Copper-catalyzed, directing group-assisted fluorination of arene and heteroarene C-H bonds

Article abstract of DOI:10.1021/ja4047125

We have developed a method for direct, copper-catalyzed, auxiliary-assisted fluorination of β-sp² C-H bonds of benzoic acid derivatives and γ-sp² C-H bonds of α,α-disubstituted benzylamine derivatives. The reaction employs a CuI cata

Full text of DOI:10.1021/ja4047125

Communication
pubs.acs.org/JACS
Copper-Catalyzed, Directing Group-Assisted Fluorination of Arene
and Heteroarene C−H Bonds
Thanh Truong, Kristine Klimovica, and Olafs Daugulis*
Department of Chemistry, University of Houston, Houston, Texas 77204-5003, United States
S
* Supporting Information
Specifically, Buchwald has shown that aryl (Ar) triflates can
be converted to Ar fluorides under Pd catalysis.4 Ritter has
ABSTRACT: We have developed a method for direct,
copper-catalyzed, auxiliary-assisted fluorination of β-sp2
developed methods for stannane, boronic acid, and phenol
C−H bonds of benzoic acid derivatives and γ-sp2 C−H
bonds of α,α-disubstituted benzylamine derivatives. The
reaction employs a CuI catalyst, a AgF fluoride source, and
DMF, pyridine, or DMPU solvent at moderately elevated
temperatures. Selective mono- or difluorination can be
achieved by simply changing reaction conditions. The
method shows excellent functional group tolerance and
provides a straightforward way for the preparation of
ortho-fluorinated benzoic acids.
conversion to fluoroaromatics.5 Hartwig has shown that Ar
iodides can be converted to Ar fluorides by a combination of a
stoichiometric copper(I) complex and AgF.6 Aryl stannanes
and Ar borates have been converted to Ar fluorides by
employing Cu(I) in combination with an electrophilic fluoride
source.7 Many of these processes have been developed on the
basis of mechanistic studies;8 however, these methods require
the use of prefunctionalized starting materials. Nondirected
fluorination of sp3 C−H bonds by radical methods has also
been investigated.9 Only a few groups have reported directed
catalytic sp2 C−H bond fluorination. In a pioneering work,
Sanford has shown that a pyridine directing group can be
employed for a Pd-catalyzed arene fluorination by electrophilic
fluorine sources. Mechanistic studies support involvement of
high-valent Pd complexes in these reactions.10 Yu has
demonstrated Pd-catalyzed benzylamine triflamide and benzoic
acid perfluoroaniline amide ortho-fluorination by N-fluoropyr-
idine derivatives.11 Recently, Sanford has shown that Pd-
(OAc)2/AgF/PhI(OPiv)2 system12 can be employed for 8-
methylquinoline benzylic C−H bond fluorination.13 A general
method for directed arene C−H bond fluorination by using a
first-row transition metal catalyst has not been reported.15 We
disclose here a method for aminoquinoline and picolinamide-
directed benzoic acid and benzylamine derivative ortho-
fluorination under Cu catalysis.
luoroaromatic compounds possess inertness; high chem-
Fical, thermal, and metabolic stability; and unique electronic
a
Table 1. Optimization of Reaction Conditions
entry
catalyst (mol %)
T, °C
1, %
2, %
3, %
b
1
Cu(OAc)2 (25%)
Cu(OAc)2 (25%)
Cu(OAc)2 (25%)
CuI (25%)
100
100
100
100
80
4
<2
20
11
20
18
4
17
13
42
54
60
70
79
80
17
52
5
5
4
b,c
2
3
4
5
6
7
8
9
8
In 2005, we introduced 8-aminoquinoline and picolinic acid
auxiliaries for Pd-catalyzed sp2 and sp3 C−H bond arylation.14a
Recently Cu-catalyzed sulfenylation and amination of C−H
bonds in 8-aminoquinoline benzamides and benzylamine
picolinamides was demonstrated.14b,c We hypothesized that 8-
aminoquinoline and picolinic acid auxiliaries would promote
Cu-catalyzed ortho-fluorination of sp2 C−H bonds on the basis
of the following considerations: (1) Cu-catalyzed Ar halide
fluorination has been reported in a macrocyclic polyamine
system,16a (2) Cu-promoted C−H activation has been reported
in the same system,16b and (3) it appears that both macrocyclic
amine and 8-aminoquinoline benzamide ligands stabilize high-
valent Cu intermediates.
6
CuI (25%)
5
CuI (15%)
80
3
d
d
f
CuI (15%)
80
7
,
e
CuI (15%)
80
16
<2
10
<2
3
CuI (20%)
80
38
33
78
e,f
10
f g
CuI (20%)
80
11 ,
CuI (20%)
80
a
Amide 0.25 mmol, AgF 3 equiv, NMO 4 equiv, DMF 1 mL. Yields
b
c
were determined by GC analysis. DMSO solvent. PhI(OPiv)2
d
e
oxidant instead of NMO. AgF 4 equiv, NMO 5 equiv. Pyridine
solvent. AgF 6 equiv, 8 equiv NMO, 1.5 h. Pyridine additive 2 equiv.
f
g
Reaction of 8-aminoquinoline p-trifluoromethyl-benzamide
was investigated with respect to Cu catalyst, fluorine source,
oxidant, and solvent (Table 1). Best results for monofluorina-
tion were obtained by using CuI catalyst, NMO oxidant, and
properties. They are widely used as pharmaceuticals, agro-
chemicals, and imaging materials.1 Classical methods for
synthesis of fluoroaromatics such as the Balz−Schiemann
reaction employ prefunctionalized starting materials and
typically require harsh reaction conditions, thus limiting the
scope of transformations.2,3 More recently, aryl-fluorine bonds
have been created by using transition-metal catalysis.
Received: May 10, 2013
Published: June 12, 2013
© 2013 American Chemical Society
9342
dx.doi.org/10.1021/ja4047125 | J. Am. Chem. Soc. 2013, 135, 9342−9345

