Journal of the American Chemical Society
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(6) For selected examples of C–H oxidation with oxaziridine spe-
anodic oxidation. This high energy species could homo-
lytically cleave an unactivated C–H bond; reaction be-
tween the ensuing carbon-centered radical (Figure 2B)
and molecular oxygen then affords the oxidation prod-
uct. HFIP is believed to serve as the electron acceptor to
generate H2 in the cathodic process.22
In summary, the oxidation of unactivated C–H bonds,
heretofore commonly achieved with highly reactive,
exotic, and expensive reagents, has been enabled in an
exceedingly simple fashion through an electrochemical
process. This practical method employs quinuclidine as
the mediator in an unsophisticated electrochemical setup
using inexpensive carbon and nickel electrodes. A di-
verse range of functional groups were shown to be com-
patible with the chemoselective process. The scalability
of the method, as evident through the successful oxida-
tion of sclareolide on a 50 gram scale, has the potential
to reshape the synthesis of complex materials.
cies, see: (a) Litvinas, N. D.; Brodsky, B. H.; Du Bois, J. An-
gew. Chem. Int. Ed. 2009, 48, 4513. (b) DesMarteau, D. D.;
Donadelli, A.; Montanari, V.; Petrov, V. A.; Resnati, G. J.
Am. Chem. Soc. 1993, 115, 4897.
1
2
3
4
5
6
7
8
(7) For some reviews on non-directed metal catalyzed oxidation
of unactivated C–H bonds, see: (a) Huang, X.; Groves, J. T. J.
Biol. Inorg. Chem. 2017, 22, 185. (b) Shilov, A. E.; Shul’pin,
G. B. Chem. Rev. 1997, 97, 2879. (c) Olivo, G.; Cussó, O.;
Costas, M. Chem. Asian J. 2016, 11, 3148. (d) Que, L. Jr.;
Tolman, W. B. Nature 2008, 455, 333.
9
(8) For selected examples of non-directed metal catalyzed oxida-
tion of unactivated C–H bonds, see: (a) Barton, D. H. R.;
Doller, D. Acc. Chem. Res. 1992, 25, 504. (b) Kim, C.; Chen,
K.; Jim, J.; Que, L. Jr J. Am. Chem. Soc. 1997, 119, 5964. (c)
Roelfles, G.; Lubben, M.; Hage, R.; Que, L. Jr; Fering, B. L.
Chem Eur. J. 2000, 6, 2152. (d) Howell, J. M.; Feng, K.;
Clark, J. R.; Trzepkowski, L. J.; White, M. C. J. Am. Chem.
Soc. 2015, 137, 14590. (e) Chen, S. M.; White, M.
C. Science, 2010, 327, 566. (f) Das, S.; Incarvito, C. D.; Crab-
tree, R. H.; Brudvig, G. W. Science 2006, 312, 1941.
(9) For a review on the use of mediators in electrochemistry, see:
Francke, R.; Little, R. D. Chem. Soc. Rev. 2014, 43, 2492.
(10) For some examples of tertiary aminium radical mediated
functionalizations of unactivated C–H bonds, see: (a)
Michaudel, Q.; Thevenet, D.; Baran, P. S. J. Am. Chem. Soc.
2012, 134, 2547. (b) Bloom, S.; Pitts, C. R.; Miller, D.; Hasel-
ton, N.; Holl, M. G.; Urheim, E.; Lectka, T. Angew. Chem.,
Int. Ed. 2012, 51, 10580. (c) Pitts, C. R.; Bloom, S.; Wol-
tornist, R.; Auvenshine, D. J.; Ryzhkov, L. R.; Siegler, M. A.;
Lectka, T. J. Am. Chem. Soc. 2014, 136, 9780.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
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60
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and
analytical data (1H and 13C NMR, MS) for all new com-
pounds. Graphical guide, FAQs, currently known limita-
tions, etc. This material is available free of charge via the
AUTHOR INFORMATION
Corresponding Authors
E-mail: pbaran@scripps.edu (P.S.B.).
Notes
(11) For the direct C2–H chlorination and bromination of sclareo-
lide through an intermolecular HLF reaction, see: (a) Quinn,
R. K.; Könst, Z. A.; Michalak, S. E.; Schmidt, Y.; Szklarski,
A. R.; Flores, A. R.; Nam, S.; Horne, D. A.; Vanderwal, C.
D.; Alexanian, E. J. J. Am. Chem. Soc. 2016, 138, 696. (b)
Schimdt, V. A.; Quinn, R. K.; Brusoe, A. T.; Alexanian, E. J.
J. Am. Chem. Soc. 2014, 136, 14389.
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support for this work was provided by NIH (GM-
118176), Pfizer, and Asymchem. We thank Prof. A. L.
