Application of an isomerization-ring-closing metathesis strategy to the synthesis of unsaturated seven-membered, benzo-fused heterocycles containing two heteroatoms

An isomerization-RCM approach was utilized to synthesize a number of seven-membered benzo-fused heterocycles containing two heteroatoms (N,O, N,S, and S,O). This approach utilized the ruthenium catalyst [RuClH(CO)(PPh₃)₃] for the isomerization of allyl groups, eventually followed by the use of the Grubbs second generation catalyst for the formation of the desired products. In most instances thermal RCM conditions were sufficient; however, in a number of cases where this methodology did not give the desired product a high temperature, short time microwave approach afforded the desired ring-closed products. In this manner, the following substituted benzo-fused scaffolds were successfully synthesized: 4,5-dihydro-1,5-benzoxazepine, 4,5- and 2,5-dihydro-1,5-benzothiazepine and 2H-1,5-benzoxathiepine.     

Hydrogen‐Bonding Catalyzed Ring‐Closing C−O/C−O Metathesis of Aliphatic Ethers over Ionic Liquid under Metal‐Free Conditions

O‐heterocycles have wide applications, and their efficient and green synthesis is very interesting. Herein, we report hydrogen‐bonding catalyzed ring‐closing metathesis of aliphatic ethers to O‐heterocycles over ionic liquid (IL) catalyst under metal‐ and solvent‐free conditions. The IL 1‐butylsulfonate‐3‐methylimidazolium trifluoromethanesulfonate ([SO₃H‐BMIm][OTf]) is discovered to show outstanding performance, better than the reported catalysts. An interface effect plays an important role in mediating the reaction rate due to the immiscibility between the products and the IL catalyst, and the products can be spontaneously separated. NMR analysis and DFT calculation suggest that a pair of cation and anion of [SO₃H‐BMIm][OTf] could form three strong H‐bonds with an ether molecule, which catalyze the ether transformation via a cyclic oxonium intermediate. A series of O‐heterocycles including tetrahydrofurans, tetrahydropyrans, morpholines and dioxane can be obtained from their corresponding ethers in excellent yields (e.g., >99 %). This work opens an efficient and metal‐free way to produce O‐heterocycles from aliphatic ethers.     

Copper fluorapatite catalyzed N-arylation of heterocycles with bromo and iodoarenes

Copper exchanged fluorapatite (CuFAP) is an effective heterogeneous catalyst for N-arylation of heterocycles with bromo- or iodoarenes using K₂CO₃ as base. N-Arylated products were isolated in good to excellent yields, demonstrating the versatility of the reaction.     

Asymmetric synthesis of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates

This study describes general methods for the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates through dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation of vinyl heterocycles with aryl- or heteroaryldiazoacetates. The reactions are highly diastereoselective and high asymmetric induction could be achieved using either (R)-pantolactone as a chiral auxiliary or chiral dirhodium tetracarboxylate catalysts. For meta- or para-substituted aryl- or heteroaryldiazoacetates the optimum catalyst was Rh₂(R-p-Ph-TPCP)₄. In the case of ortho-substituted aryl- or heteroaryldiazoacetates, the optimum catalyst was Rh₂(R-TPPTTL)₄. For a highly enantioselective reaction with the ortho-substituted substrates, 2-chloropyridine was required as an additive in the presence of either 4 Å molecular sieves or 1,1,1,3,3,3-hexafluoroisopropanol (HFIP). Under the optimized conditions, the cyclopropanation could be conducted in the presence of a variety of heterocycles, such as pyridines, pyrazines, quinolines, indoles, oxadiazoles, thiophenes and pyrazoles.

The dirhodium tetracarboxylate-catalysed asymmetric cyclopropanation has been applied to the enantioselective syntheses of pharmaceutically relevant 1-aryl-2-heteroaryl- and 1,2-diheteroarylcyclopropane-1-carboxylates.     

A manganese/copper bimetallic catalyst for C-N coupling reactions under mild conditions in water

An efficient and convenient bimetallic MnF₂/CuI catalyst in combination with trans-1,2-diaminocyclohexane has been developed for the cross-coupling of nitrogen heterocycles with aryl halides in water at moderate temperature. A variety of nitrogen nucleophiles including pyrazole, 7-azaindole, indazole, indole, pyrrole and imidazole afforded the corresponding products in moderate to good yields (up to 94%) under the described arylation conditions.     

