Electron-rich Aromatic Rings Research Articles

The pharmacological evaluation of novel and high‐affinity melatonin receptor ligands

Melatonin exerts its multiple pharmacological actions via activation of two G protein‐coupled receptors, MT1 and MT2. The exploration of the physiological role of the distinct receptor subtypes requires the use of highly selective ligands (both agonists and antagonists). The compounds being presented serve as MT2 selective ligands. The introduction of the bulky lipophilic substituent at the position corresponding with the C‐2 position of melatonin provides MT2 selectivity potentially through an interaction with the NH group of the His‐208. Competitive binding assays were performed with 2‐[125I]‐iodomelatonin in Chinese hamster ovary cells stably transfected with the human MT1 and MT2 melatonin receptors. Competition analysis showed that large electron rich aromatic ring structures enhance binding and MT2 receptor selectivity. With the creation of highly selective, high affinity ligands, the binding pockets of each receptor subtype can be better understood and further the development of novel melatonergic drugs.

A Diazonium Ion Cascade from the Nitrosation of Tolazoline, An Imidazoline-Containing Drug

Tolazoline (1-benzylimidazoline), a representative imidazoline-containing drug, reacts readily with nitrite in acetic acid to produce a complex product mixture. Fourteen compounds have been identified as products of this transformation when an 8-fold excess of HNO2 is used. The products, which include N-nitrosoamides, esters, alcohols, and phenylacetic acid, are rationalized as arising from a cascade of reactive diazonium ions. N-Nitrosotolazoline can be isolated from the nitrosation reaction in good yield when the mixture is extracted with CH2Cl2 as the transformation progresses. It nitrosates much more rapidly (50x) than tolazoline to give, among other products, the oxime [1-( N-nitroso-2-imidazolinyl)benzylidene]hydroxylamine, which can also be produced in good yield from the reaction of tolazoline with isopropyl nitrite. At low substrate and nitrite concentrations, the main reaction products are N-nitrosotolazoline, its decomposition product N-2-hydroxyethylphenylacetamide, the above-mentioned oxime, phenyl acetic acid, and 2-hydroxyethyl phenylacetate. The tolazoline nitrosation rate in three buffer systems has been determined at pH 3.4 and 37 degrees C ( kobs = 6.25 x 10 (-5) s (-1) in 0.5 M acetate buffer with a 10 * [NO2(-)] = 250 mM). Because N-nitrosotolazoline exhibits the chemical properties of a direct-acting mutagen and carcinogen, we have used the rate data to estimate its level of formation at nitrite concentrations <3 mM. Cursory examination of the nitrosation chemistry of oxymetazoline, a related drug, is primarily focused at its electron-rich aromatic ring.

Synthesis of Novel Pyrimidine Fused 8-Membered Heterocycles via Iminium Ion Cyclization Reactions

Novel tricyclic pyrimidine-fused 8-membered heterocycles were prepared by an iminium ion cyclization using pyrimidinediamine systems with electron-rich aromatic rings.

Oxidations ofN-(3-Indoleethyl) Cyclic Aliphatic Amines by Horseradish Peroxidase: The Indole Ring Binds to the Enzyme and Mediates Electron-Transfer Amine Oxidation

Although oxidations of aromatic amines by horseradish peroxidase (HRP) are well-known, typical aliphatic amines are not substrates of HRP. In this study, the reactions of N-benzyl and N-methyl cyclic amines with HRP were found to be slow, but reactions of N-(3-indoleethyl) cyclic amines were 2-3 orders of magnitude faster. Analyses of pH-rate profiles revealed a dominant contribution to reaction by the amine-free base forms, the only species found to bind to the enzyme. A metabolic study on a family of congeneric N-(3-indoleethyl) cyclic amines indicated competition between amine and indole oxidation pathways. Amine oxidation dominated for the seven- and eight-membered azacycles, where ring size supports the change in hybridization from sp3 to sp2 that occurs upon one-electron amine nitrogen oxidation, whereas only indole oxidation was observed for the six-membered ring congener. Optical difference spectroscopic binding data and computational docking simulations suggest that all the arylalkylamine substrates bind to the enzyme through their aromatic termini with similar binding modes and binding affinities. Kinetic saturation was observed for a particularly soluble substrate, consistent with an obligatory role of an enzyme-substrate complexation preceding electron transfer. The significant rate enhancements seen for the indoleethylamine substrates suggest the ability of the bound indole ring to mediate what amounts to medium long-range electron-transfer oxidation of the tertiary amine center by the HRP oxidants. This is the first systematic investigation to document aliphatic amine oxidation by HRP at rates consistent with normal metabolic turnover, and the demonstration that this is facilitated by an auxiliary electron-rich aromatic ring.

