UNIVERSITY OF PANNONIA

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1 UVERSTY F PAA MGEEUS CATALYTC AMCARBYLAT: DEVELPMET F A EW METD T SYTESZE FERRCEYL AM ACD ESTERS, FERRCEGLXAMDES AD DSUBSTTUTED FERRCEE DERVATVES TESS F TE PhD DSSERTAT Árpád Kuik Supervisor: Dr. Rita Skoda-Földes Professor Doctoral School in Chemistry and Environmental Sciences nstitute of Chemistry Department of rganic Chemistry Veszprém 2009

2 . PRELMARES, AMS F TE WRK After the discovery of ferrocene and clarification of its structure, a new era has begun in organometallic chemistry. umerous procedures were developed to synthesize different ferrocene derivatives due to the favorable properties which make them useful in diverse fields of chemistry. rrocene-based systems are excellent ligands in asymmetric catalysis, but they can also be used as redox switches, molecular and ion receptors or as biosensors. The pharmacological aspects of the research concerning these compounds are also remarkable. The main goal of my work was the synthesis of ferrocenoyl amino acid esters novel ferrocene glyoxamides and other ferrocene derivatives by homogeneous catalytic aminocarbonylation. This method had not been used in the synthesis of ferrocene derivatives before. According to the literature, the outcome of the aminocarbonylation reaction greatly depends on the reagents and reaction conditions, such as the choice of the substrate (aryl/alkenyl halides) and the base, the temperature, the C pressure, the solvent and the catalyst. n the present work, a detailed investigation of the effects of the reaction conditions has been carried out in order to find the optimal conditions leading to the ferrocene products in good yield and with high selectivity. n the experiments, iodoferrocene and 1,1 -diiodoferrocene were used as substrates. The nucleophilic reaction partners were primary and secondary amines and amino acid methyl esters. The new compounds obtained in these reactions were purified and then characterized by various spectroscopic methods. n addition, by the use of aminocarbonylation in combination of other homogeneous catalytic methods, various ferrocene derivatives with diverse structure were synthesized.. EXPERMETAL METDS APPLED A stainless steal autoclave has been applied in all of homogeneous carbonylation reactions. Anhydrous solvents have been used to avoid the formation of byproducts. The advance of the reactions and the composition of the reaction mixtures were monitored by GC, GC-MS, TLC. The products were separated and purified by column chromatography. The characterization of the products were carried out by various spectroscopic methods (GC-MS, R, 1 -, 13 C-MR, two dimensional MR techniques and X-ray diffraction). 1

3 . EW SCETFC RESULTS 1. Palladium catalyzed aminocarbonylation of iodoferrocene in the presence of amino acid methyl esters as nucleophiles were studied for the first time. The main point of these experiments was to obtain either amide-(2) or α-ketoamide-(3) type products with good selectivity. Me R 1 Cl. C Pd(Ac) 2 2PPh 3 TF base 40 bar Me Me 1 2a-e 3a-e a b c d e R 1 C 3 C 2 Ph (C 2 ) 2 SC 3 -C 2 C 2 C 2 - (Gly-Me) (L-Ala-Me) (L-Phe-Me) (L-Met-Me) (L-Pro-Me) n the course of experiments of aminocarbonylation of iodoferrocene with methyl glycinate (Gly-Me), by the systematic change of the reaction conditions, it was found that the selectivity of the reaction, in spite of the former observations, is not affected by the reaction temperature but the use of the proper base is crucial. According to the results of these experiments, the optimal reactions conditions leading to either ferrocene carboxamides (2a-e) or glyoxylic amides (3a-e) were determined. At 100 C and in presence of Et 3 as the base, -ferrocenoyl amino acid methyl esters (2a-e) were produced in good yields, at the same time with the use of DBU (1,8- diazabicyclo[5.4.0]undec-7-ene) instead of Et 3 -ferrocenylglyoxyl amino acid esters (3a-e) were obtained in moderate to good yields. 2. t was shown that under carbonylation conditions DBU was acylated, too. The structures of the new acylated products were determined. 2

