Institute of Organic Chemistry Supervisor Assoc. Univ.-Prof. Dr. Mario Waser November 2018 JOHANNES KEPLER UNIVERSITY LINZ Altenbergerstraße 69 4040 Linz, ¨Osterreich
Synthesis of
Guanidine-containing Chiral
Qua-ternary Ammonium Salt
Catalysts
Master Thesis
to obtain the academic degree of
Diplom-Ingenieurin
in the Master’s Program
Table of Contents
List of Figures 4
List of Tables 8
List of Frequently Used Abbreviations 9
Eidesstattliche Erklärung 10 Statutory Declaration 11 Acknowledgement 12 Curriculum vitae 13 Kurzfassung 15 Abstract 16 1 Introduction 17
1.1 General aspects about organic guanidines . . . 17
1.2 Guanidines in organocatalysis . . . 20
1.2.1 Br¶nsted base catalysis . . . 20
1.2.2 Hydrogen bond donor and Br¶nsted acid catalysis . . . 23
1.2.3 Lewis base catalysis . . . 24
1.2.4 Lewis acid catalysis . . . 25
1.3 General aspects about bifunctional catalysis . . . 25
1.3.1 Bifunctional ammonium salt catalysts . . . 26
1.3.2 Bifunctional hydrogen bond donor catalysts . . . 28
1.4 Synthesis strategies for organic guanidines . . . 31
1.4.1 Synthesis starting from thioureas . . . 31
1.4.2 Synthesis starting from isothioureas . . . 32
1.4.3 Synthesis via carbodiimides . . . 34
1.4.4 Alternative synthesis routes . . . 34
2 Objectives 36 3 Results and Discussion 37 3.1 Synthesis of guanidines via thioureas . . . 37
3.1.1 Synthesis of the thiourea . . . 37
3.1.3 Introduction of the guanidine moiety . . . 41
3.1.4 Benzylation of guanidine 102 . . . 43
3.1.5 Synthesis of achiral thioureas . . . 44
3.1.6 Guanidine-synthesis using iodine . . . 45
3.1.7 Guanidine-synthesis using (diacetoxy)iodobenzene . . . 46
3.2 Synthesis of guanidine via isothiourea . . . 46
3.3 Synthesis of guanidines via 2-chlorobenzimidazole . . . 47
3.3.1 Approach A - starting with the quaternisation . . . 47
3.3.2 Approach B - starting with the coupling reaction . . . 48
3.4 Synthesis of guanidines via carbodiimides . . . 51
3.4.1 Formation of carbodiimides using IBX . . . 52
3.4.2 Formation of carbodiimides using (diacetoxy)iodobenzene . . . 52
3.4.3 Formation of carbodiimides using iodine . . . 53
3.4.4 Introduction of the guanidine function . . . 53
3.5 Test reactions . . . 55
3.5.1 –-Fluorination of —-ketoesters with NFSI . . . . 55
3.5.2 –-Hydroxylation of —-ketoesters with oxaziridine . . . . 57
3.5.3 –-Hydroxylation of —-ketoesters with imine and H2O2 . . . 58
3.6 Summary and Outlook . . . 59
4 Experimental Section 61 4.1 General - Chemicals and Materials . . . 61
4.2 Resolution of (±)-trans-1,2-cyclohexanediamine . . . 62
4.2.1 Synthesis of (1R,2R)-(+)-1,2-diammoniumcyclohexane-L-tartrate 86 . . . 62
4.2.2 Synthesis of (1R,2R)-(+)-1,2-cyclohexanediamine 87 . . . . 62
4.3 Synthesis of the thiourea and urea . . . 63
4.3.1 Synthesis of mono-Boc–protected-(1R,2R)-1,2-(+)-cyclohexanediamine 88 63 4.3.2 Reductive amination with benzaldehyde - Synthesis of compound 90a . . 64
4.3.3 Methylation - Synthesis of compound 91a . . . 64
4.3.4 Boc-deprotection - Synthesis of compound 92a . . . 65
4.3.5 Coupling with isothiocyanate - Synthesis of compound 94a . . . 66
4.3.6 Reductive amination - Synthesis of compound 90b . . . 67
4.3.7 Methylation - Synthesis of compound 91b . . . 67
4.3.8 Boc-deprotection - Synthesis of compound 92b . . . 68
4.3.9 Coupling with isothiocyanate - Synthesis of compound 94b . . . 69
4.3.10 Coupling with isocyanate - Synthesis of compound 105 . . . 70
4.4 Synthesis of oxidising agents . . . 70
4.4.1 Synthesis of 2-iodoxybenzoic acid 98 . . . 70
4.5 Synthesis of guanidines from thiourea . . . 72
4.5.1 Synthesis of guanidine 102 . . . 72
4.5.2 Synthesis of guanidine 103 . . . 73
4.5.3 Synthesis of guanidine 106 . . . 73
4.6 Synthesis of achiral thiourea systems . . . 74
4.6.1 Synthesis of achiral thiourea 108 . . . 74
4.6.2 Benzylation - Synthesis of compound 109 . . . 75
4.6.3 Exchange of the counter ion - Synthesis of compound 110 . . . 75
4.6.4 Synthesis of guanidine 111a . . . 76
4.6.5 Synthesis of guanidine 111b . . . 76
4.6.6 Synthesis of methylated thiourea 112 . . . 77
4.6.7 Attempted synthesis of guanidine 111b starting from methylated thiourea 112 . . . 77
4.7 Synthesis of guanidines using 2-chlorobenzimidazole . . . 78
4.7.1 Synthesis of compound 95 . . . 78
4.7.2 Deprotection of Boc - Synthesis of compound 96 . . . 79
4.7.3 Attempted synthesis of guanidine 114c . . . 79
4.7.4 Synthesis of guanidines 115 and 116 . . . 80
4.7.5 Synthesis of guanidine 117 . . . 81
4.7.6 Benzylation - Synthesis of guanidine 114d . . . 81
4.7.7 Methylation - Synthesis of guanidine 118 . . . 82
4.7.8 Benzylation of diguanidine - Synthesis of compounds 119 and 120 . . . . 83
4.7.9 Methylation of diguanidine - Synthesis of compounds 121 and 122 . . . . 84
4.8 Synthesis of guanidines via Schreiner’s catalyst . . . 84
4.8.1 Synthesis of Schreiner’s catalyst 53 . . . 84
4.8.2 Synthesis of carbodiimide 124 . . . 85
4.8.3 Synthesis of guanidine 125 . . . 86
4.8.4 Synthesis of guanidine 126 . . . 86
4.8.5 Synthesis of guanidine 127a . . . 87
4.8.6 Attempted synthesis of guanidine 127b . . . 88
4.9 Catalyst-test reactions . . . 88
4.9.1 General experimental procedure for the enantioselective –-fluorination of —-ketoester with NFSI . . . . 88
4.9.2 General experimental procedure for the enantioselective –-hydroxylation of —-ketoester using oxaziridine 131 . . . . 89
4.9.3 General experimental procedure for the enantioselective –-fluorination of —-ketoester using imine 133 and H2O2 . . . 90
List of Figures
1 Stabilisation of guanidines due to (a) bidentate hydrogen bonding and (b) reso-nance conjugation. . . 17 2 Possible action modes for (a) free guanidines and (b) guanidinium cations
demon-strated through the example of TBO 5 (1,4,6-triazabicyclo[3.3.0]oct-4-ene). . . . 18 3 Classification of guanidines. (a) Open-chained guanidines, e.g. TMG
(1,1,3,3-tetramethylguanidine) 7, (b) monocyclic guanidine, e.g. imidazolidin-2-imine 8 and (c) bicyclic guanidines, e.g. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 9. . . 18 4 Naturally occurring organic guanidines like (a) arginine (10), (b) creatine (11)
and (c) creatinine (12). . . . 19 5 Natural products containing guanidine moieties. (a) tetrodotoxin (13), (b)
sax-itoxin (14), (c) streptomycin (15), (d) gonyautoxin 2 (16) and (e) spergualin (17). . . . 19 6 Achiral guanidines applied as Br¶nsted base catalysts (a) TMG 7, (b) BTMG
(2-tert-butyl-1,1,3,3-tetramethylguanidine) 18, (c) TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 9, (d) MTBD (N-methyl-TBD) 19 and (e) TBO (1,4,6-triazabicyclo[3.3.0]oct-4-ene) 5. . . . 20 7 Structures of chiral organocatalysts 20 (Corey et al. 1989), 21 (Corey et al. 1999)
and 22 (Tan et al. 2006). . . . 20 8 Mechanism for enantioselective addition reactions catalysed by guanidine-based
Br¶nsted base organocatalysts. . . 21
9 Michael addition reactions of cyclic enone 23 with CH-acidic 1,3-diketones 24a or malonates 24b catalysed by guanidine Br¶nsted base catalysts. . . 22
10 Alternative guanidine-based Br¶nsted base catalysts with monocyclic, open-chain
structures or additional functional groups. . . 22 11 Enantioselective Claisen rearrangement of ester activated allyl-vinyl-ethers to
–-oxohex-5-enoates. . . 23 12 (a) Bidentate hydrogen bonding catalyst 33. (b) Interactions present in the
tran-sition state. . . 23 13 Activation mode of Lewis basic guanidine catalyst TBD and formation of a neutral
catalyst-substrate adduct. . . 24 14 Examples for Lewis basic guanidines applied as enantioselective catalysts for aldol
and Michael type reactions. . . 24 15 (a) fi-system of guanidinium cations presenting an empty acceptor orbital. (b)
Guanidine-based Lewis acid catalyst. . . 25 16 Active site of the enzyme serine protease and the activation mode of this catalytic
17 Catalytic performance of an OH-containing quaternary ammonium salt based on cinchona alkaloids. . . 27 18 Example for the use of a quinine-derived bifunctional catalyst in an
