Electron-deficient Heterocycles Research Articles

Direct C−H Arylation of Electron-Deficient Heterocycles with Arylboronic Acids

A direct arylation of a variety of electron-deficient heterocycles with arylboronic acids has been developed. This new reaction proceeds readily at room temperature using inexpensive reagents: catalytic silver(I) nitrate in the presence of persulfate co-oxidant. The scope with respect to heterocycle and boronic acid coupling partner is broad, and sensitive functional groups are tolerated. This method allows for rapid access to a variety of arylated heterocycles that would be more difficult to access with traditional methods.

2-Amino-6-(3,4-ethylenedioxythiophen-2-yl)-4-(2-thienyl)-pyrimidine: Synthesis and properties

In 1988 poly(ethylenedioxythiophene) (PEDOT, BAYETRON P) was synthesized for the first time [5, 6] from ethylenedioxythiophene (EDOT) [7, 8]. The doped polymer showed a high conductivity (about 300 S/cm); its oxidized films were almost transparent and thermally stable. Molecular conductors containing fragments of electron-rich [9–12] and electron-deficient aromatic carboand heterocycles [13–15] in addition to EDOT fragments were prepared. Synthesis of such compounds attracts undoubted interest for the design of light-emitting devices [16]. In the present communication we describe the synthesis of a new heterocyclic compound containing an electron-deficient pyrimidine ring linked to two electron-donating fragments, thiophene and ethylenedioxythiophene rings. The synthetic procedure was based on a convenient approach including initial preparation of 2-acetyl-3,4-ethylenedioxythiophene (II) [8] which was brought into condensation with thiophene-2-carbaldehyde in alkaline medium to obtain previously unknown chalcone III. Cyclization of the latter in the presence of guanidine sulfate in alkaline medium according to the procedure described in [17] gave dihydropyrimidine IV, which was oxidized in situ to target product V.

Palladium- and Copper-Catalyzed Arylation of Carbon−Hydrogen Bonds

The transition-metal-catalyzed functionalization of C-H bonds is a powerful method for generating carbon-carbon bonds. Although significant advances to this field have been reported during the past decade, many challenges remain. First, most of the methods are substrate-specific and thus cannot be generalized. Second, conversions of unactivated (i.e., not benzylic or alpha to heteroatom) sp(3) C-H bonds to C-C bonds are rare, with most examples limited to t-butyl groups, a conversion that is inherently simple because there are no beta-hydrogens that can be eliminated. Finally, the palladium, rhodium, and ruthenium catalysts routinely used for the conversion of C-H bonds to C-C bonds are expensive. Catalytically active metals that are cheaper and less exotic (e.g., copper, iron, and manganese) are rarely used. This Account describes our attempts to provide solutions to these three problems. We have developed a general method for directing-group-containing arene arylation by aryl iodides. Using palladium acetate as the catalyst, we arylated anilides, benzamides, benzoic acids, benzylamines, and 2-substituted pyridine derivatives under nearly identical conditions. We have also developed a method for the palladium-catalyzed auxiliary-assisted arylation of unactivated sp(3) C-H bonds. This procedure allows for the beta-arylation of carboxylic acid derivatives and the gamma-arylation of amine derivatives. Furthermore, copper catalysis can be used to mediate the arylation of acidic arene C-H bonds (i.e., those with pK(a) values <35 in DMSO). Using a copper iodide catalyst in combination with a base and a phenanthroline ligand, we successfully arylated electron-rich and electron-deficient heterocycles and electron-poor arenes possessing at least two electron-withdrawing groups. The reaction exhibits unusual regioselectivity: arylation occurs at the most hindered position. This copper-catalyzed method supplements the well-known C-H activation/borylation methodology, in which functionalization usually occurs at the least hindered position. We also describe preliminary investigations to determine the mechanisms of these transformations. We anticipate that other transition metals, including iron, nickel, cobalt, and silver, will also be able to facilitate deprotonation/arylation reaction sequences.

