SYNTHESIS OF CHIRAL PHOSPHINE-PHOSPHITE LIGANDS AND THEIR APPLICATION IN ASYMMETRIC CATALYTIC REACTIONS. THESES OF THE PhD DISSERTATION

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1 SYNTHESIS OF CHIRAL PHOSPHINE-PHOSPHITE LIGANDS AND THEIR APPLICATION IN ASYMMETRIC CATALYTIC REACTIONS THESES OF THE PhD DISSERTATION Author: Gergely Farkas MSc in Chemistry 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

2 I. Introduction and objectives The majority of natural organic compounds constitutes of optically active molecules that have special significance in nature. The enantiomers are related as mirror images and they act the same way under achiral conditions but distinctly when chiral influences operate. This fact encumbers the application of synthetic racemic chiral compounds. A number of optically active compounds can be prepared using the chiral pool, starting from inexpensive materials. The only drawback of this methodology is that the number of optically active compounds is very limited and sometimes just one of the enantiomers is available. In the case of stochiometric and asymmetric syntheses, optically active compounds can be achieved by using chiral auxiliaries (reagent, catalyst or solvent) starting from optically inactive compounds. The homogeneous transition metal catalyzed syntheses can be realized with transition metal complexes modified by chiral ligand. In the catalytic process a small amount of the chiral modifying agent transfers its own chirality to a huge amount of substrate. The use of chiral bifunctional ligands has become a powerful strategy in catalyst design for enantioselective hydrogenation. In recent years, new series of bidentate hybrid ligands such as phosphine-phosphinite, phosphine-phosphoramidite and phosphine-phosphite have been shown to have high efficiency in asymmetric hydrogenation. Among bifunctional ligands, chiral phosphine-phosphites are a particularly interesting class of compounds due to their easy synthesis and unique electronic properties. My aim was the synthesis of a new class of chiral hybrid phosphine-phosphite ligands and the application of the palladium and rhodium complexes of these novel compounds in asymmetric allylic alkylation and in enantioselective hydrogenation reactions. Considering the structural versatility of the new ligands, my aim was to develop several novel synthetic methodologies. In order to investigate the catalytic features of the transition metal complexes modified by the ligands my aim was the evaluation of the effect of ligand structure on the catalyst activity and selectivity and thus the establishment of the relationship between the catalyst structure and catalytic behavior. The electronic and coordination features of the ligands were characterized by the spectroscopic evaluation of their rhodium and palladium complexes and selenium derivatives. 2

3 II. Experimental methods The synthetic and catalytic work was performed under an inert atmosphere using Schlenk-techniques. The solvents used were purified by standard methods. In the synthetic procedures distillation, extraction, chromatography and recrystallization were applied as efficient purification methods. The high pressure catalytic experiments were performed in an isolated 100 ml stainless steel autoclave. The conversion of the synthetic reactions was monitored by thin layer chromatography (TLC). The conversion and selectivity of the catalytic reactions was determined by means of high pressure liquid chromatography (HPLC) and gas chromatography (GC) using chiral columns. The structure of the synthetic products was determined by using mass spectroscopy (ESI-MS), infrared (IR), ultraviolet-visible (UV-VIS), 1 H, 13 C{ 1 H}, 31 P{ 1 H}, and 11 B{ 1 H} NMR spectroscopy and elemental analysis (C, H). III. New scientific results 1. Five synthetic routes have been developed for the preparation of phosphine-phosphite type ligands (Scheme 1). The desired hydroxyalkyl phosphines were synthesized by the ring opening of cyclic sulfate esters (I), the nucleophilic addition of aldehydes (II), the nucleophilic substitution of ω-halogenoalcohols (III), the ring opening of cyclic ethers (IV) and starting from natural chiral compounds (V). The chiral ligands were prepared by the reaction of the corresponding hydroxyalkyl phosphines and chlorophosphites. The synthetic methodologies developed are suitable for the design of highly modular ligand structure and therefore the fine tuning of the ligands can easily be implemented. 3

4 Scheme 1 Synthetic methods for the preparation of hydroxyalkyl phosphines 2. By means of the preparation methods 13 novel ligands have been synthesized (Scheme 2) whose structures were characterized by NMR spectroscopy and elemental analysis. The novel ligands are phosphine-phosphite type compounds possessing alkylene backbones of different length and binaphthyl or octahydrobinaphthyl terminal moieties. During the scientific work 48 new compounds were synthesized and characterized including the ligands, their precursors and derivatives. 4

