Modular Synthesis of Medium-Sized Fluorinated and Nonfluorinated Heterocyclic Lactones by Sequential CN-Bond-Cleaving Ring Expansion under Pd Catalysis

Abstract

Fluoro-functionalized heterocycles and mediumsized heterocycles are both attractive skeletons in medicinal chemistry. However, the construction of medium-sized fluorofunctionalized heterocycles remains unexplored. Their synthesis represents a formidable challenge due to the unfavorable entropic and enthalpic factors that arise from medium-sized rings and the unexpected properties induced by fluorinated groups. Here, we describe an efficient method for the preparation of highly functionalized gem-difluoromethylene N-heterocyclic lactones with 9-to 11-membered rings in a sequential CN-bond-cleaving ring-expansion process using difluoro-oxindoles, various zwitterion precursors, and a Pd catalyst. This sequential CN-cleaving expansion process was extended to synthesize nonfluorinated, medium-sized heterocycles with an α-keto-lactone moiety using isatin derivatives. Additionally, monofluorinated and nonfluorinated oxindoles were transformed into the corresponding medium-sized heterocyclic lactones using this protocol. The key for this transformation is the cleavage of the unreactive amide CN bond, which is smartly activated by the incorporation of two neighboring electron-withdrawing groups assisted with the nucleophilic attack of a Pdcoordinated zwitterion. The site-selective functionalization of a series of heterocyclic products was demonstrated to show their synthetic utility. Mechanistic details of the sequential cleavage/expansion process were proposed based on liquid chromatography− mass spectrometry (LC−MS) analyses.

Construction of poly-N-heterocyclic scaffolds via the controlled reactivity of Cu-allenylidene intermediates

“…2c). During our research into the development of efficient synthetic methods for the synthesis of fluorine-containing heterocyclic compounds for drug discovery [46][47][48][49][50][51][52][53][54][55][56][57] , we noticed that the use of a CF 3 substituent as the X group can direct the reaction pathway from mode A to B 55 . Herein, we realize the idea of a cascade of inter-and intramolecular annulations (mode B), which involves both αand β-attacks by employing 4-ethynyl-4-CF 3benzoxazinanones 1 (X = CF 3 ) and cyclic sulfamate-imines 2 (Fig.…”

Enantio‐, Diastereo‐ and Regioselective Synthesis of Chiral Cyclic and Acyclic gem‐Difluoromethylenes by Palladium‐Catalyzed [4+2] Cycloaddition

“…In our previous reports, we discovered a dramatic effect whereby α-fluoro-substitution of the substrate promotes an amide-cleavage reaction. [22] The strong electronegativity of the fluorine atoms can enhance the electrophilicity of carbonyl substrates, which can promote the cycloaddition reaction with a Pd-coordinated zwitterion. We assumed that α-fluoro-substitution of a ketone could stabilize a hemiketal intermediate to enable the Pd-catalyzed annulation reaction whilst generating a fluoro-functionalized stereogenic center.…”

Palladium‐Catalyzed [4+2] Cycloaddition of Hydroxy‐Tethered Allylic Carbonates with Alkenes: Synthesis of Functionalized Tetrahydropyrans

“…In early stage, Hayashi pioneeringly employed 2-alkylidenetrimethylene carbonates to generate π-allyl-Pd intermediates by decarboxylation, which underwent cyclopropanation or [4 + 2] cycloaddition with isocyanates. [12] Recently, this type of πallyl-Pd intermediates from decarboxylation of 2alkylidenetrimethylene carbonates were exploited to achieve [4 + 1], [13] [4 + 2], [14] and [5 + 4] [15] cycloaddition reactions. Although 1,4-C,O-dipoles could be formed through both deprotonation [9][10][11] and decarboxylation [12][13][14][15] and significant progress has been made in this field, mainly unsubstituted oxygen-containing π-allylpalladium 1,4-C,O-dipoles were used in most cases.…”

“…[12] Recently, this type of πallyl-Pd intermediates from decarboxylation of 2alkylidenetrimethylene carbonates were exploited to achieve [4 + 1], [13] [4 + 2], [14] and [5 + 4] [15] cycloaddition reactions. Although 1,4-C,O-dipoles could be formed through both deprotonation [9][10][11] and decarboxylation [12][13][14][15] and significant progress has been made in this field, mainly unsubstituted oxygen-containing π-allylpalladium 1,4-C,O-dipoles were used in most cases. [9][10][11][12][13][14][15] Expanding the substitution patterns of oxygen-containing π-allylpalladium zwitterionic intermediates is a very challenging task.…”

“…Although 1,4-C,O-dipoles could be formed through both deprotonation [9][10][11] and decarboxylation [12][13][14][15] and significant progress has been made in this field, mainly unsubstituted oxygen-containing π-allylpalladium 1,4-C,O-dipoles were used in most cases. [9][10][11][12][13][14][15] Expanding the substitution patterns of oxygen-containing π-allylpalladium zwitterionic intermediates is a very challenging task. Most recently, Lu presented a beautiful solution towards this important issue, accomplishing a Pd-catalyzed and visible light-induced asymmetric [4 + 2] cycloaddition of arylsubstituted 2-methylidenetrimethylene carbonates with adiazoketone.…”