Journal of the American Chemical Society
Article
(
2) (a) Liang, T.; Neumann, C.; Ritter, T. Angew. Chem., Int. Ed.
CONCLUSIONS
■
2
2
013, 52, 8214. (b) Hollingworth, C.; Gouverneur, V. Chem. Commun.
012, 48, 2929.
We have found that deuterium labeling can be used to estimate
the amount of Pd-aryne intermediates generated during the
catalytic fluorination of a variety of ortho- and para-substituted
aryl triflates. Using this method, we have revealed that the
transmetalation step of the desired C−F cross-coupling process
(3) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160.
(4) Yandulov, D. V.; Tran, N. T. J. Am. Chem. Soc. 2007, 129, 1342.
(5) For C−F reductive elimination from Pd(IV) intermediates, see:
(a) Perez-Temprano, M. H.; Racowski, J. M.; Kampf, J. W.; Sanford,
́
(
Figure 2) likely competes with ortho-deprotonation to form a
M. S. J. Am. Chem. Soc. 2014, 136, 4097. (b) Racowski, J. M.; Gary, J.
B.; Sanford, M. S. Angew. Chem., Int. Ed. 2012, 51, 3414. (c) Furuya,
T.; Benitez, D.; Tkatchouk, E.; Strom, A. E.; Tang, P.; Goddard, W. A.;
Ritter, T. J. Am. Chem. Soc. 2010, 132, 3793. (d) Ball, N. D.; Sanford,
M. S. J. Am. Chem. Soc. 2009, 131, 3796. (e) Furuya, T.; Ritter, T. J.
Am. Chem. Soc. 2008, 130, 10060. For additional examples of Pd-
mediated electrophilic aryl fluorination reactions, see: (f) Ding, Q.; Ye,
C.; Pu, S.; Cao, B. Tetrahedron 2014, 70, 409. (g) Lou, S.-J.; Xu, D.-Q.;
Xia, A.-B.; Wang, Y.-F.; Liu, Y.-K.; Du, X.-H.; Xu, Z.-Y. Chem.
Commun. 2013, 49, 6218. (h) Chan, K. S. L.; Wasa, M.; Wang, X.; Yu,
J.-Q. Angew. Chem., Int. Ed. 2011, 50, 9081. (i) Wang, X.; Mei, T.-S.;
Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 7520. (j) Furuya, T.; Kaiser, H.
M.; Ritter, T. Angew. Chem., Int. Ed. 2008, 47, 5993. (k) Hull, K. L.;
Anani, W. Q.; Sanford, M.S. J. Am. Chem. Soc. 2006, 128, 7134. For a
reaction proceeding via Pd(III) intermediates in which mixtures of
regioisomeric products are observed in certain cases, see: (l) Mazzotti,
A.; Campbell, M.; Tang, P.; Murphy, J.; Ritter, T. J. Am. Chem. Soc.
Pd-aryne intermediate (Figure 3). The substrate classes for
which regioisomer formation remains a significant challenge are
those bearing electron-donating groups in the para position and
those bearing certain electron-donating or -withdrawing groups
in the meta position, with no other substituents present.
Switching the solvent to cyclohexane can prove to be beneficial
in these cases by reducing the extent of products originating
7
from Pd-aryne intermediates. Most importantly, the results
herein provide corroborating evidence that the desired C−F
cross-coupling pathway outlined in Figure 2 occurs to some
degree during the Pd-catalyzed fluorination of all tested aryl
triflates. Further work in this area will involve investigating
regioisomer formation in the recently reported fluorination of
aryl bromides and iodides using AgF, elucidating the behavior
of meta-substituted substrates, and designing new catalysts that
do not allow for regioisomer formation.
39
1
8
2
013, 135, 14012. For a reaction proceeding through F-containing
Pd(IV) intermediates, see: (m) Lee, E.; Kamlet, A. S.; Powers, D. C.;
Neumann, C. N.; Boursalian, G. B.; Furuya, T.; Choi, D. C.; Hooker, J.
M.; Ritter, T. Science 2011, 334, 639.
