Gold-Catalyzed Dearomative Spirocyclization of N-Aryl Alkynamides for the Synthesis of Spirolactams

Abstract

A catalytic redox-neutral method for the synthesis of spirolactams proceeding through the dearomative spirocyclization of N-aryl alkynamides is reported. In contrast to stoichiometric activating agents employed for related transformations, we show that the use of 5 mol % of Au(PPh)Cl and AgOTf in dichloroethane at 50-80 °C leads to selective spirocyclization, furnishing the products in yields of 35-87%. The substrate scope of the reaction is good, with both electron-donating and electron-withdrawing groups being tolerated around the arene ring, as well as substitution at the amide nitrogen. The identity of the para-alkoxy group on the arene ring is key to achieving selectivity for spirocyclization over alternative mechanistic pathways. While the presence of a para-methoxy group leads to trace amounts of the desired spirolactams, the para-tert-butoxy or para-hydroxy substrate analogues furnish the spirolactams in good yield with high selectivity.

Gold-Catalyzed Reactions of Specially Activated Alkynes, Allenes, and Alkenes

“…This general process was exemplified and exploited in the case of both alkynyl esters and amides (Scheme ). The group of Vadola described that both spirolactones 581 and lactams 583 could be obtained starting from the corresponding esters 580 or amides 582 (Scheme , part A). , Interestingly, while the dearomatization occurs in the presence of a methoxy group and water for the synthesis of lactones 581 , a tert -butyl ether or more simply a OH functionality is required in the case of lactams 583 . It was also shown that an Ugi MCR allowed for the rapid synthesis of diverse N -substituted lactams that could be readily cyclodearomatized under gold catalysis (see 584 ).…”

Gold‐Catalyzed Synthesis of Spirocycles: Recent Advances

“…Synthesis of spirolactams via dearomative spirocyclization of Naryl alkynamides. [20] Scheme 4. Intramolecular dearomatization reaction of β-naphthol derivatives.…”

Ruthenium(VIII)-Catalyzed ipso-Dearomative Spiro-Etherification and Spiro-Amidation of Phenols

“…Although the reaction is carried out in open air, the required temperature is 90 °C . A recent report by Vadola delineates a gold-catalyzed synthesis of spiroamides that proceeds through a dearomative alkyne insertion; however, the temperature required for the successful reaction was 80 °C, and Ag­(OTf) 2 was employed as an activator with moderate yields ranging from 35% to 80% …”

“…From the experimental outcome mentioned above and the proposed mechanism of ruthenium-catalyzed oxidative dearomatization of indoles, a mechanistic outlook is proposed. The catalytic cycle begins with the oxidation of RuCl 3 ·3H 2 O to Ru­(VIII) in the presence of KBrO 3 .…”

“…13 A recent report by Vadola delineates a gold-catalyzed synthesis of spiroamides that proceeds through a dearomative alkyne insertion; however, the temperature required for the successful reaction was 80 °C, and Ag(OTf) 2 was employed as an activator with moderate yields ranging from 35% to 80%. 14 Herein, we report the Ru(VIII)-catalyzed synthesis of spiroazacycles and spiro-oxacycles employing oxidative dearomatization as the key step from easily available naphthols and phenols (Figure 1).…”