The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 14. 14-methylbenzo[h]naphtho-[1′2′:4,5]thieno[2,3-c][1,6]naphthyridine

Benzo[h]naphtho[1′2′:4,5]thieno[2,3-c][1,6]naphthyridine, a novel polycyclic heterocyclic ring system, has been synthesized as the 14-methyl derivative 8 in four steps from known intermediates. The structure of 8 is supported by assignment of the proton and the protonated carbon atoms by 2D-nmr techniques (COSY and a carbon-hydrogen one-bond coupling experiment).     

Guanidinium-Type resonance stabilization and its biological implications. I. the guanidine and extended-guanidine series

An unusual type of π-electron delocalization in Y-shaped molecules related to guanidine and its protonated form, the guanidinium ion, has been studied by ab initio methods at the STO -3G and 3-21G levels. Results are reported for tautomeric, rotameric, and protonated forms of the oxygen-substituted guanidine series (urea, carbamic, and carbonic acids); “extended-guanidine” (aminomethylene guanidine) including pseudocyclic forms; and simple ring systems in which the extended-guanidine group is incorporated (3-amino-1,2,4-triazole, 2,4-diaminopyrimidine). Both the guanidine and guanidinium type stabilizations have been characterized in terms of a number of structural and energetic parameters: degree of single/double bond character from bond lengths and π-bond orders, electron distributions, and protonation energies. The major finding is that the structural and energetic properties of the isolated extended-guanidinium group resemble those of the group when incorporated within 6-membered heterocyclic or heterobicyclic rings, although the details vary with the nature of the ring and possibility of reinforcement or interference with the substructure resonance from overall ring delocalization. The implications for stabilization of the protonated forms of some biologically important pteridines is discussed.     

Theoretical study of some heterocyclic amines with applications to the chemistry of 9-amino-1,2,3,4-tetrahydroacridine

9-Amino-1,2,3,4-tetrahydroacridine (THA ), a potent cholinesterase inhibitor, was recently used in the treatment of Alzheimer's disease. On attempting to prepare a dihydropyridine ? pyridinium salt-based redox chemical delivery system (CDS ) to enhance brain delivery of THA , several of the practical synthetic challenges were examined by using a theoretical MO approach. The structures, reactivities and stability of THA , derivatives of THA and a model compound, 4-aminopyridine, a simple dibasic heterocyclic amine, were studied in the framework of the AM -1 approximation. The study included the possible protonated forms of THA and 4-aminopyridine. The calculated heats of formation showed that ring nitrogen protonated forms are more stable for both THA and 4-aminopyridine. The calculated heats of formation showed that ring nitrogen protonated forms are more stable for both THA and 4-aminopyridine, consistent with experimental results. Electron delocalization is responsible for the remarkable stability of these molecules and for the observed lack of reactivity of the amino group, both in the basic and protonated forms. The site of N-alkylation of the 9-nicotinamide derivative of THA (an intermediate in the synthesis of THA -CDS ) is controlled by electronic, thermodynamic, and steric factors.     

1‐Methyl‐1H‐imidazo[4,5‐f]quinolin‐6‐ium chloride monohydrate

The title compound, C₁₁H₁₀N₃⁺·Cl^?·H₂O, belongs to the N1‐methyl‐substituted imidazo­[4,5‐f]­quinoline family, in which the heterocyclic ring is protonated at the pyridine rather than at the imidazole N atom. The mol­ecule as a whole is almost exactly planar. The molecular structure has been compared with that of the 2‐amino analogue described in the literature, and it was found that the extra amino group of the latter is involved in conjugation with the adjacent double bond, i.e. the conjugation does not extend over the entire heterocyclic system. The cation of the title compound forms a strong hydrogen bond with the Cl^? anion and the anions are interconnected by the water solvent mol­ecule.     

