Triflic Acid-Promoted 1,2-Amino Migration Reactions in α-Arylaminoacrylamides: Access to Substituted ß-Aminoamides.

A straightforward synthesis of substituted ß-aminoamides from α-arylamino-ß-hydroxyacrylamides, α-arylamino-ß-oxoamides, or their tautomeric mixture has been described. The (E)-enol triflate intermediates are readily generated in situ from these substrates in the presence of triflic anhydride (Tf2O) and triethylamine (Et3N) in a chemoselective manner and undergo triflic acid (TfOH)-promoted cyclization and ring-opening reactions with alcohols to deliver the desired products. The one-pot two-step synthetic protocol features the use of readily available starting materials, mild reaction conditions, high chemoselectivity, operational simplicity, and a wide range of synthetic potential of the products.

Highly Chemoselective Synthesis of Indole Derivatives.

A facile and efficient synthesis of polysubstituted indoles from α-arylamino-ß-hydroxy-2-enamides, α-arylamino-ß-oxo-amides, or their tautomeric mixture via electrophilic activation strategy is described. The salient feature of this methodology is the use of either combined Hendrickson reagent and triflic anhydride (Tf2 O) or triflic acid (TfOH) to control the chemoselectivity in the intramolecular cyclodehydration to provide a predictable approach to these valuable indoles with flexible substituent patterns. Moreover, the mild reaction conditions, simple execution, high chemoselectivity, excellent yields, and wide range of synthetic potential of products make this protocol much attractive for academic research and practical applications.

PIFA-Mediated Tandem Hofmann-Type Rearrangement and Cyclization Reaction of α-Acyl-ß-aminoacrylamides: Access to Polysubstituted Oxazol-2(3H)-ones.

An efficient and straightforward synthesis of polysubstituted oxazol-2(3H)-ones has been developed via a tandem Hofmann-type rearrangement and cyclization reaction of various α-acyl-ß-aminoacrylamides mediated by phenyl iodine(III) bis(trifluoroacetate) (PIFA) in the presence of trifloroacetic acid (TFA). This novel protocol features readily available starting materials, mild reaction conditions, simple execution, high chemoselectivity, good functional group tolerance, and a metal-free oxidation process.

Tf2O-Mediated Cyclization of α-Acyl-ß-(2-aminopyridinyl)acrylamides: Access to N-Substituted 4H-Pyrido[1,2-a]pyrimidin-4-imines.

A facile and efficient direct synthesis of N-substituted 4H-pyrido[1,2-a]pyrimidin-4-imines is developed from α-acyl-ß-(2-aminopyridinyl)acrylamides mediated by triflic anhydride (Tf2O) in the presence of 2-chloropyridine. This amide activation protocol features mild reaction conditions, simple execution, excellent yields, and high chemoselectivity, and is also applied to the synthesis of substituted 4H-pyrido[1,2-a]pyrimidin-4-ones via a practical one-pot procedure.

Iodosobenzene-Mediated α-Acyloxylation of 1,3-Dicarbonyl Compounds with Carboxylic Acids and Insight into the Reaction Mechanism.

A highly efficient direct α-acyloxylation of 1,3-dicarbonyl compounds with carboxylic acids mediated by hypervalent iodine reagent is presented. Treatment of a variety of 1,3-dicarbonyl compounds with carboxylic acids in the presence of iodosobenzene provides the corresponding α-acyloxylated products in good to excellent yields. The mechanistic investigation by means of NMR spectroscopy reveals that the in situ-generated phenyliodine biscarboxylate proves to be the key intermediate for the α-acyloxylation, and the loading sequence of reactants and oxidant is crucial for the generation of the active species. The mild reaction conditions, wide substrate scope, short reaction time, good yields, high chemoselectivity, excellent functional group tolerance, and metal catalyst-free conversion make this acyloxylation a significant synthetic protocol.

Oxidative Cyclization of ß-Aminoacrylamides Mediated by PhIO: Chemoselective Synthesis of Isoxazoles and 2 H-Azirines.

Cyclization of a variety of ß-aminoacrylamides in the presence of iodosobenzene (PhIO) is described. This process features mild reaction conditions, simple execution, and high chemoselectivity and thereby provides an efficient protocol for the divergent synthesis of substituted isoxazoles and 2 H-azirines via switchable N-O and N-C bond formation controlled by simply varying the ß-substituent R3 of the readily available substrates.

Controlled Growth of Metal-Organic Frameworks on Polymer Brushes.

