10^th European Organic Chemistry Congress March 21-22, 2019 Hotel Holiday Inn, Aurelia Rome, Italy

Geranyl acetate (1) was epoxidated thermally and photochemically using (mcpba, H2O2) respectively to produce mixture of (E)-5-(3,3-dimethyloxiran-2-yl)-3-methylpent-2-enyl acetate and 3-(2-(3, 3-dimethyloxiran-2-yl) ethyl) -3-methyloxiran-2-yl) methyl acetate (3) thermally. While produced epoxide (3) only photochemically. On the other hand, photooxygenation of (1) using tetraphenyl porphin (TPP) as photo sensitizer gave three hydroperoxide derivatives of Acitic acid 2,6-bis-hydroperoxy-7-methyl-3-methylene-oct-7-enyl-ester (4), Acitic acid 7-hydroperoxy-3,7-dimethyl-octa-2,5- dienyl ester (5) and Acitic acid 3-hydroperoxy-7-methyl-3,7-dimethyl-octa-1,6-dienyl ester (6). Studies on the antifungal activity especially Microsporum gypsum and Trichophyton vercossum showed that geranyl acetate, its epoxides and hydroperoxides derivatives have good antifungal action.

Basim H Asghar has completed her Bsc in Chemistry at Umm Al-Qura Uinversity Makkah, Saudi Arabia in 2000 and PhD in Physical Organic Chemistry at Durham University, UK in 2006. Currently, he is a Professor of Physical Organic Chemistry. His research interests focus on kinetic and mechanistic studies of reactions in solution. Thus, in addition to conventional UV/visible spectrophotometers. The work also involves some organic synthesis and the use of NMR spectroscopy. He has published more than 40 research articles in international indexed and refereed journals.

Much interest has been paid to the design of aromatic and hetero aromatic electron-deficient structures exhibiting a high reactivity in nucleophilic aromatic substitutions and related complex formation processes. Annelation of a nitro-substituted phenyl ring by intrinsically electron-withdrawing five-membered rings such as a furoxan ring has proved to be a nice entry to a variety of electron-deficient hetero aromatic structures which exhibit strong electrophilic behavior. Currently, there is a considerable interest in the quantitative measurement of nucleophilic and electrophilic reactivities, particularly in carbon-carbon and carbon-nitrogen bond forming reactions. Mayr and coworkers have used the reactions involving a series of benzhydryl cations to assess the nucleophilicities of carbanions stabilized by acyl, ester, cyano, and nitro groups. The ability to carry out the reactions has led to the conclusion that 4,6-dinitrobenzofuroxan (DNBF) can be a suitable probe to assess the reactivity of weakly nucleophilic carbon or nitrogen centers in general. In this work we present the quantitative assessment of the nucleophilic character of hetero aromatic amines through a kinetic study on the reactions of DNBF with five heterocyclic amines: 2-aminothiazole 2a, 2-aminobenzothiazole 2b, 2-amino-5-trifluoromethyl-1, 3, 4-thiadiazole 2c, 5-amino-3, 4-dimethylisoxazole 2d, and 2-aminopyrimidine 2e.

Máté J. Vajda has graduated in 2017 at Semmelweis University, Hungary as a pharmacist. He’s currently a PhD Student at the Department of Pharmaceutical Chemistry of Semmelweis University. He’s research field is opioid chemistry, especially research and development of novel analgesics with interesting and clinically relevant pharmacological profile. His work has been awarded at the Hungarian Scientific Days in 2018. Beside scientific work, he also works in pharmacies in his hometown.

Introduction: Opioids are generally used in medicine as the most potent analgesics. Besides their ability to relieve pain, the currently used analgesics have serious side-effects such as respiratory depression, constipation, development of tolerance, physical dependence and addiction liabilities. It is also well known that modulation of the endogen opioid system plays a key role in psychological and behavioral responses, such as feeling of content, motivation and positive reinforcement (reward). One possible approach in developing agents which possess potent analgesic properties without the undesired side-effects is to create compounds with mixed receptor binding profile. It has been proven that DOR agonists can significantly increase the efficacy of MOR agonists, thus the effective dose can be significantly lowered. DOR antagonists can prevent or diminish the development of tolerance and physical dependence by MOR agonists. Based on several previous reports of heterocycle-fused morphinan compounds through the C-ring (emphasizing oxymorphazole, an oxymorphone derived 6,7:3’,4’-pyrazolomorphinan), a great number of them shows the desired receptor binding profiles as described. Aims: Our goal in the first part of work is the synthesis of a series of substituted oxycodone, oxymorphone and hydrocodone derived pyrazolo- and isoxazolomorphinans, structural characterization with NMR spectroscopy and in vitro biological evaluation through opioid receptor binding assays. Later we are planning to synthesize the compound series with antagonist starting materials, like naloxone and naltrexone. Method: For the building of unsubstituted pyrazolo- and isoxazolomorphinan skeletons, we utilized N,N-dimethylformamide dimethyl acetal, a one carbon atom building block commonly used in heterocyclic chemistry, to synthesize 7-(N,N-dimethylaminomethylene)morphinan intermediates. For substituted compounds we synthetized 14-O-acylated compounds using acetyl, propionyl- and benzoyl-anhydride, and used the 14-O → 7-C acyl migration method reported by Nagase and Portoghese (1990) to create the 1,3-dioxo intermediates. The initial purity examination was carried out using thin-layer chromatography, for full structural evaluation and confirmation Varian 600 MHz NMR Spectometer was used for the recording of 1H, 13C, g-HMBCAD and g-HSQCAD spectra, as well as mass spectrometry. Results: So far by the date of the abstract submission 15 end product have been synthesized with high purity out of the planed 18. Conclusion: As the work is not finished yet, biological data is not yet available about the synthetized products, although based on similar structural moieties of previously reported compounds it is likely that some of our molecules may exhibit the desired receptor binding profile and may be a valuable compounds for opioid drug design with better side-effect profile.

