A six-step synthesis of (S)-5-ethenyl-3-(1-methyl-2-pyrrolidinyl)pyridine (SIB-1508Y) from (S)-nicotine

The anti-Parkinson’s agent SIB-1508Y was prepared in six steps from (S)-nicotine in 20% overall yield. The strategy involves a regioselective formylation at C-5 of a 1,4-dihydronicotine intermediate.     

A new convenient method for the synthesis of 2H‐1,4‐benzoxazine derivatives from nitroketones via intramolecular reductive cyclization

Dedicated to Professor Herbert C. Brown on the occasion of his 90^th birthday. Potentially bioactive 2H‐1,4‐benzoxazine derivatives could be conveniently prepared in one step from the corresponding nitroketones using 10% palladium on carbon with triethylamine in the presence of hydrogen (Pd/C‐TEA‐H₂) system. Several other tertiary amines such as nicotine, pyridine, and quinoline also could be used, but TEA gave the best results.     

1,4-二氢吡啶衍生物与DNA相互作用的电化学与圆二色谱研究

用电化学和圆二色谱(CD)技术研究了5个1,4-二氢吡啶(1,4-DHP)衍生物与小牛胸腺DNA(CT-DNA)的相互作用.结果表明,1,4-DHP衍生物与CT-DNA相互作用是通过嵌入的方式进行的,相互作用的强弱与1,4-DHP衍生物的立体结构有关.1,4-DHP衍生物4-取代基空间位阻越小,嵌入到CT-DNA的程度越大.相反,空间位阻较大的1,4-DHP衍生物嵌入CT-DNA程度较小.非平面结构的1,4-DHP衍生物使CT-DNA双螺旋链结构松散程度增大.     

Poly(diacetylene)-nanofibers can be fabricated through photo-irradiation using natural polysaccharide schizophyllan as a one-dimensional mold

Schizophyllan interacts with various 1,4-diphenylbutadiyne derivatives to induce their chirally-twisted packing. A series of referential experiments using other polysaccharides (amylose, pullulan, dextran, etc.) and a carbohydrate-appended detergent (dodecyl-beta-d-glucopyranoside) indicates that these 1,4-diphenylbutadiyne derivatives are accommodated within a tubular cavity constructed by a helical superstructure of schizophyllan. In these 1,4-diphenylbutadiyne derivatives, 1,4-bis(p-propionamidophenyl)butadiyne can be easily polymerized through UV-irradiation, in which schizophyllan acts as a one-dimensional mold to produce the corresponding poly(diacetylene)s with fibrous morphologies. Detailed investigations on this unique approach to prepare the nanofibers revealed that it includes two individual processes, that is, 1) UV-mediated polymerization of encapsulated 1,4-bis(p-propionamidophenyl)butadiyne to produce immature nanofibers and 2) their reorganization through hydrophobic interfiber interactions into ordered nanofibers. The other 1,4-diphenylbutadiyne derivatives could not be polymerized through UV-irradiation, indicating that the p-propionamido-functionalities play substantial roles for a suitable packing of the monomer for the polymerization. The other 1,4-diphenylbutadiyne derivatives, however, can be also polymerized through gamma-ray irradiation in the presence of schizophyllan to give the corresponding poly(diacetylene)-nanofibers, emphasizing the wide applicability of the schizophyllan-based strategy for polymerization of various 1,4-diphenylbutadiyne derivatives.     

Synthetic Methods for the Preparation of Conformationally Restricted Analogues of Nicotine

In the context of naturally occurring nitrogen heterocycles, nicotine is a chiral alkaloid present in tobacco plants, which can target and stimulate nicotinic acetylcholine receptors (nAChRs), a class of ligand-gated ion channels commonly located throughout the human brain. Due to its well-known toxicity for humans, there is considerable interest in the development of synthetic analogues; in particular, conformationally restricted analogues of nicotine have emerged as promising drug molecules for selective nAChR-targeting ligands. In the present mini-review, we will describe the synthesis of the conformationally restricted analogues of nicotine involving one or more catalytic processes. In particular, we will follow a systematic approach as a function of the heteroarene structure, considering: (a) 2,3-annulated tricyclic derivatives; (b) 3,4-annulated tricyclic derivatives; (c) tetracyclic derivatives; and (d) other polycyclic derivatives. For each of them we will also consider, when carried out, biological studies on their activity for specific nAChR subunits.     

