utilizing facile precursors; however, a few of the developed strategies could be further extended to explore their beneficiary aspects toward the synthesis of natural products and biologically active organic compounds. Moreover, considering the undeniable toxic effects of environmental pollution, eco-friendly methods have also been devised to achieve benzofuran derivatives in high yields via catalyst-free synthesis. However, these developments are few in number, and their applicability toward the accomplishment of medicinally active organic compounds and natural products has not been explored yet. These findings interpret that there is still room for research to advance the established protocols further to investigate their profitable aspects in medicinal and synthetic organic chemistry.

Acknowledgments

This work was supported and funded by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) (grant number IMSIU-RG23013), Saudi Arabia.

Data Availability Statement

All the data for this study are contained in the manuscript.

Author Contributions

A.M.: Literature review (formal analysis), writing—original draft preparation. A.F.Z.: Conceptualization, resources, writing—review and editing, supervision, project administration. S.A.: Visualization; writing—review and editing, literature survey (formal analysis). M.J.S.: Literature survey (formal analysis), writing—review and editing. A.H.: writing—review and editing, sofware. S.G.K.: software, writing—review and editing. A.A.Al-M.: writing—review and editing, formal analysis, resources. A.I.: Conceptualization, writing—review and editing, visualization, funding acquisition. S.A.Al-H.: Resources, data curation, writing—review and editing, funding acquisition. M.E.A.Z.: Visualization, project administration, writing—review and editing, and funding acquisition.

The authors declare no competing financial interest.

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