JOHANNES KEPLER UNIVERSITÄT LINZ JKU
Faculty of Engineering and Natural Sciences
Enantioselective epoxidation reactions using chiral ammonium salts
Master‘s Thesis
to confer the academic degree of
Diplom-Ingenieurin
in the Master‘s program
Technical Chemistry
Submitted by: Katharina Zielke
At the: Institute of Organic Chemistry
Advisor: Assoc. Univ.-Prof. Dr. Mario Waser
Linz, October 2015
1 Contents
Eidesstattliche Erklärung 5
Acknowledgements 6
Curriculum Vitae 7
Abstract 9
Zusammenfassung 10
1 Introduction 11 1.1 Epoxides ...... 11 1.2 Epoxides from alkenes ...... 11 1.2.1 Prilezhaev epoxidation ...... 12 1.2.2 Sharpless epoxidation ...... 13 1.2.3 Jacobsen-Katsuki epoxidation ...... 15 1.2.4 Shi asymmetric epoxidation ...... 17 1.3 Epoxides from carbonyl compounds ...... 18 1.3.1 The Darzens glycidic ester condensation ...... 19 1.3.2 The Corey-Chaykovsky reaction ...... 20 1.3.2.1 Diastereoselectivity in Sulfur-ylide-mediated reactions . . . 21 1.3.2.2 Enantioselectivity in sulfur-ylide-mediated reactions ..... 23 1.3.2.3 Catalytic use of sulfur ylides ...... 24 1.4 Ammonium ylides in epoxidation reactions ...... 27 1.4.1 Investigations by Jonczyk et al. and Kimachi et al...... 27 1.4.2 Diastereoselectivity in reactions of ammonium ylides with aldehydes 29
2 Results and Discussion 30 2.1 Motivation of this work ...... 30 2.2 Previous experiments from our group members ...... 30 2.3 DABCO-derived chiral ammonium acetamides ...... 33 2.3.1 Reactions using the DABCO-derivative 62 ...... 33 2.3.2 Reactions using the camphor-derivative 68 ...... 34
2 2.4 Proline-derived chiral ammonium acetamides ...... 35 2.4.1 Synthesis of different proline-based ammonium salts and their use . 36 2.4.2 Variations on R1 ...... 37 2.4.3 Variations on R2 ...... 39 2.4.4 Attempted synthesis of further ammonium salts ...... 40 2.4.5 Screening of the best-suited reaction conditions ...... 42 2.4.6 Crystal structure of the synthesized ammonium salt 63g ...... 43 2.4.7 Application scope ...... 44 2.4.8 Attempted catalytic use of the amine ...... 47 2.4.9 Recycling of the amine after epoxidation reactions ...... 47 2.5 Summary and Outlook ...... 49
3 Experimental part 51 3.1 General remarks ...... 51 3.2 Syntheses ...... 51 3.2.1 Synthesis of ((2S,3S)-2,3-diphenyl-1,4-diazabicyclo[2.2.2]octane) 65 51 3.2.2 Attempted synthesis of camphor-based amine 68 ...... 53 3.2.3 Synthesis of (2-bromo-N,N-diethylacetamide) ...... 55 3.2.4 Protection of L-proline ...... 55 3.2.5 General procedure I: Grignard-reaction ...... 57 3.2.6 General procedure II: Deprotection of the arylated amines ...... 57 3.2.7 General procedure III: Closing the second 5-membered ring ..... 58 3.2.8 General procedure IV: Synthesis of chiral ammonium acetamides . . 58 3.2.9 Synthesis of DABCO-derived ammonium salt 62 ...... 59 3.2.10 Synthesis of ammonium salt 63a (R1 = phenyl, R2 = H) ...... 60 3.2.11 Synthesis of ammonium salt 63b (R1 = naphthyl, R2 = H) ...... 63 3.2.12 Synthesis of ammonium salt 63c (R1 = biphenyl, R2 = H) ...... 66 3.2.13 Synthesis of ammonium salt 63d (R1 = p-OMe-phenyl, R2 = H) . . . 70 3.2.14 Synthesis of ammonium salt 63e (R1 = p-F-phenyl, R2 = H) ..... 73
1 2 3.2.15 Synthesis of ammonium salt 63f (R = p-CF3-phenyl, R = H) .... 76 3.2.16 Synthesis of ammonium salt 63g (R1 = phenyl, R2 = cyclohexyl) . . . 80 3.2.17 Synthesis of ammonium salt 63h (R1 = phenyl, R2 = tert-butyl) .... 82 3.2.18 Synthesis of ammonium salt 63i (R1 = phenyl, R2 = n-butyl) ..... 84
3 3.2.19 Synthesis of ammonium salt 63j (R1 = phenyl, R2 = benzyl) ..... 85 3.2.20 General procedure V ...... 88 3.2.21 Epoxidation reactions ...... 88 3.2.21.1 Epoxidation reaction for testing all synthesized ammonium salts 88 3.2.21.2 Application scope of the asymmetric epoxidation ...... 89
4 Literature 95
4 Eidesstattliche Erklärung
Ich erkläre an Eides statt, dass ich die vorliegende Diplomarbeit selbstständig und ohne fremde Hilfe verfasst, andere als die angegebenen Quellen und Hilfsmittel nicht benutzt bzw. die wörtlich sinngemäß entnommenen Stellen als solche kenntlich gemacht habe. Die vorliegende Diplomarbeit ist mit dem elektronisch übermittelten Textdokument identisch.
Linz, Oktober 2015
5 Acknowledgements
First, I would like to thank my parents for giving me the opportunity to study and my whole family for their love and support. I am very thankful to be blessed with very good friends who sometimes forced me to take some time off from studies when I needed to.
I am very thankful to Univ. Prof. Dr. Norbert Müller for giving me the opportunity to work at his institute. Furthermore, I would like to thank all colleagues from the Institute of Organic Chemistry for the relaxed and friendly working atmosphere.
Special gratitude goes to Assoc. Prof. Dr. Waser for his whole support, encouragement and advice.
Last but not least, I would like to thank my study colleagues for their support and friendship not only during this thesis but through my whole studies.
6 Curriculum Vitae
Personal Data
Date of Birth November 13, 1990
Place of Birth Wels
Nationality Austria
School education
09/1997 - 07/2001 VS Stadl-Paura
09/2001 - 07/2005 Hauptschule Stadl-Paura
09/2005 - 07/2010 HAK Lambach
June, 2010 Higher education entrance qualification
University education
10/2010 - 02/2014 Bachelor’s programme “Technische Chemie” at the JKU Linz
02/2014 - now Master’s programme “Technische Chemie”
Work experience abroad
07/2014 - 09/2014 Hokkaido University, Japan; Practical course ”Praktikum aus Chemis- cher Technologie Anorganischer Stoffe”
7 Work experience
07/2010 - 09/201 Sport Eybl & Sports Experts GmbH, office work
10/2010 - 04/2011 Sport Eybl & Sports Experts GmbH, part-time office work
08/2011 - 09/2011 EWE Küchen, production
07/2012 - 09/2012 BWT Austria GmbH, laboratory work, testing of ion-exchange- chomatography
11/2012 - 01/2013 Tutorium “Praktikum aus Allgemeiner Chemie”
05/2013 - 06/2013 Tutorium “Praktikum Chemie für Kunststofftechnik”
07/2013 - 09/2013 Sandoz, Oncology Incectables, laboratory work, quality control of in- coming chemicals
09/2013 - 10/2015 Forstner, part-time job as waitress
11/2013 - 02/2014 Tutorium “Praktikum aus Allgemeiner Chemie”
05/2014 - 06/2014 Tutorium “Praktikum Chemie für Kunststofftechnik”
11/2014 - 01/2015 Tutorium “Praktikum aus Allgemeiner Chemie”
05/2015 - 06/2015 Tutorium “Praktikum Chemie für Kunststofftechnik”
05/2015 - 06/2015 Tutorium “Praktikum aus Organischer Chemie II”
04/2015 - 05/2015 Tutorium “Praktikum aus Organischer Chemie für Molekulare Biolo- gen”
10/2015 - 01/2016 Tutorium “Praktikum aus Organischer Chemie I”
8 Abstract
During this master thesis the enantioselective synthesis of epoxides was investigated. Epox- ides are very important structures not only for synthetic strategies, but they are also found in many natural products. Because these three-membered rings are so important, several different approaches for their synthesis have been developed. Epoxides are usually syn- thesized starting either from alkenes or aldehydes. Known reactions starting from alkenes are the Prilezhaev, the Sharples, the Jacobsen-Katsuki and the Shi-epoxidation. Famous examples, which start from aldehydes, are the Darzens reaction and the Corey-Chaykovsky reaction. Over the last years, the synthesis of epoxides using ammonium ylides - which are generated from ammonium salts - was reported. The mechanism is closely related to the Corey-Chaykovsky-reaction because the reacting species in both cases are ylides.
Diastereoselective approaches for the synthesis of glycidic amides using ammonium ylides have been developed. It was shown that amide-stabilized ylides are very good educts and an enantioselective synthesis of epoxides using chiral ammonium ylides was developed. Promising results were obtained using a DABCO-derivative and an L-Proline-derivative. In the case of the DABCO-derivative very high enantioselectivities but low yields and for the L-Proline derivative moderate enantioselectivities but high yields were achieved.
The next step was to improve these results which was first attempted with the DABCO- derivative. However, no better results were obtained. The reaction conditions were opti- mized for the best known L-proline ammonium salt. After finding the best-suited reaction conditions, different ammonium salts for the L-proline derivative were synthesized, the best one showing high enantioselectivities (86 %) in combination with a high yield (88 %) in the tested epoxidation reaction. The reaction conditions were again optimized resulting in even higher enantioselectivity, but at lower yields. The application scope of this promising am- monium salt was tested. High yields and enantioselectivities were obtained for most tested aldehydes, however aliphatic aldehydes performed worse than aromatic ones.
9 Zusammenfassung
Ziel dieser Masterarbeit war die enantioselektive Synthese von Epoxiden. Diese cycli- schen Ether sind bekannte Strukturen welche nicht nur in vielen Naturprodukten vorkom- men, sondern auch sehr wichtige Elemente für Synthesen darstellen. Aufgrund der Be- deutung dieser dreigliedrigen Ringe wurden verschiedene Synthesewege zu deren Her- stellung entwickelt. Ausgehend von Alkenen sind die Prilezhaev, die Jacobsen-Katsuki und die Shi-epoxidierung zu nennen. Geht man von Aldehyden aus, sind die Darzens- Reaktion und die Corey-Chaykovsky-Reaktion am bekanntesten. Eine neue Art Epoxide herzustellen wurde in den letzten Jahren immer bekannter: Ausgehend von Ammonium- salzen werden Ammonium-Ylide hergestellt welche mit Aldehyden zu Epoxiden umgesetzt werden können. Der Mechanismus ist nahe an der Corey-Chaykovsky-Reaktion angelehnt, da in beiden Fällen Ylide die reagierende Spezies darstellen. In den letzen Jahren wurde gezeigt, dass Epoxide auch trans-diastereoselektiv mittels Ammonium-Yliden hergestellt werden können. Amid-stabilisierte Ylide ergaben hierbei sehr gute Ergebnisse und es wurden auch schon die ersten Schritte Richtung enantioselektiver Synthese von Epoxi- den aufgezeigt. Unter den getesteten chiralen Aminen zeigte ein DABCO-Derivat sehr hohe Enantioselektivitäten bei sehr niedriger Ausbeute, während ein Prolin-Derivat hohe Ausbeute bei moderater Enantioselektivität lieferte. Der erste Schritt dieser Masterarbeit bestand in der Optimierung der Reaktion mit den oben genannten chiralen Aminen. Es konnten keine besseren Ergebnisse mit dem DABCO-Derivat erzielt werden, daher wurde der Fokus auf die Prolin-Derivate gelegt. Es wurden verschiedene chirale Ammoniumsalze synthetisiert und deren Reaktion mit Benzaldehyd in Bezug auf Ausbeute und Enantiose- lektivität untersucht. Hierbei lieferte das beste Ammoniumsalz eine Ausbeute von 88 % und einen ee von 86%.Die Reaktionsbedingungen wurden erneut optimiert und es kon- nten noch höhere Enantioselektivitäten erreicht werden, jedoch bei niedrigerer Ausbeute. Der Anwendungsbereich auf verschiedene Aldehyde wurde getestet. Dies ergab, dass die hohen Enantioselektivitäten bei guten bis hohen Ausbeuten mit vielen der getesteten Alde- hyde erreicht werden konnte. Es zeigte sich allerdings auch, dass aliphatische Aldehyde schlechter abschneiden als aromatische.
10 1 Introduction
1.1 Epoxides
Epoxides and aziridines are highly strained three-membered rings. They can be found in many natural products and are important synthetic intermediates because nucleophilic at- tack leads to a broad variety of products. This nucleophilic attack can be done with high or complete stereo- and regioselectivity, which makes epoxides extremely useful for stere- oselective synthesis. Because this structural element is of such high importance, different strategies have been developed to synthesize these heterocycles. The strategies can be divided into two groups depending on the starting material:
• epoxide formation from alkenes
• epoxide formation from carbonyl compounds
For each of these methods racemic as well as dia- and enantioselective approaches were developed. The next few chapters shall give a short overview on these methods.
1.2 Epoxides from alkenes
Different methods for epoxidation reactions starting from alkenes have been developed, both for racemic mixtures of epoxides and highly dia- and enantioselective approaches. These are the most prominent methods:
• Prilezhaev epoxidation
• Sharpless asymmetric epoxidation
• Jacobsen-Katsuki epoxidation
• Shi epoxidation
11 1.2.1 Prilezhaev epoxidation
One of the oldest methods is the epoxidation of alkenes via a reaction with a peracid to yield the corresponding epoxides (see Fig. 1.1), which was developed by the Russian chemist Nikolai A. Prilezhaev in 1909 [1, 2]. This very useful transformation is one of the widely used methods for the synthesis of racemic or achiral epoxides[3].
O O 1 3 O 1 3 R R R5 O H R R R1 R3 + R2 R4 R2 R4 0-30 °C, R2 R4 O inert organic solvent
1 solvent: CHCl3, CH2Cl2, benzene, 2 3 ether, acetone, dioxane R1-4 = H, alkyl, 5 aryl, alkynyl, R = Ph, m-Cl-C6H4, CH3, H, CF3, 3,5-dinitrophenyl CO2R Fig. 1.1 The Prilezhaev-reaction
The reaction is stereospecific with trans-alkenes giving the trans-epoxide and the cis- alkenes yielding cis-epoxides. The oxidation proceeds via a concerted mechanism called the ”butterfly-mechanism” where the electrophilic oxygen adds syn to the alkene and the hy- drogen simultaneously migrates to the carbonyl of the acid (see Fig. 1.2). If the substituents on the alkene are electron-donating, the reaction rate is increased[4, 5]. m-chloroperoxybenzoic acid (m-CPBA) is most frequently used as epoxidation agent because it is commercially available, stable and (because it is a solid) easy to handle. Other peracids like peroxyacetic acid are very unstable and need to be generated freshly prior to use [6].
4 4 R R R5 O 3 O R3 R R1 R3 O R5 O 2 4 O O 1 R R R1 H R 2 R2 R 2 O H O
3 5 3 2 4 R R R R R 4 O 1 3 R R4 R R O 2 4 O O R R R1 R3 2 H R R2 O R1 R1 3
Fig. 1.2 The mechanism of the Prilezhaev-reaction
12 The reaction is typically carried out under mild reaction conditions and gives good to very good yields. Side reactions may occur if functional groups that are sensitive to oxidation are present, e. g. if carbonyl groups are present a Bayer-Villiger-reaction can take place.
1.2.2 Sharpless epoxidation
The first highly enantioselective epoxidation method starting from alkenes was developed by K. B. Sharpless and T. Katsuki in 1980. They showed that allylic alcohols can be trans- ferred to epoxides with high yields and excellent enantiomeric excess (above 90 % ee) using a combination of TiIVtetraisopropoxide, enantiopure diethyltartrate and tert-butyl-hydroper- oxide[7].
The Ti-tartrate can be used in catalytic amounts to achieve high enantioselectivities with reactive allylic alcohols. Slower-reacting allylic alcohols, on the other hand, only reacted in a high enantioselective fashion if a stochiometric amount of the complex was used. In 1986 this issue was overcome by the addition of molecular sieves to the reaction mixture, which lead to high enantioselectivities at low catalyst loadings for a very broad range of allylic alcohols [8].
The presence of the hydroxyl group is essential to the reaction. It not only enhances the rate of reaction by providing a selective epoxidation of the allylic olefin in the presence of other olefins, but it is also crucial for the asymmetric induction. The reaction is mostly carried out in alcohol-free dichloromethane and most functional groups are tolerated except for free
D-(-)-diethyl tartrate (unnatural)
1 O R2 R O
R3 OH R2 R1 O OH 4
3 R OH Ti(Oi-Pr)4 (5-10 mol%) 2 1 activated molecular sieves R R DCM, low temperature O
O R3 OH D-(+)-diethyl tartrate (natural) 5
Fig. 1.3 The Sharpless epoxidation
13 amines, carboxylic acids, thiols and phosphines[8].
