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Synthesis of bicyclo[5.3.0]azulene derivatives

Nature Protocols volume 4, pages 1113–1117 (2009)Cite this article

Abstract

Azulene has been recognized for its application in medicinal therapy against inflammation. Recently, azulene analogs have been used in optical technology. Nevertheless, synthesis of this family of compounds is always associated with multiple challenges. In this protocol, we describe a time-efficient and cost-effective procedure for the preparation of azulene derivatives from 2-hydroxycyclohepta-2,4,6-trienone (tropolone), a readily available starting material. The technique illustrated here involves a cycloaddition reaction of a lactone with the in situ-generated vinyl ether from 2,2-dimethoxypropane during the thermolysis reaction. The three-step synthesis should take <4 d, resulting in an overall yield of 74% with a final step yield of 91%.

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Figure 1: Synthesis scheme for the preparation of methyl 2-methylazulene-1-carboxylate (3).
Figure 2
Figure 3

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Acknowledgements

The NIA (AG026366 to W.P.), the ICMIC (P50, CA128323-01A1 to J.C.G.) and the Department of Radiology, Vanderbilt University School of Medicine provided support for this work. We also thank The Jeff Johnston Laboratory at Vanderbilt University for the use of their melting point apparatus.

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Authors and Affiliations

  1. Department of Radiology and Radiological Sciences, Vanderbilt University Institute of Imaging Science, Nashville, Tennessee, USA

    Donald D Nolting, Michael Nickels, Ronald Price, John C Gore & Wellington Pham

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  1. Donald D Nolting
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Contributions

D.D.N. performed the synthesis with some literature discussions and contributions from M.N.; W.P., R.P. and J.C.G. supervised the work. W.P. and D.D.N. prepared the manuscript.

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Correspondence to Wellington Pham.

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Nolting, D., Nickels, M., Price, R. et al. Synthesis of bicyclo[5.3.0]azulene derivatives. Nat Protoc 4, 1113–1117 (2009). https://doi.org/10.1038/nprot.2009.99

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