Istvan Koteles has obtained his Graduation at the Semmelweis University in the Faculty of Pharmacy in 2015. He has participated at the Student’s Scientific Conference for three years and has achieved 3rd place twice and 1st place once with the topic “Synthesis of morphine hapten derivatives” supervised by Sandor Hosztafi a Senior Research Fellow. He is pursuing his PhD at the Institute of Pharmaceutical Chemistry and working as an Instructor of the Hungarian and English laboratory practices for the graduate level students.

Drugs of abuse are small molecules that typically do not induce an antibody response following injection or inhalation. To induce antibodies against small molecules, structural surrogates of the molecules, which were named “haptens”, must be coupled to immunogenic proteins, called “carriers”. These structural surrogates are typically drug-linker adducts, in which the linker has a terminal functional group that forms a covalent bond with the carrier. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. We have designed two methods for the synthesis of these haptens: At the start of our experiments after the synthesis of the specific esters we hydrolyzed them to receive the N-carboxymethyl- and N-carboxyethyl-normorphine derivatives. The next step was the coupling phase with glycine ethyl ester, but the reactions didn’t work or the work-up process was unaccomplishable. As an alternative route the normorphine-compounds were reacted with N-chloroacetyl glycine ethyl ester. After column chromatography purification the structures of the new compounds were elucidated by NMR and mass spectroscopy. N-Alkylation of 4, 5-epoxy-normorphinans was achieved by the reaction with alkyl bromides which contain a protected amino group. In our research project we used N-(2-bromoethyl)-phthalimide and N-(3-bromopropyl)-phthalimide in dimethylformamide to N-alkylate the normorphine derivatives, in the presence of sodium hydrogen carbonate. After column chromatography purification boiling with hydrazine in ethanol the protecting group can be removed, and the results are N-beta-amino ethyl and N-gamma-aminopropyl-nor compounds. The structures were elucidated by NMR and mass spectroscopy as previously. At the current state of research we are going to send the samples for biological and animal experiments to screen opioid activity.

Dr. Mihail Lucian Birsa is currently a Professor in the Department of Chemistry at the Alexandru Ioan Cuza University of Iasi, Romania. He received a Bachelor of Science degree in Chemistry from the same university in 1995. He joined the master program at Alexandru Ioan Cuza University of Iasi in 1995, and in 2000 was awarded a Ph. D. degree in Organic Chemistry. From 2000 to 2002, he was a postdoctoral fellow under the mentorship of Professor Samuel Braverman at Bar-Ilan University, Israel. In 2003 he was selected as a member of the Alexander von Humboldt Foundation, working with Professor Henning Hopf in TU Braunschweig - Germany. Since then numerous return fellowships were granted by the Alexander von Humboldt Foundation.

The synthesis of new 3-dithiocarbamic flavonoids has been accomplished by the reaction of the corresponding 2-hydroxyaryl dithiocarbamates with aminals. These flavonoids were obtained as a mixture of diastereoisomers, the anti isomer being the major one. The heterocyclization of these compounds provided a little known class of tricyclic flavonoids bearing a 1,3-dithiolium-2-yl ring fused at the 3,4-carbon positions of the benzopyran moiety. Sulfur containing flavanones and tricyclic flavonoids were tested for antibacterial activity against Staphylococcus aureus ATCC 25923 (Gram-positive) and Escherichia coli ATCC 25922 (Gram-negative), using disc diffusion assay with gentamicin as reference and minimum inhibitory concentrations were determined where activity was found present.1-4 While the tested flavanones did not yield the desired results, good antibacterial activities were recorded for the tricyclic flavonoids. The introduction of the 1,3-dithiolium cation produced results comparable to those of gentamicin and in some cases, MIC values were less than 1g/ml. The ion-dissociation vs. formation of a tight ionpair appears to be of significant importance on how cationic tricyclic flavonoids interact with bacteria. The major component of bacterial cell wall is represented by negatively charged phosphatidylethanolamine (70%). Thus, the positively charged 1,3-dithiolium flavonoids target the oppositely charged biological structures such as cell walls of microorganisms which leads to the leakage of intracellular substances.5

Laura G Sarbu is an Organic Synthetic Chemist. During her doctoral research, she was working on [2.2]paracyclophane chemistry. She is currently affiliated to the Alexandru Ioan Cuza University of Iasi, Romania.