5 Scheme 2 Phosphine-phosphite ligands 3. In order to evaluate the coordination chemistry of the new ligands, rhodium and palladium complexes have been synthesized and characterized by NMR spectroscopy. It was proven that the ligands have chelating behavior except 8 in its [Pd(8)Cl 2 ] type complex. It was stated that the ligand s tether length has a profound effect on their coordination features. In the rhodium bis chelate complex of 5 the two ligands coordinate to the metal center forming cis 5

6 and trans species in a 4/1 molar ratio unlike in the cases of other ligands, were the only product is the trans complex. According to the experimental observations in the reaction of [Pd(PhCN) 2 Cl 2 ] and 8, the product has a polymeric structure due to the longer tether length of the ligand. 4. In order to evaluate the σ-donor ability of the ligands, their diseleno derivatives have been synthesized. By measuring the magnitude of the 1 J( 31 P, 77 Se) coupling constants of the corresponding selenophosphates and phosphine selenides the σ-donor ability of the phosphorous functionalities can be characterized. It was established that the σ-donor ability of the ligands increases with the increasing tether length due to hyperconjugative effects. The partially saturated nature of the ligands biaryl moiety also increases the donating ability of the corresponding phosphorus atom. 5. It has been recognized that all of the ligands form catalytically active species with palladium and rhodium in asymmetric allylic alkylation and in enantioselective hydrogenation reactions, respectively. 6. It has been proven that polar solvents have a positive effect on the catalyst activity. It was also shown that the alkali metal counterion of the nucleophile has a significant role in determining enantioselectivity. 7. A linear relationship has been established between the σ-donor ability of the phosphorus atom in the phosphine moiety and the first order rate constant of the catalytic reaction. It was proven that increasing the length of the ligands backbone and therefore the electron donating feature of the phosphorus atoms leads to an enhancement in the catalytic activity due to the increasing trans influence of the phosphine moiety. 8. It has been recognized that the palladium-catalyzed reaction can be performed in environmentally friendly green solvents such as in ethylene or propylene carbonate. In alkylene carbonates the activity of the catalytic process was found to be better than in methylene chloride. 6

7 9. It has been proven that the palladium complexes modified by phosphine-phosphite ligands provided outstanding activities (up to 486 1/h) in the allylic alkylation reactions of 1,3-diphenylallyl-2-acetate. 10. In asymmetric hydrogenation reactions it has been established that the main product of the catalytic reaction originates from the major diastereomeric substrate complex unlike in the case of the Halpern-Brown mechanism. Increasing the hydrogen pressure, the selectivity of the reaction slightly increased (from 90.1% to 94.7%). 11. It has been shown that increasing the chelate ring size causes an enhancement in the activity and selectivity of the asymmetric hydrogenation of (Z)-α-acetamidocinnamic acid methyl ester. It can be explained by the increasing σ-donor ability of the ligands applied. To the best of our knowledge, this is the first study that establishes unambiguous relationship between the catalyst activity/selectivity and the length of the backbone of heterobidentate ligands. 12. It has been proven that ligands having H 8 -binaphthyl moieties provided better enantioselectivities compared to their H 0 -analogues. 13. It has been shown that the cooperation of the stereogenic elements of the ligands has a profound effect on the enantioselectivity. In the hydrogenation of dimethyl malonate 11 provided 87.6% ee, while 10 gave the hydrogenation product with 99.2% optical yield. 14. It has been proven that the phosphine-phosphite ligands ensure outstanding activities and enantioselectivities in the rhodium-catalyzed asymmetric hydrogenation of prochiral olefins. The rhodium complex of 12 provided the hydrogenated product with 100% conversion and 99.1% ee in 2 hours, at a substrate/catalyst molar ratio of when dimethyl itaconate was used as substrate. The outstanding enantioselectivity achieved by the Rh-complex of 12 (>99%) is an excellent example for the successful fine tuning of the ligand s structure. 7

