Synthesis of Benzofurans
A convenient metal-free cyclization of ortho-hydroxystilbenes into 2-arylbenzofurans and 2-arylnaphthofurans is mediated by hypervalent iodine reagents. Using stoichiometric (diacetoxyiodo)benzene in acetonitrile, desired products can be isolated in good yields.
F. V. Singh, T. Wirth, Synthesis, 2012, 44, 1171-1177.
An iodine(III)-catalyzed oxidative cyclization of 2-hydroxystilbenes using 10 mol% (diacetoxyiodo)benzene [PhI(OAc)2] as catalyst in the presence of m-chloroperbenzoic acid provides 2-arylbenzofurans in good to excellent yields.
F. V. Singh, S. R. Mangaonkar, Synthesis, 2018, 50, 4940-4948.
Substituted benzofurans were synthesized from their corresponding substituted 1-allyl-2-allyloxybenzenes using ruthenium-catalyzed C- and O-allyl isomerization followed by ring-closing metathesis.
W. A. L. van Otterlo, G. L. Morgans, L. G. Madeley, S. Kuzvidza, S. S. Moleele, N. Thornton, C. B. de Koning, Tetrahedron, 2005, 61, 7746-7755.
An effective, Ru-catalyzed cycloisomerization of benzannulated homo- and bis-homopropargylic alcohols affords benzofurans and isochromenes chemo- and regioselectively (5-, and 6-endo cyclizations). The presence of an amine/ammonium base-acid pair is crucial for the catalytic cycle.
A. Varela-Fernández, C. González-Rodríguez, J. A. Varela, L. Castedo, Carlos Saá, Org. Lett., 2009, 11, 5350-5353.
Reactions of calcium carbide with salicylaldehyde p-tosylhydrazones or 2-hydroxyacetophenone p-tosylhydrazones provide methyl-substituted benzofuran rings in good yields in the presence of cuprous chloride as catalyst. The advantages of this method are the use of a readily available and easy-to-handle acetylene source and a simple workup procedure.
R. Fu, Z. Li, Org. Lett., 2018, 20, 2228-2231.
Easily prepared Palladium nanoparticles catalyze a one-pot synthesis of various benzofurans via Sonogashira cross-coupling reactions under ambient conditions. The catalyst can be recycled and reused without significant loss in its activity.
P. K. Mandali, D. K. Chand, Synthesis, 2015, 47, 1661-1668.
Indium(III) halides catalyze the hydroalkoxylation reaction of ortho-alkynylphenols to afford benzo[b]furans in good yields.
L. Alonso-Marańón , M. M. Martínez , L. A. Sarandeses, E. Gómez-Bengoa, J. P. Sestelo, J. Org. Chem., 2018, 83, 7970-7980.
An isocyanide-mediated and Pd-catalyzed 5-exo-dig reductive cyclization of 1-(2-hydroxyphenyl)-propargyl alcohols provides 2-alkyl/benzyl benzofurans in excellent yields. The reaction features a high substrate scope and is insensitive to air. Further, a direct metal-free C-H functionalization (azidation, alkoxylation, and hydroxylation) and selective oxidative cleavage of 2-benzylfurans are described.
M. Rajesh, N. Thirupathi, T. J. Reddy, S. Kanojiya, M. S. Reddy, J. Org. Chem., 2015, 80, 12311-12320.
A nickel-catalyzed intramolecular nucleophilic addition reaction of aryl halides to aryl ketones provides benzofuran derivatives in moderate yields. A number of substrates bearing electron-donating or electron-withdrawing groups can be converted.
X.-R. Zhu, C.-L. Deng, Synthesis, 2021, 53, 1842-1848.
Alkali-metal salts of a large number of electron-rich, electron-poor, and sterically hindered aryl- and heteroarylsilanols undergo efficient cross-coupling with a wide range of aromatic bromides and chlorides under mild conditions. The critical feature for the success of these coupling reactions and their considerable scope is the use of bis(tri-tert-butylphosphine)palladium.
