Pd-Catalyzed Cascade Heck/C(sp3)-H Activation for Spirocyclopropyl Oxindoles.

We have demonstrated a Pd(0)-catalyzed Heck/C(sp3)-H activation cascade for the synthesis of spirocyclopropyl oxindoles in high yields from easily accessible ortho-bromoacrylamides. The formation of spirocyclopropyl oxindole is guided by an unconventional four-membered palladacycle through C(sp3)-H activation. The reaction exhibits a wide range of substrate scope and operates efficiently with a mere 0.5 mol % of Pd-catalyst. In addition, the use of microwave conditions facilitates rapid completion of the reaction. Furthermore, this spirocyclopropanation strategy can be coupled with [3 + 2] cycloaddition to produce spiropyrrolidine oxindoles, offering a valuable approach for the preparation of alkaloids such as (±)-horsfiline and (±)-coerulescine.

Cu(I)/N,N-Imine Ligand Catalyzed C(sp3)-C(sp) Coupling of Alkyl Bromides with Alkynes: Scope and Mechanistic Investigation.

We have developed an efficient Cu/N,N-bidentate imine ligand catalytic system for C(sp3)-C(sp) coupling to obtain internal alkynes, di/trisubstituted allenes and strained bridged cyclic lactams in moderate to excellent yields from readily available alkyl(benzyl) bromides in one-pot transformation. Density Functional Theory (DFT) assisted mechanistic study along with control experiments support the involvement of bialkynylated copper species which undergo single electron transfer (SET) with alkyl halides to generate radical intermediate in the reaction. The N,N-bidentate imine ligand plays a vital role in stabilization of intermediate copper complex and facilitates the product formation.

Ligand-free Pd-catalyzed double Heck reaction of N-(o-bromoaryl)acrylamides with α-F/CF3-acrylates.

Herein, we have demonstrated an operationally simple Pd-catalyzed double-Heck reaction between N-(o-bromoaryl)acrylamide derivatives and α-fluoro/trifluoromethyl acrylates to enable monofluoro/trifluoromethyl alkene tethered 3,3-disubstituted oxindoles in a stereoselective manner. Remarkably, the reaction proceeds well without any external ligand in an open-air atmosphere. Control experiments and spectroscopic analysis are performed to understand the reaction mechanism.

Photoinduced Alkyl/Aryl Radical Cascade for the Synthesis of Quaternary CF3-Containing Oxindoles and Indoline Alkaloids.

Metal- and additive-free, photoinduced decarboxylative radical alkylation-cyclization of CF3-acrylamides with alkyl redox-active esters provided the corresponding quaternary CF3-oxindole derivatives in good yields. Notably, diaryliodonium salts also efficiently participated in the arylation-cyclization of CF3-acrylamides in environmentally benign H2O as a solvent. The present approach has been extended for the concise synthesis of CF3-attached indoline alkaloid analogues, i.e., CF3-(±)-desoxyeseroline, CF3-(±)-esermethole, and CF3-(±) progesterone receptor antagonists. The preliminary mechanistic studies revealed that the reaction is likely to proceed through initial photoexcitation of redox-active ester/diaryliodonium salts followed by the SET process with acrylamide.

Cu(II)-Catalyzed Unsymmetrical Dioxidation of gem-Difluoroalkenes to Generate α,α-Difluorinated-α-phenoxyketones.

A Cu-based catalyst system convergently couples gem-difluoroalkenes with phenols under aerobic conditions to deliver α,α-difluorinated-α-phenoxyketones, an unstudied hybrid fluorinated functional group. Composed of α,α-difluorinated ketone and α,α-difluorinated ether moieties, these compounds have rarely been reported as a synthetic intermediate. Computational predictions and later experimental corroboration suggest that the phenoxy-substituted fluorinated ketone's sp3-hybridized hydrate form is energetically favored relative to the respective nonether variant and that perturbation of the electronic character of the ketone can further encourage the formation of the hydrate. The more facile conversion between ketone and hydrate forms suggests that analogues should readily covalently inhibit proteases and other enzymes. Further functionalization of the ketone group enables access to other useful fluorinated functional groups.

Recent developments in decarboxylative C(aryl)-X bond formation from (hetero)aryl carboxylic acids.

Decarboxylative coupling reactions using readily available (hetero)aryl carboxylic acids are a highly efficient approach for the formation of new C-C and C-X bonds. These decarboxylative coupling reactions eliminate CO2 as a by-product, resulting in a greener and environmentally more benign approach than conventional coupling reactions. In this review, we summarize the recent developments in ipso-decarboxylative C-X (X = O/N/halo/S/Se/P/CN) bond formations using (hetero)aryl carboxylic acids. Furthermore, we highlight the current limitations and future research opportunities of aryl-decarboxylative coupling reactions.

Organocatalytic Strategy for Hydrophenolation of Gem-Difluoroalkenes.