Rheingold, Dr. C. E. Moore, and Dr. M. Gembicky (UCSD)
for X-ray crystallographic analysis, Drs. D.-H. Huang and
L. Pasternack (TSRI) for NMR analysis. We are grateful to
Dr. E. Horn for efforts during the early stage of the investi-
gation; we thank Mr. M. Collins (Pfizer Inc, La Jolla) for
providing substrates in this study. We thank Dr. E. Zhang
(Asymchem) for helpful discussions; we acknowledge Drs.
G. Che and Q. Hou (Asymchem) for technical assistance.
(12) All cyclic voltammograms were recorded in MeCN using
Me4N•BF4 as the electrolyte. For details, see the supporting
information.
(13) For the preparations of compound 3, 6, and 7 via TFDO oxi-
dation, see: Asensio, G.; Castellano, G.; Mello, R.; Gonzáles-
Núñez, M. E. J. Org. Chem. 1996, 61, 5564.
(14) Yields and selectivity of compounds 4, 8, 9, 10, and 2 through
TFDO oxidation were determined experimentally. See SI for
detailed information.
(15) Minisci, F.; Galli, R.; Galli, A.; Bernardi, R. Tetrahedron
Lett. 1967, 7, 2207.
(16) For reviews on Shono oxidation, see: (a) Shono, T. Tetrahe-
dron 1984, 40, 811. (b) Jones, A. M.; Banks, C. E. Beilstein J.
Org. Chem. 2014, 10, 3056.
(17) This was observed experimentally. See SI for details.
(18) Calculations based on prices of commercially available qui-
nuclidine, Me4N•BF4, MeCN, HFIP (for electrochemical pro-
tocol), trifluoroacetone (for TFDO oxidation), Fe(PDP) (for
Fe mediated process) from Sigma Aldrich.
REFERENCES
(1) Horn, E. J.; Rosen, B. R.; Chen, Y.; Tang, J.; Chen, K.; East-
gate, M. D.; Baran, P. S. Nature 2016, 533, 77.
(2) Eberson, L.; Nyberg, K. Tetrahedron 1976, 32, 2185.
(3) (a) Luca, O. R.; Gustafson, J. L.; Maddox, S. M.; Fenwick, A.
Q.; Smith, D. C. Org. Chem. Front. 2015, 2, 823. (b) Roth, H.
G.; Romero, N. A.; Nicewicz, D. A. Synlett 2016, 27, 714.
(4) For examples of direct anodic oxidations of unactivated sp3
C–H bonds, see: (a) Koch, V. R.; Miller, L. L. J. Am. Chem.
Soc. 1973, 95, 8631. (b) Fritz, H. P.; Würminghausen, T. J.
Chem. Soc. Perkins Trans 1 1976, 610. (c) Hembrock, A.;
Schäfer, H. J.; Zimmermann, G. Angew. Chem. Int. Ed. 1985,
24, 1055.
(5) (a) Curci, R.; D’Accolti, L.; Fusco, C. Acc. Chem. Res. 2006,
39, 1. (b) Newhouse, T. R.; Baran, P. S. Angew. Chem. Int.
Ed. 2011, 50, 3362. (c) Chen, K.; Eschenmoser, A.; Baran, P.
S. Angew. Chem. Int. Ed. 2009, 48, 9705. (d) Crandall, J. K.;
Curci, R.; D'Accolti, L.; Fusco, C.; Fusco, C.; D'Accolti, L.;
Annese, C. Methyl(trifluoromethyl)dioxirane in Encyclopedia
of Reagents for Organic Synthesis; Fuchs, P., Bode, J. W.,
Charette, A. B., Rovis, T., Eds.; Wiley: New York, 2016.
(19) Dixon, D. D.; Lockner, J. W.; Zhou, Q.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 8432.
(20) (a) Cornella, J.; Edwards, J. T.; Qin, T.; Kawamura, S.;
Wang, J.; Pan, C.-M.; Gianatassio, R.; Schmidt, M.; Eastgate,
M. D.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 2174. (b)
Qin, T.; Cornella, J.; Malins, L. R.; Edwards, J. T.; Kawamu-
ra, S.; Maxwell, B. D.; Eastgate, M. D.; Baran, P. S. Science
2016, 352, 801.
(21) Gansäuer, A.; Justicia, J.; Rosales, A.; Worgull, D.; Rinker,
B.; Cuerva, J. M.; Oltra, J. E. Eur. J. Org. Chem. 2006, 4115.
(22) This is evidenced by the observation of effervescence (puta-
tively H2 evolution) during some experiments. Nevertheless,
the potential of the cathode during the course of the reaction
was found to be –1.1 V (v.s. Ag/AgCl reference electrode):
Oxygen reduction at the cathode may also be operative.
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