A Pd-catalyzed highly regioselective 1,2-difunctionalization of vinylarenes is disclosed in which multisubstituted olefins are efficiently and conveniently constructed under ambient temperature with good compatibility and a broad substrate scope. Notably, a quarternary carbon center could be readily built up from 1,1-disubstituted styrenes, which are big challenges in the previous methods.

A novel copper(I)-catalyzed chemoselective reduction of the carbonyls of benzofuran-2-yl ketones over furan rings with B2pin2 has been developed. This reaction proceeded under mild conditions. High valuable secondary alcohol derivatives of benzofurans were obtained in good to excellent yields with a broad substrate scope. The mechanistic studies suggested that a domino-borylation-protodeboronation pathway was involved in this reaction.

An expedient and stereoselective synthesis of functionalized trisubstituted allylic boronates via direct borylation of Morita–Baylis–Hillman alcohols is disclosed. The reaction proceeds smoothly at ambient temperature with high atomic and synthetic efficiency. The desired allylic boronates can be applied in the efficient synthesis of homoallyl alcohols and α-exomethylene γ-lactones.

A Pd(II)-catalyzed ortho-olefination of aromatic acetic esters is described which features with an excellent funcitional group tolerance, good yields, mild reaction conditions, good scalability as well as high chemo- and regio-selectivity.Download high-res image (52KB)Download full-size imageA Pd(II)-catalyzed ortho-olefination of aromatic acetic esters is described which features with an excellent functional group tolerance, good yields, mild reaction conditions, good scalability as well as high chemo- and regio-selectivity.

An efficient method for the synthesis of 2-substituted indoles via a diboron/base promoted tandem reductive cyclization of o-alkynylnitroarene under Au catalysis conditions has been disclosed. This reaction is efficient and convenient, affording 2-substituted indoles with broad functional groups tolerance and excellent yields.

An efficient, convenient and mild Ru-catalyzed reductive amination reaction was developed by employing H2O as both hydrogen source and solvent via B2(OH)4/H2O systems. The reaction proceeded smoothly under air at ambient temperature and exhibited excellent chemoselectivities toward unsaturated and heteroaromatic as well as aliphatic aldehydes. Interestingly, α-deuterated amines were also obtained expediently by employing D2O in our catalytic systems.

Transition-metal-free base-controlled highly regioselective synthesis of alkyl 1,2-bis(boronates) or 1,1,2-tris(boronates) from various terminal alkynes has been disclosed. These reactions are efficient, practical and mild with good regioselectivity, excellent functional group tolerance as well as good scalability, which provide general and complementary methods to access multiborylated alkanes from various terminal alkynes.

An unconventional reductive quenching cycle was developed to realize the visible-light-induced thiotrifluoromethylation of terminal alkenes. CF3SO2Na was used as an easy to handle CF3 radical source to afford the desired products in moderate to good yields. Mild reaction conditions and a broad substrate scope feature in this transformation.

A Co-catalyzed highly chemo- and regio-selective nitration of C(sp3)–H was developed. Diverse aliphatic nitro compounds were obtained in good yields, using t-BuONO as a nitrating reagent. Specific nitration of C(sp3)–H instead of C(sp2)–H was achieved via a radical process rather than concerted metalation–deprotonation.

Novel catalytic systems consisting of cationic gold complexes, N-hydroxyphthalimide (NHPI), and transition-metal-based Lewis acids have been developed for the one-pot synthesis of functionalized oxazoles from N-propargylamides with excellent functional group tolerance. These transformations demonstrated the excellent compatibility of homogeneous gold catalysis with organocatalytic oxidative carbon–nitrogen bond formations using tert-butyl nitrite as the terminal oxidant. Moreover, oxazolecarbonitriles or carboxamides can be easily synthesized in a one-pot protocol according to the different synthetic requirements.

Hippocampus trimaculatus leach has been widely used in beverage and herbal medicine fabrication. However, the study of the molecular mechanism of its bioactivity especially the anti-inflammatory activity is still scanty. In the present study, the pure HEO isolated from the dried Hippocampus trimaculatus leach was firstly found to have anti-inflammatory activity in vitro. The molecular mechanism of the anti-inflammatory activity was detailed using the lipopolysaccharide (LPS) stimulated RAW 264.7 macrophage cells, suggesting that the HEO can significantly suppress the inflammatory factors of nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α) and interleukin (1L)-1β (1L-1β). Cellular signaling analyses demonstrated that the HEO downregulated the NF-κB and extracellular signal-regulated kinase (ERK) of mitogen-activated protein kinase (MAPK) signaling pathways. All the results suggested that the HEO is a potential natural anti-inflammatory agent.

