Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center

Abstract

The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Here, we report a general strategy for the dearomative one‐carbon insertion of azoles using fluoroalkyl N‐triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring‐expanded heterocycles in excellent yields and good functional group compatibility. The broad generality of this methodology in the late‐stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated.

Silver‐Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion

“…Based on our previous experience in the single‐atom insertion reaction of azoles, [22] we began to validate the idea of using donor‐type carbenes as single‐carbon insertion precursors. As a carbene precursor, we used N ‐ o ‐trifluoromethylbenzenesulfonylhydrazone 2 a , which is derived from 4,4′‐dichlorobenzophenone.…”

“…Our group's recent work using fluoroalkyl‐ N ‐triftosylhydrazones as carbene precursors to perform skeleton editing on azole compounds has led to the synthesis of a series of diverse heterocyclic compounds, including hydroquinazolines (Figure 1B). [22] Yet, despite these impressive examples, progress in skeletal editing via carbene insertion is hampered by the lack of available donor‐type (i. e., donor or donor‐donor) carbene precursors capable of modifying the ring size of (hetero)cyclic scaffolds. This is due to the inherently low reactivity of donor‐type carbenes, the instability of diazo compounds and the susceptibility to dimerization side reactions [23–25] …”

“…Inspired by the ring expansion of fluoroalkyl‐ N ‐triftosylhydrazones and azoles, [22] we continue to explore the reactivity of azoles with donor‐type carbene precursors. In fact, aryl/aryl or aryl/alkyl carbenes of low reactivity [23–25] have drawn particular attention because they have been shown to efficiently introduce diarylmethylene or aryl/alkylmethylene units into a variety of organic building blocks [23–29] and that are readily converted from the corresponding aldehydes and ketones.…”

Rhodium‐Catalyzed One‐Carbon Ring Expansion of Aziridines with Vinyl‐N‐triftosylhydrazones for the Synthesis of 2‐Vinyl Azetidines

“…This methodology allows for the conversion of readily available cyclic structures into ring-expanded compounds. [8][9][10][11][12][13][14] In the context of skeletal editing of saturated N-heterocycles via one-carbon insertion, one potential mechanism for achieving ring expansion involves the sequential formation of an ammonium ylide and subsequent [1,2]-stevens rearrangement, enabling efficient one-carbon ring expansion. The pioneering works of multiple research groups have demonstrated the application of this approach for achieving 4-to 5-membered ring expansions through reacting with an azetidine with a diazo compound, leading to the formation of the corresponding pyrrolidine product (Figure 1A, left).…”