Synthesis of gem-Difluorinated Oxa/Azaspiro[2.4]heptanes via Palladium-Catalyzed Spirocyclopropanation.

A palladium-catalyzed spirocyclopropanation of gem-difluoroalkenes with π-allylpalladium 1,4-dipoles has been successfully developed, which gives a powerful and straightforward synthetic strategy for the construction of novel gem-difluorinated spirocyclic compounds, 6,6-difluoro-5-oxa/azaspiro[2.4]heptanes. The scope of gem-difluoroalkenes can be extended to styrenes, acrylic esters, and acrylamides to realize the installment of various functional groups and different heteroatoms on the spirocyclic skeletons, which could be converted to valuable compounds with potential biological activity. The mechanistic investigations revealed the competition between spirocyclopropanation and ß-F elimination of π-allylpalladium zwitterionic intermediates.

Palladium-catalyzed ring-opening [5+2] annulation of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acids: rapid synthesis of 7-membered lactones.

A novel approach for the synthesis of unsaturated 7-membered lactones by Pd-catalyzed [5+2] dipolar cycloaddition of vinylethylene carbonates (VECs) and C5-substituted Meldrum's acid derivatives has been developed. Various Meldrum's acid derivatives worked well in this reaction under mild reaction conditions. A variety of 7-membered lactones can be accessed in a facile manner in moderate to good yields by employing easily prepared Meldrum's acid derivatives.

Molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes: a novel strategy for catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles.

A novel strategy for the catalytic synthesis of 2-aryl-2H-benzo[d][1,2,3]triazoles bearing a wide range of functional groups in good to excellent yields by non-noble molybdenum-catalyzed deoxygenative heterocyclization of 2-nitroazobenzenes is described. The salient features of the transformation include the use of readily available substrates, valuable products and ease of scale-up. The mechanistic study indicates that the reaction occurred via double deoxygenation by the Mo(VI)/Mo(IV) catalytic cycle from 2-nitroazobenzene, through the formation of 2-aryl-2H-benzo[d][1,2,3]triazole-N1-oxide or nitrene intermediates.

An aryl thiol-vinyl azide coupling reaction and a thiol-vinyl azide coupling/cyclization cascade: efficient synthesis of ß-ketosulfides and arene-fused 5-methylene-2-pyrrolidinone derivatives.

The addition reaction of thiol to vinyl azide has been extensively studied. Variously substituted aryl thiols are all viable for this coupling process. The scope of the other partner is successfully expanded from α-aryl vinyl azide to α-alkyl vinyl azide. A thiol-vinyl azide coupling/cyclization cascade is realized with substituted aryl vinyl azides carrying a 2-methoxycarbonyl group. The value of ß-ketosulfide products was demonstrated by its application in S-heterocycle synthesis.

Intramolecular Imino-ene Reaction of Azirines: Regioselectivity, Diastereoselectivity, and Computational Insights.

Intramolecular imino-ene reaction of 2 H-aziridine has been studied experimentally and computationally, demonstrating that (1) the concerted process takes place regioselectively on the alkene E-CH group; (2) the geometry of the N-linker impacts the reaction activation energy and diastereoselectivity significantly, with pyramidal alkyl amine as the linkage, an exclusive cis-product is achieved; (3) when the reaction has to occur with the Z-CH group, the cis-diastereoselectivity is solely observed regardless of the nature of the N-linkage.

Stereoselective synthesis of all-cis boryl tetrahydroquinolines via copper-catalyzed regioselective addition/cyclization of o-aldiminyl cinnamate with B2Pin2.

A copper catalyzed intramolecular 1,2-carboboration of o-aldiminyl cinnamate has been realized in both regio- and stereoselective fashions. This reaction provides a convenient entry to highly valuable and otherwise challenging cis-2,3,4-trisubstituted tetrahydroquinolines carrying a 4-boryl group. An unusual non-Michael addition intermediate or alternatively, a cyclic enolate is proposed to account for the intriguing all-cis configuration in the final products.

Intramolecular Imino-ene Reaction of 2H-azirines with Alkenes: Rapid Construction of Spiro NH Aziridines from Vinyl Azides.

A range of novel (poly)cyclic alkaloids incorporating an unprecedented 1,5-diazaspiro[2.4]heptane core that carry a spiro NH aziridine moiety and a 7-vinyl group are constructed from the thermal reaction of vinyl azides with tethered alkenes. Vinyl azides are converted to 2H-azirines in situ, which serve as enophiles for intramolecular imino-ene reactions with suitable alkenes. High stereoselectivity and specificity have been achieved for this novel intramolecular imino-ene reaction of azirines.

Copper-Catalyzed Borylative Cyclization of Substituted N-(2-Vinylaryl)benzaldimines.

A t-BuOCu-initiated reaction sequence of styrene borometalation and intramolecular imine addition has been achieved using a Cu(OTf)2/dppf combination as catalyst. The product of this reaction cascade is a useful 2,3-disubstituted indoline bearing a versatile boryl moiety and is formed with sole cis-selectivity. To account for the observation of the exclusive formation of cis-stereoisomers, a transition state featuring copper-imine coordination is suggested. The application to the synthesis of antioxidant tetrahydroindenoindoles is described.