4 1 C [Pd] Fc C n - 4a 4b n=1 n=2 Fc C n 5a,b 3. Aminocarbonylation of 1,1 -diiodoferrocene was investigated in the presence of various primary and secondary amines. a.) 1,1 -ferrocene diamides (7) were synthesized in good yields (77-92%). CR 1 C, R 1 Pd(Ac) 2 2PPh 3 Et 3, toluene CR b.) By the proper choice of reaction conditions, the 1-iodo-1 -carboxamides (8) and glyoxamides (9) were isolated in moderate yields (31-40%). CR 1 CCR 1 C, R 1 Pd(Ac) 2 2PPh 3 Et 3, toluene n order to explore the scope of applicability of the above-mentioned 1 -iodoferrocene compounds (8, 9) in the synthesis of heterodisubstituted derivatives, they were subjected to various homogeneous catalytic reactions, namely a.) aminocarbonylation (yield: 77-92%), 3

5 CR 1 C, R 3 R 4 CR 1 Pd(Ac) 2 2PPh 3 Et 3, toluene, 100 C CR 3 R b.) Stille-coupling (yield: 69-85%), (C) n R 1 C 2 =CSnBu 3 Pd(PPh 3 ) 4 toluene, 100 C 8, 9 11 (C) n R 1 n=1,2 c.) carbonylative coupling in the presence of abph 4 (yield: 78%). 8 CR 1 CR 1 C, abph 4 Pd(PPh 3 ) 4 toluene, 100 C CPh 12 These reactions offer a simple way for the synthesis of heterodisubstituted ferrocene derivatives. 5. A one-pot method was developed for the synthesis of unsymmetrically substituted 1,n - ferrocene diamides. 1,1 -Diiodoferrocene has been converted into diamides via carbonylation in the presence of two different nucleophiles. By the proper choice of the ratio of the two different nucleophiles, the heterodisubstituted ferrocene diamides could be isolated as major products (yield: 45-85%). 7 C (40bar) R 1 x Pd(Ac) 2 2PPh 3 Et 3, toluene, 100 C R 3 R 4 y 10xy CR 1 CR 3 R 4 CR 1 10x CR 1 10y CR 3 R 4 CR 3 R 4 4

6 6. The above-mentioned one-pot synthesis was used in the synthesis of heterodisubstituted 1,n -ferrocenoyl amino acid esters, too. n the literature there are only sporadic results concerning the synthesis of unsymmetrical derivatives bearing two different amino acids or peptides on the two Cp rings. The present method offers a simple way to synthesize such compounds. 7 C R 1 Me 2 x 2 Me Pd(Ac) 2 2 PPh 3 Cs 2C 3, touenel 100 o C, 40 bar R 1 Me Me R 1 R 1 Me Me 13xy 13x 13y Me Me y 17ac R 1 =, = C 2 Ph 17bc R 1 = Me, =C 2 Ph 17a 17b 17c 17c 17ad R 1 =, =(C 2 ) 2 SC 3 17a 17d 17bd R 1 = Me, =(C 2 ) 2 SC 3 17b 17d 17cd R 1 = C 2 Ph, =(C 2 ) 2 SC 3 17c 17d V. SGFCACE F TE SCETFC RESULTS A new and simple method has been developed for the synthesis of various ferrocene amides, ferrocenoyl amino acid esters and novel ferrocenylglyoxyl amino acid esters. The new method is more efficient in most cases than the former ones used so far. The ferrocene amide derivatives are widely used building blocks in supramolecular chemistry due to their good stability and favorable electrochemical properties. The redox feature of ferrocene derivatives are highly influenced by their substituents. f a so called guest molecule is coordinated to the ferrocene moiety, it induces a change in the redox behavior of the ferrocene unit that can be followed by cyclic voltammetry. Thus the compounds synthesized in this work are potential candidates of electrochemical sensors. With a further development of this new homogeneous catalytic method, it may be possible to attach two different peptide chains to the two Cp rings of ferrocene. f two amino acid esters bearing different protecting groups are used as nucleophiles in the aminocarbonylation reaction, the different protecting groups can be hydrolyzed under different conditions and the two amino acid moieties can be functionalized selectively. The present research was a basically preparative work. umerous new ferrocene compounds have been prepared which may have practical importance and may serve as building blocks for new electrochemical or biochemical sensors. 5

