Pyrazoles have been focus of a large number of investigations in the design and synthesis of novel biologically active agents that show remarkable medicinal activities. Although pyrazoles have been studied for over a century as an important class of heterocyclic compounds, they still continue to attract considerable attention due to the wide range of medicinal activities they possess. Recent studies have shown that combination of a ferrocenyl unit with structural features of pyrazoles can lead to products with enhanced or/and unexpected biological activity since several ferrocene derivatives have already been shown to be active against a number of tumors. As a result, we have investigated the reaction of 3-ferrocenylpropynal with hydrazinium salts. As anticipated, these reactions afforded two kinds of pyrazoles, namely 1-alkyl/aryl-5-ferrocenylpyrazoles (1,5-isomer) and 1-alkyl/aryl-3- ferrocenylpyrazoles (1,3-isomer). In most cases, 1,5-pyrazole isomers have resulted from these reactions as the single or the major product of the reactions. The structures of 1-benzyl-5-ferrocenylpyrazole, 1-phenyl-5-ferrocenyl-pyrazole and 1- (2-hydroxy-ethyl)-3-ferrocenylpyrazole were identified by X-ray single crystal analysis. The analogous reactions between 3-phenylpropynal and hydrazinium salts were also studied, which afforded 1-alkyl/aryl-5-phenylpyrazoles (1,5-isomer) and/or v 1-alkyl/aryl-3-phenylpyrazoles (1,3-isomer). The regioselectivity of the reactions is mainly governed by the nature of the substituents in hydrazine derivative.

In the first part of this thesis, it is aimed to develope methods for the synthesis of trisubstituted pyrrrole derivatives. 2-Aminopyrrroles, alkoxy and sulfonyl substittitued pyrrole derivatives as well as pirolinones show interesting biological activities and are precursor of well know drugs. Although there is a number of methods for the synthesis of pyrroles, the synthesis of 2-aminopyrroles is limited to few works and is not widely known. Therefore, it is still an important goal in organic chemistry to improve methods for the synthesis of multifunctionalized pyrrole derivatives and pyrrolinones. Alkylation of &amp / #946 / -dicarbonyl compounds with bromoacetonitrile furnishes &amp / #945 / - cyanomethyl-&amp / #946 / -dicarbonyl compounds. The condensation reaction of &amp / #945 / - v cyanomethyl-&amp / #946 / -dicarbonyl compounds with amines catalyzed by p-TsOH affords the corresponding enamines and further base catalyzed cyclization furnishes 2- aminopyrroles in high yields, moreover, zinc perchlorate-catalyzed addition of amines, alcohols and thiols to the nitrile carbon of &amp / #945 / -cyanomethyl-&amp / #946 / -ketoesters followed by annulation gives the 5-alkoxy and 5-alkylsulfanylpyrrole-3-carboxylates in high yields. In the second part of the thesis, reactions of a broad range of acyl phosphonates with &amp / #945 / -bromo acetophenones at room temperature in the presence of different bases were described to afford two diastereomeric epoxy phosphonates in good yields and high diastereoselectivities. The diastereoselectivity of this reaction is easily controlled by changing the base. Accordingly, changing the base from Cs2CO3 to DBU changes the diatereomeric ratio (trans/cis) from 5/3 to 9/1. Furthermore, the treatment of trans isomer with DBU shows a complete conversion to the corresponding cis isomer. Additionally, these highly functionalized epoxyphosphonates are shown to be useful intermediates to give several reactions

ABSTRACT SYNTHESIS OF FUROPYRROLONE AND FUROPYRIDAZINONE DERIVATIVES: A NEW CLASS OF COMPOUNDS Karahan, Emrah M.Sc., Department of Chemistry Supervisor: Prof. Dr. Metin Balci February 2011, 102 pages Furopyrrolone has a bicyclic structure consisting of furan and a pyrrolone ring. It is isoelectronic with isoindolinone which is also a heterocyclic organic compound. It has a bicyclic structure, consisting of a benzene ring fused to a five-membered nitrogen containing pyrrolone ring. Pyrrolones, pyrrolidines, pyrrolidinones, pyridazines and pyridazinones are precursors to many pharmaceuticals. In this project we developed new synthetic procedures leading to the synthesis of furopyrrolone derivatives. To do this, the starting compound, methyl 2-(2-methoxy-2-oxoethyl)-3-furoate, was converted to isocyanate, regioselectively. This isocyanate was converted into the corresponding urethane and/or urea derivatives by treatment with alcohol and amine, respectively. It is known that acyl chlorides are more reactive than esters and carboxylic acids. Therefore, ester was converted to more reactive compound acyl azide that was used for intramolecular cyclization to get desired furopyrrolone skeletons. In the second part, methyl 2-formylfuran-3-carboxylate was treated with hydrazine and hydrazine salts. Then, intramolecular molecular cyclization caused the formation of desired heterocycles via acyl chloride intermediate.

