Sulfur Versus Nitrogen Chelation in C-H Activation: Cobalt(III)-Catalyzed Unsymmetrical Double Annulation of Thioamides

An unconventional cobalt(III)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o\u27-C-H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse ‘S’ coordination over more conventional ‘N’ coordination of thioamides to Co-catalyst specifically regulates the formation of four [C-C and C-S at first and then C-N and C-C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, late-stage annulation of biologically relevant motifs and drug candidates are disclosed (17 examples). Preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6p-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation process.<br /

Harnessing sulfur and nitrogen in the cobalt(III)-catalyzed unsymmetrical double annulation of thioamides: probing the origin of chemo- and regio-selectivity

International audienceAn unconventional cobalt(III)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o′-C–H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse ‘S’ coordination over a more conventional ‘N’ coordination of thioamides to the Co-catalyst specifically regulates the formation of four [C–C and C–S at first and then C–N and C–C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, the late-stage annulation of biologically relevant motifs and drug candidates is disclosed (17 examples). The preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6π-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation proces

Photosensitized Dioxygen Enables Intermolecular Cyclopropanation of Alkenes Directly with Active Methylene Compounds

Cyclopropane, a versatile synthetic intermediate, is forged as a key structural feature in many preclinical, clinical and commercial drugs, and occur as a skeletal motif in numerous natural products. The most prolific technique for its synthesis is the metal-catalyzed reaction of an alkene with a diazoalkane, a highly energetic, reactive and explosive reagent requiring stringent safety precautions. The expedient construction of cyclopropyl ring on alkenes with convenient and innocuous reagents under nonhazardous conditions remains an ongoing challenge. Herein, we report a simple photoredox-catalyzed intermolecular cyclopropanation of unactivated alkenes with a diverse set of active methylene compounds that demonstrates striking conceptual and practical synthetic advances over the known methods. The reaction proceeds with a photoredox catalyst (PC*) excited under a blue LED light in air/O2 and neutral reaction conditions in the presence of catalytic amounts of iodine, either in the form of added molecular I2 or generated in situ from alkyl iodides. . The reaction demonstrates a remarkably broad scope on the applicability of 19 different active methylene compounds in 5 different clusters from the standpoint of synthetic tolerability, and tolerates a wide range of functional groups. Moreover, the reaction is also amenable for the cyclopropanation of alkenes in complex molecular architectures, pharmaceuticals and natural products. Mechanistic investigation through the isolation of a series of intermediate products, probes, control experiments, UV-Vis and fluorescence studies indicate that photosensitized dioxygen plays a vital role in the generation of carbon-centered radicals for both the addition of active methylene compounds to alkenes and ring closure, and catalytically generated iodine recycles the PC

Kinetic Resolution of Sulfur-Stereogenic Sulfoximines by Pd(II)-MPAA Catalyzed C-H Arylation and Olefination

A direct Pd(II)-catalyzed kinetic resolution of heteroaryl-enabled sulfoximines through an ortho-C-H alkenylation/arylation of arenes has been developed for the first time. The coordination of sulfoximine pyridyl-motif and the chiral amino acid MPAA ligand to the Pd(II)-catalyst controls the enantio-discriminating C(aryl)-H activation. This method provides access to a wide range of enantiomerically enriched unreacted aryl-pyridyl-sulfoximine precursors and C(aryl)-H alkenylation/arylation products in good yields with high enantioselectivity (up to >99% ee), and selectivity factor up to >200; which are inaccessible by conventional methods. The coordination preference of the directing group, ligand effect, geometry constraints, and the transient six-membered concerted-metalation-deprotonation species dictate the stereoselectivity; DFT studies validate this hypothesis

Transformable Sulfoximine Assisted One-Pot Double Annulation of Vinylic C–H Bonds with Unactivated Alkynes

