First Synthesis and Utilization of Oripavidine – A Concise and Efficient Route to Important Morphinans and Apomorphines

The synthesis and transformation of oripavidine ( 8 ) offer an efficient and simple route to highly active dopamine agonist apomorphines and a variety of important 14β‐hydroxy‐morphinan derivatives. Natural origin thebaine ( 6 ), the starting compound of the procedure, was converted into its N‐{[1,2‐bis(ethoxycarbonyl)hydrazinyl]methyl} counterpart. L ‐Selectride was found to be an efficient agent to perform a one‐pot O‐ and N‐deprotection at positions 3 and 17, respectively.     

Highly Enantioselective Conjugate Additions of Phosphites to α,β‐Unsaturated N‐Acylpyrroles and Imines: A Practical Approach to Enantiomerically Enriched Amino Phosphonates

The first highly enantioselective phosphonylation of α,β‐unsaturated N‐acylpyrroles has been developed. Excellent yields (91–99 %) and enantioselectivities (up to >99 % enantiomeric excess (ee)) were observed for a broad spectrum of both phosphites and N‐acylpyrroles under mild conditions. In particular, when diethyl phosphite was employed to test the scope of the N‐acylpyrroles, almost optically pure products (98 to >99 % ee) were obtained for 20 examples of N‐acylpyrroles. Moreover, optically pure α‐substituted β‐ or γ‐amino phosphonates can be obtained by several simple transformations of the pyrrolyl phosphonates. The versatility of the N‐acylpyrrole moiety makes the phosphorus adducts powerful chiral building blocks that enable the synthesis of various phosphonate‐containing compounds. Finally, the present strategy can also be applied to the asymmetric hydrophosphonylation of N‐acylimines with high enantioselectivities (93 to >99 % ee).     

Stereoselective Synthesis and Modelling‐Driven Optimisation of Carane‐Based Aminodiols and 1,3‐Oxazines as Catalysts for the Enantioselective Addition of Diethylzinc to Benzaldehyde

The reductive amination of (?)‐2‐carene‐3‐aldehyde, prepared in two steps from (?)‐perillaldehyde, furnished 2‐carene‐based allylamines. tert‐Butyloxycarbonyl (Boc) or carbobenzyloxy (Cbz) protection of the resulting amines, followed by stereoselective dihydroxylation in highly stereospecific reactions with OsO₄ and subsequent deprotection, resulted in N‐benzylaminodiols, which were transformed to primary and tertiary aminodiols. The reactions of the N‐benzyl‐ and N‐(1‐phenylethyl)‐substituted derivatives with formaldehyde led to highly regioselective ring closure, resulting in carane‐fused 1,3‐oxazines. The aminodiols and their 1,3‐oxazine derivatives were applied as chiral catalysts in the enantioselective addition of diethylzinc to aldehydes. The best (R) enantioselectivity was observed in the case of the N‐((R)‐1‐phenylethyl)‐substituted aminodiol, whereas the opposite chiral direction was preferred when the 1,3‐oxazines were applied. Through the use of molecular modelling at an ab initio level, this phenomenon was interpreted in terms of competing reaction pathways. Molecular modelling at the RHF/LANL2DZ level of theory was successfully applied for a mechanism‐based interpretation of the stereochemical outcome of the reactions leading to the development of further 1,3‐oxazine‐based ligands, which display excellent (S) enantioselectivity (95 and 98 % ee) in the examined transformation.     

Diastereo‐ and Regioselective Addition of Thioamide Dianions to Imines and Aziridines: Synthesis of N‐Thioacyl‐1,2‐diamines and N‐Thioacyl‐1,3‐diamines

Addition reactions of thioamide dianions that were derived from N‐arylmethyl thioamides to imines and aziridines were carried out. The reactions of imines gave the addition products of N‐thioacyl‐1,2‐diamines in a highly diastereoselective manner in good‐to‐excellent yields. The diastereomeric purity of these N‐thioacyl‐1,2‐diamines could be enriched by simple recrystallization. The reduction of N‐thioacyl‐1,2‐diamines with LiAlH₄ gave their corresponding 1,2‐diamines in moderate‐to‐good yields with retention of their stereochemistry. The oxidative‐desulfurization/cyclization of an N‐thioacyl‐1,2‐diamine in CuCl₂/O₂ and I₂/pyridine systems gave the cyclized product in moderate yield and the trans isomer was obtained as the sole product. On the other hand, a similar cyclization reaction with antiformin (aq. NaClO) as an oxidant gave the cis isomer as the major product. The reactions of N‐tosylaziridines gave the addition products of N‐thioacyl‐1,3‐diamines with low diastereoselectivity but high regioselectivity and in good‐to‐excellent yields. The use of AlMe₃ as an additive improved the efficiency and regioselectivity of the reaction. The stereochemistry of the obtained products was determined by X‐ray diffraction.     