Efficient palladium-catalyzed direct arylation of azines and diazines using ligand-free conditions

The use of the palladium-catalyzed direct arylation was successfully tested on different electron-deficient heterocycles. The results demonstrate the effectiveness of the method based on the intramolecular coupling reaction providing polyazacyclic systems. This new application was obtained by using ligand-free conditions with the mixture of Pd(OAc) 2 and TBAC as catalytic system. With suitable substrates different products arising from regioselective coupling were observed.

The versatile electrophilic reactivity of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile

The interaction of 4,6-dinitrobenzo[d]isoxazole-3-carbonitrile (5a) with methoxide ion has been kinetically investigated in methanol and a 20:80 (v/v) MeOH-Me2SO mixture. In methanol, stopped-flow experiments have revealed that a monomethoxyl sigma-adduct (5a-Me) is first formed, resulting from a fast MeO- addition at the unsubstituted 7-carbon. Rate and equilibrium constants for this sigma-complexation process could be determined, allowing a ranking of 5a within the pKa scale established for Meisenheimer electrophiles in methanol. With a pKa value of 13.50, the electrophilicity of 5a falls in the range of 1,3,6,8-tetranitronaphthalene, 2,4-dinitrothiophene or 4-nitrobenzofuroxan. This corresponds to a two-pKa units increase in electrophilicity from that of TNB, the common reference in sigma-complex chemistry but it is notably below that of so-called superelectrophilic molecules like 4,6-dinitrobenzofuroxan. In addition to its ease of sigma-complexation, 5a is found to undergo a slow but thermodynamically favourable addition of MeO- to the cyano group bonded to the isoxazole ring, leading to a complete conversion of the adduct 5a-Me into a dinitroimidate 6. The reactivity of 6 could be kinetically assessed. Going to 80% Me2SO still afforded initially the adduct 5a-Me but this anionic species undergoes addition of a second molecule of MeO- to the CN group, giving a dianion whose structure is unprecedented in the literature. Combining the above results with synthetic observations showing that 5a can readily contribute to S(N)Ar reactions under appropriate experimental conditions emphasizes the multifaceted electrophilic reactivity of this electron-deficient heterocycle.

Anion recognition by a novel Fipronil-based receptor: efficient deprotonation or stable intermolecular hydrogen bonding

Strong electron-deficient heterocycles of acetyl Fipronil ( F3) was designed and synthesized, its ability for anion recognition was investigated by UV and NMR analyses. This novel Fipronil-based receptor F3 shows strong binding affinity with acetate (⩾10 7 M −1), phosphate or fluoride ion through efficient deprotonation. In addition, its interaction with chloride anion or other weak base anions through stable intermolecular H-bonding was also reported.

A novel strategy to assemble the beta-diketo acid pharmacophore of HIV integrase inhibitors on purine nucleobase scaffolds.

Claisen condensation, the key step in constructing the pharmacophore of aryl beta-diketo acids (DKA) as integrase inhibitors, fails in certain cases of highly electron-deficient heterocycles such as purines. A general synthetic strategy to assemble the DKA motif on the purine scaffold has been accomplished. The synthetic sequence entails a palladium-catalyzed cross-coupling, a C-acylation involving a tandem addition/elimination reaction, and a novel ferric ion-catalyzed selective hydrolysis of an enolic ether in the presence of a carboxylic acid ester.