NHC‐CAAC Heterodimers with Three Stable Oxidation States

The synthesis of N‐heterocyclic carbene (NHC)–cyclic (alkyl)(amino) carbene (CAAC) heterodimers is presented. As the free carbenes do not react together in solution, the synthetic approach involves the addition of a free NHC to a cyclic iminium salt, which results in the formation of the protonated heterodimer. Subsequent deprotonation leads to the isolation of the corresponding mixed Wanzlick dimers. One‐ and two‐electron oxidations of these triazaolefins result in the formation of stable cationic radicals and bis(cations), respectively, which have been isolated and fully characterized. Cyclic voltammetry, UV/Vis spectroscopy, spin density, and DFT calculations suggest that these heterodimers feature complementary electronic properties to tetrathiafulvalenes (TTFs).     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 2 . Benzo[h][1]benzothieno[2,3-c]quinoline and benzo[h][1]benzothieno[2,3-c]quinoline

The synthesis of two previously unknown unsubstituted heterocyclic ring systems namely, benzo[h][1]benzothieno[2,3-c]quinoline ( 6 ) and benzo[f][1]benzothieno[2,3-c]quinoline ( 12 ) is reported. These two novel ring systems have been assembled by photocyclization of the appropriate amides.     

Mutagenic heterocyclic nitrogen compounds related to protein pyrolysates. 1. Derivatives of dipyrido[1,2-a:3′,2′-d]imidazole

2-Amino-6-methyldipyrido[1,2-a:3′-2′-d]imidazole is one of the mutagenic principles of L-glutamic acid and casein pyrolysates. We prepared several isomeric amines of this compound, as well as their homologues methylated in different positions on the heterocyclic ring, either by nitration of the ring followed by reduction or from appropriate 4-azidodipyrido[1,2-a:3′,2′-d]imidazoles. The latter compounds, the heterocyclic ring itself and various functional derivatives (hydroxylated, carboxylated, hydrazinic) were synthesized from 2-aminoimidazo[1,2-a]pyridines via various reactions which are described herein.     

Studies in the heterocyclic series. XIX. Synthesis of 1,4-diazaphenothiazine and its benzo derivatives

1,4-Diazaphenothiazine, the parent compound of this heterocyclic ring has now been prepared from 2,3-dichloropyrazine and 2-aminothiophenol. Replacement of 2,3-dichloropyrazine with 2,3-dichloroquinoxaline and 2,3,6-trichloroquinoxaline led to the corresponding 1,4-diazabenzo[b]phenothiazine in good yields. Structural assignments were made by spectroscopic studies and by certain chemical transformations.     

Tautomeric conjugate acids of 2-aminopyrroles: effect of substituents, solvation and cosolute

The tautomeric preferences of the conjugated acids of 2-aminopyrrole derivatives have been examined both in the gas phase and in aqueous solution by using a combination of quantum mechanical, self-consistent reaction field and Monte Carlo–free-energy perturbation methods. The results show that the nature of substituents, the solvent and the presence of cosolute are relevant factors in modulating the relative stability between the tautomeric conjugate acids protonated at the heterocyclic ring and at the exocyclic amino nitrogen. Thus, attachment of electron-withdrawing groups to the ring, solvation in polar solvents, and the presence of negatively charged cosolutes tend to favor protonation at the exocyclic amino nitrogen. Nevertheless, none of these factors alone suffice to change the tautomeric preference for the ring-protonated forms. The results point out that the concerted occurrence of the three factors is necessary to shift the tautomeric preference towards the conjugated species protonated at the exocyclic nitrogen.Contribution to the Jacopo Tomasi Honorary Issue     

Studies on the synthesis of heterocyclic compounds. XVI. Cleavage of 1,3-benzodioxoles and -benzoxathioles by sodium iodide-acyl chloride

The cleavage reaction of ethereal and thioethereal bonds with sodium iodide and acyl chloride has been studied. In all the 1,3-benzodioxoles and -benzoxathioles studied, the opening of the heterocyclic ring with formation of 1,2-diacetoxybenzene or 2-hydroxythiophenol diacetic ester and gem-diiodoalkanes and iodoalkenes has been observed. The structure of newly prepared compounds has been determined by analytical and spectroscopic data or comparison with authentic samples.     

