Review molecules Last Decade of Unconventional Methodologies for theReview Synthesis of Substituted Benzofurans Last Decade of Unconventional Methodologies for the Lucia Chiummiento *, Rosarita D’Orsi, Maria Funicello and Paolo Lupattelli Synthesis of Substituted Benzofurans Department of Science, Via dell’Ateneo Lucano, 10, 85100 Potenza, Italy; [email protected] (R.D.); [email protected] (M.F.); [email protected] (P.L.) Lucia Chiummiento * , Rosarita D’Orsi, Maria Funicello and Paolo Lupattelli * Correspondence: [email protected] Department of Science, Via dell’Ateneo Lucano, 10, 85100 Potenza, Italy; [email protected] (R.D.); Academic Editor: Gianfranco Favi [email protected] (M.F.); [email protected] (P.L.) Received:* Correspondence: 22 April 2020; [email protected] Accepted: 13 May 2020; Published: 16 May 2020 Abstract:Academic This Editor: review Gianfranco describes Favi the progress of the last decade on the synthesis of substituted Received: 22 April 2020; Accepted: 13 May 2020; Published: 16 May 2020 benzofurans, which are useful scaffolds for the synthesis of numerous natural products and pharmaceuticals.Abstract: This In review particular, describes new the intramolecular progress of the and last decadeintermolecular on the synthesis C–C and/or of substituted C–O bond- formingbenzofurans, processes, which with aretransition-metal useful scaffolds catalysi for thes or synthesis metal-free of numerous are summarized. natural products(1) Introduction. and (2) Ringpharmaceuticals. generation via In particular, intramolecular new intramolecular cyclization. and (2.1) intermolecular C7a–O bond C–C formation: and/or C–O (route bond-forming a). (2.2) O– C2 bondprocesses, formation: with transition-metal (route b). (2.3) catalysis C2–C3 bond or metal-free formation: are summarized. (route c). (2.4) (1) Introduction.C3–C3a bond (2) formation: Ring generation via intramolecular cyclization. (2.1) C7a–O bond formation: (route a). (2.2) O–C2 (route d). (3) Ring generation via intermolecular cyclization. (3.1) C7a-O and C3–C3a bond bond formation: (route b). (2.3) C2–C3 bond formation: (route c). (2.4) C3–C3a bond formation: formation (route a + d). (3.2) O–C2 and C2–C3 bond formation: (route b + c). (3.3) O–C2 and C3–C3a (route d). (3) Ring generation via intermolecular cyclization. (3.1) C7a-O and C3–C3a bond formation bond(route formation: a + d). (route (3.2) O–C2 b + d). and (4) C2–C3 Benzannulation. bond formation: (5) Conclusion. (route b + c). (3.3) O–C2 and C3–C3a bond formation: (route b + d). (4) Benzannulation. (5) Conclusion. Keywords: synthesis of benzofurans; intra-molecular approach; inter-molecular approach Keywords: synthesis of benzofurans; intra-molecular approach; inter-molecular approach 1. Introduction 1. Introduction Benzofuran (BF) and 2,3-dihydrobenzofuran (2,3-DBF) are key structural units in a variety of Benzofuran (BF) and 2,3-dihydrobenzofuran (2,3-DBF) are key structural units in a variety of biologically active natural products (Figure 1) and represent the core structures of many approved biologically active natural products (Figure1) and represent the core structures of many approved drugs,drugs, as well as well as lead-design as lead-design developments developments from from naturalnatural products products [1 –[1–4].4]. 3 3 2 2 O O BF 2,3-DBF Figure 1. Structures of benzofuran (BF) and 2,3-dihydrobenzofuran (2,3-DBF). Figure 1. Structures of benzofuran (BF) and 2,3-dihydrobenzofuran (2,3-DBF). BF is a completely aromatic flat structure, while 2,3-DBF bears two prochiral sp3 carbons on the heterocycle,BF is a completely placing thearomatic substituents flat structure, out of the while benzofuryl 2,3-DBF plane. bears Naturally two prochiral occurring sp3 compounds carbons on the heterocycle,bearing BFplacing and their the derivativessubstituents show out aof broad the benzofuryl range of pharmacological plane. Naturally activities. occurring Among compounds them, bearingamurensin BF and H their (or viniferifuran) derivatives show1 (Figure a broad2) displayed range anti-inflammatoryof pharmacological e ff ectactivities. on an asthma-like Among them, amurensinreaction H induced (or viniferifuran) in mice [5], while1 (Figure Anigopreissin 2) displayed A 2 showedanti-inflammatory low antimicrobial effect activityon an asthma-like against reactionStaphylococcus. induced in aureus miceand [5],S. while pyogene Anigopreissin[6] and was also A 2 discovered showed low as an antimicrobial inhibitor of HIV-1 activity reverse against Staphylococcus.transcriptase aureus (IC50 =and8 mM), S. pyogene including [6] two and mutant was enzymesalso discovered resistant to as the an clinical inhibitor drug of nevirapine HIV-1 reverse [7]. transcriptase (IC50 = 8 mM), including