Metal–organic frameworks exhibiting strong anion–π interactions

Coordination polymers offer a significant potential for applications in adsorption, guest and anion recognition and sensing. Their structure commonly provides binding sites for such specific interactions as pi-pi stacking and XH...pi hydrogen bonding. The latter reflects the ability of the pi-cloud to interact with positively polarized atoms. An electrostatic interaction between anionic species and electron deficient heterocycles, which parallels the above binding scheme, is also possible and very recently the existence of anion-pi interactions was proved in the solid state and in solution. This effect may be significant also for biomolecule/solution interfaces, as it occurs in protein structures. In fact, such interactions could be especially relevant for host-guest chemistry of coordination polymers, particularly for functionalization of hydrophobic crystal cavities and for the design of geometrically rigid anion receptors. However, typical electron deficient heterocycles such as 1,3,5-triazines and 1,2,4,5-tetrazines are very weak donors and they are hardly suitable for bridging metal ions and the generation of coordination frameworks. As a system that combines efficient donor properties towards transition metal ions and a pronounced ability for anion-pi interactions we have developed unsubstituted pyridazino[4,5-d]pyridazine, which was readily accessible by a novel one-pot synthesis involving inverse electron demand Diels-Alder cycloaddition (Scheme 1). Unusual anion binding properties of the ligand may be clearly related to its electron-deficiency (LUMO energy -1.591 vs. -0.288 eV for the parent pyridazine), influenced also by N-coordination to such Lewis acids as metal ions.

Catalytic asymmetric cyclopropanation of heteroaryldiazoacetates.

Rh(2)(S-DOSP)(4)-catalyzed decomposition of heteroaryldiazoacetates in the presence of styrene results in highly diastereoselective and enantioselective cyclopropanations. Heteroaryldiazoacetates containing both electron-rich and electron-deficient heterocycles, such as thiophene, furan, pyridine, indole, oxazole, isoxazole, and benzoxazole, are effective in this chemistry. These studies broaden the range of diazo compounds containing both electron-withdrawing and electron-donating groups, which undergo highly diastereoselective cyclopropanations.

Oligo(phenylenevinylene)s with increased electron affinity: 1,3,4-oxadiazoles in the main chain

Stilbenoid chromophores and 2,5-diaryl-1,3,4-oxadiazoles are compounds with wide technical importance. Their intense fluorescence is used in szintillators and optical whiteners and their semiconducting properties makes them valuable emissive or electron conducting layers in organic light emitting diodes (OLED). The synthesis and the electronic spectra of soluble oligo(phenylenevinylene)s with 1,3,4-oxadiazoles in the main chain are presented. The Huisgen reaction of tetrazole-terminated stilbenoid compounds with aromatic acyl chlorides yields model compounds, isophthalic acid dichlorides lead to soluble polymers with well-defined conjugated segments, as can be seen in the electronic spectra. Besides connection of the stilbenoid sections, the electron deficient heterocycles promise to increase the electron affinity of the chromophore.

Spontaneous Formation of the Bioactive Form of the Tuberculosis Drug Isoniazid.

It works even without the enzyme: The formation of the bioactive form 1 of isoniazid inside Mycobacterium tuberculosis does not depend on specific interactions within the active site of the inhibited enzyme, but rather relies on the fast addition of acyl radicals to electron-deficient heterocycles such as NAD(+).

N-Unsubstituted Sulfenamides by Electrophilic Amination of mercapto compounds

Potential mercapto compounds derived from electron deficient heterocycles as 2- and 4-thiouracils, pyridines and pyridine-1-oxide are aminated by the oxaziridine 1 to new sulfenamides (6, 9, 11 and 15 or the isothiazolo-pyridine 14) which add to phenylisocyanates forming sulfenylureas (7, 10, 12 and 16). Several other mercapto compounds gave disulfides. Attempts of oxidation of the sulfenamides and the sulfenylureas were unsuccessful. The methylmercapto compound 19 after amination was hydrolyzed to the sulfoxide 20.

Novel synthesis of 3-nitro-4-quinolone derivatives

The problem of the selective introduction of the nitro group into ~-electron-deficient nitrogen heterocycles has not been clearly resolved to date. This circumstance makes the task of developing preparative methods for the synthesis of 3-nitro-4-quinolones a vital one, as it has been previously. 3-Nitroquinoline derivatives are of interest for pharmacological research as potential drugs and also as convenient key products for the preparation of biologically active compounds.