S. E. Denmark, R. C. Smith, W.-T. T. Chang, J. M. Muhuhi, J. Am. Chem. Soc., 2009, 131, 3104-3118.
A domino intermolecular Sonogashira coupling of 2-(2-bromophenoxy)-1-phenylethan-1-ones/alkyl 2-(2-bromophenoxy)acetates/2-(2-bromophenoxy)acetonitrile/1-(2-bromophenoxy)propan-2-one with terminal acetylenes followed by an intramolecular carbanion-yne cyclization in a 5-exo-dig manner and subsequent double-bond isomerization provide 2,3-disubstituted benzo[b]furans.
D. R. Kishore, G. Satyanarayana, J. Org. Chem., 2022, 87, 10158-10172.
An efficient palladium-catalyzed addition of arylboronic acids to aliphatic nitriles provides a broad range of alkyl aryl ketones in good yields. It is noteworthy that sequential addition and intramolecular annulation reactions of 2-(2-hydroxyphenyl)acetonitriles with arylboronic acids smoothly afford 2-arylbenzofurans in good yields under the standard conditions.
X. Wang, X. Wang, M. Liu, J. Ding, J. Chen, H. Wu, Synthesis, 2013, 45, 2241-2244.
A palladium-catalyzed addition of potassium aryltrifluoroborates to aliphatic nitriles leads to a wide range of alkyl aryl ketones with good yields. The scope of the developed approach is successfully explored toward the one-step synthesis of 2-arylbenzo[b]furans via sequential addition and intramolecular annulation reactions. The methodology accepted a wide range of substrates and is applicable to library synthesis.
X. Wang, M. Liu, L. Xu, Q. Wang, J. Chen, J. Ding, H. Wu, J. Org. Chem., 2013, 78, 5273-5281.
A well-defined cationic Ru-H complex catalyzes the dehydrative C-H alkylation reaction of phenols with alcohols to form ortho-substituted phenol products. The reaction with diols delivers benzofuran derivatives via dehydrative C-H alkenylation and annulation reaction. The catalytic C–H coupling method employs cheap starting materials, exhibits a broad substrate scope, and liberates water as the only byproduct.
D.-H. Lee, K.-H. Kwon, C. S. Yi, J. Am. Chem. Soc., 2012, 134, 6571-6574.
Benzo[b]furans were prepared in one pot based on the addition/palladium-catalyzed C-H bond functionalization of phenols with bromoalkynes. The addition reactions of phenols to bromoalkynes generated (Z)-2-bromovinyl phenyl ethers exclusively. Subsequent intramolecular cyclization affords 2-substituted benzo[b]furans in good yields through palladium-catalyzed direct C-H bond functionalizations.
S. Wang, P. Li, L. Yu, L. Wang, Org. Lett., 2011, 13, 5968-5971.
A ligand-free CuBr-catalyzed coupling/cyclization of terminal alkynes with N-tosylhydrazones derived from o-hydroxy- or o-aminobenzaldehydes enables the synthesis of benzofurans or indoles. A wide range of functional groups tolerate the reaction conditions.
L. Zhou, Y. Shi, Q. Xiao, Y. Liu, F. Ye, Y. Zhang, J. Wang, Org. Lett., 2011, 13, 968-971.
NiCl2(PPh3)(IPr) catalyzes cross-coupling reactions of 2-methylsulfanylbenzofurans with alkyl Grignard reagents. The alkylation is widely applicable, including the synthesis of a couple of protein tyrosine phosphatase inhibitors, 3-(4-biphenylyl)-2-alkylbenzofurans.
A. Baralle, S. Otsuka, V. Guérin, K. Murakami, H. Yorimitsu, A. Osuka, Synlett, 2015, 26, 327-330.
Reaction of O-arylhydroxylamine hydrochlorides with either cyclic or acyclic ketones in the presence of methanesulfonic acid leads directly to the benzofuran derivative via a proposed one-pot condensation-rearrangement-cyclisation reaction sequence in good to excellent yields.
F. Contiero, K. M. Jones, E. A. Matts, A. Porzelle, N. C. O. Tomkinson, Synlett, 2009, 3003-3006.
Addition of a range of Grignard reagents to 1-(2-hydroxyphenyl)-2-chloroethanones generates alkoxide intermediates, which can form either 2-substituted benzo[b]furans via a [1,2]-aryl migration or 3-substituted benzo[b]furans via a direct cyclization and dehydration sequence. A temperature-dependent [1,2]-aryl migration mechanism for the formation of 2-substituted benzo[b]furan is proposed.
