Efficient synthesis of aryl vinyl ethers exploiting 2,4,6-trivinylcyclotriboroxane as a vinylboronic acid equivalent

The synthesis of functionalized aryl vinyl ether derivatives can be readily achieved utilizing a room-temperature copper(II) acetate mediated coupling of substituted phenols with 2,4,6-trivinylcyclotriboroxane-pyridine complex in the presence of a suitable base. The scope of the procedure was demonstrated by the generation of an array of substituted aryl vinyl ethers. The reaction was seen to be tolerant of a diverse range of functional groups yielding products in high isolated yields. We have shown that one role of an amine base in the reaction sequence is the in situ generation of an amine coordinated boroxine ring. An X-ray crystal structure and low temperature (11)B NMR study of 2,4,6-trivinylcyclotriboroxane-pyridine complex demonstrated the nature of the tetracoordinate boron species, which may have a key role to play within the reaction sequence.     

Hydrogen bonding makes a difference in the rhodium-catalyzed enantioselective hydrogenation using monodentate phosphoramidites

A new generation of monodentate phosphoramidite ligands bearing a primary amine moiety was found to display comparable or better efficiency than bisphosphines in the Rh-catalyzed asymmetric hydrogenation of challenging substrates, such as (Z)-methyl alpha-acetoxyacrylate or (E)-beta-aryl itaconate derivatives, affording the corresponding hydrogenation products with excellent enantioselectivities (up to >99% ee). The presence of intermolecular hydrogen bonding (HB) between two monodentate ligands in the catalyst was found to be critical for excellent catalyst performance. This finding provides a basis for design and development of further catalyst systems using this type of monodentate phosphoramidite ligands.     

Recent advances in transition metal-catalyzed enantioselective hydrogenation of unprotected enamines

Transition metal-catalyzed enantioselective hydrogenation of enamines is undoubtedly a useful and environment-friendly method for the preparation of optically pure chiral amines and amine derivatives. Over the last few decades, the use of transition metal catalysts containing chiral phosphorus or phosphine-oxazoline ligands attracted much attention for the hydrogenation of unprotected enamines. A number of efficient chiral catalysts have been developed, and some of them have shown high potential for the application in the synthesis of optical chiral amines in both laboratory and industry. This tutorial review focuses on the contributions concerning the transition metal-catalyzed enantioselective hydrogenation of unprotected enamines for the synthesis of chiral amines and amine derivatives.     

Combinatorial synthesis of heterocycles: solid-phase synthesis of 2-amino-4(1H)-quinazolinone derivatives

A new solid-phase synthesis of various substituted 2-amino-4(1H)-quinazolinones from a resin bound amine component is described. The amine was readily converted to the corresponding polymer bound S-methylthiopseudourea. Condensation with different substituted isatoic anhydrides afforded 2-amino-4(1H)-quinazolinone derivatives. The method is amenable for combinatorial library generation.     

Stereoelectronic Effects in Ligand Design: Enantioselective Rhodium‐Catalyzed Hydrogenation of Aliphatic Cyclic Tetrasubstituted Enamides and Concise Synthesis of (R)‐Tofacitinib

We herein report the development of a conformationally defined, electron‐rich, C₂‐symmetric, P‐chiral bisphosphorus ligand, ArcPhos, by taking advantage of stereoelectronic effects in ligand design. With the Rh‐ArcPhos catalyst, excellent enantioselectivities and unprecedentedly high turnovers (TON up to 10 000) were achieved in the asymmetric hydrogenation of aliphatic carbocyclic and heterocyclic tetrasubstituted enamides, to generate a series of chiral cis‐2‐alkyl‐substituted carbocyclic and heterocyclic amine derivatives in excellent enantiomeric ratios. This method also enabled an efficient and practical synthesis of the Janus kinase inhibitor (R)‐tofacitinib.     

