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. 2019 Mar 18;58(12):4002-4006.
doi: 10.1002/anie.201812227. Epub 2019 Feb 15.

Photoredox-Catalyzed Site-Selective α-C(sp3 )-H Alkylation of Primary Amine Derivatives

Melissa A Ashley  1 , Chiaki Yamauchi  1 , John C K Chu  2 , Shinya Otsuka  1   3 , Hideki Yorimitsu  3 , Tomislav Rovis  1   2
Affiliations

Photoredox-Catalyzed Site-Selective α-C(sp3 )-H Alkylation of Primary Amine Derivatives

Melissa A Ashley et al. Angew Chem Int Ed Engl. .

Abstract

The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivatives through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.

Keywords: amines; photochemistry; radicals; reaction mechanisms; synthetic methods.

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Figures

Figure 1.
Figure 1.
Photoredox functionalization: (a) tertiary vs secondary amines (b) installation of cleavable functionality to direct α-amino radical formation (c) acidity-controlled site-selectivity.
Scheme 1.
Scheme 1.
Olefin Scope. [a]1a (0.1 mmol), alkene (0.15 or 0.3 mmol), quinuclidine (0.2 mmol), [Ir(dF-CH3-ppy)2(dtbbpy)PF6] (2.0 mol%), DMF (0.2M), 34 W blue LED, ~ 40 °C, 16h. [b]Yield of isolated products. [c]dr was determined by 1H NMR of isolated product. [d]1.2 equiv. of 3-buten-2-one was used. [e]0.3 mmol scale. fEWG = electron withdrawing group; Ph = phenyl.
Scheme 2.
Scheme 2.
Triflamide Scope. [a]1a (0.1 mmol), alkene (0.15 or 0.3 mmol), quinuclidine (0.2 mmol), [Ir(dF-CF3-ppy)2(dtbbpy)PF6] (2.0 mol%), DMF (0.2M), 34 W blue LED, ~ 40 °C, 16h. [b]Yield of isolated products are reported. [c]dr was determined by 1H NMR of isolated product. [d]0.3 mmol scale. [f]Boc = tert-butyloxycarbonyl.
Scheme 3.
Scheme 3.
Mechanistic Interrogation. [a]No deuterium/hydrogen scrambling was observed α-to the nitrogen. Deuterium incorporation was measured in the product. Reaction was repeated under phosphate conditions in which ~1% incorporation was observed. [b]Phosphate conditions [c]trifluoroacetamide (0.1 mmol), alkene (0.15 or 0.3 mmol), K3PO4 (0.2 mmol), [Ir(dF-CF3-ppy)2(dtbbpy)PF6] (2.0 mol%), PhCF3 (0.4M), blue LED. [c]Ksv = Stervn-Volmer quenching constant.
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References

    1. McNally A, Prier K, MacMillan DWC, Science 2011, 334, 1114–1117 - PMC - PubMed
    2. Kohls P, Jadhav D, Pandey G, Rieser O, Org. Lett. 2012, 14, 672–675. - PubMed
    3. Miyake Y, Nakajima K, Nishibayashi Y, J. Am. Chem. Soc. 2012, 134, 3338–3341. - PubMed
    4. Nakajima K, Miyake Y, Nishibayashi Y, Acc. Chem. Res. 2016, 49, 1946–1956. - PubMed
    5. Prier CK, Rankic DA, MacMillan DWC, Chem. Rev. 2013, 113, 5322–5363. - PMC - PubMed
    6. Beatty JW, Stephenson CRJ, Acc. Chem. Res. 2015, 48, 1474–1484. - PMC - PubMed
    1. Dinnocenzo JP, Banach TE, J. Am. Chem. Soc. 1989, 111, 8646–8653.
    2. Zhang X, Yeh S-R, Hong S, Freccero M, Albini A, Falvey DE, Mariano PS, J. Am. Chem. Soc. 1994, 116, 4211–4220.
    1. Lewis FD, Zebrowski BE, Correa PE, J. Am. Chem. Soc. 1984, 106, 187–193.
    2. Lewis FD, Correa PE, J. Am. Chem. Soc. 1984, 106, 194–198.
    3. Lewis FD, Reddy GD, Schneider S, Gahr M, J. Am. Chem. Soc. 1989, 111, 6465–6466.
    4. Das S, Dileep Kumar JS, Shivaramayya K, George MV, J. Chem. Soc, Perkin Trans. 1, 1995, 1797–1799.
    5. Cookson RC, Costa S.M. De B., Hudec J, J. Chem. Soc. D: Chem. Commun., 1969, 13, 753–754.
    1. Yoon UC, Mariano PS, Acc. Chem. Res. 1992, 25, 233–240.
    2. Cho DW, Yoon UC, Acc. Chem. Res. 2011, 44, 204–215. - PubMed
    3. Miyake Y, Ashida Y, Nakajima K, Nishibayashi Y, Chem. Commun. 2012, 48, 6966–6968. - PubMed
    4. Nakajima K, Kitagawa M, Ashida Y, Miyake Y, Y. Nishibayashi Y. Chem. Commun. 2014, 50, 8900–8903. - PubMed
    5. Ruiz Espelt L, McPherson IS, Wiensch EM, Yoon TP, J. Am. Chem. Soc. 2015, 137, 2452–2455. - PMC - PubMed
    6. Lenhart D, Bauer A, Pothig A, Bach T, Chem. -Eur. J. 2016, 22, 6519–6523. - PubMed
    7. Chu L, Ohta C, Zuo Z, MacMillan DWC, J. Am. Chem. Soc. 2014, 136, 10886–10889. - PMC - PubMed
    8. Yasu Y, Koike T, Akita M, Adv. Synth. Catal. 2012, 354, 3414–3420.
    9. Miyazawa K, Koike T, Akita M, Adv. Synth. Catal. 2014, 356, 2749–2755.
    10. Fan L, Jia J, Hou H, Lefebvre Q, Rueping M, Chem. Eur. J. 2016, 22, 16437–16440. - PubMed
    11. Zuo Z, Cong H, Li W, Choi J, Fu GC, MacMillan DWC, J. Am. Chem. Soc. 2016, 138, 1832–1835. - PMC - PubMed
    1. Le C, Liang Y, Evans RW, Li X, MacMillan DWC, Nature. 2017, 547, 79–83. - PMC - PubMed
    2. Shaw MH, Shurtleff VW, Terrett JA, Cuthbertson JD, MacMillan DWC, Science 2016, 352, 1304–1308. - PMC - PubMed
    3. Alternately, Nicewicz and coworkers recently described the formation of α-amido alkyl radicals from photoredox catalyzed direct oxidation of the tertiary amides; see: McManus JB, Pnushka NPR, Nicewicz DA, J. Am. Chem. Soc. 2018, 140,9056–9060. - PubMed

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