Journal of the American Chemical Society
Communication
a
a
Table 2. Monofluorination of Carboxylic Acid Derivatives
Table 3. Difluorination of Carboxylic Acid Derivatives
a
Amide 0.25 mmol, DMF 1 mL. Yields are isolated yields. Please see
b
SI for details. Pyridine solvent.
Scheme 1. Fluorination of Picolinamides
a
Amide 0.25 mmol, DMF 1 mL. Yields are isolated yields. Please see
b
Supporting Information (SI) for details. Reaction scale: 5 mmol.
c
Pyridine solvent.
(entries 9−11). Longer reaction times require pyridine additive
(2 equiv) to prevent decomposition of amide substrate (entry
11).
Reaction scope with respect to monofluorination of 8-
aminoquinoline benzamides is presented in Table 2. Both
electron-rich (entries 2 and 6) and electron-poor (entries 1, 3−
5, 7, 8) benzamides are reactive. Heterocyclic carboxamides
DMF solvent. Use of PhI(OPiv)2 oxidant resulted in lower
yields (entry 2). DMSO solvent is inferior to DMF due to
starting material decomposition (entry 1 vs 4). Reaction can be
run in pyridine (entry 8) which slows decomposition of starting
material, albeit at the expense of reaction rate. Selective
difluorination can be achieved by using higher loading of CuI
9343
dx.doi.org/10.1021/ja4047125 | J. Am. Chem. Soc. 2013, 135, 9342−9345

