Ni-Catalyzed Linearizable Cyclization/Coupling with Detachable Silicon-Oxygen Linker: Access to 1,2-Oxasilolanes, 3-Hydroxysilanes and 4-Arylalkanols.

We disclose a Ni-catalyzed cyclization/alkylmetal interception reaction in which products are readily linearized to permit regiodefined alkene dicarbofunctionalization. This method offers a convenient route to access 1,2-oxasilolane heterocycles, 3-hydroxysilanes and 4-arylalkanols with the formation of C(sp3)-C(sp3) bonds at primary and secondary alkyl carbon centers. In this reaction, a silicon-oxygen (Si-O) bond functions as a detachable linker that can be delinked with several hydride, alkyl, aryl and vinyl nucleophiles to create profusely functionalized 3-hydroxysilanes. A silicon motif in the cyclic C(sp3)-Si-O construct in 1,2-oxasilolane heterocycles can also be selectively deleted by Pd-catalyzed hydrodesilylation affording Si-ablated linear alcohol products reminiscent of vicinal ethylene dicarbofunctionalization with C(sp3) and C(sp2) carbon sources.

Photosensitized O2 enables intermolecular alkene cyclopropanation by active methylene compounds.

Cyclopropanes are key features in many preclinical, clinical, and commercial drugs, as well as natural products. The most prolific technique for their synthesis is the metal-catalyzed reaction of an alkene with a diazoalkane, a highly energetic reagent requiring stringent safety precautions. Discovery of alternative innocuous reagents remains an ongoing challenge. Herein, we report a simple photoredox-catalyzed intermolecular cyclopropanation of unactivated alkenes with active methylene compounds. The reaction proceeds in neutral solvent under air or dioxygen (O2) with a photoredox catalyst excited by blue light-emitting diode light and an iodine co-catalyst that is either added as molecular iodine or generated in situ from alkyl iodides. Mechanistic investigations indicate that photosensitized O2 plays a vital role in the generation of carbon-centered radicals for both the addition of active methylene compounds to alkenes and the ring closure.

Cobalt-Catalyzed Thioamide Directed C(arene)-H Annulation with Ynamide: Regioselective Access to 2-Amidoindenones.

Demonstrated herein is an unprecedented thioamide-directed cobalt (Co)-catalyzed umpolung annulation of sulfoximines enabled aryl thioamide with ynamide for the synthesis of highly substituted 2-amidoindenones. The cyclization is regioselective, making ß-C-C and α-C-CO bonds. The transformation is even successful on a gram scale, exhibiting broad scope with labile functional group tolerance and constructing 43 unusual 2-amidoindenones of structural diversity. Control experiments and mechanistic investigation validate the regioselectivity outcome in this transformation.

Multiple annulations of inert C(sp2)-H bonds with alkynes.

Transition-metal catalyzed directing group (DG) assisted annulation of inert C-H bonds leads to the formation of complex molecular frameworks from readily accessible substrates. Thus, multiple annulation of less functionalized substrates with unsaturated species leads to the construction of structurally diverse fused poly(hetero)cycles. The directed inert C(arene)-H bond activation and the mode of TM-migration in this process could enabled obatining L-type [involves DG heteroatom, o-C(arene)-H bond, and C(arene)-H bond of aryl-motif in alkyne], Y-type [involves two heteroatoms of the DG and o-,o'-C(arene)-H bonds], and B-type [involves o-C(arene)-H bond and m-C(arene)-H bond] π-extended annulation products. The coordination preference of the DG heteroatom makes the transformation chemo- and regio-selective. This article underlines the conceptual development of unsymmetrical multiple annulation of arene C(sp2)-H bonds with alkynes, which is exceedingly appealing and highly important.

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. 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 hypothesis.

Sulfur and Nitrogen Modulated One-Pot Double Annulation of Arenes.

The sulfur and nitrogen moieties of methylphenyl sulfoximine (MPS)-enabled aryl thioamides are independently involved in annulation with unactivated alkynes to construct the unusual 6,6-fused thiopyranoisoquinoline skeletons. The MPS directing group plays a vital role in making this unprecedented Ru-catalyzed one-pot double annulation of aryl thioamides with alkynes chemo- and regioselective. Both the o,o'-C-H bonds of the aryl motif are sequentially functionalized to form four bonds [C-C, C-S and C-C, C-N] in a single operation by overcoming the undisputed challenges, viz. the "S" poisoning effect on the transition-metal catalyst and the susceptibility of S to oxidation. The novel isothiochromene-1-one skeletons are successfully constructed, as the annulation is initiated with S in preference over the N motif of thioamides with alkynes. The preliminary photophysical properties of the thiopyrano-isoquinoline derivatives are also discussed.

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

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'-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 process.

Directing Group Assisted Unsymmetrical Multiple Functionalization of Arene C-H Bonds.

Multiple C-H bond functionalizations promptly install diverse groups on the molecular framework and consequently fabricate complex molecular entities. This review briefly surveys the conceptual development of directing group assisted unsymmetrical multiple functionalization of arene C(sp2 )-H bonds, which is exceedingly appealing and highly important.

Construction of Pyranoisoquinolines via Ru(II)-Catalyzed Unsymmetrical Double Annulation of N-Methoxybenzamides with Unactivated Alkynes.

