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. 2018 Feb 23:14:506-514.
doi: 10.3762/bjoc.14.36. eCollection 2018.

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

Thaís A Rossa  1   2 , Nícolas S Suveges  3 , Marcus M Sá  2 , David Cantillo  1   4 , C Oliver Kappe  1   4
Affiliations

Continuous multistep synthesis of 2-(azidomethyl)oxazoles

Thaís A Rossa et al. Beilstein J Org Chem. .

Abstract

An efficient three-step protocol was developed to produce 2-(azidomethyl)oxazoles from vinyl azides in a continuous-flow process. The general synthetic strategy involves a thermolysis of vinyl azides to generate azirines, which react with bromoacetyl bromide to provide 2-(bromomethyl)oxazoles. The latter compounds are versatile building blocks for nucleophilic displacement reactions as demonstrated by their subsequent treatment with NaN3 in aqueous medium to give azido oxazoles in good selectivity. Process integration enabled the synthesis of this useful moiety in short overall residence times (7 to 9 min) and in good overall yields.

Keywords: azirines; continuous flow; heterocycles; oxazoles; process integration; vinyl azides.

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Figures

Figure 1
Figure 1
Examples of naturally occurring oxazoles (a); some drugs containing oxazole as the active moiety (b); general structure of fluorescent dipeptidomimetics derived from trisubstituted oxazoles (c); reactivity of the oxazole system as an azadiene (d).
Scheme 1
Scheme 1
Synthesis of oxazoles 4 by addition of acyl chlorides to azirines 2, as described by Hassner et al. [–29].
Scheme 2
Scheme 2
Preparation of 2-functionalized oxazoles 7 from 2-(chloromethyl)oxazoles 6 and their application to the synthesis of peptidomimetics 8.
Scheme 3
Scheme 3
Integrated continuous-flow synthesis of 2-(azidomethyl)oxazoles 7.
Scheme 4
Scheme 4
Side products generated during the reaction of azirine 2a with bromoacyl bromide at room temperature.
Figure 2
Figure 2
HPLC monitoring of the formation of 2-(azidomethyl)oxazole 7a.
Figure 3
Figure 3
Continuous sequential thermolysis of vinyl azides 1 and ring expansion of azirines 2 with bromoacetyl bromide to give 2-(bromomethyl)oxazoles 6.
Figure 4
Figure 4
Continuous-flow three-step sequential synthesis of 2-(azidomethyl)oxazoles 7a–c from vinyl azides 1a–c. Yields refer to isolated yields.
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