To start the reaction, the reagents form an asymmetric complex. In the first step of this com- plex formation, a ligand is exchanged from Ti(O-i-Pr)4 with DET. Subsequently, the resulting complex undergoes further ligand exchange with the allylic alcohol substrate and tert-butyl hydroperoxide. The structure of the catalyst is believed to have a dimeric structure with the hydroperoxide and the allylic alcohol occupying axial coordination sites on the titanium, which results in high enantiofacial selectivity (Fig. 1.4). This asymmetric complex can dif- ferentiate between the two faces of the allylic alcohol, if D-(-)-diethyltartrate is used, the oxygen will be delivered from the top face of the allylic alcohol, if the D-(+)-diethyl tartrate is used, the attack occurs from the bottom (see Fig. 1.3). These principles have been followed without exception in all epoxidation reactions of prochiral allylic alcohols up to now[8, 9].
1 OR R RO E O O R2 Ti O E O Ti O E 3 RO O O O R t-Bu
E = CO2R
Fig. 1.4 The proposed transition state in the Sharpless reaction
The presented principles of asymmetric epoxidation can also be used for a different purpose - namely kinetic resolution. If a substituent is positioned on C-1 (see Fig. 1.5) and the allylic alcohol is present as racemate, then in one case the larger substituent will point in the direction of oxygen delivery, whereas in the other enantiomer the larger substituent is oriented away from the oxygen delivery. The above described model is still valid, however the oxygen will be delivered faster to the less hindered side. If this rate difference becomes large enough, a kinetic resolution can be achieved[8].
14 D-(-)-diethyl tartrate (unnatural) O
2 R2 R 1 R1 R R4 H 3 R3 OH R OH 4 H R
Fig. 1.5 Diastereofacial selectivity in the epoxidation of substituted allylic alcohols[8]
1.2.3 Jacobsen-Katsuki epoxidation
One drawback of the Sharpless epoxidation is that the scope is limited to allylic (and maybe homoallylic) alcohols. This was overcome by E. N. Jacobsen and T. Katsuki who inde- pendently reported the use of chiral (salen)manganese(III)-complexes as catalysts for the enantioselective epoxidation of unfunctionalized alkyl- and aryl-substituted olefins[10, 11, 12].
R1 R2
R3 R4 N O N oxidant/solvent 8 O (III) N Mn O N Mn(V) O R1 R2 4 O oxidant: PhIO, NaOCl O -(salen)Mn(III)L R3 R L mCPBA L 6 L = Cl, OAc 7 9
2 2 R R 2 R1 = alkyl, O-alkyl, O- R = aryl, substituted aryl R3 = aryl, alkyl trialkylsilyl N N Mn N N O O Mn OAc 3 3 R1 O O R1 R R Cl
10 11 Jacobsen's catalysts Katsuki's catalysts
Fig. 1.6 The Jacobsen-Katsuki epoxidation and Jacobsen’s and Katsuki’s catalysts
Some of nature’s oxidizing agents - the porphyrin-complexes - are structurally and chemi- cally very similar to the used catalysts in the Jacobsen-Katsuki-epoxidation. Indeed, the frist
15 example of asymmetric epoxidation of simple olefins, which were catalyzed by chiral pro- phyrin complexes dates back to 1983[13]. Both, porphyrines and salen-based catalysts, are kinetically stable, sterically well defined and can catalyze the epoxidation of unfunctional- ized alkenes[14]. The advantage of salen-complexes is that they have potentially stereogenic carbon centers in the vicinity of the metal binding site, which makes it possible to transfer stereochemical information. The catalyst synthesis from chiral diamines is usually very ef- ficient and straightforward which allows the synthesis of a broad variety of catalysts[14].
The structure of the olefinic substrate, the nature of the axial donor ligand on the active oxomanganese species as well as the reaction temperature have a great influence on the enantioselectivity. It was shown that conjugated alkenes are better substrates than noncon- jugated ones and that cyclic and acyclic (Z)-1,2-disubstituted olefins are epoxidized with much higher enantioselectivities than terminal or E-alkenes[14]. The poor enantioselectivity observed for terminal alkenes was later circumvented by using m-CPBA as oxidant and by the development of a low-temperature protocol[15].
The mechanism is not fully understood because many different indermediates are possible, however, there is strong evidence that a (salen)MnV-oxo complex is the reactive intermedi- ate formed by oxidation of (salen)MnIII-complex. There exist different methods for describ- ing the enantioselectivity: either a "top-on"-approach, which is proposed by Jacobsen or a "side-on" approach, as suggested by Katsuki, of the olefin are possible (see Fig. 1.7 )[14].
S R RL
R Katsuki's proposed L Jacobsen's proposed "side-on"-approach "top-on"-approach RS
O N N Mn t-Bu O O t-Bu Cl
t-Bu t-Bu the best Jacobsen catalyst
Fig. 1.7 Model to explain the enantioselectivity in the Jacobsen-Katsuki-epoxidation
16 1.2.4 Shi asymmetric epoxidation
The limitations of the Sharpless-epoxidation to allylic alcohols was overcome with the Jacobsen- Katsuki-epoxidation, which works for many olefins. However, the epoxidation of trans- olefins having no allylic alcohol group with high enantioselectivity still remained problematic. This problem was adressed by using dioxiranes as oxygen-transferring species in a chiral surrounding. The dioxiranes are generated in-situ from oxone (potassium peroxomonosul- fate, KHSO5) and a chiral ketone and are able to transfer oxygen. The first use of dioxirane in asymmetric epoxidations dates back to 1984[16] and several other ketones have been tested in asymmetric epoxidations until 1996, when Shi et al. had a major breakthrough with fructose-derived ketone catalysts[17, 18, 19]. These new catalysts gave very high enan- tioselectivities in epoxidation reactions and could easily and cheaply be prepared via two steps from D- or L-Fructose. Fig. 1.8 shows the reaction equation with the most favorable reaction conditions as well as the used catalysts[14].
R1 R3 Shi's catalyst R1 R3 R1 R3 or R2 R2 R2 KHSO5 O O or 30% H O (3 equiv.) 12 2 2 13 14 H2O/CH3CN; pH 7-10 R1-3 = H, alkyl, aryl, 50-90% yield, >90% ee substituted alkyl, substituted aryl, alkenyl,
alkynyl O O O O O O (R) O (S) (R) O (S) O O (R) O (S) O 15 16 Shi's catalyst Shi's catalyst derived from derived from D-fructose L-fructose
Fig. 1.8 The Shi asymmetric epoxidation and Shi’s catalyst
The pH needs to be very well-controlled in this reaction: if the pH is too high, the ox- one will decompose, whereas at lower pH-values the catalyst decomposes via a Bayer- Villiger-oxidation[20]. Systematic investigations showed that the optimum pH is at around
17 10.5, which is also beneficial for the stability of the epoxides. Typically, catalyst loadings of 20-30mol% are used and the highest enantioselectivities are obtained for different un- functionalized trans- and trisubstituted olefins, whereas the enantioselectivities are lower for cis-disubstituted and terminal olefins[19]. In Fig. 1.9, the catalytic cycle for the epoxida- tion using Shi’s catalyst is given. There are two extreme transition state geometries: spiro and planar. Out of many different possible transition states, one spiro and one planar tran- sition state are the favored ones because of least steric repulsion. However, the spiro and the planar transition state give the opposite stereochemistry for the epoxide product. In Fig. 1.9 the spiro-transition state is shown and almost all examples of trans-disubstituted and trisubstituted, which were studied with Shi’s catalyst are consistent with the spiro tran- sition state[17].
R1 R3
R2 O O O HSO - O 5
R1 R3 O O O 2 R O O O O O O 3 O O 2 R O R OH 1 O O O R O O O O O O O O SO - O 3 Spiro transition state +OH -OH O O 2- O SO4 O O O O O - SO3
Fig. 1.9 Catalytic cycle for the Shi asymmetric epoxidation and the transition state[20]
1.3 Epoxides from carbonyl compounds
The main methods for the preparation of epoxides from carbonyl compounds are:
• Darzens glycidic ester condensation
• Corey-Chaykovsky epoxidation
18 1.3.1 The Darzens glycidic ester condensation
In the early 1900s, Auguste George Darzens presented a method to synthesize epoxides by reacting aldehydes or ketones and α-halo esters under basic conditions (Fig. 1.10). The products formed are α, β-epoxy esters and are also called glycidic esters [21, 22, 23].
O O NaOEt O O Cl R1 + OEt 1 2 R R R2 R3 OEt R3 17 18 19
Fig. 1.10 The Darzens glycidic ester condensation
The reaction is versatile and can be done with different aldehydes and ketones, wherein aliphatic aldehydes and ketones often give lower yields than aromatic ones. One problem when trying to perform the Darzens reaction enantioselectively is that a strong acid is gen- erated during the reaction (e. g. HCl). This could catalyze racemic backround reactions or neutralize the catalyst and lead to a slower reaction rate[24]. Different strategies for adress- ing this problem were investigated: the use of chiral auxiliaries, chiral reagents or chiral catalysts were tested.
The most succesful method was developed by Liu et. al. in 2011 by using a modified chinchona-alkaloid catalyst in combination with LiOH as base. The reaction was tested us- ing differently modified cinchona-alkaloids as chiral phase-transfer-catalyst, which showed that the best one was compound 20 with a free OH-group at 6’-OH and a 9-phenanthracylether.
The reaction proceeded with excellent enantioselectivities and very good yields. Different aldehydes were tested including aromatic aldehydes with electron withdrawing or donating substituents giving high yields (90-96 %) and excellent enantioselectivities (90-99 %). Even an aliphatic aldehyde gave a yield of 93% and an ee of 81% [24].
19 OH
N Br PHN = Ar OPHN N 20 (Ar = 3,4,5-F3Ph) (5 mol%) LiOH O O + RCHO O Cl Ar DCM, 0 °C Ar R 21 22a 23 (ee up to 99%)
Fig. 1.11 Asymmetric Darzens reaction using a chiral phase-transfer-catalyst
Other approaches like using chiral auxiliaries have not resulted in such high enantioselec- tivities yet. However, chiral auxiliaries have been used at the synthesis of some molecules, e. g. the asymmetric total synthesis of the antimalarial drug Mefloquine [25].
1.3.2 The Corey-Chaykovsky reaction
Around 1960, a new approach using sulfonium salts/ylides has been developed by John- son, Corey and Chaykovsky[26, 27, 28]. In this reaction (see Fig. 1.12), a dimethylsulfoxonium methylide or a dimethylsulfonium methylide is generated by deprotonation of trimethylsul- foxonium halides. These ylides can then react with aldehydes or ketones to give the corre- sponding epoxides. When dimethylsulfoxonium methylide is reacted with α, β -unsaturated carbonyls, epoxides are the minor product, whereas the major product is the cyclopropane through a conjugate addition[26].
20 O
R1 R2 O O O 1 O X NaH 25 R S S S CH2 DMSO H3C CH3 H3C CH2 H3C CH2 R2 CH3 CH3 CH3 -H2 26 24
O O R1 R2 R1 R2 C CH CH H2 2 NaH CH2 2 X 28 29 S DMSO S S H C CH H C CH 3 3 H3C CH3 3 3 -H2 O CH2 27 R1 R2 30
Fig. 1.12 Corey-Chaykovsky reaction
A. W. Johnson further developed this method and, in 1958, reported the first stereose- lective sulfur ylide epoxidation[28]. The first enantioselective reactions where stochiometric amounts of sulfonium ylides were used date back to 1968[29]. The trans-diastereoselectivity of this reaction was already mentioned here, but the mechanism was yet to be understood.
1.3.2.1 Diastereoselectivity in Sulfur-ylide-mediated reactions
The high trans-diastereoselectivity which was already described in early reports can be explained by the mechanism given in Fig. 1.13. Thorough investigations on the influencing factors that determine whether the reaction is trans-selective or gives a mixture of cis- and trans-products were performed by Aggarwal et al.[30].
After deprotonation to give the sulfur-ylide, the addition to the aldehyde occurs in a "cisoid"- manner, which means that the oxygen and the sulfur are on the same side. This is more favored over a "transoid"-manner due to favorable coulombic interactions leading to A and A’[31]. The next step is a bond rotation around the newly formed C-C bond leading to B and B’ followed by the ring-closing step of the anti-periplanar betaines leading to the cor- responding cis or trans-epoxides. If the formation of the betaine is non-reversible, then
21 the diastereoselectivity is regulated by the relative energies of the syn- and trans-transition states. On the other hand, if the formation of the betaine is reversible, then the diastereos- electivity would depend on the rates of conversion of the syn- and anti-betaines to cis and trans-epoxides[31].
O O SMe O R H Ph 2 H Ph O
S RH anti-betaine RH Ph R H SMe2 31 Ph AB O
H R O O Ph SMe2 H Ph O S HR syn-betaine HR Ph R H SMe2 Ph 32 A' B'
Fig. 1.13 Pathways leading to cis- and trans-epoxides in Corey-Chaykovsky reactions
When using aryl-stabilized sulfur ylides, high trans-diastereoselectivities are achieved which can be explained by the reversibility of the betaine-formation. For the syn-betaine B’ the betaine-formation is reversible, whereas the anti-betaine is formed irreversibly. The rate- determining step in this reaction is the rotation around the C-C bond which has a higher energy level for the syn-betaine than for the trans-betaine[31]. The last step, the ring-closing step, is very rapid. This means that the formed cis-betaine can be converted back to the educt, then form the trans-betaine, which results in the trans-epoxide. There are several factors which influence the reversibility of the syn-betaine formation, e. g. the solvent and the metal ions or the structure of the aldehyde and ylide. If aromatic aldehydes are used, a higher trans-selectivity is obtained than for aliphatic aldehydes. The bond-rotation step is rate-limiting, which means that if the steric hindrance is increased either on the alde- hyde or ylide, the bond rotation will be of higher energy and favor reversion leading to a higher diastereoselectivity. Stabilized aldehydes and ylides result in high diastereoselectiv- ities because the reversible betaine formation is favored. The rotation barrier is decreased if the solvent or a metal ion stabilize the alkoxide by solvation which leads to decreased diastereoselectivities[32].
22 1.3.2.2 Enantioselectivity in sulfur-ylide-mediated reactions
As discussed above, the transition state leading to the anti-betaine was the diastereose- lective step and this exact same step can also be used to render these reactions enantios- electively. Four main factors influence the enantioselectivity when using chiral sulfonium salts for such reactions[32]:
• only a single diastereomeric sulfonium ylide needs to be formed
• the ylide formation has to be controlled
• control of the facial selectivity of the ylide
• non-reversible formation of the anti-betaines
The enantioselectivity of a sulfur ylide-mediated reaction is described using the compound 33. The lone pair of the sulfur prefers an orthogonal position to the lone pair on the ylidic carbon. The shown conformers in Fig. 1.14 are the most preferred conformations because of lower steric hindrance[33]. Out of these two possiple conformers, C is the preferred conformer because of a lower steric hindrance. The facial selectivity is due to the bulky camphor group which effectively shields the Si-phase of the ylide, forcing the aldehyde to approach from the Re-phase which leads to the R, R-epoxide[34, 35].
In general, the steric hindrance of a chiral sulfide needs to be well-balanced because too much steric hindrance results in a decreased reaction rate, whereas selectivity is in- creased with bulky sulfides. The formation of one preferred anti-betaine is influenced by the control of lone-pair alkylation, ylide conformation and facial selectivity[35]. If the betaine- formation is non-reversible, controlling these factors results in highly enantioselective epox- ide formation[34].
The bond-rotation and/or ring-closure steps can be enantiodifferentiating if the anti-betaine formation is reversible. This can result in lower enantioselectivities because of differences in the reversibility of the betaine formation and following steps for the pathways starting from C and D. This explains why slightly lower ee values are obtained when benzaldehyde reacts with ylides derived from electron-poor aromatic tosylhydrazone salts[32, 34].
23 S
O
33
H O Ph H H O H H H Ph Ph H Ph H S S (R, R)-epoxide (S, S)-epoxide
O O
CD
Fig. 1.14 Aldehyde approach towards the sulfur ylide and equilibrium between the two ylide conformers[34]
1.3.2.3 Catalytic use of sulfur ylides
In 1988, first catalytic approaches were reported by Furukawa et al., who published enan- tioselective epoxidations with an ee of up to 47%(see Fig. 1.16). After this breakthrough, many different enantioselective sulfur-ylide mediated epoxidation reactions have been de- veloped by different research groups.
The catalytic cycle of these reactions is shown in Fig. 1.15. Benzyl bromide is used to alkylate the chiral sulfide, followed by the formation of the sulfur ylide through deprotona- tion by potassium hydroxyde. Now, the aldehyde enters the catalytic cycle, the epoxide is formed (this can be done dia- and enantioselectively see 1.3.2.1 and 1.3.2.2) and the chiral sulfide is recycled.