A ruthenium (Ru)-catalyzed double annulation of easily accessible N-methoxybenzamide derivatives with unactivated alkynes for the synthesis of unusual 6,6-fused pyranoisoquinolines is described. Both ortho-C-H bonds of arenes and the N- and O-moieties of N-methoxybenzamides are involved in the construction of four [(C-C)-(C-N) and (C-C)-(C-O)] bonds in one step under single catalytic conditions. The unsymmetrical annulation of N-methoxybenzamides with two distinct alkynes is also demonstrated. The oxidizable directing group N-methoxyamine (NHOMe) assists the unsymmetrical double annulations of arenes [that use both N- and O-heteroatoms] in a single operation. This synthetic method features excellent substrate scope and tolerates a wide range of functional groups. Peripheral modification of pyranoisoquinolines for the construction of complex heterocyclic compounds is also demonstrated.

Sulfoximine-Assisted One-Pot Unsymmetrical Multiple Annulation of Arenes: A Combined Experimental and Computational Study.

Discussed herein is an unprecedented Ru-catalyzed one-pot unsymmetrical C-H difunctionalization of arenes comprising intramolecular hydroarylation of olefins and intermolecular annulation of alkynes. This unprecedented 2-fold C-H functionalization is validated on the basis of experimental and density functional theory (DFT) study. The transformation readily occurs with the assistance of methylphenyl sulfoximine (MPS) directing group in the presence of Ru catalyst forming two C-C and one C-N bonds in a single operation. The overall process is atom economical and step-efficient and provides unusual dihydrofuran-fused isoquinolone heterocycles. Further annulation of NH and the proximal o-C-H-arene of isoquinolone with alkynes build highly conjugated novel polycyclic compounds. Overall, three independent annulations in arene motifs are visualized and thoughtfully executed; finally, 5 ring-fused structural entities are constructed forming three C-C and two C-N bonds.

One-Pot Unsymmetrical {[4 + 2] and [4 + 2]} Double Annulations of o/ o'-C-H Bonds of Arenes: Access to Unusual Pyranoisoquinolines.

With the aid of a transformable sulfoximine directing group, unprecedented one-pot unsymmetrical double annulations {[4 + 2] and [4 + 2]} of hetero(arenes) with alkynes are revealed under Ru(II) catalysis. Functionalization of both ortho-C-H bonds of (hetero)arene is reflected in the building of unusual 6,6-fused pyranoisoquinoline skeletons. Construction of four [(C-C)-(C-N) and (C-C)-(C-O)] bonds occurs in one step under single catalytic conditions. The challenging unsymmetrical double annulations of both o-C-H bonds of arenes with two distinct alkynes is effectively demonstrated. Control experiments and deuterium scrambling findings are shown.

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 (TfDG) in C-H activation.

C-H imidation: a distinct perspective of C-N bond formation.

The direct imidation strategy proficiently constructs C-N bonds and creates the useful amine functional group in the molecular template. This review briefly discusses the synthetic methods developed for the direct imidation of unactivated C(sp2/sp3/sp)-H bonds. Transition-metal catalysts, metal-free processes, and/or photo-induced methods are invariably employed for accomplishing C-H imidation transformations. The contents summarized herein would benefit the research community to use the C-H imidation reactions for broad synthetic applications and to unravel novel C-N bond forming processes.

Ru-Catalyzed One-Pot Diannulation of Heteroaryls: Direct Access to π-Conjugated Polycyclic Amides.

A novel Ru-catalyzed oxidative double annulation of heteroarenes with symmetrical and unsymmetrical alkynes is reported. A general method for the unsymmetrical annulation of heteroarenes with two distinct alkynes is showcased for the first time. Methylphenyl sulfoximine (MPS) plays an important role in the annulations of heteroarenes and allows the construction of structurally complex π-conjugated heteroarene-fused polycyclic amide skeletons via the formation of multiple C-C and C-N bonds in a single operation. The reaction exhibits excellent substrate scope and tolerates a wide range of functional groups.

Ruthenium-catalyzed ortho-C-H mono- and di-imidation of arenes with N-tosyloxyphthalimide.

The Ru(II)-catalyzed imidation of the o-C-H bond in arenes with N-tosyloxyphthalimide is realized with the assistance of a methyl phenylsulfoximine (MPS) directing group. This method is applicable to access the hitherto difficult o-C-H di-imidation products. The sequential C-N and C-C bond formation of o-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.

Sulfoximine assisted Pd(II)-catalyzed bromination and chlorination of primary ß-C(sp3)-H bond.

S-methyl-S-2-pyridyl-sulfoximine (MPyS) directed bromination and chlorination of the 1°-ß-C(sp(3))-H bond of MPyS-N-amides is realized under the influence of N-Br/Cl-phthalimides and a Pd(II)-catalyst. The sequential halogenation and acetoxylation of α-dimethyl MPyS-N-amides constructs highly functionalized α-trisubstituted aliphatic acid derivatives. The MPyS directing group is cleaved from the halogenated products and recovered.

Sulfoximine-directed ruthenium-catalyzed ortho-C-H alkenylation of (hetero)arenes: synthesis of EP3 receptor antagonist analogue.

The reusable sulfoximine directing-group-assisted Ru(II)-catalyzed chemo- and regioselective ortho-C-H alkenylation of arenes and heteroarenes with acrylates and α,ß-unsaturated ketones/vinyl sulfone is shown. The N-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.