Article Cite This: J. Org. Chem. 2018, 83, 15118−15127
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Vinyl-1,2,4-oxadiazoles Behave as Nucleophilic Partners in Morita− Baylis−Hillman Reactions Fab́ io S. Fernandes,† Manoel T. Rodrigues, Jr.,† Lucas A. Zeoly,† Caroline Conti,† Ceĺ io F. F. Angolini,‡ Marcos Nogueira Eberlin,‡,§ and Fernando Coelho*,† †
Institute of Chemistry, Laboratório de Síntese de Produtos Naturais e Fármacos and ‡Institute of Chemistry, Laboratório ThoMSon de Espectrometria de Massas, University of Campinas, P.O. Box 6154, Campinas, São Paulo 13083-970, Brazil § Mackenzie Presbiterian University, São Paulo, São Paulo 01302-907, Brazil
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S Supporting Information *
ABSTRACT: We describe that vinyl-oxadiazoles function as a new and efficient nucleophilic partner for the Morita−Baylis− Hillman (MBH) reaction. The reaction between 5-vinyl-3-aryl1,2,4-oxadiazoles and aromatic and aliphatic aldehydes, catalyzed by DABCO in the absence of solvent, showed high efficiency to afford a new class of heterocyclic MBH adducts with potential biological activity on yields up to 99% and short reaction times. These synthetically attractive adducts bear a heterocyclic scaffold of large pharmaceutical and commercial interest associated with a plethora of biological effects and technological applications. We also demonstrate their synthetic usefulness by a photoinduced addition reaction to a polyfunctionalized amino alcohol.
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INTRODUCTION
Bearing in mind the electronic demand required by this heterocyclic scaffold, we found a report by Burns et al.4 describing the use of 5-vinyl-1,2,4-oxadiazole as Michael acceptor for amines, alcohols, and thiophenols. Disubstitued 1,2,4-oxadiazoles are present in molecules that display interest in several branches of chemistry, such as medicinal,5 material,6 polymer,7 synthetic organic, and heterocyclic chemistries.8 This report from Burns et al. stimulated us to evaluate the use of vinyl-1,2,4-oxadiazoles as new nucleophilic partners for MBH reactions. 1,2,4-Oxadiazole is also attractive since it represents a heterocyclic scaffold of great relevance in medicinal chemistry. Its metabolic profile associated with its ability to act as hydrogen bond acceptor9 allows its use as bioisostere of esters and amides.10 Molecules bearing this heterocyclic pattern also display great diversity of biological activities, such as antitumor,11 antibacterial,12 antiviral,5b,13 anti-inflammatory,14 insecticidal,15 antiparasitic,10a,16 and muscarinic receptors agonist.17
The Morita−Baylis−Hillman reaction is a sustainable transformation which provides high synthetically useful yet small polyfunctionalized molecules.1 This C−C σ bond formation reaction presents high atom economy, low environmental impacts (all reagents used in excess can be recycled and reused), and a friendly and easily scalable experimental protocol. It also employs common organic compounds as catalysts such as tertiary amines or phosphines, which allow its classification as an organocatalytic process. MBH reactions progress via addition/elimination steps involving electrophilic and nucleophilic components. Normally, the electrophile is an aldehyde or activated imine, whereas the nucleophile is always an activated olefin. Acrylates are by far the most common nucleophilic MBH partners, but several types of Michael acceptors have been used (Figure 1).2 Despite the huge diversity of acrylates and other activated olefins employed (Figure 1), so far we found just one report on the use of olefins bearing a heterocyclic scaffold able to participate in MBH reactions.3 To add a heterocyclic scaffold that would act as a new nucleophilic MBH partner seems indeed not an easy task since this group should be able to provide to the double bond the same strong electronic effect given by the electron-withdrawing carbonyl group. If found, however, this type of activated olefin would open a new synthetic window via MBH reactions allowing the use of the new MBH adducts for the synthesis of new polyfunctionalized compounds with potential biological activities. © 2018 American Chemical Society
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RESULTS AND DISCUSSION Our study was initiated by evaluating vinyl-oxadiazole 4, which was promptly prepared in 89% yield according to the methodology described by Burns et al.4 The reaction between benzaldehyde and 4, catalyzed by DABCO, was then used as a model MBH reaction (Table 1), and fortunately indeed, the Received: September 19, 2018 Published: November 23, 2018 15118
DOI: 10.1021/acs.joc.8b02402 J. Org. Chem. 2018, 83, 15118−15127
Article
The Journal of Organic Chemistry
Figure 1. Some representative examples of nucleophilic partners already used in the MBH reactions
Table 1. Optimizing the Reaction of MBH with Vinyl 1,2,4-Oxadiazole
conversion (%) a
a
entry
4
5
Lewis base
base (equiv)
1 2 3 4 5 6 7 8 9 10 11
1.0 15.0 3.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0
1.1 1.0 1.0 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1
DABCO DABCO DABCO DABCO quinuclidinol quinuclidine PPh3 PBu3 imidazole BIAd Et3N
1.05 0.65 2.00 1.05 1.05 1.05 1.05 1.05 1.05 1.05 1.05
AcOH (equiv)
2.00 1.05
8h
14 h
24 h
43 28 72 17 40 43
