Hantzschovom ciklizacijom pripravljen je niz 1,4-dihidropiridinskih spojeva (1,4-DHP) s različitim supstituentima na položajima 3, 4 i 5. Iz njih su sintetizirani određeni piridinski spojevi koji su ...korišteni kao standardi prilikom analize omjera dealkilnog i alkilnog produkta na položaju 4 visokodjelotvornom tekućinskom kromatografijom. Za reakciju aromatizacije 1,4-DHP ispitan je niz različitih reakcijskih uvjeta i oksidansa: metalni, tritilijev i tropilijev tetrafluoroborat, 2,3-diklor-5,6-dicijano-1,4-benzokinon i tetracijanoetilen. Primjenom različitih spektroskopskih metoda je dokazano nastajanje kompleksa s prijenosom naboja prilikom prvog kontakta između 1,4-dihidropiridina i oksidansa. Na temelju dobivenih rezultata analize i detektiranih radikala, pretpostavljen je mehanizam kojim nastaje 4-dealkilni produkt u nekoliko uzastopnih koraka: početni korak je prijenos elektrona, zatim slijedi otcjepljenje karbokationa s položaja 4 pri čemu nastaje dihidropiridilni radikal, a potom prijenosom drugog elektrona i uklanjanjem protona s dušika nastaje piridinski produkt. Istim mehanizmom nastaje i 4-alkilni produkt, ali je drugi korak uklanjanje protona umjesto karbokationa. Kod tropilijevog kationa 4-alkilni produkt nastaje jednostupanjskim prijenosom hidrida, dok se kod tritilijevog kationa ne može jednoznačno odrediti nastaje li 4-alkilni produkt jednostupanjskim ili sekvencijalnim prijenosom hidrida.
1,4-Dihydropyridines with different substituents on positions 3, 4 and 5 were prepared using Hantzsch cyclisation reaction and corresponding pyridines were prepaired from them. The obtained compounds were used as standards in high perfomance liquid chromatography when analysing the ratio of alkylated and dealkylated product on position 4 resulted during aromatization. Many reaction conditions and oxidants were examined for aromatization of 1,4-DHP: metal, tropylium and trityl tetrafluoroborate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and tetracyanoethylene. Using different spectroscopic methods charge transfer complexes during the first contact of 1,4-dihydropyridine and oxidant were identified. Based on obtained results of aromatization product analysis and radicals detected, a mechanism was proposed which explains the appearance of 4-dealkylated product via few consecutive steps: initial step is electron transfer, then carbocation elimination from position 4 to give dihydropyridil radical, which is followed by second electron transfer and losing a proton from nitrogen atom results in pyridine product. The same mechanism explains the appearance of 4-nondealkylated product, but the second step involves proton elimination instead of carbocation. When using tropylium cation 4-alkylated product results by one step hydride transfer. It can not be uniquely determined whether the 4-alkylated product results by one step or sequential hydride transfer when using trityl cation.
