Diamine Synthesis via the Nitrogen-Directed Azidation of sigma- and pi-C-C Bonds

Diamines are essential building blocks for the synthesis of agrochemicals, drugs, and organic materials, yet their synthesis remains challenging, as both nitrogens need to be differentiated and diverse substitution patterns (1,2, 1,3, or 1,4) are required. We report herein a new strategy giving access to 1,2, 1,3, and 1,4 amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes, and cyclobutanes. Commercially available copper thiophene-2-carboxylate (CuTc, 2 mol %) as catalyst promoted the diazidation of both pi and sigma C-C bonds within 10 min in the presence of readily available oxidants and trimethylsilyl azide. Selective substitution of the formed alpha-amino azide by carbon nucleophiles (electron-rich aromatic, malonate, organosilicon, organoboron, organozinc, and organomagnesium compounds) was then achieved in a one-pot fashion, leading to the formation of 1,2-, 1,3-, and 1,4-diamines with the amino groups protected orthogonally as an amide/carbamate and an azide.

Ring-Opening Reactions of Aminocyclopropanes and Aminocyclobutanes

Mingming Wang

Nitrogen-containing compounds are an important class of molecules in medicinal chemistry, chemical biology, biochemistry, material sciences or environmental sciences. Organic nitrogen occurs in many forms, ranging from small building blocks such as urea, amino acids, nucleotides, to complex natural products, drug molecules, proteins, nucleic acids, among others. The transformation of easily-accessed nitrogen-containing building blocks into more complex nitrogen-containing structures is therefore important for the synthesis of bioactive compounds or functional materials. Interested in donor-acceptor aminocyclopropanes and aminocyclobutanes, we first developed a Lewis-acid catalyzed formal [4+1] cycloaddition of donor-acceptor aminocyclobutanes with isocyanides, which resulted in the formation of cyclopentene-1,2-diamines. We then attempted to develop a formal [3+2] cycloaddition of donor-acceptor aminocyclopropanes with electron-deficient alkenes, which was mechanistically inspired by the Morita-Baylis-Hillman reaction. Apart from the donor-acceptor system, we were also attracted by simple aminocyclopropanes without electron-withdrawing group at vicinal position. We anticipated that the incorporation of cyclopropylamine into carboxylic-containing compounds followed by ring opening functionalization reactions could be used for the synthesis of more complex products. Therefore, we first disclosed an oxidative ring-opening strategy to transform acyl, sulfonyl or carbamate protected aminocyclopropanes into 1,3-dielectrophilic carbon intermediates bearing a halide atom (Br, I) and a N,O-acetal. Replacing the alkoxy group of the N,O-acetal was achieved under acidic conditions via an elimination-addition pathway, while substitution of the halides by nucleophiles was done under basic conditions via a SN2 pathway, generating a wide range of 1,3-difunctionalized propylamines. Based on the transformation described above, we further discovered an efficient synthesis of 4-amino thiochromans starting from simple aminocyclopropanes and thiophenols through a formal [3+3] annulation reaction. Next, we developed an oxidative ring-opening strategy to transform cyclopropylamides and cyclobutylamides into fluorinated imines. The imines can be isolated in their more stable hemiaminal form, with the fluorine atom installed selectively at the terminal position. Both cheap benzophenone with UV A light or organic and inorganic dyes with blue light could be used as photoredox catalysts to promote this process. Various fluorinated amines were then obtained by nucleophilic attack on the hemiaminals in one pot, giving access to a broad range of useful building blocks for medicinal chemistry. Finally, we turned our attention to the synthesis of diamines, which are essential building blocks for the synthesis of agrochemicals, drugs and organic materials, yet their synthesis remains challenging, as both nitrogen moieties need to be differentiated and diverse substitution patterns (1,2-, 1,3 or 1,4) are required. We described a new strategy giving access to 1,2-, 1,3- and 1,4- amido azides as orthogonally protected diamines based on the nitrogen-directed diazidation of alkenes, cyclopropanes and cyclobutanes.Other unsuccessful efforts over the last four years have also been described, together with some preliminary results of ring-opening cyanation and arylation reactions.