(6) For Cu-catalyzed or mediated nucleophilic aryl fluorination
reactions, see: (a) Mu, X.; Zhang, H.; Chen, P.; Liu, G. Chem. Sci.
ASSOCIATED CONTENT
■
*
S
Supporting Information
2
014, 5, 275. (b) Ye, Y.; Schimler, S. D.; Hanley, P. S.; Sanford, M. S. J.
Am. Chem. Soc. 2013, 135, 16292. (c) Truong, T.; Klimovica, K.;
Daugulis, O. J. Am. Chem. Soc. 2013, 135, 9342. (d) Ichiishi, N.; Canty,
A. J.; Yates, B. F.; Sanford, M. S. Org. Lett. 2013, 15, 5134. (e) Fier, P.
S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 10795. (f) Casitas, A.;
AUTHOR INFORMATION
Canta, M.; Sola,
9386. For Cu-mediated nucleophilic fluorination with F , see:
g) Ichiishi, N.; Brooks, A. F.; Topczewski, J. J.; Rodnick, M. E.;
̀
M.; Costas, M.; Ribas, X. J. Am. Chem. Soc. 2011, 133,
1
8 −
1
Notes
(
The authors declare the following competing financial
interest(s): MIT has patents on some of the ligands and
precatalysts used in this work from which S.L.B. and former/
current coworkers receive royalty payments.
Sanford, M. S.; Scott, P. J. H. Org. Lett. 2014, 16, 3224. For Ni-
mediated nucleophilic fluorination with 18F , see: (h) Lee, E.; Hooker,
J. M.; Ritter, T. J. Am. Chem. Soc. 2012, 134, 17456.
−
(
7) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; García-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
8) (a) Milner, P. J.; Maimone, T. J.; Su, M.; Chen, J.; Muller, P.;
(
̈
ACKNOWLEDGMENTS
■
Buchwald, S. L. J. Am. Chem. Soc. 2012, 134, 19922. (b) Maimone, T.
J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.; Buchwald, S. L. J.
Am. Chem. Soc. 2011, 133, 18106.
Dedicated to the memory of Gregory L. Hillhouse. We
gratefully acknowledge Prof. Thomas J. Maimone (UC
Berkeley) for helpful discussions and guidance during this
work. We also thank Drs. Hong Geun Lee (MIT) and Aaron
Sather (MIT) for assistance with this manuscript. We thank Dr.
Mingjuan Su (MIT) for assistance with this manuscript and for
carrying out preliminary DFT calculations. Research reported
in this publication was supported by the National Institutes of
Health under award no. GM46059. The content is solely the
responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health. P.J.M.
thanks the National Science Foundation for a predoctoral
fellowship (2010094243). P.J.M also thanks Amgen for an
educational donation, for which we are grateful. T.K. thanks the
Alexander von Humboldt Foundation for a Feodor Lynen
postdoctoral fellowship.
(
9) Mann, G.; Baranano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei, I.
A. J. Am. Chem. Soc. 1998, 120, 9205.
10) Attempted trapping of the L·Pd(0) species with other agents
(
such as diphenylacetylene, 1,5-cyclooctadiene, or 4-(nBu)PhCl did not
led to an improvement in the yield of 3a.
(
11) Ortho-deprotonation of aryl chlorides and bromides by
anhydrous fluoride has been previously reported. See: Grushin, V.
V.; Marshall, W. J. Organometallics 2008, 27, 4825. However, the
ratios of products obtained using Grushin’s methodology differ greatly
from those observed using the Pd-catalyzed fluorination reaction.
(12) To rule out the possibility of deprotonation of the aryl fluoride
product by a species generated in situ, we added 4-(OMe)PhF to the
catalytic fluorination reaction of 3-OTf. No isomerization to 3-(OMe)
PhF was observed; the added 4-(OMe)PhF was recovered
quantitatively.
(13) Retbøll, M.; Edwards, A. J.; Rae, A. D.; Willis, A. C.; Bennett, M.
A.; Wenger, E. J. Am. Chem. Soc. 2002, 124, 8348.
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