Gem-difluoroalkenes are an easily accessed fluorinated functional group, and a useful intermediate for elaborating into more complex fluorinated compounds. Currently, most functionalization reactions of gem-difluoroalkenes, with or without a transition metal-based catalyst system, involve the addition or removal of a fluorine atom to generate trifluorinated or monofluorinated products, respectively. In contrast, we present a complementary "fluorine-retentive" reaction that exploits an organocatalytic strategy to add phenols across gem-difluoroalkenes to deliver ß,ß-difluorophenethyl arylethers. The products are produced in good to moderate yields and selectivities, thus providing a range of compounds that are underrepresented in the synthetic and medicinal chemistry literature.

Reductive Denitration of Nitroarenes.

The Pd-catalyzed reductive denitration of nitroarenes has been achieved via a direct cleavage of the C-NO2 bonds. The catalytic conditions reported exhibit a broad substrate scope and good functional-group compatibility. Notably, the use of inexpensive propan-2-ol as a mild reductant suppresses the competitive formation of anilines, which are normally formed by other conventional reductions. Mechanistic studies have revealed that alcohols serve as efficient hydride donors in this reaction, possibly through ß-hydride elimination from palladium alkoxides.

Buchwald-Hartwig Amination of Nitroarenes.

The Buchwald-Hartwig amination of nitroarenes was achieved for the first time by using palladium catalysts bearing dialkyl(biaryl)phosphine ligands. These cross-coupling reactions of nitroarenes with diarylamines, arylamines, and alkylamines afforded the corresponding substituted arylamines. A catalytic cycle involving the oxidative addition of the Ar-NO2 bond to palladium(0) followed by nitrite/amine exchange is proposed based on a stoichiometric reaction.

The Suzuki-Miyaura Coupling of Nitroarenes.

Synthesis of biaryls via the Suzuki-Miyaura coupling (SMC) reaction using nitroarenes as an electrophilic coupling partners is described. Mechanistic studies have revealed that the catalytic cycle of this reaction is initiated by the cleavage of the aryl-nitro (Ar-NO2) bond by palladium, which represents an unprecedented elemental reaction.

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.

Pd(II)-catalyzed ortho-C-H oxidation of arylacetic acid derivatives: synthesis of benzofuranones.

Pd(II)-catalyzed ortho-C-H acetoxylation of arylacetic acid derivatives is demonstrated with the aid of a novel S-methyl-S-2-pyridylsulfoximine (MPyS) directing group (DG). The α-mono- and α-unsubstituted arylacetic acid derivatives were readily employed in the ortho-C-H acetoxylations. The oxidation products are hydrolyzed, and the MPyS-DG is easily recovered, providing ready access to o-hydroxyarylacetic acids. 3-Mono- and 3-unsubstituted benzofuranones are synthesized from o-hydroxyarylacetic acids.

Ru(II)-catalyzed intermolecular ortho-C-H amidation of aromatic ketones with sulfonyl azides.

Ru(II)-catalyzed intermolecular ortho-C-H amidation of weakly coordinating aromatic ketones with sulfonyl azides is reported. The developed reaction protocol can be extended to various substituted aromatic ketones to afford a wide range of desired C-N bond formation products in good yields.

Sulfoximine directed intermolecular o-C-H amidation of arenes with sulfonyl azides.

The Ru(II)-catalyzed intermolecular o-C-H amidation of arenes in N-benzoylated sulfoximine with sulfonyl azides is demonstrated. The reaction proceeds with broad substrate scope and tolerates various functional groups. Base hydrolysis of the amidation product provides the anthranilic acid derivatives and methylphenyl sulfoximine (MPS) directing group. This method is successfully employed for the synthesis of HMR 1766.

Pd(II)-catalyzed primary-C(sp3)-H acyloxylation at room temperature.

With the aid of a novel S-methyl-S-2-pyridyl-sulfoximine (MPyS) directing group (DG), the unactivated primary ß-C(sp(3))-H bond of MPyS-N-amides oxidizes at room temperature. The catalytic conditions are applicable to the diacetoxylation of primary ß,ß'-C(sp(3))-H bonds, and the carboxylic acid solvent is pivotal in the formation of the C-O bond. The MPyS-DG cleaves from the oxidation products and is recovered. This method provides convenient access to α,α'-disubstituted-ß-hydroxycarboxylic acids.

Sulfoximines: a reusable directing group for chemo- and regioselective ortho C-H oxidation of arenes.

Sulfoximines direct: a new protocol for the chemo- and regioselective ortho C-H acetoxylation of arenes in N-benzoylated sulfoximines is reported. The sulfoximine directing group is easily detached from the C-H oxidation product through acid-promoted hydrolysis, isolated, and reused. The meta-substituted phenols are synthesized following this strategy and the stereointegrity of the sulfoximine is preserved in this transformation. C(sp(3))-H acetoxylation of the methyl group is also demonstrated.