Towards electrophilic cyanation and alkyne dimerisation reactions using iodine(III) reagents / Johannes Schörgenhumer

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UNIVERSITÄT LINZ JOHANNES KEPLER

JKU

Technisch-Naturwissenschaftliche Fakultät

Towards electrophilic cyanation and alkyne

dimerisation reactions using iodine(III) reagents

MASTER’S THESIS

to confer the academic degree of

Diplom-Ingenieur

in the Master’s Program

Technische Chemie

Author:

Johannes Schörgenhumer

Submission:

Institute of Organic Chemistry

Thesis Supervisor:

Assoc. Univ.-Prof. Dr. Mario Waser

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Curriculum vitae

Personal Data

Name Johannes Schörgenhumer

Date of Birth October 14, 1990 Place of Birth Wels

Nationality Austria

Parents Elisabeth and Peter Schörgenhumer

School education

09/1997 - 07/2001 VS Waizenkirchen 09/2001 - 07/2005 Gymnasium Dachsberg 09/2005 - 06/2009 BORG Grieskirchen

June 22, 2009 Higher education entrance qualification

Community service

02/2010 - 10/2010 Civil service as ambulance officer for the Austrian Red Cross in Efer-ding

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University education

10/2010 - 02/2014 Bachelor’s programme “Technische Chemie” at the JKU Linz

Bachelor thesis: “Synthesis of a chiral TADDOL-based ligand for enan-tioselective fluorination reactions”, carried out at the Institute of Or-ganic Chemistry at the JKU Linz

02/2014 - now Master’s programme “Technische Chemie”

Occupations

08/2011 Employment as ambulance officer for the Austrian Red Cross in Eferd-ing

04/2012 - 06/2014 Teaching mathematics at the “Lernfamilie” in Linz

08/2012 Employment as ambulance officer for the Austrian Red Cross in Wil-hering

11/2012 - 01/2013 Tutorium “Praktikum aus Allgemeiner Chemie” 03/2013 - 06/2013 Tutorium “Praktikum aus Analytischer Chemie I” 05/2013 - 06/2013 Tutorium “Praktikum aus Anorganischer Chemie”

11/2013 - 02/2014 Tutorium “Praktikum aus Allgemeiner Chemie” 05/2014 - 06/2014 Tutorium “Praktikum aus Anorganischer Chemie”

10/2014 - 01/2015 Tutorium “PS Organische Chemie für Molekulare Biowissenschaften” 11/2014 - 01/2015 Tutorium “Praktikum aus Allgemeiner Chemie”

05/2015 - 06/2015 Tutorium “Praktikum aus Organischer Chemie II” 05/2015 - 06/2015 Tutorium “Praktikum aus Anorganischer Chemie”

09/2015 Tutorium “Praktikum aus Organischer Chemie für Molekulare Biolo-gen”

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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 vor-liegende Masterarbeit ist mit dem elektronisch übermittelten Textdokument identisch.

Linz, September 2015 Johannes Schörgenhumer

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Acknowledgements

First, I would like to thank Univ.-Prof. Dr. Norbert Müller for letting me carry out this work at his Institute of Organic Chemistry at the JKU Linz. I want to express my gratitude to the whole institute’s staff for all kinds of support. To my fellow students of organic chemistry, my coworkers, many thanks for this most likeable and productive time.

However, one person has to be highlighted in this regard: I am most and sincerely grateful to my supervisor Assoc. Univ.-Prof. Dr. Mario Waser for his friendly guidance and his never-ending support. Working for his group was a pleasant and truly inspiring journey.

There are two other teaching figures whom I would like to thank at this point: Many thanks to Mag. Peter Krimbacher - without his chemistry lessons I might have never studied this subject in the first place. Furthermore, I would like to express my sincere gratefulness to A.Univ.-Prof. Dr. Karl Grubmayr for his unforgettable lectures in Organic Chemistry, which set me on the path I am now on.

Last but not least, I would like to thank all those, without whom I would not have been able to come to this point. A huge thank-you to my friends for their ever-lasting patience and en-couragement! The most outstanding support I received, however, was my family. For countless occasions and innumerable reasons my deepest gratitude!

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Zusammenfassung

Iod(III)-Verbindungen wurden in den letzten Jahren immer wichtiger für die organische Syn-thesechemie. Insbesondere organische Iod(III)-Heterocyclen wie zum Beispiel Benziodoxole rückten mehr ins Rampenlicht. Grund dafür sind einzigartige Reaktivitäten dieser Spezies, wie zum Beispiel der Transfer von ungewöhnlichen elektrophilen Gruppen wie Aryl-Resten oder Cyanidgruppen. Die so auf einfachem Wege erhaltenen, synthetisch interessanten Verbindun-gen sind mit herkömmlichen Methoden oft nur schwer zugänglich oder beruhen auf der Ver-wendung von hochgiftigen Stoffen oder teuren Katalysatoren.

Anfang 2015 wurde die racemische elektrophile Cyanierung von β-Ketoestern mit Cyano-Benziodoxolen veröffentlicht. Kurz darauf folgte die Publikation eines ersten enantioselektiven Ansatzes mit Cinchona-Alkaloid basierten Organokatalysatoren. In direkter Fortsetzung dieser Forschung unserer Gruppe bestand der erste Teil dieser Masterarbeit darin, das Potential unserer bifunktionellen Organokatalysatoren in der Cyanierung von β-Ketoestern zu testen. Nachdem mit einem maximal erreichten Enantiomerenüberschuss von 24% aber kein zufriedenstellendes Ergebnis erreicht werden konnte, wurden andere Strategien für eine enantioselektive Reaktion versucht. Jedoch führte weder die Verwendung von chiralen Auxiliaren noch der Einsatz von chiralen Metallkomplexen zu den gewünschten Ergebnissen.

Als nächster Teil der Arbeit wurde die elektrophile Cyanierung vom Aminen mittels Cyano-Benziodoxolon versucht. Das Iod(III)-Reagenz sollte dabei das sonst übliche, aber sehr giftige Cyanierungsreagenz Bromcyan ersetzen. Die geplante Darstellung von Benzylcyanamid konnte nicht erreicht werden, da als Produkt stattdessen die auf diese Art bisher nicht beschriebene Synthese von Guanidinen beobachtet wurde.

Den letzten Teil dieser Arbeit bildeten oxidative Dimerisierungsreaktionen von Alkinen. Nach-dem beim Versuch, terminale Alkine mit Cyano-Benziodoxolon zu cyanieren, zufällig entdeckt wurde, dass anstelle des gewünschten Produkts selektiv ein Alkindimer entstanden war, wurde diese Reaktion weiter untersucht. Acetyl-Benziodoxolon stellte sich als bestes Kupplungs-reagenz heraus und wurde erfolgreich in der experimentell einfachen oxidativen Dimerisierung verschiedener Alkine verwendet. Die Dimere von Edukten ohne funktionelle Gruppen wie Alkohole, Ester, Amide oder Ether wurden mit typischen Ausbeuten von rund 70% isoliert, funktionalisierte Alkine brachten im Schnitt etwas geringere Ergebnisse.

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Abstract

Over the past few decades, iodine(III) reagents have been increasingly applied in organic syn-thesis. Cyclic iodine(III) compounds such as benziodoxoles have been more and more inves-tigated due to their unique reactivity, enabling electrophilic transfer reactions of unusual syn-thons such as electrophilic aryl-groups or electrophilic cyanide. These transformations lead to synthetically very interesting products, which would be otherwise hard to prepare or rely on methods based on highly toxic reagents or precious catalysts.

The recent report on the successful racemic electrophilic α-cyanation of β-ketoesters using cyano-benziod-oxoles was directly followed by the first enantioselective approach using cin-chona alkaloid based organocatalysts, resulting in high yields and mediocre stereoselectivity. That publication was submitted by our group at the Institute of Organic Chemistry at the JKU Linz. In direct continuity, the first part of this work was to investigate the potential of our group’s bifunctional organocatalysts for this useful transformation. As the achieved enantioselectivity was not very high (the maximum ee was 24%), other procedures for the enantioselective α-cyanation of carbonyl compounds were tested. The use of chiral auxiliaries and chiral metal complexes, however, remained without success.