Methyl‐Selective α‐Oxygenation of Tertiary Amines to Formamides by Employing Copper/Moderately Hindered Nitroxyl Radical (DMN‐AZADO or 1‐Me‐AZADO)

Methyl‐selective α‐oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α‐oxygenation at the N‐methyl positions using molecular oxygen (O₂) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl‐selective α‐oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5‐dimethyl‐9‐azanoradamantane N‐oxyl (DMN‐AZADO) and 1‐methyl‐2‐azaadamanane N‐oxyl (1‐Me‐AZADO), was very important to promote the oxygenation effectively mainly because these N‐oxyls have longer life‐times than less hindered N‐oxyls. Various types of tertiary N‐methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine‐N‐oxyl interactions.     

An Unconventional Polymerization Route to Hydrophilic Fluorescent Organic Nanoparticles for Multicolor Cellular Bioimaging

We demonstrated an unconventional polymerization route to synthesize hydrophilic fluorescent organic nanoparticles (FONs) for multicolor cellular bioimaging in this contribution. The route benefits from our unexpected discovery of a rapid polymerization reaction between 1,6‐hexanediol dipropiolate and 2,4,6‐triazide‐1,3,5‐triazine under the catalysis of N,N,N′,N′′,N′′‐pentamethyldiethylenetriamine (PMDETA). Interestingly, the 2,4,6‐triazide‐1,3,5‐triazine and PMDETA system can also induce rapid free radical polymerization at room temperature. The as‐prepared FONs exhibited promising water solubility and stability with an average diameter of 20 nm. The excitation wavelength‐dependent fluorescent properties endow the FONs with blue, yellow, and red fluorescent emission under UV, blue, and green excitation, respectively. The cytotoxicity of FONs was investigated by using a Cell Counting Kit (CCK‐8) assay, which indicated good biocompatiblity. More importantly, the cell uptake experiment verified the FONs were excellent fluorescent nanoprobes for multicolor cellular bioimaging. Therefore, this unconventional route provides a novel fabrication strategy of highly hydrophilic FONs for biomedical applications.     

Highly Selective Addition of a Broad Spectrum of Trimethylsilane Pro‐nucleophiles to N‐tert‐Butanesulfinyl Imines

Addition of organotrimethylsilane reagents to chiral N‐tert‐butanesulfinyl imines can be achieved in good yields and with excellent diastereoselectivities by employing TMSO^?/Bu₄N⁺ as a Lewis base activator in THF. A variety of aliphatic, aromatic, heteroaromatic and organometallic chiral imines were utilised as electrophiles for the synthesis of enantioenriched N‐tert‐butanesulfinyl amides. Remarkably, the same sets of reaction conditions could be used with a highly diverse range of bench‐stable organotrimethylsilane reagents, which highlights the generality and robustness of this methodology.     

A Practical One‐Step Synthesis of 1,2‐Oxazoline Derivatives from Unprotected Sugars and Its Application to Chemoenzymatic β‐N‐Acetylglucosaminidation of Disialo‐oligosaccharide

A facile and practical method for synthesis of sugar oxazolines (=dihydrooxazoles) from the corresponding N‐acetyl‐2‐amino sugars has been developed by using 2‐chloro‐1,3‐dimethyl‐1H‐benzimidazol‐3‐ium chloride (CDMBI) as a dehydrative condensing agent. The intramolecular dehydrative reaction between the 2‐acetamido group and the anomeric OH group of unprotected N‐acetyl‐2‐amino sugars took place smoothly in H₂O, leading to the formation of a 1,2‐oxazoline (=4,5‐dihydrooxazole) moiety in good yield. Since the reaction proceeds in H₂O without using any protecting groups, the resulting oxazolines can be utilized as effective glycosyl donors for the subsequent enzymatic glycosylation. We have successfully demonstrated a highly efficient chemoenzymatic transglycosylation of a disialo‐oligosaccharide moiety to p‐nitrophenyl N‐acetylglucosaminide catalyzed by a mutant endo‐N‐acetylglucosaminidase without isolating disialo‐oligosaccharide oxazoline as synthetic intermediate.     

Screening of N,N‐bidentate and N,N,N‐tridentate pyridine‐based ligands in the catalytic allylic oxidation of cyclic olefins

A variety of chiral N,N‐bidentate and N,N,N‐tridentate ligands based on the pyridine framework, namely C2‐symmetric dipyridylmethane and terpyridine, N‐(p‐toluensulfinyl)iminopyridines and two kinds of iminopyridines, has been assessed in the asymmetric copper(I)‐catalysed allylic oxidation of cyclic olefins. Catalytic activity and enantioselectivity were found to be highly dependent upon the framework of the ligands, which afforded cycloalkenyl benzoates in low to moderate yields and enantioselectivities. The best yields (up to 70%) and enantioselectivities (up to 53% enantiomeric excess) were obtained with an iminopyridine based on camphane and quinoline skeletons. Copyright © 2014 John Wiley & Sons, Ltd.     