7 V. SCETFC PUBLCATS AD PRESETATS RELATED T TE TESS PUBLCATS: 1. Z. Szarka, R. Skoda-Földes, Á. Kuik, Z. Berente, L. Kollár Synthesis of ferrocene amides and alpha-ketoamides via palladium-catalyzed homogeneous carbonylation reaction Synthesis 2003, F: Cited: 3 2. A. Kuik, Z. Szarka, R.Skoda-Földes, L. Kollár Facile synthesis of unsymmetrically substituted ferrocene-1,1 -bis-carboxamides via homogeneous catalytic carbonylation Lett. rg. Chem. 2004, 1, F:1.122 Cited: 2 3. Z. Szarka, A. Kuik, R. Skoda-Földes, L. Kollár Aminocarbonylation of 1,1 -diiodoferrocene. Two-step synthesis of hetero-disubstituted ferrocene derivatives via homogeneous catalytic carbonylation/ coupling reactions J. rganomet. Chem. 2004, 689, F: Cited: 5 4. A. Kuik, R. Skoda-Földes, J. Balogh, L. Kollár Synthesis of ferrocenoyl amino acid derivatives via homogeneous catalytic aminocarbonylation J. rganomet. Chem. 2005, 690, F: Cited: 4 5. A. Kuik, R. Skoda-Földes, A. C. Bényei, G. Rangits, L. Kollár Formation of intramolecular hydrogen bonds in heterodisubstituted ferrocene diamides with a secondary and a tertiary amido group. X-ray structure of 1 -( -butyl-carbamoyl)- morpholino ferrocenecarboxamide J. rganomet. Chem. 2006, 691, F: Cited: 3 6. A. Kuik, R. Skoda-Földes, L. Jánosi, L. Kollár Facile synthesis of unsymmetrical 1,n -disubstituted ferrocenoyl amino acid derivatives by palladium-catalyzed aminocarbonylation Synthesis 2007, Cited: 5 F:

8 PRESETATS: 1. Z.Szarka, R. Skoda-Földes, Á. Kuik, L. Kollár: Synthesis of rrocene Diamides via omogeneous Catalytic Carbonylation (poszter) 15th FECEM Conference on rganometallic Chemistry, Zürich, August, Á. Kuik, R Skoda-Földes, L. Kollár: Facile synthesis of unsymmetrically substituted ferrocene-1,1 -bis-carboxamides via homogeneous catalytic carbonylation (poszter) 5th nternational School of rganometallic Chemistry, Camerino, taly, September, Á. Kuik, R. Skoda-Földes, L. Kollár: Synthesis of 1,1 -eteridisubstituted rrocenes via Palladium-Catalyzed Carbonylation (poszter) XV EuCheMS Conference on rganometallic Chemistry, Sofia, 1-6 September, V. FURTER SCETFC PUBLCATS 1. J. Balogh, Á. Kuik, L. Ürge, F. Darvas, J. Bakos, R. Skoda-Földes Double Carbonylation of odobenzene in a Microfluidics-based igh Throughput Flow Reactor J. Mol. Catal. A. 2009, 302, F:2.707 (2007) 2. C. hér, Á. Kuik, L. Márk, L. Kollár, R. Skoda-Földes A two-step synthesis of ferrocenyl pyrazole and pyrimidine derivatives based on carbonylative Sonogashira coupling of iodoferrocene J. rganomet. Chem. D : /j.jorganchem F: (2007) 3. Á. Kuik, Csaba hér, R. Skoda-Földes, L. Kollár: A ew Method for the Synthesis of rrocene Based Alkynyl Ketones (poszter) XX nternational Conference on rganometallic Chemistry, Rennes July,