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.). Our 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 tetrazines1, 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. CH2CH3 N N SCH3
SCH3 N N
CH3CH2MgBr THF, -78°C
N N SCH3
SCH3 N N 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 reaction2 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).
Ar
Br
+ Ar CHO
Br
Br
O
palladium ligand Ar
base
O
Figure 2. Planned synthesis of benzofuran derivatives
1 2
M. C. Wilkes J. Heterocyclic Chem. 1991, 28 1163. Z. Vincze, A.B. Bíró, M. Csékei, G. Timári, A. Kotschy Synthesis, 2006, 1375.
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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. N N
N
N N N
N
SCH 3 N N
N N
N
N N
N N
N N
N N
N Cl N N
N N
N
SCH 3 N
Ib Ia
N
O
Ic
N N
O
Id
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. Organometallic 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
N N
R N N
R
R-M
2
N HN
R R
N N R
I
1
+
1
NH N + N N
N HN
2
OR
R
2
MXn
N N + N N R
III
II
N
N
2
N N R
IV
2
V
R1 , R2 :
N
N
,
MeS
,
N
,
N
O,
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).
N N N
N
OBu BuOMBr
N N
N N
i
N N
oxidativ transformation
ii
N N HN
R
R
N N N
Bu
R R:
N
N
,
N O
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. Our developed procedure required easily available aryl aldehydes as starting materials. The main steps of the synthetic pathway (Figure 6) were the following. SH SH
Ar CHO NiCl2, DCM VI
Ar
Br
Ar
Br
S S
nBuLi
VII
S
Hg(OAc)2 / S HgCl , CaCO 2 3 aq. MeCN
Br
Br
O
Pd / L base
IX
Br
O
IX
VIII Ar
Ar
Ar O
X
Figure 6. Our synthetic strategy for the preparation of benzofuran derivatives
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- 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 obromobenzyl 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 (Pd2(dba)3, Pd(OAc)2, PdCl2, Pd(PPh3)2Cl2, allylpalladium chloride) ring closure reaction was only observed using Pd2(dba)3 and Pd(OAc)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 Cs2CO3, benzofurans could be obtained in high yield, whereas when other bases (K2CO3, TEA, DIPA, DIPEA, NaOMe, tBuOK) 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-NHC 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-NHC- ligand was efficient only in apolar solvents like o-xylene. Using Xantphos in apolar o-xylene did not yield the desired benzofuran derivatives.
5
+
N
N
N
saturated iPr-NHC
+
N
iPr-NHC PPh2
+
N
N
+
Mes-NHC
PPh2
PPh2
O
N
N
Fe PPh2
saturated Mes-NHC
PPh3
Xantphos
P(Cy) 3
dppf
P(o-tolyl)3
tBu P*HBF 3 4
Figure 7. Our 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.
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3. Scientific publications, presentations
Scientific publications 1. The azaphilic addition of organometallic reagents on tetrazines: scope and limitations János Faragó, Zoltán Novák, 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-NHC catalyzed ring closure of obromobenzyl ketones János Faragó, András Kotschy közlésre elküldve Oral presentations 1. Új tetrazinszármazékok szintézise Faragó János, Novák Zoltán, Kotschy András MTA Heterociklusos kémiai munkabizottsági ülés Balatonszemes, 2001. 2. The selective synthesis of new tetrazine derivatives János Faragó, Zoltán Novák, 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 Novák, 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 Novák, 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 Novák, 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, Nagy András, Novák Zoltán, Vincze Zoltán, Timári Géza és Kotschy András MTA Bruckner termi előadás Budapest, 2002. október 25.
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7. Tetrazinok reakciói nukleofilekkel – hol történik a támadás Bostai Beatrix, Faragó János, Novák Zoltán, Lévay Béla, Kotschy András MTA Elméleti Szerveskémiai munkabizottsági ülés Budapest, 2003. 8. Azofil addíció heterociklusokon: tények és feltételezések Faragó János, Lőrincz Krisztián, Novák Zoltán, Kotschy András MTA Heterociklusos kémiai munkabizottsági ülés Balatonszemes, 2003, Május 27-28. 9. Tetrazinok reakciói nukleofilekkel Bostai Beatrix, Faragó János, Novák Zoltán, Kotschy András MKE Vegyészkonferencia Hajdúszoboszló, 2003, Abstracts 10. Tetrazinok szelektív átalakításai nukleofilekkel Beatrix Bostai, János Faragó, Márton Csékei, Zoltán Novák, and András Kotschy EMT Vegyészkonferencia Kolozsvár, 2003, Abstracts p. 250. 11. Elektronhiányos nitrogén-heterociklusok reakciói fémorganikus reagensekkel Lőrincz Krisztián, Faragó János, Nagy Tibor, Csámpai Antal, Kotschy András MTA Elméleti szerveskémiai munkabizottsági ülés Budapest, 2005. 12. Heterociklusos vegyületek átmenetifém-katalizált szintézise Bíró A. Beatrix, Faragó János, Nagy András, Novák Zoltán, Kotschy András MKE Vegyészkonferencia, Előadásösszefoglalók, p. 32. Hajdúszoboszló, 2005.
Poster presentations 1. Synthesis of new tetrazine derivatives Zoltán Novák, János Faragó, András Kotschy Winter School on Organic Reactivity; January 7-14, 2001, Bressanone, Italy, PO B/25 2. Új tetrazinszármazékok szintézise Faragó János, Novák Zoltán, Csámpai Antal, Kotschy András MKE Országos Vegyészkonferencia Hajdúszoboszló, 2001, Előadásösszefoglalók PO-20 3. Selective synthesis of new tetrazine derivatives János Faragó, Zoltán Novák, András Kotschy 18th International Congress on Heterocyclic Chemistry Yokohama, Japan, 2001, Abstracts 2-PO-113 4. Selective synthesis of new tetrazine derivatives János Faragó, Zoltán Novák, Beatrix Bostai and András Kotschy Bürgenstock Conference on Stereochemistry Bürgenstock, Switzerland, 2002. 8
5. The synthesis of non-symmetrical tetrazines János Faragó, Zoltán Novák, Beatrix Bostai and András Kotschy 9th Blue Danube Symposium on Heterocyclic Chemistry Tatranska Lomnica, Slovakia, 2001, Abstracts PO-67 6. The synthesis of new tetrazine derivatives János Faragó, Zoltán Novák, Beatrix Bostai and András Kotschy Gordon Research Conference on Heterocyclic Chemistry Newport, RI, USA, 2002. 7. Metal mediated synthesis of asymmetrically substituted tetrazine derivatives Zoltán Novák, János Faragó, Beatrix Bostai and András Kotschy 2nd Balticum Organicum Symposium Vilnius, Lituania, 2002, Abstracts 8. The first cross-coupling reactions on tetrazines Zoltán Novák, 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 Novák, János Faragó, Beatrix Bostai, András Kotschy 9th International Kyoto Conference on Organic Chemistry Kyoto, Japan, 2003, Abstracts PB-062 10. Unprecedented Nucleophilic Attack on Tetrazines by Heterocyclic Carbenes Beatrix Bostai, János Faragó, Zoltán Novák, András Kotschy Summer School on Green Chemistry Velence, Olaszország, 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. Nagy, Antal Csámpai, János Faragó, András Kotschy XVI FECHEM Conference on Organometallic 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
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