M. D'Hooghe

Covalent Organic Framework supported Palladium Catalysts

H. Salemi, M. Debruyne, V. Van Speybroeck, P. Van der Voort, M. D'Hooghe, C. Stevens
Journal of Materials Chemistry A
2022
A1

Abstract 

Covalent organic frameworks (COFs), as highly porous crystalline structures, are newly emerging materials designed with tuneable features. They have a high potential to be a host to immobilize metal catalysts. The unique property of these materials, such as their high surface area, oriented channels, and heteroatom enrichment, make them promising materials to improve some disadvantages of heterogeneous metal catalysts. In this review, the fabrication and application of Pd anchored COFs as one of the most critical transition-metal catalysts that play a crucial role in a wide range of reactions is summarized.

Unexpected formation of 2,2-dichloro-N-(chloromethyl)acetamides during attempted Staudinger 2,2-dichloro-β-lactam synthesis

S. Deketelaere, E. Van den Broeck, L. Cools, D. Deturck, H. Naeyaert, K. Van Hecke, C. Stevens, V. Van Speybroeck, M. D'Hooghe
European Journal of Organic Chemistry
2021, 42, 5823-5830
2021
A1

Abstract 

In the quest for 3,3-dichloro-β-lactam building blocks, the serendipitous formation of 2,2-dichloro-N-(chloromethyl)acetamides was observed. This peculiar reactivity was investigated in detail, both experimentally and computationally by means of Density Functional Theory (DFT) calculations. 2,2-Dichloro-N-(chloromethyl)acetamides were thus shown to be formed experimentally through reaction of 2,2-dichloroacetyl chloride with glyceraldehyde-derived imines, i. e. (2,2-dimethyl-1,3-dioxolan-4-yl)methanimines, bearing aromatic N-substituents, in the presence as well as in the absence of a base. Deployment of aliphatic imines, however, resulted in complex reaction mixtures, pointing to the importance of a stabilizing aromatic substituent at nitrogen. The DFT results indicate that the substituents can alter the governing equilibria on the one hand and intrinsic barrier heights for the different routes on the other hand, showing that these are controlling the reaction outcome. Furthermore, the 2,2-dichloro-N-(chloromethyl)acetamides proved to be rather unstable in solution and thus difficult to isolate. Nonetheless, their molecular structure was confirmed by means of NMR analysis of several purified analogs and X-ray study of a 4-methoxyphenyl derivative.

Use of 3-Hydroxy-4-(trifluoromethyl)azetidin-2-ones as Building Blocks for the Preparation of Trifluoromethyl-Containing Aminopropanes, 1,3-Oxazinan-2-ones, Aziridines, and 1,4-Dioxan-2-ones

H.D. Thi, G. Le Nhat Thuy, S. Catak, V. Van Speybroeck, T. Van Nguyen, M. D'Hooghe
Synthesis-Stuttgart
50, 1439-1456
2018
A1

Abstract 

3-Hydroxy- 4-(trifluoromethyl)azetidin- 2-ones were efficiently synthesized from the corresponding 3-benzyloxy-β-lactams and successfully transformed into 3-chloro- 4-(trifluoromethyl)azetidin-2- one building blocks. The latter chlorides were shown to be eligible precursors for the construction of novel CF 3 -containing aminopropanes, 1,3-oxazinanes, 1,3-oxazinan-2- ones and aziridines. In addition, 3-hydroxy- 4-(trifluoromethyl)azetidin- 2-ones proved to be interesting substrates for the synthesis of novel 3-[2,2,2- trifluoro-1-(arylamino)ethyl]-1,4- dioxan-2- ones via intramolecular cyclization of 3-(2- hydroxyethoxy)-β-lactam intermediates.

Theoretical Insight into the Regioselective Ring-Expansions of Bicyclic Aziridinium Ions

E. Birsen Boydas, G. Tanriver, M. D'Hooghe, H-J. Ha, V. Van Speybroeck, S. Catak
Organic & Biomolecular Chemistry
16 (5), 796-806
2018
A1

Abstract 

Transient bicyclic aziridinium ions are known to undergo ring-expansion reactions, paving the way to functionalized nitrogen-containing heterocycles. In this study, the regioselectivity observed in the ring-expansion reactions of 1-azoniabicyclo[n.1.0]alkanes was investigated from a computational viewpoint to study the ring-expansion pathways of two bicyclic systems with different ring sizes. Moreover, several nucleophiles leading to different experimental results were investigated. The effect of solvation was taken into account using both explicit and implicit solvent models. This theoretical rationalization provides valuable insight into the observed regioselectivity and may be used as a predictive tool in future studies.

Formation of Fluorinated Amido Esters through Unexpected C3-C4 Bond Fission in 4-Trifluoromethyl-3-oxo-β-lactams

H.D. Thi, H. Goossens, D. Hertsen, V. Otte, T. Van Nguyen, V. Van Speybroeck, M. D'Hooghe
Chemistry - An Asian Journal
13 (4), 421-431
2018
A1

Abstract 

4-Trifluoromethyl-3-oxo-β-lactams were unexpectedly transformed into 2-[(2,2-difluorovinyl)amino]-2-oxoacetates as major products, accompanied by minor amounts of 2-oxo-2-[(2,2,2-trifluoroethyl)amino]acetates, upon treatment with alkyl halides and triethylamine in DMSO. This peculiar C3-C4 bond fission reactivity was investigated in-depth, from both an experimental and a computational point of view, in order to shed light on the underlying reaction mechanism.

