Synthesis Of Benzofurans Research Articles

Modular Approach to Benzofurans, 2H-Chromenes and Benzoxepines via Claisen Rearrangement and Ring-Closing Metathesis: Access to Phenylpropanoids.

Benzofurans, 2H-chromenes and benzoxepines are key structural elements present in several natural products and pharmaceuticals. Here, we describe an easy-to-execute strategy for the synthesis of benzofurans, 2H-chromenes and benzoxepines, by employing Claisen rearrangement and ring-closing metathesis as key steps. A variety of phenols were converted into useful oxacycles in good to excellent yields. The ring-closing metathesis approach has been used to produce phenylpropanoid natural products. Examples described here include, the naturally occurring benzofurans such as 7-methoxywutaifuranal, 7-methoxywutaifuranol, 7-methoxywutaifuranate and the O-prenylated natural products like boropinic acid, boropinols A and C.

Pd-catalyzed annulation of imidazo[1,2-a]pyridines with coumarins and indoles: synthesis of benzofuran and indole fused heterocycles.

Palladium-catalyzed annulation of imidazo[1,2-a]pyridines with coumarins provided benzofuran fused transannulated products in good to excellent yields via a decarbonylative approach, while imidazo[1,2-a]pyridines with N-methyl indoles in the presence of palladium and base yielded conjugated imidazopyridine fused indole derivatives. Additional experiments revealed that the presence of the phenyl ring at the C-2 position of imidazo[1,2-a]pyridines is essential for the annulation than the alkyl groups. Both transformations follow the ionic mechanism by Pd-catalyzed double C-H bond activation. All the annulated products were shown to exhibit high fluorescence characteristics and their photophysical properties were evaluated.

TfOH-promoted synthesis of indoles and benzofurans involving cyclative transposition of vinyl ketone.

A metal-free approach to construct indole rings from vinylogous amides derived from o-alkynylanilines involving a cyclization, retro-aza-Michael reaction and amine trapping cascade is reported here. This atom-economical transformation has been extended to synthesize benzofuran derivatives using analogous vinylogous esters derived from o-alkynylphenols. The excellent stereochemical outcome of the double bond geometry in the products makes it attractive.

DFT characterisation of a PdII → IIII adduct, and a PdII complex formed after oxidative alkenylation of PdII by [Ph(alkenyl)IIII]+, in Pd-mediated synthesis of benzofurans involving PdIV, annulation and chain-walking.

The synthesis of benzofurans by the reaction of the palladium(II) complex Pd{1-C6H4-2-OCH(CO2Et)-C,C}(bipy) (bipy = 2,2'-bipyridine) with hypervalent iodine(III) reagents [Ph(CHCHR)I]+ has been examined by Density Functional Theory. Results highlight the role of oxidative alkenylation to form PdIV intermediates and the role of initial adduct formation in this process, an annulation process facilitated by PdII, and the role of 'chain-walking' at PdII centres to allow formation of the lowest energy product. Computation (R = Me) allows assignment of an initially formed adduct with a 'PdII → IIII' interaction at -50 °C, and, after oxidative alkenylation of PdII and reductive elimination from a PdIV centre via Ar⋯Alkenyl coupling, formation of a second intermediate with a structure consistent with NMR detection (R = n-hexyl) at -30 °C is obtained. This PdII complex, containing a coordinated alkene group in Pd{1-(RHCγCβ)C6H4-2-OCαH(CO2Et)-η2-CαCβ,C}(bipy), undergoes a 5-exo-trig annulation by forming a Cα-Cβ bond to give a complex with a bicyclic carbon skeleton suitable for subsequent formation of benzofurans. A series of facile rearrangements including chain-walking results in formation of a lowest energy complex of three feasible hydrido(alkene)palladium(II) species, leading to decomposition and release of the observed benzofuran isomer isolated under synthesis conditions. The computational study allows reinterpretation of the NMR data reported previously, in particular the determination of barriers in the reaction pathway allowing assignment of structure for key intermediates.