T. Pei, C.-y. Chen, L. DiMichele, I. W. Davies, Org. Lett., 2010, 12, 4972-4975.
A Pd-catalyzed O-arylation of ethyl acetohydroximate as an hydroxylamine equivalent with aryl chlorides, bromides, and iodides offers short reaction times and broad substrate scope. The reaction allows access to O-arylhydroxylamines that would be difficult to prepare. Moreover, the O-arylated products can be directly transformed into substituted benzofurans in a single operation.
T. J. Maimone, S. L. Buchwald, J. Am. Chem. Soc., 2010, 132, 9990-9991.
A one-pot synthesis of benzofurans which utilizes a palladium-catalyzed enolate arylation demonstrates broad substrate scope and provides differentially substituted benzofurans in moderate yields. The utility of the method is further demonstrated by the synthesis of the natural product eupomatenoid 6 in three steps.
C. Eidamshaus, J. D. Burch, Org. Lett., 2008, 10, 4211-4214.
An effective and mild microwave-assisted route to 2-substituted benzofurans directly from carboxylic acids allows the preparation of α-alkyl-2-benzofuranmethanamines from N-protected α-amino acids without racemization in good yields.
L. De Luca, G. Giacomelli, G. Nieddu, J. Org. Chem., 2007, 72, 3955-3957.
TFAA induces a [3,3]-sigmatropic rearrangement of N-trifluoroacetyl-ene-hydroxylamines for the synthesis of dihydrobenzofurans, whereas reactions with TFAT-DMAP gives benzofurans. The synthetic utility is demonstrated by the short synthesis of natural benzofurans without protection of the hydroxy group.
N. Takeda, O. Miyata, T. Naito, Eur. J. Org. Chem., 2007, 1491-1509.
Copper-TMEDA catalyzes the transformation of readily available ketone derivatives into the corresponding benzo[b]furans in good to excellent yields. The sustainable protocol uses water as the solvent without organic cosolvents, and one example of catalyst reutilization is also presented.
M. Carril, R. SanMartin, I. Tellitu, E. Dominguez, Org. Lett., 2006, 8, 1467-1470.
An efficient, indirect anti-Markovnikov hydration of unsymmetrically substituted terminal and internal alkynes is based on TiCl4-catalyzed hydroamination reactions. Its application to ortho-alkynylhaloarenes, followed by a copper-catalyzed O-arylation, provides substituted benzo[b]furans.
L. Ackermann, L. T. Kaspar, J. Org. Chem., 2007, 72, 6149-6153.
A regioselective 5-exo-trig intramolecular oxidative cyclization of ortho-cinnamyl phenols using [PdCl2(CH3CN)2] as catalyst and benzoquinone as an oxidant provides functionalized 2-benzyl benzo[b]furans. Further, a one-pot, sequential synthesis of ortho-cinnamyl phenols, starting from readily available alcohols and phenols, followed by Pd-catalyzed oxidative annulation, has also been developed.
M. Rehan, R. Nallagonda, B. G. Das, T. Meena, P. Ghorai, J. Org. Chem., 2017, 82, 3411-3424.
Base-catalyzed condensation of o-hydroxyphenones with 1,1-dichloroethylene enables the preparation of highly functionalized benzofurans via the corresponding chloromethylene furans. These labile intermediates undergo a facile rearrangement into benzofuran carbaldehydes under mild acidic conditions.
F. Schevenels, I. E. Markó, Org. Lett., 2012, 14, 1298-1301.
An iridium-catalyzed hydrogen transfer in the presence of p-benzoquinone allows the synthesis of various substituted benzofurans, benzothiophenes, and indoles from substituted benzylic alcohols.
B. Anxionnat, D. G. Pardo, G. Ricci, K. Rossen, J. Cossy, Org. Lett., 2013, 15, 3876-3879.
A synthesis of 2-carboxybenzofurans from 2-gem-dibromovinylphenols is based on Cu-catalyzed intramolecular C-O coupling followed by Mo(CO)6-mediated intermolecular carbonylation. This protocol provides a broad range of functionalized benzofuran-2-carboxylic acids, esters, and amides in very good yields under Pd- and CO gas-free conditions.