The second part of this master’s thesis was focused on the electrophilic cyanation of benzyl-amine, using cyano-benziodoxolone instead of the traditionally applied highly toxic cyanogen bromide. However, instead of the desired cyanamide, the unexpected formation of guanidines was observed.

By chance, it was discovered that the cyanation of terminal alkynes using 1-cyano-1,2-benziod-oxol-3-one resulted in the oxidative dimerisation of the alkynes. In the last part of this work, the dimerisation reaction was further investigated, showing that acetyl-benziodoxolone was suited best as a coupling agent. In a very facile procedure, several alkynes were dimerised with high yields of about 70% for alkynes without functional groups. Alkynes with hydroxy-, ester-, amide- or ether-groups performed slightly less well.

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1 Introduction

1.1 Organic iodine(III) compounds

Organic compounds based on iodine(III), often also referred to as “hypervalent” iodine or called

λ3-iodanes (IUPAC), have been known for about 130 years, when Willgerodt first published the preparation of phenyliodo(III)dichloride PhICl₂, also known as (dichloroiodo)-benzene [1]. In the following few years, reports on hundreds of aryliodo-compounds such as PhI(OAc)₂ or Ar₂I+HSO₄– occurred [2, 3]. However, not much attention was payed to those molecules until the 1980s, when iodine(III) reagents underwent a kind of renaissance as they were found to show quite versatile reactivity similar to heavy metal complexes such as Pb(IV) compounds, but advantageously, with significantly lower toxicity [4].

During the rise of iodine(III) compounds for organic synthesis a new class of λ3-iodanes was introduced by Zhdankin et al. in 1995: cyano-derivatives of benziodoxoles 1 and 2. This new group of reagents overcame the instability of acyclic aryliodo-compounds with ligands like CN or N₃, and as a result rapidly emerged as useful reagents for organic transformations [5, 6]. Some of the first compounds prepared by the groups of Zhdankin and Kita are shown in Scheme 1.1. I O I O CN O CN I O O N3 I O ONO2 1 2 3 4

Scheme 1.1 First cyclic iodine (III) compounds by Zhdankin and Kita.

Since then, the number of reports on λ3_{-iodanes has been rapidly growing each year. The rising}

interest is based on the unique oxidising and electrophile transferring properties of iodine(III) reagents under mild conditions and with very little negative environmental impact [7].

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1.1.1 General remarks on structure, bonding and classification

In general, organic compounds containing iodine with the oxidation state of +III are more com-mon than the ones with +V. Iodine(III)-molecules appear in two different structures, as can be seen in Scheme 1.2: The 10-I-3 species 5 (10 valence electrons, 3 ligands following the rules of Martin-Arduengo [8]), for instance benziodoxoles or iodosylarene derivatives of the type ArIX₂, appear with distorted trigonal bipyramidal geometry, whereas the two more elec-tronegative ligands assume the axial positions. The 8-I-2 species 6 are represented by iodonium cations as Ar₂I+and appear with geometries between pseudotetrahedral and T-shaped similar to 10-I-3 systems, depending on the anion [4].

L I L L L I L 5 6

Scheme 1.2 Geometries of iodine(III) compounds.

The structural properties are quite illustratively explained by the hypervalent bonding theory. The hypervalence is induced by binding two ligands to a doubly occupied p-orbital of the io-dine, resulting in a 4-electron-3-center-bond, which is weaker and longer than a normal bond. As a result, the linear hypervalent bond lies axial and gets better stabilised with higher elec-tronegativity at the two ligands [9, 10]. Altough this theory is outdated by the MO-theory, it still describes the structural features and some properties of such compounds quite accurately in a very simple way. However, the theory and the term “hypervalent” itself underwent much criticism, and, therefore, shall not be used in this work [11].

Judging the bond length, iodine-carbon bonds in λ3_{-iodanes are generally considered as}

cova-lent. Non-carbon ligands are bonded to iodine with bond lengths between covalent and ionic bonds. Thus, depending on the ligand, the iodane compound shows a more ionic behaviour (e.g. Cl as ligand) or a more covalent one (e.g. OAc as ligand) [4].

Most of the carbon ligands are aromatic fragments, as most of iodane compounds with aliphatic ones are not stable and mostly just encountered as intermediates. Of course, there are some exceptions to this statement, for example alkyl moieties with strongly electron-withdrawing substituents such as CF₃[4].

There are several ways to classify iodine(III) compounds. One classification commonly applied is based on structure and, subsequently, reactivity. Thus, λ3_{-iodanes can roughly be devided in}

five groups.

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non-carbon ligand. Iodosylarenes and their derivatives are widely applied throughout organic chemistry as oxidising agents, as well as oxygenation and electrophilic transfer reagents [7].

Benziodoxoles 7 and benziodazoles 8 (Scheme 1.3) are much more stable than acyclic

com-pounds as ArIX₂even with ligands such as CN or CF₃, which otherwise either cannot be isolated in the first place or cannot be handled under convenient conditions [7].

I O X Y I N X Y R X = O, Me₂, (CF₃)₂, etc. Y = OAc, Cl, N₃, etc. R = H, Alkyl, etc. 7 8

Scheme 1.3 General structures of benziodoxoles 7 and benziodazoles 8.

Iodonium salts R₂I+X– possess the excellent leaving group R-I- and, hence, are well suited for functional group transfer. In contrast to the two groups mentioned before, iodonium salts do not show any significant oxidising behaviour [7].

Iodonium ylides ArI−−CR₂show a completely different reactivity and are best suited as precur-sors for carbenes [7].

Iodonium imides ArI−−NR are similar to the iodonium ylides and are fairly potent nitrene

pre-cursors [7].

In the following sections, only the first three groups shall be described in more detail, especially the benziodoxoles will be more thoroughly discussed as they are the essential part of this work.

1.1.2 Preparation of λ

3

-iodanes

In the following, some exemplary preparation procedures for some of the most important io-dine(III) compounds are given.

1.1.2.1 Preparation of iodosylarenes and derivatives

One of the most important and commercially available sources for other λ3_{-iodanes is}

phenyl-iodo(III)diacetate, more commonly known as (diacetoxyiodo)benzene (DIB), PhI(OAc)₂ (9). As other iodine(III)-carboxylates, it is readily obtained by oxidising iodobenzene (10) with peroxoacetic acid [13], as is depicted in Scheme 1.4.

Iodosylarenes, such as their most important example, iodosobenzene PhIO (11), are best pre-pared from (di-acetoxyiodo)benzene PhI(OAc)₂or phenyliodo(III)dihalides PhIX₂by hydroly-sis with aqueous sodium hydroxide solution [2, 12], as shown in Scheme 1.5. The route via the diacetate is the preferred one, since the educt is commercially available.

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I OAc OAc AcOOH AcOH I 10 9

Scheme 1.4 Preparation of (diacetoxyiodo)benzene (9).

I OAc OAc IO aq. NaOH 9 11

Scheme 1.5 Preparation of iodosobenzene (11).

Typically, there are two methods to prepare aryliododihalides, mostly chlorides and fluorides: Firstly, chlorides are easily prepared from iodoarenes by halogenation, as demonstrated for the synthesis of phenyliodo(III)dichlorid PhICl₂(12) in Scheme 1.6. The reaction of iodobenzene (10) with chlorine in chloroform represents the first synthesis of a iodine(III) compound ever, performed by Willgerodt in 1886 [1]. I Cl Cl Cl2 CHCl3 I 10 12

Scheme 1.6 Preparation of (dichloroiodo)benzene (12).