24 O
Ph Ph BnBr
SR2 PhCHO
R S Ph R S Ph 2 2 Br Liquid Solid
H2O OH
Fig. 1.15 The catalytic cycle for sulfur-ylide mediated epoxidation reactions[35]
In Fig. 1.16, some examples of the investigated sulfur-containing reagents are given. The reactions are usually performed at RT, open to air in a mixture of tert-BuOH/water (9 : 1) or ACN/water (9 : 1) using sodium or potassium hydroxide as a base. Different side reactions may appear, e. g. Cannizzaro reaction, Williamson alkylation or solvent hydrolysis, which are suppressed by the reaction conditions. The most frequently used halide component in this reaction is benzyl bromide, the sulfide loadings range from 100 to 10% and the reac- tion times vary from one day to one month. The rate of the reaction can be improved by increasing the concentration, however side reactions can get more dominant, hence, the loading must be well-balanced[35].
The deprotonation step is rapid, whereas the alkylation step is slow and reversible[36]. To speed up the alkylation step, additives like Bu4NI and NaI have been used to activate the benzyl bromide through halogen exchange[37]. Using additives such as catechol (5 %) or
Bu4NHSO4 can also show positive effects. As already mentioned, increasing the bulk of the sulfide can lead to higher stereoselectivity but might decrease the rate of the alkylation step. The reaction is generally limited to aldehydes with nonenolizable protons because of the basic conditions, therefore, the scope is limited. However, as it is shown by the exam- ples in Fig. 1.16, high diastereo- and enantioselectivity can be achieved with moderate to good yields[37, 38, 39, 40, 41, 42].
25 sulfide O PhCHO+ BnBr base, solvent, rt Ph Ph 22a 34 35
Me Ph
yield: 50 % yield: 97 % dr = 100:0 Et N dr = 87:13 ee = 47% (R,R) ee = 90% (S,S) OH 1.5 d, 50 mol% 19 h, 100 mol% Et S SMe 36 39
Ph Ph yield: 82 % O O yield: 41% dr = 92:8 dr = 90:10 ee = 85% (S,S) O O ee = 97% (R,R) S 4d, 10 mol% 4d, 10 mol% S 37 40
O yield: 88 % yield: 86% S dr = 83:17 dr = 95:5 O ee = 96% (R,R) ee = 98% (R,R) 1d, 20 mol% S 12-24h, 100 mol% 38 41
dr = trans : cis solvents and additives vary
Fig. 1.16 Selected chiral sulfides used in the alkylation/deprotonation methodology[35]
26 1.4 Ammonium ylides in epoxidation reactions
1.4.1 Investigations by Jonczyk et al. and Kimachi et al.
Enantioselective protocols for the epoxidation of aldehydes using chiral sulfur-ylides have been developed over the last decades and were already presented in 1.3.2. The use of ammonium ylides for these kind of reactions has been rather limited until recently. In 1999 Jonczyk et al. presented a Darzens-reaction of an ylide generated from cyanomethyl- trimethylammonium iodide, which are substituted with two electron-withdrawing groups, and aromatic aldehydes giving substituted epoxides under two-phase conditions (see Fig. 1.17). The problem here was however, that the yield was rather low[43, 44].
R1 X O 50% aq. NaOH R1 Ar + NC N NC Ar H CH2Cl2 O 42 43 44
1 R = C6H5, 2-C4H3S, Me2C=CH Ar = C6H5, p-MeC6H4, p-ClC6H4 X = MeSO4, ClO4
Fig. 1.17 Synthesis of epoxides substituted with electron-withdrawing groups
In 2004 Kimachi et al. reported a highly trans-selective Darzens-reaction via ammonium ylides. They presented reactions of benzyltriethylammonium salts with a base and benz- aldehyde giving epoxides with moderate to high yields while the diastereoselectivities de- pended on the electronic structure of the group. The reaction is shown in Fig. 1.18. In- terestingly, the diastereoselectivity was determined by the different R groups. If electron- withdrawing groups were used as substituents, the trans-epoxide was obtained exclusively while for electron-rich substituents moderate epoxide formation with poor diastereoselectiv- ity was found[45]. Triethylammonium-salts as a leaving group are however not very favorable because they are volatile and cause only poor recovery in the work-up. A good alterna- tive was found in DABCO-salts. Therefore, a DABCO-ammonium salt was prepared from DABCO and p-trifluoromethylbenzylchloride which was tested with different aldehydes giv- ing moderate to good yields and high trans-diastereoselectivities in some cases.
27 Cl O 2 t-BuOK R THF N + H RT, 1h R O 45 22a 46
Fig. 1.18 Diastereoselective Synthesis of epoxides presented by Kimachi[45]
Further investigations on aryl-stabilized ammonium ylides were done by Aggarwal et al. in 2006 [46]. Again, DABCO-derived ammonium salts were used and compared to the reac- tivity of quinuclidine-ammonium salts. This was driven by the motivation to find a thorough understanding of the factors which influence the selectivity and reactivity of ammonium ylides in epoxidation reactions. These investigations showed that a clear general correlation between the electron rich/poor character of the ylidic aromatic ring and the yield and dia- stereoselectivity was present. The yield was not affected if DABCO instead of quinuclidine was used as the amino group, which indicates that ring closure is not a significant problem. However, DABCO derivatives gave a lower trans:cis-ratio than the quinuclidine derivatives. If an electron-donating group is present as R, the yield is lower because the ylides are less stabile, whereas for electron-withdrawing groups high yields were obtained[46].
N Cl
t-BuOK O R 47 + PhCHO THF, RT Ph Ar N 22a 49 N
Cl
R 48
Fig. 1.19 Reaction to test the influence of ylide stabilisation and the nature of ammonium group on yield and diastereoselectivity[46]
28 1.4.2 Diastereoselectivity in reactions of ammonium ylides with aldehydes
In order to answer the question what influences the selectivity in ammonoum ylide reactions, Aggarwal et al. calculated energy profiles. From these calculations, the mechanism and the observed diastereoselectivity in epoxidations with ammonium ylides can be explained. The reaction steps are rather similar to those in sulfur ylide reactions (see Fig. 1.12). In Fig. 1.20, the mechanism is shown: the generated ylide adds to the aldehyde and gener- ates a cisoid-betaine intermediate which upon bond rotation is converted into the transoid conformer followed by ring closure. The first step, the addition to the aldehyde, occurs without enthalpic barrier, therefore, no (or very low) selecitivity is observed from this step. Both syn and anti betaines are formed with equal probability. The ring closure step is rate determining in the reaction of ammonium ylides with aldehydes because the ammonium is a poor leaving group. This means that the selectivity is determined by the relative energy of the two diasteromeric transition states in the elimination step. This explains why substi- tution with electron-withdrawing groups mainly gives trans-epoxides: groups that stabilize the ylide and/or increase the barrier to ring closure and lead to reversibility and, therefore, trans-selectivity, whereas electron-donating groups that destabilize the ylide and/or reduce the barrier to ring closure lead to lower trans-selectivities[46].
R N O 3 Ar O O
Ar Ph Ar Ph R3N Ph anti-betaine 51 O NR3 No selectivity High trans selectivity Ar Ph
50 22a R3N O Ar O O
Ar Ph Ar Ph R3N Ph syn-betaine 52
Fig. 1.20 Origin of the observed diastereoselectivity in reactions of ammonium ylides with aldehydes
Based on these results further investiations towards ammonium ylides used for the synthe- sis of dia- and enantioselective synthesis of epoxides were done by members of our group and will be presented in 2.2.
29 2 Results and Discussion
2.1 Motivation of this work
Enantioselective approaches towards epoxides using ammonium ylides are to this point very limited and have only recently been developed by members of our group[47]. The aim of this work was to find a highly enantioselective approach towards epoxides in high yields using synthesized chiral ammonium salts. The optimal reaction conditions need to be found and the application scope of this method has to be studied.
2.2 Previous experiments from our group members
Based on the results of Aggarwal et al.[30, 46, 48], members of our group did a thorough in- vestigation on highly trans-diastereoselective epoxidation and aziridation reactions using ammonium ylides [49, 50, 51, 52, 47]. In order to give a better understanding of the work pre- sented in this master thesis, a short overview on the work which has been done over the last years leading to the starting point of this master thesis will be given.
A key factor in ylide-based epoxidation reactions is the leaving group ability which de- creases in the order O>S>N>P[48]. Therefore, ammonium ylides are less reactive towards epoxidations and aziridations than sulfur ylides. The diastereoselectivity of epoxidation re- actions using ammonium ylides is greatly influenced by the stability of the ylide, because stabilised ylides significantly increase the barrier to ring closure and therefore lead to higher diastereoselectivities[49].
A highly stabilized ylide is produced, if the leaving group is α to a carbonyl group, which gives high diastereoselectivities. Based on these results, amide stabilized ammonium ylides were applied in epoxidation reactions to give glycidic amides. As DABCO-derived ammo- nium ylides were already known as ammonium ylides, these were employed as amide- based ammonium ylides for epoxide formation resulting in diastereoselective trans-products with different yields [49].
30 anti-betaine O O R' NR3 rotation H R' -NR O R3N R' O formation 3 + Ph H Ph H Ph R' Ph H H NR3 53 22a 54
Fig. 2.1 Proposed mechanism for the trans-selective formation of glycidic amides
The reaction conditions were optimized and the best-suited amide derivative was investigated[49]. This was followed by investigations on finding the best-suited amine leaving group.
Several different ammonium ylides were tested and some of them are shown in Fig. 2.2. The first row demonstrates the first use of ammonium ylides which started with a DABCO- derived compound 56 yielding specifically the trans-epoxide with a reasonable yield of 67 %. Following this success, also the quinuclidine-based ammonium salt 57 still gave only the trans-product, but with a decreased yield. Very high yields were obtained with 58, and the next logical step was to investigate an enantioselective approach. There- fore, Cinchona-alkaloid-derived ammonium ylides were tested in these reactions because they were already known to give good yields and high selectivities in enantioselective cyclopropanations[53].
However, when using Cinchona-alkaloid based ammonium ylides 59, no product was formed under various reaction conditions. When using DABCO- and L-proline-based chiral ammo- nium salts, enantioselective epoxidations with different yields were achieved. The other two shown compounds 60 and 61 both resulted in an enhanced stereoselectivity, but the yields were rather low. Therefore, further investigations were focussed on 62 and 63a which will be presented in the following chapters.
31 R3N CONEt2 O PhCHO base, solvent Ph CONEt2 22a 55
OMe Br N NMe3 N N N Br CONEt CONEt2 Br Br 2 OMe CONEt2 CONEt2 N 56a 57 a58 a 59b yield: 67 % yield: 32 % yield: 92 % yield: 0 %
Et2NOC Ph Et2NOC Ph Br Me2 N CONEt2 Br Br Ph N N O N
NMe2 N Ph N Et NOC 2 Br 60a61 a 62a 63a c yield: 31 % yield: 23 % yield: 7 % yield: 85 % ee: 53 % ee: 43 % ee: 89 % ee: 55 % a: DCM, 50 wt% aq. NaOH b : various solvents (THF, ACN, DCM), various bases (KO-tert-butyl, Cs2CO3, Li2CO3, NaOH c : i-PrOH, 20 eq. Cs2CO3
Fig. 2.2 Synthesized ammonium salts used in epoxidation the shown epoxidation reaction
32 2.3 DABCO-derived chiral ammonium acetamides
2.3.1 Reactions using the DABCO-derivative 62
The chiral DABCO-based ammonium salt 62 was synthesized by Lukas Roiser[47] dur- ing his master’s thesis. As shown in Fig. 2.3, this compound was prepared starting with diphenylethanediamine 64, which was converted to 65 over 3 steps with an overall yield of 35 %. This intermediate was then converted to the chiral DABCO-salt 62 with a yield of 92 %.
O O
NH2 N Br NEt2 NEt2 Ph N Br 3 steps N THF NH2 Ph N
64 65 62
Fig. 2.3 Synthesis of the already known DABCO-derivative 62[47]
This compound was then subjected to the epoxidation reaction shown in Fig. 2.4. Using liquid/liquid conditions with 50 % aqueous NaOH as base, DCM as solvent and stirring at RT for 24hours the epoxide 55a was obtained with 7 % yield and an ee of 90% (see Table 1, entry 1).
O
Br N O O N base, solvent + N time, O N temperature
62 22a 55a
Fig. 2.4 Epoxidation reaction for the synthesized DABCO-derivative
Several different reaction conditions were screened to test if the very low yield could be enhanced while maintaining the high enantioselectivity. As shown in Table 1, (entry 2-3),
33 neither using i-PrOH nor toluene as a solvent gave isolated epoxide, only traces of the crude product could be identified by 1H-NMR. Switching to a solid base (entry 2-3, 5) as well as raising the temperature (entry 5) also did not result in any product formation.
Table 1 Tested reaction conditions for 62 using general procedure VI
entry solvent base reaction time / h temperature / ◦C yield / % ee%
1 DCMNaOH 24 RT 6 90
2 i-PrOH Cs2CO3 24 RT 0 -
3 Toluene Cs2CO3 24 RT 0 -
4 TolueneNaOH 24 RT 0 -
5 Toluene Cs2CO3 24 60 0 -
2.3.2 Reactions using the camphor-derivative 68
Still encouraged by the excellent ee of DABCO-derivative 62, this strategy was further in- vestigated. Recent publications[54, 55] showed the synthesis of a similar DABCO-derivative 68, which would just miss one single step to convert it to the corresponding chiral ammo- nium acetamide. Fig. 2.5 shows the synthesis of this compound, however, compound 68 could not be synthesized as the reaction with ethylenbromide in acetonitrile over 14 h at 80 ◦C did not give any product. Therefore no epoxidation reaction could be tested.
H O N N Br Br
O N CH3CN, 80 °C N H 14 h
66 67 68
Fig. 2.5 Attempted synthesis of the recently reported DABCO-derivative 68
34 2.4 Proline-derived chiral ammonium acetamides
It was shown by Lukas Roiser in his master thesis[47] that chiral ammonium acetamides based on L-proline can result in enhanced stereoselectivity when applying them to the epoxidation reaction shown in Fig. 2.6.
O O N O + N O N Br
O 63a 22a 55a
Fig. 2.6 Epoxidation using the previously synthesized L-proline derivative [47]
The best result was obtained when running the reaction in i-PrOH and using Cs2CO3 as a base by stirring all components for 24hours at RT (see 3.2.20). This gave the epoxide 55a with a yield of 85% and an ee of 55% (see Table 2, entry 1). The initial solvent i-PrOH was superior to toluene (entries 2-3) in both yield and ee. Increasing the reaction temperature when using toluene as solvent gave an improved yield compared to running the reaction for 120h at RT, but the ee was lower with 47 % compared to using i-PrOH as a solvent.
Table 2 Tested reaction conditions for 63a using general procedure V
entry solvent base reaction time / h temperature / ◦C yield / % ee%
1 i-PrOH Cs2CO3 24 RT 85 55
2 Toluene Cs2CO3 72 60 31 47
a 3 Toluene Cs2CO3 120 RT 13 - a not isolated yield
35 2.4.1 Synthesis of different proline-based ammonium salts and their use
The reactions using 63a showed that high yields could be combined with moderate ee. The next step was to find ways to increase the enantioselectivity of the reaction while maintain- ing the high yield. There are several positions on 63 where modifications could be done, see Fig. 2.7, and we chose to test different variations on R1 and R2.
R1 R1
O N
Et N Br R2 2 H
O 63
Fig. 2.7 Possible variations on the proline-based ammonium salt
The substituents R1 and R2 can be easily modified during the synthesis, which is shown in Fig. 2.8. The reaction sequence starts with L-proline 69 which reacts with ethylchloroac- etate leading to the double-protected compound 70 in quantitative yield. This double- protection can also be done as a two-step procedure, which is shown in 3.2.4. The next step is a Grignard-reaction which makes it possible to vary R1 by using different Grignard- reagents. This was followed by a deprotection using either NaOH in ethanol or KOH in methanol. The second five-membered ring was synthesized by reacting compound 72 with the corresponding aldehyde in toluene using a Dean-Stark water separator. This allowed for the variation of R2 giving compound 73. The reaction sequence was finished by reacting 73 with bromodiethylacetamide resulting in the final chiral ammonium salt 63.
36 1 O O R R1 O 1 Cl O O R MgBr OH OH MeOH N O THF N O NH O O 69 70 71
1 R 1 O 1 O R R 1 1 R R R1 Br 2 NaOH/EtOH H R NEt2 O N OH O PTSA, Toluene N Br 2 THF Et2N R NH R2 H H O 72 73 63
Fig. 2.8 Synthesis of the L-proline derived ammonium salts
2.4.2 Variations on R1
The first changes on the proline-derived compound were done by using different Grignard- reagents. While leaving R2 unchanged as a hydrogen atom, the synthesized ammonium salts where then investigated in the epoxidation reaction under the given reaction conditions shown in Fig. 2.9.
