Cobalt(II)-Catalyzed Selective Three-Component Oxyalkylation of N-Aryl Glycinates: A Route to CF3-Labeled Threonine Analogues.

Glycinates, protected enols, and an electrophilic trifluoromethylating reagent were employed to assemble CF3-labeled threonine analogues through a radical addition cascade. To suppress the competing oxidation of the oxyalkyl radical intermediate, various redox catalysts were evaluated and Co(II) exhibited supreme selectivity control with a proper counterion. A series of glycinate and related peptides were thus successfully modified under Co-catalysis. Mechanistic studies revealed that a N-aryl glycinate could be preferentially oxidized by cobalt over the oxyalkyl radical to generate an imine intermediate, and the key to this selectivity could be ascribed to the prechelation of glycinate, as well as a weakly basic carboxylate counterion.

Construction of heterocyclic rings from cyclopropenes.

Heterocyclic rings are the fundamental building blocks of biological systems and have wide applications in synthetic chemistry and medicinal science. The development of novel synthetic methodology for heterocyclic skeletons from a variety of starting materials has made great progress in the past decades. Meanwhile, highly strained cyclopropenes as reactive reagents in organic transformations have drawn much attention from chemists. The rich chemical reactivity and reaction routes have been well investigated, and some review articles related to the reactivity of cyclopropenes and the construction of carbocycles and acyclic compounds have appeared in these years. Thus, this review mainly focuses on the progress in the construction of heterocyclic rings starting from various cyclopropenes including the reactions of commonly available stable cyclopropenes, in situ generated reactive cyclopropenes and cyclopropene precursors during this decade. Firstly, the transformations of common cyclopropenes into donor-type vinyl metal carbenes via transition metal induced ring opening, direct metalation of the CC bond of metal complexes, and cycloaddition reactions with 1,3-dipoles are described. Next, the annulation reactions of reactive cyclopropenes generated in situ with donor-acceptor reagents, intramolecular nucleophilic addition, and the cycloaddition reactions with 1,3-dipoles are introduced. Then, the transformation of cyclopropene precursors such as alkyl 1-chloro- or 1-alkoxy-2-aroylcyclopropanecarboxylates into five-membered heteroaromatic compounds is also mentioned. In addition, a brief outlook of the opportunity and challenges in the field of bio-orthogonal reactions related to cyclopropenes is given.

Formal [3 + 3] Cycloaddition Reactions between Electron-Deficient Cyclopropenes and Hydrazones: A Route to Alkyl 1,4,5,6-Tetrahydropyridazine-3-carboxylates.

A formal [3 + 3] cycloaddition reaction between alkyl 2-aroyl-1-chlorocyclopropanecarboxylates 1 and common hydrazones 2 was developed. This process readily proceeded in diastereo- and regioselective fashion and gave alkyl 1,4,5,6-tetrahydropyridazine-3-carboxylates in high yields under mild basic conditions. Treatment of the annulation products with DDQ leads to the formation of functionalized pyridazine-3-carboxylates, analogues of nicotinic acid ester.

Ethyl 6-Hydroxyfulvene-1-Carboxylate: A Reagent Discriminating Primary Amines from Secondary Amines.

A highly chemo-selective reaction was observed when ethyl 6-hydroxyfulvene-1-carboxylate 1 was treated with different nucleophiles such as primary amines, secondary amines, alcohols, and thiols. Among them, only primary amines are reactive toward 1 to afford the condensation products 3, which exhibit good stability under both weakly acidic and basic conditions. The condensation process proved to be reversible between different primary amines. On the basis of this observation, the chemical selectivity of typical primary aromatic amines was evaluated quantitatively by determining equilibrium constants of the condensation reactions with aniline as a reference. Moreover, the primary amines of 3 can be readily released upon treatment with aqueous ammonia, making 6-hydroxyfulvene-1-carboxylate 1 a promising protecting reagent for primary amines.

Site-Specific Functionalization of 1,3-Dioxolane with Imines: A Radical Chain Approach to Masked α-Amino Aldehydes.

A thiol-promoted site-specific addition of 1,3-dioxolane to imines through a radical chain process is described. This process represents a metal-free and redox-neutral way to convert inexpensive materials to a broad range of protected α-amino aldehydes in good to excellent yields using only a catalytic amount of radical precursor. Control experiments revealed that both the thiol and a small amount of oxygen from air are indispensable to the success of this reaction.

Regioselective addition of phosphites to acyl cyclopropanes and following rearrangements: a facile access to enol phosphates.

An inorganic base-promoted domino reaction with organophosphites and acyl cyclopropane derivatives is developed and proved to provide an efficient access to functionalized enol phosphates. Unlike the well-known Perkow reaction, which employs trialkyl phosphite as the nucleophile, dialkyl phosphite is the key to the success of our transformation. This method is compatible with a series of dialkyl phosphites and acyl cyclopropanes possessing electron-withdrawing substituents, and an array of functionalized enol phosphates are successfully prepared. Based on the results of isotope-labeling and control experiments, this transformation is presumably initiated by the deprotonation of dialkyl phosphite and the following nucleophilic addition/anion shift/ring opening sequence leads to the formation of enol phosphates. Both the strain release of a three-membered ring and the formation of a relatively stable anion are indispensable driving forces for this process.

