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Amine hemilability enables boron to mechanistically resemble either hydride or proton

An Author Correction to this article was published on 10 September 2018

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Abstract

Tetracoordinate MIDA (N-methyliminodiacetic acid) boronates have found broad utility in chemical synthesis. Here, we describe mechanistic insights into the migratory aptitude of the MIDA boryl group in boron transfer processes, and show that the hemilability of the nitrogen atom on the MIDA ligand enables boron to mechanistically resemble either a hydride or a proton. The first case involves a 1,2-boryl shift, in which boron migrates as a nucleophile in its tetracoordinate form. The second case involves a neighbouring atom-promoted 1,4-boryl shift, in which boron migrates as an electrophile in its pseudo-tricoordinate form. Density functional theory studies and in situ NMR measurements all suggest that MIDA can act as a dynamic switch. These findings encouraged the development of novel migration processes involving boron that exploit the chameleonic behaviour of boron by acting as both a nucleophile and an electrophile, including the first report of a compound with a boronate functionality bound to carbon in the carboxylic acid oxidation state.

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Fig. 1: MIDA-substituted boryl groups in atom transfer processes.
Fig. 2: Mechanistic analysis of BMIDA migration as a nucleophile.
Fig. 3: Hyperconjugative stabilization of MIDA boronates.
Fig. 4: Spectroscopic evidence for the loss of diastereotopicity of the MIDA ligand.
Fig. 5: Mechanistic considerations of 1,3-boryl migration and linear free energy relationship for 1,4-boryl migration.
Fig. 6: Mechanistic analysis of BMIDA migration as an electrophile.
Fig. 7: Examples of BMIDA migrations in various systems.

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Change history

  • 10 September 2018

    During the revision of this Article prior to publication, a computational study was reported (Vallejos, M. M. & Pellegrinet, S. C. Theoretical study of the BF3-promoted rearrangement of oxiranyl N-methyliminodiacetic acid boronates. J. Org. Chem. 82, 5917–5925; 2017) that evaluates the nucleophilic boryl transfer mechanism predicted in this Article; this reference has now been added as number 19, and the subsequent references renumbered.

References

  1. Fernandez, E. & Whiting, A. (eds) Synthesis and Application of Organoboron Compounds (Springer International, Cham, 2015).

  2. Hall, D. G. (ed.) Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials 2nd rev. edn (Wiley, Weinheim, 2011).

    Google Scholar 

  3. Diaz, D. B. & Yudin, A. K. The versatility of boron in biological target engagement. Nat. Chem. 9, 731–742 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Lennox, A. J. J. & Lloyd-Jones, G. C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc. Rev. 43, 412–443 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Molander, G. A. & Ellis, N. Organotrifluoroborates: protected boronic acids that expand the versatility of the Suzuki coupling reaction. Acc. Chem. Res. 40, 275–286 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Darses, S. & Genet, J.-P. Potassium organotrifluoroborates: new perspectives in organic synthesis. Chem. Rev. 108, 288–325 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Eros, G., Kushida, Y. & Bode, J. W. A reagent for the one-step preparation of potassium acyltrifluoroborates (KATs) from aryl- and heteroarylhalides. Angew. Chem. Int. Ed. 53, 7604–7607 (2014).

    Article  CAS  Google Scholar 

  8. Gillis, E. P. & Burke, M. D. A simple and modular strategy for small molecule synthesis: iterative Suzuki–Miyaura coupling of B-protected haloboronic acid building blocks. J. Am. Chem. Soc. 129, 6716–6717 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Gillis, E. P. & Burke, M. D. Multistep synthesis of complex boronic acids from simple MIDA boronates. J. Am. Chem. Soc. 130, 14084–14085 (2008).

    Article  CAS  PubMed  Google Scholar 

  10. He, Z. & Yudin, A. K. Amphoteric α-boryl aldehydes. J. Am. Chem. Soc. 133, 13770–13773 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. He, Z., Zajdlik, A., St. Denis, J. D., Assem, N. & Yudin, A. K. Boroalkyl group migration provides a versatile entry into α-aminoboronic acid derivatives. J. Am. Chem. Soc. 134, 9926–9929 (2012).

    Article  CAS  PubMed  Google Scholar 

  12. He, Z., Trinchera, P., Adachi, S., St Denis, J. D. & Yudin, A. K. Oxidative geminal functionalization of organoboron compounds. Angew. Chem. Int. Ed. 51, 11092–11096 (2012).