Chiral NADH model systems functionalized with Zn(II)-cyclen as flavin binding site

A series of chiral peptides has been prepared, bearing a 1,4-dihydronicotine amide and a zinc cyclen moiety. The metal complex reversibly binds flavins in aqueous solution, while the dihydronicotine amide serves as a NADH model transferring a hydride to the flavin within the assembly. The reaction rate of the redox reaction was monitored and determined by UV spectroscopy. The reaction rates of the substituted compounds were slower if compared to the non-substituted parent compound 1-H, but still show a 30-100 fold rate enhancement compared to the compound missing a flavin binding site. It was anticipated to probe the cryptic stereoselectivity of the hydride transfer from dihydropyridine to flavin. Spectroscopic data indicate that the introduction of deuterium labels upon reduction of the pyridinium salts to 1,4-dihydropyridine in D₂O proceeds diastereoselectively, but identical isotope effects on the rate of flavin reduction as with a non-chiral NADH model revealed that the hydride transfer within the assembly proceeds not stereoselective. A more rigid chiral NADH model compound must be prepared to achieve this goal.     

Supramolecular adsorption of alkaloids by metallosalphen complexes

Mono and bis-zinc(II)-centered salphen derivatives 1-5 are presented as efficient adsorption materials for pyridine-based alkaloid derivatives. The different alkaloid assemblies were studied by UV-vis and NMR spectroscopy, and high binding constants (Ks approximately 10(5)) were additionally determined for the supramolecular complexes based on nicotine. X-ray analyses furthermore revealed, together with spectroscopic solution data, a preferential positioning of the nicotine guest(s). Upon binding to bis-Zn(II)-bis-salphen complexes, the dinicotine assembly provokes a colorimetric change that may be useful for colorimetric analyses. The adsorption/desorption process of nicotine was studied using a polymeric bis-Zn(salphen) complex (5) and showed a recycling potential of this type of complexes in the binding of alkaloid compounds.     

Synthesis of C-4 substituted nicotine derivatives via an N-acylpyridinium salt of (S)-nicotine

[reaction: see text] A variety of novel nicotine derivatives were prepared from (S)-nicotine via a two-step sequence. Addition of a cuprate reagent to an N-acylpyridinium salt of nicotine, followed by aromatization with elemental sulfur, afforded C-4 substituted nicotines in moderate to high yield. Using this method, 4-(dimethylphenylsilyl)nicotine was prepared and oxidized to afford (S)-4-hydroxynicotine.     

Adsorption behavior of nicotine on periodic mesoporous organosilicas

In this study, we focused on the adsorption of nicotine from aqueous solution such as water and simulated body fluids (SBFs), where SBF has ion concentrations approximately equal to those of human blood plasma. We prepared periodic mesoporous organosilica (PMO) materials as adsorbents from 4,4-bis(triethoxysilyl)biphenyl (BTES-biphenyl), 1,4-bis(triethoxysilyl)benzene (BTES-benzene) and bis[3-(trimethoxy silyl)propyl]amine (BTMS-amine) as precursors and investigated on their adsorption behavior of nicotine as a guest material under different solvent conditions. For this work, two different kinds of SBF, c-SBF and r-SBF, have been chosen, where c-SBF is a transitional SBF solution, and r-SBF is a modified SBF solution that is closer to human blood plasma. Adsorption of nicotine on PMOs has been characterized by a UV-Vis spectroscopy. The adsorption behavior was strongly dependent on the isoelectric point and hydrophobicity of the PMO as well as the hydrophobicity of nicotine.     

Utilisation of electrospray time-of-flight mass spectrometry for solving complex fragmentation patterns: application to benzoxazinone derivatives

In this paper we describe the application of electrospray time-of-flight mass spectrometry (ESI-TOFMS) to structural elucidation of the fragment ions formed from a range of natural and synthetic allelochemical derivatives. The extensive mass spectrometric characterisation of ten non-glucosylated benzoxazinone derivatives using this method is described here for the first time. The analytes include six naturally occurring 1,4-benzoxazin-3(4H)-one derivatives, including the hydroxamic acids DIMBOA [2,4-dihydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one] and DIBOA [2,4-dihydroxy-2H-1,4-benzoxazin-3(4H)-one], lactams HBOA [2-hydroxy-2H-1,4-benzoxazin-3(4H)-one] and HMBOA [2-hydroxy-7-methoxy-2H-1,4-benzoxazin-3(4H)-one], benzoxazolinones BOA [benzoxazolin-2(3H)-one] and MBOA [6-methoxy-benzoxazolin-2(3H)-one] and four synthetic variations, 2'H-DIBOA [4-hydroxy-2H-1,4-benzoxazin-3(4H)-one], 2'OMe-DIBOA [2-methoxy-4-hydroxy-2H-1,4-benzoxazin-3(4H)-one], 2'H-HBOA [2H-1,4-benzoxazin-3(4H)-one] and 2'OMe-HBOA [2-methoxy-2H-1,4-benzoxazin-3(4H)-one]. Assignments of the mass spectral fragments were aided by elemental composition calculation results, comparison of structural analogues and background literature, and acquired knowledge regarding feasible structures for the compounds. The influence of substituents on the chemical reactivity of the compounds with respect to the observed MS behaviour over varying nozzle potentials is addressed and, through comparison of the structural analogues, generic fragmentation patterns have also been identified.     

