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. 2023 Feb 20;28(4):1983.
doi: 10.3390/molecules28041983.

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles

Marina V Goryaeva  1 , Olesya A Fefelova  1 , Yanina V Burgart  1 , Marina A Ezhikova  1 , Mikhail I Kodess  1 , Pavel A Slepukhin  1 , Vasily S Gaviko  2 , Victor I Saloutin  1
Affiliations

Multicomponent Domino Cyclization of Ethyl Trifluoropyruvate with Methyl Ketones and Amino Alcohols as A New Way to γ-Lactam Annulated Oxazacycles

Marina V Goryaeva et al. Molecules. .

Abstract

A new route to bicyclic γ-lactams was found, which was proposed as a three-component cyclization of ethyl trifluoropyruvate with methyl ketones and 1,2-, 1,3-amino alcohols. As a result, a series of trifluoromethyl-substituted tetrahydropyrrolo [2,1-b]oxazol-5-ones and tetrahydropyrrolo[2,1-b][1,3]oxazine-6-ones was synthesized, in which the substituent at the nodal carbon atom was varied. The introduction of a twofold excess of ethyl trifluoropyruvate in reactions with amino alcohols and acetone made it possible to obtain the same bicycles, but functionalized with a hydroxyester fragment, which are formed due to four-component interactions of the reagents. Transformations with 2-butanone and aminoethanol lead predominantly to similar bicycles, while an analogous reaction with aminopropanol gives N-hydroxypropyl-2,3-dihydropyrrol-5-one. Almost all bicycles are formed as two diastereomers, the structure of which was determined using 1H, 19F, 13C NMR spectroscopy, including two-dimensional experiments and XRD analysis. A domino mechanism for the formation of tetrahydropyrrolo[2,1-b]oxazacycles was proposed, which was confirmed by their stepwise synthesis through the preliminary preparation of the aldol and bis-aldol from ethyl trifluoropyruvate and methyl ketones.

Keywords: amino alcohols; ethyl trifluoropyruvate; methyl ketones; multicomponent domino cyclizations; tetrahydropyrrolo[2,1-b]oxazinones; tetrahydropyrrolo[2,1-b]oxazolones; γ-lactams.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Examples of bioactive γ-lactams.
Scheme 1
Scheme 1
Three-component reaction of ethyl trifluoropyruvate 1, acetone 2a and aminoethanol 3a.
Scheme 2
Scheme 2
Three-component equimolar reactions of ethyl trifluoropyruvate 1 and methyl ketones 2a–d with amino alcohols 3a,b (all yields are given for isolated products).
Scheme 3
Scheme 3
Three-component reactions of a twofold excess of ethyl trifluoropyruvate 1 with acetone 2a and amino alcohols 3a,b.
Scheme 4
Scheme 4
Three-component reactions of a twofold excess of ethyl trifluoropyruvate 1 with 2-butanone 2b and amino alcohols 3a,b.
Scheme 5
Scheme 5
Three-component reactions of a twofold excess of ethyl trifluoropyruvate 1 with 2-hexanone 2c and amino alcohols 3a,b.
Scheme 6
Scheme 6
Two-step approach to obtaining products 4a,b and 8a,b.
Scheme 7
Scheme 7
Proposed pathways for the formation of heterocyclic aldols 5tc, 5cc.
Figure 2
Figure 2
Diastereomeric structure of heterocycles 4, 5 and 8.
Figure 3
Figure 3
The ORTEP view of compounds 4dc (a) and 8cc (b) according to XRD data.
Figure 4
Figure 4
(a) The ORTEP view of compounds 5tc according to XRD data; (b) crystal packing of compounds 5tc with indication of intermolecular hydrogen bonds.
Figure 5
Figure 5
Diastereomeric structure of dihydropyrrol-5-ones 11.
Figure 6
Figure 6
(a) The ORTEP view of compounds 11b according to XRD data; (b) crystal packing of 11b with indication of intermolecular hydrogen bonds.
Scheme 8
Scheme 8
Proposed mechanism of three- and four-component domino cyclization of ethyl trifluoropyruvate 1 with methyl ketones 2a–d and amino alcohols 3a,b.
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