Efficient and Functional‐Group‐Tolerant Synthesis of Substituted Furans through the Pd‐Catalyzed 5‐exo‐dig Cyclization/Coupling of γ‐Acetylenic β‐Keto Esters with (Hetero)Aryl Bromides

Abstract

We report an efficient protocol for the synthesis of 2,3,5‐trisubstituted furans through the reaction of readily available γ‐acetylenic β‐keto esters with aryl and heteroaryl bromides. The reaction, which involves a 5‐exo‐dig cyclization, coupling, and isomerization of a double bond, proceeds smoothly with very low catalyst loading (0.1 mol‐%), and shows excellent functional‐group tolerance.

Controllable Access to Furans and Dihydrofurans through Cyclization/Coupling of Internal Acetylenic β‐Ketoesters with Aryl Bromides

“…Importantly, a similar mechanism was previously proposed by Arcadi and us for a related transformation of terminal alkynes with aryl halides, however, involvement of dihydrofuran was not experimentally proven, let alone isolated. [7,8] Moreover, an alternative cyclization mode involving syn-oxopalladation of the alkyne moiety could possibly operate and needs to be either confirmed or ruled out. Such a mechanistic scenario was proven to be involved in a related Pdcatalyzed cyclization/allylation with allyl carbonates employed as an electrophilic partner.…”

“…Two decades ago, Arcadi showed that 2,3,5‐trisubstituted furans could be accessed directly from acetylenic β‐ketoesters and aryl iodides or triflates via a Pd‐catalyzed tandem process encompassing 5‐exo‐dig cyclization, coupling and isomerization (Scheme 1). [7] Recently we developed a protocol applicable for cheaper and more readily available, but considerably less reactive, aryl bromides featuring exceptional functional group tolerance [8] . However, several issues are still to be addressed.…”

“…[7] Recently we developed a protocol applicable for cheaper and more readily available, but considerably less reactive, aryl bromides featuring exceptional functional group tolerance. [8] However, Scheme 1. Strategies and challenges in the synthesis of furanoids via cyclization of acetylenic ketones.…”

Progress in Cyclizations of 4‐Acetylenic Ketones: Synthesis of Furans and Pyrroles

“…[42] Chaładaj and co-workers reported an efficient Pd-catalyzed protocol for the synthesis of 2,3,5-trisubstituted furans 95 through the cyclization of 4-acetylenic ketones 93 with aryl and heteroaryl bromides 94 (Scheme 20). [43] The reaction proceeded under mild conditions with a low catalyst loading (0.1 mol%) and an excellent functional-group tolerance.…”

Pd-catalyzed intramolecular addition of active methylene compounds to alkynes with subsequent cross-coupling with (hetero)aryl halides

“… 11 On the other hand, propargyl-β-ketoesters underwent 5- exo-dig oxocyclization/coupling, leading to the formation of substituted furan systems due to ambident nature of enolates of β-ketoesters. 12 Interestingly, the analogous transformation involving homopropargyl-β-ketoesters possessing an internal or terminal alkyne motif clearly led to either cyclopentenes 9 or dihydropyranes, 13 respectively.…”