Another way to obtain aryliododihalides is the reaction of iodosylarenes with strong acids as HX. With regard to fluorides, the ligand-exchange-reaction of hydrogenfluoride with (dichloro-iodo)arenes aided by mercury oxide HgO is the traditional choice, as demonstrated for the example of (difluoroiodo)benzene PhIF₂ (13) in Scheme 1.7 [14]. However, as the use of hydrogenfluoride is rather disadvantageous, some other processes are based on, for instance, sulfur-tetrafluoride SF₄or Selectfluor [4, 15]. I Cl Cl I F F aq. HF, HgO 12 13

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1.1.2.2 Preparation of iodonium salts

As aryliodonium salts are the most important species of iodonium salts, only those shall be briefly discussed herein. The classical approach for their synthesis would be the reaction of aromatic molecules or silylated aromatic compounds with derivatives of iodosylarenes as elec-trophiles. Often acids such as sulfuric acid or trifluoromethanesulfonic acid are added to the reactions in order to yield HSO₄– or OTf– as counterions [4, 16, 17]. Examples for two reac-tions yielding diphenyliodonium salts 14 and 15 are given in Scheme 1.8 and Scheme 1.9.

I OAc OAc I PhH, 2 TfOH OTf DCM 9 14

Scheme 1.8 Preparation of diphenyliodonium triflate (14).

I OSO3 I OSO3H DCM IO SO3 PhH 11 ₁₆ 15

Scheme 1.9 Preparation of diphenyliodonium hydrogen sulfate (15).

There are also numerous procedures not starting from an iodine(III) species but instead using aryliodides and involving an oxidation step. A very efficient one-pot example starting from iodobenzene is presented in Scheme 1.10 [18].

I PhH, mCPBA, TfOH DCM I OTf 10 14

Scheme 1.10 Direct preparation of diphenyliodonium triflate (14) starting from iodobenzene.

1.1.2.3 Preparation of heterocyclic λ3_-iodanes

The vast majority of heterocyclic λ3-iodanes are five-membered benziodoxoles. In the follow-ing, only these compounds will be more closely discussed, however, the general preparation

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procedure stays true also for benziodazoles, benziodothiazoles and any other derivatives. The general synthetic pathway to heterocyclic iodine(III) compounds is a simple oxidation in the first step, wherein the ring is formed, followed by derivatisation and ligand exchanges [4]. There are many suitable oxidising agents that favour selectively iodine(III) over iodine(V) as a product. A few cases will be outlined in the following examples.

Scheme 1.11 shows the two elementary reactions from 2-iodobenzoic acid (17) with an oxidant such NaIO₄ via the thereby obtained iodosylbenzoic acid (18) to the acetyl-benziodoxolone 19 [19, 20]. The derivatisation with acetic anhydride in the second step is used to achieve acetate as a ligand that is easier to exchange in subsequent reactions.

COOH I NaIO4 I O O OH Ac2O I O O OAc aq. HOAc 17 18 19

Scheme 1.11 Preparation 1-acetyl-1,2-benziodoxol-3-(1H)-one (19) by oxidation of 2-iodobenzoic acid and subsequent acetylation.

The second exemplary case is depicted in Scheme 1.12, where the educt for the two main preparation steps is derived via the esterification of iodobenzoic acid 17 and subsequent reaction with a Grignard-reagent, in this case methyl magnesium iodide [21, 22]. The obtained alcohol 20 is then oxidised by tert-butyl hypochlorite to yield the chloro-benziodoxole 21 [23]. Again, to facilitate the later ligand exchange, the compound is derivatised by exchanging the chloride ligand with fluoride [24].

COOH I COOMe I H2SO4 MeOH I OH F O I MeMgI Et2O Cl O I KF ACN tBuOCl CCl4 17 22 20 21 23

Scheme 1.12 Preparation sequence to 1-fluoro-3,3-dimethyl-1,2-benziodoxole (23).

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ligands as, for instance, cyanide or acetylenes, bonding them to the iodine is crucial. Usually, those ligands are introduced using the analogous nucleophilic trimethylsilyl reagents (TMS-L). Some examples are TMS−CF₃, TMS−N₃, TMS−CN or TMS−C≡CPh [24, 6, 5, 19]. Although some of the first reports mention iodosylbenzoic acid directly taking part in the ligand exchange [5], the synthetic route via some more easily exchangeable ligands, such as acetate, fluoride or trifluoromethyl-groups is sometimes required and generally favoured due to higher yields and shorter reaction times. There are, however, two convenient synthetic possibilities: In some cases it is possible to carry out the additional ligand exchange and the step with the TMS-reagents in one-pot procedures [24]. One typical reaction scheme showing the one-pot synthesis of the nowadays well known 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (24) is depicted in Scheme 1.13. In other approaches, the addition of activating reagents (e.g. TMS-OTf) may be done in catalytic amounts by simultaneous addition of the TMS-reagents [6]. An example for a catalytic procedure is given in Scheme 1.14 [24, 6].

COOH I ACN I O O CF3 1) TCICA 2) KOAc 3) TMS-CF3 17 24

Scheme 1.13 Preparation of 1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one (24) in one pot via oxida-tion of iodobenzoic acid with trichloroisocyanuric acid and an exchange of the chloride with an acetate, followed by the nucleophilic displacement with the trifluoromethyl-group.

N3 O I OAc O I TMS-N3, cat. TMS-OTf DCM 25 26

Scheme 1.14 Synthesis of 1-azido-3,3-dimethyl-1,2-benziodoxole (26) with the ligand exchange facil-itated by catalytic addition of TMS-OTf.

1.1.3 Reactions of iodine(III) compounds

The high synthetic value of iodine(III) reagents is due to their possible application in oxidation reactions and electrophilic group transfer reactions. The oxidative behaviour is rather obvious as compounds with lower oxidation states at iodine 27 are more stable than iodine(III) species 28. A general oxidation reaction is outlined in Scheme 1.15.

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Ar I X X (+III) Ar I ("+I") + 2e -- 2X -28 27

Scheme 1.15 The reduction of an iodine(III) compound as reason for the oxidative behaviour.

The electrophilic group transfer reactions are also driven by the reduction of iodine(III). As shown in Scheme 1.16, the electrophilic iodine centre in 29 is readily attacked by the nucleo-phile Nu, which displaces the ligand X to give the intermediate 30. The following reductive elimination process transfers the formally electrophilic group G to the nucleophile to give the product 31. Ar I G X Ar I + Nu Nu G - X red. elim. Nu G Ar I 29 ₃₀ 27 31

Scheme 1.16 General reaction scheme for an electrophilic group transfer using an iodine(III) reagent.

Formally, an umpolung takes place: For instance, alkyne groups that were introduced as nu-cleophiles by ligand exchange processes become electrophilic in iodine(III) compounds due to the reduction potential of the iodine centre. The difference between the sp-hybridised carbons in a TMS-compound 32 and in an alkynylaryliodonium salt 33 is shown in Scheme 1.17. Such an umpolung of the reactivity grants access to very interesting electrophiles such as “Ar+” or “CN+” and is one of the major reasons for research in iodine(III) reagents.

TMS _I R _R Ar X nucleophilic electrophilic 32 33

Scheme 1.17 Umpolung: different reactivity of a sp-hybridised carbon.

In the following, some exemplary reactions involving some of the iodine(III) compounds pre-sented in Section 1.1.2 are given. Generally speaking, there is a vast number of reactions in-volving very special or specific educts. This chapter focusses on more universally applicable cases.

1.1.3.1 Reactions of iodosylarenes and derivatives

Two reactions were already shown in the previous Section 1.1.2, such as ligand transfers or the reaction with acids (Scheme 1.7 and Scheme 1.9). This part is, however, concentrating on the

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reactions involving other compounds rather than transformations at the iodine itself.

Oxidations are among the more important reactions in this class of compounds. Iodosobenzene

(11), for instance, shows very versatile oxidative behaviour. Due to its polymeric structure it requires often either protic polar solvents such as methanol and water, or catalysts such as Lewis acids or transition metal complexes. Procedures without any additives of this sort often appear to require very extended reaction times resulting in only moderate yields [4]. For example, iodosobenzene activated by catalytic amounts of potassium bromide converts secondary alco-hols 34 quantitatively into ketones 35 and primary alcoalco-hols into acids, respectively [25]. The reactions and a proposed oxidation mechanism are shown Scheme 1.18.

R1 R2 OH R1 R2 O PhIO, cat. KBr H2O O I Ph n + KBr Ph I O -Br K+ - HBr Ph I O -O K+ _H R1 R2 Ph-I + KBr + H2O + HBr 34 35

Scheme 1.18 Reaction scheme and mechanism for oxidation of alcohols with PhIO.

