Synthesis of heterocycles and their transformations applying organometallic reagents János Faragó MSc in chemisty Supervisor: Dr. András Kotschy associate professor Chemistry PhD School Head: Prof. György Inzelt Synthetic chemistry, materials science and biomolecular chemistry PhD program Head of the program: Prof. István Tamás Horváth Eötvös Loránd University Institute of Chemistry Budapest, 2008.
1. Introduction Metalorganic reagents play an important role in today s chemical synthesis. A vast number of examples of their application can be found in the literature, where they are used either in catalytic amounts (cross-coupling reactions, alkene metathesis, polymerization etc.) or in stoichiometric quantities (Grignard-reagents, organolithium compounds etc.). ur research was based on the above mentioned fields. The purpose of our research was to investigate how various tetrazine derivatives react with organometallic reagents. Tetrazine derivatives are generally considered as electron deficient having an affinity towards nucleophilic reagents. It was previously described in the literature that 2,6-bis(methylthio)-tetrazine reacts with Grignard-reagents to give a unique reaction typical for tetrazines 1, the so called azaphilic addition (Figure 1). The aim of our work was to find out how the polarity of the organometallic reagent and the substitution of the tetrazine compound influences the reaction. We hoped that the reaction proceeds towards nucleophilic substitution versus azaphilic addition. CH 2 CH 3 CH 3 CH 2 Mg THF, -78 C H Figure 1. Azaphilic addition on 3,6-bis(methiltio)-1,2,4,5-tetrazine Another purpose of this work was to investigate if a recently described transition metal catalyzed ring closure reaction 2 can be extended to the palladium catalyzed synthesis of benzofuran derivatives. The synthetic procedure started form aryl aldehydes, which were easily available in high quantities. The key intermediates of the ring closure were the aryl bromobenzyl ketone derivatives (Figure 2). + CH palladium ligand base Figure 2. Planned synthesis of benzofuran derivatives 1 M. C. Wilkes J. Heterocyclic Chem. 1991, 28 1163. 2 Z. Vincze, A.B. Bíró, M. Csékei, G. Timári, A. Kotschy Synthesis, 2006, 1375. 2
2. Results 2.1. Reaction of tetrazine derivatives with organometallic reagents In the first part of my PhD work the conversion of 3,6-disubstituted tetrazine derivatives (Figure 3, Ia-e) initiated by organometallic compounds was investigated. An important parameter when choosing the appropriate starting compounds was that they should contain a good leaving group. Compound Ic was an exception that was selected for comparison. Ia Ib Ic Id Cl Ie Figure 3. The studied tetrazine derivatives The organometallic compounds used in our experiments were either commercially available or could be prepared by the transmetalation reaction of n-butyllithium with the appropriate transition metal salt. rganometallic reagents were added at -78 C to the THF solution of the tetrazine derivatives under inert atmosphere and after isolation and purification the structure of the synthesized products was characterized by various spectroscopic methods. (Figure 4) R 1 R-M H R 1 R R 1 H + + H R + MXn I II III IV V R 1, :, MeS,,, Cl R: Bu-, Ph-, allil Figure 4. Reactions of tetrazin derivatives with organometallic reagents We observed that in the conversion of tetrazine derivatives (I) initiated by organometallic compounds the main reaction route was the azaphilic addition, where the reacting organic group connects to the nitrogen atom of the tetrazine ring, and 1,4-dihydro tetrazines (II) were identified 3
as products. Depending on the organometallic compound, reduction of tetrazine ring (III), nucleophilic substitution reaction initiated by a butoxide moiety (IV) and the formation of coordination compounds (V) were also observed besides the azaphilic addition. We also carried out experiments to find out where the butoxide group of products IV came from. We established that depending on the reaction circumstances either substitution by a metal butoxide that was produced from reductive ring opening of THF (used as solvent), was responsible for the above mentioned phenomenon (Figure 5, path i), or the azaphilic product (II) suffered oxidative rearrangement initiated by oxygen (air) (Figure 5, path ii). R BuM i Bu R oxidativ transformation ii H Bu R R:, Figure 5. The possible ways of formation of buthoxytetrazine derivatives II. Synthesis of benzofuran derivatives In the second part of my PhD work, we investigated the synthesis of benzofuran derivatives starting from aryl bromobenzyl ketones. ur developed procedure required easily available aryl aldehydes as starting materials. The main steps of the synthetic pathway (Figure 6) were the following. SH SH S CH S icl VI 2, DCM VII n BuLi IX Pd / L base VIII S S Hg(Ac) 2 / HgCl 2, CaC 3 aq. MeC X IX Figure 6. ur synthetic strategy for the preparation of benzofuran derivatives 4
