Journal of the American Chemical Society
Article
(4) (a) Stepan, A. F.; Mascitti, V.; Beaumont, K.; Kalgutkar, A. S.
Med. Chem. Commun. 2013, 4, 631. (b) Dossetter, A. G. Bioorg. Med.
Chem. 2010, 18, 4405.
(5) (a) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. Angew. Chem., Int.
Ed. 2012, 51, 8960. (b) Wencel-Delord, J.; Glorius, F. Nat. Chem.
2013, 5, 369. (c) Segawa, Y.; Maekawa, T.; Itami, K. Angew. Chem., Int.
Ed. 2015, 54, 66.
(6) (a) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
13864. (b) Ciana, C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 458. (c) Yu, Z.; Ma, B.;
Chen, M.; Wu, H.-H.; Liu, L.; Zhang, J. J. Am. Chem. Soc. 2014, 136,
6904. (d) Cheng, C.; Hartwig, J. F. Science 2014, 343, 853. (e) Cheng,
C.; Hartwig, J. F. J. Am. Chem. Soc. 2014, 136, 12064.
(7) For para-halogenation reactions of phenol and aniline derivatives,
see: (a) Stanforth, S. P. In Science of Synthesis: Houben−Weyl, Methods
of Molecular Transformations; Ramsden, C. A., Ed.; Georg Thieme
Verlag: Stuttgart, 2007; Vol. 31a, pp 121−160 and references therein.
(b) Waldvogel, S. R.; Wehming, K. M. In Science of Synthesis: Houben−
Weyl, Methods of Molecular Transformations; Ramsden, C. A., Ed.;
Georg Thieme Verlag: Stuttgart, 2007; Vol. 31a, pp 235−274 and
references therein.
(8) (a) Ishiyama, T.; Takagi, K.; Ishida, K.; Miyaura, N.; Anastansi,
N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124, 390. (b) Mkhalid, I.
A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem.
Rev. 2010, 110, 890. Mechanism: (c) Tamura, H.; Yamazaki, H.; Sato,
H.; Sakaki, S. J. Am. Chem. Soc. 2003, 125, 16114. (d) Boller, T. M.;
Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.; Hartwig, J. F. J.
Am. Chem. Soc. 2005, 127, 14263. (e) Chotana, G. A.; Vanchura, B. A.,
II; Tse, M. K.; Staples, R. J.; Maleczka, R. E., Jr.; Smith, M. R., III.
Chem. Commun. 2009, 5731.
was then easily converted into known caramiphen derivatives,
iodocaramiphen (25) and cyanocaramiphen (26), as well as
new derivatives 27−29 by the reported C−B functionalization
procedures (Figure 5b).19 Considering that caramiphen
derivatives 25 and 26 were synthesized through five steps
from a simple molecule in previous report,18b the highly step-
economical structure diversification shown here bodes well for
the potential of para-selective C−H borylation in medicinal
chemistry.
CONCLUSION
■
The development of predictable and truly general site-selective
C−H functionalization is at the heart of future chemical
synthesis. Although both steric and electronic effects influence
the regiochemical outcome of chemical reactions, in most cases,
devising a C−H functionalization method that relies solely on
steric factors not only represents a fundamental challenge but
also has significant impacts in numerous applications,
particularly in the rapid discovery and optimization of
pharmaceuticals and materials. The developed [Ir(cod)OH]2/
Xyl-MeO-BIPHEP catalyst is a new-generation catalyst toward
this end, affecting one of the most important reactions (para-
selective aromatic C−H functionalization) controlled by sterics.
The simple, yet powerful, concept of using a bulky catalyst to
allow exclusive chemical reactions at para-C−H bonds over
ortho- and meta-C−H bonds will likely be applicable to a range
of aromatic C−H functionalization reactions.
(9) (a) Ackermann, L.; Vicente, R.; Kapdi, A. Angew. Chem., Int. Ed.
2009, 48, 9792. (b) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed.