Journal of the American Chemical Society
Communication
studies of the transformation and attempts to isolate reaction
intermediates.
Scheme 2. Auxiliary Cleavage
ASSOCIATED CONTENT
* Supporting Information
■
S
Detailed experimental procedures and characterization data for
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
olafs@uh.edu
■
containing indole (entry 9) and pyridine (entry 10) moieties
are fluorinated in good yields. The reaction is functional-group
tolerant, with carboxylate (entry 3), nitrile (entry 4), and nitro
groups (entry 7) compatible with the fluorination conditions.
For strongly electron-deficient substrates such as 4-nitro-
benzoyl and pyridyl derivatives (entries 7 and 10), the reaction
must be run in pyridine solvent to prevent decomposition of
product. However, somewhat longer reaction times are
required if pyridine is employed.
Optimization results in Table 1 show that, by increasing CuI
and AgF loading and reaction time, clean difluorination can be
obtained. Longer reaction times require the use of pyridine to
prevent decomposition of aminoquinoline amides. Difluorina-
tion examples are presented in Table 3. Similar to
monofluorination, electron-rich (entries 4, 5, 7), electron-
poor (entries 1−3, 6), and heterocyclic (entry 8) amides can be
efficiently difluorinated in good yields. Interestingly, difluori-
nation of meta-substituted amides is possible (entries 4, 7), but
contrasts with Pd-catalyzed C−H bond functionalization, where
substitution at more hindered positions is typically not
observed.17 The observation is consistent with results obtained
in the Cu-promoted sulfenylation of sp2 C−H bonds, where
functionalization of hindered positions is possible.14b
Fluorination of benzylamine derivatives is also possible by
using a picolinamide directing group (Scheme 1). However, the
reactions are less efficient, requiring 50 mol % CuI catalyst,
higher temperature, and DMPU solvent. Reasonable con-
versions could only be obtained with α,α-disubstituted
benzylamines. This behavior is consistent with Cu-catalyzed
amination and sulfenylation of C−H bonds.14b,c
Auxiliary can be cleaved by base hydrolysis. Thus, heating
amide 6 with NaOH in ethanol for 24 h afforded high yield of
trifluorobenzoic acid (Scheme 2).
While speculations about the reaction mechanism are
premature at this point, Ribas has shown that Cu-catalyzed
nucleophilic Ar fluorination and Ar halide exchange is possible
in a geometrically constrained system.16a The reactions proceed
via Cu(III) intermediates, thus showing that C−F reductive
elimination from Cu(III) is possible under very mild
conditions.7b Given that aminoquinoline amides stabilize high
oxidation states in transition metals,14d it is likely that Cu-
catalyzed aminoquinoline amide fluorination also proceeds via
Cu(III) intermediates.
To conclude, we developed a method for direct, Cu-
catalyzed, auxiliary-assisted fluorination of β-sp2 C−H bonds of
benzoic acid derivatives and γ-sp2 C−H bonds of benzylamine
derivatives. The reaction uses catalytic CuI or AgF as the
nucleophilic fluoride source, and DMF, pyridine, or DMPU
solvent at moderately elevated temperatures. The method
allows for selective mono- or difluorination of benzamide
substrates, shows excellent functional group tolerance, and
provides a straightforward way for the preparation of ortho-
fluorinated benzoic acids. Future work involves mechanistic
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Welch Foundation (Grant E-1571), National
Institute of General Medical Science (Grant R01GM077635),
Camille and Henry Dreyfus Foundation, and Norman Hacker-
man Advanced Research Program for supporting this research.
REFERENCES
■
(1) (a) Hollingworth, C.; Gouverneur, V. Chem. Commun. 2012, 48,
2929. (b) Coenen, H. H.; Ermert, J. Curr. Radiopharm. 2010, 3, 163.
(c) Zhang, X.-J.; Lai, T.-B.; Kong, R. Y.-C. Top. Curr. Chem. 2012, 308,
365. (d) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (e) Jeschke, P. ChemBioChem 2004, 5, 570.
(2) (a) Balz, G.; Schiemann, G. Chem. Ber. 1927, 60, 1186.
(3) (a) Dawood, K. M. Tetrahedron 2004, 60, 1435. (b) Adams, D. J.;
Clark, J. H. Chem. Soc. Rev. 1999, 28, 225. (c) Rozen, S. Adv. Synth.
Catal. 2010, 352, 2691. (d) Yamada, S.; Knochel, P. Synthesis 2010,
2490. (e) Umemoto, T.; Tomizawa, G. J. Org. Chem. 1995, 60, 6563.
(4) (a) Watson, D. A.; Su, M.; Teverovskiy, G.; Zhang, Y.; Garcia-
Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science 2009, 325, 1661.
(b) Maimone, T. J.; Milner, P. J.; Kinzel, T.; Zhang, Y.; Takase, M. K.;
Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106.
(5) (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem., Int. Ed.
2008, 47, 5993. (b) Tang, P.; Wang, W.; Ritter, T. J. Am. Chem. Soc.
2011, 133, 11482. (c) Tang, P.; Furuya, T.; Ritter, T. J. Am. Chem. Soc.
2010, 132, 12150. (d) Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008,
130, 10060. Review: (e) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature
2011, 473, 470.
(6) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 10795.
(7) (a) Ye, Y.; Sanford, M. S. J. Am. Chem. Soc. 2013, 135, 4648.
(b) Fier, P. S.; Luo, J.; Hartwig, J. F. J. Am. Chem. Soc. 2013, 135, 2552.
(8) (a) Grushin, V. V. Acc. Chem. Res. 2010, 43, 160. (b) Vigalok, A.
Organometallics 2011, 30, 4802. (c) Dubinsky-Davidchik, I. S.; Potash,
S.; Goldberg, I.; Vigalok, A.; Vedernikov, A. N. J. Am. Chem. Soc. 2012,
134, 14027. (d) Zhao, S.-B.; Wang, R.-Y.; Nguyen, H.; Becker, J. J.;
́
Gagne, M. R. Chem. Commun. 2012, 48, 443. (e) Mankad, N. P.;
Toste, F. D. Chem. Sci. 2012, 3, 72.
(9) (a) Bloom, S.; Pitts, C. R.; Miller, D. C.; Haselton, N.; Holl, M.
G.; Urheim, E.; Lectka, T. Angew. Chem., Int. Ed. 2012, 51, 10580.
(b) Liu, W.; Huang, X.; Cheng, M.-J.; Nielsen, R. J.; Goddard, W. A.,
III; Groves, J. T. Science 2012, 337, 1322. (c) Yin, F.; Wang, Z.; Li, Z.;
Li, C. J. Am. Chem. Soc. 2012, 134, 10401. (d) Amaoka, Y.; Nagatomo,
M.; Inoue, M. Org. Lett. 2013, 15, 2160. (e) Katcher, M. H.; Doyle, A.
G. J. Am. Chem. Soc. 2010, 132, 17402. Review: (f) Sibi, M. P.;
Landais, Y. Angew. Chem., Int. Ed. 2013, 52, 3570.
(10) (a) Hull, K. L; Anani, W. Q.; Sanford, M. S. J. Am. Chem. Soc.
2006, 128, 7134. (b) Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc.
2009, 131, 3796.
(11) (a) Wang, X.; Mei, T.-S.; Yu, Y.-Q. J. Am. Chem. Soc. 2009, 131,
7520. (b) Chan, K. S. L.; Wasa, M.; Wang, X.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2011, 50, 9081. Review: (c) Engle, K. M.; Mei, T.-S.; Wang,
X.; Yu, J.-Q. Angew. Chem., Int. Ed. 2011, 50, 1478.
9344
dx.doi.org/10.1021/ja4047125 | J. Am. Chem. Soc. 2013, 135, 9342−9345