Ionic hydrogenation of benzofurans

Benzofurans are arranged in the order 2-methylbenzofuran > 3-methylbenzofuran > benzofuran with respect to the case with which they undergo ionic hydrogenation. Benzofuran and 2-methylbenzofuran are protonated in the 3 position of the heterocyclic ring, whereas 3-methylbenzofuran is protonated in the 2 position. Individual monodeuterated 2,3-dihydrobenzofurans can be obtained in high yields by ionic hydrogenation.     

Studies on the collision‐induced dissociation of adipoR agonists after electrospray ionization and their implementation in sports drug testing

AdipoR agonists are small, orally active molecules capable of mimicking the protein adiponectin, which represents an adipokine with antidiabetic and antiatherogenic effects. Two adiponectin receptors were reported in the literature referred to as adipoR1 and adipoR2. Activation of these receptors stimulates mitochondrial biogenesis and results in an improved oxidative metabolism (via adipoR1) and increased insulin sensitivity (via adipoR2). Hence, adipoR agonists are potentially performance enhancing substances and targets of proactive and preventive anti‐doping measures. In this study, two adipoR agonists termed AdipoRon and 112254 as well as two isotopically labeled internal standards (ISTDs) were synthesized in three‐step reactions. The products were fully characterized by nuclear magnetic resonance spectroscopy (NMR), mass spectrometry (MS) and density functional theory (DFT) computation. Collision‐induced dissociation pathways following electrospray ionization were suggested based on the determined elemental compositions of product ions, comparison to product ions derived from labeled analogs (ISTDs), H/D‐exchange experiments and the results of DFT calculations. The most abundant product ions were found at m/z 174, tentatively assigned to protonated 1‐benzyl‐1,2,3,4‐tetrahydropyridine for AdipoRon, and m/z 207, suggested as protonated 1‐(4‐methoxybenzyl)piperazine, for 112254. Notably, the loss of the heterocyclic ring (i.e. piperazine and piperidine, respectively) in a supposedly intramolecular elimination reaction was observed in both cases. A qualitative determination of both AdipoR agonists in human plasma was established and fully validated for doping control purposes. Validation items such as recovery (86–89%), specificity, linearity, lower limit of detection (1 ng/ml), intraday (3–18%) and interday (5–16%) precision as well as ion suppression or enhancement were determined. Based on these findings adipoR agonists can be implemented in sports drug testing procedures. Copyright © 2015 John Wiley & Sons, Ltd.     

Half-chair conformations of unsaturated heterocyclic compounds

The vicinal proton coupling constants were obtained for some 6-membered ring unsaturated heterocyclic compounds. The R values and ring dihedral angles were determined and found to be consistent with half-chair conformations. Relative to saturated heterocyclic compounds, the effect of the sulfur atom on ring puckering was attenuated. However, an increase in ring puckering resulted from the sulfone group and was attributed to torsional energy.     

Theoretical study of geometry and nucleophilicity of the exocyclic methylene in five-membered ring cyclic ketene acetals,neutral and protonated,containing pnictogen and chalcogen heteroatoms

A series of neutral and protonated five-membered ring cyclic ketene acetals have been examined computationally for any trends in nucleophilicity in the exocyclic methylene and for their ground state geometries. A total of 58 different species were examined, 29 neutral molecules and the corresponding 29 protonated species. The heteroatoms that were used in the heterocyclic ring were a combination of nitrogen, phosphorus, and arsenic from the pnictogen family and oxygen, sulfur, and selenium from the chalcogen family. All geometries were initially optimized at using density functional theory and all stationary points were confirmed to be either minima or transition states through vibrational analysis. All the geometries were consequentially optimized using Møller–Plesset second order perturbation theory with a polarized triple zeta basis set. The main focus of the study was the nucleophilicity of the exocyclic methylene carbon atom and its dependence on heteroatom substitution. As probes for nucleophilicity, the proton affinities of the neutral species, the bond lengths of the exocyclic double bond, and atomic charges were used. The study also resulted in some interesting molecular geometries.     