Diarylated Imidazoles via Sequential Metal-Catalyzed Suzuki and C-H Activation Reactions

Reported is the synthesis of diarylated imidazoles via sequential Suzuki and Pd/Cu C-H activation reactions. Phase-transfer conditions were necessary to achieve synthetically useful results in the Suzuki reaction. Interestingly, no N-arylation products were observed. No attempt to combine the steps into a one-pot process was reported. Direct C-5 arylation of the imidazole itself was unsuccessful. The yields of each reaction are poor to reasonable and the ranges of Ar1 and Ar2 are modest with Ar2 containing electron-rich and electron-poor aromatic rings. Non-aryl coupling partners were not investigated. When Ar1 = (2-formyl-phenyl)boronic acid was used, only benzaldehyde was isolated from the reaction, undoubtedly due to protodeboronation.

Quantitative Study of Interactions between Oxygen Lone Pair and Aromatic Rings: Substituent Effect and the Importance of Closeness of Contact

Current models describe aromatic rings as polar groups based on the fact that benzene and hexafluorobenzene are known to have large and permanent quadrupole moments. This report describes a quantitative study of the interactions between oxygen lone pair and aromatic rings. We found that even electron-rich aromatic rings and oxygen lone pairs exhibit attractive interactions. Free energies of interactions are determined using the triptycene scaffold and the equilibrium constants were determined by low-temperature 1H NMR spectroscopy. An X-ray structure analysis for one of the model compounds confirms the close proximity between the oxygen and the center of the aromatic ring. Theoretical calculations at the MP2/aug-cc-pVTZ level corroborate the experimental results. The origin of attractive interactions was explored by using aromatic rings with a wide range of substituents. The interactions between an oxygen lone pair and an aromatic ring are attractive at van der Waals' distance even with electron-donating substituents. Electron-withdrawing groups increase the strength of the attractive interactions. The results from this study can be only partly rationalized by using the current models of aromatic system. Electrostatic-based models are consistent with the fact that stronger electron-withdrawing groups lead to stronger attractions, but fail to predict or rationalize the fact that weak attractions even exist between electron-rich arenes and oxygen lone pairs. The conclusion from this study is that aromatic rings cannot be treated as a simple quadrupolar functional group at van der Waals' distance. Dispersion forces and local dipole should also be considered.

Cyclometalated and Alkoxyphenyl-Substituted Palladium Imidazolin-2-ylidene Complexes. Synthetic, Structural, and Catalytic Studies

Some new N,N‘-bis(aryl)imidazolinium salts (3a−h), in which the N-aryl groups have one unsubstituted ortho position and alkyl (Me, Pri) or alkoxy (OMe, OPri) substitution at the other ortho and/or para positions, have been prepared. They were used for the synthesis of N-heterocyclic carbene complexes of palladium in which the N-heterocyclic carbene is attached to cyclometalated or electron-rich aromatic rings (4, 5, 11d,e). The reaction of Pd(tmed)(CH3)2 with the N-heterocyclic carbene generated from 3b and base gave the dimethyl complex 6, which quantitatively eliminated ethane to form the Pd(0) complex 7. The latter was converted to a new type of “pincer” complex (8) by facile cyclometalation of both aromatic groups of the N-heterocyclic carbene ligand. The activities of the new complexes 4 and 9d,e in the Heck reaction of aryl halides were compared. At higher temperatures the complexes 9d,e show low activity in the coupling of aryl chlorides.

Controlling Regioselectivity in Cyclization of Unsaturated Amidyl Radicals: 5-Exo Versus 6-Endo

Intramolecular cyclization of an amidyl radical onto an olefin provides an appealing method for the synthesis of lactams and other nitrogen-containing heterocycles. Here we conducted the first, systematic theoretical study on the regioselectivity in the cyclization of various types of pent-4-enamidyl radicals that carried synthetically relevant substituents. It was found that the cyclization of most of the substituted pent-4-enamidyl radicals produced the 5-exo products (gamma-lactams) almost exclusively. Marcus theory analysis showed the involvement of both the thermodynamic (stabilization of the starting double bond or the resulting radical center) and intrinsic (mainly steric effects) contributions in determining the 5-exo selectivity. Nonetheless, in two types of systems we found that the delta-lactams became the favored products through the 6-endo cyclization. In one of the systems an aromatic substituent was placed at the C4-position, whereas in the other system an electron-rich aromatic ring was incorporated into the pent-4-enamidyl radical backbone at the C2- and C3-positions. This unprecedented 6-endo mode of amidyl radical cyclization provided an interesting route for the preparation of mono- and bicyclic delta-lactams (pyridinones).