2.2]Paracyclophanes ([2.2] PC) constitute an intriguing class of compounds, which have attracted a growing interest ever since their first appearance in the literature in 1949. Their molecules consist of two benzene rings arranged in two planes, one above the other in a sandwich manner, bridged by two ethanol bridges in the para positions of the benzene rings. Interesting properties derive from the dual character of cyclophanes. The cyclophane chemistry is a rapidly evolving field, as shown, inter alia, by the recent monograph of Gleiter and Hopf, which describes the use of cyclophanes in stereoselective synthesis and their incorporation into more complex molecular frameworks, such as heterocycles and polymers. Because of the rigid molecular framework provided by the paracyclophane moiety and its short interannular distance, recent studies regarding the electronic properties of these compounds suggest possible applications in charge-transfer complexes formation and polymers synthesis. The introduction of a TTF moiety into the [2.2] PC framework, the main topic of the present application, is worth investigating, as it might enhance the ability of the TTF to act as an electron-donor. Moreover, these new molecules could be used to synthesize new charge transfer complexes. A recent study presents the synthesis, electrochemical properties, as well as the ability of a [2.2] PC derivative which contains TTF units in the 4, 12 (pseudo-ortho) positions to function as a chiral dopant. Moreover, molecules with orthogonally incorporated 1, 3-dithiol-2-ylidene units to [3.3] paracyclophane are known to play an important role in intramolecular charge transfer. The synthesis of new [2.2] paracyclophanes linked with one or more tetrathiafulvalene donor units as simple, multilayered or π-extended systems is presented.

Małgorzata Bołt is a graduate student in Adam Mickiewicz University in Poznan and she is preparing her master thesis in the Department of Organometallic Chemistry in the Faculty of Chemistry. Her current research interests focuses on synthesis of transition metal catalysts and use obtained compounds in catalytic systems such as hydrosilylation and terminal acetylenes dimerization. Her current research concerns mainly on platinum(0) catalysts bearing bulky N-heterocyclic carbene ligands. Steric hindrance around metal center caused by the presence of the bulky ligand have a great influence on activity and selectivity in the studied reactions.

Hydrosilylation, which usually refers to addition of silanes to double or triple C-C bounds, is one of the most powerful synthetic methods of production organosilicon compounds (Figure 1). This reaction gives possibility for simple functionalization of many organic compounds and for synthesis wide spectrum of silanes derivatives. Although there are many different catalytic systems characterized by good activity, regio- and stereoselectivity still remains as a great problem of this process. The reaction can lead to a several different products and can also be accompanied by several side-processes like hydrogenation, isomerization, dehydrogenative silylation, olefin oligomerization or redistribution of silanes. The number of potential products increases when we use secondary silanes instead of tertiary, because of the possibility of bis-hydrosilylation. The situation gets also more complicated when we use substrates containing more functionalities which can react, for example enynes, dienes or diynes. Presented research deals with the problem of selectivity of the hydrosilylation reaction. Using platinum (0) complex bearing bulky N-heterocyclic carbene ligand and by careful tuning of the reaction conditions such as temperature and substrates ratio, we were able to control course of the reaction and obtain desired products with good yields and selectivity. The research concern hydrosilylation of terminal acetylenes with disubstituted silanes as well as hydrosilylation of dienes, diynes and enynes with trisubstituted silanes.

Milan Potáček is working in heterocyclic chemistry in the field of pericyclic reactions, their regio and stereoselectivity, especially on 1,3-dipolar cycloadditions and their new intramolecular variation - “criss-cross” cycloadditions with application of allene synthone as a dipolarophile. Following their applications lead to many various products otherwise difficult to preparation. Here presented work was carried out by his doctoral students.

ALK5 (Activin-like kinase-5) plays important roles in many pathological states including inflammation, fibrosis, cancer, asthma and cardiovascular diseases.1-3 Various low molecular weight inhibitors of ALK5 containing different substituted heterocyclic skeletons like imidazole, pyrazole, pyrrolo[1,2-b]pyrazole and pteridine were synthesized and published.4-5 Our recent work is focused on synthesis of new inhibitors of ALK5 kinases.6-7 We synthesized a series of 5,5-dimethyl-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazoles with various substitution at positions 2, 3 and 4. The most active compound in the set of almost 40 final products showed IC50 = 80 nM for ALK5. The selectivity for ALK5 in a panel of 50 protein kinases, as well as some experiments in cells (dephosphorylation of SMADF2, translocation of SMAD2/3 to nuclei) are discussed. In the literature one can find several ways for the formation of 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole ring but their synthesis is often complicated and has not always good yield.8-9 Our experience in application of homoallenyl aldehyde enabled us to find an easier route to those fused heterocyclic compounds.