enantioselec-tive aza-Henry-reaction. . . 27 19 Example for the use of a Maruoka-type bifunctional catalyst in an enantioselective
epoxidation reaction of enones. . . 27 20 Bifunctional ion pair Lewis acid catalyst used for the synthesis of trans-—-lactones. 28 21 Bifunctional betaine-based catalyst used for asymmetric Mannich-reactions. . . . 28 22 (a) Hydrogen bond donor catalyst by Schreiner et al. 53. Bifunctional
hydro-gen bond-donor catalysts and bifunctional hydrohydro-gen bond-donor catalysts (b) by Jacobsen et al. 54 (c) Takemoto et al. 55 and (d) Lassaletta, Fernandez et al. 56. 29 23 Bifunctional urea-based catalyst by Dixon et al. used for stereoselective
nitro-Mannich-reactions of –-amidosulfones. . . . 30 24 One pot desulfurisation of thiourea using copper sulfate followed by reaction with
amine to give the corresponding guanidine. . . 31 25 Preparation of protected guanidines from corresponding thioureas, amines using
Mukaiyama’s reagent. . . 31 26 Preparation of protected guanidines from corresponding thioureas, amines using
mercuric chloride and TEA. . . 32 27 Preparation of carbamoyl guanidines from corresponding carbamoyl isothiocyanates. 32 28 Preparation of guanidines from N-arylsulfonyl S-methylisothiourea in the
pres-ence of amine, TEA and mercuric perchlorate. . . 33 29 Preparation of di-Boc-protected guanidines from corresponding isothioureas,
mer-curic chloride, TEA and amines. . . 33 30 (a) Preparation of guanidines by activation of thioureas as thiazetidines. (b)
Reaction of isothioureas with amines using mercuric chloride. . . 33 31 Synthesis of a resin bound guanidine starting from an isolated carbodiimide
syn-thesised from a thiourea using Mukaiyama’s reagent. . . 34 32 Formation of carbodiimides from N-aryliminophosphoranes and isocyanates and
subsequent reaction to the guanidine. . . 34 33 Preparation of aromatic guanidines from amines via in-situ formation of cyanamides. 35 34 Preparation of guanidines from (a) pyrazole-1-carboximidamides, (b) triflyl
guani-dines, (c) aminoiminomethane-sulfonic acids and (d) benzotriazole- and imidazole-activated reagents. . . 35 35 Synthesis of bifunctional catalysts based on quaternary ammonium salts starting
from simple (1R,2R)-(+)-1,2-cyclohexanediamine. . . . 36 36 Testing of guanidine-based bifunctional catalysts in –-heterofunctionalisations of
37 Scheme of synthesis strategy for thioureas in six steps starting from (1R,2R)-(+)-1,2-diammoniumcyclohexane-L-tartrate. . . . 37 38 (a) Aldehydes used for the reductive amination. (b) Obtained products and the
corresponding yields. . . 38 39 (a) Direct quaternisation of 88 to the trimethyl-ammonium salt 95. (b) Obtained
products of the previous quaternisation steps and their corresponding yields. . . 39 40 Products and their corresponding yields obtained after the deprotection using
hydroiodic acid. . . 39 41 Preparation of the oxidising agent IBX using 2-iodobenzoic acid and oxone in an
aqueous solution. . . 40 42 Preparation of the oxidising agent (diacetoxy)iodobenzene using iodobenzene and
a solution of peracetic acid in acetic acid. . . 41 43 Chiral guanidines prepared from thiourea 94b using IBX and the corresponding
amine. . . 41 44 Reaction equation for the synthesis of guanidine 102 using IBX to in-situ form
an intermediate carbodiimide, which is then attacked by the nucleophile. Side product 105 has been formed due to the presence of water. . . . 42 45 Reaction equation for the synthesis of guanidine 103 using IBX to in-situ form
an intermediate carbodiimide, which is then attacked by the nucleophile. Side product 105 has been formed due to the presence of water. . . . 43 46 (a) Benzylation of guanidine 102. (b) Results of the purification attempt by
column chromatography. . . 43 47 Strategy for the synthesis of an achiral thiourea starting from
N,N-dimethylethane-1,2-diamine. . . 44 48 Synthesis of guanidines using achiral thiourea 110, iodine and the corresponding
amine. . . 45 49 Synthesis of guanidine 111b using achiral thiourea 110, (diacetoxy)iodobenzene
and n-butylamine. . . . 46 50 Synthesis of guanidine 111b via isothiourea 112 obtained from achiral thiourea
110 by methylation. . . . 46 51 Main approaches for the synthesis of guanidines with 2-chlorobenzimidazole
vary-ing in the sequence of quaternisation and couplvary-ing reaction. . . 47 52 Coupling reaction between (1R,2R)-(+)-1,2-cyclohexanediamine 87 and
2-chloro-benzimidazole 113. . . . 48 53 Reaction scheme summarising the different quaternisation methods in the course
of approach B. . . 49 54 Methylation and benzylation reactions of diguanidine 116 to the corresponding
55 Preparation of a carbodiimide via the synthesis of the Schreiner’s catalyst starting from an aromatic amine and an aromatic isothiocyanate. . . 51 56 Preparation of the carbodiimide starting from Schreiner’s catalyst by use of
2-iodoxybenzoic acid. . . 52 57 Coupling reaction with commercially available n-butylamine and benzylamine to
assure for the formation of the desired carbodiimide. . . 52 58 Preparation of the carbodiimide starting from Schreiner’s catalyst by use of
(di-acetoxy)iodobenzene. . . 53 59 Preparation of the carbodiimide starting from Schreiner’s catalyst by use of iodine
and ultrasonication. . . 53 60 Coupling of the previously synthesised carbodiimides with chiral amines to obtain
potential guanidine catalysts. . . 54 61 Guanidines tested as catalysts for the –-heterofunctionalisation reactions of
—-ketoesters. . . 55 62 –-Fluorination of —-ketoesters using NFSI to investigate the catalytic potential
of seven newly developed catalysts. . . 55 63 –-Hydroxylation of —-ketoesters using imine 131 to investigate the catalytic
po-tential of nine newly developed catalysts. . . 57 64 –-Hydroxylation of —-ketoesters using imine 133 and H2O2 to investigate the
List of Tables
1 Detailed data on the procedure used for the synthesis of guanidines 111a and
111b starting from the achiral thiourea 110. . . . 45 2 Detailed data on the procedure used for the synthesis of guanidines 114a and
114c starting from 2-chlorobenzimidazole. . . . 48 3 Detailed data on the procedure used for the synthesis of guanidines 127a and
127b starting from the carbodiimide 124. The carbodiimide used in the
respec-tive procedure, is described by the oxidising agent used for its previous synthesis. 54 4 Detailed data on the –-fluorination of —-ketoesters using NFSI. . . . 56 5 Detailed data on the –-hydroxylation of —-ketoesters using oxaziridine 131. . . . 57 6 Detailed data on the –-hydroxylation of —-ketoesters using imine 133 and H2O2. 58
List of Frequently Used Abbreviations
ACN aq. Asp BINOL Boc BTMG Cbz DCE DCM DMF DMSO DNA E ee equiv. e.r. ESI Gly His HPLC IBX MS MTBE MTBD NMR PG rt sat. Ser TBAF TBD TBO TEA THF TLC TMG Tos acetonitrile aqueous asparagine 1,1’-bi-2-naphthol tert-butoxycarbonyl 2-tert-butyl-1,1,3,3-tetramethylguanidine carboxybenzyl dichloroethane dichloromethane dimethylformamide dimethylsulfoxide deoxyribonucleic acid electrophile enantiomeric excess equivalences enantiomeric ratio electrospray ionisation glycine histidinehigh performance liquid chromatography 2-iodoxybenzoic acid
mass spectrometry tert-butyl methyl ether
N-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene nuclear magnetic resonance
protecting group room temperature saturated serine tetra-n-butylammoniumfluoride 1,5,7-triazabicyclo[4.4.0]dec-5-ene 1,4,6-triazabicyclo[3.3.0]oct-4-ene triethylamine tetrahydrofurane thin-layer chromatography 1,1,3,3-tetramethylguanidine toluenesulfonyl group
Eidesstattliche Erklärung
Ich erkläre an Eides statt, dass ich die vorliegende Masterarbeit selbstständig und ohne fremde Hilfe verfasst, andere als die angegebenen Quellen und Hilfsmittel nicht benutzt bzw. die wörtlich oder sinngemäß entnommenen Stellen als solche kenntlich gemacht habe.
