Trifluoroethanol Promoted Castagnoli–Cushman Cycloadditions of Imines with Homophthalic Anhydride

Abstract

Lactams are essential compounds in medicinal chemistry and key intermediates in the synthesis of natural products. The Castagnoli–Cushman reaction (CCR) of homophthalic anhydride with imines is an exciting method for accessing cyclic densely substituted lactam products. Most CCRs need to be catalyzed or heated. Herein, we report a new, efficient, metal and catalyst-free CCR for the synthesis of poly-substituted 3,4-lactams utilizing the unique properties of trifluoroethanol (TFE). This procedure provides high-speed and smooth access to a broad range of densely substituted 3,4-lactams in good yields and a 100% atom-economical fashion.

The Castagnoli–Cushman Reaction

“…In some cases, the reaction takes place at room temperature, preferentially yielding the cis isomers [ 30 , 31 , 32 , 33 ]. Trifluoroethanol has proven to be an advantageous solvent for the CCR, allowing a variety of lactams with high diastereoselectivity for cis -kinetic diastereoisomers to be obtained in minutes at −40 °C [ 34 ]. In recent years, greener reaction conditions have been developed, such as solvent-free methods [ 35 ] and the use of microwaves as an alternative activation technology [ 36 , 37 , 38 ].…”

One-Pot Sequence of Staudinger/aza-Wittig/Castagnoli–Cushman Reactions Provides Facile Access to Novel Natural-like Polycyclic Ring Systems

“…Encouraged by this success, we pondered if the same cyclic imine substrates could be coupled to other ring-forming reactions. Our positive recent experience [ 10 , 11 , 12 ] with the imines (cyclic and acyclic) reacting with cyclic anhydrides via the formal [4+2] cycloaddition dubbed the Castagnoli–Cushman reaction (CCR) [ 13 , 14 ] prompted us to investigate the possibility of employing imines 2 as substrates for the CCR. As the starting point for this investigation, we considered reacting them with homophthalic anhydrides (HPA, 5 ), one of the most popular and reactive anhydrides that have been involved in the CCR [ 15 , 16 , 17 ].…”

The Use of Aryl-Substituted Homophthalic Anhydrides in the Castagnoli–Cushman Reaction Provides Access to Novel Tetrahydroisoquinolone Carboxylic Acid Bearing an All-Carbon Quaternary Stereogenic Center

“…Homophthalic anhydride (HPA) is one of the most popular and most reactive anhydrides used in the CCR. The reaction with HPA delivers tetrahydroisoquinolones (THIQs) with good control of diastereoselectivity [ 6 , 7 , 8 ]. The THIQ scaffold is of undisputable medicinal relevance, as evidenced by various molecular series possessing diverse biological activities reported in the literature.…”