EPFL2022

Synthesis, structural characterization and applications of hyperbranched polymers based on L-lysine

Markus Scholl

L-lysine is an essential a-amino acid and a necessary building block for all proteins in the body. As an essential amino acid, L-lysine is not synthesized by humans or animals. Industrially produced L-lysine has therefore a big market as food additive, e.g. in pig food. In the body, L-lysine plays a major role in calcium absorption, building muscle proteins, recovering from surgery or sports injuries, and the body's production of hormones, enzymes, and antibodies.1 From a chemical point of view, L-lysine is an AB2 building block that contains two amino groups and one carboxylic acid group, which makes it an interesting monomer for the synthesis of dendrimers and hyperbranched polymers. L-lysine indeed has been extensively used to synthesize dendrimers2-4 or conjugates of dendrimers and linear polymers.5,6 These dendrimers and linear-dendritic hybrid architectures have attracted interest for various medical applications, including gene delivery,3,6-8 as drug carriers,9 for the development of multiple antigen peptide systems,10,11 and as magnetic resonance imaging agents.12 The drawback of these dendrimers and linear-dendritic hybrid architectures is their time consuming synthesis and their expensive large scale production. This thesis evaluates the feasibility of L-lysine as a monomer to synthesize hyperbranched polymers and investigates the potential of these materials as encapsulation agents and for various biomedical applications. As the hyperbranched polylysines are prepared in a single step and can be produced conveniently at a large scale, they may offer an interesting alternative to their widely used dendritic analogues. Including this introduction, this thesis consists of 8 chapters, which are briefly described below. Chapter 2 gives a general overview of dendritic and hyperbranched polymers build up of amide bonds. Their synthesis and applications in medicine and catalysis as well as their self-assembling and encapsulation properties will be discussed. Chapter 3 reports on the synthesis of hyperbranched polylysines via the thermal polymerization of L-lysine hydrochloride.13 Different catalysts were investigated to improve the reaction kinetics. The structure of the polymers was determined by 1H-NMR spectroscopy, and the degree of branching and the average number of branches were calculated. Chapter 4 will discuss the feasibility of different approaches to control polymer architecture during the thermal hyperbranched polymerization of L-lysine hydrochloride.14 The reactivity of the more reactive ε-NH2 group was modulated by introducing temporary protective groups. The distribution of structural units was analyzed by 1H-NMR spectroscopy and the degree of branching and the average number of branches were calculated. Chapter 5 will describe the dilute solution and solid state structure of hyperbranched polylysines and polyelectrolyte complexes generated from hyperbranched polylysine and various anionic, sodium alkyl sulfate surfactants.15 Structural models for the obtained liquid crystalline phases will be proposed. Chapter 6 will show some preliminary results of the end group modification of hyperbranched polylysine with different hydrophilic and hydrophobic agents. The feasibility of these hydrophobically modified hyperbranched polylysines to encapsulate hydrophilic dyes and transfer them from aqueous to organic media has been investigated. Chapter 7 provides a first insight into the biological properties of hyperbranched polylysine. In this chapter the results from preliminary cytotoxicity and cellular uptake experiments will be discussed. Chapter 8 will give a short summary of the work done in this thesis and an outlook. References Nelson, D. L.; Cox, M. M. "Lehninger, Principles of Biochemistry" 3rd Ed. Worth Publishing: New York, 2000. ISBN 1-57259-153-6. Denkewalter, R. G.; Kolc, J. F.; Lukasavage, W. J. In U.S. Pat. 4289872; Allied Corporation, 1981; Chem. Abstr. 1981, 102, 79324. Ohsaki, M.; Okuda, T.; Wada, A.; Hirayama, T.; Niidome, T.; Aoyagi, H. Bioconjugate Chem. 2002, 13, 510-517. Driffield, M.; Goodall, D. M.; Smith, D. K. Org. Biomol. Chem. 2003, 1, 2612-2620. Lübbert, A.; Nguyen, T. Q.; Sun, F.; Sheiko, S. S.; Klok, H.-A. Macromolecules 2005, 38, 2064-2071. Choi, J. S.; Joo, D. K.; Kim, C. H.; Kim, K.; Park, J. S. J. Am. Chem. Soc. 2000, 122, 474-480. Vlasov, G. P.; Korol'kov, V. I.; Pankova, G. A.; Tarasenko, I. I.; Baranov, A. N.; Glazkov, P. B.; Kiselev, A. V.; Ostapenko, O. V.; Lesina, E. A.; Baranov, V. S. Russ. J. Bioorg. Chem. 2004, 30, 12-20. Choi, J. S.; Lee, E. J.; Choi, Y. H.; Jeong, Y. J.; Park, J. S. Bioconjugate Chem. 1999, 10, 62-65. Sakthivel, T.; Toth, I.; Florence, A. T. Pharm. Res. 1998, 15, 776-782. Tam, J. P. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 5409-5413. Pessi, A.; Bianchi, E.; Bonelli, F.; Chiappinelli, L. J. Chem. Soc., Chem. Commun. 1990, 8-9. Nicolle, G. M.; Tóth, E.; Schmitt-Willich, H.; Radüchel, B.; Merbach, A. E. Chem. Eur. J. 2002, 8, 1040-1048. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. J. Polym. Sci. Part A Polym. Chem. 2007, 45, 5494-5508. Scholl, M.; Nguyen T. Q.; Bruchmann, B.; Klok, H.-A. Macromolecules 2007, 40, 5726-5734. Canilho, N.; Scholl, M.; Mezzenga, R.; Klok, H.-A. Macromolecules 2007, 40, 8374-8383.