In a quite similar way, primary amines 36 can be oxidised to nitriles 37, as Scheme 1.19 shows [26]. R1 NH2 R1 C H2O PhIO N 36 37

Scheme 1.19 Reaction of primary amines to nitriles with PhIO as oxidising agent.

Epoxidations of unsaturated compounds are also possible using iodosobenzene. Under acidic conditions high yields are possible within minutes [27]. Using chiral transition metal complexes allows asymmetric epoxidations with enantiomeric excesses of over 90%, as the example shown in Scheme 1.20 for E-methylstyrene (38) as educt [7, 28].

Oxidation reactions can also occur with decarboxylation, rearrangements or hydroxylations, as the oxidising species is often varied by solvent molecules, added Lewis acids or nucleophiles [4, 29, 30].

An example for an oxidative rearrangement is given in Scheme 1.21, where cyclohexene (40) reacts to the cyclopentanecarbaldehyde (41) with the adduct 42 of iodosobenzene 11 and boron trifluoride BF₃ as the oxidising agent, while the same conditions with an external nucleophile OX– lead to the di-substituded product 43 [29].

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O Cr O N N O O POPh3 PhIO, ACN 38 39

Scheme 1.20 Chiral epoxidation reaction with an ee up to 92% using iodosobenzene as oxidant.

PhIO BF3 Ph I + O BF3 -M+OX -DCM DCM O OX OX 11 42 40 41 43

Scheme 1.21 Influencing the reactivity by adding BF₃as Lewis acid and additional nucleophiles.

An example for a hydroxylation in the α-position of a ketone 44 by (diacetoxyiodo)benzene in alkaline solution is depicted in Scheme 1.22. The primary resulting diacetal 45 is hydrol-ysed under acidic conditions to yield the final α-hydroxylated ketone 46 [30]. The additional hydrolysis step can be avoided by using other iodine reagents, such as the di-trifluoroacetate PhI(OCOCF₃)₂ [31]. R1 O R2 PhI(OAc)2, KOH MeOH R1 MeO R2 OH OMe HCl acetone R1 R2 OH O 44 45 46

Scheme 1.22 α-Hydroxylation of ketones with (diacetoxyiodo)benzene.

Halogenation reactions belong to the very common uses of aryliododihalides PhIX₂. Two quite general examples are given in Scheme 1.23 for an unsaturated compound 47 and an α-acidic keto-compound 44 as pronucleophile, respectively [32, 33]. The reaction works for a broad variety of nucleophiles from alkanes over ethers to activated aromatic compounds [4, 7, 34].

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Ar IX2 Ar = Ph, Tol X = F, Cl R3 R4 R1 R2 R2 R1 O DCM R3 R4 R1 R2 X X R2 R1 O X 28 47 44 48 49

Scheme 1.23 Dihalogenation of alkenes 47 and α-halogenation of keto-compounds 44 with aryliododi-halides ArIX₂28 as two casual examples for iodine(III) in halogenation reactions.

Worth mentioning with regard to halogenation are (difluoroiodo)arenes with their selective cleavage of thioethers: Even in more complex molecules like steroids or glycosides, the thio-ethers are cleaved selectively and substituted by fluoride while other functional groups remain unaffected. This is demonstrated by the reaction of 1-arylthioglycoside 50 with (difluoroiodo)-arenes in Scheme 1.24. In this case, the mechanism does not involve any reductive exchange processes at the iodine centre but can be rather classified as a mixture of SN1 and SN2, as

indi-cated by partial inversion of the C-1 atom [35].

O H RO OR H H H OR H SAr' OR ArIF2 O H RO OR H H OR H F OR 50 51

Scheme 1.24 Selective substitution of thioether-groups with fluoride using (difluoroiodo)arenes.

Keeping this reactivity in mind, it seems obvious that iodosylarene derivatives are suited for the deprotection of dithioketals 52. Analougously to Scheme 1.24, (difluoroiodo)toluene gives the difluoride, but using PhI(OAc)₂, the deprotection to the ketone 35 is performed smoothly within minutes at r.t. [35, 37]. This is shown in Scheme 1.25.

R1 R2 O PhI(OAc)2 H2O/acetone R1 R2 S S 52 35

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1.1.3.2 Reactions of aryliodonium salts

Aryl-transfer reactions are the main applications of aryliodonium salts. By supplying “Ar+” as an electrophile, iodonium salts are very powerful aryltransfer agents in organic synthesis. Suc-cessful and very efficient arylations have been reported for an extremely broad range of nucle-ophiles, ranging from enolates to main group elements such as tellurium [4, 7]. In Scheme 1.26, a very general mechanistic example is given, also featuring the 10-I-3 intermediate 53, which shows that the reaction proceeds via the attack on the iodine first, followed by reductive elim-ination. A closer look reveals that the elimination step most probably proceeds via radical cleavage of the I-C bond and that steric factors play an important role in regioselectivity: Bulky ligands (Ar’ in Scheme 1.26) are usually transferred faster as their equatorial position in the intermediate 53 is preferred in the reductive elimination [38].

ArAr'I+ X -Nu -Ar' I Nu Ar - X -- ArI Ar' Nu 54 53 55

Scheme 1.26 General scheme of an arylation reaction using aryliodonium salts. Ar’ represents a bulkier ligand than Ar and, therefore, is in equatorial position in the intermediate 53.

Many arylation reactions can be catalysed by transition metals. For instance, conditions similar to palladium catalysed coupling reactions allow very efficient arylations of alkyl-compounds, as exemplary presented in Scheme 1.27. Applying typical Sonogashira conditions, terminal alkynes 56 are arylated in a one pot procedure using bis(triphenyl)palladiumdichloride, copper iodide and potassium carbonate as catalyst [39].

R Ar2I

+_X- cat. Pd(Ph3)Cl2, CuI, K2CO3

H₂O/DMF _R

Ar

56 57 ₅₈

Scheme 1.27 General scheme for the arylation of terminal alkynes using aryliodonium salts applying Sonogashira conditions.

Arylations with Ar₂I+X– can be carried out stereoselectively using copper salts as catalysts. As shown in Scheme 1.28, one approach is the use of chiral ligands which induce stereoselectivity as the copper coordinates the silylenolether-compounds 59 [40].

A different procedure is depicted in Scheme 1.29, where aldehydes 61 are arylated stereoselec-tively using an organic catalyst. The reaction is only possible if catalytic amounts of copper(I) salts are added. In this example, the aryliodonium salt Ar₂I+X– reacts with the copper salt Cu+X′−to give Ar−CuXX′ as the actually active arylation species [41].

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O N O OSiMe3 R Ar2I+ X -N O O N Ph Cu Ph TfO OTf cat. DCM O N O O R Ar 59 57 60

Scheme 1.28 Enantioselective α-arylation with an ee up to 95% using a chiral copper complex.

Ar2I+ X -cat. CuBr, NaHCO3, toluene/Et2O O R N N H O Ph tBu O Ar R 61 57 62

Scheme 1.29 Enantioselective α-arylation applying chiral iminium catalysis resulting in an ee up to 94%.

Electrophilic alkyne-transfer reactions are performed using arylalkynyliodonium salts.

Basi-cally, most of the previously mentioned reaction schemes for arylations apply to alkynylations too. Scheme 1.30 can be seen as general representation for an alkyne-transfer reaction. Alkyny-lation with these acyclic iodine(III) reagents 33 is not as common as aryAlkyny-lation, but the spectrum of possible nucleophilic educts is at least equally as broad [4, 7].

Y I+ Ar X -Nu -- X -Y Nu - ArI 33 63

Scheme 1.30 General reaction scheme for an electrophilic alkyne-transfer reaction.

Alkynylaryliodonium salts 33 show interesting reactivity, as the alkyne-group cannot just be transferred but is also activated to take part in further reactions. As a first example, as given in Scheme 1.31 with cyclopentadiene (64) as an exemplary educt, alkynylaryliodonium salts 65 serve as dienophiles for Diels-Alder reactions, bearing the advantage that the moiety Y at the alkyne-part allows for later functionalisation of the Diels-Alder product 66. The cycloaddition reaction itself is quite tolerant towards different groups Y and a broad range of dienes [42]; high yields are achieved within minutes.