Synthesis of Functionalized o‐, m‐, and p‐Terphenyl Derivatives by Consecutive Cross‐Coupling Reactions of Triazene‐Substituted Arylboronic Esters

Triazene‐substituted arylboronic esters were prepared readily from the corresponding aryl magnesium derivatives and shown to function as a new class of donor–acceptor‐substituted coupling reagents. The selective functionalization of these aromatic derivatives led to a wide variety of terphenyl derivatives in which the original bifunctional unit (often further substituted with another functional group) formed the central aromatic ring. The functionalized terphenyl derivatives were formed in two efficient cross‐coupling steps from the triazene‐substituted boronic esters: Suzuki cross‐coupling with an aryl halide was followed by BF₃?OEt₂‐induced palladium‐catalyzed coupling of the diazonium salt generated in situ from the triazene with an arylboronic acid.     

Reductive Hydroformylation of Isosorbide Diallyl Ether

Isosorbide and its functionalized derivatives have numerous applications as bio-sourced building blocks. In this context, the synthesis of diols from isosorbide diallyl ether by hydrohydroxymethylation reaction is of extreme interest. This hydrohydroxymethylation, which consists of carbon-carbon double bonds converting into primary alcohol functions, can be obtained by a hydroformylation reaction followed by a hydrogenation reaction. In this study, reductive hydroformylation was achieved using isosorbide diallyl ether as a substrate in a rhodium/amine catalytic system. The highest yield in bis-primary alcohols obtained was equal to 79%.     

Novel and efficient supramolecular synthesis of pyrroles in the presence of β-cyclodextrin in water

A simple and efficient synthesis of highly substituted pyrroles was achieved in water medium via multi-component strategy, using amine,DMAD/DEAD as well as phenacyl bromide catalyzed by β-CD.Utilizing this protocol various pyrrole derivatives were synthesized in good to excellent yields.     

Asymmetric Hydrogenation of Furans and Benzofurans with Iridium–Pyridine–Phosphinite Catalysts

Enantioselective hydrogenation of furans and benzofurans remains a challenging task. We report the hydrogenation of 2‐ and 3‐substituted furans by using iridium catalysts that bear bicyclic pyridine–phosphinite ligands. Excellent enantioselectivities and high conversions were obtained for monosubstituted furans with a 3‐alkyl or 3‐aryl group. Furans substituted at the 2‐position and 2,4‐disubstituted furans proved to be more difficult substrates. The best results (80–97 % conversion, 65–82 % enantiomeric excess) were obtained with monosubstituted 2‐alkylfurans and 2‐[4‐(trifluoromethyl)phenyl]furan. Benzofurans with an alkyl substituent at the 2‐ or 3‐position also gave high conversions and enantioselectivity, whereas 2‐aryl derivatives showed essentially no reactivity. The asymmetric hydrogenation of a 3‐methylbenzofuran derivative was used as a key step in the formal total synthesis of the cytotoxic naphthoquinone natural product (?)‐thespesone.     

Gold(III) Salen complex-catalyzed synthesis of propargylamines via a three-component coupling reaction

[reaction: see text] Propargylamines have been synthesized by a gold(III) salen complex-catalyzed three-component coupling reaction of aldehydes, amines, and alkynes in water in excellent yields at 40 degrees C. With chiral prolinol derivatives as the amine component, excellent diastereoselectivities (up to 99:1) have been attained. This coupling reaction has been applied to the synthesis of propargylamine-modified artemisinin derivatives with the delicate endoperoxide moieties remaining intact. Cytotoxicities with IC(50) values up to 1.1 microM against a human hepatocellular carcinoma cell line (HepG2) were exhibited by these artemisinin derivatives.     

Polymer supported synthesis of novel benzoxazole linked benzimidazoles under microwave conditions: in vitro evaluation of VEGFR-3 kinase inhibition activity

An efficient soluble polymer-supported method has been developed for the parallel synthesis of substituted benzimidazole linked benzoxazoles using focused microwave irradiation. The key step involves the amidation of 4-hydroxy-3-nitrobenzoic acid with polymer-immobilized o-phenylenediamine. Application of mild acidic conditions promoted the ring closure to furnish the benzimidazole ring. After hydrogenation of the nitro-group to amine, the resulted polymer conjugates underwent efficient ring closure with various alkyl, aryl and heteroaryl isothiocyanates to generate the polymer-bound benzimidazolyl benzoxazoles. The polymer-bound compounds were finally cleaved from the support to furnish benzimidazole linked benzoxazole derivatives. The efficacy of the resultant angular bis-heterocyclic library was studied against vascular endothelial growth factor receptor (VEGFR-3). The preliminary screening of these novel compounds exhibits moderate to high inhibition (IC(50) = 0.56-1.42 μM). This protocol provides an easy access to novel angular bis-heterocycles which have potential for the discovery of novel leads for targeted cancer therapeutics.     