Die vorliegende Masterarbeit ist mit dem elektronisch übermittelten Textdokument identisch. Linz, November 2018
Victoria Haider
Diese Arbeit entstand in der Zeit von Oktober 2017 bis November 2018 am Institut für Organ-ische Chemie der Technisch-Naturwissenschaftlichen Fakultät der Johannes Kepler Universität Linz unter der Betreuung von Assoc. Prof. Dr. Mario Waser.
Statutory declaration
I hereby declare that the thesis submitted is my own unaided work, that I have not used other than the sources indicated, and that all direct and indirect sources are acknowledged as refer-ences. This printed thesis is identical with the electronic version submitted.
Linz, November 2018
Victoria Haider
This master thesis was developed in the period of october 2017 to november 2018 at the Institute of Organic Chemistry of the Faculty of Natural Sciences of the Johannes Kepler University Linz under the guidance of Assoc. Prof. Dr. Mario Waser.
Acknowledgement
At this point I would like to thank all those who have contributed to the success of my master thesis by their technical and personal support.
I express my deep gratitude to my supervisor Mario Waser for giving me the opportunity to write my master thesis in the field of organic synthesis, for the straight and patient guidance and for the valuable and constructive advices. Further I want to thank the whole institute of organic chemistry, especially Prof. Norbert Müller, for the supply with chemicals and for providing facilities which were necessary for my master thesis. I am particularly grateful for the help of Christian Rückl concerning HPLC analysis. I would also like to offer my special thanks to Maximilian Tiffner for facilitating familiarisation with the topic during the initial stage of the thesis and for the useful remarks on my practical work. Finally I want to thank all my colleagues from the institute, my friends and my family for supporting me throughout the entire duration of my master thesis.
Victoria Haider
Curriculum vitae
Rosenleiten 157
4101 Feldkirchen an der Donau 0676 814283285
vicky.hai@gmx.at 13.05.1994 in Linz
Education and Qualification
08/2016 - 12/2018
10/2012 - 08/2016
09/2008 - 07/2012
09/2000 - 07/2008
Johannes Kepler University, Linz, Master studies in Technical
Chem-istry, Master Thesis at the Institute of Organic Chemistry: Synthesis of Guanidine-containing Chiral Quaternary Ammonium Salt Catalysts
Johannes Kepler University, Linz, Bachelor studies in Technical
Chemistry, Bachelor Thesis at the Institute of Inorganic Chemistry: Immobilisation and Characterisation of Photosensitive Esters on SAM Functionalised Gold Electrodes and their Testing as PS I Analogon
BRG Körnerschule, Linz, General Qualification for University
En-trance with focus on Chemistry, Special Subject: Aluminium and Anodic Oxidation Treatment
Elementary School, Feldkirchen an der Donau
Work Experience
10/2017 - 07/2018 07/2017 - 08/2017 10/2016 - 07/2017 10/2016 - 01/2017 07/2016 - 08/2016 03/2016 - 07/2016 07/2015 - 08/2015Johannes Kepler University, Linz, Student Assistant, Institute of
Organic Chemistry
Voestalpine AG, Linz, Student Employee in the Department of
Produkt- und Betriebsstoffanalytik
Johannes Kepler University, Linz, Student Assistant, Institute of
In-organic Chemistry
Johannes Kepler University, Linz, Student Assistant, Institute of
Analytical Chemistry
Voestalpine AG, Linz, Student Employee in the Department of
Produkt- und Betriebsstoffanalytik
Johannes Kepler University, Linz, Student Assistant, Institute of
Analytical Chemistry
Voestalpine AG, Linz, Student Employee in the Department of
Work Experience
08/2012
10/2011 - 08/2014
Borealis Polyolefine GmbH, Linz, Internship in the Department of
Chemical Products - Applied Chemistry
Raiffeisenlandesbank OÖ AG, Linz, Event support, promotion,
con-struction and dismantling of advertising material
Additional Skills
Languages Hobbies Other
German (native language), English (fluent), Spanish, French
Photography, Biological Microscopy, Hiking, Climbing, Styrian harmon-ica
Successful participation in the project "Young Polymer Scientists", JKU Linz, Borealis Linz and Institute of Polymer Science
Knowledge of Scientific Writing and Layouting with LaTeX
Successful participation in the NMR Summerschool 2018 in Niederöblarn, Austria
Kurzfassung
Diese Arbeit beschäftigt sich mit der Synthese 13 verschiedener, auf Guanidinen basierender, chi-raler Katalysatoren, wobei für deren Synthese unterschiedliche Routen gewählt wurden. Dabei war es möglich, neun dieser Guanidine zu isolieren. Die Existenz der restlichen vier konnte durch Verwendung von Massenspektrometrie bestätigt werden. Da die Aufreinigung der entsprechen-den Rohprodukte einige Probleme darstellte, wurentsprechen-den diese nicht als Reinsubstanzen erhalten. Im Allgemeinen wurden vier verschiedene Synthesewege basierend auf der Verwendung von Thio-harnstoffen, IsothioThio-harnstoffen, 2-Chlorbenzimidazol und Carbodiimiden untersucht.
Der für den ersten Ansatz notwendige Thioharnstoff konnte über eine siebenstufige Synthesese-quenz, welche in unserer Gruppe entwickelt wurde, hergestellt werden. Im Zuge der Reaktion dieser chiralen Thioharnstoffe mit einem Oxidationsmittel wie 2-Iodoxybenzoesäure (IBX) oder (Diacetoxy)iodbenzol konnten zwei vielversprechende, bifunktionelle, auf Guanidinen basierende Katalysatoren synthetisiert werden. Außerdem wurde eine Benzylierung eines dieser Guanidine erfolgreich durchgeführt.
Ausgehend von einem Isothioharnstoff wurde im Zuge der zweiten Syntheseroute kein gewün-schtes Guanidin gebildet. Aus diesem Grund wurde dieser Syntheseweg nicht weiter verfolgt. Der Einsatz von 2-Chlorbenzimidazol ermöglichte die Darstellung acht verschiedener Guanidine. Darunter konnten fünf in hoher Reinheit isoliert werden und standen somit für anschließende Testreaktionen zur Verfügung.
Zusätzlich wurde eine Syntheseroute beginnend mit Carbodiimiden hinsichtlich ihrer Anwend-barkeit für die Synthese der Guanidin-Katalysatoren untersucht. Zwei chirale Guanidine konnten dadurch synthetisiert werden. Jedoch wurde nur deren Existenz durch MS geprüft. Ihre Isola-tion aus dem Rohprodukt wurde nicht durchgeführt.
