Palladium-catalyzed carbomonofluoromethylation of unactivated alkenes: rapid access to γ-monofluoromethyl carboxylic acid derivatives.

Herein, we report a palladium-catalyzed regioselective carbomonofluoromethylation of unactivated alkenes. The reaction uses easily available fluorobis(phenylsulfonyl)methane (FBSM) as a fluoromethylating reagent, and proceeds smoothly with a wide variety of carbon electrophiles, including (hetero)aryl iodides, styrenyl iodides and TIPSBr. A range of remote γ-CH2F/CD2F carboxylic acid derivatives were constructed rapidly after a simple reductive desulfonylation step. The reaction features high regioselectivity, mild and simple reaction conditions and a broad substrate scope, and is easy to scale up.

Palladium-Catalyzed Regioselective Diarylation/Deamination of Homoallylamines: Modular Assembly of 1,1,4,4-Tetraaryl-1,3-butadienes.

Herein, a novel palladium-catalyzed regioselective diarylation/deamination of homoallylamines is described. During the process, a ubiquitous free amine (NH2) was used as the directing group to accomplish the regioselective δ,δ-diarylation and it was removed in situ to form the privileged 1,1,4,4-tetraaryl-1,3-butadiene motif. This chelate-controlled Heck-type approach eliminates the traditional need of preinstalled and hard removable directing groups, proceeds under simple conditions, and exhibits good tolerance to a wide range of synthetically useful functional groups.

Visible-light photocatalytic radical addition-translocation-cyclization to construct sulfonyl-containing azacycles.

Herein, a novel visible-light photocatalytic radical addition-translocation-cyclization (RATC) approach for the efficient synthesis of sulfonyl-containing azacycles is described. The reaction delivers a wide range of monocyclic, bicyclic and polycyclic azacycles by using easily prepared sodium sulfinates and N-homopropargylic amines as starting materials. Instead of the traditionally used toxic tin reagents and thermally hazardous azos in the RATC process, clean, renewable and sustainable visible light combined with a catalytic amount of photosensitizer is used in this process. Moreover, the successful transformation of some drug derivatives further highlights the potential application of this procedure.

Ruthenium(II)-Catalyzed Chelation-Assisted Desulfitative Arylation of Benzo[h]quinolines with Arylsulfonyl Chlorides.

Herein, a novel chelation-assisted C-H arylation reaction of benzo[h]quinoline is described. This transformation, using [RuCl2(p-cymene)]2 as the catalyst and cheap and easily accessible arylsulfonyl chlorides as the arylation source, featured simple reaction conditions, a broad substrate scope, and functional group tolerance. The successful application of some bioactive-molecule-based sulfonyl chlorides further highlighted the potential utility and importance of this desulfitative C-H arylation protocol.

A Radical Addition/Cyclization and Se-Group Transfer Strategy for the Facile Synthesis of Se-Containing Cyclopentenes under Metal-Free and Peroxide-Free Conditions.

A novel intermolecular radical addition/cyclization and Se-group transfer reaction of terminal alkynes and unsaturated alkyl selenide is presented which offers a straightforward and facile approach for the synthesis of valuable Se-containing cyclopentenes. Remarkable features of this strategy include easily accessible starting materials, metal-free and peroxide-free conditions, high atom economy, simple operation and broad substrate scope. More importantly, the reaction is easy to scale up and can be extended to the construction of six-membered carbon ring.

Divergent synthesis of α-functionalized amides through selective N-O/C-C or N-O/C-C/C-N cleavage of aza-cyclobutanone oxime esters.

Herein, a novel sequential ring opening reaction of aza-cyclobutanone oxime esters with isocyanides is described. The reaction proceeded smoothly under redox-neutral and mild conditions, leading to a divergent synthesis of α-cyanomethylaminoamides, α-acyloxyamides and α-acylaminoamides. In these transformations, a selective N-O/C-C or N-O/C-C/C-N cleavage was achieved only by changing the iron-catalyst system. Among them, a rare sequential N-O/C-C/C-N cleavage process with a classical Passerini or Ugi multicomponent reaction can be executed in a single step. To the best of our knowledge, this work creates a novel reaction mode of cycloketone oximes and provides new opportunities for reaction design.

Amidation-Ketonization-Selenation of Terminal Alkynes Using TEMPO and Elemental Selenium.

Herein, we present a novel silver- or copper-mediated direct amidation-ketonization-selenation of terminal alkynes for the synthesis of α-oxo-selenoamides. The reaction utilized easily accessible elemental selenium as the source of selenium. In addition, the 18O labeling experiment revealed that TEMPO is the oxygen source of the carbonyl group. The reaction takes advantage of an unsaturated C≡C bond to construct new C═O, C═Se, and C-N bonds in one step.