    Article  CAS  Google Scholar 

  13. Zajdlik, A. et al. α-Boryl isocyanides enable facile preparation of bioactive boropeptides. Angew. Chem. Int. Ed. 52, 8411–8415 (2013).

    Article  CAS  Google Scholar 

  14. He, Z., Zajdlik, A. & Yudin, A. K. Air- and moisture-stable amphoteric molecules: enabling reagents in synthesis. Acc. Chem. Res. 47, 1029–1040 (2014).

    Article  CAS  PubMed  Google Scholar 

  15. St Denis, J. D., He, Z. & Yudin, A. K. Amphoteric α-boryl aldehyde linchpins in the synthesis of heterocyles. ACS Catal. 5, 5373–5379 (2015).

    Article  CAS  Google Scholar 

  16. Adachi, S. et al. Condensation-driven assembly of boron-containing bis(heteroaryl) motifs using a linchpin approach. Org. Lett. 17, 5594–5597 (2015).

    Article  CAS  PubMed  Google Scholar 

  17. Diaz, D. B. et al. Synthesis of aminoboronic acid derivatives from amines and amphoteric boryl carbonyl compounds. Angew. Chem. Int. Ed. 55, 12659–12663 (2016).

    Article  CAS  Google Scholar 

  18. Lee, C. F. et al. Oxalyl boronates enable modular synthesis of bioactive imidazoles. Angew. Chem. Int. Ed. 56, 6264–6267 (2017).

    Article  CAS  Google Scholar 

  19. Vallejos, M. M. & Pellegrinet, S. C. Theoretical study of the BF3-promoted rearrangement of oxiranyl N-methyliminodiacetic acid boronates. J. Org. Chem. 82, 5917–5925 (2017).

    Article  CAS  PubMed  Google Scholar 

  20. Lee, S. J., Gray, K. C., Paek, J. S. & Burke, M. D. Simple, efficient, and modular synthesis of polyene natural products via iterative cross-coupling. J. Am. Chem. Soc. 130, 466–468 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, C. & Glorius, F. Controlled iterative cross-coupling: on the way to the automation of organic synthesis. Angew. Chem. Int. Ed. 48, 2–7 (2009).

    Article  Google Scholar 

  22. Woerly, E. M., Roy, J. & Burke, M. D. Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction. Nat. Chem. 6, 484–491 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Gillis, E. P. & Burke, M. D. Iterative cross-coupling with MIDA boronates: towards a general platform for small molecule synthesis. Aldrichimica Acta 42, 17–27 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. St. Denis, J. D. et al. Boron-containing enamine and enamide linchpins in the synthesis of nitrogen heterocycles. J. Am. Chem. Soc. 136, 17669–17673 (2014).

    Article  CAS  Google Scholar 

  25. Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gonzalez, J. A. et al. MIDA boronates are hydrolysed fast and slow by two different mechanisms. Nat. Chem. 8, 1067–1075 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. & Hartwig, J. F. C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931 (2010).

    Article  CAS  PubMed  Google Scholar 

  28. Blackett, B. N., Coxon, J. M., Hartshorn, M. P. & Richards, K. E. The deuterium isotope effect for the boron trifluoride catalyzed rearrangement of 2-methyl-1,2-epoxypropane. Aust. J. Chem. 23, 839–840 (1970).

    Article  CAS  Google Scholar 

  29. Fraile, J. M., Mayoral, J. A. & Salvatella, L. Theoretical study on the BF3-catalyzed Meinwald rearrangement reaction. J. Org. Chem. 79, 5993–5999 (2014).

    Article  CAS  PubMed  Google Scholar 

  30. Tomasi, J., Mennucci, B. & Cance, E. The IEF version of the PCM solvation method: an overview of a new method addressed to study molecular solutes at the QM ab initio level. J. Mol. Struct. 464, 211–226 (1999).

    Article  CAS  Google Scholar 

  31. Frisch, M. J. et al. Gaussian 09, Revision C.01 (Gaussian, Inc., 2009).

  32. Dean, J. A. (ed.) Lange’s Handbook of Chemistry 15th edn (McGraw-Hill. New York, NY, 1998).

  33. Eberlin, L., Bertrand, C. & Whiting, A. Regioisomeric and substituent effects upon the outcome of the reaction of 1-borodienes with nitrosoarene compounds. J. Org. Chem. 80, 6574–6583 (2015).