Um die Einsetzbarkeit dieser neu synthetisierten Katalysatoren zu testen, wurden diese einer Reihe an Testreaktionen, wie –-Fluorierungen und –-Hydroxylierungen von —-Ketoester, unter-zogen. Für alle Experimente wurden die bereits durch unsere Gruppe optimierten Reaktions-bedingungen gewählt. Dabei zeigte nur ein einziger Katalysator enantioselektive Eigenschaften. Im Zuge der –-Fluorierung konnte ein ee von 30 % erreicht werden. Ein deutlich höherer ee von 78 % wurde vom gleichen Katalysator in der –-Hydroxylierung unter Verwendung eines speziellen Imins in Kombination mit H2O2 erzielt. Alle weiteren untersuchten Guanidine führten in diesen
Abstract
In summary, this work demonstrates the syntheses of 13 chiral hydrogen bond donor catalysts based on guanidines. Among them, it was possible to isolate nine potential guanidine-based catalysts. Due to the problematic isolation procedure in terms of elution during column chro-matography, the existence of the remaining four guanidines was only proven by MS, but they have not been isolated yet. In general, four different approaches based on the use of thioureas, isothioureas, 2-chlorobenzimidazole and carbodiimides for the synthesis of these guanidines have been investigated.
Chiral thiourea starting material, necessary for the first approach, has been prepared in seven steps following the synthesis strategy developed by our group. By reaction of these thioureas with an oxidising agent, like 2-iodoxybenzoic acid (IBX) or (diacetoxy)iodobenzene, two promis-ing bifunctional guanidine-based catalysts carrypromis-ing a quaternary ammonium group have been synthesised. In addition, the benzylation reaction of one of these guanidines succeeded.
The second approach, starting from isothiourea, did not give any desired guanidine product and has therefore not been investigated further.
In the course of the third approach using 2-chlorobenzimidazole, it was possible to obtain eight different guanidines. Among them, five have been isolated and were available for subsequent test reactions.
Finally, syntheses starting from carbodiimides have also been examined, resulting in the suc-cessful synthesis of two chiral bifunctional catalysts based on guanidines. However, it was only possible to prove their formation with MS, but they have not been isolated from the crude re-action product yet.
To investigate the applicability of these newly developed catalysts, they were subjected to a se-ries of test reactions. –-Fluorination and –-hydroxylation of —-ketoesters have been tested in the course of these experiments. With regard to the reaction conditions, all test reactions have been performed according to the optimal parameters described by our group. In the –-fluorination of —-ketoesters solely one catalyst showed enantioselective properties resulting in an enantiomeric excess of 30 %. All others gave racemic product mixtures. Again only one catalyst lead to an enantioselectivity in the –-hydroxylation of —-ketoesters using an imine in combination with H2O2. An enantiomeric excess of 78 % was achieved in this reaction.
1 Introduction
1.1 General aspects about organic guanidines
The outstanding properties of guanidines in regard to basicity were already displayed more than 150 years ago, as Adolph Strecker synthesised the compound guanidine 1 for the first time [1]. Starting from guanidiniumsulfate it was possible to obtain guanidine only in its protonated form, due to the strong basic characteristics of this molecule. Initially, guanidines were therefore known as strong organic superbases. Their extraordinary properties are ascribed to a series of factors like resonance stabilisation with favourable distribution of the positive charge, stabili-sation by intramolecular hydrogen bond interaction or Y-aromaticity [2]. As shown in figure 1, protonation of organic guanidines 3 leads to the formation of a highly effective conjugated system with a large number of possible isoelectronic forms. Furthermore, stabilisation can be achieved through bidentate hydrogen bond formation, as it is shown for biguanide 2 in figure 1.
Figure 1: Stabilisation of guanidines due to (a) bidentate hydrogen bonding and (b) resonance
conjugation.
Y-aromaticity is a special form of aromaticity exhibited from planar molecules with resonant fi-electrons in y-shaped configuration, like guanidines, esters, thioureas and many others [3]. It explains the exceptional stability of guanidinium cations and the strong basic properties of guanidines. Another aspect, that should not be forgotten, is the behaviour of the protonated guanidinium cation in organic solvents. The formation of strong hydrogen bonds between the cation and solvent molecules has a remarkable impact on the stability of these molecules. However, guanidines feature a series of additional promising properties and functionalities defin-ing them as another important class of compounds, especially in the field of organocatalysis [4]. Figure 2 demonstrates these useful functionalities. Free guanidines can act as Br¶nsted bases
and acids at the same time. Additionally, the formation of hydrogen bonds is possible, whereas the free guanidine is able to act as hydrogen bond donor and acceptor. However, despite the hydrogen bonding donor property and Lewis acidity, the protonated guanidinium form exhibits only weak Br¶nsted acidity [4].
All these properties lead to a wide range of applications for guanidines making them a promising and indispensable class of organic substances for numerous syntheses und processes. However,
due to their high polarity in combination with the strong basicity the synthesis and purification of guanidines and guanidine derivatives may be a difficult task.
Figure 2: Possible action modes for (a) free guanidines and (b) guanidinium cations
demon-strated through the example of TBO 5 (1,4,6-triazabicyclo[3.3.0]oct-4-ene).
Guanidines can be classified with regard to their carbon skeleton that carries the guanidine moiety. It can be differentiated between open-chain, monocyclic and polycyclic guanidines. Examples are presented in figure 3. Particularly in the case of cyclic species, the conformational flexibility varies compared to open-chain guanidines resulting in different properties [4].
Figure 3: Classification of guanidines. (a) Open-chained guanidines, e.g. TMG
(1,1,3,3-tetramethylguanidine) 7, (b) monocyclic guanidine, e.g. imidazolidin-2-imine 8 and (c) bicyclic guanidines, e.g. TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 9.
As a consequence of their exceptional functionalities, guanidines are an important basic struc-tural element in numerous nastruc-tural substances [5]. These include, in particular, well-known compounds of great biological importance, like arginine (10), creatine (11) and creatinine (12), which are present in large quantities in natural products and also in the human body. Figure 4 shows the corresponding chemical structures of these molecules.
Figure 4: Naturally occurring organic guanidines like (a) arginine (10), (b) creatine (11) and
(c) creatinine (12).
Other guanidine based natural products occur in far smaller amounts and are produced by terres-trial and marine microorganisms, marine invertebrates, marine sponges and some plants. Note-worthy examples at this point are tetrodotoxin (13), saxitoxin (14), streptomycin (15), gonyau-toxin 2 (16) and spergualin (17), which are depicted in figure 5. The neurogonyau-toxin tetrodogonyau-toxin is accumulated by puffer fish, snails, blue-ring octopuses and salamanders from their natu-ral environment as protection against predators. Specialised bacteria species, as for example Pseudomonas and Shewanella, have the ability to produce this organic guanidine. Further on, guanidine based toxins of great interest, e.g. streptomycin, can be isolated from cyanobacteria strains found in brown algae.
Some of these compounds exhibit remarkable abilities as anti-tumor or anti-bacterial agents and are applied in medical research [5].
Figure 5: Natural products containing guanidine moieties. (a) tetrodotoxin (13), (b) saxitoxin
1.2 Guanidines in organocatalysis
Emerging as a powerful class of organocatalysts, the number of available guanidines applied for enantioselective and diastereoselective transformations increases steadily. Because of their promising properties and the numerous above named modes of action, guanidines are widely used in organocatalysis. Up to now most attention is payed to guanidine-based catalysts acting as Br¶nsted bases or hydrogen bond donor catalysts in combination with Br¶nsted acid catalysis.
In addition there is also the possibility for Lewis base or Lewis acid catalysis and for bifunctional catalysis [4].
1.2.1 Br¶nsted base catalysis
Guanidines are well-known for their Br¶nsted basicity and therefore primarily applied as organic
bases. Figure 6 depicts some common, achiral guanidines used as Br¶nsted base catalysts.
Among them bicycles of [3.3.0]-type proved to be the most preferable fundamental structure for enantioselective catalysis [4].
Figure 6: Achiral guanidines applied as Br¶nsted base catalysts (a) TMG 7, (b) BTMG
(2-tert-butyl-1,1,3,3-tetramethylguanidine) 18, (c) TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene) 9, (d) MTBD (N-methyl-TBD) 19 and (e) TBO (1,4,6-triazabicyclo[3.3.0]oct-4-ene) 5.