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Y I+ Ar X -ACN Y 33 64 ₆₆

Scheme 1.31 Diels-Alder reaction involving an alkynylaryliodonium compound.

A possible mechanistic proposal states that when an alkynylaryliodonium compound 33 is at-tacked by a nucleophile, an intermediary alkylidenecarbene 67 is generated. From this inter-mediate, two pathways exist for further reaction: Either a 1,2-insertion takes place to give the normally expected alynylated product 63, or an intramolecular insertion can appear [43], typi-cally forming cyclic compounds. A general reaction pathway is shown in Scheme 1.32.

Y I+ Ar X -Nu -C I Ar Y Nu - X -C I Ar Y Nu - ArI Y C: Nu 1,2-migration intramol. insertion cyclic compounds 33 67 63

Scheme 1.32 General reaction pathway for the reaction of alkynylaryliodonium salts with nucleophiles.

As depicted in Scheme 1.33, the intramolecular insertion can be effectively applied in the prepa-ration of benzofuran systems 68 using phenolates as nucleophilic educts. However, the yields of the reaction are just mediocre because of 1,2-migration of the substituent Y that leads to the alkynylated side product 69 [43].

Y I+ Ar X -PhONa MeOH O Y O Y 33 68 69

Scheme 1.33 Formation of benzofuran by 1,5-C-H-insertion.

1.1.3.3 Reactions of heterocyclic iodine(III) reagents

Besides the use as oxidising agent similar to iodosylarene derivatives, benziodoxoles and the less commonly applied benziodazoles have become quite important primarily for their use in

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the oxidative transfer of electrophilic groups such as −N₃, −CF₃, −C≡CR or −CN [44, 45, 46, 47, 48]. As a result, products are obtained that are not easily accessible by other means. A very general reaction scheme for an electrophilic group transfer by benziodoxoles 7 is given in Scheme 1.34. First, the nucleophile substitutes the oxygen-ligand to give the intermediate 70, then the reductive elimination yields the product 71 and a derivative of o-iodobenzoic acid 72. Depending on the reaction conditions and additives such as some transition metals, also radical mechanisms are possible, though.

I O Y Nu -I O -Y Nu red. elimination I O -Y Nu X X _X X = O, Me2, (CF3)2 7 ₇₀ 71 72

Scheme 1.34 General pathway of an electrophilic group transfer using benziodoxoles.

As can be seen in Scheme 1.35, strong nucleophiles such as thiols 73 react quite readily with benziodoxoles under basic conditions, while aliphatic compounds 74 require radical starters such as dibenzoylperoxide (DBPO) to initiate the reaction [47, 44], as shown in Scheme 1.36.

R SH I O O CN DBU, THF R S CN 73 75

Scheme 1.35 Group transfer with benziodoxoles applied to a strong nucleophile.

I O O N3 cat. DBPO, ClCH2CH2Cl N3 74 76

Scheme 1.36 Group transfer with benziodoxoles applied to an aliphatic educt.

Stereoselective group transfer reactions involving benziodoxoles with α-acidic keto-compounds as pronucleophiles appear in very recent literature. Examples for a highly enantioselective α-trifluoro-methylation and α-alkynylation are given in Scheme 1.37 and Scheme 1.38, respec-tively [45, 46]. The cyanation-analogon will be presented in Section 1.2.2.

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cat. CuCl, TFA, O R N N H O O CF3 R I O CF3 Ph CHCl3 61 77 78

Scheme 1.37 Iminium catalysed stereoselective α-trifluoromethylation of aldehydes with an ee up to 97%. I O F3C _CF 3 C K2CO3, DCM CR O OR' O O OR' O C CR Ar Ar N Bu Bu Br -79 80 81

Scheme 1.38 Organocatalysis in the stereoselective α-alkynylation of β-ketoesters 79 with an ee up to 94%.

The steroselectivity is induced due to the negatively charged intermediate (82 in Scheme 1.39), which allows for the formation of chiral ion pairs. A closer look into mechanistic DFT-studies reveals that with an enolate 83 as nucleophile, the intermediate 82 is formed by the enolate’s oxygen attacking at the iodine centre. The following reductive elimination then proceeds as a 2,3-rearrangement, as outlined in Scheme 1.39 [49].

I O Y R' O -I O -Y O R' 2,3-rearr. O-attack at I R' O Y X X X = O, Me2, (CF3)2 83 7 82 84

Scheme 1.39 Mechanistic details for group transfer using enolates as nucleophiles. As previously mentioned in Scheme 1.26, the intermediate 82 is a trigonal-bipyramidal 10-I-3 species. However, the three-dimensional structure was neglected here for reasons of simplification.

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1.2 Cyanide as electrophile

Nitriles are very interesting functional groups in organic molecules, which carry a high syn-thetic potential for transformation into other functional groups such as, for instance, carboxylic acids, amines or heterocycles [50]. In the preparation of nitriles, cyanide is most commonly used as nucleophile in organic synthesis, both on laboratory and industrial scale. In most cases substitution reactions are performed, as well as addition reactions to electrophilic compounds such as aldehydes or ketones, including asymmetric cyanations, for instance, various versions of the asymmetric Strecker synthesis [51]. However, most of these nucleophilic cyanide reagents, for instance, alkali cyanides, TMS-CN or hydrogen cyanide, are highly toxic. There are other ways leading to nitriles, for example the oxidation of amines, however, an umpolung of cyanide would be most convenient with regard to the variety of nucleophilic or pronucleophilic com-pounds that are commonly used. As the Section Scheme 1.40 shows, there are some examples of electrophilic cyanide transfer reagents. These reagents allow for very facile preparations of nitriles, some of which would not be possible via nucleophilic cyanations. Besides the quite mild reaction conditions, some of those reagents (e.g. iodine(III) compounds) also avoid high toxicity.

1.2.1 Electrophilic cyanation reagents

Scheme 1.40 shows some known electrophilic cyanation reagents, which will be briefly dis-cussed in the following. There are not many of those compounds to be found by exploring literature and the presented selection shows those reagents that have found some application in the past. Cl Cl N+ Cl -BrCN N N CN N N N CN N+ N CN BF4 -N CN S O O I O Y CN ClSO2NCO N C+ N S R R CN X -Y = O, Me2 X = Br, Cl R = Me, iPr 85 86 87 88 89 90 91 92 93

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Dichloromethylene-dimethyliminium chloride (85), also known as Viehe’s salt or Vielsmeyer reagent, can be applied for the formal electrophilic cyanation. Enamine and activated aromatic compounds easily attack the electrophilic reagent 85 by liberating one chloride ion. The re-sulting adduct thermally decomposes to a nitrile-compound, however, in yields lower than 50% [52].

Cyanogen bromide (86) is the most prominent representative of the cyanogen halides, all of which can be used as electrophilic cyanation reagents. Cyanogen bromide shows high reactivity towards strong nucleophiles such as amines, thiols or alcohols, while reactions with weaker nucleophiles such as enolates result in very low yields. The real downside of cyanogen bromide is its high toxicity [47, 53, 54]. There are some reports of the electrophilic cyanation of amines using TMS-CN. This does not count as electrophilic source though, as sodium hypochlorite has to be added to the reaction, which generates cyanogen chloride as active agent [55].

Chlorosulfonylisocyanate (87) was shown to be useful for the α-cyanation of β-diketones. How-ever, the reported scope just included three different educt derivatives, resulting in only moder-ate yields [56].

N-Cyanobenzimidazole (88) was only found in reports of the fairly efficient electrophilic

cya-nation of aromatic compounds. As for other educts, it might be assumed to be very similar to

N-cyanobenzo-triazole 89, which shows only moderate reactivity towards other nucleophiles

such as terminal ethynyl arenes and no reaction with enolates [50, 57, 54]. In one report, 1-cyanoimidazole is shown to lead to decent yields in the cyanation of amines and carbon nu-cleophiles such as lithium organyls or grignard-reagents [58].