two mutant enzymes resistant to the clinical drug nevirapine [7]. Molecules 2020, 25, 2327; doi:10.3390/molecules25102327 www.mdpi.com/journal/molecules Molecules 2020, 24, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 2327 2 of 52 Molecules 2020, 24, x 2 of 54 Figure 2. RepresentativeRepresentative pharmacologica pharmacologicallylly active BF derivatives. Permethylated anigopreissin anigopreissin A A (PAA) (PAA) 3 showed inhibitory activity for human hepatoma cell proliferation [[8,9],8,9], whilewhile di differentfferent benzofuran benzofuran derivatives derivatives have have shown shown pharmacological pharmacological properties properties such suchas anticancer as anticancer [10,11], antiviral[10,11], [12an,tiviral13], anti-Alzheimer [12,13], anti-Alzheimer0s disease [14′,s15 disease], together [14,15], with antiparasitic together with [16], antiparasiticantitubercular [16], [17 antitubercular], and antibacterial [17], and [18, 19antibacter] activities.ial [18,19] Prescribed activities. agents Prescribed featuring agents the benzofuran featuring scaffold include the antidepressant ( )-BPAP 4, the antiarrythmic amiodarone 5 [20], the clinical the benzofuran scaffold include the antidepressant− (−)-BPAP 4, the antiarrythmic amiodarone 5 [20], β thecandidate clinical drug candidate for renal drug and for ovarian renal and cancers ovarian BNC105 cancers6 [BNC10521], and 6 the [21], inhibitor and the of inhibitor A fibril of formation Aβ fibril formation7 [2]. Such 7 a variety[2]. Such of a biological variety of and biological pharmacological and pharmacological activities make activities BF an important make BF pharmacophore an important pharmacophorefor the development for the of newdevelopment drugs. of new drugs. Thus, synthetic accessaccess toto benzofurans benzofurans is is of of considerable considerable interest, interest, and and numerous numerous approaches approaches to this to thisscaff scaffoldold have have been been disclosed disclosed in the in literature. the literature. Herein, Herein, we deal we with deal the with most the recent most literature, recent literature, which is whichnot included is not included in the appeared in the appeared reviews ofreviews the last of decade the last (2009–2020) decade (2009–2020) [22]. [22]. The review ofof DeDe Luca Luca et et al. al. [23 [23]] dealt dealt with with the the synthesis synthesis of 2-substituted-benzofurans of 2-substituted-benzofurans up to up 2009, to 2009,while while the one the of Abu-Hashemone of Abu-Hashem et al. [24 ]et was al. an[24] overview was an aboutoverview the diaboutfferent the approaches different toapproaches benzofurans. to benzofurans.Very recently, Very from recently, the same from authors, the same a chapter authors, in Advances a chapter in in Heterocyclic Advances in Chemistry Heterocyclic [25 ]Chemistry and three [25]reviews and havethree beenreviews published have been in which published the full in which perspective the full of perspective reactivity of of benzofurans reactivity of [26 benzofurans], advances [26],in the advances synthesis in of the biologically synthesis potentof biologically compounds potent bearing compounds at least bearing one benzofuran at least one moiety benzofuran in their moietystructures in [their27] and structures the recent [27] reports and onthe therecent total re synthesisports on of the natural total productssynthesis containing of natural at products least one containingbenzofuran at moiety least one in their benzofuran complex moiety structures in [their28] have complex been structures discussed. [28] A review have onbeen synthetic discussed. routes A reviewfor synthesis on synthetic of benzofuran-based routes for synthesis compounds of benzof appeareduran-based in 2017 compounds [29] and at appeared the least onein 2017 summarizes [29] and atthe the recent least studies one summarizes on the various the aspectsrecent studies of benzofurans on the various derivatives, aspects including of benzofurans their natural derivatives, sources, includingbiological their activities natural and sources, drug prospects, biological and activities chemical and synthesis, drug prospects, as well asand the chemical relationship synthesis, between as wellthe bioactivities as the relationship and structures between [30 the]. bioactivities and structures [30]. In this this plethora plethora of methodologies, of methodologies, different different classifications classifications were used, were subdividing used, subdividing the data into the synthesisdata into of synthesis 2- or 3-substituted of 2- or 3-substitutedor 2,3-disubstituted or 2,3-disubstituted benzofurans [31,32], benzofurans or into transition-metal- [31,32], or into catalyzedtransition-metal-catalyzed