In 1989 Corey et al. published compound 20, which was the first chiral guanidine organocatalyst based on TBO [6]. About ten years of further investigation were necessary to report guanidine
21 as enantioselective catalyst for strecker reactions (Corey, 1999) [7]. The most successful
TBO-based organocatalyst 22 available today was introduced 2006 by Tan et al. providing tert-butyl groups to increase steric bulkiness, which results in a high catalytic performance [8].
Figure 7: Structures of chiral organocatalysts 20 (Corey et al. 1989), 21 (Corey et al. 1999)
The underlying mechanism to which all types of addition reactions catalysed by guanidines as Br¶nsted bases proceed is demonstrated in figure 8. The substrate AH is deprotonated by the
basic, free guanidine I, whereby the newly formed ion pair II interacts by hydrogen bonding. A second substrate B coordinates via hydrogen bonds, forming the transition state complex III. This coordination of both AH and B enables the desired reaction between the two substrates, leading to the formation of the product complex IV. After protonation, the product ABH is released resulting in the liberation of the original catalyst, which is then again available for further catalysis cycles. In the course of this mechanism, the stereochemical information for enantioselective reactions arises out of the coordination and interactions in the transition state
III [4].
Figure 8: Mechanism for enantioselective addition reactions catalysed by guanidine-based
Br¶nsted base organocatalysts.
Using catalyst 22, a large number of transformations with high yields and excellent stereoselec-tivity can be performed. Among others, these include Diels-Alder reactions [9], phospha-Michael additions [10], enantioselective protonation reactions [11] and Michael additions of CH-acidic substrates [12]. The latter is exemplified by the reaction given in figure 9. Acidic 1,3-diketones
24a or malonates 24b react with a cyclic enone 23 in a Michael addition reaction catalysed by 22 to give addition products 25a or 25b [12].
Figure 9: Michael addition reactions of cyclic enone 23 with CH-acidic 1,3-diketones 24a or
malonates 24b catalysed by guanidine Br¶nsted base catalysts.
Up to now, only bicyclic guanidine catalysts with Br¶nsted basic function were discussed.
How-ever, there is also the possibility of monocyclic, open-chain or functionalised guanidine-based catalysts. One promising alternative 27 was reported by Terada et al. in 2006 and is ap-plicable for phospha-Michael additions [13], vinylogous aldol reactions [14] and amination of –-ketoesters [15]. Due to the higher flexibility in monocyclic ring structures, a greater degree of steric hindrance is necessary for these catalysts. The application of open-chained guani-dines, which are more easily accessible by organic synthesis suffers the disadvantage of lacking steric restrictions. Therefore, either additional steric demanding residues or sites for substrate-catalyst interactions have to be introduced. This is achieved using BINOL-based guanidines 26 or multifunctional guanidine catalysts 28-30. Multifunctional guanidine catalysts can be based on amides (Feng, 2009) [16], thiourea (Nagasawa, 2010) [17] or can contain hydroxy groups (Ishikawa, 2000) [18] for additional hydrogen bonding. In these cases, activation of the nucle-ophile is enabled by the guanidine via deprotonation and complexation, while the electrnucle-ophile is simultaneously activated by H-bonding to the corresponding functionality [4].
Figure 10: Alternative guanidine-based Br¶nsted base catalysts with monocyclic, open-chain
1.2.2 Hydrogen bond donor and Br¶nsted acid catalysis
Protonated guanidines show excellent performance as bidentate hydrogen bond donor catalysts. In 2008, Jacobsen et al. first introduced compound 33 as a catalyst for enantioselective Claisen rearrangements, as it is presented in figure 11 [19]. The mode of action relies on the stabilisation of the transition state via noncovalent interactions, shown in figure 12. Beside the hydrogen bonding interaction between the guanidinium moiety and the ether- and ester-oxygen atoms, an additional electrostatic interaction appears. The aryl-fi-system interacts with the allylic carbon atom of the substrate implying an increased stabilisation of this transition state.
Figure 11: Enantioselective Claisen rearrangement of ester activated allyl-vinyl-ethers to
–-oxohex-5-enoates.
Figure 12: (a) Bidentate hydrogen bonding catalyst 33. (b) Interactions present in the
1.2.3 Lewis base catalysis
To be suitable for Lewis base catalysis, guanidines have to exhibit sufficient nucleophilic and Lewis basic properties enabling the formation of VI with high rates. Additionally, a sufficient stability and lifetime of VI has to be provided to allow for subsequent reactions. If the guanidine catalyst 9 carries protons, a neutral catalyst-substrate adduct VII might be generated by proton transfer, leading to a decrease in reactivity. In that case, high Br¶nsted basicity is necessary for
the reformation of VI via reversible proton transfer [20].
Figure 13: Activation mode of Lewis basic guanidine catalyst TBD and formation of a neutral
catalyst-substrate adduct.
Due to the fact that the nucleophilicity of guanidines is often exceeded by their Br¶nsted basicity,
only few publications about Lewis base catalysts based on guanidines have been reported. MTBD
19 is known for its ability to catalyse carbondioxide fixations [21], ring opening polymerisations
of lactide can be catalysed by TBD 9 [22] and catalysts 34 and 35 are used for enantioselective aldol reactions [23] and Michael type additions [24]. All these guanidine-based Lewis base catalysts have in common, that their exact catalysis mechanism has not been properly defined yet.
Figure 14: Examples for Lewis basic guanidines applied as enantioselective catalysts for aldol
1.2.4 Lewis acid catalysis
Up to now, Lewis acid catalysis is almost entirely restricted to metal salt or metal complex based catalysts. Beside these commonly used catalysts, guanidinium cations also deserve to be mentioned. As depicted in figure 15, the large delocalised fi-system of a guanidinium cation 36 provides an empty orbital located at the central carbon atom, acting as an electron acceptor [4]. One of the few examples for metal-free Lewis acid catalysis 37 reported by Göbel et al. in 2011, is applied as anion receptor for phosphates and has a significant effect on the cleavage of DNA strands [25].
Figure 15: (a) fi-system of guanidinium cations presenting an empty acceptor orbital.
(b) Guanidine-based Lewis acid catalyst.
1.3 General aspects about bifunctional catalysis
Nature uses specialised ensembles of functionalities to catalyse various different types of reac-tions. These systems are well-known as enzymes. Their impressive success story can be traced back to the exceptional configuration of their active sites, which are responsible for the recogni-tion and activarecogni-tion of the substrates. In metal-free enzymes this process takes place at binding pockets with accurately defined constitution. It is further dominated by several different in-teraction mechanisms like hydrogen bonding, hydrophobic inin-teractions, aromatic fi-stacking, van-der-Waals interactions and dipole-dipole-interactions. As an example, figure 16 illustrates the action mode of the active site of serine protease, providing a double hydrogen bonding interaction to the substrate [26].
Figure 16: Active site of the enzyme serine protease and the activation mode of this catalytic
system.
The use of bifunctional organocatalysis for enantioselective and diastereoselective organic trans-formations takes its origin from the enzyme catalysis in nature. This natural catalytic systems serve as template for the concept of organocatalysts. It uses multiple non-covalent interactions to activate substrate molecules and brings them into the appropriate arrangement for reaction. Using a chiral bifunctional catalyst both reaction partners get coordinated and therefore are activated simultaneously. The formation of a highly ordered transition state is enabled resulting in high selectivities.
1.3.1 Bifunctional ammonium salt catalysts
A broad variety of differently functionalised bifunctional catalysts, based on complementary catalytically active motives, have been reported in the past. One class of non-covalent asym-metric organocatalysts, that has attracted a lot of interest, are chiral quaternary ammonium salts [27,28]. These compounds can either be used as monofunctional catalysts, only carrying a quaternary ammonium ion, or as bifunctional systems in combination with a second function-ality. In this context, catalysts carrying free OH-groups, phenoxides, multiple hydrogen bond donors or fi-stacking moieties in addition to the quaternary ammonium salt have already been reported [29-31].