Polymer brushes are for the first time used to induce the synthesis of metal-organic frameworks (MOFs). The semi-fixed polymer chains provide a confined environment, which allows a mild growth of MOFs in between polymer chains to give surface-attached spherical MOF nanoparticles, in contrast to the larger MOF cubes/plates formed simultaneously in solution. Polymer brushes bearing carboxylate acid functionalities are indispensable for the formation of surface bound MOFs, while no MOF nanoparticles are observed on neutral polymer brushes. Characterization of the resultant MOF/polymer brushes hybrid film indicates the formation of crystalline MOF structure. The dimension of surface-attached MOFs can be fine-tuned from 20 nm to 1.4 µm simply by varying the structural parameter of polymer brushes and the nucleation duration. The method is not only applicable to the synthesis of MOF-5 and MIL-125, but shows great potential for the preparation of other surface-attached MOFs.

Formal [4 + 1] Annulation of α-Arylhydrazonoketones and Dimethylsulfoxonium Methylide: One-pot Synthesis of Substituted Pyrazoles and Dihydropyrazoles.

A formal [4 + 1] annulation of readily available α-arylhydrazonoketones and trimethylsulfoxonium iodide in the presence of cesium carbonate is described involving a sequential Corey-Chaykovsky reaction and intramolecular nucleophilic cyclization process. Substituted pyrazoles were obtained exclusively from the reactions of α-arylhydrazono-ß-oxo-amides and trimethylsulfoxonium iodide in moderate to good yields, whereas the reactions of α-arylhydrazono-ß-oxo-ketone/α-arylhydrazono- ß-oxo-ester afforded the corresponding dihydropyrazoles in good yields.

The development of copper-catalyzed aerobic oxidative coupling of H-tetrazoles with boronic acids and an insight into the reaction mechanism.

The development of a highly efficient and practical protocol for the direct C-N coupling of H-tetrazole and boronic acid was presented. A careful and patient optimization of a variety of reaction parameters revealed that this conventionally challenge reaction could indeed proceed efficiently in a very simple system, that is, just by stirring the tetrazoles and boronic acids under oxygen in the presence of different Cu(I) or Cu(II) salts with only 5 mol % loading in DMSO at 100 °C. Most significantly, the reaction could proceed very smoothly in a regiospecific manner to afford the 2,5-disubstituted tetrazoles in high to excellent yields. A mechanistic study revealed that both tetrazole and DMSO are crucial for the generation of catalytically active copper species in the reaction process in addition to their role as reactant and solvent, respectively. It is demonstrated that in the reaction cycle, the Cu(I) catalyst could be oxidized to Cu(II) by oxygen to form a [CuT2D] complex (T = tetrazole anion; D = DMSO) through an oxidative copper amination reaction. The Cu(II) complex thus formed was confirmed to be the real catalytically active copper species. Namely, the Cu(II) complex disproportionates to aryl Cu(III) and Cu(I) in the presence of boronic acid. Facile elimination of the Cu(III) species delivers the C-N-coupled product. The results presented herein not only provide a reliable and efficient protocol for the synthesis of 2,5-disubstituted tetrazoles, but most importantly, the mechanistic results would have broad implications for the de novo design and development of new methods for Cu-catalyzed coupling reactions.

Tandem halogenation/Michael-initiated ring-closing reaction of α,ß-unsaturated nitriles and activated methylene compounds: one-pot diastereoselective synthesis of functionalized cyclopropanes.

An efficient one-pot synthetic route to highly substituted cyclopropanes has been developed from readily available α,ß-unsaturated nitriles and doubly activated methylene compounds under very mild conditions in a highly diastereoselective manner, which involves halogenation, Michael addition and intramolecular ring-closing reaction sequences.

Divergent synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from 2,4-pentadienenitriles and isocyanides.

An efficient and divergent one-pot synthesis of 2,3-dihydro-1H-pyrroles, 3-alkyl-1H-pyrroles and 3-alkenyl-1H-pyrroles from readily accessible 2,4-pentadienenitriles with isocyanide based on reaction condition selection has been described. The reaction of 2,4-pentadienenitriles with ethyl isocyanoacetate undergoes a formal [2 + 3] annulation either to generate 2,3-dihydro-1H-pyrroles in the presence of DBU (0.3 equiv.) in EtOH at room temperature or to give 3-alkyl-1H-pyrroles in the presence of DBU (2.0 equiv.) in EtOH under reflux. Moreover, the 2,3-dihydro-1H-pyrroles could be converted to 3-alkenyl-1H-pyrroles with DDQ as an oxidant.

Polymer brushes on planar TiO2 substrates.

A facile and universal method is presented for the preparation of polymer brushes on amorphous TiO2 film. Homogeneous and stable poly(methyl methacrylate), polystyrene, poly(4-vinylpyridine), and poly(N-vinyl imidazole) (PNVI) brushes up to 550 nm are directly created onto TiO2 via UV-induced photopolymerization of corresponding monomers. Kinetic studies reveal a linear increase in thickness with the polymerization time. Characterization of the resulting polymer brushes by FTIR spectroscopy, X-ray photoelectron spectroscopy, contact angle, and atomic force microscopy (AFM) indicates an efficient UV-grafting reaction. Finally, we have demonstrated the possibility in converting the PNVI brushes to poly(vinyl imidazolium bromide), i.e., poly(ionic liquid) brushes by polymer-analogous reactions.