The highly regio- and stereoselective hydroborations of unactivated internal alkynes with diboron compound catalyzed by Cu(OTf)2 with spiro(phosphoamidite) as ligand in the presence of Cs2CO3 in water was developed. This protocol was applied efficiently in the aqueous synthesis of multi-substituted vinylboranes.Download high-res image (131KB)Download full-size image

AbstractAn efficient and convenient synthesis of valuable disulfanes and benzenesulfonothioates, having a 2-aminofuran framework, has been developed by employing a copper-catalyzed transformation of readily available N-tosylhydrazone-bearing thiocarbamates. This method features an inexpensive metal catalyst, mild reaction conditions, good functional-group tolerance, short reaction times, and delivers valuable and complex products. A copper carbene generated from an N-tosylhydrazone-bearing thiocarbamate is proposed as the key intermediate for the transformation and it triggers the subsequent cascade. Remarkably, the Ts anion released from N-tosylhydrazone further serves as a nucleophile, thus rendering the formation of benzenesulfonothioates under controlled conditions.

AbstractAn efficient and convenient synthesis of valuable disulfanes and benzenesulfonothioates, having a 2-aminofuran framework, has been developed by employing a copper-catalyzed transformation of readily available N-tosylhydrazone-bearing thiocarbamates. This method features an inexpensive metal catalyst, mild reaction conditions, good functional-group tolerance, short reaction times, and delivers valuable and complex products. A copper carbene generated from an N-tosylhydrazone-bearing thiocarbamate is proposed as the key intermediate for the transformation and it triggers the subsequent cascade. Remarkably, the Ts anion released from N-tosylhydrazone further serves as a nucleophile, thus rendering the formation of benzenesulfonothioates under controlled conditions.

An iron-catalyzed aerobic oxidative amidation reaction of the inert C–CN bond of aryl acetonitriles to afford aryl amides has been developed. Urea is used as an efficient and convenient nitrogen source. This reaction provides practical access toward amide synthesis.

A copper(I)-catalyzed three-component reaction of sulfoximines, alkynes and azides is described. This reaction proceeds under mild conditions with copper salt as a catalyst and atmospheric oxygen as an oxidant to afford a variety of 1,2,3-triazolyl-5-sulfoximines in moderate to good yields.

An efficient Pd-catalyzed three components reaction involving the 1,2-diarylation of vinylarenes has been disclosed. This reaction introduces two different aryl groups across vinylarenes at ambient temperature giving rise to multi-aryl substituted ethanes which are biologically relevant compounds prevailing in organic chemistry, medicinal chemistry and materials science.

A Ag-catalyzed phosphorus radical promoted cyclization of cinnamamides to give exclusively 2-phosphinoyl-3H-pyrrolo[1,2-a]indoles derivatives via a 5-endo-trig manner is described. This novel reaction leads to the simultaneous formation of C–C and C–P bonds in one step with excellent chemo- (only 5-endo) and diastereoselectivity (dr >20:1) under mild conditions in moderate to good yields.

An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C–H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield.

H2O is routinely described as a proton donor, however, in the presence of diboron compounds, the umpolung reaction of H2O under metal-free conditions was successfully developed, which could afford hydride species, leading to a highly efficient and chemoselective reduction of CO bonds. This strategy exhibits excellent chemoselectivities toward carbonyl groups in the presence of ester, olefin, halogen, thioether, sulfonyl, cyano as well as heteroaromatic groups.

A transition-metal-free synthesis of alkylboronates, utilizing arylacetylenes or vinyl arenes and bis(pinacolato)diboron through tandem borylation and protodeboronation, has been developed. This reaction is efficient, practical and environmentally benign, leading to anti-Markovnikov products with excellent regioselectivity, broad functional group tolerance and excellent yields in both small and gram scales.

A novel domino palladium-catalyzed nitration of Meyer–Schuster intermediates which were generated in situ from propargylic alcohols was developed, by the use of t-BuONO, leading to α-nitro enones in good to excellent yields at room temperature with a broad functional group tolerance.

A mild, transition metal-free, diborane-mediated deoxygenation of nitro groups was discovered that in situ generates nitrosoarene reactive intermediates. This new reactivity mode of B2pin2 was leveraged to construct indoles from o-nitrostyrenes through a reductive-cyclization reaction that exhibits a Hammett ρ-value of +0.97 relative to σpara values. Our new deoxygenation reaction is efficient, practical, and scaleable, enabling access to a broad range of indoles.

