Pd⁰‐Catalyzed Intramolecular α‐Arylation of Sulfones: Domino Reactions in the Synthesis of Functionalized Tetrahydroisoquinolines

Abstract

A new strategy for the synthesis of tetrahydroisoquinolines based on the Pd(0)-catalyzed intramolecular α-arylation of sulfones is reported. The combination of this Pd-catalyzed reaction with intermolecular Michael and aza-Michael reactions allows the development of two- and three-step domino processes to synthesize diversely functionalized scaffolds from readily available starting materials.

Pd-Catalyzed α-Arylation of Sulfones in a Three-Component Synthesis of 3-[2-(Phenyl/methylsulfonyl)ethyl]indoles

“…During the optimization of the domino process leading to tetrahydroisoquinolines, 12 we realized that the most challenging step of the sequence was the sulfone α-arylation reaction. 21 So, before embarking on the development of a domino process to access 3-substituted indoles, we first examined the palladium-catalyzed α-arylation of β-(2-iodoanilino) sulfones.…”

“…Treatment of 1a with the Pd 2 (dba) 3 /xantphos couple as the precatalyst and K 3 PO 4 as the base in DMF, an effective combination for the domino sequence starting from closely related 2-iodobenzylamines, 12 resulted in the decomposition of the starting material (entry 1, Table 1). …”

“…11 This research allowed us to recently achieve an efficient synthesis of highly functionalized tetrahydroisoquinolines by a domino aza-Michael/α-arylation/Michael addition process based on the use of sulfones either as electrophiles or nucleophiles. 12 Continuing these studies, we decided to explore the synthesis of indole derivatives by means of a multistep sequence involving the use of sulfones (Scheme 1). When 3 starting from 2-haloaniline A, the aforementioned three-step domino process could be expected to generate a 3-(sulfonyl)indoline intermediate (i. e. D), a type of compound known to undergo β-elimination of sulfinic acid to afford indoles.…”

Recent Progress in the Transition Metal Catalyzed Synthesis of Indoles

“…Solé and co-workers reported a domino four-step aza-Michael/α-arylation/Michael addition/β-elimination strategy to achieve 3-[2-(phenylsulfonyl)ethyl]indoles (Scheme 29) [54]. From the results of a previous similar synthesis of tetrahydroisoquinolines [55], the authors knew that, conversely from acrylates, the competitive Heck reaction did not interfere with the initial aza-Michael addition and that the sulfone α-arylation was the most important step to be optimized. Then, the authors found that the higher electrophilicity and the higher acidity of phenyl sulfone allowed recovering of higher yields than methyl sulfone.…”

Exploring Partners for the Domino α‐Arylation/Michael Addition Reaction Leading to Tetrahydroisoquinolines

“…In recent years, different domino processes combining palladium‐catalyzed transformations with Michael addition reactions have been developed for the synthesis of a variety of aza‐heterocycles . In this context, we have recently reported the efficient synthesis of highly functionalized tetrahydroisoquinolines and indoles by domino aza‐Michael/Pd‐catalyzed α‐arylation/Michael addition processes based on the use of sulfones both as electrophiles and nucleophiles. To further generalize the application of these synthetic methodologies and access diversely functionalized heterocycles, we were interested in exploring the feasibility of other electron‐withdrawing groups in the domino α‐arylation/Michael addition strategy.…”