ASYMMETRIC CATALYTIC REACTIONS USING MODULAR PHOSPHINE PHOSPHORAMIDITE LIGANDS

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1 ASYMMETRIC CATALYTIC REACTIONS USING MODULAR PHOSPHINE PHOSPHORAMIDITE LIGANDS THESES OF THE PhD DISSERTATION Author: Szabolcs Balogh Chemist Supervisor: Dr. József Bakos Professor of Chemistry University of Pannonia Doctoral School of Chemical and Environmental Sciences Institute of Chemistry Department of Organic Chemistry Veszprém 2013

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3 I. Introduction and aims of the work Vast majority of chiral compounds are showing biological activity. Wide range of optically active organic molecules like amines, amino acids or alcohols is used as pharmaceutics. The optical purity of the active substance is essential, because only one of the two enantiomers has the curing potential. Moreover, in many cases the other one might be harmful. By the use of catalysts, the atom economy and energy efficiency of chemical processes can be increased, because a small amount of catalyst is able to convert a high amount of substrate. Transition metal complexes modified with chiral ligand/ligands provide optically active compounds with high chemo-, regio- and enantioselectivity under mild reaction conditions. The research of phosphine-phosphoramidites started with the preparation of the first example in the year Quickly became apparent, that these compounds can be used as highly efficient ligands in asymmetric hydrogenation, asymmetric allylic substitutuion and asymmetric hydroformylation. It was found, that these ligands provide better catalytic properties and stability towards air and moisture compared to their monodentate analogues. Despite of this, only a few examples were developed and all of them having rigid or semirigid linker. My aim was the preparation of new phosphine-phosphoramidite ligands bearing only aliphatic bridge moiety. The new catalytic system showed excellent properties, therefore the stereoelectronic properties of the ligands and of their complexes was thoroughly studied. The relationship between enantioselection and ligand structure was examined. In chemical processes it is desirable to eliminate harsh solvents or replacing them with environmentally benign ones. Alcohols and cyclic carbonates were evaluated as solvents in the catalytic reactions. Besides easy separation, immobilization opens up new opportunities such as the use of continuous flow reactors or further tuning of the catalyst environment, which in some cases can lead to improved catalytic performance. The catalyst was immobilized on mesoporous Al 2 O 3 carrier and evaluated in batch and flow reaction modes using the H-Cube TM hydrogenation reactor.

4 II. Experimental methods All reactions were carried out under argon atmosphere using standard Schlenk technique. The solvents were dried according to standard procedures. Catalytic reactions were carried out in an isolated stainless steel autoclave. Purification of the ligands was performed by extraction, by recrystallization or by chromatographic methods. Products of the catalytic experiments were analyzed by GC or high-performance liquid chromatography utilizing chiral columns. GC-MS, IR, UV, 1 H, 13 C-, 13 C{ 1 H}-, 31 P-, 31 P{ 1 H}-, 1 H- 1 H COSY- and 13 C{ 1 H}APT- NMR spectroscopic methods, elemental analysis (C, H, N, S) and in some cases X-ray crystallography were used in determination of molecular structure of the new compounds. III. New scientific results 1. Three-step synthetic route starting from cyclic sulfates leading to new modular chiral phosphine-phosphoramidite ligands bearing aliphatic bridge moiety was developed (Scheme 1 and Scheme 3). It was proved, that the ring opening of chiral cyclic sulfates with secondary amines and the following reaction with LiPPh 2 are both chemo- and enantioselective processes. These reactions have S N 2 mechanism. Scheme 1 Preparation of aminoalkyl-phosphanes from cyclic sulfates 2. Chiral N-phenylazetidine analogue was synthesized for the first time from aminoalkylsulfate (Scheme 2). Scheme 2 Preparation of (2S,4S)-2,4-dimethyl-1-phenylazetidine

5 3. It was shown, that the aminoalkyl-phosphines are too weak nucleophiles to start the reaction having addition-elimination mechanism with the phosphorochloridous acid diester analogue. This reaction can't be accomplished by following the reaction procedures described in the literature (Scheme 3, A method). It was demonstrated however, that enhanced yields towards the phosphoramidite compound is possible by increasing the nucleophile power of the secondary amine (Scheme 3, B method), by applying by-pass reaction through -NPCl 2 compound (Scheme 3, C method) or by activating the substrate (Scheme 3, D method). Scheme 3 Methods to form phosphoramidites 4. According the literature 4-dimethylaminopiridine (DMAP) is used as catalyst in acylation reactions, but to the best of my knowledge, it was first applied in the reaction of chlorophosphites and amines to form phosphoramidites. By the addition of catalytic amount of DMAP, the ligands were prepared with up to 83 % yield. 5. I have synthesized 22 new compounds including 8 new phosphine-phosphoramidite ligands (Scheme 4) and intermediates, which are potential highly selective ligands for other asymmetric transformations. The structures of the new compounds were verified by NMR spectra, X-ray crystallographic measurements and CHN(S) elemental analysis. 6. The σ-donor and π-acceptor abilities of the phosphorous in the amidite and the phosphine sites were determined based on the 1 J P-Se coupling constants measured in the 31 P{ 1 H}-NMR spectra of their diselenides. Congruent to the literature, high resistance of the new ligands towards protic solvents and weak acids was observed. Careful investigation of the phosphine-phosphoramidite (24) and its rhodium complex revealed, that the n N σ* OPO hyperconjugation effect in amidites leading not only to increased electron density at the nitrogen, but also resulting in orthogonal planar configuration around the P-N bond blockig a