Triflic Acid-Catalyzed Cycloisomerization Reactions of Donor-Acceptor Cyclopropanes: Access to Alkyl 5-Arylfuran-2-carboxylates.

A direct synthetic strategy starting from alkyl 1-alkoxy-2-aroylcyclopropanecarboxylates was developed for the construction of alkyl 5-arylfuran-2-carboxylates. These donor-acceptor cyclopropanes smoothly undergo a simple ring-opening reaction or/and cycloisomerization reaction in the presence of acid at room temperature, which greatly depends on the properties of the acid used in the experiment. Alkyl 5-arylfuran-2-carboxylates were afforded in high yields in triflic acid, whereas alkyl 2,5-dioxo-5-phenylpentanoate became the major product in other protic acids and Lewis acids.

Construction of 2-Pyrone Skeleton via Domino Sequence between 2-Acyl-1-Chlorocyclopropanecarboxylate and Amines.

A base-promoted domino reaction of 2-acyl-1-chlorocyclopropaneformic esters with amines is described. In the presence of inorganic bases like Cs2CO3 or Mg(OEt)2, the reaction proceeded smoothly in acetonitrile to afford 2-pyrone derivatives in modest to excellent yields (up to 97%). This reaction provides a straightforward and transition metal-free protocol to efficiently construct 2-pyrone skeleton. A possible mechanistic process involving 1,2-elimination of hydrogen chloride, aza-Michael addition, ring-opening, and intramolecular lactonization was suggested to rationalize the formation of the target 2-pyrone derivatives.

Merging asymmetric Henry reaction with organocatalytic cascade reaction for the construction of a chiral indolizidine alkaloid skeleton.

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C1-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral ß-nitro alcohol and α,ß-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Formation and aromatization of strained bicyclic pyrazolidines via tandem reaction of alkyl 2-aroyl-1-chlorocyclopropanecarboxylates with acylhydrazones.

A base-promoted reaction between alkyl 2-aroyl-1-chlorocyclopropanecarboxylates and acylhydrazones is described. In common solvents, the reactions proceed smoothly under mild conditions, providing mainly the formal substitution product , as well as a little amount of the formal [3 + 2] cycloaddition product . This strained bicyclic pyrazolidine , however, became the predominant product in DMSO. Moreover, a novel aromatization process of the fused pyrazolidine into 2,3,5-trisubstituted pyrrole has been successfully achieved in excellent yield via treatment with a HCl-pyridine system.

Stereoselective cascade formal nucleophilic substitution and Mannich reaction of ethyl 2-aroyl-1-chlorocyclopropanecarboxylates.

A highly regio- and diastereoselective cascade formal nucleophilic substitution and Mannich reaction of ethyl 2-aroyl-1-chlorocyclopropanecarboxylates with salicylaldimines is described. Under basic conditions, ethyl 2-aroyl-1-chlorocyclopropanecarboxylate is easily converted into a cyclopropene intermediate via simple 1,2-elimination of hydrogen chloride. The highly reactive cyclopropene quickly combines with salicylaldimine through regioselective oxa-addition to the strained C═C bond and subsequent diastereoselective addition to C═N bond, constructing C-O and C-C bonds at one time. This provides a highly stereoselective novel methodology for synthesis of conformationally constrained cis-tetrahydrocyclopropa[b]chromene derivatives.

Synthesis of functionalized fulvenes: [3 + 2] annulation of ethyl α-chlorocyclopropaneformates with 1,3-dicarbonyl compounds.

A base-promoted [3 + 2] annulation reaction of ethyl α-chlorocyclopropaneformates with 1,3-dicarbonyl compounds is described. This method provides an efficient and straightforward route to acidic multi-substituted fulvenes with distinctive properties.

Synthesis of fluorine-containing multisubstituted phenanthridines by rhodium-catalyzed alkyne [2+2+2] cycloaddition and tandem sp² C-H difluoromethylenation.

A highly efficient method for the synthesis of fluorine-containing multisubstituted phenanthridines through Rh-catalyzed alkyne [2+2+2] cycloaddition reactions has been developed. This method exhibits excellent functional-group compatibility. When a bromodifluoromethyl group, rather than a trifluoromethyl group, was employed in the cycloaddition reaction, more-complicated polycyclic compounds were obtained through tandem Rh-catalyzed cycloaddition/C-H difluoromethylenation. This route provides convenient access to fluorine-containing polycyclic compounds.

Cu-catalyzed tandem reactions of fluorinated alkynes with sulfonyl azides en route to 2-trifluoromethylquinolines.

A novel method for the synthesis of 2-trifluoromethylquinolines via Cu-catalyzed tandem reactions was reported. A strong electronic effect was observed, but the steric effect was negligible.

Photoredox-Enabled Dearomatization of Protected Anilines: Access to Cyclohexadienone Imines with Contiguous Quaternary Centers.