In Table 3, the results for the synthesized ammonium salts are given. Entry 1 is the al- ready discussed ammonium salt 63a, giving a good yield with a moderate ee. The first attempt was to use bigger aromatic substituents like napht-2-yl (entry 2, 63b) and biphenyl (entry 3, 63c). In the case of napht-2-yl, the ee was the same as for 63a but the yield dropped to 32%. Changing the substituent to biphenyl, the ee dropped to 42% and the yield was 69 %. When using a more electron-rich substituent like 4-MeO-Ph (entry 4, 63d), both the yield and the ee dropped significantly to around 30%. When placing electron- withdrawing substituents as R1, both the yield and ee were very different for the tested salts. 4-F-Ph (entry 5, 63e) yielded only 35% but gave a reasonable ee of 48 %. Using
1 even more electron-withdrawing groups as R as with 4-CF3-Ph (entry 6, 63f) the yield in- creased to an excellent value of 96 % but the ee dropped to low 28% compared to other results.
37 R1 R1
O O O N + Ph H 20 eq. Cs2CO3 Ph CO NEt2 Et N Br H 2 H i-PrOH RT, 24 h O 63 22a 55a
Fig. 2.9 Test reaction for the synthesized Proline-derivatives with different aryl groups as R1
Table 3 Test results for various groups R1
entry R1 yield / % ee%
1 Phenyl (63a) 85 55
2 Napht-2-yl (63b) 32 55
3 Biphenyl (63c) 69 42
4 4-MeO-Ph (63d) 30 34
5 4-F-Ph (63e) 35 48
6 4-CF3-Ph (63f) 96 28
These investigations showed that the best suited R1 were phenyl substituents because compound 63a gave the best combination in yield and ee. However, attempts to introduce aliphatic substituents as Rf failed (see 2.4.4). Based on these results, the next step was to modify R2.
38 2.4.3 Variations on R2
As mentioned above, different R2 groups could be introduced by using different aldehydes when closing the second ring while leaving R1 as phenyl-groups. In Fig. 2.10, the test reaction with the used reaction conditions is given and Table 4 shows the results of the tested ammonium salts with different R2. Entry 1 is the already shown ammonium salt 63a with a yield of 85% and an ee of 55 %. The first modification on R2 was to use a cyclohexyl- group (entry 2, 63g), which showed very promising results with a very good yield of 88% and a high ee of 86%. Compared to 63a, this indicates that a bigger substituent as R2 can result in higher enantioselectivity. Encouraged by this result, t-butyl was introduced as R2 (entry 3, 63h) which gave almost the same ee with 84 % but the yield dropped to 69 %. With n-butyl as a substituent (entry 4, 63i) the yield dropped to 55% and also the ee decreased to 76%. When using aromatic substituents as benzyl (entry 5, 63j), the yield dropped significantly to 30% and also the ee at a value of 66 % was significantly lower than for 63a.
Ph Ph O O O + N Ph H 20 eq. Cs2CO3 Ph CO NEt2 Et N Br R2 i-PrOH 2 H RT, 24 h O 63 22a 55a Fig. 2.10 Test reaction for the synthesized Proline-derivatives with different R2
Table 4 Test results for various groups R2
entry R2 yield / % ee%
1 H (63a) 85 55
2 Cyclohexyl (63g) 88 86
3 t-butyl (63h) 69 84
4 n-butyl (63i) 55 76
5 Benzyl (63j) 30 66
To summarize, the ammonium salt with a cyclohexane-ring as R2 and phenyl as R1 gave
39 the best combination in yield and ee. Attempts to introduce a phenyl group as R2 did not succeed, this will be discussed in 2.4.4.
2.4.4 Attempted synthesis of further ammonium salts
During the synthesis of the above described ammonium salts some attempts synthesizing further derivatives failed at different stages which will now be described. The synthesis of the proline-based ammonium salts can be divided into different steps (see 2.4.1):
(a) Protecting the proline
(b) Grignard-reaction
(c) Deprotection
(d) Closure of the second ring
(e) Reaction with bromo-diethylacetamide to give the ammonium salts
In Table 5, the different attempted synhteses are shown. Either R1 or R2 were varied and the last column shows, which step did not result in any product any more.
In entry 1, an aliphatic side-group was to be used as R2 while leaving the two hydrogens on the second ring unattached. The insertion of the cyclohexyl as R2 and the deprotection with NaOH still worked, but the ring closing step (d) did not result in any product formation. However, it needs to be mentioned that only one attempt was made to synthesize this prod- uct, so using other reaction conditions might lead to success. For entry 2, exactly the same is valid.
For entry 3, the protection, grignard and deprotection steps are not necessary as the L- proline simply needs to be reduced, which was done with LiAlH4. However, this reduced product was very instable and refluxing in toluene for closing the second ring did not result in any product. Milder reaction conditions were tried by stirring the reactants in a solvent for 24hours, but also did not give any product as well.
40 The attempt to synthesize an ammonium salt having a phenyl-group (entry 4) as R2 failed because the closing of the second ring was not possible. This was probably due to the fact that it can re-open again and the opened form is sterically less hindered.
Any attempts to synthesize a derivative with two methyl groups instead of two hydrogens (entry 5) on the second formed ring failed again in the ring closing step. Different attempts were made with acetone using the Dean-Stark method, by stirring at RT with a 4 Å molec- ular sieve, adding BF3 or using dimethoxypropane instead of acetone, but all of them failed and no product could be synthesized.
The synthesis of the derivatives with Cyclohexyl as R2 different from phenyl on R1 all failed at the last step - the ammonium salt formation. Different reaction conditions were tried, however, not even refluxing for 48 hours in THF resulted in any product formation.
Table 5 Test results for various combinations in R1 and R2 which failed at different stages.
entry R2 R1 bottleneck
1 Cyclohexyl H (d)
2 Methyl H (d)
3 H H (d)
4 Phenyl Phenyl (d)
a 5 CH3 Phenyl (d)
6 Cyclohexyl 4-F-Ph (e)
7 Cyclohexyl 4-CF3-Ph (e)
8 Cyclohexyl 4-MeO-Ph (e)
a second hydrogen also replaced by CH3
41 2.4.5 Screening of the best-suited reaction conditions
Having identified the best-performing ammonium salt 63g, the reaction needed some op- timization. The different tested reaction conditions are shown in Table 6. To begin with, the influence of different solvents on the yield and ee were tested. i-PrOH as solvent and
Cs2CO3 (entry 1) were the already known reaction conditions which were used in optimizing R1 and R2. When applying liquid/liquid-conditions with DCM as solvent and NaOH as base (entry 2), only a slight decrease in yield was detected, the ee remained exactly the same.
Using toluene and THF as a solvent and using Cs2CO3 (entry 2+3) gave interesting results. The yield dropped to 66 and 68%, but the ee increased by around 5% to 91 and 90%. Applying higher temperatures (entry 5+6) decreased the yield and ee in both tested cases with i-PrOH and toluene slightly, therefore, a decrease in temperature might increase the selectivity. However, when running the reaction at 0 ◦C, no product was detected.
Table 6 Tested reaction conditions for 63g
entry solvent base reaction time / h temperature / ◦C yield / % ee%
1 i-PrOH Cs2CO3 24 RT 85 86
2 DCMNaOH 24 RT 80 86
3 Toluene Cs2CO3 24 RT 66 91
4 THF Cs2CO3 24 RT 68 90
5 Toluene Cs2CO3 24 60 65 87
6 i-PrOH Cs2CO3 24 60 80 80
6 Toluene Cs2CO3 24 0 0-
42 2.4.6 Crystal structure of the synthesized ammonium salt 63g
The stereocenter at position 3, which is formed when closing the second ring, was proposed by Literature[56] to be S (or cis to the other stereocenter). To check if this is truly the case, NOESY-spectra of ammonium salt 63g were recorded. However, these spectra did not allow unambiguous identification whether the two stereocenters are cis or trans with respect to each other. Therefore, ammonium salt 63g was crystallized and an X-ray-diffraction was performed resulting in the crystal structure in Fig. 2.11. Here the formed stereocenter can be identified as cis (S) to the second stereocenter which is given from using L-proline as starting material.
Fig. 2.11 Crystal structure of compound 63g
43 2.4.7 Application scope
Having found the best suited reaction conditions for 63g, the next step was to investigate the application scope of this compound. Table 7 shows the tested aldehydes and Fig. 2.12 gives the reaction with the used reaction conditions.
Ph Ph O O O + N 3 3 R H 20 eq. Cs2CO3 R CO NEt2 Et N Br Cy RT, 24 h 2 H
O 63g 22 55
Fig. 2.12 Test reaction for the synthesized L-proline-derivative 63g with different aldehydes
Each reaction was tested in i-PrOH and toluene because the previous experiments showed that in i-PrOH both the yield and enantioselectivity were very good while in toluene the yield dropped slightly but enhanced enantioselectivity could be achieved. Entries 1-2 in Table 7 show the already mentioned test reaction using benzaldehyde which gave a high yield and enantioselectivity for i-PrOH while the ee was increased and the yield decreased when us- ing toluene as a solvent. This correlation of higher yield for i-PrOH compared to toluene in combination with a lower ee for i-PrOH than for toluene was valid for all tested aldehydes. Furthermore, when carrying out the reaction in i-PrOH, the benzylalcohol resulting from the Cannizzaro side reaction could be detected, which was not the case for toluene.
Using ortho- and para-methylbenzaldehyde, the results varied compared to using ben- zaldehyde 22a. For 4-methylbenzaldehyde (entry 3+4, 22b), the yield was decreased for both solvents to 72 and 52 % while the ee remained almost unchanged for toluene but dropped for i-PrOH. When using 2-methylbenzaldehyde (entry 5+6, 22c), almost quantita- tive yield could be achieved when using i-PrOH and maintaining a high ee while the results in toluene were almost the same as for using benzaldehyde 22a.
Halide-substituted aldehydes showed very different behavior in i-PrOH compared to toluene. For 4-bromobenzaldehyde (entry 7+8, 22d), the yield in i-PrOH was comparable to ben- zaldehyde 22a, but the ee was significantly decreased. When using 4-chlorobenzaldehyde
44 (entry 9+10, 22e), both the yield and ee dropped about 10% in i-PrOH. In toluene the yield dropped to 21 % but a high enantioselectivity was observed.
The next tested aldehydes were the more electron-rich aldehydes substituted with OMe groups. Tests of 4-methoxybenzaldehyde (entry 11+12, 22f) showed a comparable result to 4-chlorobenzaldehyde 22e: the yield and ee dropped slightly in i-PrOH and in toluene a very low yield but high ee was found. In the case of 2-methoxybenzaldehyde (entry 13+14, 22g), the yield and ee were very high both for i-PrOH and toluene.
When using more reactive aldehydes like the 3-nitrobenzaldehyde (entry 15+16, 22h), the yield dropped significantly to 50 % in both solvents while maintaining a high ee. In the case of cyclohexanecarboxaldehyde (entry 17+18, 22i), the yield dropped to 35 and 25%, how- ever, the ee has not been measured yet as a suitable UV-detection needs to be found. The less active dimethylaminobenzaldehyde (entry 19+20, 22j) and undecanal (entry 21+22, 22k) did not result in any product for both solvents used.
45 Table 7 Test results for 63g with different aldehydes entry R3 solvent yield / % ee%
1 i-PrOH 88 85 Phenyl (22a) 2 toluene 66 91
3 i-PrOH 72 78 4-MeC6H4 (22b) 4 toluene 52 90
5 i-PrOH 98 82 2-MeC6H4 (22c) 6 toluene 62 92
7 i-PrOH 85 70 4-BrC6H4 (22d) 8 toluene 75 72
9 i-PrOH 77 74 4-ClC6H4 (22e) 10 toluene 21 82
11 i-PrOH 60 88 4-MeOC6H4 (22f) 12 toluene 9 88
13 i-PrOH 94 82 2-MeOC6H4 (22g) 14 toluene 93 92
15 i-PrOH 50 86 3-NO2C6H4 (22h) 16 toluene 50 88
17 i-PrOH 35 - Cyclohexyl (22i) 18 toluene 25 -
19 i-PrOH - - 4-Me2NC6H4 (22j) 20 toluene - -
21 i-PrOH - - n-undecyl (22k) 22 toluene - -
46 2.4.8 Attempted catalytic use of the amine
After succeeding in creating a useful synthetic method by using the ammonium salt in sto- chiometric amounts, the next logical step was to try to render these reactions so that the amine can be used in a catalytic fashion. Therefore, four different reactions were tested (see Fig. 2.13) with different amounts of 73g and different reaction temperatures.
O O x mol% 73g O Br N + 3 Ph H 20 eq. Cs2CO3 R CONEt2 RT, 24 h 74 22a 55
Fig. 2.13 Test reaction with catalytic amounts of 73g
The reactions were done using 10mol% of 73g: once at RT and once at 60 ◦C each for 24 hours. However, for neither of these conditions any epoxide could be detected. In both cases only the Cannizzaro side products were detected. To check if any ammonium salt (and therefore also the reacting ammonium ylide) is formed under the used reaction condi- tions, a stochiometric amount of 73g was used again once at RT and once at 60 ◦C while stirring for 24hours. Again, no epoxide was formed and only unreacted educts and the Cannizzaro-products were obtained.
2.4.9 Recycling of the amine after epoxidation reactions
A very interesting result was found when comparing the reactions of 63g with the other synthesized ammonium salts: the amine, which acted as a leaving group, could not be re- generated after it was used in the epoxidation. This is a quite crucial aspect, as in theory the amine should be easily regenerated, which is the case for all the other synthesized amines. The crude 1H-NMR showed that the amine was there, however, the shifts in the NMR were changed compared to pure amine.
To check if the amine decomposes under the used reaction conditions, the amine was stirred for 24h under the reaction conditions used in the application scope. However, the
47 1H-NMR showed that the amine remained unchanged after the usual work-up. Further investigations then suggested that the amine could decompose during the column chro- matography. After synthesizing the amine, the product was usually purified by column chromatography before reacting it with bromo-diethylacetamide. By looking at the 1H-NMR of the crude amine-product, one would deduce that the pure product would yield around 80-90 %. However, after column chromatography only 50 % of the pure amine could be isolated.
This indicates that the amine must somehow decompose during the column chromato- graphy. This is supported by the fact that 1H-NMR of later fractions of the amine in column chromatography look very similar to those spectra which were obtained when trying to re- cover the amine by column chromatography after the epoxidation reaction. These facts would imply that the amine partly decomposes during the column chromatography, but to proof this speculation further investigations need to be performed.
48 2.5 Summary and Outlook
In this master thesis, the synthesis of chiral ammonium salts which, upon deprotonation react as ylides with aldehydes in an enantioselective fashion, was investigated. Two main backbones for the chiral ammonium ylides were synthesized and tested: DABCO- and L- proline-derived ones.
When using DABCO-derived ammonium salts, in one case very high enantioselectivitiy was achieved, but the yield was very low and and could not be increased by changing the conditions. After failing to synthesize a second DABCO-derivative, the focus was put on L-proline-derived bicyclic ammonium ylides.
One of these L-proline ammonium salts has already been synthesized and to begin with, the reaction conditions were optimized. When using this chiral L-proline backbone, different substituents can be exchanged leading to a large variety of different compounds. The tested substituents for R1 included naphthyl-, biphenyl-, aryls with electron-donating and electron- withdrawing substituents as well as aliphatic groups. For R2 phenyl, benzyl, cyclohexyl, tert-butyl and others were among the tested substituents. The corresponding ammonium salts were synthesized over 5 steps and tested in an epoxidation reaction with benzalde- hyde. However, not all combinations of different substituents could be synthesized leaving room for further improvement. The best results where obtained when leaving substituent R1 as a phenyl and a cyclohexyl-group as substitent 2. This gave a very good ee of 86% in combination with a yield of 88 %. The reaction conditions were varied, which lead to the conclusion that an even higher ee of 91 % but with a lower yield of 66 % could be achieved when running the reaction in toluene.
To be able to unambiguously identify the newly formed sterocenter, a crystal structure of this ammonium salt was measured using X-ray-diffraction, which showed that the two stere- ocenters are cis-oriented with respect to each other. This ammonium salt was then reacted with very different aldehydes to test the application scope of this reaction. For many cases, high yields in combination with high enantioselectivities were obtained. Aliphatic aldehydes performed worse than aromatic ones, and when using N,N-dimethylbenzaldehyde or unde-
49 canal no epoxide was formed at all. In all tested reactions using toluene as a solvent lead to higher enantioselectivities, whereas with i-PrOH as solent higher yields can be achieved.
Further improvement still needs to be done in optimizing the synthesis of the proline- derivatives because the yields are only moderate. A few other combinations concerning the substituents on the Proline should be synthesized, especially aliphatic groups as R2 could not be incorporated yet. Other groups than amides which also stabilize the ylide could be synthesized, e. g. benzyl-groups, and reacted with aldehydes to check if the high enantioselectivity can be maintained or even increased.