SYNTHESIS OF MACROMOLECULAR CATALYST SYSTEMS AND APPLICATIONS Oguzkaya, Funda PhD., Department of Chemistry Supervisor: Prof. Dr. Cihangir Tanyeli September 2011, 144 pages The thesis mainly proposed to design macromolecular catalyst systems. Such catalysts should follow the way of &quot / Green Chemistry&quot / with including no metallic ions and have also the ability of reusability. Hence, nitroxide chemistry was chosen as the key point. Catalysts were synthesized with surely including TEMPO as the functional part as the most preferable nitroxide derivative. As a skeleton, norbornene was chosen firstly. Following obtaining 3-(methoxycarbonyl) bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (49), 4-aminoTEMPO was attempted to be inserted in the structure. In this case, 4-aminoTEMPO was preferred as a TEMPO derivative so as to include reactive amine functional group. As a result, two different monomers were obtained. Then, Ring Opening Metathesis Polymerization via first generation Grubbs catalyst was adjusted to reach target macromolecules. Furthermore, as a second type skeleton for the catalyst, Thiophene-Pyrrole-Thiophene (SNS) structure was chosen, since these well-known structures have the ability to polymerize easily. Anelli Oxidation protocol including corresponding catalysts in combination with NaOCl+NaHCO3 (pH 9.1) and KBr resulting in remarkable high activity with low catalyst concentrations typically 1 mol % was chosen for the oxidation of alcohols so as to reach to target aldehydes and ketones. Investigation of other applicable areas via collaborative studies was thought to open the way of electrochromic and biosensor studies as the different points of view. Electropolymerization was performed in a three-electrode cell consisting of an Indium Tin Oxide coated glass slide (ITO) as the working electrode, platinum wire as the counter electrode and Ag wire as the pseudo reference electrode. As the biosensor part, glucose oxidase (GOx) was used as the model enzyme for glucose oxidation in the presence of molecular oxygen. Poly-SNS-based carboxylic acid served as an excellent immobilization matrix for glucose sensing. Key words: TEMPO, Anelli Oxidation

Chiral aromatic nitrogen heterocycles are finding many applications in asymmetric organic synthesis, particularly as ligands in the preparation of chiral metal complexes. Since camphor-based chiral auxiliaries are known to be especially effective, a number of pyridines fused to the camphor skeleton have been reported. It is well known that nicotinic acid and its derivatives exhibiting qualitatively the biological activity of nicotinamide, which acts as an electron acceptor in many biological redox reactions. In connection to our works, we attempted to develop short and convenient way to prepare various camphorderived chiral pyridine or nicotinic acid derivatives. Here we report our results obtained from the annulation of (+)-&amp / #946 / -hydroxymethylenecamphor as the feasible chiral pool with various enamines derived from active methylene compounds. (+)-&amp / #946 / -Hydroxymethylenecamphor prepared from cheap and easily available natural (+)-camphor and enamines were transformed into chiral camphor-based pyridine derivatives via tandem condensation reaction in good yields.

This study presents synthetic studies on camptothecin, a potent antitumor agent in order to improve its stability and solubility without reducing its activity. The study consists of the modification of camptothecin at 20-OH position a new strategy for the targeted and controlled release of the drug and modification at C-7 position to overcome the stability and solubility problems of the free drug. In the first part of the study, the 20-OH functional group of camptothecin was replaced with an unsymmetrical benzoin derivative that is able to release the drug under photolysis at 350 nm. The new prodrugs synthesized possessed higher stability than the camptothecin itself. The in vitro irradiation of the prodrugs at 350 nm was satisfactory without any decomposition of the active substance. The second part of the study comprises the studies on the modification of the 7th position of camptothecin, which is the most suitable position for the modification. In this part of the study, 7-amino and silyl substituted camptothecins were synthesized.Combination of camptothecin with some other drugs such as cisplatin was also investigated in this study. The synthetic efforts showed that the reactions are very promising and the combination studies can be studied as a major subject in the future.

