Microwave-assisted C-H bond activation: a rapid entry into functionalized heterocycles

[reaction: see text] Microwave irradiation strongly accelerates the rhodium-catalyzed intramolecular coupling of a benzimidazole C-H bond to pendant alkenes. The cyclic products were formed in moderate to excellent yields with reaction times less than 20 min. Additionally, the use of microwave irradiation allowed the reactions to be performed without any solvent purification and with minimal precautions to exclude air.     

Metal-catalysed approaches to amide bond formation

Amongst the many ways of constructing the amide bond, there has been a growing interest in the use of metal-catalysed methods for preparing this important functional group. In this tutorial review, highlights of the recent literature have been presented covering the key areas where metal catalysts have been used in amide bond formation. Acids and esters have been used in coupling reactions with amines, but aldehydes and alcohols have also been used in oxidative couplings. The use of nitriles and oximes as starting materials for amide formation are also emerging areas of interest. The use of carbon monoxide in the transition metal catalysed coupling of amines has led to a powerful methodology for amide bond formation and this is complemented by the addition of an aryl or alkenyl group to an amide typically using palladium or copper catalysts.     

Selective Si--C bond cleavage as synthetic entry to a functionalized lithiosilane

Treatment of the phenyl-substituted silane 4 with lithium metal afforded the functionalized lithiosilane rac-2 by selective cleavage of one Si-C bond between silicon and a phenyl group. The resulting lithiosilane rac-2 crystallizes as the dimer (2.THF)2, which represents the first example of a dimeric organyl-substituted lithiosilane in the presence of THF.     

Rapid access to oxindoles by the combined use of an Ugi four-component reaction and a microwave-assisted intramolecular Buchwald-Hartwig amidation reaction

A two-step sequence involving an Ugi four-component reaction (Ugi-4CR) and a palladium-catalyzed intramolecular amidation of aryl iodide has been developed for rapid access to functionalized oxindole (1). Microwave heating was used to accelerate and to improve the efficiency of the intramolecular Buchwald-Hartwig reaction.     

An intramolecular ionic hydrogen bond stabilizes a cis amide bond rotamer of a ring-opened rapamycin-degradation product

Rapamycin (1), a macrolide immunosuppressant, undergoes degradation into ring-opened acid products 2 and 3 under physiologically relevant conditions. The unsaturated product (3) was isolated and studied in this work. Unlike 1, which has its amide primarily in a trans conformation in solution, 3 has both cis and trans conformations in approximately a 1:1 ratio in dimethyl sulfoxide (DMSO). The amount of cis rotamer was increased dramatically in the presence of an organic base such as triethylamine. The detailed NMR results indicate that the cis rotamer is stabilized through an intramolecular ionic hydrogen bond of the carboxylate anion with the tertiary alcohol as part of a nine-membered ring system. This hydrogen bond was characterized further in organic media and the trans-cis rotamer equilibria were used to estimate the relative bond strengths in several solvents. The additional stabilization arising from this ionic hydrogen bond in the cis rotamer was determined to be 1.4 kcal mol(-1) in DMSO-d6, 2.0 kcal mol(-1) in CD3CN and 1.1 kcal mol(-1) in CD3OD.     

Efficient entry to diversely functionalized spirocyclic oxindoles from isatins through carbonyl-addition/cyclization reaction sequences

A novel approach to diversely functionalized spirocyclic oxindoles has been developed by using different metal-mediated carbonyl-addition/cyclization reaction sequences. Spirocyclization precursors, 2-indolinone-tethered homoallylic alcohols, (buta-1,3-dien-2-yl)methanols, and alpha-allenols have been obtained by regioselective addition of stabilized organoindium reagents to isatins in aqueous environment. Ruthenium-, silver-, and palladium-catalyzed reactions of the above unsaturated alcohol derivatives provided oxaspiro oxindoles.     

Palladium-catalyzed domino intramolecular N-arylation/intermolecular C-C bond formation for the synthesis of functionalized benzodiazepinediones

A divergent and regiocontrolled Pd-catalyzed domino sequence involving an intramolecular N-arylation and an intermolecular Heck reaction has been developed, providing rapid access to functionalized benzodiazepine-2,5-diones 3. The starting materials were synthesized by the Ugi four-component reaction. An unprecedented X-ray structure of bispalladacycle 6 was documented.     

Synthesis of annelated pyranosides: a rapid and efficient entry to highly functionalized optically pure branched-pyrazoles

Pyrazolo-pyranosides prepared from methyl-2,3:4,6-di-O-benzylidene-α-d-mannopyranoside were functionalized to design new scaffolds suitable for peptidomimetic construction. Under certain acidic conditions, they undergo only pyranose ring-opening generating highly functionalized optically pure pyrazoles bearing an aldehyde function.     