Reaction of thiosalicylic acid with 1,4-quinones and cyclization of the resulting arylsulfanylbenzoic acids

Thiosalicylic acid reacts with 1,4-benzoquinone to give 2-(1,4-dihydroxyphenylsulfanyl)benzoic acid which undergoes intramolecular cyclization to 1,4-dihydroxythioxanthen-9-one in the presence of dehydrating agents. Cyclization of arylsulfanylbenzoic acids obtained by reaction of thiosalicylic acid with 1,4-naphtho- and anthraquinones leads to 1,4-quinone derivatives, benzo- and naphthothioxanthenetriones.     

Reactions of substituted (1,3-butadiene-1,4-diyl)magnesium, 1,4-bis(bromomagnesio)butadienes and 1,4-dilithiobutadienes with ketones, aldehydes and PhNO to yield cyclopentadiene derivatives and N-Ph pyrroles by cyclodialkenylation

1,4-Dilithiobutadiene derivatives 1, 1,4-bis(bromomagnesio)butadiene derivatives 2 and metallacyclic (1,3-butadiene-1,4-diyl)magnesium reagents 3 were prepared and their reactions with ketones, aldehydes, and PhNO were investigated. Multiply substituted cyclopentadienes and N-Ph pyrroles were formed by unprecedented reaction conditions. The carbonyl group of aldehydes and ketones was deoxygenated during the reaction and behaved formally as a one-carbon unit; the N==O moiety of PhNO was cleaved to afford N-Ph pyrrole derivatives. Furthermore, different reactivities among these three types of reagents 1, 2 and 3 were revealed. The 1,4-dilithium reagents 1 readily reacted with both aldehydes and ketones; the 1,4-dimagnesium reagents 2 reacted with aldehydes, but not ketones; the metallacyclopentadiene reagents of magnesium 3 showed higher reactivity and did react with ketones.     

4,4-Dimethyl-1,4-thiasilinane and Its S-Functional Derivatives

Synthetic approaches to 4,4-dimethyl-1,4-thiasilinane and its S-functional derivatives, 4,4-dimethyl-1,4-thiasilinane S-oxide, 4,4-dimethyl-1,4-thiasilinane S,S-dioxide, 4,4-dimethyl- 1-(phenylsulfonylimino)-1,4-thiasilinane, and 1,4,4-trimethyl-1,4-thiasilinan-1-ylium iodide, were studied. The S-functional derivatives of 4,4-dimethyl-4-thiasilinane, unlike 3,3-dimethyl-3-thiasilinane, are hydrolytically stable.     

Quantum-Chemical Study of Electronic Structure and Reactivity of Diphospha-1,3-Butadienes

Abstract

Quantum-chemical calculations of the electronic structure of 1,3-, 1,4- and 2,3-diphospha-1,3-butadienes (DPB) and their derivatives with different substituents were performed. The MNDO method was used to describe the electronic structure of phosphaalkenes. The frontier orbitals of all unsubstituted DPB are of π-type. The highest occupied molecular orbital (HOMO) is delocalized through both double phosphorus-carbon bonds; the next occupied MO is a combination of two phosphorus lone pairs (n-MO). The HOMO of 2,3-DPB differs markedly from those of 1,3- and 1,4-isomers: the contributions of phosphorus and carbon p-orbitals are nearly equal, and the energy gap between HOMO and n-MO is very small (0.008 eV). The introduction of the electron-withdrawing substituents results in the reverse order of these MO's. In contrast with 1,3- and 1,4-isomers, the double bonds of 2,3-DPB are almost non-polar. Effect of substituents upon the electron density distribution are considered. The results indicate that orbitally controlled 1,4-additions should be characteristic for the derivatives of 1,3- and 1,4-DPB, similar to 1,3-butadiene. In case of 2,3-DPB, tendency to 1,4-addition should be lower; for its derivatives the reaction type depends greatly upon the electronic effects of substituents. In particular, reactions involving phosphorus lone pairs should be typical for the derivatives of 2,3-DPB with electron-withdrawing substituents.     