50 3 Experimental part
3.1 General remarks
Nuclear magnetic resonance experiments were performed using a 300 MHz Avance III spectrometer from Bruker with broad band probe head or a Bruker 700 MHz Avance III setup with an Ascend magnet and a TCI cryoprobe. 1H NMR spectra were recorded with frequencies of 300 or 700 MHz and 13C NMR spectra were recorded with frequencies of 75 or 176 MHz. The spectra were measured at 298 K and chemical shifts were referenced on the solvent peaks. The numbers below the counter of the structure represent the molar masses of the compounds in gmol-1.
3.2 Syntheses
3.2.1 Synthesis of ((2S,3S)-2,3-diphenyl-1,4-diazabicyclo[2.2.2]octane) 65
O Cl NH2 NH O + Cl Cl NH2 HN Cl O 64 75 76 212.29 112.94 365.25
In analogy to literature [57], 64 (2.01 g, 9.5 mmol) was dissolved in 40 mL of DCM and DMAP (44.9mg, 0.37mmol) and triethylamine (6.42mL, 4.65g, 45.97mmol) were added. The re- action mixture was cooled to 5 ◦C and 75 (2.25mL, 3.19g, 28.26mmol) was added dropwise over 30 min. The reaction mixture was allowed to warm to RT and stirred for 3 hours. After- wards, the reaction was cooled to 0 ◦C and filtered by suction filtration. The precipitate was washed with ice-cold water and dried in vacuo to give 76 (3.44g, 9.41mmol, >99%) as a brown solid.1H-NMR data were consistent with literature[58].
51 1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 4.04 (d, J = 15.1 Hz, 2H, 2x-CHAHBCl), 4.11
(d, J = 15.1 2x-CHAHB-Cl), 5.28-5.38 (m, 2H, 2x-N-CH-Ph), 7.10-7.16 (m, 4H, Ar-H), 7.21- 7.27 (m, 6H, Ar-H).
O Cl Cl NH NH
+ BH3
HN HN Cl Cl O
76 77 78 365.25 13.83 337.29
According to literature [57], 76 (1.63g, 4.46mmol) was dissolved in 40mL THF and a 1M solution of 77 (20mL, 20mmol) was added dropwise. The mixture was refluxed for 2 hours, cooled to 0 ◦C and excess of 77 was quenched with 8mL MeOH. The mixture was evapo- rated to dryness, the residue was redissolved in 40 mL of 5 wt% aqueous HCl solution and extracted with 20 mL DCM. The organic phase was discarded, the aqueous phase was basi- fied by adding aqueous NaOH (15 wt%) and extracted with DCM. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield 78 (0.69g, 2.05mmol, 46 %) as a yellow-brown residue.
Cl NH N
N HN Cl
78 65 337.29 264.37
In analogy to literature[57, 58], 78 (0.69g, 2.05mmol) was dissolved in 7mL DMF and re- fluxed for 4 hours. The solvent was removed under reduced pressure and the residue was dissolved in water, basified with 15 wt% of aqueous NaOH and extracted with DCM.
52 The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield 65 (0.50g, 1.90mmol, 94%) as a brown oil. 1H-NMR data were consistent with literature[58].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 2.55-2.67 (m, 2H, -N-CH2), 2.72-2.85 (m,
2H, -N-CH2), 2.94-3.04 (m, 4H -N-CH2), 4.14-4.20 (s, 2H, 2x-N-CH-Ph), 7.25-7.51 (m, 10H, Ar-H).
3.2.2 Attempted synthesis of camphor-based amine 68
O N
+ H2N NH2 O N
66 79 80 166.22 60.10 190.29
In accordance to literature[54], 66 (1.00 g, 6.02 mmol) was dissolved in 10 mL toluene. 79 (0.40mL, 0.36g, 6.02mmol) was added in one portion followed by slow addition of PTSA (0.30mmol, 51.7mg). The reaction mixture was refluxed using a Dean-Stark water sepa- rator for 2 hours. After cooling to RT, the toluene layer was separated, dried over Na2SO4 and evaporated to dryness to yield 80 (1.13 g, 5.95 mmol,>99 %) as a yellow oil in sufficient purity for further transformations.
H N N
+ NaBH4 N N H
80 81 67 190.29 37.83 194.32
In accordance to literature[54], 80 (1.13g, 5.95mmol) was dissolved in 30mL MeOH at 0 ◦C. 81 (0.68g, 17.7mmol) was added in portions over a period of 1 hour. The reaction mixture
53 was allowed to warm to RT and stirred for another 5 hours. MeOH was removed under reduced pressure and 15mL DCM and 5mL water were added at 0 ◦C. The organic layer was separated and washed with brine. The organic phase was dried over Na2SO4 and evaporated to dryness to yield 67 (1.07g, 5.51mmol, 93%) as a pale-yellow oil.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.84 (s, 3H, -CH-C-CH3), 0.90 (s, 3H, -CH-
C-CH3), 1.07-1.16 (m, 2H, 2x -CH2-CHAHB), 1.48 (s, 3H, CH2-C-CH3), 1.63-1.85 (m, 3H,
2x -CH2-CHAHB, -NH-C-CH-), 2.47-2.66 (m, 5H, -NH-CH-CH3 -NH-CH2-CH2-NH-), 2.99 (d, J = 10.6 Hz, 1H, -C-CH-NH-), 2.88-3.07 (m, 2H, 2x -NH).
H N N Br + Br N N H
67 82 68 194.32 187.86 220.36
In accordance to literature[55], 67 (1.07g, 5.51mmol) and KI (0.18g 1.1mmol) were dis- solved in 45 mL acetonnitrile. Subsequently, triethylamine (1.54mL, 1.12g, 11.02mmol) and 82 (1.89mL, 4.14g, 22.05mmol) were added and the reaction mixture was refluxed for 14 hours. After cooling to room temperature, the solvent was removed under reduced pressure and 50mL of 2M NaOH were added. The aqueous layer was extracted with DCM three times and the combined organic phases were washed with brine and water. The organic phases were dried over Na2SO4 and evaporated to dryness. NMR of the crude product showed that no product had been formed.
54 3.2.3 Synthesis of (2-bromo-N,N-diethylacetamide)
O O Br + N N Br H Br
83 84 74 201.85 73.14 194.07
According to literature[59], 83 (1.75mL, 4.04g, 20mmol) dissolved in 3mL DCM was added dropwise to a solution of 84 (4.18mL, 2.93g, 40mmol) in 25mL DCM at −10 ◦C. The re- action was stirred at −10 ◦C for 15minutes and then warmed to RT over 1 hour. The white crystals, which formed while stirring, were filtered off and the filtrate was poured into 25 mL of water. The phases were separated and the aqueous phase was extracted with DCM and then twice with chloroform. The combined organic phases were dried over Na2SO4 and evaporated to dryness to yield 74 (3.38g, 17.44mmol, 87%) as orange liquid in sufficient purity for further reactions. 1H-NMR data were consistent with literature[59].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.12 (t, J = 7.2 Hz, 3H, -N-CH2CH3), 1.24
(t, J = 7.2 Hz, 3H, -N-CH2CH3), 3.37 (q, J=7.2Hz, 4H, 2x -N-CH2-Ch3), 3.84 (s, 2H, CO-
CH2-Br-).
3.2.4 Protection of L-proline
O O + MeOH N OH N O H H2 Cl 69 85 86 115.13 32.04 165.62
In accordance to literature[60], 69 (5.01g, 43.51mmol) was dissolved in 30mL MeOH at 0 ◦C and thionylchloride (3.50mL, 5.74g, 48.24mmol) was added dropwise over 30min. The reaction mixture was refluxed for one hour and evaporated to dryness to yield 86 (7.49g, 45.22 mmol, >99 %) as a yellow wax.
55 O O
+ Boc2O N N O O H Cl 2 Boc 86 87 88 165.62 218.25 229.28
In analogy to literature[60] 86 (7.20g, 43.50mmol) was dissolved in 20mL DCM, cooled to 0 ◦C and triethylamine (12.47mL, 9.10g, 89.92mmol) was added dropwise over 30 min- utes. The mixture was stirred for 30 minutes followed by dropwise addition of a solution of 87 (9.70g, 44.44mmol) in 20mL DCM. The mixture was allowed to warm to RT and was then stirred for 18 hours. 100mL saturated Na2CO3-solution was added and the biphasic mixture was stirred for 5 hours. Subsequently, the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with brine, dried over Na2SO4 and evaporated to dryness to yield 88 (8.62g, 37.51mmol, 86%) as a pale yellow oil. 1H-NMR data were consistent with literature[60].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): two rotamers: 1.40 + 1.46 (s +s, 9H, -C-
(CH3)3), 1.77-2.04 (m, 3H, CH-CHAHB-CH2-), 2.07-2.31 (m, 1H, CH-CHAHB-CH2), 3.32-
3.61 (m, 2H, -N-CH2), 3.72 (s, 3H, -O-CH3), 4.22 + 4.31 (dd + dd, J=11.3Hz, 1H, -N-CH).
O O O O + N N OH Cl O MeOH H O O 69 89 70 115.13 108.52 201.22
According to literature[61], 69 (5.0g, 43.51mmol) was dissolved in 100mL MeOH followed ◦ by the addition of K2CO3 (6.01g, 43.51mmol). The mixture was cooled to 0 C and 89 (9.11mL, 10.39g, 95.72mmol) was added dropwise over 30minutes. The mixture was stirred for 4hours at 0 ◦C and 12hours at RT. The solvent was removed under reduced pressure, and 40 mL water were added and extracted with DCM. The combined organic
56 phases were dried over Na2SO4 and evaporated to dryness to yield 70 (8.53g, 42.36mmol, 97 %) as a colourless liquid. 1H-NMR data were consistent with literature[61].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]) (mixture of rotamers): 1.13 (t, J=7.1Hz, 3H,
-CH2-CH3-), 1.20 (t, J = 7.1 Hz, 3H, -CH2-CH3-), 1.75-2.00 (m, 6H, -CH-CH2-CHAHB-), 2.01-
2.52 (m, 2H, -CH-CH2–CHAHB-), 3.31-3.57 (m, 4H, -CH2-N-), 3.65 (s, 3H, -O-CH3), 3.66 (s,
3H, -O-CH3), 3.92-4.12 (m, 4H, -CH2-CH3), 4.24 (dd, J=3.6, 8.7Hz, 1H, -CH-N-), 4.30 (dd, J = 3.6, 8.7 Hz, 1H, -CH-N-).
3.2.5 General procedure I: Grignard-reaction
According to literature [62], 4eq. Mg-turnings were overlayed with THF (3mL/10mmolMg) and 4eq. of the corresponding arylbromide dissolved in THF (8 mL/10mmolarylbromide) was added dropwise over 30 minutes. The reaction mixture was stirred for 30minutes and refluxed for 1 hour to obtain the Grignard reagent. The reaction mixture was cooled to 0 ◦C and either 1eq. of 88 or 70 was added as a solution in THF (15mL/10mmol) over 30 minutes. The reaction mixture was stirred for 1 hour at 0 ◦C and 4 hours at room tem- perature. Subsequently the reaction mixture was cooled to 0 ◦C and quenched by adding water and Et2O. The mixture was filtrated by suction filtration and washed with Et2O (three times). The organic phase was dried over Na2SO4 and evaporated to dryness to yield the corresponding products.
3.2.6 General procedure II: Deprotection of the arylated amines
In analogy to literature [63], 10eq. of NaOH were dissolved in ethanol (0.5mL/mmolNaOH) by use of an ultrasonic bath. 1eq. of the protected amine was added and the mixture was refluxed (duration of refluxing is found at the individual reactions). Afterwards, the reaction was allowed to cool to room temperature and the solvent was removed under reduced pressure. Water (7mL/mmolBoc-protected amine) and Et2O (15mL/mmolBoc-protected amine) were added and the biphasic mixture was stirred until the solids dissolved. The
57 phases were separated and the aqueous phase was extracted with Et2O. The combined organic phases were dried over Na2SO4 and evaporated to dryness to give the deprotected amines in the given yields below.
3.2.7 General procedure III: Closing the second 5-membered ring
In accordance to literature [56], 1eq. of unprotected amine was dissolved in toluene (20mL/mmol) followed by the addition of 0.125 eq. PTSA and 1.3 eq. aldehyde. The reaction mixture was refluxed (duration of reflux see the individual reactions) using a Dean-Stark water separator. Subsequently the reaction mixture was cooled to RT and the reaction mixture was washed with saturated aqueous sodium bicarbonate solution, saturated sodium bisulfite solution, brine and water. The organic phase was dried over Na2SO4 and evaporated to dryness to yield the corresponding products.
3.2.8 General procedure IV: Synthesis of chiral ammonium acetamides
In analogy to literature[50], 1eq. of 2-bromo-N,N-diethylacetamide 74 was dissolved in THF (10mL/g amide), 1eq. of amine was added and the resulting mixture was stirred either at room temperature or at reflux for the time given below. The reaction mixture was evapo- rated to dryness and the crude product was purified by column chromatography as stated below.
58 3.2.9 Synthesis of DABCO-derived ammonium salt 62
O
N N O N Br + N N Br N
65 74 62 264.37 194.07 458.44
Ammonium salt 62 was prepared from 65 (0.46g, 1.73mmol) and 74 (0.34g, 1.75mmol) after general procedure IV. Column chromatography (silica gel, DCM:MeOH=3:1) of the crude product yielded 62 (0.73g, 1.59mmol, 92%) as a beige solid.
O i q h p j o N r g q' i' N r' h' e c a l d f b m N k Br n l' m'
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.72 (t, J=7.2Hz, 3H, (r)), 1.11 (t, J=7.2Hz,
3H, (r’)), 2.93-3.21 (m, 4H, (d1 + d2 + q)), 3.24-3.33 (m, 2H, (q’)), 3.36-3.49 (m, 1H, (o1)),
3.52-3.74 (m, 3H, (b1 + b2 +a1), 4.12-4.27 (m, 1H, (c1)), 4.63 (d, J=9.3Hz, 1H, (f)), 4.66-
4.74 (m, 1H, (c2)), 4.75-4.87 (m, 1H, (a2), 5.16-5.36 (m, 1H, (o2)), 5.92 (d, J=9.2Hz, 1H, (e)), 7.20-7.33 (m, 5H, ( i + i’ + m + m’ + n)), 7.43- 7.52 (m, 3H, (j + l + l’)), 7.63-7.75 (m, 2H, (h + h’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 13.2 (Cr), 13.9 (Cr’), 40.2 (Cd), 41.6 (Cq),
42.4 (Cq’), 47.2 (Cb), 50.5 (Ca), 53.7 (Cc), 58.7 (Co), 63.5 (Cf), 69.2 (Ce), 127.3 (Cm + Cm’),
128.7 (Cn), 129.2 (Ci + Ci’), 130.5 (Cl + Cl’), 130.9 (Ch + Ch’), 131.9 (Cj), 136.8 (Cg + Ck),
59 163.1 (Cp).
Assignments were achieved using HMBC and HSCQ data.
3.2.10 Synthesis of ammonium salt 63a (R1 = phenyl, R2 = H)
O
+ PhMgBr N O Boc N OH Boc 88 90 91 229.28 181.32 353.46
According to general procedure I, 91 was synthesized using 88 (2.50g, 10.90mmol) and 90 (7.90g, 46.60mmol). The pale yellow product 91 (3.65g, 10.31mmol, 95%) was in suf- ficient purity for further transformations. 1H-NMR data were consistent with literature[64].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.76 (br s, 1H, -CH-CH2-CHAHB-), 1.43 (s,
9H, -C-(CH3)3), 1.36-1.53 (m, 1H,-CH-CH2-CHAHB-), 1.82-1.97 (m, 1H, -CH-CHAHB-CH2),
1.99-2.17 (m, 1H, -CH-CHAHB-CH2), 2.86 (br s, 1H, -N-CHAHB-), 3.34 (br q, J=9.0Hz, 1H,
-N-CHAHB-), 4.89 (dd, J=8.9Hz, 1H, -N-CH-), 7.19-7.42 (m, 6H, Ar-H), 7.35-7.42 (m, 4H, Ar-H).
+ NaOH
N OH N OH H Boc 91 92 72a 353.46 40.00 253.35
60 According to general procedure II, 72a was prepared from 91 (3.65g, 10.31mmol) and 92 (4.40g, 110mmol). The reaction mixture was refluxed for 4 hours followed by the work-up as specified above yielding 72a (2.32 g, 9.16 mmol, 89 %) as a slightly brown solid. 1H-NMR data were consistent with literature[65].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.52-1.95 (m, 5H, NH-CHAHB-CH2-CH2-),
2.92-3.13 (m, 2H, -NH-CHAHB-, -NH-CH2-), 4.30 (t, J = 7.5 Hz, 1H, -CH2-CH-), 4.9 (br s, 1H, -OH), 7.20-7.29 (m, 2H, Ar-H), 7.32-7.43 (m, 4H, Ar-H), 7.59-7.65 (m, 2H, Ar-H), 7.66- 7.71 (m, 2H, Ar-H).
