Practical olefin hydroamination with nitroarenes

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Practical olefin hydroamination with nitroarenes by Jinghan Gui, Chung-Mao Pan, Ying Jin, Tian Qin, Julian C. Lo, Bryan J. Lee, Steven H. Spergel, Michael E. Mertzman, William J. Pitts, Thomas E. La Cruz, Michael A. Schmidt, Nitin Darvatkar, Swaminathan R. Natarajan, and Phil S. Baran Science Volume 348(6237):886-891 May 22, 2015 Published by AAAS

Fig. 1 Amine synthesis via coupling of nitroarenes and olefins. Amine synthesis via coupling of nitroarenes and olefins. (A) Amine retrosynthesis: a case study from drug discovery. (B) Invention and optimization of a nitroarene-based olefin hydroamination. Cbz, benzyloxycarbonyl; PG, protecting group; Me, methyl; Ph, phenyl; Et, ethyl; acac, acetylacetonate; dpm, 2,2,6,6-tetramethylheptane-3,5-dionate; dibm, 2,6-dimethylheptane-3,5-dionate; OTMS, trimethylsilyloxy; ND, not determined. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 2 Olefins explored in the hydroamination process. Olefins explored in the hydroamination process. Bn, benzyl; D, deuterium. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 3 Scope of the olefin hydroamination. Scope of the olefin hydroamination. Isolated yields are shown in parentheses along with the donor olefin used. Standard conditions: nitro(hetero)arene (1 equiv), olefin (3 equiv), Fe(acac)3 (30 mol %), PhSiH3 (2 equiv), EtOH, 60°C, 1 hour; Zn (20 equiv), HCl(aq), 60°C, 1 hour. Bu, butyl; Pr, propyl. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 7 Limitations of the hydroamination. Limitations of the hydroamination. (A) Nitroalkanes give low yields. (B) Limitations of functional group tolerance. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 5 Olefin hydroamination applied to shorter syntheses of known pharmaceutical targets. Olefin hydroamination applied to shorter syntheses of known pharmaceutical targets. (A) Glucocorticoid receptor modulator intermediate 108. (B) HIV-1 reverse transcriptase inhibitor intermediate 111. Boc, tert-butyloxycarbonyl. (C) ORL1 receptor inhibitor intermediate 113. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 6 Creative uses of the olefin hydroamination technique. Creative uses of the olefin hydroamination technique. (A) Cascade reductive aminations for amine annulation. (B) An efficient method to access hindered Michael adducts. (C) Application to deuterium labeling using isobutylene-d8 (AA). (D) Temperature profile of the formation of a current intermediate in process chemistry over 6 hours shows the absence of an induction period. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS

Fig. 4 Scope of the olefin hydroamination, continued. Scope of the olefin hydroamination, continued. Isolated yields are shown in parentheses along with the donor olefin used. Standard conditions: nitro(hetero)arene (1 equiv), olefin (3 equiv), Fe(acac)3 (30 mol %), PhSiH3 (2 equiv), EtOH, 60°C, 1 hour; Zn (20 equiv), HCl(aq), 60°C, 1 hour. Jinghan Gui et al. Science 2015;348:886-891 Published by AAAS