EPFL2007

A Well-Defined Ni Pincer Catalyst for Cross Coupling of Non-Activated Alkyl Halides and Direct C-H Alkylation

Oleg Vechorkin

Carbon-carbon bond forming reactions are among the most important and useful methods for organic synthesis. During the last years, significant progress has been made in this field. Whereas many catalysts were developed for the coupling of aryl, alkenyl, and alkynyl halides, non-activated alkyl halides remain challenging substrates, mainly due to unproductive β-hydride elimination and difficulty in oxidative addition of alkyl halides. This dissertation is devoted to the development of a well-defined nickel catalyst for cross coupling of non-activated alkyl halides and direct alkylation of C–H bonds. Chapter 2 describes the synthesis of a new pincer MeN2N ligand and its Ni complexes. This ligand can be obtained by Pd-catalyzed C–N coupling of 2-amino-N,N-dimethylaniline and 2-bromo-N,N-dimethylaniline. Reaction of its Li salt with Ni(dme)Cl2 gives [(MeN2N)Ni-Cl] (1). Complex 1 can be akylated with Grignard reagents to give [(MeN2N)Ni-Alkyl] species. Stability of the alkyl complexes against β-hydride elimination inspired us to use the [(MeN2N)Ni-Cl] complex as a catalyst for cross coupling of carbon nucleophiles with alkyl halides. After investigating different experimental conditions, we found that complex 1 is an active catalyst for cross coupling of non-activated alkyl polyhalides (Chapter 3) and alkyl monohalides (Chapter 4) with alkyl Grignard reagents. The reaction with alkyl monohalides can be done at -35 °C in DMA and only 30min is required to accomplish the formation of the desired products. The high activity of the catalyst resulted in a high group tolerance. Ester, ketone, amide, nitrile, heterocyclic, and acetal groups didn't pose problems. In Chapter 5, the catalysis was extended to include aryl and heteroaryl Grignard reagents as nucleophiles. The best results were obtained with primary alkyl bromides and iodides and cyclic secondary alkyl iodides in THF and at room temperature. Addition of an additive such as TMEDA or bis[2-(N,N-dimethylaminoethyl)]ether (O-TMEDA) was necessary to prevent the formation of undesired homocoupling products. Functionalized Grignard reagents could be readily coupled. The [(MeN2N)Ni-Cl] catalyst was then used for the Sonogashira coupling of alkyl halides with alkynes (Chapter 6). A wide range of functionalized alkyl halides could be used for this reaction. Not only alkyl iodides and bromides but also alkyl chlorides can be used. Moreover, by changing reaction conditions (additive and temperature), selective coupling of C–Br bond in the presence of C–Cl bond, and of C–I bond in the presence of both C–Br and C–Cl bonds can be achieved. This feature allowed us to carry out multiple and selective Sonogashira coupling of the substrates containing different alkyl halide bonds. We could combine Sonogashira coupling with Kumada-Corriu-Tamao coupling. Utilization of these two methods leads to a simple and rapid synthesis of organic molecules. Similar conditions were then applied for the direct alkylation of aromatic heterocycles in Chapter 7. Aromatic heterocyclic compounds are widely used as bio-active molecules, pharmaceuticals, and organic materials. Direct C–H functionalization represents the most straightforward way for the derivatization of these compounds. Despite of the developments during the last years, direct alkylation of C–H bond with alkyl halides is still challenging. Utilization of our [(MeN2N)Ni-Cl] catalyst gives the desired products in high yields and a wide range of aromatic heterocyclic compounds can be used for the reaction. The well-defined nature and a high stability of [(MeN2N)Ni-Cl] complex and its derivatives enabled us to perform detailed mechanistic investigations of the catalytic transformations. Presumed intermediates of catalytic cycles were determined and some of them were synthesized or separated from the reaction mixture. The resting states of the catalysts were also defined in most of the cases, giving important information for the mechanistic elucidation. In the last part (Chapter 8) we developed a direct C–H carboxylation chemistry for aromatic heterocycles. The carboxylation can be done under catalyst-free conditions and with a mild base Cs2CO3. The unstable carboxylic acids were converted to the more stable esters by a one-pot reaction with MeI. A wide substrate scope was achieved.

EPFL2011