Asymmetric Henry reactions of aldehydes with various nitroalkanes catalyzed by copper(II) complexes of novel chiral N‐monoalkyl cyclohexane‐1,2‐diamines

A number of novel chiral diamines 3 , (1R,2R)‐N‐monoalkylcyclohexane‐1,2‐diamines, were designed and synthesized from trans‐cyclohexane‐1,2‐diamine and applied to the catalytic asymmetric Henry reaction of benzaldehyde and nitromethane to provide β‐nitroalcohol in high yield (up to 99%) and good enantiomeric excess (up to 89%). By using ligand (1R,2R)‐N¹‐(4‐methylpentan‐2‐yl)cyclohexane‐1,2‐diamine ( 3g ), the reaction was optimized in terms of the metal ion, temperature, solvent and base. Further experiments indicated that the complex, 3g –Cu(OAc)₂, was an efficient catalyst in the asymmetric Henry reaction between different aldehydes and nitromethane, and the desired products have been obtained with high chemical yields (up to 99%) and high enantiomeric excess (up to 93%). The optimized catalyst promoted the diastereoselective Henry reaction of various aldehyde substrates and nitroalkane, which gave the corresponding anti‐selective adduct with up to 99% yield and 83:17 anti/syn selectivity. Upon scaling up to gram quantities, the β‐nitroalcohol was obtained in good yield (96%) with excellent selectivities (93% ee). The chiral induction mechanism was tentatively explained on the basis of a previously proposed transition‐state model. Copyright © 2014 John Wiley & Sons, Ltd.     

Ruthenium‐Catalyzed Alkylation of Indoles with Tertiary Amines by Oxidation of a sp3 C?H Bond and Lewis Acid Catalysis

Ruthenium porphyrins (particularly [Ru(2,6‐Cl₂tpp)CO]; tpp=tetraphenylporphinato) and RuCl₃ can act as oxidation and/or Lewis acid catalysts for direct C‐3 alkylation of indoles, giving the desired products in high yields (up to 82 % based on 60–95 % substrate conversions). These ruthenium compounds catalyze oxidative coupling reactions of a wide variety of anilines and indoles bearing electron‐withdrawing or electron‐donating substituents with high regioselectivity when using tBuOOH as an oxidant, resulting in the alkylation of N‐arylindoles to 3‐{[(N‐aryl‐N‐alkyl)amino]methyl}indoles (yield: up to 82 %, conversion: up to 95 %) and the alkylation of N‐alkyl or N‐H indoles to 3‐[p‐(dialkylamino)benzyl]indoles (yield: up to 73 %, conversion: up to 92 %). A tentative reaction mechanism involving two pathways is proposed: an iminium ion intermediate may be generated by oxidation of an sp³ C? H bond of the alkylated aniline by an oxoruthenium species; this iminium ion could then either be trapped by an N‐arylindole (pathway A) or converted to formaldehyde, allowing a subsequent three‐component coupling reaction of the in situ generated formaldehyde with an N‐alkylindole and an aniline in the presence of a Lewis acid catalyst (pathway B). The results of deuterium‐labeling experiments are consistent with the alkylation of N‐alkylindoles via pathway B. The relative reaction rates of [Ru(2,6‐Cl₂tpp)CO]‐catalyzed oxidative coupling reactions of 4‐X‐substituted N,N‐dimethylanilines with N‐phenylindole (using tBuOOH as oxidant), determined through competition experiments, correlate linearly with the substituent constants σ (R²=0.989), giving a ρ value of ?1.09. This ρ value and the magnitudes of the intra‐ and intermolecular deuterium isotope effects (k_H/k_D) suggest that electron transfer most likely occurs during the initial stage of the oxidation of 4‐X‐substituted N,N‐dimethylanilines. Ruthenium‐catalyzed three‐component reaction of N‐alkyl/N‐H indoles, paraformaldehyde, and anilines gave 3‐[p‐(dialkylamino)benzyl]indoles in up to 82 % yield (conversion: up to 95 %).     

