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Deacylative transformations of ketones via aromatization-promoted C–C bond activation

Nature volume 567, pages 373–378 (2019)Cite this article

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Abstract

Carbon–hydrogen (C–H) and carbon–carbon (C–C) bonds are the main constituents of organic matter. Recent advances in C–H functionalization technology have vastly expanded our toolbox for organic synthesis1. By contrast, C–C activation methods that enable editing of the molecular skeleton remain limited2,3,4,5,6,7. Several methods have been proposed for catalytic C–C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force4,6 or directing groups5,7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes5. Here we report a general C–C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.

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Fig. 1: C–C activation driven by aromatization.
Fig. 2: Iridium-catalysed cleavage of unstrained ketones.
Fig. 3: Deacylative C–C forming reactions of linear ketones.
Fig. 4: Deconstructive pyrazole synthesis from ketones.

Data availability

The data supporting the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding authors upon request. Metrical parameters for the structure of 123 are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1876535.

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Acknowledgements

This project was supported by NIGMS (R01GM109054). Y.X. acknowledges financial support from a Charles H. Viol Fellowship and a William Rainey Harper Dissertation Fellowship from the University of Chicago and a Bristol-Myers Squibb Graduate Fellowship. P.Z. acknowledges a Joint PhD Student Scholarship 2016 from China Scholarship Council (file number 201603170182). P.L. thanks the NSF (CHE-1654122) for funding. Calculations were performed at the Center for Research Computing at the University of Pittsburgh. L. Deng is acknowledged for the donation of substrate 140. J. Zhu is acknowledged for conducting several control experiments.

Reviewer information

Nature thanks Vy Maria Dong and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Chemistry, University of Chicago, Chicago, IL, USA

    Yan Xu, Pengfei Zheng, Carlo C. Berti & Guangbin Dong

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, PA, USA

    Xiaotian Qi & Peng Liu

  3. College of Pharmacy, Army Medical University, Chongqing, China

    Pengfei Zheng

Authors
  1. Yan Xu
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Contributions

Y.X. discovered the reaction. Y.X., P.Z., C.C.B. and G.D. conceived and conducted the experimental investigation. X.Q. and P.L. designed and conducted the density functional theory calculations. Y.X., X.Q., P.L. and G.D. wrote the manuscript. P.L. and G.D. directed the research.

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Correspondence to Peng Liu or Guangbin Dong.

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Extended data figures and tables

Extended Data Fig. 1 Additional substrate scope for deconstructive pyrazole synthesis from ketones.

Ac, acetyl. MS, molecular sieves. aAll yields are isolated yields. bThe yield refers to the key C–C activation reaction using pre-formed hydrazone as the substrate. For detailed experimental procedures, see Supplementary Information.

Extended Data Fig. 2 Introducing pyrazoles into complex ketones via C–C cleavage.

aAll yields are isolated yields. bThe yield refers to the key C–C activation reaction using pre-formed hydrazone as the substrate. c15 mol% Ir catalyst and 15 mol% L1 were used. For detailed experimental procedures, see Supplementary Information.

Extended Data Fig. 3 Computational studies of the aromatization-driven C–C bond activation.

a, Free-energy profiles of the aromatization-driven C–C bond activation of dihydropyrazole 165. Calculations were performed at the M06-L/6-311+G(d,p)‒SDD/SMD(1,4-dioxane)//B3LYP/6-31G(d)‒SDD level of theory. The less favourable β-C elimination pathways with and without pyridine coordination (168-TS and 167-TS, respectively) are shown in blue. The NICS(1)zz aromaticity index was calculated at the B3LYP/6-311+G(d,p)‒SDD level of theory to describe the aromaticity of the pyrazole ring (highlighted in green) in 159, 160-TS and 161. The variation of NICS(1)zz indicates a substantial increase in aromaticity during the homolytic C–C bond cleavage. ΔG, change in Gibbs free energy; ΔH, change in enthalpy. b, Comparison between homolytic C–C bond cleavage of dihydropyrazole 165 and pyrazolidine 165ʹ (165ʹ without the driving force of aromatization). See Supplementary Information section 3.2.2 for details.

Supplementary information

Supplementary Information

This file contains Supplementary Text and Data Sections 1–5; see contents page for details.

Supplementary Data

This file contains the X-ray data.

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Xu, Y., Qi, X., Zheng, P. et al. Deacylative transformations of ketones via aromatization-promoted C–C bond activation. Nature 567, 373–378 (2019). https://doi.org/10.1038/s41586-019-0926-8

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