10.1002/anie.201910602
Angewandte Chemie International Edition
COMMUNICATION
A mechanistic proposal consistent with these data is
outlined in Scheme 2C. Photoexcitation of the Ir(III) catalyst
affords a triplet excited state that is oxidatively quenched by Cu(II)
to afford a strongly oxidizing Ir(IV) complex. Subsequent oxidation
of the arene affords an arene radical cation that undergoes
benzylic deprotonation and rapid oxidation by Cu(II). The resulting
quinone methide undergoes nucleophilic attack by the alcohol
coupling partner to afford the observed benzylic ether products.
The reaction proceeds to completion with only 1.2 equiv of Cu(II).
Thus both oxidizing equivalents of Cu(II) are consumed in this
reaction, which could be attributed to the disproportionation of the
Cu(I) byproduct of either oxidation step to Cu(II) and Cu(0), the
latter of which we observe precipitating from solution during the
reaction.
excess of the alcohol reaction partner, which enables the
formation of new benzylic ether compounds from the coupling of
two structurally complex units. From a broader perspective, these
results are intriguing because they demonstrate that the
organoradical intermediates that are readily generated by
photoredox activation can be diverted towards cationic reactivity
via in situ oxidation by Cu(II). This combination thus provides a
promising new platform to design new bond-forming oxidative
functionalization reactions with broad utility in synthetic and
medicinal chemistry.
Acknowledgements
In summary, we have developed a new photocatalytic
strategy to introduce diverse alkoxide functionalities into complex
organic molecules by functionalization of benzylic C–H bonds.
The site selectivity and broad functional group compatibility of this
method renders it amenable to the late-stage functionalization of
complex bioactive compounds. Importantly, the efficiency of the
reaction provides synthetically useful yields using only a two-fold
We gratefully acknowledge the NIH (GM095666) for funding this
work. We thank Prof. Shannon Stahl and Sijie Chen (UW–
Madison) for sharing unpublished data.
Keywords: C–H alkoxylation • copper • oxidation •
photocatalysis • radicals
[1]
a) L. McMurray, F. O’Hara, M J. Gaunt, Chem. Soc. Rev. 2011, 40, 1885–
1898. b) W. R. Gutekunst, P. S. Baran, Chem. Soc. Rev. 2011, 40, 1976–
1991. c) J. Yamaguchi, A. D. Yamaguchi, K. Itami, K. Angew. Chem. Int.
Ed. 2012, 51, 8960–9009; Angew. Chem. 2012,124, 9092–9142.
a) J. Wencel-Delord, F. Glorius, Nature Chem. 2013, 5, 369–375. b) T.
Cernak, K. D. Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem.
Soc. Rev. 2016, 45, 546–576.
[8]
Stahl has articulated the characteristics of what might be considered a
cross-coupling reaction to afford C–O bonds. See ref. 7f.
[9]
For recent reviews of photoredox catalysis, see: a) J. M. R. Narayanam,
C. R. J. Stephenson, Chem. Soc. Rev. 2011, 40, 102–113. b) C. K. Prier,
D. A. Rankic, D. W. C. MacMillan, Chem. Rev. 2013, 113, 5322–5363.
c) J. Twilton, C. Le, P. Zhang, M. H. Shaw, R. W. Evans, D. W. C.
MacMillan, Nature Rev. Chem. 2017, 1, 0052. d) Y. Q. Zou, F. M.
Hörmann, T. Bach, T. Chem. Soc. Rev. 2018, 47, 278–290. e) M. Silvi,
P. Melchiorre, Nature 2018, 554, 41–49.
[2]
[3]
a) J. Ma, S. Li, Org. Chem. Front. 2014, 1, 712–715. b) J.-Q. Yu, Z. Shi,
Eds. CH Activation: Topics in Current Chemistry, Vol. 292; Springer-
Verlag: Berlin, 2010.
[10] N. L. Reed, M. I. Herman, V. P. Miltchev, T. P. Yoon, Org. Lett. 2018, 20,
[4]
[5]
S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451–3479.
a) N. L. Weinberg, E. A. Brown, J. Org. Chem. 1966, 31, 4058–4061. b)
K. Ponsold, H. Kasch, Tetrahedron Lett. 1977, 46, 4463–4464. c) T.
Shono, Y. Matsumura, O. Onomura, Y. Yamada, Synthesis 1987, 1099–
1100. d) K.-D. Ginzel, E. Steckhan, D. Degner, Tetrahedron 1987, 43,
5797–5805. e) K. J. Frankowski, R. Liu, G. L. Milligan, K. D. Moeller, J.
