Rh(III)-Catalyzed C-H Functionalizations as Strategies for Versatile Organic Building Blocks

Transition-metal catalyzed C-H functionalizations have impacted and changed synthetic approaches towards the construction of relevant complex molecules, comprising natural products, active pharmaceutical ingredients, and organic materials. This thesis describes the development of Rh(III)-catalyzed reactions via directed C-H functionalization and non-directed C-H functionalization. In this respect, acylated sulfonamides and N-sulfonyl ketimines were successfully employed as suitable directing groups, enabling directed C-H bond activation in the presence of a rhodium(III) catalyst. Subsequent migratory insertion of internal alkynes delivered a rich array of versatile benzosultams and chiral spirocyclic sultams, both of which are relevant structures in medicinal chemistry. Notably, the use of rhodium(III) complexes equipped with a suitable atropchiral cyclopentadienyl ligand enables enantioselective and high yielding access to the challenging spirocyclic sultam scaffolds. Complementary to the directed C-H bond functionalizations, application of CpRh(III) complexes in non-directed C-H functionalization reactions have been disclosed. Specific applications of this challenging strategy include the synthesis of highly valuable polyarenes from completely unbiased arenes via double C-H activation, and subsequent addition of internal alkynes. This method provides a convenient handle to access highly substituted and highly soluble acenes, possessing valuable electronic and photo physical properties. Furthermore, non-directed C-H functionalization of electron-rich heterocycles was also developed. In this context, a CpRh(III) catalyst enables a C2-selective activation of heteroarenes. Upon addition across an alkyne, a transmetalation to Cu(II) allows reductive C-O bond formation to deliver tetrasubstituted enol esters in a trans-selective fashion. A three-component coupling of heteroarenes, alkynes, and carboxylic acids was successfully demonstrated.

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

Developing Reactions of Strained Rings

Daniele Perrotta

Carbo- and heterocyclic structures containing nitrogen-substituted stereocenters are recurrent structural motifs in natural and bioactive compounds, therefore constituting a privileged class of synthetic targets. In this regard, substituted three- and four-membered carbocycles are powerful building blocks. Activation by a catalyst allows for an efficient exploitation of their ring strain, enabling a large variety of transformations. In particular, activation via oxidative addition by transition metals has been widely applied in annulations of these rings. Another common mode of activation consists in the use of Lewis acids to promote heterolytic ring opening of electron-poor strained rings, among which donor-acceptor cyclopropanes and cyclobutanes stand out for their well-established and broad chemistry. In this thesis, intermolecular annulations of three-membered carbocycles via oxidative addition by transition metals were first investigated. We mainly focused on the use of aminocyclopropanes as well as more strained aminomethylidenecyclopropanes. Despite a broad screening of transition metal complexes and modifications of the cyclopropane structure, no desired product could be formed. The use of aminomethylidene cyclopropanes in Lewis acid catalyzed intermolecular annulations was also studied. Employing aldehydes as reaction partners delivered highly functionalized 2-aminotetrahydrofurans. Instead, the use of all-carbon dipolarophiles for the synthesis of carbocycles was not successful. Subsequently, we explored enantioselective transformations of donor-acceptor cyclopropanes. We first investigated a new Lewis acid catalyzed DYKAT of donor-acceptor aminocyclopropanes with 2-siloxyfurans as dipolarophiles. After a thorough optimization, the desired product could be obtained in high er. However, the yield was not satisfactory, and any attempt to improve it by modifying the structure of the aminocyclopropane or by screening additives and reaction conditions was unsuccessful. On the other hand, we succeeded in the development of the first Lewis Acid catalyzed enantioselective desymmetrization of donor-acceptor meso-diaminocyclopropanes. The methodology consists in a copper(II) catalyzed Friedel-Crafts alkylation of indoles and a pyrrole, and delivers enantioenriched urea derivatives, which are recurrent structures in natural and bioactive compounds. The reaction tolerates electronically and sterically diverse substituents on the benzene ring of the indole. The choice of appropriate protecting groups on the cyclopropane was required to guarantee its solubility and to maintain good levels of enantioselectivity. The modification of an underexplored subclass of bisoxazoline ligands, bearing bulky diarylmethanol groups in alpha to the nitrogen atoms, was essential for obtaining high enantiomeric ratios, and led to the synthesis of several novel ligands. Finally, we developed Lewis acid catalyzed [4+2] annulations of donor-acceptor aminocyclobutanes with aromatic aldehydes, which afforded useful 2-aminotetrahydropyrans. A scandium catalyst was employed for the annulation of unsubstituted aminocyclobutanes, which delivered products in yields up to 95% and diastereoselectivities up to 17:1. On the other hand, one equivalent of a cheap and non-toxic iron Lewis acid was required for substituted aminocyclobutanes, which afforded densely functionalized six-membered heterocycles bearing three stereocenters in diastereoselectivities up to 5:1.

EPFL2018

Aliphatic Carboxylic Acids as Coupling Partners in Carbon-Heteroatom Bond-Forming Reactions

Runze Mao

Carboxylic acids are one of the most suitable starting materials for synthesis. They are readily available and therefore inexpensive, stable and non-toxic. Many carboxylic acids can be obtained directly from natural resources, thus avoiding the extraction of fossil resources, such as oil or natural gas, in the production of chemicals. Furthermore, renewable carboxylic acids derived from biomass have a wide structural diversity (e.g., amino acids, fatty acids and sugar acids), which not only holds greater potential for the synthesis of complex molecules, but also advances the development of green chemistry. In this context, this thesis aims at establishing new carbon-heteroatom coupling reactions with carboxylic acids as versatile coupling partners. These reactions are hitherto unknown, which not only fill some of the gaps in synthetic organic chemistry, but also provide solutions for the rapid assembly of bioactive molecules. In order to overcome the challenge of forming C(sp3)-heteroatom bonds, Chapters 4, 5 and 6 detail the development of photoredox/copper bi-catalytic systems and their applications in decarboxylative C(sp3)-N and C(sp3)-O coupling reactions. These methods are not only compatible with numerous functional groups, but also allow for rapid late-stage functionalization. More importantly, these methods can simplify the pathway for building drug core skeletons, highlighting the potential of these methods to expedite drug discovery. To bridge the disconnection in the synthesis of trifluoromethylthioesters from carboxylic acids, Chapter 7 describes the establishment of a "umpolung" strategy and its application in the conversion of carboxylic acids to trifluoromethylthioesters. This approach provides the most concise synthetic pathway to date for the synthesis of trifluoromethylthioesters, which not only accommodates a variety of functional groups, but also allows for the rapid functionalization of carboxylic acid-containing natural products and drug molecules. In summary, this thesis illustrates how novel catalytic methods can be used to convert inexpensive, readily available and environmentally benign aliphatic carboxylic acids into high value-added compounds.

EPFL2020