Mechanism and Linear Free Energy Relationships in Michael‐Type Addition of 4‐Substituted Anilines to Activated Olefin in Acetonitrile

Kinetic studies for the Michael‐type reactions of ethyl‐3‐(4′‐N,N‐dimethylaminophenyl)‐2‐(nonafluorobutane)sulfonylpro‐penoate 1 with 4‐X‐substituted anilines 2a–e (X = OCH₃, CH₃, H, F, and Cl) have been investigated in acetonitrile at 20°C. A quadratic dependence of the pseudo–first‐order rate constants (k_obsd) versus [ 2a–e ] has been observed and has been interpreted in terms of a dimer nucleophile mechanism. The finding of a relatively large negative ρ value (?3.09) for the Hammett plot suggests that the intermediate ( I^± ) is highly zwitterionic in nature. A linear correlation (r² = 0.9989) between the Hammett's substituent constants σ and nucleophilicity parameters N of 4‐X‐substituted anilines in acetonitrile has been observed. The electrophilicity parameters E of the olefin 1 is evaluated, using the correlations σ versus N and log k versus σ and compared with the electrophilicities of analogously Michael acceptors.     

Unlocking the N2 Selectivity of Benzotriazoles: Regiodivergent and Highly Selective Coupling of Benzotriazoles with Allenes

The rhodium‐catalyzed, highly N²‐ and N¹‐selective coupling of benzotriazoles with allenes is reported. The exceptionally high N² and N¹ selectivities were achieved by using a rhodium(I)/DPEphos and rhodium(I)/JoSPOphos catalyst, respectively. This method permits the atom‐economic synthesis of valuable branched N²‐ and N¹‐allylated benzotriazole derivatives and allows for preliminary studies of their reactivity.     

A Roadmap to Uranium Ionic Liquids: Anti‐Crystal Engineering

In the search for uranium‐based ionic liquids, tris(N,N‐dialkyldithiocarbamato)uranylates have been synthesized as salts of the 1‐butyl‐3‐methylimidazolium (C₄mim) cation. As dithiocarbamate ligands binding to the UO₂²⁺ unit, tetra‐, penta‐, hexa‐, and heptamethylenedithiocarbamates, N,N‐diethyldithiocarbamate, N‐methyl‐N‐propyldithiocarbamate, N‐ethyl‐N‐propyldithiocarbamate, and N‐methyl‐N‐butyldithiocarbamate have been explored. X‐ray single‐crystal diffraction allowed unambiguous structural characterization of all compounds except N‐methyl‐N‐butyldithiocarbamate, which is obtained as a glassy material only. In addition, powder X‐ray diffraction as well as vibrational and UV/Vis spectroscopy, supported by computational methods, were used to characterize the products. Differential scanning calorimetry was employed to investigate the phase‐transition behavior depending on the N,N‐dialkyldithiocarbamato ligand with the aim to establish structure–property relationships regarding the ionic liquid formation capability. Compounds with the least symmetric N,N‐dialkyldithiocarbamato ligand and hence the least symmetric anions, tris(N‐methyl‐N‐propyldithiocarbamato)uranylate, tris(N‐ethyl‐N‐propyldithiocarbamato)uranylate, and tris(N‐methyl‐N‐butyldithiocarbamato)uranylate, lead to the formation of (room‐temperature) ionic liquids, which confirms that low‐symmetry ions are indeed suitable to suppress crystallization. These materials combine low melting points, stable complex formation, and hydrophobicity and are therefore excellent candidates for nuclear fuel purification and recovery.     

Electrophilic Cyanation of Boron Enolates: Efficient Access to Various β‐Ketonitrile Derivatives

The highly efficient electrophilic cyanation of boron enolates using readily available cyanating reagents, N‐cyano‐N‐phenyl‐p‐toluenesulfonamide (NCTS) and p‐toluenesulfonyl cyanide (TsCN), is reported. Various β‐ketonitriles were prepared by this new protocol, which has a remarkably broad substrate scope compared to existing methods. The present method also allowed efficient synthesis of β‐ketonitriles containing a quaternary α‐carbon center. In addition, a preliminary result with the use of a chiral boron enolate for the enantioselective cyanation reaction is described.     