In 1976 Wynberg et al. first introduced cinchona alkaloid based quaternary ammonium salt catalysts containing a free OH-group as a second functionality. On the one hand, this additional site of interaction allows for the coordination of the nucleophile resulting in a better orientational control. On the other hand it enables the activation of an electrophile [32]. These two possible modes of action are demonstrated in figure 17. Catalysts of this type, like 38, can be used for enantioselective aza-Henry-reactions [33,34], asymmetric Strecker reactions [35], Mannich-type reactions [36] and several more.
Figure 17: Catalytic performance of an OH-containing quaternary ammonium salt based on
cinchona alkaloids.
Figure 18: Example for the use of a quinine-derived bifunctional catalyst in an enantioselective
aza-Henry-reaction.
Another example for OH-containing bifunctional quaternary ammonium salt catalysts are the Maruoka-type catalysts based on a binaphthyl ammonium salt. Catalyst 42, shown in fig-ure 19, was introduced 2004 by Maruoka et al. and used for the asymmetric epoxidation of enones [27]. Further modifications resulted in the report of a number of different catalysts ap-plied for Michael additions [37], aldol reactions [38], amination reactions [39] and –-fluorinations of —-ketoesters [40].
Figure 19: Example for the use of a Maruoka-type bifunctional catalyst in an enantioselective
As an alternative for the already known catalysts, in 2008, Peters et al. introduced a new class of bifunctional ammonium salts based on ion pair interactions combined with Lewis acidic func-tionality. An example of this type of catalysts, compound 45, is applied for the synthesis of —-lactones and is depicted in figure 20. The catalytic effects and the high enantio- and diastere-oselectivity are thought to stem from the activation of the aldehyde by binding to the aluminium and from the coordination of the in-situ formed enolate to the pyridinium group [41].
Figure 20: Bifunctional ion pair Lewis acid catalyst used for the synthesis of trans-—-lactones.
Betaines, zwitterionic ammonium group-containing compounds like 49, are also worth mention-ing. Their bifunctional catalytic effect originates from hydrogen bonding and ionic interactions between catalyst and substrate molecules. This class of bifunctional catalysts finds its applica-tion in asymmetric Mannich-reacapplica-tions, as it is presented in figure 21 [42].
Figure 21: Bifunctional betaine-based catalyst used for asymmetric Mannich-reactions. 1.3.2 Bifunctional hydrogen bond donor catalysts
A major group of catalysts is based on hydrogen bond-donor functionality, e.g. the Schreiner’s catalyst 53. This kind of interaction is also of crucial importance for selective substrate recog-nition in nature. Especially combined with other functionalities it shows a promising strategy obtaining excellent catalysts. Some examples are depicted in figure 22.
Figure 22: (a) Hydrogen bond donor catalyst by Schreiner et al. 53. Bifunctional hydrogen
bond-donor catalysts and bifunctional hydrogen bond-donor catalysts (b) by Jacobsen et al. 54 (c) Takemoto et al. 55 and (d) Lassaletta, Fernandez et al. 56.
The formation of hydrogen bonds between catalyst and substrate allows for the stabilisation of intermediates and transition states. In addition, acceleration and stereoselectivity of the respec-tive reaction are achieved by the simultaneous activation of both reaction partners. Enabling the control of reactivity, high catalyst performances can be achieved [30]. Hydrogen bond-donating catalysts can be based on hydroxy, thiourea, urea, guanidinium and amidinium functionalities. In 1998, Jacobsen et al. reported a chiral thiourea-based bifunctional catalyst 54 for asymmet-ric Strecker reactions [43]. The Schreiner catalyst 53, published in 2001 by Schreiner et al., has shown itself to be particularly applicable for Diels-Alder reactions [26]. Another example for a bifunctional catalyst based on chiral thiourea is 55, first introduced 2003 by Takemoto et al. [44]. Catalyst 56, first introduced by Lassaletta et al. in 2010, combines the function-ality of a hydrogen bond donor with that of a quaternary ammonium salt. This catalyst has been successfully applied for cyanosilylation of nitroalkenes [45]. Only few reports in the field of bifunctional catalysis using this combination of a quaternary ammonium salt with an urea or thiourea have been published up to know, primary due to the challenging synthesis of these compounds [30].
Urea-based bifunctional catalysts like 57, reported by Dixon et al. in 2012, exhibit high enan-tioselectivity and diastereoselectivity in nitro-Mannich-reactions of –-amidosulfones [46].
Figure 23: Bifunctional urea-based catalyst by Dixon et al. used for stereoselective
nitro-Mannich-reactions of –-amidosulfones.
As already mentioned above, examples for bifunctional catalysts based on guanidines are also known. These include for instance the catalyst (+)-Chiba-G 28 introduced by Ishikawa in 2000 [18], the guanidine-amide-based catalyst 29 by Feng in 2009 [16] and catalyst 30 containing thiourea- and guanidine-functionalities, which was reported by Nagasawa in 2010 [17]. Bifunc-tional catalysts based on guanidines have been successfully employed for various different organic reactions, including hydrazinations, isomerisations of alkyneoates to allenoates, intramolecular oxa-Michael-additions and epoxidation reactions [28]. However, no example for a bifunctional guanidine catalyst containing an additional quaternary ammonium group has been reported so far.
1.4 Synthesis strategies for organic guanidines
The increasing demand for organic guanidines evoked by their promising and unique proper-ties has induced the investigation of various different synthetic routes to this emerging class of molecules. Up to now, many approaches for guanidine synthesis have been introduced, including the synthesis starting from thioureas, isothioureas, carbodiimides or cyanamides. In addition, some less-known alternatives via pyrazole-1-carboximidamides, triflyl guanidines, aminoiminomethane-sulfonic acids and benzotriazole- and imidazole-activated reagents have been reported [47].
1.4.1 Synthesis starting from thioureas
Thioureas proved to be one of the most common starting materials for the synthesis of guanidines. This approach involves the formation of intermediate carbodiimides in the course of initial activation. These intermediates are usually neither isolated nor characterised [47].
Reacting thioureas with copper sulfate in the presence of TEA followed by reaction of the intermediate carbodiimide with an amine represents one way for guanidine synthesis. This route allows for short reaction times and further enables the availability of a wide range of different guanidines [48].
Figure 24: One pot desulfurisation of thiourea using copper sulfate followed by reaction with
amine to give the corresponding guanidine.
Protected thioureas can be transformed to the corresponding guanidine by reaction with an appropriate amine and Mukaiyama’s reagent 62. The solvent influence is of crucial importance due to the instability of the intermediately formed carbodiimide, whose decomposition competes with the nucleophilic attack of the amine [49].
Figure 25: Preparation of protected guanidines from corresponding thioureas, amines using
An important approach to guanidines involves the use of mercuric chloride and triethylamine. Di-Boc-protected thioureas like compound 61 can be reacted with amines to obtain guanidines by oxidation with HgCl2 in the presence of TEA. This method enables high yields of up to 90
%, however toxic mercury is present in this process [50].
Figure 26: Preparation of protected guanidines from corresponding thioureas, amines using
mercuric chloride and TEA.
Due to the increased reactivity compared to alkylisothiocyanates, carbamoyl isothiocyanates actually react readily with sterically hindered amines. Additional advantages of this starting material are the facilitated purification and the providing of a protecting group during the whole reaction. In the course of this route to guanidines, which can be performed stepwise or in one pot, carbamoyl isothiocyanates are coupled with the first amine to give the corresponding carbamoyl thiourea. A subsequent reaction with a second amine results in the formation of the desired guanidine [51].
Figure 27: Preparation of carbamoyl guanidines from corresponding carbamoyl
isothio-cyanates.
In addition, methods starting from amides [52] or solid phase supported synthesis approaches [53] have been reported to obtain organic guanidines from thioureas.
1.4.2 Synthesis starting from isothioureas
Isothioureas, in particular S-methylisothioureas, are commonly used as starting material for the preparation of guanidines due to their straightforward synthesis and good availability [47]. Starting from N-arylsulfonyl S-methylisothiourea 67, the corresponding guanidine can be pre-pared by reaction with an amine in the presence of TEA and mercuric perchlorate, as it is shown in figure 28 [54].
Figure 28: Preparation of guanidines from N-arylsulfonyl S-methylisothiourea in the presence
of amine, TEA and mercuric perchlorate.
The reaction of di-Boc-protected S-methylisothiourea 69 to guanidines can be carried out using a wide range of different amines. Both aliphatic and aromatic amines, as well as sterically de-manding amines are suitable for this transformation reaction, which involves again the presence of mercuric chloride [55].
