Journal Club Pyrrolidine synthesis via C–H bond amination

Methods of accessing chiral pyrrolidines Pyrrolidine pharmaceuticals • 5th most common N-heterocycle in FDA approved drugs 1. Selective deprotonation followed by transmetallation • Most frequent five-membered non-aromatic N-heterocycle (Chen et al., 2006) in FDA approved drugs • Asymmetric pyrrolidines are common building blocks for numerous bioactive materials

Some traditional methods of accessing pyrrolidines 2. Asymmetric addition to Ellman’s aldimines 1. Metal-catalyzed alkylation of primary amines with diols (Reddy and Prashad, 2009) (Watson, Maxwell and Williams, 2011)

2. Intramolecular Schmidt reaction (Wang, Su, Li and Gu, 2018) 3. Enantioselective catalytic hydroamination (Buchwald et al., 2019)

January 21, 2021 1 Journal Club “Enantioselective C–H Amination Catalyzed by Nickel Iminyl Complexes Pyrrolidine synthesis via Supported by Anionic Bisoxazoline (BOX) Ligands” C–H bond amination Y. Dong, C. J. Lund, G. J. Porter, R. M. Clarke, S.-L. Zheng, T. R. Cundari, T. A. Betley* (Harvard)

Abstract Catalyst synthesis and characterization Previously reported (Betley et al., 2020) (AdFL)Ni(py)

• Use nitrene insertion catalysis for enantioselective pyrrolidine synthesis • Improve on previous methods’ yields, ee and atom economy

Use bisoxazoline (BOX) ligand to simulate the electronic features of dipyrrin ligands Literature Background (novel monoanionic BOX ligand) de Bruin et al., 2017 cat.: First prepared Ni(I) synthon for characterization and comparison • doublet spin ground state (S = 1/2) • T-shape geometry around the Ni(I) center

• NL–Ni–Npy angle of 146.4(2)° (features all similar to the Ni(I) dipyrrato- complex) 29-46% ee can be achieved 4

Meggers et al., 2019 cat.:

4 5 6 • solid-state molecular structure of 5, bond lengths and angles of 5 and 6 similar to up to 99% ee, 15-57% yields those reported for dipyrrinato-supported nickel nitrenoid adducts • both S = 1/2 paramagnetic species

J. Am. Chem. Soc. 2021, 143, 2, 817–829 Jenya Semenova January 21, 2021 2 Journal Club “Enantioselective C–H Amination Catalyzed by Nickel Iminyl Complexes Pyrrolidine synthesis via Supported by Anionic Bisoxazoline (BOX) Ligands” C–H bond amination Y. Dong, C. J. Lund, G. J. Porter, R. M. Clarke, S.-L. Zheng, T. R. Cundari, T. A. Betley* (Harvard)

Scope (TrFBOX)Ni(py) Proposed mechanism • Two possible mechanisms for C–H activation (radical-mediated vs concerted) gives two possibilities for enantio- determining step (optimized reaction conditions) • Probed mechanism using extended deuterium studies, KIE • Determine both HAA and radical recombination can contribute to enantioselectivity

Radical oxidative recombination group transfer

H-atom abstraction (HAA)

J. Am. Chem. Soc. 2021, 143, 2, 817–829 Jenya Semenova January 21, 2021 3 Journal Club “Enantioselective intramolecular C–H amination of aliphatic azides by dual Pyrrolidine synthesis via ruthenium and phosphine catalysis” C–H bond amination Jie Qin, Zijun Zhou, Tianjiao, Marcel Hemming, and Eric Meggers

Chem. Sci., 2019, 10, 3202-3207 Sara E. Kearney January 21, 2021 Journal Club “Enantioselective intramolecular C–H amination of aliphatic azides by dual Pyrrolidine synthesis via ruthenium and phosphine catalysis” C–H bond amination Jie Qin, Zijun Zhou, Tianjiao, Marcel Hemming, and Eric Meggers

Summary: Enantioselective dual catalytic ring-closing benzylic C(sp3)-H amination of primary aliphatic azides via combined chiral-at-metal transition metal/nucleophilic phosphine catalysis.

Chem. Sci., 2019, 10, 3202-3207 Sara E. Kearney January 21, 2021 Journal Club “Cobalt-Porphyrin-Catalysed Intramolecular Ring-Closing C-H Amination of Pyrrolidine synthesis via Aliphatic Azides: A Nitrene-Radical Approach to Saturated Heterocycles” C–H bond amination P. F. Kuijpers, M. J. Tiekink, W. B. Breukelaar, D. L. J. Broere, N. P. van Leest, J. I. van der Vlugt, J. N. H. Reek, B. de Bruin

Abstract Representative catalysts in this Work

Literature Precedent Mechanistic Studies

Chem. Eur. J. 2017, 23,7945 –7952 Kristin Sobie January 21, 2021 Journal Club “Cobalt-Porphyrin-Catalysed Intramolecular Ring-Closing C-H Amination of Pyrrolidine synthesis via Aliphatic Azides: A Nitrene-Radical Approach to Saturated Heterocycles” C–H bond amination P. F. Kuijpers, M. J. Tiekink, W. B. Breukelaar, D. L. J. Broere, N. P. van Leest, J. I. van der Vlugt, J. N. H. Reek, B. de Bruin

Mechanism Notable members of the scope Applications

Chem. Eur. J. 2017, 23,7945 –7952 Kristin Sobie January 21, 2021 Journal Club Ammonium Ylide Additional References [2,3] Rearrangements

Introduction: Literature detailed in this presentation: 1. E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257–10274. 7. Y. Dong, C. J. Lund, G. J. Porter, R. M. Clarke, S.-L. Zheng, T. R. Cundari, T. A. Betley, J. Am. Chem. Soc. 2021, 143, 817–829. 2. A. J. A. Watson, A. C. Maxwell, J. M. J. Williams, J. Org. Chem. 2011, 76, 2328–2331. 8. P. F. Kuijpers, M. J. Tiekink, W. B. Breukelaar, D. L. J. Broere, N. P. van Leest, J. I. van der 3. X.-J. Wang, Y. Su, R. Li, P. Gu, J. Org. Chem. 2018, 83, 5816–5824. Vlugt, J. N. H. Reek, B. de Bruin, Chem: Eur. J. 2017, 23, 7945–7952. 4. K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C. Chen, J. Am. Chem. Soc. 2006, 9. J. Qin, Z. Zhou, T. Cui, M. Hemming, E. Meggers, Chem. Sci. 2019, 10, 3202–3207. 128, 3538–3539. 5. L. R. Reddy, M. Prashad, Chem. Commun. 2010, 46, 222–224. 6. X.-J. Dai, O. D. Engl, T. León, S. L. Buchwald, Angew. Chem. Int. Ed. 2019, 58, 3407– 3411.

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