Kinetic Resolution of Racemic Mandelic Acid Esters by N,N′‐Dioxide–Scandium‐Complex‐Catalyzed Enantiomer‐Selective Acylation

A simple and efficient acylative kinetic resolution of racemic mandelic acid esters was accomplished with a chiral N,N’‐dioxide–scandium(III) complex under mild and base‐free reaction conditions. A variety of mandelic acid esters performed well in the reaction, obtaining both acylated products (up to 49% yield, 97% ee) and recovered substrates (up to 49% yield, 95% ee) in high enantioselectivities with perfect selectivity factors (up to 247). The enantioselective recognition and catalytic models were also proposed for the catalytic KR reaction.     

Synthesis of oxazines and N-arylpyrroles by reaction of unfunctionalized dienes with nitroarenes and carbon monoxide,catalyzed by palladium-phenanthroline complexes

The reaction between an unfunctionalized conjugated diene and a nitroarene under CO pressure and at 100 degrees C, catalyzed by [Pd(Phen)2][BF4]2 (Phen = 1,10-phenanthroline), affords the corresponding hetero-Diels-Alder adduct (oxazine) in up to 91% yields in one pot. If the reaction mixture is then heated to 200 degrees C, the oxazines are converted into the corresponding N-arylpyrroles in good yields. Pressures as low as 5 bar can be employed, and 0.08% catalyst is sufficient to effect the transformation. The reaction can be equally run by employing the nitroarene or the diene as limiting agent and works well for nitroarenes bearing either electron-withdrawing or mildly electron-donating substituents. A moderate steric hindrance on the nitroarene (o-methyl) is well tolerated, but 1,4-disubstituted-1,3-dienes are not suitable substrates.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Asymmetric Synthesis of Monofluorinated Carbocyclic Alcohols and Vicinal Difluorinated Heterocycles and Carbocycles

A straightforward method to access novel families of enantioenriched cis-monofluorinated carbocyclic alcohols has been developed through ATH/DKR in up to 97 % yield, up to 99 : 1 dr and enantioinductions up to 97 % ee. Trans-difluorinated indans, tetrahydronaphthalenes, tetrahydroquinolines and chromans have been synthesized as well by deoxofluorination of the corresponding cis-fluoro alcohols. The reaction was performed on a series of variously substituted 3-fluorochromanols, 3-fluorotetrahydroquinolinols, 2-fluoro inden-1-ols and 2-fluoro 1,2,3,4-tetrahydronaphthalen-1-ols in up to 86 % yields, with diastereoselectivities up to 97 : 3 and enantioselectivities up to >99 % ee.     

Enantioselective Construction of Functionalized Thiochromans via Squaramide‐Catalyzed Asymmetric Cascade Sulfa‐Michael/Michael Addition

An efficient enantioselective cascade sulfa‐Michael/Michael addition reaction of trans‐3‐(2‐mercaptophenyl)‐2‐propenoic acid ethyl ester with nitroalkenes catalyzed by a chiral squaramide catalyst was disclosed. This cascade reaction afforded thiochroman derivatives with three contiguous stereocenters in high yields (up to 94%), excellent diastereoselectivities (up to >25:1 dr) and enantioselectivities (up to 99% ee).     

Design,Synthesis, and Application of Chiral C2‐Symmetric Spiroketal‐Containing Ligands in Transition‐Metal Catalysis

We present an expedient and economical route to a new spiroketal‐based C₂‐symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium‐catalyzed hydroarylations (up to 95 % ee), palladium‐catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium‐catalyzed Heck couplings (up to 94 % ee), and rhodium‐catalyzed dehydroalanine hydrogenation (up to 93 % ee).     

Design,Synthesis, and Application of Chiral C2‐Symmetric Spiroketal‐Containing Ligands in Transition‐Metal Catalysis

We present an expedient and economical route to a new spiroketal‐based C₂‐symmetric chiral scaffold, termed SPIROL. Based on this spirocyclic scaffold, several chiral ligands were generated. These ligands were successfully employed in an array of stereoselective transformations, including in iridium‐catalyzed hydroarylations (up to 95 % ee), palladium‐catalyzed allylic alkylations (up to 97 % ee), intermolecular palladium‐catalyzed Heck couplings (up to 94 % ee), and rhodium‐catalyzed dehydroalanine hydrogenation (up to 93 % ee).     