O +
H H O N OH H N
72a 93 73a 253.35 30.03 265.36
According to general procedure III, 73a was prepared from 72a (1.40g, 5.53mmol) and 93 as 37% aqueous formaldehyde solution (0.50mL, 6.7mmol). The reaction mixture was refluxed for 4 hours followed by the work-up as specified above yielding 73a (0.68 g, 2.54mmol, 46%) as a brown oil. H-NMR data were consistent with literature[56].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.98-1.19 (m, 1H, -CHAHB-CH2-CH-), 1.49-
1.63 (m, 3H, -CHAHB-CH2-CH-), 2.69-2.75 (m, J 1H, -N-CHAHB-CH2), 3.12-3.22 (m, 1H,
-N-CHAHB-CH2), 4.19 (d, J=6.2Hz, 1H, -N-CHAHB-O-), 4.33 (t, J=7.1Hz, 1H, -CH2-CH-N-
), 4.40 (d, J=6.2Hz, 1H, -N-CHAHB-O-), 7.02-7.23 (m, 6H, Ar-H), 7.25-7.31 (m, 2H, Ar-H), 7.38-7.45 (m, 2H, Ar-H).
61 O + N O Br N O N N Br
O 73a 74 63a 265.36 194.07 459.43
Ammonium salt 63a was prepared from 73a (0.38g, 1.44mmol) and 74 (0.28g, 1.44mmol) after general procedure IV. Column chromatography (silica gel, DCM:MeOH=9:1) of the crude product yielded 63a (0.60g, 1.30mmol, 90%) as a beige solid.
j i h' m i' l g n e h a k f m' d r O l' q N c b N p r' o q' Br O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.97 (t, J=7.2Hz, 3H, (r)), 1.07 (t, J=7.2Hz,
3H, (r’)), 1.48-1.65 (m, 1H, (e1)), 1.98-2.15 (m, 1H, (d1)), 2.43-2.67 (m, 2H, (d2, e2)), 3.00-
3.30 (m, 2H, (q)), 3.37-3.62 (m, 2H, (q’)), 3.74-3.86 (m, 1H, o1), 3.89 (d, J=16.9Hz, 1H,
(c1)), 4.07-4.20 (m, 1H, o2), 4.57 (d, J=7.3Hz, 1H, (b1)), 5.64 (d ,J=7.3Hz, 1H, (b2) ), 6.31
(d, J=16.9Hz, 1H, (c2)), 6.76 (t, J=7.9Hz, (f)), 7.20-7.42 (m, 6H, (i + i’ + l + l’ + m + m’)), 7.43-7.52 (m, 2H, (j + n)), 7.79-7.87 (m, 2H, (h +h’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 13.7 (Cr), 13.9 (Cr’), 25.4 (Cd), 30.1 (Ce),
40.6 (Cq), 42.1 (Cq’), 64.7 (Cc), 67.8 (Co), 80.5 (Cf), 94.1 (Cb), 124.9 (Cn), 126.0 (Ch+h’),
128.1 (Cl+l’), 128.8 (Ci+i’), 129.2 (Cm+m’), 129.9 (Cj), 138.7 (Ck), 139.5 (Cg), 163.0 (Cp).
62 Assignments were achieved using HMBC and HSCQ data.
3.2.11 Synthesis of ammonium salt 63b (R1 = naphthyl, R2 = H)
O MgBr O N + O OH N O O O 70 95 96 201.22 231.38 425.53
According to general procedure I, 96 was synthesized using 70 (0.5g, 2.49mmol) and 95 (2.29g, 9.40mmol). The orange product 96 was used without further purification for the following transformations. 1H-NMR data were consistent with literature[66].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.32 (t, J = 7.1 Hz, 3H, -O-CH2-CH3), 1.44-
1.59 (m, 1H, -CH-CHAHB-CH2-), 1.84-1.96 (m, 3H, -CH-CHAHB-CH2-), 2.99-3.18 (br s, 1H, -
N-CHAHB), 3.45-3.62 (m, 1H, -N-CHAHB), 4.06-4.33 (m, 2H, -O-CH2-CH3), 5.25 (dd, J=4.3,
8.1 Hz, 1H, -N-CH-CH2-), 7.49-7.61 (m, 8H, Ar-H), 7.83-7.96 (m, 6H, Ar-H).
+ NaOH OH N OH O NH O
96 92 72b 425.53 40.00 353.47
63 According to general procedure II, 72b was prepared from 96 and 92 (1.00g, 25.00mmol). The reaction mixture was refluxed for 24 hours followed by the work-up as specified above yielding 72b (0.66g, 1.88mmol, 75% over 2 steps) as slight beige solid. 1H-NMR data were consistent with literature[67].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.58-1.87 (m, 5H, -CH-CH2-, -CH-CH2-CH2-,
-NH), 2.87-3.12 (m, 1H, HN-CHAHB-), 3.05-3.14 (m, 1H, HN-CHAHB-), 4.56 (t, J = 6.8 Hz,
-CH2-CH-NH-), 7.39-7.53 (m, 6H, Ar-H), 7.56-7.63 (m, 2H, Ar-H), 7.66-7.96 (m, 6H, Ar-H).
O + H H O OH NH N
72b 93 73b 353.47 30.03 365.48
According to general procedure III, 73b was prepared from 72b (0.17g, 0.47mmol) and 93 as 37% aqueous formaldehyde solution (421 µL, 5.25mmol). The reaction mixture was refluxed for 4 hours followed by the work-up as specified above yielding 73b (0.15g, 0.41 mmol, 88 %) a a brown solid.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.12-1.33 (m, 1H, -CH-CHAHB-CH2-), 1.66-
1.82 (m, 3H, -CH-CHAHB-CH2), 2.80-2.96 (m, 1H, -N-CHAHB-), 3.36-3.47 (m, 1H, -N-
CHAHB-), 4.37 (d, J=6.5Hz, 1H, -N-CHAHB-O-), 4.61 (d, J=6.2Hz, 1H, -N-CHAHB), 4.81
(t, J = 7.0 Hz, 1H, -CH2-CH-N-), 7.23-7.35 (m, 2H, Ar-H), 7.41-7.57 (m, 6H, Ar-H), 7.67-7.96 (m, 6H, Ar-H).
64 O + N O Br N O Br N N
O 73b 74 63b 365.48 194.07 559.55
Ammonium salt 63b was prepared from 73b (0.15g, 0.41mmol) and 74 (79.9mg, 0.41mmol) after general procedure IV by stirring in 1.5mL THF at RT for 24hours. Column chromatog- raphy (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63b (0.16g, 0.29mmol, 70 %) as a beige solid.
k' j' k i n o' j h'm' p h g p' e a f l m o d O t' N s' c b N q t r s Br O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.83 (t, J = 7.1 Hz, 3H, (z)), 1.05 (t, J = 7.1 Hz,
3H, (z’)), 1.55-1.72 (m, 1H, (e1)), 1.97-2.21 (m, 1H, (d1)), 2.39-2.60 (m, 2H, (d2,e2)), 2.94-
3.25 (m, 2H, (r)), 3.31-3.59 (m, 2H, (r’)), 3.71-3.86 (m, 1H, p1), 4.13 (d, J=17.0Hz, 1H,
(b1)), 4.31-4.47 (m, 1H, p2), 4.57 (d, J=7.3Hz, 1H, (b2)), 5.75 (d, J=7.3Hz, 1H, (b2)), 6.21
(d, J=17.0Hz, 1H, (c2)), 7.06 (t, J=7.7Hz, (f)), 7.38-7.61 (m, 8H, (k + k’ + h + h’ + m + m’ + p + p’)),7.69-7.94(m, 6H, (o + o’ + j + j’ + i + n)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.7 (Ct), 13.7 (Ct’), 25.4 (Cd), 30.2 (Ce),
40.6 (Cs), 42.1 (Cs’), 64.8 (Cb), 67.6 (Cq), 79.8 (Cf), 94.5 (Cb), 122.9 (Ar-C), 126.4 (Ar-C),
65 126.8 (Ar-C), 127.2 (Ar-C), 127.3 (Ar-C), 127.7 (Ar-C), 128.3 (Ar-C)), 129.0 (Ar-C), 129.1
(Ar-C), 130.2 (ar-C), 163.0 (Cv).
Assignments were achieved using HMBC and HSCQ data.
3.2.12 Synthesis of ammonium salt 63c (R1 = biphenyl, R2 = H)
O
O N + O BrMg O OH N O O
70 97 98 201.22 257.41 477.60
According to general procedure I, 98 was synthesized using 70 (1.0g, 4.97mmol) and 97 (5.12g, 19.88mmol). The yellow product 98 was used without further purification for the following transformations.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.29 (t, J = 7.0 Hz, 3H, -O-CH2-CH3), 1.51-
1.67 (m, 1H, -CH-CHAHB-CH2-), 1.87-1.94 (m, 3H, -CH-CHAHB-CH2-), 2.98-3.15 (br s, 1H, -
N-CHAHB), 3.41-3.60 (m, 1H, -N-CHAHB), 4.04-4.32 (m, 2H, -O-CH2-CH3), 5.05 (dd, J=3.7,
8.7 Hz, 1H, -N-CH-CH2-), 7.36-7.72 (m, 18H, Ar-H).
66 + NaOH
OH N OH O NH O
98 92 72c 477.60 40.00 405.54
According to general procedure II, 72c was prepared from 98 and 92 (2.02g, 50.5mmol). The reaction mixture was refluxed for 24 hours followed by the work-up as specified above yielding 72c (0.92g, 2.27mmol, 46% over 2 steps) as an orange solid. 1H-NMR data were consistent with literature [68].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.58-1.87 (m, 6H, -CH-CH2-, -CH-CH2-CH2-,
-OH, -NH), 2.96-3.05 (m, 1H, HN-CHAHB-), 3.05-3.14 (m, 1H, HN-CHAHB-), 4.35 (t, J = 7.5 Hz,
-CH2-CH-NH-), 7.30-7.38 (m, 2H, Ar-H), 7.39-7.47 (m, 4H, Ar-H), 7.52-7.61 (m, 8H, Ar-H), 7.61-7.66 (m, 2H, Ar-H), 7.67-7.73 (m, 2H, Ar-H).
O + H H
OH O NH N
72c 93 73c 405.54 30.03 417.55
According to general procedure III, 73c was prepared from 72c (0.23g, 0.57mmol) and 93 as 37% aqueous formaldehyde solution (510 µL, 6.36mmol). The reaction mixture
67 was refluxed for 4 hours followed by the work-up as specified above yielding 73c (0.18g, 0.44 mmol, 78 %) as a brown solid.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.25-1.48 (m, 1H, -CH-CHAHB-CH2-), 1.73-
1.90 (m, 3H, -CH-CHAHB-CH2), 2.93-2.99 (m, 1H, -N-CHAHB-), 3.43-3.56 (m, 1H, -N-
CHAHB-), 4.46 (d, J=6.2Hz, 1H, -N-CHAHB-O-), 4.65 (d, J=6.2Hz, 1H, -N-CHAHB), 4.68
(t, J = 7.0 Hz, 1H, -CH2-CH-N-), 7.20-7.71 (m, 18H, Ar-H).
O + N Br O N O N N Br
O 73c 74 63c 417.55 194.07 611.62
Ammonium salt 63c was prepared from 73c (0.18g, 0.43mmol) and 74 (83.6mg, 0.43mmol) after general procedure IV by stirring in 2mL THF at RT for 24hours. Column chromatog- raphy (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63c (0.23g, 0.38mmol, 88 %) as a beige solid.
68 n m' m l' l k u j t v i' q s i h' r u' p t' h g o e a q' f p' z d O y N c b z' N x w y' Br O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.00 (t, J = 7.1 Hz, 3H, (z)), 1.09 (t, J = 7.1 Hz,
3H, (z’)), 1.59-1.77 (m, 1H, (e1)), 2.01-2.19 (m, 1H, (d1)), 2.48-2.68 (m, 2H, (d2,e2)), 3.00-
3.32 (m, 2H, (y)), 3.37-3.64 (m, 2H, (y’)), 3.78-3.93 (m, 1H, w1), 3.99 (d, J=16.9Hz, 1H,
(c1)), 4.08-4.23 (m, 1H, w2), 4.67 (d, J=7.3Hz, 1H, (b1)), 5.72 (d, J=7.3Hz, 1H, (b2) ), 6.25
(d, J=16.9Hz, 1H, (c2)), 6.83 (t, J=7.7Hz, (f)), 7.29-7.63 (m, 14H, (h + h’ +i + i’+ m +m’+ n + p + p’ + q + q’ + u + u’ + v)), 7.70-7.78(m, 2H, (t + t’)), 7.93-8.02 (m, 2H, (l + l’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.7 (Cz), 13.9 (Cz’), 25.3 (Cd), 30.2 (Ce),
40.7 (Cy), 42.1 (Cy’), 64.7 (Cc), 67.9 (Cw), 80.7 (Cf), 94.1 (Cb), 125.4 (Ar-C), 126.6 (Cl+l’),
126.9 (Ar-C), 127.0 (Ar-C), 127.5 (Ar-C), 127.7 (Ar-C), 128.0 (Cj + r), 128.5 (Ct+t’), 128.8
(Ck+s), 129.0 (Cg + o), 163.0 (Cx).
Assignments were achieved using HMBC and HSCQ data.
69 3.2.13 Synthesis of ammonium salt 63d (R1 = p-OMe-phenyl, R2 = H)
O
O O O O N + O OH BrMg N O O O
70 99 100 201.22 211.34 385.46
According to general procedure I, 100 was synthesized using 70 (2.0g, 9.94mmol) and 99 (8.40g, 39.76mmol). The pale-yellow solid 100 was used without further purification for the following transformations.
1 H-NMR (300 MHz, CDCl3, 298.0 K, δ [ppm]): 1.26 (t, J = 7.3 Hz, 3H, -O-CH2-CH3), 1.42-
1.58 (m, 1H, -CH-CHAHB-CH2-), 1.78-1.98 (m, 3H, -CH-CHAHB-CH2), 2.89-3.09 (br s, 1H,
-N-CHAHB), 3.36-3.51 (m, 1H, -N-CHAHB), 3.82 (s, 6H, -O-CH3) 4.04-4.27 (m, 2H, -O-CH2-
CH3), 4.90 (dd, J=3.4, 8.8Hz, 1H, -N-CH-CH2-), 6.87-6.00 (m, 4H, Ar-H), 7.27-7.37 (m, 4H, Ar-H).
O O O O + NaOH OH N OH O NH O
100 92 72d 385.46 40.00 313.40
According to general procedure II, 72d was prepared from 100 and 92 (4.06g, 101.50mmol). The reaction mixture was refluxed for 16 hours followed by the work-up as specified above
70 yielding 72d (2.48g, 7.92mmol, 85% over 2 steps) as orange solid. 1H-NMR data were consistent with literature[67].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.49-1.90 (m, 5H, -CH-CH2-, -CH-CH2-CH2-,
-NH), 2.86-3.09 (m, 2H, HN-CH2-), 3.77 (s, 6H, -O-CH3), 4.20 (t, J = 7.5 Hz, -CH2-CH-NH-), 6.80-6.89 (m, 4H, Ar-H), 7.37-7.44 (m, 2H, Ar-H), 7.45-7.52 (m, 2H, Ar-H).
O O
O O O + H H
OH O NH N
72d 93 73d 313.40 30.03 325.41
According to general procedure III, 73d was prepared from 72d (0.18g, 0.57mmol) and 93 as 37% aqueous formaldehyde solution (100 µL, 6.0mmol). The reaction mixture was re- fluxed for 4 hours followed by the work-up as specified above yielding 73d (0.17g, 0.51mmol, 90 %) as orange solid.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.23-1.41 (m, 1H, -CH-CHAHB-CH2-), 1.68-
1.94 (m, 3H, -CH-CHAHB-CH2), 2.93 (m, 1H, -N-CHAHB), 3.70-3.82 (m, 1H, -N-CHAHB),
3.77 (s, 6H, -O-H3), 4.44 (d, J=6.4Hz, 1H, -N-CHAHB-O-), 4.62 (d, J=6.4Hz, 1H, -N-
CHAHB), 4.83 (t, J = 7.4 Hz, 1H, -CH2-CH-N-), 6.78-6.92 (m, 4H, Ar-H), 7.19-7.24 (m, 2H, Ar-H), 7.41-7.48 (m, 2H, Ar-H).
