Scalable Multicomponent Synthesis of (Hetero)aryl‐Substituted Phenyls: Focus on Metal‐Free Halogenated Biaryls, 3‐Arylindoles, and Isourolithine A Synthesis

Abstract

In the context of the growing interest of the scientific community for the development of sustainable synthetic strategies to access aromatic structures, we present a practical and metal-free approach to (hetero)biaryls which exploits the advantages of multicomponent reactions in sustainable solvents. In situ acid-catalysed generation of (hetero)aryl acetoxy dienes from the corresponding (hetero)arylidene acetones in a metal vessel, followed by Diels-Alder reaction using an electronpoor alkyne as dienophile, delivers the expected aromatic prod- [a] 7711 Scheme 1. Thermal activation of alkynes in multicomponent metal-free synthesis of (hetero)aryl-substituted phenyls in metal vessel. 7712 field of research under hyperbaric, thermal and microwave activation, [48][49][50] due to the scarce reactivity of this compound with consequently unsatisfying yields. [51] Eur.

Multicomponent and Metal‐Free Diels–Alder/Aromatization Approach to the Stereospecific Synthesis of E‐(Hetero)Stilbenes and Diarylacetylenes

“…Starting from the conditions recently developed in our group for the preparation of substituted benzene derivatives, [48,49] we performed the hypothesized reaction with (3E,5E)-6-phenylhexa-3,5-dien-2-one 1 a. To our pleasure, the reaction under the previously optimized reaction conditions gave the product 5 a in 52 % yield after the oxidation with DDQ of the cycloadduct intermediate in toluene at 60 °C (Table 1, Entry 1).…”

Relevant Developments in the Use of Three‐Component Reactions for the Total Synthesis of Natural Products. The last 15 Years

“…[76] The reaction, which should be performed in a metal vessel, affords a cyclohexadiene oxidation product, which can be further oxidized to obtain the corresponding aromatic products (Scheme 12). [77] The strategy was employed in 2019 by the group of Temperini for the total synthesis of isourolithin A, as an alternative to the previous synthesis of the natural product, made by the condensation of resorcinol with 4-hydroxysubstituted 2-bromobenzoic acid in an alkaline medium under CuSO 4 catalysis (Hurtley reaction). [78] In this recent approach, the reaction of 4-methoxy-arylbutenone 83 (prepared by the aldol condensation of p-anisaldehyde with acetone) [79] with isopropenyl acetate ( i PEA) and methyl propiolate in EtOAc at 145 °C gave 85 through 84 in a Diels-Alder reaction with methyl propiolate.…”

“… [76] The reaction, which should be performed in a metal vessel, affords a cyclohexadiene oxidation product, which can be further oxidized to obtain the corresponding aromatic products (Scheme 12 ). [77] …”