Intramolecular Schmidt Reaction of Vinyl Azides with Cyclic Ketones.

Cyclic ketones tethered with a vinyl azide group undergo a Schmidt-hydrolysis sequence to give secondary lactams bearing a ketone side chain. Secondary lactams are obtained in a regioselective manner that is not possible in a conventional Schimdt reaction. In addition to the well-documented C-2 nucleophilicity, the N nucleophilicity of vinyl azide disclosed in this work opens a new direction for reaction invention involving vinyl azides.

Selective S-arylation of 2-oxazolidinethiones and selective N-arylation of 2-benzoxazolinones/2-benzimidazolinones.

There exist three possible patterns for the reaction of cyclic 2-oxazolidinethione and 2-benzoxazolidinethione with arynes, namely (a) S-arylation, (b) N-arylation, and (c) aryne insertion into the thiocarbonyl group (C[double bond, length as m-dash]S). Our studies demonstrate that S-arylation wins out affording S-aryl dihydrooxazoles. In contrast, for related reactions of cyclic 2-benzoxazolinone and 2-benzimidazolinone with arynes, it is found that N-arylation outcompetes O-arylation and aryne insertion into the C[double bond, length as m-dash]O group to give N-aryl 2-benzoxazolinones and N-aryl 2-benzimidazolinones.

One-Pot Conversion of N-Allyl-α-cyano Esters to α-Allyl-α-cyano Lactams through a Hydrolysis/Ketene Formation/Cyclization/Claisen Rearrangement Sequence.

An intramolecular ketene aza-Claisen rearrangement is developed for the first time to enable the stereoselective synthesis of α-ally-α-cyano-lactams from N-allyl amino esters. This reaction also exhibits outstanding chemoselectivity when an unsymmetrical bis-N-allyl group is present in the starting molecule. The usefulness of this method is demonstrated by a short synthesis of optically active bicyclolactam from l-proline.

Stereoselective Synthesis of Polycycles Containing an Aziridine Group: Intramolecular aza-Diels-Alder Reactions of Unactivated 2H-Azirines with Unactivated Dienes.

Vinyl azide with a pendent diene can undergo thermal decomposition to a related azirine intermediate, which was used immediately in an intramolecular aza-Diels-Alder reaction to furnish an aziridine-containing trans-fused tricyclic core structure with excellent stereoselectivity. The method provides a facile entry to complex polycyclic alkaliods which can be further elaborated by ring-opening reactions and ring expansion of the aziridine moiety, as well as by dihydroxylation of the alkene group.

Facile synthesis of aza-spirocyclopropanyl oxindoles by the reaction of 3-(2-bromoethyl)-indole with 2,3-dimethylimidazole-1-sulfonyl azide triflate.

3-(2-Bromoethyl)indole reacts with 2,3-dimethylimidazole-1-sulfonyl azide triflate to give an intermediate N-(2,3-dimethylimidazole)-1-sulfonyl aza-spirocyclopropanyloxindole. This reactive species is captured by an alcohol or amine to afford the corresponding aza-spirooxindole sulfonate and sulfonamide.

Multi-tissue metabolic responses of goldfish (Carassius auratus) exposed to glyphosate-based herbicide.

Most genetically modified crops are engineered for herbicide tolerance, among them, glyphosate tolerant crops have the greatest share. Glyphosate is one of the most extensively used herbicides worldwide. The popularity of glyphosate stems from its low cost, low environmental impact, and effectiveness while being safe for animals. The toxicity of glyphosate to untargeted organisms was studied using goldfish (Carassius auratus) after exposure to different concentrations of glyphosate isopropylamine salt, a glyphosate based herbicide for 96 hours. Tissues of brain, kidney and liver were collected and subjected to NMR-based metabolomics analysis and histopathological inspection. Plasma was collected and the hematological parameters of glutamic-oxaloacetic transaminase (GOT), glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH), blood urea nitrogen (BUN) and creatinine (CRE) were quantified. Glyphosate produced an increase in the hematological parameters of BUN and CRE and dose-dependent injuries. Metabolomics analysis revealed significant perturbations in neurotransmitter equilibrium, energy metabolism and amino acid metabolism in glyphosate dosed fish, which are associated with the toxicity of glyphosate. The results highlight the vulnerability of glutaminergic neurons to glyphosate and enlighten the potential of glutamine as an early marker of glyphosate induced neurotoxicity.

(1)H NMR based metabolomics approach to study the toxic effects of dichlorvos on goldfish (Carassius auratus).