Front Cover Picture: Biocatalytic Application of a Membrane‐Bound Coumarin C‐Glucosyltransferase in the Synthesis of Coumarin and Benzofuran C‐Glucosides (Adv. Synth. Catal. 22/2021)

The front cover picture, designed by D. Chen and J. Dai, illustrates the enzymatic synthesis of coumarin C-glucosides by a membrane-bound C-glucosyltransferase MaCGT from Morus alba, a traditional Chinese medicinal herb. The whole-cell biocatalyst harboring MaCGT were developed and displayed efficiently regio- and stereo-specific C-glucosylation capacity towards structurally different coumarins. Details can be found in the communication by Dawei Chen and co-workers (D. Chen, S. Fan, Z. Yang, J. Dai, Adv. Synth. Catal. 2021, 363, 5072–5078; DOI: 10.1002/adsc.202100041).

Design, synthesis, biological evaluation, and molecular docking of new benzofuran and indole derivatives as tubulin polymerization inhibitors.

Microtubules and the mitotic spindle have become an important target for cancer treatment due to their critical role in cell division. In this work, a novel series of benzofuran and indole derivatives were designed and synthesized, to be evaluated as tubulin polymerization inhibitors. 2-Acetylbenzofuran derivatives 1a,b and 3-acetylindole 1c were condensed with Wittig reagents 2a-d and Wittig-Horner reagents 3a-e to afford the respective 2-ethylidene derivatives 5a-j and 7a-e. Also, iminomethylene triphenylphosphine (2e) reacted with 1a,b to afford benzofuran-2-ylethylidene aniline derivatives 6a,b. In addition, compounds 1a,b reacted with trialkylphosphites 4a-c to give 1:1 adduct for which the Oxaphospholo[4,3-b]benzofuran-7-yl)diazene derivatives 8a-f, were assigned. The possible reactions mechanisms were discussed and structural reasoning for the new compounds were based upon spectroscopic data. Their antiproliferative activities against two cell lines namely, HepG2 and MCF7 cells were then evaluated. It was found that the benzofuran compounds 5b, 6a, and 8c exhibited the strongest antiproliferative activities against both cell lines compared to doxorubicin. By studying the mechanism of action, compound 6a showed good inhibition of tubulin polymerization which leads to mitotic spindle formation disruption, cell cycle arrest in the G2/M phase, and apoptosis of HepG2 cells. A conducted docking study confirmed the in vitro results indicating that compound 6a fitted properly at the colchicine binding site of tubulin. Based on these findings, compound 6a can be considered as a promising anticancer candidate that can be subjected for further development as a tubulin polymerization inhibitor for treating liver and breast cell carcinoma.

Experimental and Computational Studies on the Ruthenium-Catalyzed Dehydrative C-H Coupling of Phenols with Aldehydes for the Synthesis of 2-Alkylphenol, Benzofuran, and Xanthene Derivatives.

The cationic Ru-H complex [(C6H6)(PCy3)(CO)RuH]+BF4- (1) was found to be an effective catalyst for the dehydrative C-H coupling reaction of phenols and aldehydes to form 2-alkylphenol products. The coupling reaction of phenols with branched aldehydes selectively formed 1,1-disubstituted benzofurans, while the coupling reaction with salicylaldehydes yielded xanthene derivatives. A normal deuterium isotope effect was observed from the coupling reaction of 3-methoxyphenol with benzaldehyde and 2-propanol/2-propanol-d8 (kH/kD = 2.3 ± 0.3). The carbon isotope effect was observed on the benzylic carbon of the alkylation product from the coupling reaction of 3-methoxyphenol with 4-methoxybenzaldehyde (C(3) 1.021(3)) and on both benzylic and ortho-arene carbons from the coupling reaction with 4-trifluorobenzaldehdye (C(2) 1.017(3), C(3) 1.011(2)). The Hammett plot from the coupling reaction of 3-methoxyphenol with para-substituted benzaldehydes p-X-C6H4CHO (X = OMe, Me, H, F, Cl, CF3) displayed a V-shaped linear slope. Catalytically relevant Ru-H complexes were observed by NMR from a stoichiometric reaction mixture of 1, 3-methoxyphenol, benzaldehyde, and 2-propanol in CD2Cl2. The DFT calculations provided a detailed catalysis mechanism featuring an electrophilic aromatic substitution of the aldehyde followed by the hydrogenolysis of the hydroxy group. The calculations also revealed a mechanistic rationale for the strong electronic effect of the benzaldehdye substrates p-X-C6H4CHO (X = OMe, CF3) in controlling the turnover-limiting step. The catalytic C-H coupling method provides an efficient synthetic protocol for 2-alkylphenols, 1,1-disubstituted benzofurans, and xanthene derivatives without employing any reactive reagents or forming wasteful byproducts.

