Hydrogen-Bonding (Thio)urea Organocatalysts in Organic Synthesis : State of the art and practical methods for acetalization, tetrahydropyranylation, and cooperative epoxide alcoholysis

Thumbnail Image

Files

KotkeMike_2009_10_08.pdf (7.27 MB)

Date

2009

Authors

Advisors/Reviewers

Further Contributors

Contributing Institutions

Publisher

Journal Title

Journal ISSN

Volume Title

Publisher

License

In Copyright
In Copyright

Quotable link

DOI:
http://dx.doi.org/10.22029/jlupub-10168

Abstract

In synthetic organic chemistry the activation of the electrophile, e.g, in nucleophile-electrophile reactions is the domain of Brønsted-acid and metal(-ion) centered Lewis-acid catalysts. They are highly efficient, but suffer from drawbacks resulting from their covalent substrate binding (e.g., product inhibition, high loading, harsh conditions), heavy metal(-ion) contamination (toxicity, lability, costs, time-consuming purification), and/or acidity (substrate/product decomposition, side reactions).To circumvent these drawbacks heavy metal(-ion)- and acid-free, non-covalent and, however, powerful, cost-efficient, stable, and sustainable catalysts operating under mild, (nearly) neutral conditions are highly desirable, e.g., for applications in pharmaceutical and nutrition chemistry. Hydrogen-bonding (thio)urea organocatalysts, purely organic compounds utilizing non-covalent substrate binding, were suggested to meet these requirements. However, their catalytic potential for organic synthesis had been unutilized.This PhD thesis therefore aims at the development of hydrogen-bonding (thio)urea organocatalysts and their implementation in useful preparative-scale organic syntheses. Experimental, analytical (NMR, IR, GC, GC/MS, HPLC, HRMS) as well as computational approaches were utilized. Six chapters document the research projects and results achieved in course of this PhD thesis:The chapter "(Thio)urea Organocatalysts" based on intensive literature research critically and comprehensively reviews the success story and applications of all hydrogen-bonding mono- and bifunctional (thio)urea organocatalysts in (non-)stereoselective organic synthesis for the period 1984 2008; (184 schemes; 64 figures). It is entirely published as core contribution (204 printed pages, chapter 6) in the Wiley-book "Hydrogen Bonding in Organic Synthesis": "Chapter 6, dedicated to organocatalysis using thioureas, is a real gem! ... The chapter is self-contained and could be easily reprinted as a separate book." (cited from book review: J. Am. Chem. Soc. 2010, 132, 6863)Five practical organocatalytic procedures (1.) (5.) were developed; the resulting three original journal publications are given in chapter 2:(1.) The acetalization of aldehydes and ketones in the presence of orthoester as alcoholate source (14 substrate examples), (2.) the tetrahydropyran (THP) protection (tetrahydropyranylation), and (3.) the 2-methoxypropene (MOP) protection of diverse alcohols, phenols, and other ROH derivatives (more than 40 examples) were found to be catalyzed by the N,N´-bis[3,5-(trifluoromethyl)phenyl]thiourea at very low loadings (0.001 1 mol%). Catalytic efficiency is high with TON values of 100,000 and TOF values of up to 5700/h. These are the most efficient organocatalytic reaction reported to date. A recyclable polystyrene-bound thiourea catalyst was introduced to improve the practicability further as demonstrated in selected THP protections.The (4.) completely regioselective alcoholysis of styrene oxides (18 examples) and (5.) the direct formation of 1,3-dioxolanes from carbonyl compounds and styrene oxides (11 examples) turned out to require a cooperative Brønsted acid-type organocatalytic system; it comprises of the individual components mandelic acid (1 mol %) and N,N´-bis[3,5-(trifluoromethyl)phenyl]thiourea (1 mol %). This "Cooperative organocatalysis" is an innovative and seminal catalysis concept developed herein; various applications appear to be feasible such as "activity tailoring".The procedures (1.) (5.) operate under mild (25 or 50 °C), (nearly) neutral conditions, tolerate a broad substrate scope, e.g., stericallyhindered, acid- and T-sensitive substrates. Excellent yields at high purities (more than 99.5%) and ready work-up even inroutine preparative-scale experiments (up to 200 mmol) underline their synthetic utility. Acyclic, cyclic acetals (1,3-dioxolanes) (from 1. and 5.), THP (2.) and MOP ethers (3.) as well as beta-alkoxy alcohols (4.), all synthetically useful compound classes, for the first time have become organocatalytically accessible.Based on both experiments and high-level computations for each method a detailed mechanistic scenario is visualized as catalytic cycle to interpret product formation and the catalyst s mode of action through explicit double hydrogen bonding; novel activation concepts were identified.Additionally, this PhD thesis presents a straightforward multi-gram preparation of the privileged N,N´-bis[3,5-(trifluoromethyl)phenyl]thiourea catalyst (scale: 100 mmol; yield 36.1 g; 84%) and 3,5-bis(trifluoromethyl)phenyl isothiocyanate (scale: 40 mmol; yield: 8.0 g; 74%).Eight Chiral oxazoline-thiourea derivatives incorporating the 3,5-bis(trifluoromethylphenyl)thiourea moiety were prepared utilizing the experimental protocol elaborated herein. They were envisioned to serve as bifunctional enantioselective hydrogen-bonding catalysts; test reactions revealed this novel thiourea class to be catalytically inactive likely owing to a strong intramolecular hydrogen bond; modified oxazoline-thiourea structures and synthetic routes are suggested and discussed.The crystal structure of N,N´-bis[3,5-(trifluoromethyl)phenyl]thiourea was measured with X-ray diffraction, solved, and refined; it is illustrated with all crystallographic key data, selected bond lengths, and angles. The syn orientation of the NH protons (trans/trans rotamer) crucial for the catalyst s clamp-like double hydrogen-bonding interactions is confirmed.Beyond catalysis: The gram-scale syntheses of 4-(methylthio)butyl isothiocyanate (ITC) (Erucin) and 5-(methylthio)pentyl isothiocyanate (Berteroin) were developed. These four-step, cost-efficient syntheses provided these ITCs in high grade (more than 99.9%) for a series of cancer research studies in human HepG2 cells test systems. The interdisciplinary medical chemistry project demonstrated the ITCs to be "Janus" compounds with ambivalent character both significant genotoxicity and antigenotoxicity.

Link to publications or other datasets

Description

Notes

Original publication in

Original publication in

Anthology

Collections

Dissertationen/Habilitationen

URI of original publication

Forschungsdaten

Series

Citation