Reductive ability of 1,4-dihydropyridine derivatives in relation to ions of trivalent iron

3,5-Dicarbonyl derivatives of 2,6-dimethyl-1,4-dihydropyridine (1,4-DHP) can reduce Fe³⁺ to Fe²⁺ depending on the nature of the substituents at position 4 and in the 3,5-ester group. This ability is less pronounced for the 1,4-DHP derivatives investigated than for ascorbic acid, but among derivatives possessing antioxidant activity it is less than that of the known antioxidants ionol (BOT) and trolox. Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 661–663, May, 1999.     

Reaction of (2-amino-5,10,15,20-tetraphenylporphyrinato)nickel(II) with quinones

(2-Amino-5,10,15,20-tetraphenylporphyrinato)nickel(II) reacts with 1,4-benzoquinone, 1,4-naphthoquinone and 2-hydroxy-1,4-naphthoquinone, in the presence of a catalytic amount of sulfuric acid, to afford new porphyrin-quinone dyads and π-extended heterocyclic-fused porphyrin derivatives.     

Synthesis of substituted 1,4-diazepines and 1,5-benzodiazepines using an efficient heteropolyacid-catalyzed procedure

An efficient and improved procedure for the synthesis of 1,4-diazepine and 1,5-benzodiazepine derivatives via the reaction of ketimine intermediates with aldehydes in the presence of Keggin-type heteropolyacids (HPAs) was developed. High yields and short reaction times were obtained for both electron-releasing and electron-withdrawing substituted 1,4-diazepine and 1,5-benzodiazepines derivatives.     

Three-component cascade reaction synthesis of polycyclic 1,4-dihydropyridine derivatives in water

An efficient and straightforward synthesis of polycyclic 1,4-dihydropyridine derivatives has been developed by reacting heterocyclic ketene aminals (HKAs) with 1,3-cyclohexanedione derivatives and a number of substituted salicylaldehyde, respectively, via three-component cascade reactions in water. This strategy provides an efficient and environmentally friendly approach for easy access to various new fused polycyclic 1,4-dihydropyridine derivatives without the need of organic solvents in moderate to good yields.     

Novel 1,4-benzothiazine derivatives: synthesis,crystal structure,and anti-bacterial properties

In order to develop relatively small molecules as pharmacologically active molecules, novel 1,4-benzothiazine derivatives with triazole and oxazolidinone were synthesized. In this study, a series of 1,2,3-triazolylmethyl-1,4-benzothiazine derivatives were developed by exploiting a click chemistry reaction using a CuI-catalyzed Huisgen [3 + 2] cycloaddition. Starting from 2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one, a number of 1,4-benzothiazine derivatives were also synthesized using different alkylating agents to give a 4-(substituted)-2-(substituted)-3,4-dihydro-2H-1,4-benzothiazi-3-one in good yields. The crystal and molecular structure of compound oxazolidin-2-one in basic benzothiazine was established by single-crystal X-ray diffraction. The newly synthesized products were subjected to in vitro biological evaluation. The result indicated that the compounds show convincing antibacterial activities against different microorganisms. All structures of the synthesized compounds were elucidated on the basis of spectral analyses and chemical reactions.     

Heterocycles containing nitrogen and sulfur. Part 49. Synthesis of derivatives of new heterocyclic systems: 1,2-Dioxocyclopenta(hexa)[g]oxazolidino-[3,2-f] pyrimido[4,5-b][1,4]thiazine, 1,2-dioxocyclopenta(hexa)-[g] imidazolidino[3,2-f]pyrimido[4,5-b][1,4]thiazine, and 1,2-oxazino[5,4-g]pyrimidino[4,5-b][1,4]thiazine

The reaction of 4-methoxy-5-amino-6-mercaptopyrimidine with 2-oxo-1-chlorocyclopentyl(hexyl)glyoxalate esters gave derivatives of the previously unknown tetracyclic systems 1,2-dioxocyclopenta (hexa)[g]oxazolidino[3,2-f]pyrimido[4,5-b][1,4]thiazines, which are transformed by ammonium acetate into derivatives of 1,2-dioxocyclopenta(hexa) [g]imidazolidino[3,2-f]pyrimido[4,5-b]-[1,4] thiazines. Derivatives of the new tricyclic 1-oxazino [5,4-g]pyrimido[4,5-b][1,4]thiazine system were obrtained by reaction of 6-carbethoxy-7-acetylpyrimido [4,5-b] [1,4] thiazines with hydroxylamine.