Direct 1,1-Bisphosphonation of Isocyanides: Atom- and Step-Economical Access to Bisphosphinoylaminomethanes.

An atom- and step-economical strategy for the synthesis of bisphosphinoylaminomethanes is reported. This metal-free bisphosphinylation reaction proceeded smoothly through a base-mediated direct 1,1-bisphosphonation of phosphine oxides and isocyanides under mild conditions. The present method offers a facile, efficient, and general approach to a broad range of bisphosphinoylaminomethane derivatives in moderate to good yields.

Total Synthesis and Target Identification of the Curcusone Diterpenes.

The curcusone natural products are complex diterpenes featuring a characteristic [6-7-5] tricyclic carbon skeleton similar to the daphnane and tigliane diterpenes. Among them, curcusones A-D demonstrated potent anticancer activity against a broad spectrum of human cancer cell lines. Prior to this study, no total synthesis of the curcusones was achieved and their anticancer mode of action remained unknown. Herein, we report our synthetic and chemoproteomics studies of the curcusone diterpenes which culminate in the first total synthesis of several curcusone natural products and identification of BRCA1-associated ATM activator 1 (BRAT1) as a cellular target. Our efficient synthesis is highly convergent, builds upon cheap and abundant starting materials, features a thermal [3,3]-sigmatropic rearrangement and a novel FeCl3-promoted cascade reaction to rapidly construct the critical cycloheptadienone core of the curcusones, and led us to complete the first total synthesis of curcusones A and B in only 9 steps, C and D in 10 steps, and dimericursone A in 12 steps. The chemical synthesis of dimericursone A from curcusones C and D provided direct evidence to support the proposed Diels-Alder dimerization and cheletropic elimination biosynthetic pathway. Using an alkyne-tagged probe molecule, BRAT1, an important but previously "undruggable" oncoprotein, was identified as a key cellular target via chemoproteomics. We further demonstrate for the first time that BRAT1 can be inhibited by curcusone D, resulting in impaired DNA damage response, reduced cancer cell migration, potentiated activity of the DNA damaging drug etoposide, and other phenotypes similar to BRAT1 knockdown.

Synthesis of organoselenyl isoquinolinium imides via iron(III) chloride-mediated tandem cyclization/selenation of N'-(2-alkynylbenzylidene)hydrazides and diselenides.

This report describes the synthesis of organoselenyl isoquinolinium imides through a tandem cyclization between N'-(2-alkynylbenzylidene)hydrazides and diselenides. The reaction was carried out at room temperature under an ambient atmosphere using cheap iron(iii) chloride as the metallic source. The strategy shows good tolerance to a broad range of N'-(2-alkynylbenzylidene)hydrazides and diselenides, and forms C-N and C-Se bonds in one step. The obtained product is further transformed into a bioactive H-pyrazolo[5,1-a]isoquinoline skeleton easily via a silver catalyzed [3 + 2] cycloaddition.

Thioketone-directed rhodium(I) catalyzed enantioselective C-H bond arylation of ferrocenes.

Planar chiral ferrocenes have received great attention in both academia and industry. Although remarkable progresses have been made over the past decade, the development of efficient and straightforward methods for the synthesis of enantiopure  planar chiral  ferrocenes remains highly challenging. Herein, we report a rhodium(I)/phosphonite catalyzed thioketone-directed enantioselective C-H bond arylation of ferrocenes. Readily available aryl iodides are used as the coupling partners in this transformation, leading to a series of planar chiral ferrocenes in good yields and excellent enantioselectivities (up to 86% yield, 99% ee). Of particular note, heteroaryl coupled ferrocenes, which are difficult to access with previous approaches, can be obtained in satisfactory results.

Rhodium-Catalyzed Atroposelective C-H Arylation: Efficient Synthesis of Axially Chiral Heterobiaryls.

Rhodium(I)-catalyzed atroposelective C-H arylation of heterobiaryls was presented. In the presence of a Rh catalyst derived from [Rh(C2H4)2Cl]2 and a TADDOL-derived monodentate phosphonite, with 2-pyridine, 2-isoquinoline and their analogs as directing groups, a series of axially chiral heterobiaryls were obtained in excellent yields and enantioselectivities (up to 99% yield, 97% ee) via C-H direct functionalization reaction. The products obtained from this method provide a platform for the synthesis of axially chiral biaryl ligands and catalysts. As a demonstration, a chiral N-oxide synthesized from the product in one step could act as an efficient catalyst for asymmetric allylation of benzaldehyde with allyltrichlorosilane, leading to homoallyl alcohol with excellent enantiocontrol.