Reactivity of 3-oxo-β-lactams with respect to primary amines - an experimental and computational approach

N. Piens, H. Goossens, D. Hertsen, S. Deketelaere, L. Crul, L. Demeurisse, J. De Moor, E. Van den Broeck, K. Mollet, K. Van Hecke, V. Van Speybroeck, M. D'Hooghe
Chemistry - A European Journal
2017 (23), 1-9
2017
A1

Abstract 

The reactivity of 3-oxo-β-lactams with respect to primary amines was investigated in depth. Depending on the specific azetidin-2-one C4 substituent, this reaction was shown to selectively produce 3-imino-β-lactams (through dehydration), α-aminoamides (through CO elimination) or ethanediamides (through an unprecedented C3-C4 ring opening). In addition to the experimental results, the mechanisms and factors governing these peculiar transformations were also examined and elucidated by means of density functional theory calculations.

Asymmetric synthesis of 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines through rearrangement of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines

J. Dolfen, E. Birsen Boydas, V. Van Speybroeck, S. Catak, K. Van Hecke, M. D'Hooghe
Journal of Organic Chemistry
82 (19), 10092–10109
2017
A1

Abstract 

Enantiopure 4-formyl-β-lactams were deployed as synthons for the diastereoselective formation of chiral 2-(2,2,2-trifluoro-1-hydroxyethyl)azetidines via trifluoromethylation through aldehyde modification followed by reductive removal of the β-lactam carbonyl moiety. Subsequent treatment of the (in situ) activated 2-trifluoroethylated azetidines with a variety of nitrogen, oxygen, sulfur and fluorine nucleophiles afforded chiral 3,4-disubstituted 2-(trifluoromethyl)pyrrolidines in good to excellent yields (45-99%) and high diastereoselectivities (dr > 99/1, 1H NMR) via interception of bicyclic aziridinium intermediates. Furthermore, representative pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce e.g. a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system.

Nucleophile-Dependent Regio- and Stereoselective Ring Opening of 1-Azoniabicyclo-[3.1.0]hexane Tosylate

Mi-Kyung Ji, D. Hertsen, D.-H. Yoon, H. Eum, H. Goossens, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe, H.-J. Ha
Chemistry - An Asian Journal
2014 (9), 1060-1067
2014
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Abstract 

1-[(1R)-(1-Phenylethyl)]-1-azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2-(3-hydroxypropyl)aziridine upon reaction with p-toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH3CN to afford either piperidines or pyrrolidines through regio- and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring-opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways.

Synthesis of 2-Hydroxy-1,4-oxazin-3-ones through Ring Transformation of 3-Hydroxy-4-(1,2-dihydroxyethyl)--lactams and a Study of Their Reactivity

K. Mollet, H. Goossens, N. Piens, S. Catak, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe
Chemistry - A European Journal
19 (10), 3383-3396
2013
A1

Abstract 

The reactivity of 3-hydroxy-4-(1,2-dihydroxyethyl)-β-lactams with regard to the oxidant sodium periodate was evaluated, unexpectedly resulting in the exclusive formation of new 2-hydroxy-1,4-oxazin-3-ones through a C3C4 bond cleavage of the intermediate 4-formyl-3-hydroxy-β-lactams followed by a ring expansion. This peculiar transformation stands in sharp contrast with the known NaIO4-mediated oxidation of 3-alkoxy- and 3-phenoxy-4-(1,2-dihydroxyethyl)-β-lactams, which exclusively leads to the corresponding 4-formyl-β-lactams without a subsequent ring enlargement. In addition, this new class of functionalized oxazin-3-ones was further evaluated for its potential use as building blocks in the synthesis of a variety of differently substituted oxazin-3-ones, morpholin-3-ones and pyrazinones. Furthermore, additional insights into the mechanism and the factors governing this new ring-expansion reaction were provided by means of density functional theory calculations.

Solvent-controlled selective transformation of 2-Bromomethyl-2-methylaziridines to functionalized aziridines and azetidines

S. Stankovic, H. Goossens, S. Catak, M. Tezcan, M. Waroquier, V. Van Speybroeck, M. D'Hooghe, N. De Kimpe
Journal of Organic Chemistry
77, 3181-3190
2012
A1

Abstract 

The reactivity of 2-bromomethyl-2-methylaziridines toward oxygen, sulfur, and carbon nucleophiles in different solvent systems was investigated. Remarkably, the choice of the solvent has a profound influence on the reaction outcome, enabling the selective formation of either functionalized aziridines in dimethylformamide (through direct bromide displacement) or azetidines in acetonitrile (through rearrangement via a bicyclic aziridinium intermediate). In addition, the experimentally observed solvent-dependent behavior of 2-bromomethyl-2-methylaziridines was further supported by means of DFT calculations.

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