N-Cyano-dimethylaminopyridinium tetrafluoroborate (90) is only found in the cyanation of

aro-matic systems, resulting in moderate yields. Like cyanogen bromide this cyanation reagent too carries the disadvantage of severe toxicity [50, 47].

N-Cyano-N-phenyl-p-methylbenzenesulfonamide (91) is another reagent for electrophilic

aro-matic substitution, however, no applicability for other educts is reported [59].

Cyanobenziodoxoles 92 are among the most promising electrophilic cyanation agents. Since this work is focused on these compounds, they are described in more detail in Section 1.2.2. Thiocyanoimidazolium salts 93 are the most recent finding in electrophilic cyanation reactions. The sulfur-based compound is isolobal to iodine(III) compounds and shows a very broad scope regarding different educts, for instance, aromatic compounds, enolates, amines or thiols are cyanated under mild conditions in moderate to very high yields. This new kind of compounds may represent the most important breakthrough in this field since the first reports of iodine(III) cyanation reagents [60].

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1.2.2 Cyano-1,2-benziodoxole compounds

λ3-Iodanes are mentioned to be quite promising as electrophilic cyanide transfer agents due to the mild reaction conditions, their easy handling, the low environmental impact and their low toxicity [47, 50, 59]. However, there are less than ten reports on iodine(III) mediated cyanations. Interestingly, the first report on the synthesis of benziodoxoles marked also the first time of an electrophilic cyanation using cyano-benziodoxolone 1, as shown in Scheme 1.41 [5].

N I O O CN ClCH2CH2Cl N CN 94 1 95

Scheme 1.41 The first electrophilic cyanation reaction with the first benziodoxolone compound.

Since then, not many electrophilic cyanations involving benziodoxoles have been reported. Only very recently, the first heteroatom-cyanation was reported. The mild cyanation of thi-ols was previously described in Section 1.1.3.3 (Scheme 1.35). The reaction of cyanoben-ziodoxoles with α-acidic keto-compounds is also reported. In analogy to the very successful trifluoromethylations and alkynylations of β-ketoesters (Scheme 1.37 and Scheme 1.38), one report features the racemic cyanation [54], while two reports of a stereoselective version ex-ist: One moderately selective approach by our group [61] and a highly selective approach that was published during the writing of this thesis [62]. The highly enantioselective version using a chiral phase transfer catalyst (PTC) based on a cinchona alkaloid is shown in Scheme 1.42. Mechanistic details have already been discussed previously in Section 1.1.3.3.

I O O CN tBu O OR' O R N O O Ph N+ CF3 CF₃ Br -cat. O OR' O R CN DMAP, THF/toluene 96 ₉₇ 98

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2 Objectives

As main objective of this work, different electrophilic cyanation reactions with cyano-1,2-benziodoxoles were investigated. As mentioned in Section 1.2.2, not many reports on this topic exist. In 2015, the racemic α-cyanation of β-ketoesters 99 was published [54]. This set the idea of an enantioselective procedure, which was reported by our group at the Institute of Organic Chemistry at the JKU Linz shortly after the racemic version. This first step towards an enantioselective electrophilic cyanation was performed with cinchona alkaloid based catalysts, resulting in yields of up to 86% and an ee of up to 52% [61].

The first objective of this work was to test the stereocontrol using our group’s bifunctional catalysts in the test reaction shown in Scheme 2.1. The stereoselectivity should also be further explored by using different cyano-benziodoxoles as well as chiral auxiliaries and chiral metal complexes. I O O CN O OtBu O O OtBu O CN var. conditions * 99 1 100

Scheme 2.1 Testreaction for the stereoselective α-cyanation of β-ketoesters.

Cyano-benziodoxoles were quite successfully applied in the cyanation of thiols in 2014 [47]. Thus, another part of this work was to explore amines 101 as a new class of nucleophilic educts and create a convenient one-step procedure for the preparation of cyanamides using an iodine(III) reagent 1, which would be a non-toxic alternative to the usual method with cyanogen bromide [53]. The intended reaction is outlined in Scheme 2.2.

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I O O CN var. conditions R NH2 _R H N CN 101 1 102

Scheme 2.2 Reaction scheme for the preparation of cyanamides using 1-cyano-1,2-benziodoxol-3-one.

As one of our group’s recent bachelor theses had shown, the intended cyanation of terminal alkynes 103 resulted in the formation of the alkyne-dimer 104 [63]. A detailed investigation of this reaction was another major objective of this work. A general reaction is presented in Scheme 2.3. I O O CN var. conditions R R R 103 1 105

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3 Results and discussion

3.1 Preparation of cyano-benziodoxoles

In order to investigate the influence of the iodine(III) reagent on the stereocontrolled elec-trophilic cyanation reaction as shown in Section 2, various cyano-benziodoxoles had to be prepared. The following sections describe the different approaches for the preparation of the five target compounds shown in Scheme 3.1.

I O O CN I O CN I O Ph CN Ph I O F3C CN CF3 I O S O CN O 1 2 106 107 108

Scheme 3.1 Targeted cyanation reagents.

3.1.1 Synthesis of 1-cyano-1,2-benziodoxol-3-one

This reagent was most easily prepared from 2-iodobenzoic acid (17) in a well known three step procedure, as shown in Scheme 3.2 [19, 20, 54]. As described in Section 1.1.2.3, the first step was an oxidation with sodium periodate in aqueous acetic acid to result in iodosylbenzoic acid (18) in high yields of 83 to 98%. The following acetylation of iodosylbenzoic acid by refluxing in acetic anhydride was acomplished within less than an hour. The product 19 precipitated upon cooling to r.t. and was isolated in yields of around 70%. The acetyl-benziodoxolone 19 had to be dried thoroughly before the last step. The cyanation was carried out at r.t. by stirring the educt 19 with TMS-CN and catalytic amounts of caesium fluoride in acetonitrile. The cyanide 1 was obtained in typical yields of about 75%, while literature states about 90%.

The yield for each of the last two steps was a little less than reported in literature [20, 54]. Probably, the reactions are better to perform at a larger scale, as will be discussed further in Section 3.1.6. However, the yields were not considered as a problem, as the starting material 17

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COOH I NaIO4 I O O OH Ac2O I O O OAc aq. HOAc I O O CN TMS-CN cat. CsF ACN 17 18 19 1

Scheme 3.2 Preparation of 1-cyano-1,2-benziodoxol-3-(1H)-one 1 by oxidation of 2-iodobenzoic acid, subsequent acetylation and ligand exchange using TMS-CN.

was readily available and the procedure was quite conveniently performed. The cyanide-reagent 1 was generally obtained as quite pure compound, unless the acetate 19 was not dried properly, which was observed in one case.

As the drying procedure is very time-consuming for larger batches, an alternative route de-picted in Scheme 3.3 was also tested. This procedure was reported for 1-trifluoromethyl-1,2-benziodoxol-3-one using TMS−CF₃ [24], it was assumed also to work for the cyanide com-pound. After the oxidation of 2-iodobenzoic acid (17) with trichloroisocyanuric acid (109; TCICA), the chloride 110 was obtained within minutes in high purity and yields of up to 95%. The following one-pot reaction via the acetate to the cyanide 1, however, was not successful. As the acetate could also not be obtained by only reacting 110 with potassium acetate, the missing success could possibly be explained by the potassium acetate not being dry or pure enough. This was, however, not investigated in more detail, as the procedure shown in Scheme 3.2 was working well enough.

COOH I I O O Cl I O O CN 1) KOAc 2) TMS-CN ACN ACN N N N O O Cl O Cl Cl (not isolated) 17 109 110 1

Scheme 3.3 Alternative preparation procedure 1-cyano-1,2-benziodoxol-3-(1H)-one 1.

The first report on benziodoxoles states a direct reaction of iodosylbenzoic acid (18) with TMS-CN, as shown in Scheme 3.4 [5]. This could not be reproduced in this work, though. Possibly, ligand exchange is too slow under these conditions and may be inhibited by any water present in the solvent, as in all recent works on benziodoxoles preparation procedures like the two previously described are applied.