Front Cover: A Monomer‐Polymer‐Monomer (MPM) Organic Synthesis Strategy: Synthesis and Application of Polybenzofuran for Functionalizing Benzene Ring of Benzofuran (Asian J. Org. Chem. 8/2021)

The cover picture shows a novel Monomer-Polymer-Monomer (MPM) synthetic method for the synthesis of 5-substituted benzofuran (5-E-BF) through the steps of preparation of polybenzofuran (PBF), the regiochemical SEAr reaction of 2,3-dihydrobenzofuran units in PBF with electrophiles (E+) giving E-PBF, and the depolymerization of E-PBF. The down-left light blue gradient background represents the low temperature for polymerization of BF, and the down-right red gradient represents the high temperature for depolymerization of E-PBF. The back of the reaction scheme are the CPK models of BF, PBF, E-PBF, and 5-E-BF indicating the MPM procedure. More information can be found in the Communication by Hua and co-workers.

Biocatalytic Application of a Membrane‐Bound Coumarin C‐Glucosyltransferase in the Synthesis of Coumarin and Benzofuran C‐Glucosides

AbstractA number of plant C‐glycosyltransferases (CGTs) have been recently identified, whereas the coumarin CGTs have not been found. Here we reported the first identification of a coumarin C‐glucosyltransferase MaCGT fromMorus alba. The whole‐cell biocatalyst harboring MaCGT was exploited and exhibited strictly and efficiently regio‐ and stereo‐specific C‐glucosylation capacity toward structurally different coumarins. The whole‐cell of MaCGT was further applied to chemo‐enzymatically synthesize benzofuran C‐glucosides. Moreover, MaCGT is reported as the first characterized membrane‐bound CGT from plants, although sequence homology search has shown other potentially membrane‐bound CGTs fromM. notabilis; and the presence of the transmembrane domain is critical for its catalytic activity and stability as demonstrated by the C‐glucosylation activity of truncated MaCGT proteins. In addition, the key residues involved in the C‐glucosylation of MaCGT were explored. These findings suggest the diversity of CGTs in the plant kingdom and demonstrate the significant potential of biocatalytic approach to produce structurally diverse C‐glycosides for drug discovery.magnified image

One-pot synthesis of benzofurans via heteroannulation of benzoquinones

Abstract Three different reactions were explored leading to the synthesis of various benzofurans. All reactions took place under AcOH catalysis in a one-pot manner. As a result, benzoquinone derivatives underwent heteroannulation with either itself or cyclohexanones to produce furanylidene-benzofuran or benzofuran structures, respectively.

Recent Advances in the Microwave Assisted Synthesis of Benzofuran and Indole Derivatives

Recent Advances in the Microwave Assisted Synthesis of Benzofuran and Indole Derivatives

Furan oxidation by Mn(iii)/Co(ii) catalysts - application to benzofuran synthesis.

Furans containing a β-ketoester group at 2-position undergo oxidative ring-opening by Mn(iii)/Co(ii) catalysts under an O2 atmosphere to produce 1,4-dicarbonyl moieties through an endoperoxide intermediate, which consecutively cyclized with the β-ketoester unit to afford 4-hydroxy-2-cyclohexen-1-ones. This oxidation/cyclization products were efficiently transformed into versatile benzofuran derivatives after consecutive aromatization and Paal–Knorr reaction.