A photoredox-enabled alkylative dearomatization of protected anilines is reported. Under Ir catalysis and light irradiation, an N-carbamoyl-protected aniline and an α-bromocarbonyl compound could be simultaneously activated, and the two resulting radical species then recombine with each other to afford a dearomatized cyclohexadienone imine as the major product. A series of such imines with contiguous quaternary carbon centers were prepared, which can be further converted into cyclohexadienones, cyclohexadienols, and cyclohexyl amines.

PEI-modified chitosan/activated carbon composites for Cu(II) removal from simulated pyrophosphate plating rinsing wastewater.

It is a challenging task to remove heavy metal ions efficiently from the wastewater containing high concentrations of complexants. In this work, a novel PEI-modified chitosan/activated carbon composite adsorbent (PCA) was prepared and applied to the removal of Cu(II) from pyrophosphate plating rinsing wastewater. The main species of Cu(II) in the pyrophosphate wastewater was [Cu(HP2O7)2]4- or [Cu(P2O7)2]6-, which were denoted as [Cu(II)-PP] anions. The maximum adsorption capacity of PCA for Cu(II) reached 1.41 mmol g-1 under the condition of pH = 8 and molar ratio of pyrophosphate to Cu(II) = 4:1. The adsorption kinetic behavior of Cu(II) on PCA followed the Elovich model best and PCA attained adsorption equilibrium within 36 h. The thermodynamic studies showed that the adsorption process of Cu(II) by PCA was endothermic and spontaneous. The PCA fixed bed column was used to remove Cu(II) from simulated pyrophosphate plating rinsing wastewater. After three consecutive adsorption-desorption cycles, the adsorption performance, hydraulic conductivity, and mechanical stability of PCA column did not decrease. The FTIR and XPS analysis results indicated that [Cu(II)-PP] anions can be adsorbed on PCA by electrostatic attraction with protonated amine groups or coordination with the amine groups of PCA via ligand substitution.

Camphor-derived C1-symmetric chiral diamine organocatalysts for asymmetric Michael addition of nitroalkanes to enones.

A series of stable C(1)-symmetric chiral diamines (2a­2l) were conveniently synthesized by condensing exo-(-)-bornylamine or (+)-(1S,2S,5R)-menthylamine with various commercially available Cbz-protected amino acids. Among them, 2a can efficiently promote the Michael addition of nitroalkanes to a broad scope of enones with high yields (up to 96%) and excellent enantioselectivities (up to 98%) under mild conditions.

Synthesis of C1-symmetric chiral secondary diamines and their applications in the asymmetric copper(II)-catalyzed Henry (nitroaldol) reactions.

A small library of C(1)-symmetric chiral diamines (L1-L9) was constructed via condensing exo-(-)-bornylamine or (+)-(1S,2S,5R)-menthylamine with various Cbz-protected amino acids. Among them, ligand L1/CuCl(2)·2H(2)O complex (2.5 mol %) shows outstanding catalytic efficiency for Henry reaction between a variety of aldehydes and nitroalkanes to afford the expected products in high yields (up to 98%) with excellent enantioselectivities (up to 99%) and moderate to good diastereoselectivities (up to 90:10). This process is air- and moisture tolerant and has been applied to the synthesis of (S)-2-amino-1-(3,4-dimethoxyphenyl)ethanol (9), a key intermediate for (S)-epinephrine and (S)-norepinephrine. On the basis of HRMS and X-ray diffraction analysis of the L1/CuCl(2) complex, a transition-state model was proposed to explain the origin of asymmetric induction. The low catalyst loading, excellent yields and enantioselectivities, inexpensive copper salt, and mild reaction conditions make our catalytic system to be practically useful.

Copper(II)-catalyzed asymmetric henry reaction of o-alkynylbenzaldehydes followed by gold(I)-mediated cycloisomerization: an enantioselective route to chiral 1H-isochromenes and 1,3-dihydroisobenzofurans.

By combining the copper(II)-catalyzed asymmetric Henry reaction of o-alkynylbenzaldehydes with subsequent gold(I)-catalyzed cycloisomerization, optically active 1H-isochromenes and 1,3-dihydroisobenzofurans were successfully synthesized in good overall yields with good to excellent enantioselectivities (up to 98%). Various substrates were investigated, and a correlation between the regioselectivity and electronic nature of the substrates was studied. The substrates with electro-donating groups at the alkynyl moiety preferred a 6-endo-dig manner to generated 1H-isochromenes 3 as main products (up to >30:1) while the ones with electron-withdrawing groups were inclined to undergo 5-exo-dig cyclization to form 1,3-dihydroisobenzofurans 4 (up to 1:5).

Selective synthesis of poly-substituted fluorine-containing pyridines and dihydropyrimidines via cascade C-F bond cleavage protocol.

Fluorinated azaheterocycles are frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials, so efficient methods for the synthesis of these compounds are of significant value. We herein describe a selective strategy for the synthesis of poly-substituted pyridines and fluoroalkyl dihydropyrimidines based on C-F bond breaking of the anionically activated fluoroalkyl group. An array of pyridines and dihydropyrimidines were prepared through this domino process in high yields under noble metal catalyst-free conditions, making this method a valuable supplement to azaheterocycle synthesis.