Bioactive constituents of Iris hybrida (Iridaceae): Processing effect

Iris genus plants are a valuable source of bioactive compounds, which are an important component for pharmaceutical development. The present article shows the potential for mineral nutrition with application of magnesium sulfate, iron chelates and potassium oxide affecting the phenolic compound contents in Iris hybrida ‘Tsikavynka’, I. hybrida ‘Tambo’ and I. hybridа ‘Widecombe Fire’. The effect of mineral processing was specific to plant organs and varied in the component composition. The Iris rhizomes had an increased total phenolic compound content after treatment (up to 10% of the total isoflavonoid content, up to 8% of phenolic acids, up to 5% of γ-pyrones and up to 13% of flavonoids), determined using UV–vis spectroscopy. A positive effect of nutrition on the biosynthesis and content of individual isoflavonoids (tectoridin, nigricin d -glucoside, genistin, iristectorigenin B, nigricin, irigenin and irisolidone) and xanthone mangiferin in Iris rhizomes by HPLC was established. In addition, an increase in the chlorogenic acid amount in Iris leaves was noted. The results demonstrate the sensitivity of Iris phenylpropanoid metabolism to mineral nutrition and can be used to predict medical plant cultivation with increased content of bioactive constituents.     

Enantioselective Organocatalytic Aza-Michael Additions of Phthalimide Derivatives to α,β-Unsaturated Aldehydes

Phthalimide derivatives as nitrogen nucleophiles with α,β‐unsaturated aldehydes for asymmetric aza‐Michael additions have been reported. The reactions proceed smoothly to afford corresponding Michael adducts in good yields (up to 98%) and enantioselectivities (up to 95% ee).     

Direct Alkylation of Amines with Primary and Secondary Alcohols through Biocatalytic Hydrogen Borrowing

The reductive aminase from Aspergillus oryzae (Asp RedAm) was combined with a single alcohol dehydrogenase (either metagenomic ADH‐150, an ADH from Sphingobium yanoikuyae (SyADH), or a variant of the ADH from Thermoanaerobacter ethanolicus (Te SADH W110A)) in a redox‐neutral cascade for the biocatalytic alkylation of amines using primary and secondary alcohols. Aliphatic and aromatic secondary amines were obtained in up to 99 % conversion, as well as chiral amines directly from the racemic alcohol precursors in up to >97 % ee , releasing water as the only byproduct.     

Isosteviol‐amino Acid Conjugates as Highly Efficient Organocatalysts for the Asymmetric One‐pot Three‐component Mannich Reactions

Isosteviol‐amino acid conjugates were synthesized and used as chiral catalysts for the asymmetric three‐component Mannich reaction with hydroxyacetone as donor molecule. Good yields (up to 98%) and excellent stereoselectivities (up to 97:3 dr and 99% ee) were achieved in a short reaction time. In addition, syn‐ or anti‐configurations of α‐hydroxy‐β‐amino carbonyl compounds were obtained as main products with different chiral catalysts.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.     

Palladium-catalyzed allylic substitution assisted by 1,3,2-diazaphospholidine derivatives of (<Emphasis Type="Italic">R,R</Emphasis>)-<Emphasis Type="Italic">N</Emphasis>-naphthyltartarimide

P,P-Bidentate diamidophosphite ligands containing the (3R,4R)-3,4-dioxy-1-(1-naphthyl)pyrrolidine-2,5-dione framework and 1,3,2-diazaphospholidine rings with the stereogenic P atoms were obtained. The use of these ligands provides up to 85% ee in Pd-catalyzed asymmetric amination of (E)-1,3-diphenylallyl acetate and up to 95% ee in its asymmetric alkylation with dimethyl malonate.     