8 IV. Publications, presentations and posters related to the dissertation Publications 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, IF: 2,652 (2011). Gergely Farkas, Szabolcs Balogh, József Madarász, Áron Szöllősy, László Ürge, Farkas Darvas, Maryse Gouygou, József Bakos: Phosphine-phosphite ligands: chelate ring size vs. activity and enantioselectivity relationships. Dalton Transactions 2012, 41, IF: 3,838 (2011). 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, 36, IF: 2,986 (2011) Gergely Farkas, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos: Foszfortartalmú királis hibrid ligandumok szintézise és alkalmazása enantioszelektív katalitikus hidrogénezésben. XXXIII. Kémiai Előadói Napok, Szeged, 2010, Book of Abstracts p Gergely Farkas, Zsófia Császár, Áron Szöllősy, József Bakos: Kelátképző hibrid ligandumok vizsgálata palládium-katalizált aszimmetrikus allil-helyzetű szubsztitúciós reakciókban. XXXV. Kémiai Előadói Napok, Szeged, 2012, Book of Abstracts p Patent József Bakos, Gergely Farkas, Béla Édes, László Ürge, Ferenc Darvas: Novel phosphinephosphite compounds and their use for preparation of new catalysts. P ( ). (Hungarian Intellectual Property Office) Presentations/Posters Gergely Farkas, Áron Szöllősy, József Bakos: New hybrid phosphorous ligands for asymmetric catalytic hydrogenation. International Symposium on Homogeneous Catalysis, 8

9 Poznan, Poland, 2010, Book of Abstracts P-71. Gergely Farkas, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos: Foszfortartalmú királis hibrid ligandumok szintézise és alkalmazása enantioszelektív katalitikus hidrogénezésben. XXIII. Kémiai Előadói Napok, Szeged, 2010, Book of Abstracts p Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Bakos: Új hibrid foszfortartalmú ligandumok szintézise és katalitikus tulajdonságainak vizsgálata. MKE 1. Nemzeti Konferencia, Sopron, 2011, Book of Abstracts P-100. Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Bakos: New phosphine-phosphite ligands for asymmetric catalytic hydrogenation. 19th EuCheMS International Conference on Organometallic Chemistry, Toulouse, France, 2011, Book of Abstracts P-168. Gergely Farkas, Zsófia Császár, Szabolcs Balogh, Áron Szöllősy, József Bakos: Hibrid foszfortartalmú ligandumok katalitikus és koordinációs tulajdonságainak vizsgálata, 46. Komplexkémiai Kollokvium, Mátrafüred, 2012, Book of Abstracts p. 21. Gergely Farkas, Zsófia Császár, Szabolcs Balogh, Áron Szöllősy, Maryse Gouygou, József Bakos: Phosphine-phosphite ligands in Pd(II)-catalyzed asymmetric allylic alkylation, International Symposium on Homogeneous Catalysis, Toulouse, France, 2012, Book of Abstracts P-80. Gergely Farkas, Zsófia Császár, Áron Szöllősy, József Bakos: Kelátképző hibrid foszfortartalmú ligandumok vizsgálata aszimmetrikus katalitikus reakciókban: a kelátgyűrű méretének jelentősége. XVIII. Nemzetközi Vegyészkonferencia, Félixfürdő (Nagyvárad), Románia, 2012, Book of Abstracts p. 39. Gergely Farkas, Zsófia Császár, Áron Szöllősy, József Bakos: Kelátképző hibrid ligandumok vizsgálata palládium-katalizált aszimmetrikus allil-helyzetű szubsztitúciós reakciókban. XXXV. Kémiai Előadói Napok, Szeged, 2012, Book of Abstracts p

10 V. Further publications, presentations and posters Publications 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. Műszaki Kémiai Napok, Veszprém, 2010, Book of Abstracts p József Madarász, Gergely Farkas, Szabolcs Balogh, Áron Szöllősy, József Kovács, Ferenc Darvas, László Ürge, József Bakos: A continues flow system for asymmetric hydrogenation using supported chiral catalysts. Journal of Flow Chemistry 2011, 1, Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, Ferenc Darvas, László Ürge, József Bakos: Fine tuning of the structure of phosphine-phosphoramidites: application for rhodiumcatalyzed asymmetric hydrogenation. Tetrahedron: Asymmetry 2013, 24, IF: 2,652 (2011) Szabolcs Balogh, Gergely Farkas, József Madarász, József Kovács, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos: Aszimmetrikus hidrogénezés a zöld kémia alapelveinek figyelembevételével 40. Műszaki Kémiai Napok, Veszprém, 2012, Book of Abstracts p 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, IF: 6,32 (2011) 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 (under construction) Presentations/Posters József Madarász, Eszter Takács, Balázs Nánási, Gergely Farkas, Ferenc Darvas, László 10

