The Baran group at The Scripps Research Institute (http://www.scripps.edu/baran/html/publications.html) have recently reported an interesting reagent-based methodology to enable “any-stage functionalisation” of both simple and complex amines with small cyclic motifs such as bicyclo[1.1.1] pentanes, azetidines and cyclobutanes [1].
The strategy employs a turbo-amide to break a “spring-loaded” C-C or C-N bond, and in doing so directly aminates a strained species (Fig 1), enabling simpler syntheses and expanding retrosynthetic logic of some traditionally challenging targets.

Fig 1. A – Strain-release amination using turbo amide and “strain-release reagent”, propellane, to afford bicyclo[1.1.1]pentan-1-amine on large scale after deprotection. B – Strain-release amination using turbo amide of late stage intermediate and “strain release” reagent, propellane, to afford a “propellerized” tertiary amine. Image taken directly from [1] without permissions

Fig 2. Conventional and ‘new’ retrosynthetic analysis to obtain Pfizer’s precursor, bicyclo[1.1.1]pentan-1-amine. Image adapted from [3] and [1] without permissions

Fig 3. The concept of strain-release amination: using the turbo amide of a lead with “strain-release reagent” A, B or C to append a strained ring system at “any stage” of synthesis onto the lead. Image taken directly from [1] without permissions
For a more complete account of the development of strain-release amination, further applications and in-depth details of the methodology (> 400 pages of supporting info!) visit http://openflask.blogspot.co.uk/ and read the primary reference [1].
Blog written by Scott Henderson
References
- Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R. Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego, N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu, P. S. Baran. Science. 351, 6270, 241 (2016)
- A. Meanwell. J. Med. Chem. 54, 2529 (2011)
- D. Bunker, N. W. Sach, Q. Huang, P.F. Richardson. Org. Lett. 13, 4746 (2011).