Addition reactions of nucleophilic trifluoromethyltrimethylsilane (CF3TMS) to acyl phosphonates were investigated. Various acyl phosphonates reacted readily with CF3TMS in the presence of K2CO3 to give 1-alkyl-2,2,2-trifluoro-1-trimethylsilyloxyethylphosphonate in 70-90% yields. When benzoyl phosphonates were used as starting material, after addition of CF3, the formed alcoholate undergoes phosphonatephosphate rearrangement to form the acyl anion, followed by elimination of F- to give 1-aryldifluoroethenyl phosphates in 87-97% yields. The proline&ndash / thiourea host&ndash / guest complex catalyzed intermolecular aldol reaction of aromatic aldehydes with cyclohexanone is developed. The anti-configured products were obtained in high yields and exclusively excellent nantioselectivities. The reaction is proposed to proceed according to a modified Houk&ndash / List model, in which the carboxylate moiety of the proline forms an assembly with the thiourea. These results clearly demonstrate the enormous effect of the thiourea on the reactivity and selectivity, even in an unconventional non-polar reaction medium, without the need to use low temperatures. A proline&ndash / thiourea host&ndash / guest complex is described as a good catalyst for the enantioselective nitro-Michael addition of aldehydes to nitroalkenes. The reaction is efficient with 5% of the thiourea, to give moderate to good enantioselectivity (up to 76% ee). High syn-selectivity was obtained with both branched and unbranched aliphatic aldehydes. This is the first example of self-assembly of organocatalysts with an achiral additive in a Michael addition wherein aldehydes are utilized as donors. An aldol reaction catalyzed by a proline&ndash / thiourea host&ndash / guest complex in a nonpolar solvent shows excellent nonlinear effects. This proline&ndash / thiourea system has the ability to form a hydrogen-bonding network. The enantiomeric excess of proline in a solution can be significantly enhanced by its incorporation with a urea molecule into its solid racemate. This suggests a general and facile route to homochirality, which may be involved in the origin of chirality on earth.

Design of new chiral ligands for asymmetric synthesis is important. The ligand should be economical and efficient in enantioselective transformations. For the synthesis of some natural products and biologically active compounds, optically active amines are used as important intermediates. For this reason, it is significant to develop new catalyst system which can produce optically active amines in an economical and efficient way. Our group developed PFAM ligands and used successfully for the enantioselective synthesis of organic compounds. In this work, these ligands were tested as chiral catalysts for enantioselective synthesis of amines. N-sulphonyl and N-phosphinoyl imines synthesized from aromatic aldehydes were used as the starting material for enantioselective diethylzinc addition reaction in the presence of copper salt and PFAM ligands. By improving the known procedure, N-benzylidine sulphonylaldimine was obtained in excellent yield (98%). Asymmetric diethylzinc addition reaction to N-sulphonyl and N-phosphinoyl aryaldimines provided chiral amines in up to 81% enantioselectivity and 99% yield.

Aldol addition reaction is one of the most important and most studied carbon-carbon bond forming reactions in organic chemistry. Recent studies focused on the catalytic version of this chemistry. Different from the classical Mukaiyama-type aldol reactions, chiral lewis bases have been used as promoters. In the presence of SiCl4, these reactions proceed through a cyclic transition state leading to anti aldol product as a major product with moderate-to-good diastereo and enantioselectivities. Phosphoramide derivatives, BINAPO, BINAPO derivatives, N,N-dioxides and N-oxides have been extensively used for this purpose. Recently, our group has designed new phosphine oxy aziridinyl phosphonates (POAP) as chiral Lewis bases. These promoters were used for the asymmetric aldol addition reaction between cyclohexanone and different aldehydes in the presence of SiCl4. Moreover, our previously designed phosphine oxy ferrocenyl substituted aziridinyl methanol (POFAM) ligands were also tested as Lewis bases. Among these 6 potential promoters, POAP-A gave the best results, and the aldol product were obtained in moderate to good yields up to 80%, and with moderate enantioselectivities (the highest, 66%) after standard optimization studies. Aldehyde screening experiments provided the highest enantioselectivity (68%) with 2- naphthaldehyde.

Furopyranones and furopyrrolones are furan-fused bicyclic heterocycles containing pyranone and pyrrolone framework respectively. Many natural products and pharmaceutical agents include these core structures. In this study, new synthetic methodologies were developed for the synthesis of furopyranone and furopyrrolone derivatives. In the first section of this thesis, methyl 2-(2-methoxy-2-oxoethyl)-3-furoate was hydrolyzed forming 2-(carboxymethyl)-3-furoic acid which underwent intramolecular cyclization reaction using two different methodologies forming furopyranone derivatives. In the second part of the study, 2-(carboxymethyl)-3-furoic acid was regioselectively converted to acyl azide, which was accomplished by utilizing the reactivity differences between the two acid functionalities within the molecule. This acyl azide was then transformed into urea derivative to perform cyclization reaction yielding a new furan-fused heterocycle, furopyrrolone. In both parts of this study, ring closure reactions were achieved benefiting from the reactivities of different carbonyl groups within the molecules.