Heterocyclic Substrates Research Articles

Reactivity of the ester group attached isoxazoline, benzisoxazole, and isoxazole: a facial preparation of 3-acyl-substituted these heterocycles

A facile preparation of 3-acyl-substituted isoxazolines, benzisoxazoles, and isoxazoles from the corresponding 3-carboxylate esters is described. The process, involving reaction of the ester derivative of 3-carboxylic acid substituted heterocycles with Grignard or alkynyl lithium reagents, leads to direct generation of the corresponding 3-acyl heterocycle. The presence of α-imino ester moieties in the heterocyclic substrates for the reactions is thought to be a key feature governing the nature of these transformations. The synthetic utility of the new methodology is demonstrated by its application in a two-step route for the preparation of novel linked bis-heterocycles.

ChemInform Abstract: Efficient Iodination of Aromatic Compounds Using Potassium Ferrate Supported on Montmorillonite.

Abstract Potassium ferrate impregnated on montmorillonite is a mild, cheap, and non-toxic reagent for the iodination of phenols, including naphthol, aromatic amines, and heterocyclic substrates in fair to excellent yields by a simple isolation procedure.

ChemInform Abstract: A Simple Conversion of Azlactones into Indenones via H3PW12O40/Al2O3 Catalyzed Intramolecular Friedel—Crafts Reaction.

AbstractA convenient synthesis of indenone derivatives (II) is achieved by the title method which is further successfully applied to heterocyclic azlactone substrates (III) and (V).

ChemInform Abstract: Efficient Cyanation of Aryl Bromides with K4[Fe(CN)6] Catalyzed by a Palladium‐Indolylphosphine Complex.

Abstract This study describes a general palladium-catalyzed cyanation of aryl bromides using K 4 [Fe(CN) 6 ] as the cyanide surrogate. The reactions can be successfully conducted under mild reaction conditions (at 50 °C) in mixed solvents (water/MeCN = 1:1) without any surfactant additives, and afford the desired aryl nitriles in good-to-excellent yields. Particularly noteworthy is that this system allows the mildest reaction temperature reported so far for palladium-catalyzed cyanation of aryl bromides with K 4 [Fe(CN) 6 ] source in general. Common functional groups, including keto, aldehyde, free amine, and heterocyclic substrates are compatible under this system. Interestingly, the phosphine ligands bearing –PCy 2 moiety, which usually show excellent activity in aryl halide couplings, are found less effective than the corresponding ligands with –PPh 2 group.

Double CH Functionalization in Sequential Order: Direct Synthesis of Polycyclic Compounds by a Palladium‐Catalyzed CH Alkenylation–Arylation Cascade

Palladium-catalyzed cascade C-H alkenylation and arylation provides convenient access to polycyclic aromatic compounds. Treatment of 3-bromoaniline derivatives bearing a bromocinnamyl group on the nitrogen atom with a catalytic amount of [Pd(OAc)(2)] and PCy(3)·HBF(4) in the presence of Cs(2)CO(3) in dioxane affords naphthalene-fused indole derivatives in good yields. This double cyclization reaction is also applicable to heterocyclic substrates, giving fused indoles containing a heteroaromatic ring such as dibenzofuran, dibenzothiophene, carbazole, indole, or benzofuran through heterocyclic C-H arylation. When using a 2,6-unsubstituted aniline derivative, the first C-H arylation preferentially proceeds at the more hindered position of the aniline ring.

DFT Studies on Copper-Catalyzed Arylation of Aromatic C–H Bonds

Cu-catalyzed arylation of aromatic C–H bonds with phenyl iodide has been investigated with the aid of density functional theory calculations at the B3LYP level. Both the neutral and anionic catalytic cycles have been examined by considering the neutral (phen)Cu–OMe and anionic [MeO–Cu–OMe]− complexes, respectively, as the active species. Various heterocycle and polyfluorobenzene substrates were studied. The relationship between the overall reaction barrier and the acidity of the cleaved C–H bond was studied in both the neutral and anionic catalytic cycles. Comparing the overall reaction barriers based on the neutral and anionic catalytic cycles, we were able to understand that some substrates prefer the anionic mechanism while others prefer the neutral mechanism. We also examined how different ligands influence the overall barriers in the neutral catalytic cycles by employing N,N′-dimethylethylenediamine (DMEDA) and N-methylpyrrolidine-2-carboxamide as the ligands.

Highly regioselective aminobromination of α,β-unsaturated nitro compounds with benzyl carbamate/N-bromosuccinimide as nitrogen/bromine source

Aminobromination of α,β-unsaturated nitro compounds with benzyl carbamate and N-bromosuccinimide as nitrogen/bromine sources was reported. This new catalytic system tolerates a wide range of aromatic substrates, as well as heterocyclic and aliphatic substrates, resulting in good chemical yields. The reaction also proceeds smoothly with water as a medium in high efficiency. This practical aminobromination method was also proved to be suitable for large-scale preparation. Furthermore, the N-carbobenzoxy protecting group could be easily cleaved to afford the free vicinal haloamines.