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I O O OH I O O CN TMS-CN ACN (not isolated) 18 1

Scheme 3.4 Alternative preparation of 1-cyano-1,2-benziodoxol-3-(1H)-one 1 by direct reaction of iodosylbenzoic acid (18) with TMS-CN.

3.1.2 Preparation of 1-cyano-3,3-dimethyl-1,2-benziodoxole

The complete reaction sequence for the synthesis of 1-cyano-3,3-dimethyl-1,2-benziodoxole (2) is shown in Scheme 3.5. COOH I COOMe I H2SO4 MeOH I OH F O I MeMgI Et2O Cl O I KF ACN TCICA ACN CN O I TMS-CN ACN 17 22 20 21 23 2

Scheme 3.5 Complete sequence for the preparation of 1-cyano-3,3-dimethyl-1,2-benziodoxole.

The procedure starts with a simple acid catalysed esterification of 2-iodobenzoic acid 17 with methanol, which afforded the ester 22 in quantitative yield, as reported in literature [21]. The following steps were all performed in analogy to a well established route leading to the analo-gous trifluoromethyldimethylbenziodoxole [24]. The first step with the Grignard-reagent af-forded 2-(2-iodophenyl)-propan-2-ol (20) in a moderate yield of 50%. The product was not very pure, containing 2-phenylpropanol as side product. However, this was not regarded as problematic, since literature states that the impurity does not influence the oxidative cyclisation [64]. The cyclisation with TCICA was conducted affording the chloro-benziodoxole 21 in a low yield of 23%. The following ligand exchange with potassium fluoride was performed with 97% conversion. The last step was successfully carried out and the target compound 2 was obtained in excellent purity and a mediocre yield of 57%.

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As mentioned in Section 3.1.1, the yields generally were lower than the values reported in litera-ture. The cyclisation is reported to proceed quantitatively, perhaps the impurities of 20 impaired the reaction. For future attempts, they could be possibly avoided by purification through column chromatography. And as mentioned before, also the small batch size might have been a severe problem in the crystallisation of 21 and 2.

3.1.3 Preparation of 1-cyano-3,3-diphenyl-1,2-benziodoxole

In analogy to 1-cyano-3,3-dimethyl-1,2-benziodoxole (2), the diphenyl-compound 106 should be prepared, as outlined in Scheme 3.6. The Grignard-step was slightly altered in accordance to a general procedure for the reaction of phenylmagnesiumbromide with esters [65]. The resulting alcohol 111 was obtained in 70% yield and oxidised with TCICA yielding chloro-diphenylbenz-iodoxole 112 with quantitative conversion. The following ligand exchange with potassium fluoride proceeded as well with almost quantitative conversion and some impurities, which were, however, neglected. The exchange form 113 to the cyanide 106 could not be per-formed as smoothly, though. The product was obtained in approximately 50% yield, but showed some impurities in the NMR-spectrum that could not be removed by washing or crystallisation processes. COOH I COOMe I H2SO4 MeOH I OH Ph Ph F Ph Ph O I PhMgBr THF Cl Ph Ph O I KF ACN TCICA ACN CN Ph Ph O I TMS-CN ACN 17 22 111 112 113 106

Scheme 3.6 Complete sequence for the preparation of 1-cyano-3,3-diphenyl-1,2-benziodoxole.

3.1.4 Synthesis of 3,3-bis(trifluoromethyl)-1-cyano-1,2-benziodoxole

The first approach to the target compound was a published procedure for the preparation of the alkyne-derivatised analogon [66]. As shown in Scheme 3.7, n-butyllithium (n-BuLi) and tetra-methylethylendiamine (TMEDA) were first used for the lithiation of bis(trifluoromethyl)phenyl-methanol (114), then addition of iodine followed to give the desired compound 115. However,

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the product was only obtained in 8% yield, which was not enough for the intended following procedure analogue to Scheme 3.5. The reason for the low conversion and yield, respectively, was probably the inertisation of the reaction system, as the lithiation was done over a period of 17 hours. OH CF3 CF3 OH CF3 CF3 I 1) n-BuLi, TMEDA 2) I2 THF 114 115

Scheme 3.7 First step in the approach for the synthesis of 3,3-bis(trifluoromethyl)-1-cyano-1,2-benziodoxole.

The entire reaction sequence for the alternative approach is given in Scheme 3.8. The first four steps were performed within a practical labratory course by a student under my supervision [67]. OH CF3 CF3 I TMS CF3 CF3 I COOH I COOC6F5 I C₆F₅OH DCC THF TMS-CF₃ cat. CsF toluene aq. HCl THF I O F3C _CF 3 Cl I O F3C _CF 3 F I O F3C _CF 3 CN ACN TCICA ACN KF TMS-CN cat. CsF ACN 17 116 117 115 118 119 107

Scheme 3.8 Complete reaction sequence to 3,3-bis(trifluoromethyl)-1-cyano-1,2-benziodoxole 107.

According to [68], the first step was the preparation of a pentafluorophenyl ester 116 of the 2-iodobenzoic acid (17), which was performed using pentafluorophenol and catalytic amounts of dicyclohexylcarbodiimide (DCC) and resulted in 93% yield after column chromatography. The next step was the reaction of the ester 116 with an excess of TMS−CF₃ activated with caesium fluoride to give the TMS-protected alcohol 117 in a poor yield of 29% after column chromatography. The deprotection of 117 with hydrochloric acid afforded the alcohol 115 in 92% yield.

The second part of the preparation sequence was performed in analogy to the one mentioned in Section 3.1.2 [24]. The cyclisation step, however, proved to be rather problematic, as the chloro-benziodoxole compound 118 was quite soluble, which made crystallisation very inefficient. The

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yield for the oxidation step was only 29%. The following ligand exchange with potassium fluoride could be done with quantitative conversion, while the last step to obtain the targeted cyanide 107 had to be carried out twice, in order to reach a sufficient conversion of 85% and a yield of 66%.

The encountered problems of low yields can be attributed again to the small batch size, which makes crystallisation processes quite inefficient and impractical.

3.1.5 Preparation of 1,2,3-benziodoxathioles

In order to make use of the previously described pathways, 2-iodobenzenesulfonic acid (120) as a precursor for the benziodoxathiazoles had to be prepared. This was done in accordance to literature by the diazotation of 2-aminobenzenesulfonic acid (121) and subsequent reaction with potassium iodide resulting in 66% yield of the target molecule, as shown in Scheme 3.9 [69]. SO3H NH2 1) Na2CO3 2) NaNO2, HCl 3) KI H2O SO3H I 121 120

Scheme 3.9 Synthesis of 2-iodobenzenesulfonic acid.

As the oxidation of the 2-iodobenzenesulfonic acid with sodium periodate analogously to the route given in Scheme 3.2 did not result in any product formation, a different and known strat-egy was applied. As shown in Scheme 3.10, 2-iodobenzenesulfonic acid (120) was oxidised with oxone to give the iodine(V) compound 122 in quantitative yield [70]. The known reduc-tive decomposition of this iodine(V) species in methanol was used to obtain 1-hydroxy-1,2,3-benziodoxathiole 3,3-dioxide (123) with quantitative conversion. The subsequently attempted acetylation with acetic anhydride could not be successfully performed, though.

SO3H I I O S HO O O O I O S OH O O oxone H2O MeOH 120 122 123

Scheme 3.10 Preparation of 1-hydroxy-1,2,3-benziodoxathiole 3,3-dioxide by reductive decomposi-tion of 1-hydroxy-1,2,3-benziodoxathiole 1,3,3-trioxide.

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In analogy to the procedure described in Section 3.1.2, the oxidative cyclisation was performed using trichloroisocyanuric acid, affording the chloro-benziodoxathiole 124 in almost quantita-tive yield. The reaction is depicted in Scheme 3.11. However, due to the low insolubility of this species, the subsequent ligand exchange reactions could not be carried out with success despite trying many different conditions.

SO3H I I O S Cl O O TCICA ACN TMP2 120

Scheme 3.11 Preparation of 1-chloro-1,2,3-benziodoxathiole 3,3-dioxide.