PS-IIDQ: a supported coupling reagent for efficient and general amide bond formation

Polystyrene-IIDQ, a polymer-supported coupling reagent, was synthesized in three steps from Merrifield resin in 86% overall conversion. This reagent efficiently coupled carboxylic acids to amines in good yields and high purities, required no pre-activation step, and was tolerant of the order of reagent addition. PS-IIDQ was observed to be more efficient than polymer-supported carbodiimides (PS-EDC and PS-DCC) and gave higher yields than HATU for general amide bond formation, including the coupling of anilines and hindered substrates. When evaluated with five carboxylic acids and nine amines (including anilines and secondary amines) PS-IIDQ gave an average isolated yield of 73%.     

Ab initio study of catalyzed and uncatalyzed amide bond formation as a model for peptide bond formation: Ammonia-Glycine reactions

As a model reaction for peptide and bond formation, the S_N2 reactions between glycine and ammonia have been studied with and without amine catalysis: using ab initio molecular-orbital methods. For each of the catalyzed and uncatalyzed reactions, two reaction mechanisms have been examined: a two-step and a concerted mechanism. The stationary points of each reaction, including intermediate and transition states, have been identified and free energies calculated for all geometry-optimized reaction species to determine the thermodynamics and kinetics of the reaction. The calculations demonstrate that a second ammonia molecule catalyzes amide bond formation, and that the two-step mechanism is more favorable than the concerted one for the catalyzed reaction, while for the uncatalyzed reaction both mechanisms are competitive.     

An efficient sequential one-pot base mediated C-O and Pd-mediated C-C bond formation: synthesis of functionalized cinnamates and isochromenes

An efficient sequential one-pot intermolecular oxy-Michael addition and intermolecular Heck coupling for the synthesis of functionalized cinnamates is presented. Bulky tert-butyl acrylate was identified as a more suitable Michael acceptor for initial oxy-Michael addition, as it precludes the formation of undesired cross condensed ester. Most importantly, the present method was further divergently extended to the successful synthesis of isochromenes via a sequential one-pot O-allylation and subsequent intramolecular Heck cyclization.     

Photoinduced switching of intramolecular hydrogen bond between amide NH and carboxyl oxygen

In this study, we synthesized two novel carboxylic acid and carboxylate compounds, both of which had an amide group linked with an azomethine moiety to introduce photoinduced switching of the intramolecular NH...O hydrogen bond. We suggest that the cis-carboxylate compound forms a stronger intramolecular NH...O hydrogen bond than the cis-carboxylic acid compound.     

Polyhydroxylated indolines and oxindoles from C-glycosides via sequential Henry reaction, Michael addition, and reductive amination/amidation

6-nitro-2'-carbonyl-C-glycofuranosides synthesized via Henry reaction from 1-C-allyl 5-aldo-C-glycoside underwent an intramolecular Michael addition to afford nitrocyclohexanol derivatives in good to excellent yield. Reduction of the nitro group followed by intramolecular amination with ketone and aldehyde and amidation with ester produced indoline and oxindole derivatives, respectively, in excellent yield.     

Copper-catalyzed one-pot synthesis of imidazo/benzoimidazoquinazolinones by sequential Ullmann-type coupling and intramolecular C-H amidation

A simple, practical, and highly efficient copper-catalyzed one-pot synthesis of imidazo/benzoimidazoquinazolinones has been developed. The procedure is based on a sequential copper-catalyzed Ullmann-type N-arylation and aerobic oxidative intramolecular C-H amidation. This method should provide a new and useful strategy for construction of N-heterocycles.     

Facile amide bond formation from carboxylic acids and isocyanates

A wide variety of carboxylic acids in the form of their salts condense with aryl isocyanates at room temperature with loss of carbon dioxide to give the corresponding amides in high yield. Application of the reaction to acyl isocyanates gives unsymmetric imides. The reaction is compatible with hydroxyl groups and both Fmoc and Boc protecting groups for amines and is applicable to aliphatic, aromatic, and heteroaromatic acids.     

Copper- and palladium-catalyzed intramolecular C-S bond formation: a convenient synthesis of 2-aminobenzothiazoles

Copper- and palladium-catalyzed intramolecular C-S bond formation by cross-coupling between an aryl halide and thiourea functionality is demonstrated for the synthesis of 2-aminobenzothiazoles, wherein the Cu-catalyzed protocol is generally superior and more cost effective than the Pd-catalyzed protocol; the Cu-catalyzed reaction also further expands recent studies exploring the utility of Cu salts as replacements for Pd in carbon-heteroatom bond-forming reactions. A one-pot variant combining the synthesis of the thiourea and the cyclization was also demonstrated.     

Dithiocarbamate and DBU-promoted amide bond formation under microwave condition

Dithiocarbamate and DBU-promoted amide bond formation under microwave condition has been reported. The versatility of this synthetic protocol has been demonstrated with various carboxylic acids and different dithiocarbamates. The products thus obtained have been characterized by mp, IR, ¹H NMR, and mass spectroscopy.     

Copper-catalyzed amide bond formation from formamides and carboxylic acids

A highly efficient copper-catalyzed approach to form amide bonds from formamides and carboxylic acids was developed.This protocol shows broad substrate scopes and high yields in the presence of 1 mol% catalyst and 4.0 equiv.formamides.