A novel approach for the one-pot synthesis of linear and angular fused quinazolinones

A convenient and inexpensive one step methodology has been developed for the synthesis of linear and angular fused quinazolinones. The protocol, which uses amino heterocycles and o-bromo benzyl/naphthyl bromides as reactants, CuI as catalyst, Cs₂CO₃ as base, l-proline as ligand, and DMF as solvent, proceeds via nucleophilic aromatic substitution of the N-heteroaromatic cationic intermediate followed by in situ aerial oxidation at the benzylic position to the quinazolinone scaffold.     

Homodimerization of hyaluronan and heparan sulfate derivatives by olefin metathesis reaction

Hyaluronan and heparan sulfate disaccharides of the type β-d-glucuronic acid-(1→3)-N-acetyl-β-d-glucosamine and α-l-iduronic acid-(1→4)-N-acetyl-β-d-glucosamine, respectively, with an n-pentenyl group at the reducing end have been synthesized. Homodimerization of these derivatives using Grubbs catalyst furnished dimerized disaccharides separated by a C₈ spacer arm.     

An efficient RuCl3·H2O/I2 catalytic system: A facile access to 3-aroylimidazo[1,2-a]pyridines from 2-aminopyridines and chalcones

A simple and efficient protocol has been demonstrated for the preparation of densely functionalized 3-aroylimidazo[1,2-a]pyridines from 2-aminopyridines and chalcones using RuCl₃·H₂O/I₂ catalytic system. The advantages, such as low catalyst loading, broad substrate scope with respect to substitutions on aminopyridines as well as chalcones, stability of heterocycles such as thiophene under the reaction conditions, operationally simple procedure and higher yields makes this approach remarkable for synthetic applications.     

Electrochemically reduced tungsten‐based active species as catalysts for cross‐metathesis reactions: cross‐metathesis of erucic acid with 2‐octene

The cross‐metathesis of erucic acid, (CH₃(CH₂)₇CH?CH(CH₂)₁₁COOH), with an excess of 2‐octene in the presence of an electrochemically produced tungsten‐based catalyst has been studied. Cross‐ and self‐hydrocarbon products, viz. 2‐undecene (C₁₁), 6‐dodecene (C₁₂) and 6‐pentadecene (C₁₅), were detected. The influence of several parameters, such as the 2‐octene/erucic acid and 2‐octene/catalyst ratios and the reaction time, on the yield of the cross‐metathesis product, 6‐pentadecene, was studied. The cross‐metathesis of functionalized olefins in the presence of an Al–e^?–WCl₆–CH₂Cl₂ system has not been reported in the literature so far. The cross‐metathesis products in the presence of this catalyst system can be obtained with high yield and high specificity. Copyright © 2004 John Wiley & Sons, Ltd.     

The WCl6-e-Al-CH2Cl2 catalyzed polypentenamer formation via ring-opening metathesis polymerization (ROMP)

The synthesis of polypentenamer by an electrochemically generated metathesis polymerization catalyst from methylene chloride solution of WCl₆ was investigated. The active species formed by electroreduction of this salt under controlled potential of +900 mV at a platinum cathode with an aluminum anode were found to catalyze the ring-opening metathesis polymerization (ROMP) of cyclopentene, monocyclic olefin of relatively low strain, in high yield (89%) and at short period (32 min) under mild conditions. The effect of reaction parameters, e.g., olefin/catalyst ratio, reaction time, electrolysis time, catalyst aging, on the polymerization yield have been studied. The resulting polymer has been characterized by ¹H and ¹³C NMR, IR and gel permeation chromatography (GPC) techniques. Analysis of the polypentenamer microstructure by means of ¹³C NMR spectroscopy indicates that the polymer contains a mainly trans stereoconfiguration of the double bonds (σ_c = 0.31) and a slightly blocky distribution (r_tr_c > 1) of cis and trans double bond dyads (r_tr_c = 1.44). However, this electrochemical system is reluctant to facilitate the competing vinyl type addition polymerization reactions.     