Journal of the American Chemical Society
Communication
(12) Wu, T.; Yin, G.; Liu, G. J. Am. Chem. Soc. 2009, 131, 16354.
(13) McMurtrey, K. B.; Racowski, J. M.; Sanford, M. S. Org. Lett.
2012, 14, 4094.
(14) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem.
Soc. 2012, 134, 18237. (c) Tran, L. D.; Roane, J.; Daugulis, O. Angew.
Chem., Int. Ed. 2013, 52, 6043. (d) Shabashov, D.; Daugulis, O. J. Am.
Chem. Soc. 2010, 132, 3965.
(15) CuF2-mediated fluorination of benzene: Subramanian, M. A.;
Manzer, L. E. Science 2002, 297, 1665.
́
(16) (a) Casitas, A.; Canta, M.; Sola, M.; Costas, M.; Ribas, X. J. Am.
Chem. Soc. 2011, 133, 19386. (b) Ribas, X.; Jackson, D. A.; Donnadieu,
B.; Mahía, J.; Parella, T.; Xifra, R.; Hedman, B.; Hodgson, K. O.;
Llobet, A.; Stack, T. D. P. Angew. Chem., Int. Ed. 2002, 41, 2991.
(c) Huffman, L. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 9196.
(d) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
(17) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009,
42, 1074.
9345
dx.doi.org/10.1021/ja4047125 | J. Am. Chem. Soc. 2013, 135, 9342−9345