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Divergent Strain-Release Amino-Functionalization of [1.1.1]Propellane with Electrophilic Nitrogen-Radicals

Affiliations

  • 1 Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
  • 2 Department of Chemistry, College of Science, King Faisal University, P.O. Box 380, Al-Ahsa, 31982, Saudi Arabia.
  • PMID: 32003916
  • PMCID: PMC7318212
  • DOI: 10.1002/anie.202000140

Free PMC article

Divergent Strain-Release Amino-Functionalization of [1.1.1]Propellane with Electrophilic Nitrogen-Radicals

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Authors

Affiliations

  • 1 Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK.
  • 2 Department of Chemistry, College of Science, King Faisal University, P.O. Box 380, Al-Ahsa, 31982, Saudi Arabia.
  • PMID: 32003916
  • PMCID: PMC7318212
  • DOI: 10.1002/anie.202000140

Abstract

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen-radicals to undergo strain-release reaction with [1.1.1]propellane. This reactivity is facilitated by the electrophilic nature of these open-shell intermediates and the presence of strong polar effects in the transition-state for C-N bond formation/ring-opening. With the aid of a simple reductive quenching photoredox cycle, we have successfully harnessed this novel radical strain-release amination as part of a multicomponent cascade compatible with several external trapping agents. Overall, this radical strategy enables the rapid construction of novel amino-functionalized building blocks with potential application in medicinal chemistry programs as p-substituted aniline bioisosteres.

Keywords: amino-functionalization; bioisosteres; nitrogen radicals; strain-release.

© 2020 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

Conflict of interest statement

The authors declare no conflict of interest.

Herein we report the development of a photocatalytic strategy for the divergent preparation of functionalized bicyclo[1.1.1]pentylamines. This approach exploits, for the first time, the ability of nitrogen-radicals to undergo strain-release reaction with [1.1.1]propellane. This reactivity is facilit …

Strain release

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Chemical Communications

Strain release – an old tool for new transformations

a Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52, Warsaw 01-224, Poland
E-mail: [email protected]

b Department of Chemistry, Warsaw University of Technology, Noakowskiego 3, Warsaw 00-664, Poland

Abstract

Strain-release driven transformations give access to attractive bioisosteric motifs highly prized by medicinal chemists and they are characteristic of molecules possessing distorted bond lengths and angles. By broadening the chemical space in drug discovery, recently, these compounds have attracted a lot of interest. Their reactivity stems mainly from an increased energy and destabilization. As a result, the opening of the bridging bond occurs under the action of both nucleophiles and electrophiles as well as radical species and transition metals. Though the bridge bond dominates their reactivity, it is also influenced by the substitution pattern. This feature article focuses on strain-release driven strategies paying particular attention to the most recent (year > 2010) advances.

Article information

Strain release – an old tool for new transformations

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Strain-release driven transformations give access to attractive bioisosteric motifs highly prized by medicinal chemists and they are characteristic of molecules possessing distorted bond lengths and angles. By broadening the chemical space in drug discovery, recently, these compounds have attracted a lot of