Asymmetric Synthesis of Furo[3,4‐b]indoles by Catalytic [3+2] Cycloaddition of Indoles with Epoxides

A highly efficient N,N′‐dioxide–Ni^II catalyst system for the catalytic [3+2] cycloaddition of indoles with epoxides through C?C cleavage of oxiranes was accomplished under mild conditions. It provided a promising approach for chiral furo[3,4‐b]indoles in up to 98 % yield with up to 91 % enantiomeric excess (ee) and >95:5 diastereomeric ratio (d.r.).     

Alkylation‐, Heating‐, and Doping‐Induced Emission Enhancement of a Polyaromatic Tube in the Solid State

A polyaromatic tube with a subnanometer‐sized cavity was efficiently prepared on a gram‐scale through the stereo‐controlled cyclotrimerization of a diphenylanthracene derivative as a key step. The facile exterior alkylation of the polyaromatic framework leads to a moderately fluorescent tube (R=‐OC₁₀H₂₁; Φ_F=20 %) in the solid state. The emission intensity of the solid‐state alkyl‐substituted tube is remarkably enhanced upon heating (up to 1.6 times, Φ_F=31 %) as well as doping with fluorescent dyes (up to 4.2 times, Φ_F=83 %) through efficient energy transfer.     

Rhodium(II)‐Catalyzed Inter‐ and Intramolecular Enantioselective Cyclopropanations with Alkyl‐Diazo(triorganylsilyl)acetates

The intermolecular cyclopropanation of styrene with ethyl diazo(triethylsilyl)acetate ( 1a ) proceeds at room temperature in the presence of chiral Rh^II carboxylate catalysts derived from imide‐protected amino acids and affords mixtures of trans‐ and cis‐cyclopropane derivatives 2a in up to 72% yield but with modest enantioselectivities (<54%) (Scheme 1 and Table 1). Protiodesilylation of a diastereoisomer mixture 2a with Bu₄NF is accompanied by epimerization at C(1) (→ 3 ). The intramolecular cyclopropanation of allyl diazo(triethylsilyl)acetate ( 8a ), in turn, affords optically active 3‐oxabicyclo[3.1.0]hexan‐2‐one ( 9a ) with yields of up to 85% and 56% ee (Scheme 3 and Table 2). Similarly, the (2Z)‐pent‐2‐enyl derivative 8d reacts to 9d in up to 77% yield and 38% ee (Scheme 3 and Table 3). In contrast, the diazo decomposition of (2E)‐3‐phenylprop‐2‐enyl and 2‐methylprop‐2‐en‐1‐yl diazo(triethyl‐silyl)acetates ( 8b and 8c , resp.) is unsatisfactory and gives very poor yields of substituted 3‐oxabicyclo[3.1.0]hexan‐2‐ones 9b and 9c , respectively (Table 3).     

Development of a syn‐Selective Mannich Reaction of Aldehydes with Propargylic Imines by Dual Catalysis: Asymmetric Synthesis of Functionalized Propargylic Amines

Direct coupling of enolizable aldehydes with C‐alkynyl imines is realized affording the corresponding propargylic Mannich adducts of syn configuration, thus complementing previous methods that gave access to the anti‐isomers. The combination of proline and a urea Brønsted base cocatalyst is key for the reactions to proceed under very mild conditions (3–10 mol % catalyst loading, dichloromethane as solvent, ?20 °C, 1.2 molar equivalents of aldehyde) and with virtually total stereocontrol (syn/anti ratio up to 99:1; ee up to 99 %). Some possibilities of further chemical elaboration of adducts are also briefly illustrated.     

Atroposelective Synthesis of Axially Chiral Biaryls by Palladium-Catalyzed Asymmetric C−H Olefination Enabled by a Transient Chiral Auxiliary

Atroposelective synthesis of axially chiral biaryls by palladium-catalyzed C−H olefination, using tert-leucine as an inexpensive, catalytic, and transient chiral auxiliary, has been realized. This strategy provides a highly efficient and straightforward access to a broad range of enantioenriched biaryls in good yields (up to 98 %) with excellent enantioselectivities (95 to >99 % ee). Kinetic resolution of trisubstituted biaryls bearing sterically more demanding substituents is also operative, thus furnishing the optically active olefinated products with excellent selectivity (95 to >99 % ee, s-factor up to 600).