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Urea group-directed organocatalytic asymmetric versatile dihalogenation of alkenes and alkynes

Abstract

The textbook alkene halogenation reaction establishes straightforward access to vicinal dihaloalkanes. However, robust catalytic methods to perform dihalogenation in a stereoselective manner are lacking, despite the ubiquity of contiguous halogen-bearing stereocentres in natural products, bioactive and pharmaceutical molecules. Here we show that a urea directing moiety judiciously installed on alkenes could anchor the halogen nucleophiles and thus circumvent the regioselectivity issue in this transformation. Additionally, common alkali halides could be used as halogenating reagents. Our organocatalytic strategy granted modular and streamlined access to diverse homo-/hetero-dihalogenation products with exquisite stereo- and regiocontrol, irrespective of the alkene geometry. Pseudoenantiomeric catalysts could relay chiral information in bromofluorination of isomeric alkenes, providing unified access to the full complement of stereoisomers. Extending this synthetic tactic to alkynes culminated in their atroposelective dihalogenation affording axially chiral alkenes.

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Fig. 1: Background of alkene dihalogenation and our strategy.
Fig. 2: Substrate scope of catalytic asymmetric bromochlorination of alkenes.
Fig. 3: Substrate scope of catalytic asymmetric dibromination of alkenes.
Fig. 4: Substrate scope of catalytic asymmetric bromofluorination of alkenes.
Fig. 5: Extension and transformations.
Fig. 6: Substrate scope of catalytic atroposelective dihalogenation of alkynes.
Fig. 7: Control experiments and deprotection of the directing group.

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Data availability

The X-ray crystallographic coordinates for the structures of compounds 1, 14, 23 and 56 reported in this paper have been deposited at the Cambridge Crystallographic Data Centre, under deposition nos. CCDC 1992079 (1, https://doi.org/10.5517/ccdc.csd.cc24vxmk), CCDC 2025495 (14, https://doi.org/10.5517/ccdc.csd.cc25zpkf), CCDC 1992078 (23, https://doi.org/10.5517/ccdc.csd.cc24vxlj) and 1992077 (56, https://doi.org/10.5517/ccdc.csd.cc24vxkh). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. Experimental procedures and the characterization of new compounds are available in the Supplementary Information. All other data are available from the authors upon reasonable request.

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Acknowledgements

We are grateful for financial support from the National Natural Science Foundation of China (grant nos. 21825105), Guangdong Provincial Key Laboratory of Catalysis (grant no. 2020B121201002), Guangdong Innovative Programme (grant no. 2019BT02Y335), Shenzhen Nobel Prize Scientists Laboratory Project (grant no. C17213101) and SUSTech Special Fund for the Construction of High-Level Universities (grant no. G02216402). We appreciate the assistance of SUSTech Core Research Facilities.

Author information

Authors and Affiliations

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Contributions

B.T., S.-H.X. and S.L. conceived and directed the project. S.W. designed and performed experiments. S.-H.X., W.-Y.D., L.Z., P.-Y.J. and Z.-A.Z. helped with the collection of some new compounds and data analysis. B.T., S.W. and S.-H.X. wrote the paper with input from all other authors. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Bin Tan.

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The authors declare no competing interests.

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Peer review information Nature Catalysis thanks the anonymous reviewers for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 The binding interaction between urea and LiCl as observed by 1H NMR and HRMS.

The binding interaction between urea and LiCl as observed by 1H NMR and HRMS. a, The interaction of alkene-urea S1 with halide anion as observed by 1H NMR. b, The interaction of alkene-urea S1 with halide anion as observed by HRMS. c, The interaction of alkyne-urea S38 with halide ion as observed by 1H NMR. d, The interaction of alkyne-urea S38 with halide ion as observed by HRMS.

Supplementary information

Supplementary Information

Supplementary Figs. 1–6, Tables 1–5 and Methods.

Supplementary Dataset 1

Crystal data of compound 1.

Supplementary Dataset 2

Crystal data of compound 14.

Supplementary Dataset 3

Crystal data of compound 23.

Supplementary Dataset 4

Crystal data of compound 56.

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Wu, S., Xiang, SH., Li, S. et al. Urea group-directed organocatalytic asymmetric versatile dihalogenation of alkenes and alkynes. Nat Catal 4, 692–702 (2021). https://doi.org/10.1038/s41929-021-00660-8

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