Photoinduced Electron-Transfer-Promoted Redox Fragmentation of N-Alkoxyphthalimides

A new photoinduced electron-transfer-promoted redox fragmentation of N-alkoxyphthalimides has been developed. Mechanistic experiments have established that this reaction proceeds through a unique concerted intramolecular fragmentation process. This distinctive mechanism imparts many synthetic advantages, which are highlighted in the redox fragmentation of various heterocyclic substrates.

Regio‐ and Chemoselective Metalation of Arenes and Heteroarenes Using Hindered Metal Amide Bases

The preparation of highly functionalized organometallic compounds can be achieved by direct C-H activation of a broad range of unsaturated substrates using lithium chloride solubilized 2,2,6,6-tetramethylpiperidide bases (TMP(n)MX(m)⋅p LiCl). These are excellent reagents for converting a wide range of aromatic and heterocyclic substrates into valuable organometallic reagents with broad applications in organic synthesis.

Efficient cyanation of aryl bromides with K4[Fe(CN)6] catalyzed by a palladium-indolylphosphine complex

This study describes a general palladium-catalyzed cyanation of aryl bromides using K4[Fe(CN)6] as the cyanide surrogate. The reactions can be successfully conducted under mild reaction conditions (at 50°C) in mixed solvents (water/MeCN=1:1) without any surfactant additives, and afford the desired aryl nitriles in good-to-excellent yields. Particularly noteworthy is that this system allows the mildest reaction temperature reported so far for palladium-catalyzed cyanation of aryl bromides with K4[Fe(CN)6] source in general. Common functional groups, including keto, aldehyde, free amine, and heterocyclic substrates are compatible under this system. Interestingly, the phosphine ligands bearing –PCy2 moiety, which usually show excellent activity in aryl halide couplings, are found less effective than the corresponding ligands with –PPh2 group.

Palladium-Catalyzed Direct Arylation of Heteroaromatic Compounds: Improved Conditions Utilizing Controlled Microwave Heating

A versatile and rapid microwave-assisted procedure for the palladium-catalyzed direct arylation of heterocycles by aryl bromides and heteroaryl bromides is described. This novel protocol features short coupling times (10-60 min) and low catalyst loadings (1 mol %) and allows the successful arylation of previously unreactive heterocyclic substrates.

Efficient iodination of aromatic compounds using potassium ferrate supported on montmorillonite

Abstract Potassium ferrate impregnated on montmorillonite is a mild, cheap, and non-toxic reagent for the iodination of phenols, including naphthol, aromatic amines, and heterocyclic substrates in fair to excellent yields by a simple isolation procedure.

Theoretical estimation of the relative stability of tetrahydro-1,3-oxazine associates with water molecule

The interest in tetrahydro-1,3-oxazines is related to their structural features, valuable pharmacological properties, and use as reagents in fine chemical synthesis [1–4]. Due to the presence of heteroatoms with p-electron pairs, these compounds are capable of forming complexes with Lewis acids, making them useful in the computer modeling of the mechanisms of the interaction of heterocyclic substrates with various solvents. In the present work, HF/6-31G(d) and PBE/3z calculations using the HyperChem [5] and PRIRODA program packages [6], respectively, were carried out in the first study of the relative stability and conformational behavior of aggregates of tetrahydro-1,3-oxazine with the water molecule. The formation of four types of exothermal associates 1–4 was found to be possible. The calculated H values are relatively similar to the experimental results for water (4.8–6.0 kcal/mol [7]) and depend both on the type of hydrogen bond and whether its orientation is axial or equatorial. In Ca conformers 1 and 2, the O···H bond is stronger than the N···H bond. However, for the Ce forms (complexes 3 and 4), the opposite is found. We should also note that the  value for O···H in associates 1 and 3 is higher than the value calculated for the adduct of 1,3-dioxane with a water molecule: –5.0 kcal/mole (HF/6-3G(d)) [8]. The N···H bond (2, Ca, 2.101 A, HF/6-31G(d), 1.889 A, PBE/3z; 4, Ce, 2.199 A, HF/6-31G(d)), 1.938 A, PBE/3z) is longer than the O···H bond (1, Ca, 2.019 A, HF/6-31G(d), 1.845 A, PBE/3z; 3, Ce, 2.062 A, HF/6-31G(d), 1.916 A, PBE/3z), while the O···H bond is shorter than the corresponding experimental value for water (2.74–2.77 A [7]). We should also note that the O···H bond is retained during the pyramidal inversion of the nitrogen atom. The O···H bond in the transition state with planar configuration of the nitrogen atom (TS) (2.019 A, HF/6-31G(d), 1.869 A, PBE/3z) is shorter than in complex 3 and slightly longer (PBE/3z) than in associate 1. These results show that the probabilities for the formation of molecular complexes 1–4 are approximately equal. On the other hand, the differences in the energies of associates 1 and 3 are greater than for the corresponding conformers of the nonbonded tetrahydro-1,3-oxazine molecule. Formation of an intermolecular ______________ * To whom correspondence should be addressed, e-mail: kuzmaggy@mail.ru.