Fragmentation of Nitrone Triflates to 9-Membered Rings

A new fragmentative rearrangement of nitrone derivatives to form 9-membered rings is reported. The fragmentations are triggered when nitrones are treated with triflic anhydride; a C-C bond antiperiplanar to the cleaving N-O bond is activated either by an oxygen lone pair or by an electron-rich aromatic ring. In the former case, further cyclization of the 9-membered intermediate leads to a rearranged condensed ring system, but when triggered by arenes, 9-membered ring amides are isolated.

Synthesis of 2H-Benzopyran via Electrophilic Cyclization

A general synthesis of benzopyrans from propargylic aryl ethers triggered by electrophilic cyclization using inexpensive electrophiles such as I2, ICl and PhSeBr is reported. The reactions proceed under mild conditions tolerating a small range of substituents in both coupling partners. Starting propargylic ethers are conveniently available from phenols; the product benzopyrans incorporate a handle, R5 = I for further chemistry. The cyclization undoubtedly proceeds by the formation of iodonium or selenonium intermediates followed by electrophilic attack from the electron-rich aromatic ring. Interestingly, the cyclization occurs in a 6-endo-dig mode.

Nucleophilic Addition to a p-Benzyne Derived from an Enediyne: A New Mechanism for Halide Incorporation into Biomolecules

Biosynthesis of haloaromatics ordinarily occurs by electrophilic attack of an activated halogen species on an electron-rich aromatic ring. We now present the discovery of a new reaction whereby a nucleophilic halide anion can be attached even to an aromatic ring without activating substituents. We show that the enediyne cyclodeca-1,5-diyn-3-ene, in the presence of lithium halide and a weak acid, is converted to 1-halotetrahydronaphthalene. The kinetics are consistent with rate-limiting cyclization to a p-benzyne biradical that rapidly adds halide and is then protonated. This reaction has interesting mechanistic features and important implications for incorporation of halide into biomolecules.

Tuning the Polarization Along Linear Polyaromatic Strands for Rationally Inducing Mesomorphism in Lanthanide Nitrate Complexes

The opposite orientation of the ester spacers in the rodlike ligands L 4C12 (benzimidazole-OOC-phenyl) and L 5C12 (benzimidazole-COO-phenyl) drastically changes the electronic structure of the aromatic systems, without affecting their meridional tricoordination to trivalent lanthanides, Ln(III), and their thermotropic liquid crystalline (i.e., mesomorphic) behaviors. However, the rich mesomorphism exhibited by the complexes [Ln(L 4C12)(NO3)3] (Ln=La-Lu) vanishes in [Ln(L 5C12)(NO3)3], despite superimposable molecular structures and comparable photophysical properties. Density functional theory (DFT) and time-dependant DFT calculations performed in the gas phase show that the inversion of the ester spacers has considerable effects on the electronic structure and polarization of the aromatic groups along the strands, which control residual intermolecular interactions responsible for the formation of thermotropic liquid-crystalline phases. As a rule of thumb, an alternation of electron-poor and electron-rich aromatic rings favors intermolecular interactions between the rigid cores and consequently mesomorphism, a situation encountered for L 4C12, L 5C12, [Ln(L 4C12)(NO3)3], but not for [Ln(L 5C12)(NO3)3]. The intercalation of an additional electron-rich diphenol ring on going from [Ln(L 5C12)(NO3)3] to [Ln(L 6C12)(NO3)3] restores mesomorphism despite an unfavorable orientation of the ester spacers, in agreement with our simple predictive model.

A convenient and regioselective oxidative bromination of electron-rich aromatic rings using potassium bromide and benzyltriphenylphosphonium peroxymonosulfate under nearly neutral reaction conditions

Regioselective oxidative bromination of electron-rich aromatic rings has been studied using potassium bromide as a bromine source in the presence of benzyltriphenylphosphonium peroxymonosulfate as oxidant under nearly neutral reaction conditions. In most cases we obtained monobrominated derivatives regioselectively and in good to high yields without the aid of strong acids.

Oxaaza cyclophanes in the recognition of nucleotides. The role of oxygen and electron-rich aromatic rings

Dioxapolyaza cyclophanes derived from resorcinol and different polyamine chains have been studied in aqueous solution as abiotic receptors for nucleotides. The presence of the additional ethyleneoxy subunits is reflected in a higher basicity and in a significant increase in the log K values for the interaction with nucleotides relative to that of related polyazacyclophanes.

A Facile Method for Oxidation of Primary Alcohols to Carboxylic Acids and Its Application in Glycosaminoglycan Syntheses

A convenient two-step, one-pot procedure was developed for the conversion of primary alcohols to carboxylic acids. The alcohol was first treated with NaOCl and TEMPO under phase-transfer conditions, followed by NaClO2 oxidation in one pot. This reaction is applicable to a wide range of alcohols and the mild reaction conditions are compatible with many sensitive functional groups, including electron-rich aromatic rings, acid-labile isopropylidene ketal and glycosidic linkages, and oxidation-prone thioacetal, p-methoxybenzyl, and allyl moieties. Several glycosaminoglycans such as heparin, chondroitin, and hyaluronic acid oligosaccharides have been synthesized in high yields by using this new oxidation protocol.