Hydrogen bond-assisted 6π-azaelectrocyclization of penta-2,4-dienamides: synthesis of dihydropyridin-2(3H)-ones.

A facile and efficient synthesis of substituted dihydropyridin-2(3H)-ones is developed from penta-2,4-dienamides, in which an intramolecular C-N bond was formed through thermal 6π-azaelectrocyclization. The intramolecular hydrogen bonding-assisted cyclization reaction opens access to a variety of dihydropyridin-2(3H)-ones.

Homogeneous and stereoselective copper(II)-catalyzed monohydration of methylenemalononitriles to 2-cyanoacrylamides.

A facile and efficient route for the homogeneous and highly stereoselective monohydration of substituted methylenemalononitriles to (E)-2-cyanoacrylamides catalyzed by copper(II) acetate monohydrate in acetic acid containing 2% water is described, and a mechanism is proposed. The protocol has proved to be suitable for the monohydration of dicyanobenzenes and 2-substituted malononitriles.

[5C + 1N] Annulation of 2,4-pentadienenitriles with hydroxylamine: a synthetic route to multi-substituted 2-aminopyridines.

A facile and efficient synthetic route to multi-substituted 2-aminopyridines has been developed via a formal [5C + 1N] annulation of readily available 2,4-pentadienenitriles with hydroxylamine (NH(2)OH) under very mild conditions, which involves sequential intermolecular aza-nucleophilic addition of hydroxylamine, intramolecular aza-cyclization, and dehydration reactions.

Novel glycosyl prodrug of RXP03 as MMP-11 prodrug: design, synthesis and virtual screening.

Like most phosphinic acids, the potent and selective RXP03 inhibitor of different MMPs exhibited moderate absorption and low bioavailability, which impaired its use. In an unprecedented attempt, we present an interesting synthetic approach to a new class of phosphinate prodrug, glycosyl ester of RXP03, to provide a potentially improved blood-brain barrier (BBB) behavior compared to the former lead compound RXP03. To validate this speculation, a predictive study for permeability enhancer of glycosyl ester of RXP03 showed encouraging insights to improve drug delivery across biological barriers.

Lawesson's reagent-initiated domino reaction of aminopropenoyl cyclopropanes: synthesis of thieno[3,2-c]pyridinones.

A convenient and efficient synthesis of substituted 2,3-dihydrothieno[3,2-c]pyridin-4(5H)-ones has been developed and relies upon a domino reaction of dimethylaminopropenoyl cyclopropanes initiated by Lawesson's reagent. A mechanism involving regioselective thionation, ring-enlargement, and an intramolecular aza-cyclization sequence is proposed. This protocol was utilized as a one-pot route to thieno[3,2-c]pyridin-4(5H)-ones with DDQ as an oxidant.

Facile and efficient synthesis of quinolin-2(1H)-ones via cyclization of penta-2,4-dienamides mediated by H2SO4.

A facile and efficient synthesis of substituted quinolin-2(1H)-ones is developed via intramolecular cyclization of penta-2,4-dienamides mediated by concentrated H(2)SO(4) (98%), and a mechanism involving the formation of a dicationic superelectrophile, and subsequent intramolecular nucleophilic cyclization reactions is proposed.

Polyureas from diamines and carbon dioxide: synthesis, structures and properties.

Polyureas were synthesized from diamines and carbon dioxide in the absence of any catalyst or solvent, analogous to the synthesis of urea from condensation of ammonia with carbon dioxide. The method used carbon dioxide as a carbonyl source to substitute highly toxic isocyanates for the synthesis of polyureas. FTIR and DFT calculations confirmed that strong bidentate hydrogen bonds were formed between urea motifs, and XRD patterns showed that the PUas were highly crystalline and formed a network structure through hydrogen bonds, which served as physical cross-links. The long chain PUas presented a microphase separated morphology as characterized by SAXS and showed a high melting temperature above 200 °C. The PUas showed high resistance to solvents and excellent thermal stability, which benefitted from their special network structures. The PUas synthesized by this method are a new kind of functional material and could serve some areas where their analogues with similar functional groups could not be applied.

Design, Synthesis, and Study of a Novel RXPA380-Proline Hybrid (RXPA380-P) as an Antihypertensive Agent.

In drug discovery, molecular modification over the lead molecule is often crucial for the development of a drug. Herein, we report the molecular hybridization design of a novel RXPA380-proline hybrid via linking the parent compound, phosphinic peptide RXPA380, with a proline analogue. The presented synthetic route is straightforward and produces the desired product RXPA380-P in moderate yield. The C- and N-domain constructs of the angiotensin-converting enzyme of RXPA380-P appeared to be poor inhibitors of ACE as compared to the parent compound RXPA380.