A palladium-catalyzed 1,2-arylboration of vinylarenes with aryldiazonium tetrafluoroborates and bis(pinacolato)diboron has been disclosed. It is reported for the first time that styrene derivatives can be successfully employed as good substrates for 1,2-arylboration of alkenes. Mechanistic studies suggest that no Pd–H reinsertion occurred under our standard conditions, which is the key for the success of this transformation.

Pd-catalyzed 1,2-addition (instead of 1,4-addition) of arylboronic acids to 2-alkylenecyclobutanones followed by β-carbon elimination from the resulting palladium cyclobutanolates to afford γ,δ-unsaturated ketones was developed. The desired γ,δ-unsaturated ketones were obtained in good to excellent yields with Z/E selectivities of up to >99:1 and a broad spectrum of functional group tolerability.

A Pd-catalyzed transfer hydrogenation of various N-heteroaromatic compounds with B2pin2 as a mediator and environmentally benign water as both solvent and hydrogen donor has been disclosed. This reaction proceeded under ambient temperature with a broad range of N-heteroaromatic compounds among which imidazo[1,2-a]pyridine derivatives were for the first time selectively reduced to 5,6,7,8-tetrahydroimidazo[1,2-a]pyridines, which are the core structural motifs of an inhibitor of human O-GlcNAcase. Mechanistic studies suggested that the new protons in products are from water and Pd–H might be the key intermediate with B2pin2 as the H2O activator.

An efficient copper-catalyzed decarboxylative hydroboration of phenylpropiolic acids with bis(pinacolato)diboron was developed, affording β-vinylboronates as the only products in high yields. Extra hydrogen sources such as methanol are not needed in this catalytic system. This reaction could be performed successfully under ligand- and base-free conditions. It demonstrated that phenylpropiolic acids can be employed as alkyne synthons in the hydroboration reaction and exhibited good reactivity and higher selectivity than terminal alkynes.Copper-catalyzed decarboxylative hydroboration of phenylpropiolic acids with bis(pinacolato)diboron proceeds under ligand-free or both ligand- and base-free conditions, affording β-vinylboronates in high yields.

An efficient and general method for C(sp2)–H difluoroalkylation of aldehyde derived hydrazones via a CuII/B2pin2-catalyzed reaction between difluoroalkyl bromides and hydrazones was developed. In this reaction, both aromatic and aliphatic difluoroalkylated aldehyde derived hydrazones could be achieved in good to excellent yields. For some heteroaromatic aldehyde derived hydrazones, two fluoroacetates could be introduced onto the final products. A preliminary mechanism study manifested that a difluoroalkyl radical via SET pathway was involved in the reaction. In addition, the catalytic diboron reagent plays an indispensable role in this transformation.

A palladium-catalyzed arylboration of norbornene or norbornadiene with aryl halides and bis(pinacolato)diboron has been disclosed. Mechanistic studies suggest that the reaction proceeds under a Catellani-type coupling to render versatile multifunctionalized alkylboranes in good yields. This reaction is complementary to the existing methods and is well tolerable with a variety of functional groups and readily scaled-up to a gram scale without deteriorating the yield.

Fe-catalyzed aerobic oxidative esterifications of arylacetonitriles with alcohols, tri alkoxsilanes, silicate esters, or borate esters have been developed. The acyl groups which were in situ generated via chemoselective C(CO)-CN bond cleavage were directly used as electrophiles, leading to corresponding aryl esters in good to excellent yields under molecular oxygen when attacked by alcohols or alcohol surrogates. Dioxygen serves as both oxidant and reactant in this protocol. The reaction has a very broad substrate scope. Cheap starting materials as well as environmentally benign and inexpensive iron catalyst and ideal oxidant O2 feature this transformation and make it a practical and sustainable protocol to afford esters.

An unprecedented substituent-controlled chemoselective cleavage of C═C double bond or C(sp2)–C(CO) bond along with aerobic phosphorylation of α,β-unsaturated carbonyl compounds with H-phosphonates through a radical process has been disclosed. The current strategy provides an access to β-ketophosphonates under mild conditions with a wide substrate scope.

Copper-catalyzed aerobic oxidative esterification of acetophenones with alcohols using molecular oxygen has been developed to form a broad range of α-ketoesters in good yields. In addition to reporting scope and limitations of our new method, mechanism studies are reported that reveal that the carbonyl oxygen in the ester mainly originated from dioxygen.