Figure 29: Preparation of di-Boc-protected guanidines from corresponding isothioureas,
mer-curic chloride, TEA and amines.
Only naming a few, additional synthesis routes to guanidines starting from isothioureas are presented in figure 30. Thioureas can be activated as thiazetidines to give highly substituted guanidines [56]. Further, the reaction of Cbz-protected isothioureas to guanidines using mercuric chloride, TEA and corresponding amines has also been reported [57].
Figure 30: (a) Preparation of guanidines by activation of thioureas as thiazetidines. (b)
1.4.3 Synthesis via carbodiimides
As already mentioned, carbodiimides can be prepared by oxidation and desulfurisation of thio-ureas. Methods to obtain solid supported guanidines have been reported using isolated inter-mediate carbodiimide, which is then reacted with a resin bound amine to the corresponding guanidine [58]. Vice versa it is also possible to prepare a supported carbodiimide and to couple it with an amine [59].
Figure 31: Synthesis of a resin bound guanidine starting from an isolated carbodiimide
syn-thesised from a thiourea using Mukaiyama’s reagent.
Triarylguanidines are available by reaction of N-aryliminophosphoranes with isocyanates, as depicted in figure 32 [60].
Figure 32: Formation of carbodiimides from N-aryliminophosphoranes and isocyanates and
subsequent reaction to the guanidine.
1.4.4 Alternative synthesis routes
In addition to the above described methods for guanidine synthesis, there have been fur-ther approaches investigated using cyanamides, pyrazole-1-carboximidamides, triflyl guanidines, aminoiminomethane-sulfonic acids and benzotriazole- and imidazole-activated reagents.
Starting from aromatic amines, cyanamides can be formed in-situ and further reacted with an excess of a second amine to the corresponding guanidine [61].
Figure 33: Preparation of aromatic guanidines from amines via in-situ formation of cyanamides.
Figure 34 presents some examples for the additional synthesis routes via pyrazole-1- carboximid-amides, triflyl guanidines, aminoiminomethane-sulfonic acids and benzotriazole- and imidazole-activated reagents. [62-65].
Figure 34: Preparation of guanidines from (a) pyrazole-1-carboximidamides, (b) triflyl
guani-dines, (c) aminoiminomethane-sulfonic acids and (d) benzotriazole- and imidazole-activated reagents.
2 Objectives
Bifunctional catalysts based on quaternary ammonium salts and hydrogen bond donors proved their applicability in various different asymmetric transformation reactions. Due to the promis-ing properties of this emergpromis-ing class of organocatalysts, the number of available compounds and possible applications increases steadily. Up to now, urea- and thiourea-based bifunctional catalysts have already been introduced and demonstrated their versatile usability. The aim of this thesis is to design alternative bifunctional organocatalysts carrying a guanidine-moiety as hydrogen bond donor instead of the urea- or thiourea-group. This guanidine function is intended to combine its powerful properties as an excellent hydrogen bond donor and a strong organic base.
Figure 35: Synthesis of bifunctional catalysts based on quaternary ammonium salts starting
from simple (1R,2R)-(+)-1,2-cyclohexanediamine.
Since a promising strategy for the synthesis of thioureas has already been established in our group [66], this thesis is mainly focussed on the synthesis of guanidines via thioureas. However, different synthesis routes starting from 2-chlorobenzimidazole, carbodiimides or isothioureas have also been investigated. To make first statements concerning the applicability of these guanidine-based bifunctional catalysts, a series of test reactions has been performed using the recently synthesised organocatalysts. In the course of these transformations —-ketoesters were functionalised in the –-position, as it is summarised in figure 35.
Figure 36: Testing of guanidine-based bifunctional catalysts in –-heterofunctionalisations of
3 Results and Discussion
Several promising synthesis routes for bifunctional guanidines, including the synthesis via thio-ureas, isothiothio-ureas, carbodiimides and 2-chlorobenzimidazole, have been introduced in the course of this thesis. In addition, test reactions were performed using the recently prepared catalysts.
3.1 Synthesis of guanidines via thioureas 3.1.1 Synthesis of the thiourea
The general preparation of the thiourea starting material has been achieved following the syn-thesis strategy investigated by our group. This approach starts from the racemic (±)-trans-1,2-cyclohexanediamine, which is initially resolved using L-(+)-tartaric acid affording an ee of >95 % [66]. Continuing with (1R,2R)-(+)-1,2-diammoniumcyclohexane-L-tartrate 86 six fur-ther reaction steps are necessary to obtain the desired thiourea 101. A general scheme of this synthesis route is presented in figure 37.
Figure 37: Scheme of synthesis strategy for thioureas in six steps starting from
(1R,2R)-(+)-1,2-diammoniumcyclohexane-L-tartrate.
The release of the free diamine 87 from (1R,2R)-(+)-1,2-diammoniumcyclohexane-L-tartrate 86 was done using aq. NaOH-solution (1.8 M), which was added dropwise to the educt suspended in DCM. The isolation of the desired product 87 had to be done with great carefulness. Due to the fact, that 87 tends to sublime, evaporation of the DCM was only possible at 0°C and 100 mbar. Otherwise, sublimation would have lead to a reduced yield. As it was not possible to remove the solvent completely, yields >100 % were achieved. Therefore, an alternative possibil-ity of solvent evaporation was performed. After the extraction procedure most of the DCM was evaporated at 45 °C and 700 mbar. Subsequently the resulting dark brown liquid was frozen to
-20 °C and immediately put onto the high vacuum to obtain 87 as a beige solid in a yield of 67 %. The next step was to protect one amino function of 87 with a Boc-protecting group. According to the literature [67], this reaction was performed in MeOH at 0 °C in the presence of 1 equiv. concentrated HCl. Addition of a solution of 1 equiv. Boc2O in MeOH lead to the formation of
a white precipitate. Adding a few drops of water enables the redissolution in the case the stirrer comes to a standstill. After a reaction time of 20 h and evaporation of the solvent, the residue was suspended in water followed by the extraction of the double-Boc-protected product with diethylether. Due to the acidic reaction conditions, the product was present in its protonated form and had to be deprotonated to obtain 88. This was achieved by addition of 4 M NaOH (aq.) to the aqueous phase, followed by extraction with DCM to obtain product 88 in yields almost similar to the 80 % given in literature [67].
The first step for quaternisation was the reductive amination with an appropriate aldehyde 89a or 89b. These reactions were performed in accordance to the procedure reported by Katsuki et al. [68]. The aldehyde was added in equimolar amounts to a solution of 88 in a 1:1-mixture of THF and MeOH. After addition of 1.5 equiv. NaBH4 foaming caused by hydrogen evolution
and warming of the reaction mixture due to the exothermic reaction could be observed. The reaction was quenched with water and the product was extracted with diethylether to obtain the desired products 90a and 90b in high yields. Since their purity has already been sufficient for the next step, no further purification was necessary. The aldehydes used for this reductive amination and the corresponding products are depicted in figure 38.
Figure 38: (a) Aldehydes used for the reductive amination. (b) Obtained products and the
corresponding yields.
To form the corresponding quaternary ammonium salt, compounds 90a and 90b were methy-lated using 6 equiv. MeI in DMF in the presence of 1.2 equiv. K2CO3 at 60 °C. After a reaction
time of 3 d, excess MeI was removed by reduced pressure. The crude product obtained after extraction with DCM was further purified by column chromatography (silica gel, DCM:MeOH, 1:0 ≠æ 10:1). To enable complete removal of the high-boiling DMF, the residue was evaporated several times with heptane. Alternatively, mono-Boc-protected diamine 88 could be quaternised in a single step by converting it into the trimethyl ammonium salt 95. This reaction was
per-formed at rt in ACN in the presence of 2 equiv. K2CO3 and 5 equiv. MeI. After a reaction
time of 5 d, toxic MeI was removed by reduced pressure and the base was removed by filtration. Evaporation of the solvent gave the product 95 as a white, solid foam in a yield of 98 %. This reaction and the products obtained by the aforesaid quaternisations are illustrated in figure 39.
Figure 39: (a) Direct quaternisation of 88 to the trimethyl-ammonium salt 95. (b) Obtained
products of the previous quaternisation steps and their corresponding yields.