2013, 52, 11726. (c) Davies, H. M. L.; Manning, J. R. Nature 2008,
451, 417. (d) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius,
F. Angew. Chem., Int. Ed. 2012, 51, 10236. (e) Cho, S. H.; Kim, J. Y.;
Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (f) Zheng, C.; You,
S.-L. RSC Adv. 2014, 4, 6173. (g) Baudoin, O. Chem. Soc. Rev. 2011,
40, 4902. (h) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(i) Tang, R.-Y.; Li, G.; Yu, J.-Q. Nature 2014, 507, 215. (j) McNally,
A.; Haffemayer, B.; Collins, B. S. L.; Gaunt, M. J. Nature 2014, 510,
129. (k) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon,
D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M.
́
R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (l) Chen, M. S.;
White, M. C. Science 2010, 327, 566.
(10) (a) Cho, J.-Y.; Iverson, C. N.; Smith, M. R., III. J. Am. Chem. Soc.
2000, 122, 12868. (b) Yinghuai, Z.; Chenyan, K.; Peng, A. T.; Emi, A.;
Monalisa, W.; Louis, L. K.-J.; Hosmane, N. S.; Maguire, J. A. Inorg.
Chem. 2008, 47, 5756. (c) Rentzsch, C. F.; Tosh, E.; Herrmann, W. A.;
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral data for all
compounds. This material is available free of charge via the
AUTHOR INFORMATION
■
Corresponding Authors
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the ERATO program from JST
(K.I.), the Funding Program for Next Generation World-
Leading Researchers from JSPS (220GR049 to K.I.), and Asahi
Kasei Pharma Award in Synthetic Organic Chemistry, Japan
(Y.Se.). Y.Sa. thanks the Integrative Graduate Education and
Research Program in Green Natural Sciences for support.
Keiko Kuwata and Kin-ichi Oyama are acknowledged for
assistance with the HRMS measurements. Cathleen M.
Crudden is acknowledged for critical comments. We thank
Takasago International Corporation for a gracious donation of
diphosphine ligands (P1−P3). ITbM is supported by the
World Premier International Research Center (WPI) Initiative,
Japan.
Kuhn, F. E. Green Chem. 2009, 11, 1610. (d) Chotana, G. A.; Rak, M.
̈
A.; Smith, M. R., III. J. Am. Chem. Soc. 2005, 127, 10539. (e) Tajuddin,
H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A.
S.; Cheung, M. S.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris,
J.; Lin, Z.; Marder, T. B.; Steel, P. G. Chem. Sci. 2012, 3, 3505.
(f) Hata, H.; Yamaguchi, S.; Mori, G.; Nakazono, S.; Katoh, T.;
Takatsu, K.; Hiroto, S.; Shinokubo, H.; Osuka, A. Chem.Asian J.
2007, 2, 849. (g) Del Grosso, A.; Ayuso Carrillo, J.; Ingleson, M. J.
Chem. Commun. 2015, 51, 2878.
(11) (a) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (b) Qiao, J. X.;
Lam, P. Y. S. Synthesis 2011, 829.
(12) 3,3′-Dialkylbipyridines and 2,9-dialkylphenanthrolines were
used for iridium-catalyzed C−H silylation. Saiki, T.; Nishio, Y.;
Ishiyama, T.; Miyaura, N. Organometallics 2006, 25, 6068.
(13) (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.;
Smith, M. R., III. Science 2002, 295, 305. (b) Preshlock, S. M.; Ghaffari,
B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III.
J. Am. Chem. Soc. 2013, 135, 7572.
REFERENCES
■
(1) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem.
2014, 57, 5845.
(14) The yield of borylation of 1a by (mesitylene)Ir(Bpin)3/P5 was
(2) Segura, J. L.; Martín, N. J. Mater. Chem. 2000, 10, 2403.
(3) Ullrich, R.; Hofrichter, M. Cell. Mol. Life Sci. 2007, 64, 271.
very low (∼5%).
E
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX