Endeavors in synthetically oriented organometallic chemistry

This thesis work aimed to show the potentialities of the organometallic approach and, in particular, the organoalkali one, in Organic Synthesis (whose possibilities cannot be underestimated). A wide opening on the big landscape of possibilities has been reached by the study of functionalization of minimally acidic hydrocarbons with the Schlosser LICKOR superbase. This has allowed selective functionalization of a biphenylic system with different functional groups and the preparation of molecules of interest in catalysis. The study of the organometallic approach in organic synthesis continued with the functionalization of the virtually "no-cost" substrate 1-fluoronaphthalene with a big variety of functional groups like phosphinic, aldehydic, carboxylic, halides etc.. This preliminary study was useful in order to develop a strategy in the preparation of binaphthylic systems, obtained by a method that uses copper (II) as an arene coupling agent. This method was developed in the laboratories of Prof. Schlosser's Group and gave good results in the preparation of molecules that can be used as ligands in Asymmetric Catalysis. A complementary study was done on the possibility of using chloride as a protecting group in metalation to have also access to the functionalization of 1-fluoronaphthalene in positions different from the 2-position derived from an ortho-metalation. The preparation of hydrazines using organoalkali reagents was the other target studied because hydrazines are useful starting materials for Pharmaceuticals. A preliminary study was done using the addition of organolithium reagents to azobisformamides. At the end, after the encouraging results obtained, an unexpected result was obtained on the reactivity of azobisformamides. Pyrazoles are an important class of heterocycles, widely used as drugs for the therapy of various diseases. In particular, the trifluoromethylpyrazoles are a class of substances that show some activity as antiinflammatory drugs or as selective insecticides. The organometallic approach in preparation and functionalization of these substrates again showed its power.

Development of Catalytic Umpolung

Jonathan Brand

The development of efficient synthetic methodologies is crucial to access complex molecules in an economic, eco-friendly and safe way. The reversal of the intrinsic reactivity of functional groups, called Umpolung, allows alternative synthetic strategies and can improve synthetic efficiency. In this thesis, two new Umpolung methods have been investigated. First a novel approach for the direct alkynylation of aromatic C-H bonds has been developed to access aromatic alkynes. Secondly, novel bifunctional (thio)urea carbene catalysts have been synthesized and their use in asymmetric intermolecular heterocouplings has been investigated. Aromatic alkynes are compounds of utmost prominence as synthetic intermediates and for application in materials science. Classical synthetic methods require a prefunctionalization of the aromatic ring in addition to the alkynylation step. An alternative emerging strategy to introduce triple bonds is based on the Umpolung of acetylenes by the use of electrophilic acetylene reagents. In addition, the use of metal catalysis has recently arisen to couple aromatic C-H bonds with electrophiles in a single step. However, direct alkynylation has been only scarcely investigated. In this thesis, alkynyl hypervalent iodines, highly electrophilic acetylenes, were used for the metal-catalyzed direct alkynylation of aromatic C-H bonds. Indoles were alkynylated in C3 position using AuCl as catalyst and TIPS-EBX (1- [(triisopropylsilyl)ethynyl]-1λ3,2-benziodoxol-3(1H)-one) as source of electrophilic acetylene. The reaction proceeded under mild open-flask conditions (room temperature under air, commercial solvents). Importantly, it was the first example showcasing the superiority of alkynyl benziodoxolones over alkynyl iodoniums in alkyne transfer reactions. On contrary to other alkynylation methods, which have either a limited scope or require indole protection, this reaction tolerated a large range of functional groups and worked for unprotected indoles. Furthermore in the presence of pyridine, pyrroles were alkynylated in C2 position in high yields. This development was important in light of the instability of unprotected halogeno- pyrroles, which makes their use in cross-coupling reactions difficult. A one-pot 2- alkynylaniline cyclization/direct alkynylation was next developed. The influence of substituents on the acetylene, the iodoxole ring structure and the benzene ring substitution on the alkynyl benziodoxolones were examined. This study revealed that bulky silyl groups were ideal alkyne substituents. Preliminary mechanistic investigations indicated that the reaction proceeded either via a π activation mechanism or via an oxidative AuI/AuIII mechanism. iii Unfortunately it has not yet been possible to distinguish between both mechanisms. The alkynylation of electron-rich arenes was next explored. N,N-dialkylanilines were alkynylated with high para regioselectivity using iPrOH as solvent. This transformation represented the first one-step synthesis of para-alkynylanilines and was then extended to 1,3,5- trimethoxybenzenes.

EPFL2012

Novel Applications of Nitrous Oxide and Transition Metals for C-C and C-N Bond Formation

Gregor Kiefer

This thesis describes novel methods for and investigations into C–C and C–N bond formation reactions. Chapter 1 gives a very brief overview of established strategies for the formation of new C–C bonds in organic synthesis. In chapter 2, a multi‐step one‐pot synthesis is described. Arylalkynes and ethylene are converted to 2‐arylbutadienes by ruthenium catalyzed enyne metathesis. Upon addition of polyhalogenated substrates, the butadienes react in a 1,4‐atom transfer radical addition (ATRA) to yield 1,5‐dichloropen‐2‐enes. These form substituted vinylcyclopropanes via reductive 1,5 dechlorination with magnesium or manganese. Chapter 3 describes a study about two complex organometallic structures that form by reaction of rhodium(III) chloride with tert‐butylacetylene. The reaction products demonstrate the ability of rhodium to mediate various reactions of alkynes such as [2+2+1] cycloadditions, oxidative cleavages and others. Cobalt‐catalyzed reactions for C–C bond formation are reported in chapter 4. In the first part, the focus lies on the putative pre‐catalysts [CoX2(dppe)] (X = Cl, Br, I; dppe = diphenylphosphinoethane), which are used together with a reducing agent (e. g. zinc) in a wide range of C–C bond formation reactions. It is shown that they are, in reality, complex salts of the formula [CoX(dppe)2]2[X3Co(dppe)CoX3]. The second part describes the synthesis and characterization of the complexes [CoX(dppe)(PPh3)] and [CoX(dppe)(η4‐isoprene)]. Without addition of a reducing agent, these cobalt(I) complexes catalyze reactions that are usually accomplished with the catalyst system Co(II)/dppe/Zn. These results provide evidence that the active species in these reactions are indeed Co(I) complexes as supposed. In the fifth chapter, two methods for the use of nitrous oxide (N2O, laughing gas) in organic reactions are described. The challenge of using N2O in synthetic chemistry is to overcome its kinetic inertness. In the oxidative homo‐ and cross‐coupling of Grignard reagents, N2O takes the role of an oxidizing agent. The reactions proceed under mild conditions with copper, iron and cobalt salts as catalysts and exhibit high turnover numbers. The utilization of N2O has advantages compared to established methods with other oxidation agents such as oxygen. Furthermore, a procedure for the synthesis of triazenes from lithium dialkylamides, N2O and Grignard reagents is described. This method enables the synthesis of aryl and alkyl triazenes, but also alkenyl and alkynyl triazenes that are difficult to access via established procedures. Some alkynyl triazenes are selectively cytotoxic against certain cancer cell lines.

EPFL2015

Stereoselective synthesis of alkenes via base-metal-catalyzed addition reactions to alkynes and activation of hydrogen peroxide and carbon dioxide by iron complexes

Fedor Zhurkin

Alkene functionality can be found in the majority of natural products, drugs, catalysts and organic materials. Therefore, methods of C-C double bond formation constitute a cornerstone of organic synthesis. Selective formation of either (Z)- or (E)-isomer is especially desirable. 1,2-Addition to alkynes unites a large arsenal of methods of C-C double bond formation, among which the addition of carbon-centered species is the most interesting, since it offers a possibility of construction of the carbon skeleton. The first part of the present dissertation is devoted to the development of methods of selective addition of carbon reagents to alkynes. Chapter 1 reviews the existing methods of addition of carbon-centered species, generated from organometallic reagents, organic halides or carbonyl compounds to C-C triple bond with the accent on their stereoselectivity. Carbometalative mechanisms lay in the background of the majority of the reactions in this chemistry. The Z/E selectivity of 1,2-addition to triple bond can be controlled via predominance of either syn- or anti-addition or via Z/E isomerization of the addition intermediates. In Chapter 2 a novel method of disubstituted alkene synthesis via reductive addition of alkyl halides to terminal arylalkynes is described. The remarkable feature of this method is highly selective formation of (Z)-alkenes (generally Z/E > 10:1). Minor modifications of the reducing agent allowed the extension of the substrate scope to the primary alkyl iodides. Mechanistic studies revealed that this reaction proceeds as a formal anti-carbozincation. The resulting organozinc species form disubstituted (Z)-alkenes upon aqueous work-up. On the other hand, it would be interesting to utilize these species in cross-coupling reactions to allow the selective synthesis of trisubstituted alkenes. In Chapter 3 a catalytic system for highly regioselective copper-catalyzed allylation of these reagents is described. In Chapter 4 the results on stereoselective intermolecular addition of aldehydes and ketones to alkynes in the presence of zinc and trimethylchlorosilane are summarized. This reaction gives 1-chloro-1,3-dienes as products. The activation of small molecules has become an increasingly attractive area of research over the last years. In Chapter 5 an outline is given of the literature examples of small-molecule activation, namely activation of carbon dioxide and hydrogen peroxide, by iron complexes. In Chapter 6 the studies on small-molecule activation by iron-sulfur cubane clusters are presented. Electrochemical reduction of carbon dioxide and hydrogenation of alkenes were studied. As an additional result, synthesis and characterization of an unprecedented organic iron(I) ate-complex is reported. Structural modification of a non-heme iron complex with hydrogen-bond-donating substituents is described in Chapter 7. The deep impact of these modifications on the structure and reactivity of the resulting complex is discussed.

EPFL2017