11 Ürge, József Bakos: Enantioselective catalytic hydrogenations in a microfluidics-based high throughput flow reactor. New Horizons in Catalysis, Clearwater, Florida, USA, 2008, Book of Abstracts P-11. Gergely Farkas, Balázs Nánási: Nagy szelektivitású katalitikus rendszer kifejlesztése nagy áteresztőképességű H-Cube mikroreaktorban biológiailag aktív vegyületek előállítására. Közép-Dunántúli Regionális Innovációs Ügynökség Diákinnovátor Pályázata, Székesfehérvár, (2 nd place) Gergely Farkas, Balázs Nánási: Nagy szelektivitású katalitikus rendszer kifejlesztése nagy áteresztőképességű H-Cube mikroreaktorban biológiailag aktív vegyületek előállítására. Ötletek, melyek pénzt hoznak a vállalkozásnak Konferencia, Székesfehérvár, Balázs Nánási, József Madarász, Szabolcs Balogh, Gergely Farkas, László Ürge, Ferenc Darvas, József Bakos: Biológiailag aktív vegyületek királis építőelemeinek szintézise enantioszelektív hidrogénezéssel folyamatos átáramlásos csatornareaktorban. Kombinatorikus kémiai és új szintézistechnológiai szakcsoport ülése, Budapest, Gergely Farkas, Balázs Nánási, József Bakos: Foszforamidit ligandummal módosított katalizátor alkalmazása enantioszelektív hidrogénezésre folyamatos átáramlásos csatornareaktorban. Kombinatorikus kémiai és új szintézistechnológiai szakcsoport ülése, Budapest, 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. Fall 2011 National Meeting & Exposition, Denver, Colorado, USA, 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 1. Nemzeti Konferencia, Sopron, Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos: Aszimmetrikus 11

12 homogénkatalitikus hidrogénezés új foszfán-foszforamidit ligandumok Rh-komplexeivel. MKE 1. Nemzeti Konferencia, Sopron, 2011, Book of Abstracts P-102. Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos: Foszfán-foszforamidit ligandumokkal képzett aszimmetrikus hidrogénező ródiumkomplexek vizsgálata és felhasználása zöld kémiai reakciókban, 46. Komplexkémiai Kollokvium, Mátrafüred, 2012, Book of Abstracts p. 20. Szabolcs Balogh, Gergely Farkas, József Madarász, József Kovács, Áron Szöllősy, László Ürge, Ferenc Darvas, József Bakos: Aszimmetrikus hidrogénezés a zöld kémia alapelveinek figyelembevételével 40. Műszaki Kémiai Napok, Veszprém, 2012, Book of Abstracts p Szabolcs Balogh, Gergely Farkas, Áron Szöllősy, József Bakos: Asymmetric catalytic hydrogenation with rhodium complexes of new phoshine-phosphoramidite ligands. 19th EuCheMS International Conference on Organometallic Chemistry, Toulouse, France, 2011, Book of Abstracts P-173. Gergely Farkas, Szabolcs Balogh, Zsófia Császár, Alíz Tresztenyák, Áron Szöllősy, József Bakos: Nagyhatékonyságú katalizátorrendszerek kifejlesztése biológiailag aktív vegyületek királis építőelemeinek előállítására. MKE Vegyészkonferencia, Hajdúszoboszló, 2013, Book of Abstracts O-19 (p. 43). Szabolcs Balogh, Gergely Farkas, Alíz Tresztenyák, Áron Szöllősy, József Bakos: Highly effective phosphine-phosphoramidite ligands for asymmetric hydrogenation of α,βunsaturated enol ester phosphonates. 20th EuCheMS Conference on Organometallic Chemistry, St Andrews, Scotland, 2013, Book of Abstracts. Szabolcs Balogh, Gergely Farkas, Alíz Tresztenyák, Áron Szöllősy, József Bakos: Highly effective phosphine-phosphoramidite ligands for asymmetric hydrogenation of α,βunsaturated enol ester phosphonates. 20th EuCheMS Conference on Organometallic Chemistry, St Andrews, Scotland, 2013, Book of Abstracts P-76A. 12