Catalytic Conia-ene and related reactions

Abstract

Since its initial inception, the Conia-ene reaction, known as the intramolecular addition of enols to alkynes or alkenes, has experienced a tremendous development and appealing catalytic protocols have emerged. This review fathoms the underlying mechanistic principles rationalizing how substrate design, substrate activation, and the nature of the catalyst work hand in hand for the efficient synthesis of carbocycles and heterocycles at mild reaction conditions. Nowadays, Conia-ene reactions can be found as part of tandem reactions, and the road for asymmetric versions has already been paved. Based on their broad applicability, Conia-ene reactions have turned into a highly appreciated synthetic tool with impressive examples in natural product synthesis reported in recent years.

Indium(III)‐catalyzed Aza‐Conia‐Ene Reaction for the Synthesis of Indolizines

“…Furthermore, the presence of an electron‐withdrawing group on the aromatic ring is tolerated. In accordance with previous observations, product 2 p could not be obtained from a non‐terminal alkyne under the present reaction conditions (see below). We were pleased to observe that a scale‐up of the cycloisomerization of 1 a on a 1 mmol scale with 0.5 mol % In(OAc) 3 afforded 2 a in 95 % yield in 3 h (Scheme ).…”

“…Surprisingly, there are, to the best of our knowledge, no metal‐catalyzed 5‐ exo ‐ dig cycloisomerization reactions for the synthesis of indolizines and pyrrolo‐quinolines. Inspired by the success of 5‐ exo ‐ dig cyclizations such as the Conia‐ene reaction, we envisioned a new approach for the synthesis of indolizines and related/fused heterocycles through an aza‐Conia‐ene type reaction that would be complementary to the previous methodologies (Scheme , top).…”

Gold(I)‐Catalyzed Conia‐ene Cyclization of Internal ϵ‐Acetylenic β‐Ketoesters under High Pressure.

“…Although the classic reaction requires extremely harsh conditions, it has attracted much attention owing to its atom efficiency and the potential synthetic utility of the products . As a consequence, many catalytic procedures that enable the cyclization of acetylenic β‐ketoesters, malonates, and related compounds have been developed . Cationic phosphine gold complexes were shown to be extraordinarily active catalysts for the Conia‐ene cyclization of ϵ ‐acetylenic β‐ketoesters .…”

Catalytic Intramolecular Ketone Alkylation with Olefins by Dual Activation

“…[2][3][4][5] In contrast, few cyclization reactions of an unactivated alkene and ar egular ketone are known, which is likely due to the reduced coordination ability of olefins (compared to alkynes) and ap oor enol/ketone ratio with normal ketones.T he thermal Conia-ene reaction typically requires very high temperatures (300-400 8 8C), which limits the substrate scope and functionalgroup tolerance. [1] To the best of our knowledge,o nly two catalytic Conia-ene-type reactions involving simple ketone/ olefin substrates have been reported to date ( Figure 1B). Widenhoefer [6] and co-workers first developed ap alladiumcatalyzed 6-endo-trig cyclization of g,d-enones for cyclohexanone synthesis;C he [7] et al recently described ag oldcatalyzed intramolecular hydroalkylation of ketones with aliphatic mono-and 1,1-disubstituted alkenes.While efficient, both methods require strong Brønsted or Lewis acids for ketone enolization, which potentially leads to incompatibility with acid-sensitive functional groups.F urthermore,C oniaene-type cyclizations of aryl-substituted olefins have not been reported to date.…”

“…Intramolecular ketone-olefin/alkyne couplings,n amely the Conia-ene reaction, [1] represent ap owerful strategy for constructing ring systems through CÀCb ond formation, particularly owing to the orthogonal reactivity of carbonyl and alkenyl/alkynyl groups.W ith the advancement of p-acid catalysis,anumber of elegant approaches have been developed for alkyne-mediated couplings,p articularly those involving 1,3-dicarbonyl compounds. [2][3][4][5] In contrast, few cyclization reactions of an unactivated alkene and ar egular ketone are known, which is likely due to the reduced coordination ability of olefins (compared to alkynes) and ap oor enol/ketone ratio with normal ketones.T he thermal Conia-ene reaction typically requires very high temperatures (300-400 8 8C), which limits the substrate scope and functionalgroup tolerance.…”