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Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis

Nature Protocols volume 16, pages 5559–5591 (2021)Cite this article

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Abstract

Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopure N-alkyl bis-urea organocatalysts derived from (S)-(–)-1,1′-binaphthyl-2,2′-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized by N-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuring N-ethyl alkylation and meta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling between N-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.

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Fig. 1: Hydrogen bonding for electrophile and nucleophile activation.
Fig. 2: Reaction scheme for the synthesis of (S)-1.
Fig. 3: Reaction scheme for the synthesis of (S)-2.
Fig. 4: Equipment setup.
Fig. 5: HPLC traces of the catalysts.
Fig. 6: Experimental setup for Step 9.
Fig. 7
Fig. 8
Fig. 9: Suzuki-Miyaura cross-coupling of 3,5-dibromoaniline and 3,5-bis(trifluoromethyl)phenyl)boronic acid.
Fig. 10: Setup for the synthesis of isocyanate 7 (stage F).
Fig. 11
Fig. 12

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Data availability

The authors declare that additional data related to this protocol are available in the key references using this protocol (see ‘Related links’). Analytical data for all compounds described in the Procedure are included directly within this paper.

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Acknowledgements

This work was supported by the EU Horizon 2020 Research and Innovation Programme (Marie Sklodowska-Curie agreement 675071 and 789553), the Engineering and Physical Sciences Research Council (EP/R010064) and the European Research Council (Agreement 832994).

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Authors and Affiliations

  1. Chemistry Research Laboratory, University of Oxford, Oxford, UK

    Anna Chiara Vicini, Gabriele Pupo, Francesco Ibba & Véronique Gouverneur

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  1. Anna Chiara Vicini
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  2. Gabriele Pupo
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  3. Francesco Ibba
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  4. Véronique Gouverneur
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Contributions

All authors contributed to the design and development of these catalysts. G.P. and F.I. developed the first synthesis of this class of catalysts, and A.C.V. has modified the process for scale-up. V.G. conceived and directed the project. All authors contributed to drafting and commenting on the manuscript.

Corresponding author

Correspondence to Véronique Gouverneur.

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Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature Protocols thanks Ryan Gilmour, Xi-Sheng Wang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

Key references using this protocol

Pupo, G. et al. Science 360, 638–642 (2018): https://doi.org/10.1126/science.aar7941

Pupo, G. et al. J. Am. Chem. Soc. 141, 2878–2883 (2019): https://doi.org/10.1021/jacs.8b12568

Roagna, G. et al. J. Am. Chem. Soc. 142, 14045–14051 (2020): https://doi.org/10.1021/jacs.0c05131

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Vicini, A.C., Pupo, G., Ibba, F. et al. Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis. Nat Protoc 16, 5559–5591 (2021). https://doi.org/10.1038/s41596-021-00625-y

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