    Article  CAS  PubMed  Google Scholar 

  34. Kisu, H., Sakaino, H., Ito, F., Yamashita, M. & Nozaki, K. A qualitative analysis of a ‘Bora-Brook rearrangement’: the ambident reactivity of boryl-substituted alkoxide including the carbon-to-oxygen migration of a boryl group. J. Am. Chem. Soc. 138, 3548–3552 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Brook, A. G. & Yu, Z. Reactions of amines with silenes and acylsilanes. Organometallics 19, 1859–1863 (2000).

    Article  CAS  Google Scholar 

  36. Brook, A. G., MacRae, D. M. & Bassindale, A. R. The mechanism of the β-ketosilane to siloxyalkene thermal rearrangement. J. Organomet. Chem. 86, 185–192 (1975).

    Article  CAS  Google Scholar 

  37. Blackmond, D. G. Reaction progress kinetic analysis: a powerful methodology for mechanistic studies of complex catalytic reactions. Angew. Chem. Int. Ed. 44, 4302–4320 (2005).

    Article  CAS  Google Scholar 

  38. Blackmond, D. G. Kinetic profiling of catalytic organic reactions as a mechanistic tool. J. Am. Chem. Soc. 137, 10852–10866 (2015).

    Article  CAS  PubMed  Google Scholar 

  39. Garrett, G. E. & Taylor, M. S. A nonlinear ordinary differential equation for generating graphical rate equations from concentration versus time data. Top. Catal. 60, 554–563 (2017).

    Article  CAS  Google Scholar 

  40. Hansch, C. & Leo, A. Substituent Constants for Correlation Analysis in Chemistry and Biology (Wiley, New York, NY, 1979).

  41. Hansch, C., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91, 165–195 (1991).

    Article  CAS  Google Scholar 

  42. Swain, C. G. & Lupton, E. C. Jr Field and resonance components of substituent effects. J. Am. Chem. Soc. 90, 4328–4337 (1968).

    Article  CAS  Google Scholar 

  43. Swain, C. G., Unger, S. H., Rosenquist, N. R. & Swain, M. S. Substituent effects on chemical reactivity. Improved evaluation of field and resonance components. J. Am. Chem. Soc. 105, 492–502 (1983).

    Article  CAS  Google Scholar 

  44. Brook, A. G. Molecular rearrangements of organosilicon compounds. Acc. Chem. Res. 7, 77–84 (1974).

    Article  CAS  Google Scholar 

  45. Glendening, E. D., Reed, A. E., Carpenter, J. E. & Weinhold, F. NBO Version 3.1 (TCI, Univ. Wisconsin, Madison, WI, 1998).

  46. Carroll, F. A. (ed.) Perspectives on Structure and Mechanism in Organic Chemistry (Brooks/Cole Publishing Company, Pacific Grove, CA, 1998).

  47. Kende, A. S. (ed.) Organic Reactions Vol. 35 (Wiley, New York, NY, 1988).

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Acknowledgements

A.K.Y. acknowledges financial support from the Natural Science and Engineering Research Council (NSERC). T.D. acknowledges the computing infrastructure provided by SHARCNET (www.sharcnet.ca). The authors also acknowledge NSERC and the Canadian Foundation for Innovation, Project Number 19119, and the Ontario Research Fund for funding of the Centre for Spectroscopic Investigation of Complex Organic Molecules and Polymers. Helpful discussions with A.P. Dicks (University of Toronto), H. Soor (University of Toronto) and C. Apte (University of Toronto) are appreciated. The authors thank D. Burns, J. Sheng and S. Nokhrin for assistance with NMR spectroscopic experiments, and H. Foy (Brock University) for assistance in the computational calculations on the 1,4-migration. C.F.L., D.B.D. and A.H. thank NSERC for PGS-D funding. S.J.K. thanks NSERC for CGS-D funding. This paper is in memory of Dr Zhi He.

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A.K.Y. conceived the idea. Experimental work was conducted by C.F.L., D.B.D., A.H., S.J.K. and S.K.L. Kinetic data were processed and analysed by G.E.G. Computational work was conducted by T.D. The manuscript was written by C.F.L., D.B.D. and A.K.Y.

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Correspondence to Travis Dudding or Andrei K. Yudin.

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Lee, C.F., Diaz, D.B., Holownia, A. et al. Amine hemilability enables boron to mechanistically resemble either hydride or proton. Nature Chem 10, 1062–1070 (2018). https://doi.org/10.1038/s41557-018-0097-5

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