3.1.6 General remarks on the synthesis of benziodoxoles

Some difficulties occured in the preparation of the iodine(III) reagents. As often mentioned above, the low yields were especially problematic in longer reaction sequences. For the tri-fluoromethyl-compound and the dimethyl-reagent 2 the overall yield was desperately low. As already stated above, a possible reason was the small scale of the batches. Typically, the cyclic iodine compounds are precipitated at low temperature, then filtered off and washed with some cold solvent. However, at a very small scale, each of these three operations proved dif-ficult. The residual solubility even at low temperatures led to considerable loss of products, as the solvent volume could not be reduced arbitrarily. As a consequence, this makes purifi-cations based on crystallisation and washing very difficult or even impossible. Unfortunately, chromatographic methods are not possible as the iodine(III) compounds decompose on silica gel.

Sensitivity towards heat and light may have been another issue. Although most iodine(III) reagents are reported to be quite stable, most of them show slow deterioration at room temper-ature. The longer the workup takes, the higher the risk of product decomposition, especially when the workup involves exposure to higher temperatures, as the 40◦_{C waterbath of the rotary}

evaporator. This problem was observed in the case of the cyano-bis(trifluoromethyl) reagent 107.

In the case of the benziodoxathioles, the very low solubility was the major obstacle that has not been overcome until now. Although suspension or theoretically also solid phase reactions are thinkable options, separation from other insoluble reactants, by-products or inorganic com-pounds were impossible in all attempts performed.

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3.2 Electrophilic α-cyanation of carbonyl compounds

3.2.1 Organocatalytic cyanation of β-ketoesters

3.2.1.1 Screening of bifunctional catalysts and testing of various conditions

Since our groups recent report on first enantioselective cyanations did mainly rely on literature known catalysts but did not feature too many of our group’s bifunctional catalysts [61, 71], the same reaction conditions were applied in a screening of different derivatives of those catalysts, as shown in Scheme 3.12. I O O CN O OtBu O O OtBu O X organocatalyst * CHCl3, 40 h, r.t. N HO N H NH N O NH NH N O NH NH N O O NH N O NH NO2 NH N O NH NO2 N HO N H N HO N H H N O H N X = CN X = Br X = I Br _Br I I I 99 1 100 125 126 127 128 129 130 131 132 ₁₃₃ 134

Scheme 3.12 Screening reaction and tested catalysts. All reactions were carried out at r.t. with 40 hours reaction time.

The results of the screening are stated in Table 3.1. The two reactions with the cinchona alkaloid based catalysts 127 and 128 (entries 1 and 2) were originally done for the scope of the

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publication [61], but serve as references in this context. As can be seen, cinchonidine performed best under these conditions and was not matched by any of the bifunctional catalysts. Another finding of this catalyst screening was the occurrence of side products, whenever ionic catalyst systems were applied. This was observed to be especially salient for the ammonium bromides 128 and 129 (entries 2 and 3). The side product was found to be the α-bromide 125 of the

β-ketoester, appearing in slightly less than equal molar amounts as the catalyst loading. For the iodide salts 132, 133 and 134, the α-iodide 126 was less readily formed, but could be also isolated and identified by1_{H-NMR spectroscopy and mass spectrometry. The α-halides did not}

show any enantioenrichment, though.

Table 3.1 Results of the catalyst screening. The given yields represent the isolated yields after column chromatography.

Entry Catalyst ncat. / mol % Yield / % ee / %

1 127 5 56 34 2 128 20 53 12 3 129 5 25 11 4 130 5 52 20 5 131 5 53 16 6 132 5 50 0 7 133 5 40 20 8 134 5 38 24

The catalyst 133 (entry 7 in Table 3.1) was used in the screening of different conditions to deter-mine the potential of this class of catalyst systems, the results of which are given in Table 3.2. For this, the same pronucleophilic educt 99 was used, however, the solvents were varied using either no base, two equivalents of potassium carbonate as a solid or two equivalents potassium carbonate as aqueous solution.

The value in brackets in entry 5 represents the yield calculated using the conversion observed in the NMR spectrum and the mass of the raw product. Some problems occured in the purification process resulting in product loss, thus the isolated yield is is not a representative value in this case.

As can be seen from the screening results, the stereocontrol by the bifunctional catalyst was found to be generally quite low and even lower than in chloroform (entry 7 in Table 3.1). Hence, it can be stated, that the optimal conditions in regard to enantiomeric excess were possibly not found in the screening. However, the yields in methyl t-butyl ether (MTBE) and toluene (entries 5, 7, and 8) were observed to be considerably higher than in previously performed experiments. It was also found that biphasic conditions are not suited for this reaction (entries 3,6 and 9).

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Table 3.2 Screening of different reaction conditions using the bifunctional organocatalyst 133. In all cases, the reactions were stirred at r.t. for 24 hours using a catalyst loading of 10 mol%. The given yields represent isolated yields after column chromatography.

Entry Solvent Base (2eq) Yield / % ee / %

1 DCM - 52 14 2 DCM K₂CO₃ 70 6 3 DCM K₂CO₃in H₂O 53 0 4 toluene - 36 14 5 toluene K₂CO₃ 27 (84) 14 6 toluene K₂CO₃in H₂O 44 0 7 MTBE - 75 14 8 MTBE K₂CO₃ 75 8 9 MTBE K₂CO₃in H₂O 0 0

3.2.1.2 Testing alternative iodine(III) cyanation reagents

Using the findings from the screening of catalysts and conditions, other iodine(III)-based cyana-tion reagents were tested. A general reaccyana-tion and the used catalysts are shown in Scheme 3.13.

I O CN O OtBu O O OtBu O CN organocatalyst * var. conditions N HO N H NH N I -O NH N O N Br -H O OtBu O OH R R 99 135 100 136 127 137 133

Scheme 3.13 Reaction scheme for the screening of other iodine(III) cyanation reagents.

The results for this screening are summed up in Table 3.3. The applied conditions were chosen based on the previous screenings or analogue reported procedures [61]. As can be seen from the results, only the dimethyl-reagent led to the formation of product. However, predominantly the

α-hydroxide was obtained and its formation could not be surpressed by repeated degassing of the solvent, though. The hydroxide as major product was obtained as racemic compound only. Entries 2 and 4 show the best outcome that could be achieved: mixtures of about 30% cyanide 100 and 70% hydroxide 136, as well as traces of α-iodide (entry 4). The stereoselectivity still was at an unsatisfactory level and no more experiments with organocatalysts were performed.

Towards electrophilic cyanation and alkyne dimerisation reactions using iodine(III) reagents / Johannes Schörgenhumer

JKU

Towards electrophilic cyanation and alkyne

dimerisation reactions using iodine(III) reagents

MASTER’S THESIS

Diplom-Ingenieur

Technische Chemie

Johannes Schörgenhumer

Institute of Organic Chemistry

Assoc. Univ.-Prof. Dr. Mario Waser

Contents

Curriculum vitae

Personal Data

School education

Community service

University education

Occupations

Eidesstattliche Erklärung

Acknowledgements

Zusammenfassung

Abstract

1

Introduction

1.1

Organic iodine(III) compounds

1.1.1

General remarks on structure, bonding and classification

1.1.2

Preparation of λ

-iodanes

1.1.3

Reactions of iodine(III) compounds

1.2

Cyanide as electrophile

1.2.1

Electrophilic cyanation reagents

1.2.2

Cyano-1,2-benziodoxole compounds

2

Objectives

3

Results and discussion

3.1

Preparation of cyano-benziodoxoles

3.1.1

Synthesis of 1-cyano-1,2-benziodoxol-3-one

3.1.2

Preparation of 1-cyano-3,3-dimethyl-1,2-benziodoxole

3.1.3

Preparation of 1-cyano-3,3-diphenyl-1,2-benziodoxole

3.1.4

Synthesis of 3,3-bis(trifluoromethyl)-1-cyano-1,2-benziodoxole

3.1.5

Preparation of 1,2,3-benziodoxathioles

3.1.6

General remarks on the synthesis of benziodoxoles

3.2

Electrophilic α-cyanation of carbonyl compounds

3.2.1

Organocatalytic cyanation of β-ketoesters