To enable the final coupling with an isothiocyanate, compounds 91a and 91b had to be depro-tected. This was achieved by using 57% hydroiodic acid (aq.), which was added to a solution of 91a or 91b in DCM, followed by extraction and column chromatography. It was found, that different stoichiometry of HI had to be applied, depending on the quality of the hydroiodic acid to achieve sufficiently high yields. In the case of compound 95, the deprotection procedure only differs in the work-up method. Here, the product was crystallised by dropwise addition of the reaction mixture to precooled diethylether. The white precipitate, representing product 96, was collected by suction filtration. The deprotected compounds and their yields are depicted in figure 40.
Figure 40: Products and their corresponding yields obtained after the deprotection using
hydroiodic acid.
After that, the free amines 91a and 91b have been coupled with 3,5-bis(trifluoromethyl)phenyl-isothiocyanate 93 to give the desired thioureas. This reaction was performed in DCM using 1.2 equiv. of the isothiocyanate. After purification by column chromatography (silica gel, DCM:MeOH, 1:0 ≠æ 10:1) products 94a and 94b were obtained in high yields of 74-75 % and served as starting material for further transformation to guanidines.
3.1.2 Synthesis of the oxidising agents IBX and (diacetoxy)iodobenzene
To synthesise guanidines starting from thioureas, an oxidising agent is necessary to enable the in-situ formation of a reactive carbodiimide-intermediate in the course of a desulfurisation reac-tion. The carbodiimide-species immediately reacts with an amine, which is also present in the reaction mixture. Many procedures using mercuric chloride [50] or other mercury-containing reagents have been published exhibiting excellent yields and qualities of the produced guani-dines. However, due to the toxicity of mercuric compounds, alternative oxidising agents have to be investigated. Beside the readily available iodine, also 2-iodoxybenzoic acid (IBX) and (diacetoxy)iodobenzene have been examined as oxidising agents in the course of this thesis. IBX 98 was prepared in analogy to the procedure reported by Schmidt et al. [69]. 2-Iodobenzoic acid 97 was added to a solution of 1.3 equiv. oxone (2 KHSO5 . KHSO4 . K2SO4) in water and
heated to 73 °C for 3 h. After additional stirring at 5 °C for 1.5 h, the white precipitate was removed by suction filtration and washed with cold water and acetone to obtain IBX 98 in a yield of 91 %, almost reaching the value reported by the literature.
Figure 41: Preparation of the oxidising agent IBX using 2-iodobenzoic acid and oxone in an
aqueous solution.
In addition, a second oxidising agent, (diacetoxy)iodobenzene 101, was synthesised according to the procedure reported by Koser et al. [70]. The authors emphasised the importance of keeping the temperature at 25-30 °C during the reaction. Iodobenzene 99 was precooled to 10 °C before 1.3 equiv. of 36-40 w% peracetic acid 100 were added dropwise, so that the temperature did not exceed 30 °C. The reaction mixture was stirred for 4 h at rt. As soon as some seed crystals were present, for instance as a consequence of scratching with the thermometer, the white product precipitated immediately. After the reaction had been finished, water was added to dilute any remaining oxidant and to enable complete precipitation. The solid (diacetoxy)iodobenzene 101 was removed by suction filtration and washed with water and diethylether.
During the practical work of this thesis, the synthesis of 101 was performed twice. It turned out, that only the second attempt lead to the formation of the desired product 101. The NMR-spectrum of the product obtained by the first attempt did not show the signals corresponding to the expected product. The exact chemical structure of this product has not been determined yet. However, considering the NMR-peaks, the formation of a higher oxidised species can be
stated. Although both reactions were performed exactly in the same way, the different results can be explained by two facts, which are obviously not to forget. The successful attempt has been performed at fourfold scale. In addition, the temperature during the addition of peracetic acid has been kept at 10-15 °C and reached 20 °C only for a very short time. On the contrary, the temperature in the case of the higher oxidised product stayed at 25 °C for several minutes. Furthermore, a higher yield was achieved in the case of the higher oxidised species probably due to the higher temperature.
Figure 42: Preparation of the oxidising agent (diacetoxy)iodobenzene using iodobenzene and
a solution of peracetic acid in acetic acid.
3.1.3 Introduction of the guanidine moiety
In the course of this thesis, the synthesis of the chiral guanidines 102 and 103 was performed by reaction of thiourea 94b with IBX and the corresponding amine. Both reactions succeeded, as the mass spectra showed signals for the desired products. However, the purification of the guanidines posed serious problems. Figure 43 shows the guanidines formed in the course of this synthesis approach.
Figure 43: Chiral guanidines prepared from thiourea 94b using IBX and the corresponding
amine.
For the synthesis of guanidine 102, IBX and 94b were combined in a molar ratio of 1.1:1 and dissolved in ACN resulting in a 0.21 M solution considering the amount of thiourea. After
ad-dition of 51 equiv. of 25 % NH3 in H2O the reaction mixture was stirred for 1 d at rt. Mass
spectrometry proved the presence of the desired product and of unreacted IBX. Subsequent in-vestigations revealed, that a urea as a side product was also contained in this reaction mixture. During the work-up procedure, the mixture was extracted with NaHCO3-solution (aq.) and
EtOAc. The reaction equation regarding this guanidine synthesis is given in figure 44.
Figure 44: Reaction equation for the synthesis of guanidine 102 using IBX to in-situ form
an intermediate carbodiimide, which is then attacked by the nucleophile. Side product 105 has been formed due to the presence of water.
Several different purification methods, like crystallisation and column chromatography, have been examined resulting in poor outcome.
During column chromatography it was not possible to collect any product due to dilution and detection problems. Due to the presence of water during the reaction, significant amounts of urea have been formed as side products. Using preparative HPLC (ACN/H2O, reversed phase),
a separation of the product 102 and the corresponding urea-side product 105 did not succeed by reason of their almost equal polarities.
Crystallisation tests in heptane and diethylether posed the problem, that no separation was achieved. The product was detectable both in the precipitate and in the solution.
The NMR-signals indicate the presence of some iodobenzoate species as counter ion for the qua-ternary ammonium salt. Due to the fact, that certain test reaction catalysed by this kind of bifunctional catalysts only succeed with iodine as counter ion, it had to be exchanged. There-fore a special work-up procedure has been investigated. The crude product was dissolved in DCM and 90 equiv. of 57% HI (aq.) was added dropwise during stirring. After extraction with Na2CO3-solution (aq.), drying over Na2SO4 and evaporation, the first step was repeated two
more times. NMR-spectroscopy proved the almost complete exchange of the counter ions after three repetitions. Concerning the mixture of guanidine 102 and urea 105 an overall yield of 83 % could be attained.
The synthesis procedure for guanidine 103, carrying a n-butyl-group, proceeds in the same manner as that for guanidine 102. The only difference is the applied nucleophile. In this case, n-butyl amine has been used instead of the ammonia. Varying the amount of water present
during this reaction, the urea-side product 105 was formed in different quantities. This sug-gests, that, if this reaction was performed under waterfree conditions, the formation of the undesired side product 105 might have been avoided. Purification by column chromatography (silica gel, DCM/MeOH, 1:0 ≠æ 0:1) again resulted in a mixture of product 103 and side prod-uct 105 in an overall yield of 23 %. The corresponding reaction equation is depicted in figure 45.
Figure 45: Reaction equation for the synthesis of guanidine 103 using IBX to in-situ form
an intermediate carbodiimide, which is then attacked by the nucleophile. Side product 105 has been formed due to the presence of water.
3.1.4 Benzylation of guanidine 102
The benzylation of crude guanidine 102 was performed in EtOAc at 0 °C by addition of 1.1 equiv. benzylbromide, according to figure 46 (a).
Figure 46: (a) Benzylation of guanidine 102. (b) Results of the purification attempt by column
chromatography.
Derivatisation of the guanidine 102 with a benzyl group lead to a decrease in polarity, resulting in better eluation properties using the system silica gel and DCM/MeOH. Compared to the initial guanidine 102 elution has already been achieved with less polar eluent. However, the desired product 106 could not be separated from a side product, also eluting at a ratio of DCM:MeOH = 30:1. The nature of this undesired product has not been under further investigations yet. An overall yield of 63 % for the mixture of 106 and its side product can be stated.