Biginellijevom reakcijom, pripravljeni su razliĉito supstituirani derivati 3,4-dihidropirimidinona. Koristeći modelni derivat 124-I-b provedena su opsežna preliminarna ispitivanja u svrhu pronalaska ...odgovarajućih uvjeta aromatizacije sintetiziranih derivata. Opseg preliminarnih ispitivanja potkrepljuje literaturno poznatu ĉinjenicu kako se ovaj tip spojeva vrlo teško aromatizira. Rezultat istraţivanja u sklopu ove doktorske disertacije urodio je ĉetirima novim, do sad nepoznatim metodama aromatizacije 3,4-dihidropirimidinona. Efikasna, brza i selektivna metoda aromatizacije razvijena je uz molekularni jod i kalijev t-butoksid u suhom tetrahidrofuranu pri sobnoj temperaturi (konverzija 80 % - 100 %). Ispitan je i predloţen mehanizam aromatizacije koji upućuje na nastanak t-butilhipojodita kao aktivne vrste pri reakciji aromatizacije. Aromatizacija 3,4-dihidropirimidinona uz t-butilhidro-peroksid, molekularni jod i kalijev t-butoksid u t-butilacetatu, pri temperaturi povrata otapala, modificirana je, katalitiĉka verzija prethodno opisane metode ĉiji je mehanizam dehidrogenacije također predloţen. Zabilježena je konverzija reaktanata u produkte od vrlo visokih 98 % - 100 %. Niz supstituiranih derivata oksidiran je i efikasnom metodom uz t-butilhidroperoksid i kalijev hidroksid uz kalijev jodid kao katalizator. Reakcije su provedene u metanolu pri sobnoj temperaturi (konverzija 98 % - 100 %). Derivati 4-aril-pirimidin-2(1H)-ona dehidrogenirani su u odgovarajuće 4-aril-pirimidin-one metodom uz tetracijanoetilen u acetonitrilu pri povišenoj temperaturi. Aromatizacijom razliĉito supstituiranih derivata ovom metodom postignuta je maksimalna konverzija reaktanata u produkte (100 %). U završnoj fazi istraživanja provedena je i vezana sinteza prva tri koraka pri sintezi rosuvastatin kalcija na 17 razliĉito supstituiranih derivata 3,4-dihidropirimidinona. Ova sinteza ukljuĉuje aromatizaciju 3,4-dihidropirimidinona, aktivaciju dobivenog pirimidinona na položaju 2 azaheterocikliĉke jezgre te reakciju supstitucije tako pripremljenog produkta s odgovarajućim nukleofilom. Sva tri stupnja nadogradnje provedena su u jednoj reakcijskoj tikvici, bez izolacije međuprodukata, uz iskorištenje od 12 % - 71 %.
Differently substituted 3,4-dihydropyrimidinones were prepared using a three component Biginelli reaction. By using a model compound 124-I-b, extensive preliminary research was done in order to find a new appropriate 3,4-dihydropyrimidinone aromatization method. A wide range of reaction conditions, reagents, catalysts and solvents were examined. The scope of the preliminary examination supports the literature known fact that this kinds of compounds are very difficult to be aromatized. The research in the context of this PhD thesis has resulted in four new, so far unknown methods of 3,4-dihydropyrimidinone aromatization. Efficient, rapid and selective aromatization method was developed using molecular iodine and potassium t-butoxide in dry tetrahydrofuran at room temperature (conversion 80 % - 100 %). 3,4-Dihydropyrimidinone aromatization mechanism was proposed. It includes the formation of t-butil hypoiodite as an active species during aromatization. The second aromatization method is catalytic modification of the previously described method - aromatization of 3,4-dihydropyrimidinones using t-butyl hydroperoxide, molecular iodine and potassium t-butoxide in t-butyl acetate at reflux temperature (conversion 98 % - 100 %). The series of differently substituted derivatives were oxidized using on efficient method that includes t-butyl hydroperoxide as an oxidant, potassium hydroxide as a base and potassium iodide as a catalyst. Reactions were carried out in methanol at room temperature (conversion 98 % - 100 %). In the last aromatization method, the 4-aryl-pyrimidin-2(1H)-one derivatives were dehydrogenated to the corresponding 4-aryl-pyrimidine-ones using tetracyanoethylene in acetonitrile at elevated temperatures (conversion 100 %). The final stage was one pot synthesis of the first three steps in the synthesis of rosuvastatin calcium. This synthesis includes 3,4-dihydropyrimidinone aromatization, the activation of dehydrogenated product and a substitution reaction with an appropriate nucleophile. All three stages were carried out in a single reaction flask without isolation of intermediates. The corresponding products were obtained in a yield of 12 % - 71 %, depending on the derivative.
Težnje i suvremene sirarske tehnologije idu ka povećanju asortimana sireva, a naročito u stvaranju novih varijeteta na bazi autohtone tehnologije. Posebnu ulogu u stvaranju varijeteta sireva igraju ...aromatske primjese koje se dodaju ili se njima tretiraju sirevi. Primjese ili aromatske tvari koje se dodaju sirevima u stvaranju novih varijeteta nisu nove, poznate su kod drugih vrsta sireva ili drugih prehrambenih proizvoda, ali njihova upotreba u proizvodnji travničkog sira postavlja nove i originalne oglede.
