Page 7 of 8
Journal of the American Chemical Society
ble 10 with 84% regiochemical purity. Thus, our cobalt-
Supporting Information. Complete experimental details,
1
2
3
4
catalyzed method enables a four-step synthesis, streamlined
from the eight-step route reported previously29 and highlights
the utility of regioselective C-H functionalization in synthetic
applications.
characterization data, NMR spectroscopic and crystallo-
graphic data in CIF format. This material is available free
5
6
AUTHOR INFORMATION
Corresponding Author
*pchirik@princeton.edu
7
8
9
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
52
53
54
55
56
57
58
59
60
Notes
The authors declare the following competing financial
interests(s): J.V.O. and P.J.C. are inventors on U.S. Patent
Application 61/913,522 (Filed: December 9, 2014, Pub-
lished: June 18, 2015).
Scheme 5. Application of Ortho to Fluorine Selective C-H
Borylation to the Synthesis of Flurbiprofen (11).
Cobalt-Catalyzed C-H Borylation:
O
O
O
Me
Me
Me
ACKNOWLEDGMENT
I
OMe
(b)
72%
OMe
(c), (d)
OH
(a)
J.V.O. acknowledges the 2015 Howard Hughes Medical
Institute International Student Research Fellowship and
the 2016 Harold W. Dodds Honorific Fellowship (awarded
by the Graduate School at Princeton University). M.J.B.
thanks the Natural Sciences and Engineering Research
Council of Canada for a pre-doctoral fellowship (PGS-D).
We also thank AllyChem for a generous gift of B2Pin2.
77%
71%
over 2 steps
F
F
F
F
BPin
Ph
11
10
3j
4j
[81:19 o: m]
[84:16 o: m]
Flurbiprofen
[33% overall yield]
Reagents and conditions: (a) Methyl-2-chloropropionate (5.2
equiv.), Mn powder (6 equiv.), TFA (30 ꢀL), (bpy)NiBr2 (7 mol%),
DMF, 50 °C, 16 h; (b) B2Pin2 (1 equiv.), 1 (5 mol%), THF, 50 °C,
48 h; (c) PhBr (1.1 equiv.), Pd(dppf)Cl2 (5 mol%), K2CO3 (4
equiv.), THF/H2O (20 : 1), 50 °C, 16 h; (d) NaOH (5 equiv.),
THF/H2O (1:1), 90 °C, 24 h, then 12 M HCl. Reported numbers
are isolated yields after column chromatography. Regioselectiv-
ities were determined by 19F NMR spectroscopy. Overall yield
of Flurbiprofen (11) is corrected for the meta-phenylated regi-
oisomer.
REFERENCES
(1) (a) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (b)
Hagmann, W. K. J. Med. Chem. 2008, 51, 4359. (c) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (d) Ilardi,
E. A.; Vitaku, E.; Njardson, J. T. J. Med. Chem. 2014, 57, 2832. (e) Wang,
J.; Sánchez-Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.;
Fustero, S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2014, 114, 2432.
(2) (a) Jeschke, P. ChemBioChem 2004, 5, 570.; (b) Jeschke, P. Pest
Manage. Sci. 2010, 66, 10.; (c) Fujiwara, T.; O’Hagan, D. J. Fluorine
Chem. 2014, 167, 16.
CONCLUSIONS
(3) (a) Babudri, R.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Com-
mun. 2007, 1003. (b) Berger, R.; Resnati, G.; Metrangolo, P.; Weber, E.;
Hulliger, J. Chem. Soc. Rev. 2011, 40, 3496.
An efficient, highly ortho to fluorine selective cobalt-catalyzed
method for the C(sp2)-H borylation of fluorinated arenes has
been developed. An air stable, pincer-ligated cobalt(II)
bis(pivalate) was synthesized in a single step from the free lig-
and and appropriate cobalt precursor and was effective for
catalytic C(sp2)-H functionalization of electronically diverse
substrates regardless of the substitution pattern on the arene.
Common directing groups in iridium-catalyzed C-H functionali-
zation such as a benzylic dimethylamino substituent or a hy-
dridosilane did not alter the electronically enhanced site selec-
tivity of the cobalt catalyst, highlighting the complementarity of
earth abundent and precious metal catalysts. The improved
regioselectivity of the cobalt catalyzed C(sp2)-H borylation was
applied to a streamlined synthesis of the anti-inflammatory
drug, Flurbiprofen. These studies represent one of the rare
examples of selective C-H functionalization that in the absence
of directing groups, offers new opportunities for reaction de-
velopment and applications in synthesis.
(4) Hall, D. G. Boronic Acids; Wiley-VCH: Weinheim, Germany, 2005.
(5) (a) Mkhalid, I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hart-
wig, J. F. Chem. Rev. 2010, 110, 890. (b) Hartwig, J. F. Chem. Soc. Rev.
2011, 40, 1992. (c) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864.
(6) (a) Cho, J.−Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith,
M. R., III Science 2002, 295, 305. (b) Ishiyama, T.; Takagi, J.; Ishida, K.;
Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. J. Am. Chem. Soc. 2002, 124,
390. (c) Ishiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew.
Chem. Int. Ed. 2002, 41, 3056. (d) Preshlock, S. M.; Ghaffari, B.;
Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Smith, M. R. J. Am. Chem.
Soc. 2013, 135, 7572.
(7) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.; Miyaura, N.;
Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263.
(8) Tamura, H.; Yamazaki, H.; Sato, H.; Sakaki, S. J. Am. Chem. Soc.
2003, 125, 16114.
(9) Green, A. G.; Liu, P.; Merlic, C. A.; Houk, K. N. J. Am. Chem. Soc.
2014, 136, 4575.
(10) (a) Hall, G. E.; Piccolini, R.; Roberts, J. D. J. Am. Chem. Soc. 1955,
77, 4540. (b) Streitwieser, A. Jr.; Scannon, P. J.; Niemeyer, H. M. J. Am.
Chem. Soc. 1972, 94, 7936.
(11) Palladium-catalyzed C-H arylation has been shown to occur or-
tho to fluorine selectively. For representative examples: (a) Campeau,
L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128,
ASSOCIATED CONTENT
ACS Paragon Plus Environment