The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles

Abstract

There is a continuous need for designing new and improved synthetic methods aiming at minimizing reaction steps while increasing molecular complexity. In this respect, catalytic, one-pot cascade methodologies constitute an ideal tool for the construction of complex molecules with high chemo-, regio-, and stereoselectivity. Herein, we describe two general and efficient cascade procedures for the synthesis of spiro-fused heterocylces. This transformation combines selective nucleophilic substitution (SN2′), palladium-catalyzed Heck and C–H activation reactions in a cascade manner. The use of allylic ammonium salts and specific Pd catalysts are key to the success of the transformations. The synthetic utility of these methodologies is showcased by the preparation of 48 spiro-fused dihydrobenzofuranes and indolines including a variety of fluorinated derivatives.

3,3-Difluoroallyl ammonium salts: highly versatile, stable and selective gem-difluoroallylation reagents

“…Although quaternary allyl ammonium salts are known for more than a century 51 , they received surprisingly little attention 52 – 55 . While investigating palladium-catalyzed cascade processes for the synthesis of spiro-fused heterocycles 56 , recently we noticed the utility and advantages of this class of compounds compared to other allylic electrophiles such acetates, halides, and so on. Inspired by this work and our interest in organofluorine building blocks 56 – 61 , we became interested in the synthesis and applications of DFAAs.…”

“…While investigating palladium-catalyzed cascade processes for the synthesis of spiro-fused heterocycles 56 , recently we noticed the utility and advantages of this class of compounds compared to other allylic electrophiles such acetates, halides, and so on. Inspired by this work and our interest in organofluorine building blocks 56 – 61 , we became interested in the synthesis and applications of DFAAs. Surprisingly, the parent 3,3-difluoropropen-1-yl ammonium salts (DFPAs) have not been described before.…”

Palladium/N-CD3-Xu-Phos-catalyzed enantioselective cascade Heck/remote C(sp2)−H alkylation reaction

“…Instead of using a DG that is covalently bound to a substrate for site-selective C-H activation, an alternative approach that utilizing a transient DG can be generated in situ under the reaction conditions would open the door to new reactivities (Fig. 1a, 1b) [31][32][33][34][35][36][37][38][39][40] . As a pioneering study, Grigg et al successfully implemented this strategy in the Pd-catalyzed remote-C-H functionalization of the heteroaromatic tethered alkene moiety through carbopalladation of alkenes to form neopentyl-type σalkylpalladium intermediate as the DG 32 .…”

“…Notably, continued interest in this reaction has recently culminated with the highly strained spiro-fused benzocyclobutene derivatives by Lautens 39 . Very recently, Beller's group combines selective nucleophilic substitution (S N 2'), Pd-catalyzed Heck and C-H activation reaction in a cascade manner, affording the highly strained racemic 5,4-spiroheterocycles in good to high yields 40 . In the classic domino Heck/intramolecular C-H alkylation reaction, the carbopalladation step is a chiral-determining step, but this step is reversible 31,33 .…”

Palladium-catalyzed stereoselective domino arylation–acylation: an entry to chiral tetrahydrofluorenone scaffolds

“…Palladium-catalyzed domino reactions provide an efficient means of rapidly constructing bi-, tri-and tetracyclic molecules, 1 and have been applied in the formation of various natural products 2 and heterocycles. 1b, 3 The tricyclic hydrofluorenone motif is well suited to benefit from such a synthesis and is present in a number of known bioactive compounds, such as taiwaniaquinol, 4 asterogynin B, 5 and kinamycin F 6 (Fig. 1).…”