Q. Mo, N. Sun, L. Jin, B. Hu, Z. Shen, X. Hu, J. Org. Chem., 2020, 85, 11490-11500.
A cascade reaction composed of a [2+2] annulation of DMF with an aryne followed by a trapping with a sulfur ylide enables the synthesis of a broad range of 2-aroyl benzofurans with high functional-group tolerance.
P. Gouthami, L. N. Chavan, R. Chegondi, S. Chadrasekhar, J. Org. Chem., 2018, 83, 3325-3332.
A Rh(III)-catalyzed annulation between salicylaldehydes and diazo compounds offers good functional group tolerance, scalability, and a controllable chemoselectivity. AgNTf2 as additive favored benzofurans via a tandem C-H activation/decarbonylation/annulation process, while AcOH led to chromones through a C-H activation/annulation pathway.
P. Sun, S. Gao, C. Yang, S. Guo, A. Lin, H. Yao, Org. Lett., 2016, 18, 6464-6467.
A highly effective cocatalysis system (PdI2-thiourea and CBr4) enables a carbonylative cyclization of a broad range of o-hydroxylarylacetylenes to the corresponding methyl benzo[b]furan-3-carboxylates.
Y. Nan, H. Miao, Z. Yang, Org. Lett., 2000, 2, 297-299.
A gold(I) complex catalyzes the cycloisomerization of a broad range of 2-(iodoethynyl)aryl esters to give 3-iodo-2-acyl benzofurans via a [1,2]-iodine shift, a C-O ring-closure step, and a C-C bond-formation that installs the ketone functionality into the new ring.
P. Fernández-Canelas, E. Rubio, J. M. González, Org. Lett., 2019, 21, 6566-6569.
One-pot reactions of acyl chlorides, phosphorus ylides, and o-iodophenols in the presence of a copper catalyst enable a rapid synthesis of functionalized benzofurans.
Y. Liu, H. Wang, J.-P. Wan, J. Org. Chem., 2014, 79, 10599-10604.
In the presence of palladium(II) acetate and copper(I) iodide, unsymmetrical buta-1,3-diynes were selectively obtained from the reaction of (E)-1,2-diiodoalkenes with terminal alkynes in moderate to good yields at room temperature. Using the same conditions, the coupling of 2-ethynylphenol with (E)-1,2-diiodoalkenes followed by a cyclization at 100°C gives ethynylbenzofurans.
Y. Liang, L.-M. Tao, Y.-H. Zhang, J.-H. Li, Synthesis, 2008, 3988-3994.
Zn(OTf)2 catalyzed the cyclization of propargyl alcohols with anilines and phenols in toluene at 100°C without additive and gave various indole and benzofuran products with different structures. The cyclization of propargyl alcohols and amides gave oxazoles. Mechanisms for the different substituation patterns are discussed.
M. P. Kumar, R.-S. Liu, J. Org. Chem., 2006, 71, 4951-4955.
An ortho-selective Sonogashira coupling of dichlorophenols and terminal alkynes, followed by cyclization and Suzuki-Miyaura coupling in one pot enabled the synthesis of disubstituted benzo[b]furans using a palladium-dihydroxyterphenylphosphine (Cy-DHTP) catalyst. This protocol was also successfully applied to the one-pot synthesis of disubstituted indoles from dichloroaniline derivatives.
M. Yamaguchi, T. Akiyama, H. Sasou, H. Katsumata, K. Manabe, J. Org. Chem., 2016, 81, 5450-5463.
A simple and highly efficient protodecarboxylation of various heteroaromatic carboxylic acids is catalyzed by Ag2CO3 and AcOH in DMSO. This methodology enables also a selective monoprotodecarboxylation of several aromatic dicarboxylic acids.
P. Lu, C. Sanchez, J. Cornella, I. Larrosa, Org. Lett., 2009, 11, 5710-5713.
A convenient high-yielding, efficient, selective and simple one-pot procedure for the synthesis of 3-ethoxycarbonylbenzofurans from commercially available salicylaldehydes and ethyl diazoacetate has been developed.
M. E. Dudley, M. M. Morshed, M. M. Hossain, Synthesis, 2006, 1711-1714.
CuI-catalyzed coupling of 1-bromo-2-iodobenzenes with β-keto esters in THF at 100°C provides 2,3-disubstituted benzofurans. This domino transformation involves an intermolecular C-C bond formation and a subsequent intramolecular C-O bond formation process.
