Flexible metathesis-based approaches to highly functionalised furans and pyrroles

A range of differentially functionalised furans and pyrroles have been synthesised in short order by the judicious use of a ring-closing metathesis/aromatisation strategy. Two contrasting approaches are described exploiting a palladium-catalysed union of allylic alcohols and sulfonamides in one case, and a titanium mediated methylenation of homoallylic esters in another. A number of groups that are difficult to install via traditional methods were incorporated successfully.     

Microwave-assisted Paal-Knorr reaction. A rapid approach to substituted pyrroles and furans

[reaction: see text] An array of tetrasubstituted pyrroles (and trisubstituted furans) was obtained using a simple three-step procedure. Functional homologation of a beta-ketoester with an aldehyde followed by oxidation gave a series of differently substituted 1,4-dicarbonyl compounds that can be rapidly cyclized with the Paal-Knorr procedure carried out under microwave irradiation.     

Aza-pinacol rearrangement: acid-catalyzed rearrangement of aziridines to imines

A series of di-, tri-, and tetra-substituted N-tosylaziridines [N-(toluene-p-sulfonyl)aziridines] 1, prepared by aziridination of the corresponding alkenes with N-[(tolyl-p-sulfonyl)imino]phenyliodinane (TsN = IPh), was found to undergo a BF3-catalyzed rearrangement (aza-pinacol rearrangement) under mild conditions to give the corresponding N-tosylimines 2 generally in satisfactory yields.     

Synthesis of substituted acetylenic epoxides followed by indium-catalyzed rearrangement to 2,3,5-trisubstituted furans

Syntheses of various aromatic and aliphatic 2,3,5-trisubstituted furans from acetylenic epoxides are described. These epoxides are directly prepared by nucleophilic ring closure of propargylic alkoxides generated by lithium acetylide addition to α-haloketones.     

Stevens rearrangement of unsaturated ammonium salts. Synthesis of substituted furans

Ammonium salts bearing but-2-ynyl and phenacyl or 2-(naphth-2-yl)-2-oxoethyl moieties at the nitrogen atom underwent Stevens rearrangement to form substituted furan-3-amines. Quaternization of the latter afforded appropriate iodomethylates.     

Formation of substituted pyrroles via an imine condensation/Aza-Claisen rearrangement/imine-allene cyclization process by MAOS

A diverse collection of pyrroles has been prepared using a one-pot, domino aldehyde/amine condensation, [3,3]-aza-Claisen rearrangement, imine-allene cyclization strategy. This protocol was accelerated by microwave irradiation and provided very good levels of conversion after reacting for only 30 min.     

Gold-catalysed rearrangement of O-vinyl oximes for the synthesis of highly substituted pyrroles

O-Vinyl oximes were synthesised from the reaction of oximes with activated alkynes and subsequently rearranged using gold catalysis to afford highly substituted pyrroles in an efficient and regiocontrolled process. Additionally, pyrroles were formed directly from oximes and activated alkynes in a multifaceted catalysis process.     

A new facile approach to the synthesis of 3-methylthio-substituted furans, pyrroles, thiophenes, and related derivatives

2-(methylthio)-1,4-diaryl-2-butene-1,4-dione (3) are prepared from readily available aryl methyl ketones in the presence of copper(II) oxide, iodine, and dimethyl sulfoxide. The success of the cross-coupling reaction of 4-chloroacetophenone with 2-acetylthiophene confirms a proposed self-sorting tandem reaction mechanism. Both Z- and E-isomers of compound 3 are readily converted into the corresponding 3-methylthio 2,5-diaryl furan 7 in good yield through a domino process involving the reduction of the double bond followed by the Paal-Knorr furan synthesis. Meanwhile, 4-bromo-3-methylthio 2,5-diaryl furan 10 is obtained either by the treatment of furan 7 with molecular bromine or by the treatment of diketone 3 with 30% hydrogen bromide in acetic acid solution in one pot. Removal of the methylthio group is accomplished by the treatment of 7 with Raney Ni in ethanol, which affords the diaryl-substituted furan 11 in excellent isolated yield. Selective reduction of the double bond of compound 3 leads to the formation of the saturated 1,4-diketone 13, which is easily converted to the corresponding 3-methylthio-2,5-diaryl-substituted pyrrole 14 and thiophene 15 via the Paal-Knorr cyclization reaction.     

Pd/Cu-catalyzed cascade Sonogashira coupling/cyclization reactions to highly substituted 3-formyl furans

An efficient palladium/copper-catalyzed approach to the synthesis of highly substituted 3-formyl furans from the reactions of readily available α-bromoenaminones with terminal alkynes has been developed. This methodology was realized by the cascade reactions of Sonogashira coupling and the subsequent intramolecular cyclization.     

Regioselective dicouplings: application to differentially substituted pyrroles

[reaction: see text] In an effort to develop a more concise route to differentially substituted pyrroles (such as that found in the lamellarins), a completely regioselective one-pot double Suzuki coupling has been discovered. The key feature is the use of a ligand-free palladium catalyst under optimized conditions, which results only in coupling of the C5 bromide. At this point, addition of a second boronic acid and a phosphine ligand enables coupling at the remaining C4 bromide.     