Synthesis, anticancer and antimicrobial evaluation of new benzofuran based derivatives: PI3K inhibition, quorum sensing and molecular modeling study

A new series of benzofuran derivatives has been designed and synthesized. The structures of the synthesized compounds have been confirmed by the use of 1H NMR, 13C NMR, 2D 1H–1H NOESY NMR, and IR. Anticancer activity is evaluated against Hepatocellular carcinoma (HePG2), mammary gland breast cancer (MCF-7), Epitheliod carcinoma cervix cancer (Hela) and human prostate cancer (PC3). Compounds 8, 9, and 11 showed the highest activity towards the four cell lines with an IC50 range of 8.49–16.72 µM, 6.55–13.14 µM and 4–8.99 µM respectively in comparison to DOX (4.17–8.87 µM). Phosphatidylinositol-3-kinases (PI3K) inhibition was evaluated against the most active anticancer compounds 8, 9 and 11. Compounds 8, 9 and 11 showed good inhibitory activity against PI3Kα with IC50 values 4.1, 7.8, and 20.5 µM, respectively in comparison to 6.18 µM for the reference compound LY294002. In addition, activity of compounds 8 and 9 on cell cycle arrest and induction of apoptosis in different phases of MCF-7 cells were assessed and detected pre-G1 apoptosis and cell growth arrest at G2/M. Also, both extrinsic and intrinsic apoptosis in MCF-7 cells induced by compounds 8 and 9. Molecular docking, binding affinity surface mapping, and contact preference of the synthesized compounds 8, 9 and 11 against PI3K were estimated and studied computationally using molecular operating environment software (MOE) and showed good interaction with essential residues for inhibition Val851. In addition, antimicrobial activity was evaluated against gram positive isolates as Staphylococcus aureus and Bacillus cereus, gram negative isolate as Escherichia coli, Pseudomonas aeruginosa and antifungal potential against Candida albicans. Compound 17 showed outstanding anti Gram-positive activity with MIC values 8 and 256 µg/mL in Staphylococcus aureus and Bacillus cereus respectively. Also, compounds 15, 17, 18 and 21 showed good anti Gram-negative activity with MIC value 512 µg/mL for all compounds. In addition, the state-of-art quorum sensing (QS) inhibiting effects were detected using Chromobacterium violaceum and compounds 7, 9, 10, 11, and 12 showed good QS inhibition (3, 3, 5, 2, and 7 mm).

Synthesis of Benzofurans Modified by Coumarin and Pyrazole Heterocycles

Reactions of 7-hydroxy-2-methyl-8-formylisoflavone with 4-chloromethylcoumarins synthesized 8-(coumarin-4-yl)furo[2,3-h]chromones, which reacted with 2-bromoacetylbenzofuran to produce 8-(benzofuroyl)furo [2,3-h]chromone. Recyclization of the corresponding furochromones through the action of hydrazine hydrate gave 4-hydroxybenzofurans with pyrazole and coumarin or benzofuroyl substituents.

Brønsted Acid Ionic Liquid-Catalyzed Ring Opening of 3,3-Disubstituted Oxetanes in Water: Efficient Access to Furans and Benzofurans

By using water as a solvent, an eco-friendly and practical protocol for the synthesis of furans and benzofurans through a Bronsted acid ionic liquid-catalyzed ring opening of 3,3-disubstituted oxet...

Brønsted acid-induced synthesis of methyl benzofurans via Grob type fragmentation of norbornyl derivatives

An efficient Brønsted acid-induced one-pot syntheses of 2-methylbenzofurans from norbornyl derivatives have been reported. The construction of new C–O bond proceeds via Grob-type fragmentation followed by cyclization and aromatization respectively. This synthetic strategy facilitates the efficient synthesis of 2-methylbenzofurans under acidic conditions. Significantly, this methodology is successfully applied to the synthesis of 6,7-bisaryl benzofurans.