Aubé, Angew. Chemie Int. Ed. 2015, 54, 10555–10558; Angew. Chem.
2015, 127, 10701–10704.
7345–7350.
[11] For
a related photoredox strategy to accomplish decarboxylative
elimination, see: K. C. Cartwright, S. B. Lang, J. A. Tunge, J. Org. Chem.
2019, 84, 2933–2940.
[12] a) J. K. Kochi, A. Bemis, J. Am. Chem. Soc. 1968, 90, 4038−4051. b) J.
K. Kochi, A. Bemis, C. L. Jenkins, J. Am. Chem. Soc. 1968, 90, 4616–
4625. c) C. L. Jenkins, J. K. Kochi, J. Am. Chem. Soc. 1972, 94, 856–
865.
[6]
[7]
a) R. M. Moriarty, H. Hu, Tetrahedron Lett. 1981, 22, 2747–2750. b) R.
M. Moriarty, R. K. Vaid, V. T. Ravikumar, B. K. Vaid, T. E. Hopkins,
Tetrahedron 1988, 44, 1603–1607. c) C. Zhu, Y. Zhang, H. Zhao, S.
Huang, M. Zhang, W. Su, Adv. Synth. Catal. 2015, 357, 331–338. d) H.
Yu, Y. Xu, Y. Fang, R. Dong, Eur. J. Org. Chem. 2016, 5257–5262. c) R.
Kotagiri, R. Adepu, Eur. J. Org. Chem. 2018, 4556–4564.
[13] a) A. M. de P. Nicholas, D. R. Arnold, Can. J. Chem. 1982, 60, 2165–
2179. b) F. G. Bordwell, J.-P. Cheng, J. Am. Chem. Soc. 1989, 111
1792–1795. C) D. D. M. Wayner, V. D. Parker, Acc. Chem. Res.1993,
26, 287–294.
[14] G. Pandey, S. Pal, R. Laha, Angew. G. Pandey, S. Pal, R. Laha, Angew.
Chem. Int. Ed. 2013, 52, 5146–5149; Angew. Chem. 2013, 125, 5250–
5253.
a) A. R. Dick, K. L. Hull, M. S. Sandford, J. Am. Chem. Soc. 2004, 126,
2300–2301. b) S. Y. Zhang, H. Gang, Y. Zhao, K. Wright, W. A. Nack, G.
Chen, J. Am. Chem. Soc. 2012, 134, 7313–7316. c) F.-J.Chen, S. Zhao,
F. Hu, K. Chen, Q. Zhang, S.-Q. Zhang, B.-F. Shi, Chem. Sci. 2013, 4,
4187–4192. d) G. Shan, X. Yang, Y. Zong, Y. Rao, Angew. Chemie Int.
Ed. 2013, 52, 13606–13610; Angew. Chem. 2013, 125, 13851–13855.
e) T. A. F. Nelson, S. B. Blakey, Angew. Chem. Int. Ed. 2018, 57, 14911–
14915; Angew. Chem. 2018, 130, 15127–15131. f) H. Hu, S.-J. Chen, S.
Krska, S. Stahl ChemRxiv 2019, DOI 10.26434/chemrxiv.8159645.v1.
[15] H. Im, D. Kang, S. Choi, S. Shin, S. Hong, S. Org. Lett. 2018, 20, 7437–
7441.
[16] G. J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016,
539, 268–271.
[17] E. V. Karpova, A. I. Boltalin, M. A. Zakharov, N. I. Sorokina, Y. M.
Korenev, S. I. Troyanov, Anorg. Allg. Chem. 1998, 624, 741–744.
[18] D. Hanss, J. C. Freys, G. R. Bernardinelli, O. S. Wenger, Eur. J. Inorg.
Chem. 2009, 4850–4859.
[19] N. A. Romero, D. A. Nicewicz, Chem. Rev. 2016, 116, 10075–10166.
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