6 successful nucleophile attack. My conclusion is that the use of good electron donating groups at the nitrogen is highly recommended. Scheme 4 New phosphine-phosphoramidite ligands 7. It was stated, that the ligand structure is folded and rigid despite the flexible aliphatic backbone. This is caused probably by the bulky substituents, by the CH/π interaction revealed between the terminal groups, and by n N σ* OPO hyperconjugation on the P-N bond. I have discovered, that the structure of the free and the complexated ligand are fairly identical, indicating the formation of thermodynamically stable complexes. It was foud, that the folded ligand structure remains in solvent phase which was proved by the "through space" P-P coupling manifested in the 31 P{ 1 H}-NMR spektrum of ligands 22, 24 and 25. The interaction was verified by the single crystal structure and by the elevated temperature NMR measurements of the ligand. 8. Based on 31 P{ 1 H}-NMR and XRD measurements it is concluded, that the new phosphine-phosphoramidite is forming one monometallic thermodinamically stable chelate complex with [Rh(COD) 2 ]BF 4, in which the coordination occurs through the two phosphorous. By the addition of two equivalent of the ligand to [Rh(COD) 2 ]BF 4 only the square planar trans-complex could be detected showing the high space demanding feature of the terminal moieties.

7 9. The key finding of the work is, that the rhodium complexes of the new ligands are highly active and enantioselective catalysts in the asymmetric hydrogenation of prochiral compounds containing C=C double bond. For example, (Z)-methyl-acetamidocinnamate (MAC) and some of its derivatives could be hydrogenated with 99.9 % enantiomeric excess using complex [Rh(COD)(20)]BF 4. Up to ~3750 1/h TOF could be reached by using concentrated reaction mixture at elevated temperature. 10. It was demonstrated, that the ligands and their complexes are reasonably resistant towards hydrolysis and oxidation allowing the use of the catalysts in less harsh solvents, for example in alcohols instead of the commonly used dichloromethane. It was demonstrated, that the new ligands can be applied in environmental friendly cyclic carbonate solvents with outstanding enantioselectivity. Moreover, dimethyl-itaconate and the L-DOPA precursor were hydrogenated with higher enantioselectivity in propylene-carbonate than in methanol. 11. Simple economical benign processes were also developed. The acidic form of the L- DOPA precursor was hydrogenated with high 99,6 % ee in propylene-carbonate and it was realized that the product can be simply filtered from the reaction mixture with 70 % yield without any optimization at room temperature. The catalyst remained in the solvent phase. Moreover, dimethyl-itaconate could be completely hydrogenated without any solvent with up to 99.5 % ee using substrate/catalyst ratio of 2500 or The comparison of the ligands in catalytic reactions showed, that the (S c,s c,s a ) constellation of the chiral elements stands for the diastereomer with the matched configuration. It was also elucidated, that the binaphtyl moiety has less impact on the optical purity of the product and stem dominantly from the chiral elements of the bridge. 13. The catalyst immobilized on mesoporous Al 2 O 3 is remarkably active, selective and stable in the asymmetric hydrogenation reaction in heterogeneous batch and in continuous flow conditions using the H-Cube TM reactor. It was shown, that the use of non-polar solvents with good coordinating ability leads to increased catalyst stability and activity. For example, MAC could be hydrogenated in flow mode using n-butanol as solvent over 5 hour continuous run with over 99 % ee and with over 80 % conversion. 14. The new phosphine-phosphoramidites and aminoalkyl-phosphines (P,N ligand system) showed remarkable high activity (TOF = /h) and selectivity (ee up to 91,9 %) in the Pd-catalyzed allylic substitution reaction.