Discovery of orthogonal synthesis using artificial intelligence: Pd(OAc)2-catalyzed one-pot synthesis of benzofuran and bicyclo[3.3.1]nonane scaffolds

A synthetic route for the common intermediate, methyl 2-formylbenzofuran-7-carboxylate (7a), to efficiently assemble three bioactive benzofurans 4–6 was explored using the artificial intelligence system SYNSUP. Among the routes proposed by SYNSUP, we investigated a three-step synthesis of 7a using methyl 4-ally-3-oxohept-6-enoate (10). A new catalytic reaction was found in which 7a was directly obtained from 10 in a single step with a yield of 24%. It was found that this chemical yield could be increased to 74% when methyl 3-allyl-2-hydroxybenzoate (9a), an intermediate of the above one-pot transformation, was subjected to the catalytic process. In addition, in this catalytic process, 8a (76%) and 11 (77%) were each selectively synthesized from 10 by changing only the solvent. Therefore, we created a novel orthogonal synthesis of methyl 2-methylbenzofuran-7-carboxylate (8a) and methyl 9-oxobicyclo[3.3.1]nona-3,6-diene-1-carboxylate (11). Finally, the total syntheses of bioactive benzofurans 4–6 were completed smoothly using 7a and 8a.

One-pot Tandem Heck alkynylation/cyclization reactions catalyzed by Bis(Pyrrolyl)pyridine based palladium pincer complexes

Ligand assisted palladium catalyzed one-pot tandem Heck alkynylation/cyclization reactions for the synthesis of benzofurans was reported in this paper. Well-defined palladium-pincer complexes exhibited excellent catalytic activities for the one-pot tandem Heck alkynylation/cyclization reactions yielding benzofuran derivatives using 0.1 mol% catalyst. All the catalytic reactions are performed in air. The effects of variables such as solvents, the temperature on the catalytic activity are also reported. High product conversion was obtained for differently substituted 2-iodophenol at 120 °C in 10 h.

Ultrasound Assisted Synthesis of 2-Substituted Benzofurans via One-Pot and Sequential Method: Their In Vitro Evaluation.

The 2-substituted benzofuran framework has attracted enormous attention due to its presence in a range of bioactive compounds and natural products. While various methods for the synthesis of 2- substituted benzofuran derivatives are known, several of them suffer from certain drawbacks. The main objective of this work was to explore a series of 2-(het)aryl substituted benzofurans derivatives for their cytotoxic properties against cancer cell lines in vitro. In our efforts, we have developed a one-pot synthesis of this class of compounds via sequential C-C coupling followed by C-Si bond cleavage and subsequent tandem C-C/C-O bond-forming reaction under ultrasound irradiation. The methodology involved coupling of (trimethylsilyl)acetylene with iodoarenes in the presence of 10% Pd/C-CuI-PPh3-Et3N in MeOH followed by treating the reaction mixture with K2CO3 in aqueous MeOH and finally coupling with 2-iodophenol. A variety of 2-substituted benzofurans were synthesized using this methodology in good yield. All the synthesized compounds were tested in vitro against two cancer cell lines, e.g. MDAMB-231 and MCF-7 cell lines subsequently against SIRT1. The benzofuran derivative 3m showed encouraging growth inhibition of both MDAMB-231 and MCF- 7 cell lines and significant inhibition of SIRT1. The compound 3m also showed a concentration-dependent increase in the acetylation of p53. Our efforts not only accomplished a one-pot and direct access to 2-(het)aryl substituted benzofurans but also revealed that the benzofuran framework presented here could be a potential template for the identification of potent inhibitors of SIRT1.

Cascade Claisen and Meinwald Rearrangement for One-Pot Divergent Synthesis of Benzofurans and 2H-Chromenes.

A new cascade approach has been developed for the one-pot four-step divergent synthesis of polysubstituted benzofurans and 2H-chromenes, featuring a novel cascade aromatic Claisen rearrangement/Meinwald rearrangement/dehydrative or oxidative cyclization. This new method was demonstrated with 39 examples tolerating different substitutions at an epoxide, allylic ether, and aromatic ring, and we showcased its utility with the first total synthesis of natural product liparacid A in seven steps.