One-pot enyne metathesis/Diels-Alder reaction for the construction of highly functionalized novel polycyclic aza-compounds

Various tricyclic dienes were synthesized via enyne metathesis using the first generation Grubbs catalyst. The enyne metathesis proceeded smoothly in refluxing CH₂Cl₂ with a low catalyst loading (3.0 mol %), giving good yields (72-89%) of the tricyclic products 6 and 16. The resulting 1,3-dienes are suitable precursors of polycyclic structures via a Diels-Alder process. One-pot RCM/Diels-Alder reactions of the enyne products with dienophiles proceeded smoothly to afford polycyclic compounds as a single cycloadduct. The structures of the Diels-Alder adducts were determined by ¹H NMR spectra and X-ray analysis. The cycloadducts were formed via the approach of the dienophiles towards the diene in endo mode.     

A new and highly efficient water-soluble copper complex for the oxidation of secondary 1-heteroaryl alcohols by tert-butyl hydroperoxide

The water-soluble copper complex generated in situ from CuCl₂ and 2,2′-biquinoline-4,4′-dicarboxylic acid dipotassium salt (BQC), has been revealed as a highly efficient and selective catalyst for the oxidation of secondary 1-heteroaryl alcohols to the corresponding heteroaromatic ketones with aqueous tert-butyl hydroperoxide, under mild conditions. The catalytic system is compatible with different heterocycles such as pyridines, pyrroles, indoles, thiophens, furans, thiazoles, and imidazoles.     

Lewis acid catalyzed intramolecular halo-arylation of tethered alkenes using N-halosuccinimide (NXS) as the halogen source: a general method for the synthesis of chromanones, chromans, quinolones, tetrahydroquinolines and tetralins

Lewis acid catalyzed intramolecular halo-arylation of tethered alkenes was performed using N-halosuccinimide (NXS) as the halogen source. Among the Lewis acids investigated, Sm(OTf)₃ was found to be the best catalyst. This catalytic process provides a general method for the regio- and stereoselective synthesis of annulated arene heterocycles and carbocycles such as 2-chromanones, chromans, 2-quinolones, tetrahydroquinolines and tetralins possessing a halo-functionality.     

Polyaniline-supported tungsten-catalyzed oxidative deoximation reaction with high catalyst turnover number

Polyaniline-supported tungsten (W@PANI) was easily prepared by immersing polyaniline (PANI) in the aqueous solution of Na₂WO₄. It was found to be an efficient catalyst for oxidative deoximation reaction, the very important transformation for pharmaceutical industry. Besides the green features, the method employed very few of catalytic tungsten (0.048 mol% vs. oxime substrates), resulting in the high turnover numbers (TONs) of the catalyst (ca. 10³ mol/mol) and the low metal residues in product (<0.1 ppm). The reaction is applicable for a variety of substrates, including those containing heterocycles, which are key intermediates in medicine synthesis. It has also been successfully magnified to kilogram scale production to afford the desired carbonyl products smoothly.     

Pyrrole synthesis using a tandem Grubbs’ carbene-RuCl3 catalytic system

A straightforward pyrrole synthesis from diallylamines is developed by using a tandem catalyst system leading to ring-closing metathesis with the second generation Grubbs’ catalyst (10%) followed by dehydrogenation in the presence of RuCl₃ × H₂O (2%).     

Latent ruthenium olefin metathesis catalysts featuring a phosphine or an N-heterocyclic carbene ligand

The synthesis and characterization of latent 18-electron ruthenium benzylidene complexes (PCy₃)((^κN,O)-picolinate)₂RuCHPh (5) and (H₂IMes)((^κN,O)-picolinate)₂RuCHPh (6) are described. Both complexes appear as two isomers. The ratio between the isomers is dependent on l-type ligand. The complexes are inactive in ring-closing metathesis and ring-opening metathesis polymerization reactions even at elevated temperatures in the absence of stimuli. Upon addition of HCl, complexes 5 and 6 become highly active in olefin metathesis reactions. The advantage of the latent catalysts is demonstrated in the ring-opening metathesis polymerization of dicyclopentadiene, where the latency of 6 assures adequate mixing of catalyst and monomer before initiation. Trapping experiments suggests that the acid converts the 18-electron complexes into their corresponding highly olefin metathesis active 14-electron benzylidenes.     