Efficient Synthesis of N-[(2-Hydroxyethoxy)methyl]-2-alkyl-3-hydroxy-4-pyridinone by a Modified Hilbert-Johnson Reaction

Ethyleneglycol derivatives of 2-methyl (and ethyl)-3-hydroxy-4-pyridinone were synthesized by a modified Hilbert-Johnson reaction. The synthesis proceedes by reaction of O-protected 2-alkyl-3-hydroxy-4-pyridinone with hexamethyldisilazane in the presence of chlorotrimethylsilane followed by trimethylsilyl trifluoromethanesulfonate catalized alkylation with benzyloxy-ethoxymethylchloride in dichloroethane and deprotection by hydrogenation. The overall yield was 87%. This method provides a useful way to produce oligo- or polyethyleneglycol substituted hydroxypyridinones.     

Asymmetric cyclopalladation in the ferrocene series as a tool for enantioselective synthesis. Preparation of some analogues of natural products

The previously described asymmetric cyclopalladation has been applied to the esters of 7-dimethylamino-7-ferrocenylenanthic acid, I, to afford the optically active palladium derivative, II. The absolute configuration of the chiral plane is determined by the configuration of the inductor: the acylamino acid salt. The palladium atom in II was then substituted by a σ-ketovinyl group using the reaction with pentyl vinyl ketone, to yield III. The latter substance undergoes full reduction when treated with Et₃SiH + CF₃COOH (the ionic hydrogenation reaction) resulting in the optically active prostanoic acid analogue, IV. On the other hand, III in the form of the methiodide is reduced by NaBH₄ with the elimination of the amine group and the and the formation of allyl alcohol V. This kind of side chain is characteristic of many prostaglandins. Bromination of II followed by the repeated cyclopalladation opens the way to trisubstitute derivatives. The pathway outlined provides a rapid synthesis of optically active compounds which are the ferrocene analogues of natural prostaglandins.     

Synthesis of Functionalized Aza-macrocycles and the Application of Their Metal Complexes in Binding Processes

Although aza-macrocycles have beenthoroughly investigated ever since their discoverybecause of their interesting binding properties,recent applications of their metal complexes inmedical concepts or as binding sites for recognitionin water have increased the demand for efficientsyntheses of functionalized derivatives. We presenthere two approaches to functionalized aza-macrocycles:substituted cyclams have been obtained byheterogeneous hydrogenation of unsaturatedheterocycles, and with established coupling methodsfrom peptide chemistry the selective introduction offunctional groups and tethering of cyclens wasachieved. The ability of Lewis-acidic complexes ofsuch substituted aza-macrocycles to reversibly formdefined aggregates even in neutral aqueous solutionwas demonstrated with the synthesis of an electrondonor – electron acceptor dyad, which is capable ofundergoing a very efficient intramolecular photoinducedelectron transfer.     

Self-supported heterogeneous catalysts for enantioselective hydrogenation

"Self-supported" catalysts were prepared by the reaction of bis-MonoPhos ligand with rhodium(I) metallic ion on the basis of molecular assembling through coordination. These polymeric metal-organic assemblies are insoluble in common organic solvents and, as a result, provide an excellent opportunity for running asymmetric catalysis heterogeneously. The application of the self-supported Rh(II) catalysts in the asymmetric hydrogenation of olefin derivatives afforded a variety of enantioenriched amino acid and amine derivatives with high yields and enantioselectivities. This strategy might provide a new direction in asymmetric catalysis, particularly for the development of practical heterogeneous asymmetric synthesis of optically active compounds.     