15N n.m.r.: Substituent effects on nitrogen chemical shifts in anilinium ions

¹⁵N chemical shifts were measured in a series of anilinium fluorosulfonate salts and compared with chemical shift data from a comparable series of ¹⁵N-enriched aniline derivatives. A smaller overall range of nitrogen chemical shifts was observed for the protonated aniline series compared with that for the unprotonated anilines and is attributed to the elimination of nitrogen lone pair delocalization in the former series. Further-more, it was found that the range of nitrogen chemical shifts in the protonated anilines is determined primarily by substituent electronic effects from the ortho ring position with almost negligible contributions from the para position.     

Acidity and alkylation of 4-phenyl-3,5-dihydroxypyrazole and its derivatives. C versus O and N alkylation

4-Phenyl-3,5-dihydroxypyrazole is a relatively strong acid, with a pKa of 3.70. The effect of substitution, both in the phenyl ring and on the heterocyclic ring, on the acidity was studied. Electron attracting groups on the phenyl group enhance the acidity. Selective replacement by an alkyl group of one or two of the heterocyclic hydrogens lowers the acidity. Meerwein reagent, as well as methyl iodide bring about alkylation on carbon, whereas diazomethane and diethyl sulfate do not. Michael addition proceeds through both carbon and nitrogen.     

Neighboring group participation in cyclodehydration. A regiospecific isoxazole synthesis

The regiospecific synthesis of isoxazoles 2, 11, 14 , and 15 is explained in terms of neighboring group participation of the ortho nitrogen of the heterocyclic ring in the cyclodehydration step.     

Ab initio study of mechanism of forming bis-heterocyclic compound with Si and Ge between dimethylsilylene germylidene (Me2Si=Ge:) and ethene

The mechanism of the cycloaddition reaction between singlet dimethylsilylene germylidene (Me₂Si=Ge:) and ethene has been investigated with the CCSD(T)//MP2/6-31G* method. From the potential energy profile, it could be predicted that the reaction has one dominant reaction pathway. The reaction rules presented is that the two reactants firstly form a Si-heterocyclic four-membered ring germylene through the [2+2] cycloaddition reaction. Due to the sp ³ hybridization of the Ge: atom in Si-heterocyclic four-membered ring germylene, the Si-heterocyclic four-membered ring germylene further combined with ethene to form a bis-heterocyclic product with Si and Ge (P2).     

13C, 14N, 15N and 17O NMR spectra of nitropyrroles and nitroimidazoles

Carbon, nitrogen and oxygen NMR spectra of some nitro derivatives of pyrrole and imidazole have been investigated. The ¹³C chemical shifts of para-carbons and the ¹⁷O chemical shifts of the nitro group correlate qualitatively with the electron densities on these carbon and oxygen atoms, which in turn depend upon the degree of conjugation of the nitro groups with the heterocyclic ring. Conjugation of several nitro groups with the benzene ring is in most cases not impaired by mutual interactions and the ¹³C shifts show good additivity. Such additivity is much worse in pyrrole and imidazole derivatives. Taken together with the diamagnetic nature of these deviations from additivity, this leads to a possible conclusion about the less pronounced conjugation of the nitro groups with the heterocyclic ring in heterocyclic dinitro derivatives.     

Hétérocyclisation intramoléculaire par réaction d'oxymercuration. II. Oxymercuration intramolécuxlaire des allyl-2 cyclohexanols cis et trans

The intramolecular oxymercuration of two isomeric 2-allyl-cyelohexanols, has been realized with different mercuric salts. The reaction is always regiospecific, but not stereoselective, and leads to five membered mercurated heterocyclic. The reduction of organomercury compounds obtained from trans-2-allylcyclo-hexanol leads, in some cases, to a ring rearrangement, that permit us to obtain from the trans cyclised product, under different conditions either pyran or furan compounds.