- In the first step of the synthesis 2-substituted 1,3-dithianes were prepared in excellent yield from aryl aldehydes (VII). - In the second step of the synthesis dithiane-protected ketones (VIII) were prepared in good yield. We introduced the benzyl group by deprotonating the aryldithianes and alkylation with o- bromobenzyl bromide. - Removing the protecting group of the dithiane-protected ketones (VIII) was carried out in various yields. We found that the preparation of aryl 2-bromobenzyl ketones (IX), which were starting materials of the ring closure was complicated. If the 1,3-dithiane had a 4-pyridyl group or an ortho-substituted aryl group as substituent in the 2-position, then removal of the protecting group was impossible or worked with only with very low efficiency. - We carried out the optimization of the palladium catalyzed ring closure of aryl 2-bromobenzyl ketones (IX) leading to 2-arylbenzofurans (X). The optimum temperature of the reaction was 100-110 C. At lower temperatures the reaction rate considerably decreased, and at higher temperatures decomposition of the starting material was observed. From the available palladium sources (Pd 2 (dba) 3, Pd(Ac) 2, PdCl 2, Pd(PPh 3 ) 2 Cl 2, allylpalladium chloride) ring closure reaction was only observed using Pd 2 (dba) 3 and Pd(Ac) 2, respectively. We investigated also the effect of bases on the ring closure reaction and we concluded that the choice of base has a big importance. When applying Cs 2 C 3, benzofurans could be obtained in high yield, whereas when other bases (K 2 C 3, TEA, DIPA, DIPEA, ame, t BuK) were used, the desired product was not present. We also studied the effect of various ligands on the ring closure reaction. We only observed mentionable ring closure reaction using Xantphos and ipr-hc ligands from the tested ligands listed in Figure 7. We also observed that matching of the ligand and solvent has particular importance. Xantphos proved to be efficient in DMA and DMF, whereas the ipr-hc- ligand was efficient only in apolar solvents like o-xylene. Using Xantphos in apolar o-xylene did not yield the desired benzofuran derivatives. 5
+ + + saturated ipr-hc ipr-hc Mes-HC + PPh 2 PPh 2 PPh 2 Fe PPh 2 saturated Mes-HC Xantphos dppf PPh 3 P(Cy) 3 P(o-tolyl) 3 t Bu 3 P*HBF 4 Figure 7. ur studied ligands Using the optimized ring closure reaction circumstances we successfully managed to synthesize several benzofuran derivatives. The efficiency of the reactions was strongly dependent on the connecting aryl group. 6
3. Scientific publications, presentations Scientific publications 1. The azaphilic addition of organometallic reagents on tetrazines: scope and limitations János Faragó, Zoltán ovák, Gitta Schlosser, Antal Csámpai and András Kotschy Tetrahedron, 2004, 60, 1991-1996. 2. The Inverse Electron-Demand Diels-Alder Reaction in Polymer Synthesis 5. Preparation and Model Reactions of some Electron-Rich Bis-dienamines. András Kotschy, János Faragó, Antal Csámpai, David M. Smith Tetrahedron, 2004, 60, 3421-3425. 3. The synthesis of benzo[b]furans in the palladium-hc catalyzed ring closure of o- bromobenzyl ketones János Faragó, András Kotschy közlésre elküldve ral presentations 1. Új tetrazinszármazékok szintézise Faragó János, ovák Zoltán, Kotschy András MTA Heterociklusos kémiai munkabizottsági ülés Balatonszemes, 2001. 2. The selective synthesis of new tetrazine derivatives János Faragó, Zoltán ovák, András Kotschy 18th International Congress on Heterocyclic Chemistry Yokohama, Japan, 2001, Abstracts D-25 3. Transition Metal Catalyzed Synthesis of Heterocyclic Compounds Beatrix Bostai, Márton Csékei, János Faragó, Zoltán ovák, Zoltán Vincze and András Kotschy Hungarian-American Workshop on Molecular Catalyst Design for Green Chemistry Budapest, Magyarország, 2002, Abstracts p. 12. 4. Metal Mediated Synthesis of Heterocyclic Compounds János Faragó, Zoltán ovák, András Kotschy Invited lecture at the University of Miami University of Miami at Coral Gables, FL, USA 2002. 5. Transition Metal Catalyzed Synthesis of Heterocyclic Compounds Beatrix Bostai, Márton Csékei, János Faragó, Zoltán ovák, Zoltán Vincze and András Kotschy Green Chemistry in Hungary Symposium Budapest, Magyarország, 2002. 6. Átmenetifém-katalízis a heterociklusos kémiában Bostai Beatrix, Csékei Márton, Faragó János, agy András, ovák Zoltán, Vincze Zoltán, Timári Géza és Kotschy András MTA uckner termi előadás Budapest, 2002. október 25. 7