Copper Catalyzed C−H Activation

Activation of C?H bonds and their application in cross coupling chemistry has received a wider interest in recent years. The conventional strategy in cross coupling reaction involves the pre‐functionalization step of coupling reactants such as organic halides, pseudo‐halides and organometallic reagents. The C?H activation facilitates a simple and straight forward approach devoid of pre‐functionalization step. This approach also addresses the environmental and economical issues involved in several chemical reactions. In this account, we have reported C?H bond activation of small organic molecules, for example, formamide C?H bond can be activated and coupled with β‐dicarbonyl or 2‐carbonyl substituted phenols under oxidative conditions to yield carbamates using inexpensive copper catalysts. Phenyl carbamates were successfully synthesized in moderate to good yields by cross dehydrogenative coupling (CDC) of phenols with formamides using copper catalysts in presence of a ligand. We have also prepared unsymmetrical urea derivatives by oxidative cross coupling of formamides with amines using copper catalysts. Synthesis of N,N‐dimethyl substituted amides, 5‐substituted‐γ‐lactams and α‐acyloxy ethers was carried out from carboxylic acids using recyclable CuO nanoparticles. Copper nanoparticles afforded N‐aryl‐γ‐amino‐γ‐lactams by oxidative coupling of aromatic amines with 2‐pyrrolidinone. Reusable transition metal HT‐derived oxide catalyst was used for the synthesis of N,N‐dimethyl substituted amides by the oxidative cross‐coupling of carboxylic acids and substituted benzaldehydes. Overview of our work in this area is summarized.     

Study of chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters with iridium–PˆN complexes

In this paper we report the first chemoselective asymmetric hydrogenation of (1-bromo-1-alkenyl)boronic esters, which constitutes a new route to (α-bromoalkyl)boronic esters. The study demonstrates that excellent chemoselectivities along with full conversions can be obtained for hydrogenation of alkyl substituted derivatives with iridium–PˆN complexes. Moreover, acyclic alkyl derivatives afford (α-bromoalkyl)boronic esters in good enantioselectivities ranging from 64 to 73% ee. A cyclic alkyl derivative was obtained only in a nearly racemic form. The (1-bromo-1-alkenyl)boronic esters appear to be less reactive towards homogenous hydrogenation conditions than their chloro analogues as demonstrated by the higher catalyst loadings required to achieve full conversions for alkyl derivatives and lower conversions observed for the aryl substituted derivatives.     

Dehydro side coupling of substituted pentacene derivatives

1,2,3,4,8,9,10,11-Octaalkylpentacenes were synthesized in high yields from tetrahydropentacenes by the pentacene-DDQ adduct method in the presence of amine. Dehydro side-coupling reactions of pentacene derivatives proceeded to give the corresponding 6,6'-dipentacenyl derivatives in high yields in the presence of a catalytic amount of CSA and 0.5 equiv of DDQ. The structures of dehydro side-coupling products of substituted pentacenes were determined by NMR and X-ray analysis. The combination of acid and DDQ was necessary for the dehydro side coupling of substituted pentacenes.     

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

Pd^II‐catalyzed enantioselective C(sp³)?H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.     

A Scalable Metal‐, Azide‐, and Halogen‐Free Method for the Preparation of Triazoles

A scalable metal‐, azide‐, and halogen‐free method for the synthesis of substituted 1,2,3‐triazoles has been developed. The reaction proceeds through a 3‐component coupling of α‐ketoacetals, tosyl hydrazide, and a primary amine. The reaction shows outstanding functional‐group tolerance with respect to both the α‐ketoacetal and amine coupling partners, providing access to 4‐, 1,4‐, 1,5‐, and 1,4,5‐substituted triazoles in excellent yield. This robust method results in densely functionalised 1,2,3‐triazoles that remain challenging to prepare by azide–alkyne cycloaddition (AAC, CuAAC, RuAAC) methods and can be scaled in either batch or flow reactors. Methods for the chemoselective reaction of either aliphatic amines or anilines are also described, revealing some of the potential of this novel and highly versatile transformation.