Comparison of the reactivity of N‐(p‐toluenesulfonyl)‐sulfinimidoyl fluorides and chlorides toward triphenylphosphine

The path of the reaction of aryl‐N‐(p‐toluenesulfonyl)‐sulfinimidoyl fluorides and triphenylphosphine is highly dependent on the order of the reactants addition. Addition of triphenylphos‐phine to aryl‐N‐(p‐toluenesulfonyl)‐sulfinimidoyl fluorides results in the formation of triphenyl(aryl‐thio)phosphonium salts of N,N′‐bis(p‐toluenesul‐fonyl)aryl‐sulfinamidines and triphenyldifluorophosphorane. By changing the reagent addition order, we obtained triphenyldifluorophosphorane, P,P,P‐triphenyl‐N‐(p‐toluenesulfonyl)‐phosphine imide, and diaryl disulfides. The outcome of the reaction aryl‐N‐(arenesulfonyl)‐sulfinimidoyl chlorides and triphenylphosphine does not depend on the order of addition of the reactants. P,P,P‐Triphenyl‐N‐(arenesulfonyl)‐phosphine imides, triphenyldichloro‐phosphorane, and diaryl disulfides were formed as a result. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:66–71, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20408     

Multicomponent Approach to Hydantoins and Thiohydantoins Involving a Deep Eutectic Solvent

We report an efficient synthetic strategy to diverse hydantoins and thiohydantoins involving a three‐component reaction with the aid of deep eutectic solvent. Here, N,N′‐dimethyl urea and N,N′‐dimethyl thiourea play a dual role as reactant and reaction medium along with l ‐(+)‐tartaric acid. The three‐component reaction provides an easy access to 5‐amino‐1,3‐dialkyl‐substituted hydantoins and thiohydantoins in good yields.     

Regioselective and Stereoselective Addition of Tetrazole Derivatives to Electron‐poor Acetylenic Esters in the Presence of Triphenylphosphine

Protonation of the highly reactive 1:1 intermediates produced in the reaction between triphenylphosphine and acetylenic esters by tetrazole derivatives leads to the formation of vinyltriphenylphosphonium salts. The cation of these salts undergoes an addition reaction with the counter anion in CH₂Cl₂ at room temperature to yield the corresponding stabilized phosphorus ylides. Elimination of triphenylphosphine from the stabilized phosphorus ylides leads to the corresponding electron‐poor N‐vinyl tetrazoles in fairly high yields. Structures of N‐vinyl tetrazoles were determined by IR, ¹H NMR, ¹³C NMR and single crystal X‐ray structure analyses. The reaction is fairly regioselective and stereoselective.     

Microwave‐Assisted Oxidation of Alcohols with N,N,N′,N′‐Tetrabromobenzene‐1,3‐Disulfonamide and Poly(N‐Bromobenzene‐1,3‐Disulfonamide) under Solvent‐Free Conditions

An efficient and mild methodology for the oxidation of primary and secondary alcohols to the corresponding carbonyl functions is described with N,N,N′,N′‐tetrabromobenzene‐1,3‐disulfonamide and poly(N‐bromobenzene‐1,3‐disulfonamide) using microwave irradiation under solvent‐free conditions. Aliphatic, benzylic and allylic alcohols are rapidly oxidized without over‐oxidation to carboxylic acids. Secondary carbinols are slowly oxidized so that the reaction is highly chemoselective.     

Pyridine-N-oxide:An Efficient Organocatalyst for Ring-Opening Reactions of Aziridines with Aryl Thiols

Pyridine‐N‐oxide serves as an efficient catalyst for the ring‐opening reactions of N‐tosylaziridines with various aryl thiols under mild conditions. This transformation is highly effective, which gives rise to the corresponding β‐amino sulfides in good to excellent yields.     

Capping Methodology in Cyclodextrin Chemistry: Use of a Symmetrical Diketone Reagent for Regiospecific Installation of Unsymmetrical Imine–Enamine and Imidazole Caps

Methylated α‐ and β‐cyclodextrin skeletons were both equipped with an unsymmetrical N‐(2‐N‐alkylaminoacenaphthenyl)alkylimine rigid handle. The capping reaction, which consists of condensing a diaminocyclodextrin with highly symmetrical acenaphthenequinone, was found to be regiospecific when starting from cyclodextrin‐diamines without any symmetry element. All modified cyclooligosaccharides have intra‐annular nitrogen donor atoms. They undergo further cyclization on oxidation, whether chemically with 2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone or electrochemically, to give highly strained cyclodextrins capped with an unsymmetrical 1,2‐disubstituted 1H‐imidazole unit.     

Metal‐Free Oxidation of α‐Hydroxy Ketones to 1,2‐Diketones Catalyzed by Mesoporous Carbon Nitride with Visible Light

As a photocatalyst, mesoporous carbon nitride (mpg‐C₃N₄) shows higher photocatalytic activities in organic synthesis. Herein we report an mpg‐C₃N₄‐catalyzed oxidation of α‐hydroxy ketones to synthesize 1,2‐diketones using visible light. This transformation represents a green and highly efficient synthetic route to synthesize 1,2‐diketones for which catalytic approaches are scarce.