71 O
O O
O O + N Br O N O Br N N
O 73d 74 63d 325.41 194.07 519.48
Starting from 73d (0.19g, 0.57mmol) and 74 (0.11g, 0.57mmol) ammonium salt 63d was prepared by stirring for 24hours at RT in 1mL THF after general procedure IV. Column chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63d (0.24g, 0.54 mmol, 93 %) as a brown solid.
k O j i' p i n' h' m' O o h g a n e f l m d O t' N s' c b t N r q s Br O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.02 (t, J = 7.1 Hz, 3H, (t)), 1.09 (t, J = 7.1 Hz,
3H, (t’)), 1.49-1.63 (m, 1H, (e1)), 1.97-2.18 (m, 1H, (d1)), 2.32-2.56 (m, 2H, (d2, e2)), 3.05- 3.32 (m, 2H, (s)), 3.37-3.58 (m, 2H, (s’)), 3.77 (s, 3H, (k)), 3.78 (s, 3H, (p)) 3.67-3.81 (m,
1H, q1), 3.92 (d, J=16.8Hz, 1H, (c1)), 4.03-4.14 (m, 1H, q2), 4.53 (d, J=7.2Hz, 1H, (b1)),
5.61 (d, J=7.2Hz, 1H, (b2) ), 6.11 (d, J=16.8Hz, 1H, (c2)), 6.54 (t, J=7.8Hz, (f)), 6.77-6.86 (m, 2H, (i + i’), 6.92-7.02 (m, 2H, (n + n’)), 7.18-7.30 (m, 2H, (h + h’)), 7.40-7.47 (m, 2H, (m + m’)).
72 13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.7 (Ct), 14.0 (Ct’), 25.3 (Cd), 30.3 (Ce),
40.7 (Cs), 42.1 (Cs’), 55.4 (Ck), 56.8 (Cp), 64.5 (Cc), 67.7 (Co), 80.7 (Cf), 93.9 (Cb), 113.5
(Ci), 113.9 (Ci’), 114.0 (Cn), 115.1 (Cn’), 126.2 (Ch), 126.8 (Ch’), 127.5 (Cm), 128.4 (Cm’),
163.0 (Cr).
Assignments were achieved using HMBC and HSCQ data.
3.2.14 Synthesis of ammonium salt 63e (R1 = p-F-phenyl, R2 = H)
F
O F F O N + O OH BrMg N O O O
70 101 102 201.22 199.31 361.39
According to general procedure I, 102 was synthesized using 70 (1.0g, 4.97mmol) and 101 (3.47g, 19.88mmol). The pale-yellow solid 102 was used without further purification for the following transformations. 1H-NMR data were consistent with literature [69].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.16 (t, J = 7.1 Hz, 3H, -O-CH2-CH3), 1.38-
1.46 (m, 1H, -CH-CHAHB-CH2-), 1.73-1.80 (m, 3H, -CH-CHAHB-CH2), 2.82-2.95 (br s, 1H, -
N-CHAHB), 3.28-3.42 (m, 1H, -N-CHAHB), 3.95-4.11 (m, 2H, -O-CH2-CH3), 4.77 (dd, J=3.8,
8.8 Hz, 1H, -N-CH-CH2-), 6.86-6.96 (m, 4H, Ar-H), 7.22-7.31 (m, 4H, Ar-H).
73 F F F F + NaOH OH N OH O NH O
102 92 72e 361.39 40.00 289.33
According to general procedure II, 72e was prepared from 102 and 92 (2.02g, 50.5mmol). The reaction mixture was refluxed for 16 hours followed by the work-up as specified above yielding 72e (1.11 g, 3.84 mmol, 78 % over 2 steps) as pale-yellow solid. 1H-NMR data were consistent with literature [69].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.48-1.91 (m, 5H, -CH-CH2-, -CH-CH2-CH2-
, NH), 2.89-3.09 (m, 2H, HN-CH2-), 4.22 (t, J = 7.7 Hz, -CH2-CH-NH-), 6.93-7.05 (m, 4H, Ar-H), 7.40-7.48 (m, 2H, Ar-H), 7.48-7.58 (m, 2H, Ar-H).
F F
F O F + H H
OH O NH N
72e 93 73e 289.33 30.03 301.34
According to general procedure III, 73e was prepared from 72e (0.18g, 0.62mmol) and 93 as 37% aqueous formaldehyde solution (560 µL, 6.9mmol). The reaction mixture was re- fluxed for 4 hours followed by the work-up as specified above yielding 73e (0.10g, 0.35mmol, 56 %) as a yellow solid.
74 1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.11-1.25 (m, 1H, -CH-CHAHB-CH2-), 1.60-
1.79 (m, 3H, -CH-CHAHB-CH2), 2.82 (m, 1H, -N-CHAHB), 3.27-3.37 (m, 1H, -N-CHAHB),
4.27 (d, J=6.3Hz, 1H, -N-CHAHB-O-), 4.40 (t, J=7.2Hz, 1H, -CH2-CH-N-), 4.53 (d, J=6.2Hz,
1H, -N-CHAHB), 6.93-7.06 (m, 4H, Ar-H), 7.27-7.36 (m, 2H, Ar-H), 7.43-7.51 (m, 2H, Ar-H).
F
F F
F O + N Br O N O Br N N
O 73e 74 63e 301.34 194.07 495.41
Starting from 73e (0.10g, 0.35mmol) and 74 (67.1mg, 0.35mmol) ammonium salt 63e was prepared by stirring for 24hours at RT in 1mL THF after general procedure IV. Column chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63e (0.14g, 0.29 mmol, 80 %) as a brown solid.
F j i' m i h' l F n h g m' e a k f l' d O r' q' N c b r N p o q Br
O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.04 (t, J=7.1Hz, 3H, (r)), 1.09 (t, J=7.1Hz,
3H, (r’)), 1.44-1.61 (m, 1H, (e1)), 1.97-2.18 (m, 1H, (d1)), 2.38-2.62 (m, 2H, (d2, e2)), 3.06-
75 3.42 (m, 2H, (q)), 3.37-3.60 (m, 2H, (q’)), 3.70-3.81 (m, 1H, o1), 3.87 (d, J=16.9Hz, 1H,
(c1)), 4.05-4.16 (m, 1H, o2), 4.52 (d, J=7.4Hz, 1H, (b1)), 5.66 (d, J=7.4Hz, 1H, (b2)), 6.20
(d, J=16.9Hz, 1H, (c2)), 6.70 (t, J=7.7Hz, (f)), 6.98-7.06 (m, 2H, (i + i’), 7.13-7.22 (m, 2H, (l +l’)), 7.29-7.39 (m, 2H, (h + h’)), 7.80-7.92 (m, 2H, (k + k’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.7 (Cr), 14.0 (Cr’), 25.2 (Cd), 30.3 (Ce), 40.7
(Cq), 42.2 (Cq’), 64.8 (Cc), 67.8 (Co), 80.4 (Cf), 93.8 (Cb), 115.8 (Ci), 116.1 (Ci’), 116.9 (Cm),
117.2 (Cm’), 126.7 (Ch), 126.9 (Ch’), 128.2 (Cl), 128.4 (Cl’), 163.0 (Cp).
Assignments were achieved using HMBC and HSCQ data.
1 2 3.2.15 Synthesis of ammonium salt 63f (R = p-CF3-phenyl, R = H)
F F F F O F F F F O F N + O BrMg OH O N O O
70 103 104 201.22 211.34 461.40
According to general procedure I, 104 was synthesized using 70 (0.48g, 2.38mmol) and 103 (1.00mL, 1.61g, 7.14mmol (3eq instead of 4eq because there was not more in stock)). The orange oil 104 was used without further purification for the following transformations. 1H-NMR data were consistent with literature[70].
1 H-NMR (300 MHz, CDCl3, 298.0 K, δ [ppm]): 1.21 (t, J = 7.2 Hz, 3H, -O-CH2-CH3), 1.49-
1.71 (m, 1H, -CH-CHAHB-CH2-), 1.77-2.04 (m, 3H, -CH-CHAHB-CH2), 2.88-3.11 (br s, 1H, -
76 N-CHAHB), 3.36-3.59 (m, 1H, -N-CHAHB), 4.04-4.16 (m, 2H, -O-CH2-CH3), 4.87 (dd, J=4.1,
8.8 Hz, 1H, -N-CH-CH2-), 7.37-7.74 (m, 8H, Ar-H).
F F F F F F F F F F F + NaOH F
OH N OH O NH O
104 92 72f 461.40 40.00 389.34
According to general procedure II, 72f was prepared from 104 and 92 (1.00g, 25mmol). The reaction mixture was refluxed for 17 hours followed by the work-up as specified above yielding 72f (0.50 g, 1.28 mmol, 57 % over 2 steps) as pale-yellow solid. 1H-NMR data were consistent with literature[70].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.44-1.83 (m, 5H, -CH-CH2-, -CH-CH2-CH2-,
-NH), 2.84-3.01 (m, 2H, HN-CH2-), 4.34 (t, J = 7.6 Hz, -CH2-CH-NH-), 7.31-7.68 (m, 8H, Ar-H).
F F F F F F F F F O F F + F H H
OH O NH N
72f 93 73f 389.34 30.03 401.35
According to general procedure III, 73f was prepared from 72f (0.25g, 0.64mmol) and 93 as 37% aqueous formaldehyde solution (64.0 µL, 0.72mmol). The reaction mixture
77 was refluxed for 4 hours followed by the work-up as specified above yielding 73f (0.15g, 0.37 mmol, 56 %) as a yellow solid.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.13-1.34 (m, 1H, -CH-CHAHB-CH2-), 1.65-
1.80 (m, 3H, -CH-CHAHB-CH2), 2.78-2.88 (m, 1H, -N-CHAHB), 3.28-3.38 (m, 1H, -N-CHAHB),
4.28 (d, J=6.4Hz, 1H, -N-CHAHB-O-), 4.47 (t, J=7.1Hz, 1H, -CH2-CH-N-), 4.59 (d, J=6.4Hz,
1H, -N-CHAHB), 7.45-7.80 (m, 8H, Ar-H).
F F F F F F F F F F F O F + N Br O N O N N Br
O 73f 74 63f 401.35 194.07 595.42
Starting from 73f (0.15g, 0.36mmol) and 74 (77.6mg, 0.40mmol) ammonium salt 63f was prepared by stirring for 24hours at RT in 1mL THF after general procedure IV. Column chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63f (65.1mg, 0.11 mmol, 30 %) as a yellow solid.
78 F F F k j i' F F i n' h' m' p o F h g a n e f l m d O t' s' N c b N q t r s Br O
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.00 (t, J = 7.1 Hz, 3H, (t)), 1.08 (t, J = 7.1 Hz,
3H, (t’)), 1.44-1.62 (m, 1H, (e1)), 2.02-2.19 (m, 1H, (d1)), 2.45-2.65 (m, 2H, (d2, e2)), 3.06-
3.34 (m, 2H, (s)), 3.37-3.55 (m, 2H, (s’)), 3.73-3.89 (m, 1H, q1), 3.83 (d, J=16.7Hz, 1H,
(c1)), 4.08-4.21 (m, 1H, q2), 4.54 (d, J=7.6Hz, 1H, (b1)), 5.75 (d, J=7.2Hz, 1H, (b2) ),
6.17 (d, J=16.7Hz, 1H, (c2)), 7.20 (t, J=8.1Hz, (f)), 7.52-7.64 (m, 4H, (h + h’+ m + m’)), 7.74-7.81 (m, 2H, (i + i’)), 8.08-8.16 (m, 2H, (n + n’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.7 (Ct), 13.9 (Ct’), 25.2 (Cd), 30.5 (Ce),
40.7 (Cs), 42.1 (Cs’), 65.05 (Cc), 68.01 (Cq), 80.7 (Cf), 93.9 (Cb), 125.4 (Cp+k) , 126.0 (Ci),
126.1 (Ci’), 126.1 (Cn), 126.2 (Cn’), 126.8 (Ch), 127.1 (Ch’), 127.1 (Cm), 127.2 (Cm’), 127.2
(Cg + l), 163.0 (Cr) .
Assignments were achieved using HMBC and HSCQ data.
79 3.2.16 Synthesis of ammonium salt 63g (R1 = phenyl, R2 = cyclohexyl)
O
+ H O N
N OH H
72a 22i 73g 253.35 112.17 347.50
According to general procedure III, 73g was prepared from 72a (8.29g, 32.73mmol) and 22i (7.00mL, 6.48g, 57.8mmol). The reaction mixture was refluxed for 16 hours followed by the work-up as specified above. Column chromatography (silica gel, heptanes:EtOAc = 1:1) of the crude product yielded 73g (5.52g, 15.88mmol, 49%) as a brown oil.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.71-1.92 (m, 15H, -CH-CH2-CH2-CH2-, 5x-
CH2 (cyclohexanering), N-CH-CH-CH2- ), 2.57-2.69 (m, 1H, -N-CHAHB-CH2), 2.94-3.05 (m,
1H, -N-CHAHB-CH2), 4.22 (t, J=6.5, 1H, -CH2-CH-N-), 4.34 (d, J=7.0, 1H, N-CH-O-), 7.00- 7.29 (m, 8H, Ar-H), 7.35-7.44 (m, 2H, Ar-H).
O O + O N N N Br N Br
O
73g 74 63g
347.50 194.07 541.57
Ammonium salt 63g was prepared from 73g (0.92g, 2.64mmol) and 74 (0.51g, 2.64mmol) according to general procedure IV by refluxing them for 24hours in 7mL THF. Column
80 chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63g (0.61g, 1.12mmol, 43%) as a beige solid.
j i' i m' h' l' n h g a k m e f l s' d O r' N b c p Br o s N q o' r o' o'' O o'' o'''
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.73 (t, J = 7.2 Hz, 3H, (s)), 1.04 (t, J = 7.2 Hz,
3H, (s’)), 1.09-1.58 (m, 5H, (o’ + o’1 + o”1 + e1), 1.63-1.94 (m, 6H, (o” + o”’ + o’2 + o”2),
1.96-2.09 (m, 1H, d2), 2.10-2.21 (m, 1H, e2), 2.71-3.08 (m, 4H, d2 + p1 + r), 3.35-3.55 (m,
2H, (r’)), 3.76-4.00 (m, 2H, (o + p1)), 3.89 (d, J=16.8Hz, 1H, (c1)), 4.37 (br, 1H, (b)), 6.09
(d, J=16.8Hz, 1H, (c2)), 6.81 (dd, J= 6.3, 11.1Hz, 1H, (f)), 7.39-7.52 (m, 4H, (m + m’, j+ n)), 7.18-7.36 (m, 4H, (l + l’, i + i’)), 7.83-7.97 (m, 2H, (h + h’)).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.8 (Cs), 13.7 (Cs’) , 24.8 (Cd), 25.5 (Cy- ring), 26.0 (Cy-ring), 26.4 (Cy-ring), 27.1 (Cy-ring), 30.0 (Ce), 32.5 (Cy-ring), 38.9 (Co),
40.7 (Cs), 41.9 (Cs’), 61.2 (Cp), 66.2 (Cc), 81.9 (Cf), 87.2 (Ca), 108.2 (Cb), 124.8 (Ar-C), 125.7 (Ar-C), 128.0 (Ar-C), 128.7 (Ar-C), 129.0 (Ar-C), 130.0 (Ar-C), 139.3 (Ar-C), 139.9
(Ar-C), 162.9 (Cr).
Assignments were achieved using HMBC and HSCQ data.
81 3.2.17 Synthesis of ammonium salt 63h (R1 = phenyl, R2 = tert-butyl)
O + H O N N OH H
72a 105 73h 253.35 86.13 321.46
According to general procedure III, 73h was prepared from 72a (0.22g, 0.88mmol) and 2 eq. 105 (0.19mL, 0.15g, 1.75mmol). The reaction mixture was refluxed for 16 hours followed by the work-up as specified above yielding 73h (0.18g, 0.56mmol, 64%) as a yellow oil.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.82 (s, 9H, -CH-CH3), 0.96-1.10 (m, 1H,
-CH-CH2-CHAHB–CH2-), 1.46-1.64 (m, 1H, -CH-CH2-CHAHB-CH2-), 1.74-1.91 (m, 1H, -CH-
CHAHB-CH2-CH2-), 1.91-2.08 (m, 1H, -CH-CHAHB-CH2-CH2-) 2.53-2.65 (m, 1H, -N-CHAHB-
CH2), 2.87-3.00 (m, 1H, -N-CHAHB-CH2), 4.10 (dd, J=4.0, 7.4Hz, 1H, N-CH-O-), 4.55 (s,
1H, -O-CH-CH3), 7.02-7.60 (m, 10H, Ar-H).
