Gold-Catalyzed Cycloisomerization of 1,6-Cyclohexenylalkyne: An Efficient Entry to Bicyclo[3.2.1]oct-2-ene and Bicyclo[3.3.1]nonadiene

Abstract

An efficient and mild synthetic route for the preparation of functionalized bicyclo[3.2.1]­oct-2-ene and bicyclo[3.3.1]­nonadiene via gold-mediated cycloisomerization of 1,6-enynes has been developed. This atom-economical catalytic process was optimized and relied on the efficiency of IPrAuNTf2 allowing the formation of functionalized bicyclic adducts in 55–91% isolated yields (18 products). The reliable access to bicyclic derivatives was demonstrated on a 3 g scale with a low catalyst loading. The process occurred on a 5-exo versus 6-endo pathway depending on the substitution of the alkynyl moiety. Density functional theory (DFT) calculations were performed on the stability of intermediates, and this study corroborated the endo/exo ratio and the mechanistic pathway with key intermediates. Reduction of the ester moiety and hydrogenation of the exo-methylene double bond of the bicyclo[3.2.1]­oct-2-ene adduct illustrated the potential postfunctionalization of bicyclic derivatives.

Indium-Catalyzed Cycloisomerization of 1,6-Cyclohexenylalkynes

“…At the outset of our study, we prepared several functionalized 1,6-enynes, starting from ethyl 4-cyclohexanone-carboxylate according to a straightforward three-step route implying a triflate formation, a Suzuki-Miyaura coupling and a propargylation (Scheme 2). We prepared non-substituted alkynes 1a-d as well as substituted ones such as Mesubstituted 1e, and Ar-substituted 1f-1p, the latter being obtained via classical Sonogashira cross-coupling reactions on 1a [22]. Scheme 1.…”

“…At the outset of our study, we prepared several functionalized 1,6-enynes, starting from ethyl 4-cyclohexanone-carboxylate according to a straightforward three-step route implying a triflate formation, a Suzuki-Miyaura coupling and a propargylation (Scheme 2). We prepared non-substituted alkynes 1a-d as well as substituted ones such as Me substituted 1e, and Ar-substituted 1f-1p, the latter being obtained via classical So nogashira cross-coupling reactions on 1a [22]. Based on our gold-catalyzed experience, we have recently studied the cycloisomerization reactions of the known ethyl 4-oxocyclohexane carboxylate 1a and showed that the use of gold catalysts allowed the formation of bicyclo[3.2.1]oct-2-ene 2a as well as the isomerized 3a in various ratio depending on the gold catalyst (Table 1, entries 1-3) [22].…”

“…We prepared non-substituted alkynes 1a-d as well as substituted ones such as Me substituted 1e, and Ar-substituted 1f-1p, the latter being obtained via classical So nogashira cross-coupling reactions on 1a [22]. Based on our gold-catalyzed experience, we have recently studied the cycloisomerization reactions of the known ethyl 4-oxocyclohexane carboxylate 1a and showed that the use of gold catalysts allowed the formation of bicyclo[3.2.1]oct-2-ene 2a as well as the isomerized 3a in various ratio depending on the gold catalyst (Table 1, entries 1-3) [22]. The reaction allowed the formation of 2a in 81% conversion after 1 h with 2 mol % catalyst, but 3a was observed in high ratio (Entry 1).…”

“…The high reactivity of indium salts could also generate a double activation as shown by Nakamura's group in the case of the β-ketoester substrate containing the acetylene function [11][12][13]. We have also investigated the use of indium trichloride in alkyne activation for carbocyclization reactions by describing an efficient synthesis of exo-methylene α-disubstituted cyclopentane derivatives [14][15][16] and following our continuous work on gold catalysis [17][18][19][20][21], we wondered if we could promote cycloisomerization processes on cyclohexenylalkynes [22] in the presence of indium salts. These bicyclic derivatives are key building blocks and represent privileged scaffolds for biologically active molecules and natural products [23][24][25][26][27][28].…”

Gold‐Catalyzed Reactions Towards Diversity: From Simple Substrates to Functionalized Carbo‐ and Heterocycles

“…These novel building blocks contribute to the “escape from flat‐land” concept [17] and prompt us to further explore this type of skeleton by studying the unprecedented gold‐catalyzed cyclization of alkynyl cyclohexenyl derivatives [18] . The gold‐catalyzed cycloisomerization of 1,6‐enynes derived from ethyl 4‐oxocyclohexane carboxylate was thus recently optimized leading to the preparation of functionalized bicyclo[3.2.1]oct‐2‐ene and bicyclo[3.3.1]nonadiene under mild conditions (Scheme 5, Table 2).…”