Luc Neuville

Activation of a C(sp3)H Bond by a Transient σ‐Alkylpalladium(II) Complex: Synthesis of Spirooxindoles Through a Palladium‐Catalyzed Domino Carbopalladation/C(sp3)C(sp3) Bond‐Forming Process

Heck shortens the distance. Palladium-catalyzed activation of C(sp3)-H bond by a σ-alkyl Pd(II) complex generated in situ from a remote arylhalide function is developed. The novel domino carbopalladation/C(sp3)-C(sp3) bond forming process allowed a rapid access to biologically relevant spirooxindoles.

Copper-catalyzed oxidative diamination of terminal alkynes by amidines: synthesis of 1,2,4-trisubstituted imidazoles.

An efficient copper-catalyzed synthesis of 1,2,4-trisubstituted imidazoles using amidines and terminal alkynes has been developed. Overall, the oxidative process, which involves Na2CO3, pyridine, a catalytic amount of CuCl2·2H2O, and oxygen (1 atm), consisted of a regioselective diamination of alkynes allowing the synthesis of diverse imidazoles in modest to good yields.

Iodo-carbocyclization of electron-deficient alkenes: synthesis of oxindoles and spirooxindoles.

Cyclisative carbo-iodination of N-alkyl-N-arylacrylamide derivatives (3) in the presence of PhI(OAc)(2)/I(2) afforded functionalized 3-(iodomethyl)-3-substituted-indolin-2-ones (4) in good to excellent yields. With a suitably functionalized linear amide, spirooxindole 8 was prepared in a one-pot fashion via a sequence of iodo-arylation followed by an in situ base-promoted intramolecular S(N)2 reaction.

Ugi-post functionalization, from a single set of Ugi-adducts to two distinct heterocycles by microwave-assisted palladium-catalyzed cyclizations: tuning the reaction pathways by ligand switch

Linear amides 4, prepared in one step by the Ugi four-component reaction, were converted to 3,4-dihydroquinoxalin-3-ones (5) or to 2-(2-oxoindolin-1-yl)acetamides (6) dependent on the catalytic conditions. While microwave irradiation was found to be determinant on the reaction efficiency, the choice of ligand diverged the reaction pathways. Heating a solution of 4 in dioxane/MeCN (v/v = 85/15) under microwave irradiation conditions in the presence of Pd(dba)(2) (0.05 equiv) and Cs(2)CO(3) (2 equiv), using XPhos as a supporting ligand, afforded the 3,4-dihydroquinoxalin-3-ones (5) via an intramolecular N-arylation of the secondary amide. On the other hand, using BINAP as ligand under otherwise identical conditions, intramolecular alpha-CH arylation of tertiary amide occurred to furnish the oxindoles (6).

Palladium‐Catalyzed Through‐Space C(sp3)H and C(sp2)H Bond Activation by 1,4‐Palladium Migration: Efficient Synthesis of [3,4]‐Fused Oxindoles

Palladium two step: Linear anilides were converted into the title compounds in good to excellent yields through a palladium-catalyzed domino carbopalladation/1,4-palladium shift sequence. The C(sp(3) )-H activation involves a seven-membered palladacycle, and is chemoselective in the presence of competitive C(sp(2) )H bonds. DMA=N,N-dimethylacetamide, OPiv=pivalate.

Copper Catalyzed N-Arylation of Amidines with Aryl Boronic Acids and One-Pot Synthesis of Benzimidazoles by a Chan–Lam–Evans N-Arylation and C–H Activation/C–N Bond Forming Process

Mono-N-arylation of benzamidines 1 with aryl boronic acids 2 was effectively achieved in the presence of a catalytic amount of Cu(OAc)(2) and NaOPiv under mild aerobic conditions. Combining this step with an intramolecular direct C-H bond functionalization, catalyzed by the same catalytic system but under oxygen at 120 °C, afforded benzimidazoles 3 in good to excellent yields.

Spirocyclization by Palladium-Catalyzed Domino Heck–Direct C–H Arylation Reactions: Synthesis of Spirodihydroquinolin-2-ones

Treatment of a DMA solution of anilide 1 with a catalytic amount of palladium acetate (0.025 equiv) and XPhos (0.05 equiv) in the presence of potassium carbonate (2.0 equiv) at 100 °C afforded dihydroquinolin-2-ones spiro-fused to dihydrofuranyl, indolinyl, and indanyl 2 in good to excellent yields. The reaction went through a domino sequence involving a 5-exo-trig Heck cyclization followed by an intramolecular direct C-H functionalization.

Trifluoroacetic Acid-Promoted Synthesis of 3-Hydroxy, 3-Amino and Spirooxindoles from α-Keto-N-Anilides

Ketoanilides containing alkyl side chains were readily cyclized to 3-hydroxy-2-oxindoles or spirooxindoles by a single or double intramolecular Friedel-Crafts reaction in the presence of trifluoroacetic acid (TFA) at room temperature or at 45 °C. α-Iminocarboxamides, generated in situ from ketoamides, cyclized similarly to 3-aminooxindoles under identical conditions.

Palladium-Catalyzed Domino Intramolecular N-Arylation/Intermolecular C−C Bond Formation for the Synthesis of Functionalized Benzodiazepinediones

A divergent and regiocontrolled Pd-catalyzed domino sequence involving an intramolecular N-arylation and an intermolecular Heck reaction has been developed, providing rapid access to functionalized benzodiazepine-2,5-diones 3. The starting materials were synthesized by the Ugi four-component reaction. An unprecedented X-ray structure of bispalladacycle 6 was documented.

Protecting-Group-Free Total Synthesis of (E) and (Z)-Alstoscholarine

Looking for hidden symmetry: The first asymmetric total synthesis of pentacyclic (E)- and (Z)-alstoscholarines is accomplished starting from cyclic meso-anhydride 9. The absolute configuration was set by an organocatalytic desymmetrization of 9. Other key steps involved a regioselective hemiaminal formation to differentiate two aldehydes with concurrent creation of the D-ring, a chemoselective palladium-catalyzed indole synthesis and a Takeda olefination to install the ethylidene moiety. Each step of this eight-stage synthesis led to the constructive C-C, C-N or C-O bond formation. The synthesis is protecting-group-free, with high synthetic economy, and confirms the absolute configuration assigned to the natural products.