Enantioselective Friedel–Crafts reactions of ethenetricarboxylates and substituted pyrroles and furans and intramolecular reaction of benzene derivatives

Compared to enantioselective Friedel–Crafts reactions of indoles, reactions of alkylidene malonates with monocyclic aromatic compounds generally proceed with low enantioselectivity. The Friedel–Crafts reactions of ethenetricarboxylates 1 and monocyclic heteroaromatic compounds, such as substituted pyrroles and furans were investigated. The reaction of 1 with 2,4-dimethylpyrrole in the presence of a chiral bisoxazoline–copper(II) complex (10 mol %) in tetrahydrofuran at room temperature gave alkylated products in up to 72% ee. The reaction of 1 with 2-substituted furans gave alkylated products in 46–62% ee. The absolute stereochemistry of the furan Friedel–Crafts product 7e was determined by transformation to the known 2,3-dimethylbutyric acid. The intramolecular reaction of benzene derivatives gave cyclized products up to 56% ee.     

Magnesium monoperoxyphtalate: A new reagent for the oxidative ring opening of furans to cis-enediones

Ring opening of furans can be accomplished with the title reagent to afford cis-enediones stereospecifically, with great advantages over the hazardous MCPBA.     

Nitrogen NMR spectroscopy: Application to some substituted pyrroles

A series of ¹⁵N labeled 2-acylpyrroles was prepared and the nitrogen and proton n.m.r. spectra obtained. ¹⁵N chemical shifts for these compounds are reported for the first time. No correlation between the nitrogen chemical shift and any Hammett substituent constant could be found. No variation in J(¹⁵N? H) was observed for any compound with changes in solvent, temperature or concentration, ruling out any observable tautomeric equilibria for these systems. An increase in J(¹⁵N? H) with the addition of electron withdrawing groups indicates increasing polarization of the N? H bond and acidity of these molecules. Two and three bond ¹⁵N couplings are also reported.     

Pd-catalyzed addition of boronic acids to vinylogous imines: a convenient approach to 3-sec-alkyl substituted indoles

A convenient approach to 3-sec-alkyl substituted indoles was developed via palladium-catalyzed addition of arylboronic acids to vinylogous imines generated in situ from sulfonylindoles under mild conditions.     

Palladium-catalyzed rearrangement of α-cyanoallylic acetates application to a new synthetic method for furans

Various types of α-cyanoallylic acetates were undergone the palladium-catalyzed rearrangement to give the γ-acetoxy-α,β-unsaturated nitriles in high yields. These rearranged acetates were conveniently transformed into the furan derivatives often encountered in natural products by the reduction using diisobutylaluminum hydride.     

Addition of boranes to N-aryl-salicylaldimines: intramolecular hydrogenation of imines

Addition of boranes to N-aryl-salicylaldimines takes place initially at the reactive phenolic O-H bond to give an activated boron-containing imine and dihydrogen. In some cases a subsequent intramolecular hydrogenation step is observed and the C=N imine bond is reduced to the corresponding amine. Reactions with dimesitylborane in THF are unique in that the reduced amine product is the major product observed in solution.     

Synthesis of highly substituted pyrroles via oxidative free radical reactions of β-aminocinnamates

Oxidative free radical reactions of β-aminocinnamates are described. Imine radicals produced by tetra-n-butylammonium cerium(IV) nitrate (TBACN) oxidation of enamines undergo efficient addition to the C-C double bond of β-aminocinnamates. This TBACN mediated free radical reaction between β-aminocinnamates and enamines provides a novel method for the synthesis of highly substituted pyrroles. The direct TBACN oxidation of β-aminocinnamates gave the dimerization products effectively.     

A simple and convenient synthesis of substituted furans and pyrroles by CuCl2-catalyzed heterocyclodehydration of 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols

A simple and economical synthesis of substituted furans and pyrroles, by ligand-free CuCl₂-catalyzed heterocyclodehydration of readily available 3-yne-1,2-diols and N-Boc- or N-tosyl-1-amino-3-yn-2-ols, respectively, is presented. Reactions are carried out in MeOH at 80-100 °C for 1-24 h and afford the corresponding heterocyclic derivatives in 53-99% isolated yields.     

A novel palladium-catalyzed rearrangement of acetylenic ketones to furans

A novel rearrangement of 1-aryl-4-alkyl-2-butyn-1-one in the presence of Pd(dba)₂-PPh₃ catalyst gave 2,4-substituted furans in moderate yields.     

Diels-alder reactions of pyrroles as an entry to substituted 3-oxatropanes and tetrasubstituted pyrrolidines

The Diels-Alder adduct of N-(p-toluenesulfonamido)pyrrole and dimethyl acetylenedi-carboxylate, 2,3-dimethyl N-(p-toluenesulfonamido)-7-azabieyclo[2.2.1]-2,5-heptadiene-2,3-di-carboxylate ( 1c ), was obtained in good yield and converted to remarkably stable 3-oxatropanes ( 6 and 8 ) in 25% yield.