PdII -Catalyzed Regio- and Enantioselective Oxidative C-H/C-H Cross-Coupling Reaction between Ferrocenes and Azoles.

Asymmetric C-H bond functionalization reaction is one of the most efficient and straightforward methods for the synthesis of optically active molecules. Herein we disclose an asymmetric C-H/C-H cross-coupling reaction of ferrocenes with azoles such as oxazoles and thiazoles. Palladium(II)/monoprotected amino acid (MPAA) catalytic system which exhibits excellent reactivity and regioselectivity for oxazoles and thiazoles. This method offers a powerful strategy for constructing planar chiral ferrocenes. Mechanistic studies suggest that the C-H bond cleavage of azoles is likely proceeding through a SE Ar process and may not be a turnover limiting step.

Thioketone-Directed Palladium(II)-Catalyzed C-H Arylation of Ferrocenes with Aryl Boronic Acids.

A palladium(II)-catalyzed thioketone-chelation-assisted direct C-H arylation of ferrocenes is described. With thioketone as an efficient directing group, various monoaryl- and diaryl-substituted thiocarbonylferrocenes were obtained by palladium-catalyzed direct C-H functionalization in high yields under mild and base-free reaction conditions. Furthermore, the arylated thiocarbonylferrocene could undergo diverse transformations.

Silver-Catalyzed Regioselective Fluorination of Carbonyl Directed Alkynes: Synthesis of α-Fluoroketones.

A novel silver-catalyzed fluorination reaction of carbonyl directed alkynes in the presence of N-fluorobenzenesulfonimide and water with high regioselectivities has been developed. The established protocol provides an alternative method for rapid assembly of α-fluoroketone derivatives under simple and mild reaction conditions. The reaction pathway involves a ring closure and opening process for the construction of new C-O and C-F bonds. In addition, a fluorine-containing indanone was observed through further N-heterocyclic carbene catalyzed intramolecular crossed-benzoin reaction of α-fluoroketone.

A tetra-n-butylammonium iodide mediated reaction of indoles with Bunte salts: efficient 3-sulfenylation of indoles under metal-free and oxidant-free conditions.

A highly efficient tetra-n-butylammonium iodide (TBAI) triggered procedure for 3-sulfenylation of indoles with Bunte salts is demonstrated. This protocol provides a simple strategy to prepare 3-alkylthioindoles and 3-arylthioindoles from the corresponding indoles under metal-free and oxidant-free conditions.

Palladium-Catalyzed Cascade Arene/Alkyne Annulation: Synthesis of Fluorene-Benzoxazine Derivatives.

A palladium-catalyzed cascade arene/alkyne annulation reaction for the synthesis of fluorene-benzoxazine derivatives is developed. This transformation involves a 6-exo-dig cyclization, a 1,3-oxazine vinylpalladium intermediate, and a C-H bond activation.

Palladium-catalyzed highly regioselective 6-exo-dig cyclization and alkenylation of ortho-ethynylanilides: the synthesis of polyene-substituted benzo[d][1,3]oxazines.

A Pd-catalyzed highly regioselective 6-exo-dig cyclization/alkenylation reaction of ortho-ethynylanilides has been developed. This tandem cross-coupling protocol represents a simple, efficient, step- and atom-economic approach for the construction of scarcely known polyene-substituted benzo[d][1,3]oxazines in moderate to excellent yields with a broad substrate scope.

Palladium-Catalyzed Regioselective C-H Acylation of Biaryl-2-amines.

A palladium-catalyzed efficient C-H acylation reaction of biaryl-2-amines and aromatic aldehydes is developed. This dehydrogenative cross-coupling protocol could furnish monoacylation and diacylation products in moderate to good yields with a broad substrate scope and good regioselectivity.

Aerobic Oxidative Cycloaddition of α-Chlorotosylhydrazones with Arylamines: General Chemoselective Construction of 1,4-Disubstituted and 1,5-Disubstituted 1,2,3-Triazoles under Metal-Free and Azide-Free Conditions.

A novel synthetic approach toward 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles by aerobic oxidative cycloaddition of α-chlorotosylhydrazone with primary aryl amine has been developed. Significantly, the reaction proceeds smoothly to afford 1,4-disubstituted 1,2,3-triazoles and 1,5-disubstituted 1,2,3-triazoles under catalyst-free, metal-free, azide-free, and peroxide-free conditions.