The methylphenyl sulfoximine (MPS) directing group (DG) successfully promotes the one-pot double annulation of acrylic acids with alkynes under Ru catalysis, which is unprecedented. Diverse arrays of pyrido-fused-isoquinolinone skeletons are fabricated from acrylamides, creating two C–C and two C–N bonds in a single operation. The unsymmetrical annulation with two distinct alkynes is presented. The recovery of methylphenyl sulfoxide, a precursor of MPS, validates the synthetic adaptability of transformable-DG (T^fDG) in C–H activation

Kinetic resolution of sulfur-stereogenic sulfoximines by Pd(ll)–MPAA catalyzed C–H arylation and olefination

International audienceA direct Pd(II)-catalyzed kinetic resolution of heteroaryl-enabled sulfoximines through an ortho-C–H alkenylation/arylation of arenes has been developed. The coordination of the sulfoximine pyridyl-motif and the chiral amino acid MPAA ligand to the Pd(II)-catalyst controls the enantio-discriminating C(aryl)–H activation. This method provides access to a wide range of enantiomerically enriched unreacted aryl-pyridyl-sulfoximine precursors and C(aryl)–H alkenylation/arylation products in good yields with high enantioselectivity (up to >99% ee), and selectivity factor up to >200. The coordination preference of the directing group, ligand effect, geometry constraints, and the transient six-membered concerted-metalation–deprotonation species dictate the stereoselectivity; DFT studies validate this hypothesi

An Orchestrated Unsymmetrical Annulation Episode of C(sp²)–H Bonds with Alkynes and Quinones: Access to Spiro-isoquinolones

A nontrivial Ru-catalyzed one-pot sequential oxidative coupling of a (hetero)­arene/vinylic/chromene system with alkyne and quinone is presented; the methyl phenyl sulfoximine (MPS) directing group is vital. This cyclization forms four (two C–C and two C–N) bonds in a single operation and produces unusual spiro-fused-isoquinolones with a broad scope. The release of phenyl methyl sulfoxide makes the MPS group transformable. A deuterium scrambling study sheds light on the reaction path

Transformable Sulfoximine Assisted One-Pot Double Annulation of Vinylic C–H Bonds with Unactivated Alkynes

The methylphenyl sulfoximine (MPS) directing group (DG) successfully promotes the one-pot double annulation of acrylic acids with alkynes under Ru catalysis, which is unprecedented. Diverse arrays of pyrido-fused-isoquinolinone skeletons are fabricated from acrylamides, creating two C–C and two C–N bonds in a single operation. The unsymmetrical annulation with two distinct alkynes is presented. The recovery of methylphenyl sulfoxide, a precursor of MPS, validates the synthetic adaptability of transformable-DG (T^fDG) in C–H activation

Sulfoximine-Directed Ruthenium-Catalyzed <i>ortho</i>-C–H Alkenylation of (Hetero)Arenes: Synthesis of EP3 Receptor Antagonist Analogue

The reusable sulfox­imine directing-group-assisted Ru­(II)-catalyzed chemo- and regio­selective <i>ortho</i>-C–H alkenylation of arenes and hetero­arenes with acrylates and α,β-unsaturated ketones/vinyl sulfone is shown. The <i>N</i>-aroyl sulfoximine undergoes annulation with diphenyl­acetylene, delivering iso­quinoli­nones and methyl phenyl sulfoxide. The present protocol is successfully employed for the synthesis of the EP3 receptor antagonist analogue

Ruthenium-Catalyzed <i>ortho</i>-C–H Mono- and Di-imidation of Arenes with <i>N</i>‑Tosyloxyphthalimide

The Ru­(II)-catalyzed imidation of the <i>o</i>-C–H bond in arenes with <i>N</i>-tosyloxyphthalimide is realized with the assistance of a methyl phenylsulfoximine (MPS) directing group. This method is applicable to access the hitherto difficult <i>o</i>-C–H di-imidation products. The sequential C–N and C–C bond formation of <i>o</i>-C–H arenes creates peripherally decorated benzoic acid derivatives. The readily removable MPS-DG and easily modifiable phthaloyl moiety make this strategy synthetically viable for constructing highly functionalized C–N bearing arenes and heteroarenes