University of Groningen
Carbon-nitrogen bond formation via catalytic alcohol activation
Yan, Tao
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Publication date: 2017
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Yan, T. (2017). Carbon-nitrogen bond formation via catalytic alcohol activation. University of Groningen.
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English Sumary
143
English Sumary
This thesis describes the development of novel methodologies for carbon-nitrogen bond formation through catalytic alcohol activation, mainly focusing on the direct amination of alcohols through borrowing hydrogen strategy.
Alcohols are cheap, low-toxic and abundant chemicals. They are common alkylation reagents used in organic synthesis. However, the direct amination of alcohols is highly challenging, as the hydroxyl group (-OH) is a poor leaving group. Alcohols are conventionally activated through converting the –OH to a better leaving group, such as a tosylate (-OTs), mesylate (-OMs) or halide (-X), which produces stoichiometric amounts of potentially toxic salts as waste. An alternative pathway is oxidizing the alcohols to the corresponding carbonyl compounds, followed by reductive amination, which requires stoichiometric amount of oxidants and reductants and also produces large amounts of waste.
The presented catalytic method, avoids the common limitations encountered by the classical amine formation reactions through employing a redox-active catalyst. The catalyst dehydrogenates alcohols to the corresponding carbonyl compounds which undergo imine formation with the amine reaction partner. The hydrogen “borrowed” from the alcohol is temporarily stored on the metal catalyst and returned back to the formed imine to obtain the desired amine product. The reaction is direct, applies no stoichiometric reagents and produces water as the only byproduct.
Chapter 1 is an introduction to this thesis. It starts with an overview of the role and importance of catalysis in general. Then, it presents the literature background of metal-ligand bifunctional complexes including the Knölker complex and the Shvo catalyst, which are the two main catalysts employed in this thesis. The following content shows the current state-of-the-art in borrowing hydrogen type catalysis. The last part of this chapter is a conclusion of the above parts and contains the outline of this thesis.
Chapter 2 describes the first example of a well-defined iron complex catalyzed alkylation of amines with alcohols. Direct alkylation of amines with alcohols through borrowing hydrogen strategy is an area dominated by noble metals, e.g. ruthenium and iridium based catalytic systems. The pioneers of this field stated that the next challenge was replacing noble metals with cheap metals, such as iron. This work shows that amines can be selective alkylated with alcohols using a homogeneous iron catalyst, the Knölker complex, achieving comparable reactivity as noble metals did in this transformation. The scope of this novel method includes the selective mono-alkylation of primary anilines and benzylamines with alcohols as well as the formation of 5, 6 and 7 membered nitrogen containing heterocycles from benzylamines and diols – moieties highly relevant for the pharmaceutical industry. Moreover, anti-Parkinson drug has been synthetized in one step from 2 commercially available substrates in good yield. The aldehyde and imine intermediates have been observed in an in situ 1H NMR study.
English Sumary
144
Chapter 3 focuses on the direct amination of benzyl alcohols to form benzylamines. In Chapter 2 it was found that benzyl alcohols are rather challenging substrates since the corresponding imines that are conjugated to aromatic rings are more difficult to be reduced using the Knölker complex. Therefore this chapter’s focus is devoted to finding reaction conditions and substrate combinations which allow for benzyl alcohols to be aminated efficiently with a large variety of amines. Otherwise synthetically challenging products were obtained this way.
In chapter 4, iron catalyzed pyrrole formation from primary amines and unsaturated diols is described. Chapter 2 shows that benzylamines and 1,4-butandiol provide pyrrolidines, while this chapter shows that primary amines and 1,4-butendiol or 1,4-butyndiol provide pyrroles. The reaction is believed to occur via iron catalyzed isomerization of unsaturated diols to the corresponding aldehydes followed by in situ Paal-Knorr pyrrole synthesis. Using this method, a large variety of primary anilines, benzylamines and aliphatic amines have been converted to pyrroles in moderate to good yields. Gel permeation chromatography (GPC) showed that oligomers and polymers, presumably formed via the condensation of instable carbonyl intermediates, are the main side products during these transformations.
Selective N-alkylation of amines of amino acids and oligopeptides without the need for protecting groups is an essential chemical transformation in the pharmaceutical and materials industry. Chapter 5 demonstrates a novel, general method for the direct N-alkylation of unprotected amino acids and oligo-peptides with alcohols in excellent yields and retention of stereochemistry. In this work, both iron and ruthenium based catalysts are used. For most cases, N-alkyl amino acids can be obtained in quantitative yields upon removing the volatiles from the reaction mixture. Selective dialkylation of N-terminus of di- and tripeptides with alcohols are also presented. Finally, iron catalyzed mono-N-alkylation of amino acids with fatty alcohols are shown. The formed long-chain N-alkyl amino acids were shown to act as surfactants.
Chapter 6 presents the ruthenium (Shvo catalyst) catalyzed N-alkylation of amino acid esters with alcohols. It provides a general method for direct mono-N-alkylation of amino acid esters with a variety of benzyl alcohols and 1-pentanol in excellent yields and retention of stereochemistry. When a proline ester or prolinamide is employed, significant racemization is observed.
To conclude, this thesis demonstrates that metal-ligand bifunctional catalysts are able to promote N-alkylation of amine with alcohols. The work has addressed highly challenging goals within this research field; the development of efficient methods employing iron-based catalytic system as well as functionalizing highly challenging substrates such as unprotected amino acids. Due to these achievements that are well in-line with the principles of green-chemistry the presented methods offer new sustainable catalytic strategies for the pharmaceutical and chemical industries.