Synthesis and SAR study of acridine, 2-methylquinoline and 2-phenylquinazoline analogues as anti-prion agents

Transmissible spongiform encephalopathies (TSEs) are thought to arise from aggregation of a protease resistant protein denoted PrP Sc, which is a misfolded isoform of the normal cellular prion protein PrP C. Using virtual high-throughput screening we have selected structures analogous to acridine, 2-methyquinoline and 2-phenylquinazoline as potential therapeutic candidates for the treatment of TSEs. From the synthesis and screening of constructed libraries we have shown that an electron-rich aromatic ring attached through an amine linker to the position para to the ring nitrogen is beneficial to both binding to PrP C and the suppression of PrP Sc accumulation for acridine and 2-methylquinoline analogues. 2-Phenylquinazoline analogues appear to utilise a different mode of action by binding at a different location and/or pose. We report IC 50s in the nanomolar range.

Synthesis and Structure Revision of Calyxin Natural Products

Tandem Prins cyclization and Friedel-Crafts reaction with an electron-rich aromatic ring were used to prepare the core structures of calyxin natural products. The proposed structure of epicalyxin F was prepared and shown to be incorrect. Several calyxin natural products, including calyxin F and L, were synthesized, and the structures were reassigned on the basis of NMR data and synthetic correlations.

Role of aromatic π-bridge on electron transport property in a donor–bridge–acceptor system: A computational study on frontier molecular orbitals

Density functional calculations are performed to analyze the conduction process through various aromatic bridges in a donor–bridge–acceptor molecular wire through frontier molecular orbital analysis. The systematic study on the molecular orbital populations shows that when five-membered hetero-aromatic rings (electron-rich aromatic rings) are inserted in the conduction path between the donor–acceptor complex, a large decrease in the potential barrier (PB) is observed as compared to the six-membered hetero-aromatic ring (electron-deficient aromatic ring) inserted molecular systems. In addition, the systematic variation of the PB with various donor/acceptor substitution and increasing the number of intervening bridging aromatic rings in these molecular systems clearly points out to a structure-property correlation which will be further helpful in designing new polymeric/oligomeric molecular wires.

Synthetic Studies toward Ecteinascidin 743

An efficient synthesis of a fully functionalized tetracycle (A-B-C-H) 7 containing a 1,4-bridged 10-membered lactone was developed. Phenolic aldol condensation between 2-methylsesamol (15) and Garner's aldehyde provided the protected amino diol 16, which was converted to free amine 11 in excellent yield. A Pictet-Spengler reaction between 11 and ethyl glyoxylate under carefully controlled conditions (LiCl, toluene, 1,1,1,3,3,3-hexafluoro-2-propanol, room temperature) provided the acid-sensitive tetrahydroisoquinoline (18) in high yield, which was converted to the amino alcohol 9. Enantioselective alkylation of a glycine template in the presence of a catalytic amount of chiral cinchonidium salt was the key step for the access of enantiomerically pure amino aldehyde 10. Union of the two fragments 9 and 10 via oxazolidine intermediate afforded amino nitrile 39, which upon esterification of the primary alcohol with (R)-N-(S-4,4',4' '-trimethoxyltrityl) Cys (42) afforded 43. Cyclization of 43 (1% trifluoroacetic acid in trifluoroethanol) provided compound 44 by a domino process involving (a) unmasking of the S-trimethoxytrityl group, (b) fragmentation of dioxane assisted by an electron-rich aromatic ring, and (c) formation of a 1,4-bridged 10-membered lactone via formation of a sulfide linkage. Treatment of 7, obtained in two steps from 44b, under acidic conditions (0.5% methyl sulfonic acid in acetonitrile) afforded the pentacyclic compound 51 via fragmentation of the 10-membered cyclic sulfide followed by an intramolecular Pictet-Spengler reaction.

Synthesis of Novel Triphenylene-Type Cations Containing Both Thiophene Rings and a Tropylium Ion Ring. Cyclohepta[e]thieno[2,3-g]benzodithiophenylium Ion and Cyclohepta[e]thieno[3,2-g]benzodithiophenylium Ion

An isomeric pair of cyclohepta[e]thieno[g]benzodithiophenylium ions has been synthesized by an intramolecular Friedel-Crafts type reaction of 2(3)-thienyl-3(2)-cycloheptatrienylthiophenes in a one-pot reaction. These are the isoelectronic cations of triphenylene having both electron-rich and electron-deficient aromatic rings, thiophene and tropylium ion, respectively, in place of phenyl rings.