M. D'Hooghe

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
A1

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.

Open Access version available at UGent repository

Nucleophile-dependent regioselective ring opening of 2-substituted N,N-dibenzylaziridinium ions: bromideversushydride

S. Young Yun, S. Catak, W. Koo Lee, M. D'Hooghe, N. De Kimpe, V. Van Speybroeck, M. Waroquier, Y. Kim, H-J. Ha
Chemical Communications
(18), 2508-2510
2009
A1

Abstract 

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide exclusively occurs at the substituted aziridine carbon atom in a stereospecific way, whereas the opposite regioselectivity was observed for hydride-induced ring opening at the unsubstituted position; furthermore, this unprecedented hydride-promoted reactivity was validated by means of Density Functional Theory (DFT) calculations.

Novel Synthesis of 3,4-Diaminobutanenitriles and 4-Amino-2-butenenitriles from 2-(Cyanomethyl)aziridines through Intermediate Aziridinium Salts:  An Experimental and Theoretical Approach

M. D'Hooghe, V. Van Speybroeck, A. Van Nieuwenhove, M. Waroquier, N. De Kimpe
Journal of Organic Chemistry
72 (13), 4733-4740
2007
A1

Abstract 

1-Arylmethyl-2-(cyanomethyl)aziridines were transformed into 4-(N,N-bis(arylmethyl)amino)-3-(pyrrolidin-1-yl)butanenitriles and 4-(N,N-bis(arylmethyl)amino)-2-butenenitriles via 4-(N,N-bis(arylmethyl)amino)-3-bromobutanenitriles in high yields and purity. The key steps involve the unprecedented regiospecific ring opening of intermediate 2-(cyanomethyl)aziridinium salts by bromide and pyrrolidine in acetonitrile, exclusively at the substituted aziridine carbon atom. The results were rationalized on the basis of ab initio calculations.

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