Chemical synthesis and evaluation of 17α-alkylated derivatives of estradiol as inhibitors of steroid sulfatase

Steroid sulfatase (STS) controls the levels of 3-hydroxysteroids available from circulating steroid sulfates in several normal and malignant tissues. This and the known involvement of active estrogens and androgens in diseases such as breast and prostate cancers thus make STS an interesting therapeutic target. Here we describe the chemical synthesis and characterization of an extended series of 17α-derivatives of estradiol (E2) using different strategies. A variant of the samarium-Barbier reaction with stoichiometric samarium metal and catalytic Kagan reagent formation was used for introducing low reactive benzyl substrates in position 17 of estrone (E1) whereas heterocyclic substrates were metalated and reacted with either the carbonyl or the 17-oxirane of E1. In vitro evaluation of the inhibitory potency of the new compounds against STS identified new inhibitors and allowed a more complete structure–activity relationship study of this family of 17α-derivatives of E2.

ChemInform Abstract: Pd(0)‐Catalyzed Diarylation of sp3 C—H Bond in (2‐Azaaryl)methanes.

AbstractIn most cases, a selective diarylation takes place at the C‐2 methyl group of the heterocyclic substrate.

ChemInform Abstract: Palladium‐Catalyzed Denitrogenation Reaction of 1,2,3‐Benzotriazin‐4(3H)‐ones Incorporating Isocyanides.

AbstractThe process is successful for various heterocyclic substrates and isocyanides to produce isoindoline and thiaisoindoline products.

An Effective Nitrilimine Cycloaddition for the Synthesis of 1,3,5-Trisubstituted 1,2,4-Triazoles from Oximes with Hydrazonoyl Hydrochlorides

An effective 1,3-dipolar cycloaddition for the synthesis of 1,3,5-trisubstituted1,2,4-triazole derivatives was developed by reacting oximes withhydrazonoyl hydrochlorides using triethyl-amine as a base.The desired 1,3,5-trisubstituted 1,2,4-triazoles were obtained ingood yields and the reaction was applicable to aliphatic, cyclicaliphatic, aromatic and heterocyclic oxime substrates.

Differential heterocyclic substrate recognition by, and pteridine inhibition of E. coli and human tRNA-guanine transglycosylases

tRNA-guanine transglycosylases (TGTs) are responsible for incorporating 7-deazaguanine-modified bases into certain tRNAs in eubacteria (preQ 1), eukarya (queuine) and archaea (preQ 0). In each kingdom, the specific modified base is different. We have found that the eubacterial and eukaryal TGTs have evolved to be quite specific for their cognate heterocyclic base and that Cys145 ( Escherichia coli) is important in recognizing the amino methyl side chain of preQ 1 (Chen et al., Nuc. Acids Res. 39 (2011) 2834 [15]). A series of mutants of the E. coli TGT have been constructed to probe the role of three other active site amino acids in the differential recognition of heterocyclic substrates. These mutants have also been used to probe the differential inhibition of E. coli versus human TGTs by pteridines. The results indicate that mutation of these active site amino acids can “open up” the active site, allowing for the binding of competitive pteridine inhibitors. However, even the “best” of these mutants still does not recognize queuine at concentrations up to 50 μM, suggesting that other changes are necessary to adapt the eubacterial TGT to incorporate queuine into RNA. The pteridine inhibition results are consistent with an earlier hypothesis that pteridines may regulate eukaryal TGT activity (Jacobson et al., Nuc. Acids Res. 9 (1981) 2351 [8]).

Rapid Access to Stereochemically Defined Heterocyclic Scaffolds

This work describes the rhodium(I)-mediated ring opening of hetaryne-furan Diels-­Alder adducts, the unexplored class of compounds in the context of transition-metal catalysis. Various types of heterocyclic substrates 2-5 have been screened. The resulting derivatives are interesting as being analogous to bioactive products (2-aminotetralins), and thus can be used in diversity-oriented synthesis of potential drug ­candidates.

Enantioselective organocatalytic α-fluorination of cyclic ketones.

The first highly enantioselective α-fluorination of ketones using organocatalysis has been accomplished. The long-standing problem of enantioselective ketone α-fluorination via enamine activation has been overcome via high-throughput evaluation of a new library of amine catalysts. The optimal system, a primary amine functionalized Cinchona alkaloid, allows the direct and asymmetric α-fluorination of a variety of carbo- and heterocyclic substrates. Furthermore, this protocol also provides diastereo-, regio-, and chemoselective catalyst control in fluorinations involving complex carbonyl systems.