7. Tetrazinok reakciói nukleofilekkel hol történik a támadás Bostai Beatrix, Faragó János, ovák Zoltán, Lévay Béla, Kotschy András MTA Elméleti Szerveskémiai munkabizottsági ülés Budapest, 2003. 8. Azofil addíció heterociklusokon: tények és feltételezések Faragó János, Lőrincz Krisztián, ovák Zoltán, Kotschy András MTA Heterociklusos kémiai munkabizottsági ülés Balatonszemes, 2003, Május 27-28. 9. Tetrazinok reakciói nukleofilekkel Bostai Beatrix, Faragó János, ovák Zoltán, Kotschy András MKE Vegyészkonferencia Hajdúszoboszló, 2003, Abstracts 10. Tetrazinok szelektív átalakításai nukleofilekkel Beatrix Bostai, János Faragó, Márton Csékei, Zoltán ovák, and András Kotschy EMT Vegyészkonferencia Kolozsvár, 2003, Abstracts p. 250. 11. Elektronhiányos nitrogén-heterociklusok reakciói fémorganikus reagensekkel Lőrincz Krisztián, Faragó János, agy Tibor, Csámpai Antal, Kotschy András MTA Elméleti szerveskémiai munkabizottsági ülés Budapest, 2005. 12. Heterociklusos vegyületek átmenetifém-katalizált szintézise Bíró A. Beatrix, Faragó János, agy András, ovák Zoltán, Kotschy András MKE Vegyészkonferencia, Előadásösszefoglalók, p. 32. Hajdúszoboszló, 2005. Poster presentations 1. Synthesis of new tetrazine derivatives Zoltán ovák, János Faragó, András Kotschy Winter School on rganic Reactivity; January 7-14, 2001, essanone, Italy, P B/25 2. Új tetrazinszármazékok szintézise Faragó János, ovák Zoltán, Csámpai Antal, Kotschy András MKE rszágos Vegyészkonferencia Hajdúszoboszló, 2001, Előadásösszefoglalók P-20 3. Selective synthesis of new tetrazine derivatives János Faragó, Zoltán ovák, András Kotschy 18th International Congress on Heterocyclic Chemistry Yokohama, Japan, 2001, Abstracts 2-P-113 4. Selective synthesis of new tetrazine derivatives János Faragó, Zoltán ovák, Beatrix Bostai and András Kotschy Bürgenstock Conference on Stereochemistry Bürgenstock, Switzerland, 2002. 8
5. The synthesis of non-symmetrical tetrazines János Faragó, Zoltán ovák, Beatrix Bostai and András Kotschy 9th Blue Danube Symposium on Heterocyclic Chemistry Tatranska Lomnica, Slovakia, 2001, Abstracts P-67 6. The synthesis of new tetrazine derivatives János Faragó, Zoltán ovák, Beatrix Bostai and András Kotschy Gordon Research Conference on Heterocyclic Chemistry ewport, RI, USA, 2002. 7. Metal mediated synthesis of asymmetrically substituted tetrazine derivatives Zoltán ovák, János Faragó, Beatrix Bostai and András Kotschy 2nd Balticum rganicum Symposium Vilnius, Lituania, 2002, Abstracts 8. The first cross-coupling reactions on tetrazines Zoltán ovák, János Faragó, Beatrix Bostai and András Kotschy 13th International Symposium on Homogenous Catalysis Tarragona, Spain, 2002, Abstracts P-127 9. Cross-coupling vs. azaphilic addition of organometallic reagents and tetrazines Zoltán ovák, János Faragó, Beatrix Bostai, András Kotschy 9th International Kyoto Conference on rganic Chemistry Kyoto, Japan, 2003, Abstracts PB-062 10. Unprecedented ucleophilic Attack on Tetrazines by Heterocyclic Carbenes Beatrix Bostai, János Faragó, Zoltán ovák, András Kotschy Summer School on Green Chemistry Velence, laszország, 2004. 11. Palladium catalysed synthesis of nitrogen and oxygen heterocycles János Faragó, A. Beatrix Bíró, András Kotschy 21st European Colloquium on Heterocyclic Chemistry Sopron, September 12-15, 2004, Book of abstracts MP-33 12. Azaphilic addition a transformation unique to heterocycles Krisztián Lőrincz, János Faragó, András Kotschy 21st European Colloquium on Heterocyclic Chemistry Sopron, September 12-15, 2004, Book of abstracts TP-04 13. Azaphilic addition - the irregular attack of organometallic reagents on heterocycles, Synthesis of 6-ethynylpurine derivatives with palladium catalysis Krisztián Lőrincz, Tibor Zs. agy, Antal Csámpai, János Faragó, András Kotschy XVI FECHEM Conference on rganometallic Chemistry Budapest, September 3-8, 2005, Abstracts p. 250. 14. Palladium catalyzed formation and functionalization of five membered heterocycles János Faragó, A. Beatrix Bíró, András Kotschy Frontiers in catalysis symposium Visegrád, September 8-10, 2005, Book of abstracts 9