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Catalytic formal [2+2+1] synthesis of pyrroles from alkynes and diazenes via TiII/TiIV redox catalysis

Nature Chemistry volume 8, pages 63–68 (2016)Cite this article

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Abstract

Pyrroles are structurally important heterocycles. However, the synthesis of polysubstituted pyrroles is often challenging. Here, we report a multicomponent, Ti-catalysed formal [2+2+1] reaction of alkynes and diazenes for the oxidative synthesis of penta- and trisubstituted pyrroles: a nitrenoid analogue to classical Pauson–Khand-type syntheses of cyclopentenones. Given the scarcity of early transition-metal redox catalysis, preliminary mechanistic studies are presented. Initial stoichiometric and kinetic studies indicate that the mechanism of this reaction proceeds through a formally TiII/TiIV redox catalytic cycle, in which an azatitanacyclobutene intermediate, resulting from [2+2] alkyne + Ti imido coupling, undergoes a second alkyne insertion followed by reductive elimination to yield pyrrole and a TiII species. The key component for catalytic turnover is the reoxidation of the TiII species to a TiIV imido via the disproportionation of an η2-diazene-TiII complex.

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Figure 1: Ti-mediated oxidative pyrrole formation.
Figure 2
Figure 3: Mechanism of Ti-catalysed formal [2+2+1] oxidative cyclization of alkynes and diazenes.
Figure 4: Mechanistic scheme explaining selectivity differences between various unsymmetric alkynes.

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Change history

  • 02 December 2015

    In the original version of this Article published online, the structure of 4n (shown in Table 1) was incorrect. The structure has been corrected in all versions of the Article.

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Acknowledgements

Financial support was provided by the University of Minnesota (start-up funds). Equipment purchases for the Chemistry Department NMR facility were supported by a grant from the National Institutes of Health (S10OD011952) with matching funds from the University of Minnesota. The Bruker-AXS D8 Venture diffractometer was purchased through a grant from NSF/MRI (1224900) and the University of Minnesota.

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  1. Department of Chemistry, University of Minnesota – Twin Cities, 207 Pleasant St SE, Minneapolis, 55455, Minnesota, USA

    Zachary W. Gilbert, Ryan J. Hue & Ian A. Tonks

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  1. Zachary W. Gilbert
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  2. Ryan J. Hue
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Z.W.G. and I.A.T. conceived and designed the experiments. Z.W.G. and R.J.H. performed the experiments and analysed the data. I.A.T. wrote the manuscript. All authors contributed to revising the manuscript.

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Correspondence to Ian A. Tonks.

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Gilbert, Z., Hue, R. & Tonks, I. Catalytic formal [2+2+1] synthesis of pyrroles from alkynes and diazenes via TiII/TiIV redox catalysis. Nature Chem 8, 63–68 (2016). https://doi.org/10.1038/nchem.2386

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