Regioselective synthesis of oxepinones and azepinones by gold-catalyzed cycloisomerization of functionalyzed cyclopropyl alkynes

Abstract

A regioselective synthesis of oxepinones and azepinones in good to excellent yields from alkynylcyclopropanecarboxylic acid derivatives is described. This novel cycloisomerization cascade process consists of a nucleophilic addition followed by a cyclopropane ring-opening, where both donor and acceptor groups are required as substituents of the cyclopropane ring.

Gold‐Catalyzed Cycloisomerizations of Functionalyzed Cyclopropyl Alkynes: the Cases of Carboxamides and Alcohols

“…On the other hand, while checking the necessity of the “push‐pull” nature of the substituents at the cyclopropane ring, we found that under the typical reaction conditions alkynylcyclopropylmethanol 3 a , which lacks of an acceptor group, does not experience ring‐expansion, leading to bicyclic enol ethers 7 a and 8 a in excellent yield although with moderate regioselectivity . A very similar result was also reached when warming at 50 °C (Scheme , bottom ).…”

“…Fischer methoxy cyclopropylethynyl chromium carbene complex, [37] alkynylcyclopropanecarboxylic esters, [10,12] alkynylcyclopropanecarboxylic acids 1, [12] alkynylcyclopropanecarboxamides 2a-c, [12] and alcohol 3 a [12] have been previously synthesized and were prepared as described. All reactions involving air sensitive compounds were carried out under inert atmosphere (Ar or N 2 , !…”

“…The mixture was stirred during 2 hr at room temperature, the final of the reaction was verified by TLC. The corresponding alkynylcyclopropanecarboxylic ester [10,12] [1 mmol, used as mixture of diastereomers] was dissolved in THF (10 mL) in a 50 mL round bottomed flask under inert atmosphere. The combined organic phase was dried over Na 2 SO 4 , filtered and solvents were removed under vacuum.…”

“…Indeed, we have already disclosed the potential of the proposed route for the synthesis of oxepinones 4 in good to excellent yields [12] (Scheme 1, top). Remarkably, the cascade process takes place with complete regioselectivity under mild reaction conditions (room temperature) provided that the cyclopropane ring bears both donor and acceptor substituents, due to the known intrinsic vulnerability of DA cyclopropanes to undergo ring-opening reactions.…”

“…[22] Interestingly, the gold-catalyzed synthesis of azepinone derivatives has some precedents, for instance, in the preparation of pyrroloazepinones [23] and azepino- [c,d]indolones. [12] A very similar result was also reached when warming at 50 8C (Scheme 1, bottom). [25] This work represents one of the scarce examples of direct gold-catalyzed hydroamidation of alkynes, [26] as carbamates [27] and tosylamides have been more often used as nitrogen nucleophiles.…”