The Cascade [1,5]-Hydride Shift/Intramolecular C(sp3)–H Activation: A Powerful Approach to the Construction of Spiro-Tetrahydroquinoline Skeleton

Abstract

The direct functionalization of inert C–H bonds is regarded as one of the most powerful strategies to form various chemical bonds and construct complex structures. Although significant advancements have been witnessed in the area of transition metal-catalyzed functionalization of inert C–H bonds, several challenges, such as the utilization and removal of expensive transition metal complexes, limited substrate scope and large-scale capacity, and poor atom economy in removing guiding groups coordinated to the transition metal, cannot fully fulfill the high standard of modern green chemistry nowadays. Over the past decades, due to its inherent advantage compared with a transition metal-catalyzed strategy, the hydride shift activation that applies “tert-amino effect” into the direct functionalization of the common and omnipresent C(sp3)–H bonds adjacent to tert-amines has attracted much attention from the chemists. In particular, the intramolecular [1,5]-hydride shift activation, as the most common hydride shift mode, enables the rapid and effective production of multifunctionally complex frameworks, especially the spiro-tetrahydroquinoline derivatives, which are widely found in biologically active natural products and pharmaceuticals. Although great accomplishments have been achieved in this promising field, rarely an updated review has systematically summarized these important progresses despite scattered reports documented in several reviews. Hence, in this review, we will summarize the significant advances in the cascade [1,5]-hydride shift/intramolecular C(sp3)-H functionalization from the perspective of “tert-amino effect” to build a spiro-tetrahydroquinoline skeleton, and the content is categorized by structure type of final spiro-tetrahydroquinoline products containing various pharmaceutical units. Besides, current limitations as well as future directions in this field are also pointed out. We hope our review could provide a quick look into and offer some inspiration for the research on hydride shift strategy in the future.

Assembly of spirocyclic pyrazolone-pyrrolo[4,3,2-de]quinoline skeleton via cascade [1,5] hydride transfer/cyclization by C(sp3)–H functionalization

“…17 This strategy eliminates the need for expensive transition metals, additional oxidants, and additives, while maintaining high atomic economy and efficiency. 18 Although cascade [1,5] hydride transfer/cyclization has successfully produced various spirocyclic skeletons containing diverse pharmaceutical cores, 19 to our knowledge, there are very limited studies reporting the synthesis of spirocyclic pyrazolone skeletons using this approach. 20 In this study, we present an efficient cascade [1,5] hydride transfer/cyclization strategy that employs simple pyrazolones and oxindoles attached to C4 amines to deliver structurally novel spirocyclic pyrazolone-pyrrolo[4,3,2- de ]quinoline skeleton, involving C(sp 3 )–H functionalization processes (Scheme 1c).…”