Intramolecular Ullmann-type C−N coupling for the synthesis of substituted benzo[4,5]imidazo[1,2-a]pyrrolo[3,4-c]pyridines

An efficient CuI catalyzed intramolecular Ullmann-type C−N coupling reaction is described here. Newly substituted 1H-benzo[4,5]imidazo[1,2-a]pyrrolo[3,4-c]pyridine-1,3,5(2H, 11H)-trione has been easily synthesized from ortho halogenated N-substituted pyrrolo[3,4-c]pyridine-1,3,6(5H)-triones in presence of CuI catalyst and K₂CO₃ base without any ligand. This procedure is based on intramolecular Ullmann-type reaction and provides a proficient method of making fused tetracyclic heterocycles.     

Silacarbocycles from ring expansion

Ring enlargement of silicon heterocycles is accomplished from derivatives which contain an exocyclic chloromethyl substituent by reaction with aluminum halide catalyst or with potassium fluoride. Tricyclic derivatives with a silicon atom in a central five-, six-, or seven-membered ring form silins, silepins and silocins, respectively, and are isolated by quenching the product chlorosilanes with H₂O, MeOH, Na/MeOH, LiAlH₄, MeMgBr or MeLi. A stoichiometric quantity of fluoride ion also results in conversion of 9-chloromethyl-9-silaanthracene to 5-fluoro-dibenzo[b,e] silepin but the percent conversion of the 9-iodomethyl precursor is higher. The limitations of the two methods are discussed briefly.     

Detailed study of the ring-opening metathesis polymerization of norbornene bearing a five- or six-membered ring cyclic carbonate along with volume expansion

The ring-opening metathesis polymerization (ROMP) of norbornene derivatives bearing five- or six-membered cyclic carbonate ( 2 or 3 ) was carried out with a typical ruthenium catalyst [bis(tricyclohexylphosphine)benzylidene ruthenium(IV) dichloride], the so-called first-generation Grubbs catalyst, under various reaction conditions, to smoothly obtain the corresponding polyalkenamers ( 5 and 6 ) along with volume expansion. The number-average molecular weights (M_n's), 10% weight loss decomposition temperatures, glass-transition temperatures (T_g's), and volume expansion ratios of the resulting products depended on the polymerization conditions. The degree of volume expansion was mainly affected by M_n, T_g, and the cis/trans configuration of the exocyclic double bonds of the resulting polymers. The volume expansion was confirmed to specifically occur during the polymerization of the monomer bearing cyclic carbonate moieties, and similar ROMPs of monomers without cyclic carbonate, such as norbornene itself, the monomer 5,5-bis(methoxymethyl)bicyclo[2.2.1]hept-2-ene, and the monomer endo-N-methylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylimide, proceeded along with volume shrinkage. Furthermore, an investigation of another type of polymerization, a vinyl-type one, of monomer 2 suggested that the volume expansion specifically took place in the ring-opening type of polymerization. In addition, the Sc(OTf)₃-mediated cationic ring-opening reaction of the cyclic carbonate moiety of polyalkenamer 5 smoothly proceeded along with volume expansion or nearly zero volume shrinkage to yield the corresponding networked polymer. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 395–405, 2006     

Electrochemically reduced tungsten‐based active species as catalysts for cross‐metathesis reactions: cross‐metathesis of non‐functionalized olefins

The electrochemical reduction of WCl₆ results in the formation of an active olefin (alkene) metathesis catalyst. The application of the WCl₆–e^?–Al–CH₂Cl₂ catalyst system to cross‐metathesis reactions of non‐functionalized acyclic olefins is reported. Undesirable reactions, such as double‐bond shift isomerization and subsequent metathesis, were not observed in these reactions. Cross‐metathesis of 7‐tetradecene with an equimolar amount of 4‐octene generated the desired cross‐product, 4‐undecene, in good yield. The reaction of 7‐tetradecene with 2‐octene, catalyzed by electrochemically reduced tungsten hexachloride, resulted in both self‐ and cross‐metathesis products. The cross‐metathesis products, 2‐nonene and 6‐tridecene, were formed in larger amounts than the self‐metathesis products of 2‐octene. The optimum catalyst/olefin ratio and reaction time were found to be 1 : 60 and 24 h, respectively. The cross‐metathesis of symmetrical olefins with α‐olefins was also studied under the predetermined conditions. Copyright © 2003 John Wiley & Sons, Ltd.