8 IV. Publications and presentations related to the dissertation Publications: Patent: Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos Electronic and steric effects in phosphine-phosphoramidite ligands bearing 2,4- pentanediyl backbone and their use in asymmetric catalysis Advanced Synthesis and Catalysis 2013, under construction. Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, Ferenc Darvas, László Ürge, József Bakos Fine tuning of the structure of phosphine-phosphoramidites: application for rhodiumcatalyzed asymmetric hydrogenations Tetrahedron: Asymmetry 2013, 24, 66. I.F.: (5-Year Impact Factor) Szabolcs Balogh, Gergely Farkas, József Madarász, Áron Szöllősy, József Kovács, Ferenc Darvas, László Ürge, József Bakos Asymmetric hydrogenation of C=C double bonds using Rh-complex under homogeneous, heterogeneous and continuous mode conditions Green Chemistry 2012, 14, I.F.: 6.32 (2011) Dr. József Bakos, Szabolcs Balogh, Dr. László Ürge, Dr. Ferenc Darvas Novel chiral phosphorous ligands and the use thereof in the production of optically active products ThalesNano Nanotechnology Inc. 26th october P Proportion: 36% Presentations: Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos Asymmetric catalytic hydrogenation with Rh-complexes of new phosphane/phosphoramidite ligands XIX. EuCheMS Conference on Organometallic Chemistry, Toulouse, 4-7 July, book of abstracts p173. Szabolcs Balogh, Gergely Farkas, József Madarász, József Kovács, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos Aszimmetrikus hidrogénezés a zöld kémia alapelveinek figyelembevételével XL. Chemical Engineering Days, Veszprém, April book of abstracts p15.

9 Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos Foszfán-foszforamidit ligandumokkal képzett aszimmetrikus hidrogénező ródiumkomplexek vizsgálata és felhasználása zöld kémiai reakciókban (Application and characterization of rhodium-complexes modified with phosphanephosphoramidite ligands and their use in asymmetric hydrogenation under green conditions) XLVI. Complexchemical Conference, Mátrafüred, May book of abstracts p20. Szabolcs Balogh, Attila Tóth, Áron Szöllősy, József Bakos Foszfán-foszforamidit ligandumok aszimmetrikus katalitikus allil helyzetű szubsztitúciós reakcióban MKE I. Hungarian National Conference, Sopron, May book of abstracts p285. Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos Aszimmetrikus homogénkatalitikus hidrogénezés új foszfán-foszforamidit ligandumok Rh-komplexeivel MKE I. Hungarian National Conference, Sopron, May book of abstracts p86. V. Further publications and presentations Publications: Gergely Farkas, Zsófia Császár, Szabolcs Balogh, Áron Szöllősy, Maryse Gouygou, József Bakos "Phosphine-phosphite ligands in the palladium-catalyzed asymmetric allylic alkylation: electronic and steric effects" Catalysis Communications 2013, accepted with minor revision. I.F.: (5-Year Impact Factor) Gergely Farkas, Szabolcs Balogh, József Madarász, Áron Szöllősy, Ferenc Darvas, László Ürge, Maryse Gouygou, and József Bakos Hybrid Phosphorus Ligands for Highly Enantioselective Asymmetric Hydrogenation: Chelate Ring Size vs. Activity and Enantioselectivity Relationships Dalton Transactions, 2012, 41, I.F.: (2011) Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos Novel phosphine phosphites and their use in asymmetric hydrogenation Tetrahedron: Asymmetry 2011, 22, I.F.: (5-Year Impact Factor) József Madarász, Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Kovács, Ferenc Darvas, László Ürge and József Bakos A Continues Flow System for Asymmetric Hydrogenation Using Supported Chiral Catalysts Journal of Flow Chemistry, 2011, 2, 62.

10 Presentations: József Madarász, Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Kovács, Ferenc Darvas, László Ürge, József Bakos Continuous Flow System for Asymmetric Hydrogenation Using Supported Chiral Catalysts ACS CCXLII. National Meeting & Exposition, Denver, Colorado, 28 Aug. 1 Sept Technical Session, book of abstracts p71. Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Bakos New phosphane-phosphite ligands for asymmetric catalytic hydrogenation XIX. EuCheMS Conference on Organometallic Chemistry, Toulouse, 4-7 July book of abstracts p168. József Madarász, Balázs Nánási, Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos Királis építőelemek szintézise enantioszelektív hidrogénezéssel folyamatos átáramlásos mikrofluid csatornareaktorban MKE I. Hungarian National Conference, Sopron, May book of abstracts F-0-5, p151. Balázs Nánási, József Madarász, Szabolcs Balogh, Gergely Farkas, László Ürge, Ferenc Darvas, József Bakos Biológiailag aktív vegyületek királis építőelemeinek szintézise enantioszelektív hidrogénezéssel folyamatos átáramlásos mikrofluidikai csatornareaktorban XXXVIII. Chemical Engineering Days, Veszprém, 2010, book of abstracts p222. KMOP 1.1.4, TÁMOP-4.2.1/B-09/1/KONV , TÁMOP-4.2.2/A-11/1/KONV TÁMOP-4.2.2/B-10/

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