B. Lu, B. Wang, Y. Zhang, D. Ma, J. Org. Chem., 2007, 72, 5337-5341.
Cyclodehydration of various α-aryloxy ketones proceeded to give various multisubstituted benzofurans by using an Ir(III) catalyst. The presence of Cu(OAc)2 and a cationic iridium complex salt, which was prepared from [Cp*IrCl2]2 and AgSbF6, realized an efficient transformation at ambient temperature.
T. Shibata, Y.-k. Hashimoto, M. Otsuka, K. Tsuchikama, K. Endo, Synlett, 2011, 2075-2079.
The Pt-catalyzed cyclization of o-alkynylphenyl acetals produces 3-(-alkoxyalkyl)benzofurans in good to high yields. The mechanism is discussed.
I. Nakamura, Y. Mizushima, Y. Yamamoto, J. Am. Chem. Soc., 2005, 127, 15022-15023.
A one-pot method for the preparation of alkyl aryl ethers from aryl halides and the preparation of substituted benzofurans via a Pd-catalyzed phenol formation/cyclization protocol starting from 2-chloroaryl alkynes are described.
K. W. Anderson, T. Ikawa, R. E. Tundel, S. L. Buchwald, J. Am. Chem. Soc., 2006, 128, 10694-10695.
2,3-Disubstituted benzo[b]furans are readily prepared under very mild reaction conditions by the Sonogashira coupling of various o-iodoanisoles and terminal alkynes, followed by an electrophilic cyclization. Aryl- and vinylic-substituted alkynes give cyclization products in excellent yields.
D. Yue, T. Yao, R. C. Larock, J. Org. Chem., 2005, 70, 10292-10296.
Potassium trinitromethanide can be used as a 1,1-ambiphilic synthon equivalent for the construction of a benzofuran moiety mediated by triethylamine. The method tolerates various functional groups. Formation of an o-quinone methide is postulated as a key intermediate of this cascade process.
V. A. Osyanin, D. V. Osipov, M. R. Demidov, Y. N. Klimochkin, J. Org. Chem., 2014, 79, 1192-1198.
CuCl catalyzes a highly efficient electrophilic amination reaction of readily available heteroarenes with O-benzoyl hydroxylamines via a one-pot C-H alumination to afford various heteroaryl amines in very good yields. The reaction can be performed in a single vessel on gram scales.
H. Yoon, Y. Lee, J. Org. Chem., 2015, 80, 10244-10251.
Electrophilic cyclization reaction of o-anisole- and o-thioanisole-substituted ynamides with I2, NBS and NCS gives 3-halogenated 2-amidobenzofurans and 2-amidobenzothiophenes. Some 3-iodo-2-amidobenzofurans were further transferred into 3-aryl-, 3-alkynyl, and 3-vinyl-2-amidobenzofurans via Pd-catalyzed cross coupling reactions.
Y. Kong, L. Yu, L. Fu, J. Cao, G. Lai, Y. Cui, Z. Hu, G. Wang, Synthesis, 2013, 45, 1975-1982.
A room temperature copper-catalyzed annulative amination of ortho-alkynylphenols with O-acylated hydroxylamines as electrophilic amination reagents proceeds efficiently to provide the corresponding 3-aminobenzofurans of biological and pharmaceutical interest.
K. Hirano, T. Satoh, M. Miura, Org. Lett., 2011, 13, 2395-2397.
A rhodium(III)-catalyzed cascade cyclization/electrophilic amidation using N-pivaloyloxylamides as the electrophilic nitrogen source provides 3-amidoindoles and 3-amidofurans under mild conditions with good functional group tolerance. The 3-amidoindoles can be converted to several heterocycle-fused indoles.
Z. Hu, X. Tong, G. Liu, Org. Lett., 2016, 18, 2058-2061.
Gold(I) catalysis enables an efficient synthesis of N-protected pyrroles and 5,6-dihydropyridin-3(4H)-ones from N-protected and unprotected 5-aminopent-2-yn-1-ol, respectively. Atom-economic syntheses of hydroxyalkyl indoles and benzofurans are also described. The methods offer short reaction time, low catalyst loading, high yield, and simple open-flask reaction conditions.
N. Bera, B. S. Lenka, S. Bishi, S. Samanta, B. Sarkar, J. Org. Chem., 2022, 87, 9729-9754.