Dichlorvos (DDVP), one of the most widely used organophosphorus pesticides (OPs), has caused serious pollution in environment. In this study, (1)H nuclear magnetic resonance (NMR) based metabolomics approach combined with histopathological and immunohistochemical examination, and biochemical assays were used to investigate toxicities of DDVP on goldfish (Carassius auratus). After 10 days' exposure of DDVP at three dosages of 5.18, 2.59 and 1.73 mg/L, goldfish tissues (gill, brain, liver and kidney) and serum were collected. Histopathology revealed severe impairment of gills, livers and kidneys, and immunohistochemistry disclosed glial fibrillary acidic protein (GFAP) positive reactive astrocytes in brains. Orthogonal signal correction-partial least squares-discriminant analysis (OSC-PLS-DA) of NMR profiles disclosed that DDVP influenced many metabolites (glutamate, aspartate, acetylcholine, 4-aminobutyrate, glutathione, AMP and lactate in brain; glutathione, glucose, histamine in liver; BCAAs, AMP, aspartate, glutamate, riboflavin in kidney) dose-dependently, involved with imbalance of neurotransmitters, oxidative stress, and disorders of energy and amino acid metabolism. Several self-protection mechanisms concerning glutamate degradation and glutathione (GSH) redox system were found in DDVP intoxicated goldfish.

The Reaction of 2,3-Dimethylimidazole-1-sulfonyl Azide Triflate with 3-Substituted Indoles: Reactivity and Scope.

2,3-Dimethylimidazole-1-sulfonyl azide triflate reacts with 3-substituted indoles to deliver 2-iminoindolines, 2-aminoindoles, or 2-imino-3-aminoindolines by using different conditions. This imidazolium sulfonyl azide shows higher reactivity toward carbon nucleophile indoles than ordinary alkyl/aryl sulfonyl azides.

An efficient approach to 1,2,3-trisubstituted indole via rhodium catalyzed carbene C(sp(3))-H bond insertion.

A method for convenient synthesis of N-alkyl-2-aryl-indole-3-carbaldehyde has been described. A variety of highly valuable indolyl aldehydes have been prepared through this method. Electron donating groups on both aromatic rings (anilinyl and benzyl) facilitate the formation of the desired products. A benzylic C-H insertion by rhodium carbene is the key step for this transformation.

One-pot protocol to functionalized benzopyrrolizidine catalyzed successively by Rh2(OAc)4 and Cu(OTf)2: a transition metal-Lewis acid catalysis relay.

4-N-allylarylpropylamino-1-sulfonyl triazoles are converted to structurally unique benzopyrrolizidinyl sulfonamides in a one-pot operation. Intramolecular capture of rhodium carbene with arylamino nitrogen gives rise to the formation of an ammonium ylide immediate. A [2,3]- or [1,2]-rearrangement occurs to give a 2-allylpyrrolidinyl-2-carbimine intermediate which undergoes Cu(OTf)2 catalyzed aza-Friedel-Crafts cyclization to finish a highly functionalized tricyclic system decorated with a synthetically difficult quaternary carbon center, a sulfonamide group, and an allyl segment.

(1)H NMR based metabolomics approach to study the toxic effects of herbicide butachlor on goldfish (Carassius auratus).

Butachlor, one of the most widely used herbicides in agriculture, has been reported with high ecotoxicity to aquatic plants and animals. In this study, a (1)H NMR based metabolomics approach combined with histopathological examination and biochemical assays was applied to comprehensively investigate the toxic effects of butachlor on four important organs (gill, brain, liver and kidney) of goldfish (Carassius auratus) for the first time. After 10 days' butachlor exposure at two dosages of 3.2 and 0.64 µmol/L, fish tissues (gill, brain, liver and kidney) and serum were collected. Histopathological inspection revealed severe impairment of gill filaments and obvious cellular edema in livers and kidneys. The increase of glutathione peroxidase (GSH-Px) activity in gill and methane dicarboxylic aldehyde (MDA) level in four tissues reflected the disturbance of antioxidative system in the intoxicated goldfish. Serum lactate dehydrogenase (LDH) activity and creatinine (CRE) level were increased in butachlor exposure groups, suggesting liver and kidney injuries induced by butachlor. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) of NMR profiles disclosed metabolic changes that were related to the toxic effects of butachlor including oxidative stress, disorder of energy metabolism and amino acids metabolism, and disturbance of neurotransmitter balance in butachlor exposed goldfish. This integrated metabolomics approach provided a molecular basis underlying the toxicity of butachlor and demonstrated that metabolomics was a powerful and highly effective approach to elucidate the toxicity and underlying mechanisms of herbicides and pesticides, applicable for their risk assessment.

Copper-catalyzed cyclization/aza-Claisen rearrangement cascade initiated by ketenimine formation: an efficient stereocontrolled synthesis of α-allyl cyclic amidines.

An efficient and convenient synthesis of α-allyl cyclic amidines has been achieved by applying a novel cascade reaction. Copper(I)-mediated in situ N-sulfonyl ketenimine formation from the reaction of a terminal alkyne with sulfonyl azide is followed by an intramolecular nucleophilic attack on the central carbon atom by an allylic tertiary amine, and then an aza-Claisen rearrangement takes place through a chair transition state to furnish the titled amidines with complete stereocontrol.