A copper-catalyzed highly efficient protocol for the synthesis of bis-deuterated β-borylated α,β-styrene derivatives, which can be further transformed to practical isotopically labeled compounds, has been developed. Alkynyl carboxylic acids are employed as alkyne synthons yet demonstrate a sharp discrepancy in reactivity and selectivity compared to terminal alkynes. Meanwhile, this reaction offers a novel and efficient strategy for highly selective trifunctionalization of the carbon–carbon triple bond at ambient temperature.

The palladium-catalyzed Sonogashira-type aerobic oxidative coupling of arylhydrazines with terminal alkynes via C–N bond cleavage has been developed; internal alkynes were afforded with a broad substrate scope. This reaction proceeds under copper- and base-free conditions with molecular oxygen as the sole oxidant and nitrogen and water as the only by-products.

Fe-catalyzed tandem cross-dehydrogenative coupling of the methyl group in arylmethanes with 1,3-dicarbonyl compounds has been developed. The reaction affords one new C(sp3)–C(sp2) bond and one new C(sp3)–C(sp3) bond in a one-pot protocol. Further study suggests that this reaction might start with a Friedel–Crafts-type reaction (cross-dehydrogenative arylation) followed by cross-dehydrogenative coupling with an activated methylene group under mild oxidative conditions.

A synergistic Cu/Fe-catalyzed aerobic oxyphosphorylation of alkynes or alkynyl carboxylic acids with H-phosphonate is disclosed. The useful β-ketophosphonate products were obtained in good yields under oxygen atmosphere in a novel way. This reaction exhibits a wide substrate scope, and the mechanistic experiments indicate that a radical mechanism forms both C–P and C═O bonds simultaneously. This mechanism contrasts existing aerobic difunctionalization of alkynes.

A phenol-catalyzed aerobic oxidative styryl ether formation method was developed with benzyl alcohol under basic DMSO. Styryl ether was obtained after 12 hours of heating at 60–80 °C where DMSO was involved in the reaction as the extra carbon source. Control experiments indicated that both phenol and DMSO are crucial for the success of the reaction. A variety of styryl ethers were prepared smoothly from benzyl alcohols in good to excellent yields in an environmentally friendly way.

We report here an unprecedented Fe/Cu synergistically catalyzed deesterificative or deamidative oxyphosphorylation of unsaturated carboxylates or amides with H-phosphonates. The valuable β-ketophosphonates were obtained along with chemoselective cleavage of Csp2–C(CO) or Csp–C(CO) bonds in good yields under oxygen atmosphere with a wide substrate scope.

A Cu2O-catalyzed aerobic oxidative decarboxylative ammoxidation to primary benzamides from phenylacetic acids and α-hydroxyphenylacetic acids is developed. A variety of primary benzamides could be prepared smoothly, in good to excellent yields, by means of a one-pot domino protocol combining decarboxylation, dioxygen activation, oxidative C–H bond functionalization, and amidation reactions.

Aromatic aldehydes or ketones from copper catalyzed aerobic oxidative decarboxylation of phenylacetic acids and α-hydroxyphenylacetic acids have been synthesized. This reaction combined decarboxylation, dioxygen activation, and C–H bond oxidation steps in a one-pot protocol with molecular oxygen as the sole terminal oxidant. This reaction represents a novel decarboxylation of an sp3-hybridized carbon and the use of a benzylic carboxylic acid as a source of carbonyl compounds.

A Cu(II)-catalyzed oxidative decarboxylative synthesis of 2-aryl benzothiazole from phenylacetic acids and α-hydroxyphenylacetic acids has been developed. This reaction proceeds via Cu(II)-catalyzed decarboxylation, C–H bond oxidation, ring-opening, and condensation steps in a one-pot protocol with dioxygen as the sole terminal oxidant. Various functional groups were tolerated under standard conditions, and isolated yields were as high as 95%.

Dichloromethane (DCM) as a C1 source has been discovered: methylene diesters from DCM and carboxylic acids or aldehydes with TBHP in water were efficiently synthesized. The reactions proceed under mild conditions and afford both aliphatic and aromatic methylene diesters in good to excellent yields (up to >99%). 2-Chloroethyl benzoates and 3-chloropropyl benzoates are easily obtained in the same way from 1,2-dichloroethane and 1,3-dichloropropane, respectively, in good to excellent yields.

A phenol-catalyzed aerobic oxidative styryl ether formation method was developed with benzyl alcohol under basic DMSO. Styryl ether was obtained after 12 hours of heating at 60–80 °C where DMSO was involved in the reaction as the extra carbon source. Control experiments indicated that both phenol and DMSO are crucial for the success of the reaction. A variety of styryl ethers were prepared smoothly from benzyl alcohols in good to excellent yields in an environmentally friendly way.