O + O N O N Br N N Br
O
73h 74 63h 321.46 194.07 515.54
Ammonium salt 63h was prepared from 73h (0.92g, 2.64mmol) and 74 (0.51g, 2.64mmol) according to general procedure IV by refluxing them for 24hours in 7mL THF. Column
82 chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63h (0.61g, 1.12 mmol, 43 %) as a yellow solid.
j i' i m' h' l' n h g e a m f k l d t' O N b s' c q o t N r p s p'' p'
O Br
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.74 (t, J = 7.3 Hz, 3H, (t)), 0.98 (t, J = 7.3 Hz,
3H, (t’)), 0.84-1.22 (m, 9H, -CH-C-(CH3)3), 1.79.2.01 (m, 2H, (e1, d1)), 2.29-2.43 (m, 1H,
(e1)), 2.43-2.56 (m, 1H, (d2,), 2.58-2.77 (m, 1H, (q1)), 2.79-3.09 (m, 3H, (s + q2)), 3.31-3.53
(m, 1H, (s’)), 3.87 (d, J=16.7Hz, 1H, (c1)), 4.52 (dd, J=6.3, 9.0Hz, 1H, (b)), 6.02 (d, 1H,
J = 16.7 Hz, (c2)), 6.78 (t, J=8.1 Hz, 1H, (f)), 7.02-7.50 (m, 6, Ar-H), 7.55-7.61 (m, 2H, (h + h’), 7.77-7.87 (m, 2H, (l + l’).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.9 (Ct), 13.9 (Ct’), 22.4 (Cp), 25.1 (Cd),
28.5 (Cp’), 29.5 (Cp”), 31.4 (Ce), 40.8 (Cs), 42.0 (Cs’),54.6 (Cq), 65.0 (Cc), 82.6 (Cf), 104.3
(Cb), 124.8 (Ar-C), 125.4 (Ar-C), 125.5 (Ar-C), 125.7 (Ar-C), 126.3 (Ar-C), 128.0 (Ar-C),
128.2 (Ar-C), 128.8 (Ar-C), 129.0 (Ar-C), 130.0 (Ar-C), 163.2 (Cr).
83 3.2.18 Synthesis of ammonium salt 63i (R1 = phenyl, R2 = n-butyl)
O + O H N N OH H
72a 106 73i 253.35 86.13 321.46
According to general procedure III, 73i was prepared from 72a (0.10g, 0.41mmol) and 106 (87.2 µL, 0.07g, 1.75mmol). The reaction mixture was refluxed for 16 hours followed by the work-up as specified above yielding 73i as a brown oil in sufficient purity for further transformations.
O + O N O N Br N N Br
O 73i 74 63i 321.46 194.07 515.54
Ammonium salt 63i was prepared from 73i (0.13g, 0.41mmol) and 74 (78.8mg, 0.41mmol) according to general procedure IV by refluxing them for 24hours in 7mL THF. Column chromatography (silica gel, DCM:MeOH = 9:1) of the crude product yielded 63i (0.15g, 0.29mmol, 28% over 2 steps) as an orange solid.
84 j i' m' i h' l' n h g e a m f k l d v' O u' N c b p v N t s o u q r O Br
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.81 (t, J = 7.3 Hz, 3H, (v)), 1.02 (t, J = 7.5 Hz,
3H, (r)), 1.05 (t, J=7.3Hz, 3H, (v’)), 0.66-1.59 (m, 6H, (p, q,e1,d1)), 1.81-2.09 (m, 1H, (o1)),
2.34-2.49 (m, 1H, (e2)), 2.49-2.62 (m, 1H, (d2), 2.85-3.16 (m, 3H, (u, o2)), 3.20-3.60 (m, 4H, u’, s), 3.94 (d, J=16.8Hz, 1H, (c2)), 4.59 (d, J=8.8Hz, 1H, (b)), 6.06 (d, J=16.8Hz, 1H,
(c1)), 6.85 (t, J=8.1Hz, 1H, (f)), 7.03-7.53 (m, 6, Ar-H), 7.53-7.69 (m, 2H, (h + h’), 7.82-7.93 (m, 2H, (l + l’).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.8 (Cv), 13.9 (Cv’), 20.8 (Cr), 22.3 (Cq),
24.2 (Cp), 24.9 (Co), 25.3 (Cd), 29.5 (Ce), 40.6 (Cu), 42.0 (Cu’), 50.8 (Cs), 60.5 (Ca), 65.1
(Cc), 82.3 (Cf), 104.1 (Cb), 124.8 (Ar-C), 125.7 (Ar-C), 128.0 (Ar-C), 128.8 (Ar-C), 130.0
(Ar-C), 163.0 (Ct)
3.2.19 Synthesis of ammonium salt 63j (R1 = phenyl, R2 = benzyl)
O
+ O N N OH H
72a 107 73j 253.35 120.15 355.48
85 According to general procedure III, 73j was prepared from 72a (0.35g, 1.40mmol) and 2 eq. 107 (0.33mL, 0.34g, 2.80mmol). The reaction mixture was refluxed for 16 hours fol- lowed by the work-up as specified above yielding 73j as an orange-brown oil in sufficient purity for further transformations.
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.75-1.08 (m, 1H, -CHAHB-CH2-CH-), 1.19-
2.05 (m, 3H, -CHAHB-CH2-CH-), 2.55-2.68 (m, J 1H, -N-CHAHB-CH2), 3.01-2.98 (m, 1H,
-N-CHAHB-CH2), 4.12 (dd, J=2.0, 7.5Hz, 1H, -N-CH-CHAHB-Phenyl), 4.24 (t, J = 7.3 Hz,
1H, -CH2-CH-N-), 4.31 (dd, J = 2.0, 7.5 Hz, 1H, -N-CH-CHAHB-Phenyl), 4.98 (t, J = 6.5 Hz, 1H, -N-CH-O-), 7.09-7.71 (m, 15H, Ar-H).
O + O N O N Br N N Br
O
73j 74 63j
341.45 194.07 549.55
Ammonium salt 63j was prepared from 73j and 74 (0.28g, 1.40mmol) according to gen- eral procedure IV by refluxing them for 24hours. Column chromatography (silica gel, DCM:MeOH=9:1) of the crude product yielded 63j (0.27g, 0.49mmol, 35%) as a dark- beige solid.
86 j i' m' i h' l' n h g m e a f k l d v O u N p c b q N s v' t o u' r p' O Br q'
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 0.82 (t, J = 7.2 Hz, 3H, (v)), 1.11 (t, J = 7.2 Hz,
3H, (v’)), 1.48-1.68 (m, 1H, (e1)), 1.70-1.82 (m, 2H, (e2), 2.43-2.67 (m, 2H, (d1+2), 2.87-3.28
(m, 3H, (u, o1)), 3.30-3.55 (m, 3H, (u’, s1)), 3.52-3.76 (m, 2H, (s2,o2)), 3.91 (d, J=16.7Hz,
1H, (c1)), 4.87 (t, J=8.4Hz, 1H, (b), 5.94 (d, J=16.7Hz, 1H, (c2)), 6.75 (t, J=8.2Hz, (f)), 7.02-7.59 (m, 15H, Ar-H).
13 C-NMR (75 MHz, CDCl 3, 298.0 K, δ [ppm]): 12.9 (Cv), 13.6 (Cv’) , 25.0 (Cd) 31.1 (Ce),
38.1 (Co), 40.1 (Cu), 42.2 (Cu’), 60.5 (Cs),65.5 (Cc), 77.3 (Ca), 83.4 (Cf), 104.1 (Cb), 124.8 (Ar-C), 125.7 (Ar-C), 128.0 (Ar-C), 125.2 (Ar-C), 126.6 (Ar-C), 127.6 (Ar-C), 127.7 (Ar-C), 128.1 (Ar-C), 128.3 (Ar-C), 128.8 (Ar-C), 129.0 (Ar-C), 129.5 (Ar-C), 129.9 (Ar-C), 163.5
(Ct).
87 3.2.20 General procedure V
R1 R1
O O O N + N 3 3 R N R Br R2 O O
109 110 111
109 (0.10 mmol, 1 eq) was dissolved in 1 mL solvent (A: i-PrOH, B: toluene). Cs2CO3 (0.65g, 2.00mmol, 20eq) was added and after 5minutes of stirring 110 (0.20mmol, 2eq.) was added and the reaction was stirred at RT for 24hours. The reaction wasquenched by addition of H2O and extracted with DCM. The combined organic phases were dried over
Na2SO4 and evaporated to dryness. Column chromatography (silica gel, heptanes:EtOAc = 7:3) of the crude product afforded the epoxides in reported yields.
3.2.21 Epoxidation reactions
3.2.21.1 Epoxidation reaction for testing all synthesized ammonium salts
O O N O + N O N Br
O 63a 22a 55a 459.43 106.12 219.28
Prepared according to general procedure V from 63a (45.7mg, 0.10mmol, 1eq.) and 22a (20.3 µL, 21.1mg, 0.2mmol, 2eq.), yielding 55a (A: 18.6mg, 0.085mmol, 85%, ee = 55 %; B: 72h, 60 ◦C: 6.8mg, 0.031mmol, 31%, ee = 47 %) a white solid. HPLC: Chiralcel OD-H,
88 hexane–i:PrOH (80:20), 10 ◦C; 15.0min (major: 2S, 3R), 17.0min (minor: 2R, 3S). 1H- NMR and HPLC data were consistent with literature[71].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.22 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.26 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.39-3.60 (m, 4H, -CH2-CH3), 3.64 (d, J=1.8Hz, 1H, -CH-CH-), 4.14 (d, J = 1.8 Hz, 1H, -CH-CH-), 7.35-7.47 (m, 5H, Ar-H).
3.2.21.2 Application scope of the asymmetric epoxidation
O O N O + N O N Br
O
63g 22b 55b 541.57 120.15 233.31
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22b (23.6 µL, 24.0mg, 0.2mmol, 2eq.), yielding 55b (A: 16.7mg, 0.072mmol, 72%, ee = 78 %; B: 12.2mg, 0.052mmol, 52%, ee = 90 %) as light-yellow solid. HPLC: Chiralcel OD-H, hexane–i:PrOH (80:20), 10 ◦C; 13.8min (major: 2S, 3R), 15.9min (minor: 2R, 3S). 1H- NMR and HPLC data were in accordance with literature[71].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.15 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.19 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 2.34 (s, 3H, -C-CH3), 3.35-3.51 (m, 4H, -CH2-CH3), 3.56 (d, J = 1.9 Hz, 1H, -CH-CH-), 4.03 (d, J = 1.9 Hz, 1H, -CH-CH-), 7.13-7.26 (m, 4H, Ar-H).
89 O O N O + N N Br O
O
63g 22c 55c 541.57 120.15 233.31
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22c (23.2 µL, 24.0mg, 0.2mmol, 2eq.), yielding 55c (A: 22.8mg, 0.098mmol, 98%, ee = 82 %; B: 14.4mg, 0.062mmol, 62%, ee = 92 %) as light-yellow solid. HPLC: Chiralcel OD-H, hexane:i-PrOH (85:15), 10 ◦C; 19.2min (minor: 2R,3S), 19.5min (major: 2S,3R). 1H-NMR data were in accordance with literature[50].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.15 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.19 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 2.38 (s, 3H, -C-CH3), 3.36-3.49 (m, 4H, -CH2-CH3), 3.46 (d, J = 1.9+ Hz, 1H, -CH-CH-), 4.21 (d, J = 1.9 Hz, 1H, -CH-CH-), 7.11-7.24 (m, 4H, Ar-H).
O O N O + N O N Br Br Br
O
63g 22d 55d 541.57 185.02 298.18
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22d (37.0mg, 0.2mmol, 2eq.), yielding 55d (A: 25.5mg, 0.086mmol, 89%, ee = 70 %; B: 22.3mg, 0.075mmol, 75%, ee = 72 %) as a colourless oil. HPLC: Chiralcel OD-H, hex- ane:i-PrOH (80:20), 10 ◦C; 19.0min (major: 2S, 3R), 23.2min (minor: 2R, 3S). 1H-NMR data were in accordance with literature[50].
90 1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.10 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.14 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.28-3.43 (m, 4H, -CH2-CH3), 3.46 (d, J=1.9Hz, 1H, -CH-CH-), 4.00 (d, J = 1.9 Hz, 1H, -CH-CH-), 7.14 (d, J=8.5Hz, 2H, Ar-H), 7.43 (d, J=8.5Hz, 2H, Ar-H).
O O N O + N O N Br Cl Cl
O
63g 22e 55e 541.57 140.57 253.73
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22e (28.1mg, 0.2mmol, 2eq.), yielding 55e (A: 19.5mg, 0.077mmol, 77%, ee = 74 %; B: 5.4mg, 0.075mmol, 21%, ee = 82 %) as a colourless oil. HPLC: Chiralcel OD-H, hexane:i- PrOH (80:20), 10 ◦C; 18.3min (major: 2S, 3R), 21.3min (minor: 2R, 3S). 1H-NMR data were in accordance with literature[50].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.16 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.21 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.36-3.49 (m, 4H, -CH2-CH3), 3.53 (d, J=1.9Hz, 1H, -CH-CH-), 4.07 (d, J = 1.9 Hz, 1H, -CH-CH-), 7.25 (d, J=8.4Hz, 2H, Ar-H), 7.34 (d, J=8.4Hz, 2H, Ar-H).
O O N O + N O N Br O O
O
63g 22f 55f 541.57 136.15 249.31
91 Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22f (22.1 µL, 27.2mg, 0.2mmol, 2eq.), yielding 55f (A: 15.0mg, 0.060mmol, 60%, ee = 66 %; B: 2.3mg, 0.009mmol, 9%, ee = 88 %) as a colourless oil. HPLC: Chiralcel OD-H, hex- ane:iPrOH (85:15), 10 ◦C; 26.6min (major: 2S, 3R), 31.7min (minor: 2R, 3S). 1H-NMR data were in accordance with literature[50].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.15 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.20 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.36-3.50 (m, 4H, -CH2-CH3), 3.57 (d, J=2.0Hz, 1H, -CH-CH-),
3.80 (s, 3H, -O-CH3), 4.02 (d, J=2.0Hz, 1H, -CH-CH-), 6.89 (d, J=8.7Hz, 2H, Ar-H), 7.24 (d, J=8.7Hz, 2H, Ar-H).
O O O O N O + N N Br O
O
63g 22g 55g
541.57 136.15 249.31
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22g (27.2mg, 0.2mmol, 2eq.), yielding 55g (A: 20.7mg, 0.094mmol, 94%, ee = 82 %; B: 20.5mg, 0.093mmol, 93%, ee = 92 %) as a yellow solid. HPLC: Chiralcel OD-H, hexane:i- PrOH (80:20), 10 ◦C; 19.2min (major: 2S, 3R), 26.6min (minor: 2R, 3S). 1H-NMR data were in accordance with literature[50].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.14 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.18 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.29-3.55 (m, 4H, -CH2-CH3), 3.46 (d, J=2.0Hz, 1H, -CH-CH-),
3.81 (s, 3H, -O-CH3), 4.31 (d, J=2.0Hz, 1H, -CH-CH-), 6.86 (d, J=8.2Hz, 1H, Ar-H), 6.93 (t, J = 7.4 Hz, 1H, Ar-H), 7.20 (d, J=7.9Hz, 1H, Ar-H), 7.25 (t, J=7.9Hz, 1H, Ar-H).
92 O O N O + N O N Br NO2 NO2 O
63g 22h 55h 541.57 151.12 264.28
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22h (30.2mg, 0.2mmol, 2eq.), yielding 55h (A: 13.2mg, 0.050mmol, 50%, ee = 86 %; B: 13.2mg, 0.050mmol, 50%, ee = 88 %) as a colourless oil. HPLC: Chiralcel OD-H, hex- ane:i-PrOH (80:20), 10 ◦C; 36.7min (major: 2S, 3R), 44.7min (minor: 2R, 3S). 1H-NMR and HPLC data were in accordance with literature[71].
1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.18 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.25 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 3.39-3.52 (m, 4H, -CH2-CH3), 3.59 (d, J=1.9Hz, 1H, -CH-CH-), 4.24 (d, J = 1.9 Hz, 1H, -CH-CH-), 7.50-7.72 (m, 2H, Ar-textbfH), 8.15-8.27 (m, 2H, Ar-H).
O O N O + N N Br O
O
63g 22i 55i 541.57 112.17 225.33
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22i (24.2 µL, 22.4mg, 0.2mmol, 2eq.), yielding 55i (A: 7.8mg, 0.035mmol, 35%; B: 5.6mg, 0.025 mmol, 25%,) as a colourless oil. 1H-NMR data were in accordance with literature[50].
93 1 H-NMR (300 MHz, CDCl 3, 298.0 K, δ [ppm]): 1.10 (t, J = 7.1 Hz, 3H, -CH2-CH3), 1.21 (t,
J = 7.1 Hz, 3H, -CH2-CH3), 1.09-1.36 (m, 6H, -CH2- (ring)), 1.59-1.87 (m, 5H, -CH2- (ring)),
2.92 (dd, J=2.1, 6.6Hz, 1H, -CH-CH-), 3.27-3.48 (m, 4H, -CH2-CH3, -CH-CH-).
O O N O + N O N N N Br
O
63g 22j 55j
541.57 149.19 262.35
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22j (29.8mg, 0.2mmol, 2eq.). NMR of the crude product showed that no product 55j had been formed.
O O O + N N (CH2)9 (CH2)9 N Br O
O
63g 22k 55k 541.57 170.30 283.46
Prepared according to general procedure V from 63g (54.2mg, 0.10mmol, 1eq.) and 22k (41.3 µL, 34.1mg, 0.2mmol, 2eq.). NMR of the crude product showed that no product 55k had been formed.
94 4 Literature
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