Experimental and Computational Studies of Palladium-Catalyzed Spirocyclization via a Narasaka–Heck/C(sp³ or sp²)–H Activation Cascade Reaction

Abstract

The first synthesis of highly strained spirocyclobutane-pyrrolines via a palladium-catalyzed tandem Narasaka−Heck/ C(sp 3 or sp 2 )−H activation reaction is reported here. The key step in this transformation is the activation of a δ-C−H bond via an in situ generated σ-alkyl-Pd(II) species to form a five-membered spiropalladacycle intermediate. The concerted metalation-deprotonation (CMD) process, rate-determining step, and energy barrier of the entire reaction were explored by density functional theory (DFT) calculations. Moreover, a series of control experiments was conducted to probe the rate-determining step and reversibility of the C(sp 3 )−H activation step.

Regioselective synthesis of spirocyclic pyrrolines via a palladium-catalyzed Narasaka–Heck/C–H activation/[4 + 2] annulation cascade reaction

“…Recently, our group made a significant breakthrough, synthesizing a series of highly strained spirocyclobutane-pyrrolines through a Narasaka–Heck/C–H activation cascade reaction ( Scheme 1a ), which is the first case of using the σ-alkyl-Pd( ii ) intermediate from Narasaka–Heck cyclization for intramolecular C–H activation. 77 Despite numerous achievements, the ring size of spirocyclic pyrrolines is limited. Consequently, methods to obtain more diverse spirocyclic pyrrolines are highly desirable, which can be accomplished via employing external reagents to capture the palladacycle from Narasaka–Heck/C–H activation cascade.…”

“…Scheme 1a), which is the rst case of using the s-alkyl-Pd(II) intermediate from Narasaka-Heck cyclization for intramolecular C-H activation 77. Despite numerous achievements, the ring size of spirocyclic pyrrolines is limited.…”

Stereoselective Synthesis of Cyclobutanes by Contraction of Pyrrolidines

“…We expanded the substrate scope by preparing challenging spirocyclobutanes. 62 Spirocyclobutanes, including 30 – 33 , were obtained stereoselectively from the corresponding pyrrolidines in 42–65% yields. The natural-product-derived spirocyclobutanes 34 (from carvone) and 35 (from (+)-sclareolide) were prepared successfully.…”

“…Notably, a pyrrolidine containing a quaternary carbon contiguous to the nitrogen atom successfully gave cyclobutane 29 . We expanded the substrate scope by preparing challenging spirocyclobutanes . Spirocyclobutanes, including 30 – 33 , were obtained stereoselectively from the corresponding pyrrolidines in 42–65% yields.…”

Synthesis of Indolyl-Tethered Spiro[cyclobutane-1,1′-indenes] through Cascade Reactions of 1-(Pyridin-2-yl)-1H-indoles with Alkynyl Cyclobutanols

“…In the meantime, compounds bearing a cyclobutyl moiety have been frequently exploited as lead compounds for the discovery of anticancer, human TLF4 agonizing, and neuropathic pain-relieving drugs. , In addition, cyclobutane derivatives are widely used as important building blocks for the preparation of a broad spectrum of fine chemicals due to their inherent ring strain nature and diverse reactivity. Therefore, how to synthesize spirocarbocyclic compounds containing a cyclobutyl unit constitutes a highly desirable yet still challenging synthetic mission …”