The palladium-catalyzed Sonogashira-type aerobic oxidative coupling of arylhydrazines with terminal alkynes via C–N bond cleavage has been developed; internal alkynes were afforded with a broad substrate scope. This reaction proceeds under copper- and base-free conditions with molecular oxygen as the sole oxidant and nitrogen and water as the only by-products.

A copper-catalyzed highly efficient protocol for the synthesis of bis-deuterated β-borylated α,β-styrene derivatives, which can be further transformed to practical isotopically labeled compounds, has been developed. Alkynyl carboxylic acids are employed as alkyne synthons yet demonstrate a sharp discrepancy in reactivity and selectivity compared to terminal alkynes. Meanwhile, this reaction offers a novel and efficient strategy for highly selective trifunctionalization of the carbon–carbon triple bond at ambient temperature.

A copper(I)-catalyzed three-component reaction of sulfoximines, alkynes and azides is described. This reaction proceeds under mild conditions with copper salt as a catalyst and atmospheric oxygen as an oxidant to afford a variety of 1,2,3-triazolyl-5-sulfoximines in moderate to good yields.

H2O is routinely described as a proton donor, however, in the presence of diboron compounds, the umpolung reaction of H2O under metal-free conditions was successfully developed, which could afford hydride species, leading to a highly efficient and chemoselective reduction of CO bonds. This strategy exhibits excellent chemoselectivities toward carbonyl groups in the presence of ester, olefin, halogen, thioether, sulfonyl, cyano as well as heteroaromatic groups.

An expedient and stereoselective synthesis of functionalized trisubstituted allylic boronates via direct borylation of Morita–Baylis–Hillman alcohols is disclosed. The reaction proceeds smoothly at ambient temperature with high atomic and synthetic efficiency. The desired allylic boronates can be applied in the efficient synthesis of homoallyl alcohols and α-exomethylene γ-lactones.

Chemoselective cleavage of the C(CO)–C(alkyl) bond in aryl ketones leading to azole amides is disclosed with a broad substrate scope. Aryl ketones with a variety of long-chain alkyl groups have been demonstrated to be active substrates and mechanism studies suggested that molecular oxygen serves both as an oxidant and a reactant in this strategy.

A novel copper-catalyzed chemoselective reduction of a carbon–carbon double or triple bond to a carbon–carbon single bond in α,β-unsaturated ketones is developed. This reaction proceeds under hydrogen gas or stoichiometric metal hydride free conditions. Saturated ketones were obtained in good to excellent yields with a broad substrate scope. Mechanistic studies reveal that the two hydrogen atoms come from H2O in the system. Thus this reaction represents a highly efficient, and remarkably chemoselective strategy.

Catalyzed by a simple copper salt, the reaction of an aryl aldehyde and a terminal alkyne in the presence of piperidine delivers the valuable chalcone products, which were rarely found in previous A3 coupling reactions. This reaction can be applied to a wide range of substrates. Mechanistic studies indicate that this reaction experiences a tandem process containing A3 coupling, copper assisted isomerization of propadienamine to allenylamine and subsequent hydrolysis.

An efficient Pd-catalyzed three components reaction involving the 1,2-diarylation of vinylarenes has been disclosed. This reaction introduces two different aryl groups across vinylarenes at ambient temperature giving rise to multi-aryl substituted ethanes which are biologically relevant compounds prevailing in organic chemistry, medicinal chemistry and materials science.

C–N bond formation via a copper-catalyzed aerobic oxidative decarboxylative tandem protocol was realized. The phenylacetic acids which contain ortho-X (X = F or Br) on the aromatic ring will render a fused five-membered heterocycle via a tandem aromatic nucleophilic substitution and aerobic oxidative decarboxylative acylation at the C(sp2)–H bond of benzimidazoles under the Cu(OAc)2/K2CO3/BF3·Et2O catalytic system, while with CuBr as the catalyst and pyridine as the base, N-acylation occurred and tertiary amides were obtained.

An original and efficient synthesis of 3,3-difluoro-2-oxindole derivatives has been developed via copper/B2pin2-catalyzed difluoroacetylation of aniline via C–H activation followed by intramolecular amidation. In this method, amino groups in primary, secondary or tertiary anilines act as directing groups, providing ortho-difluoroacetylated products regioselectively. And in the first two cases, further intramolecular amidation affords 3,3-difluoro-2-oxindole derivatives via a one-pot strategy. This method facilitates the synthesis of compound A as a potent and selective EP3 receptor antagonist in only five steps in 13% yield instead of the previously reported nine steps in overall 4% yield.