Cu(II)-catalyzed functionalizations of aryl C-H bonds using O2 as an oxidant

Article abstract of DOI:10.1021/ja061715q

Cu(II)-catalyzed acetoxylation and halogenation of aryl C-H bonds are developed. ortho-Selectivity was observed with a wide range of 2-arylpyridine substrates. Both mono- and difunctionalizations are achieved by tuning the reaction conditions. Excellent functional group tolerance and use of O₂ as a stoichiometric oxidant are significant advantages over our recently developed Pd-catalyzed C-H functionalization reactions. These newly discovered reaction conditions are also applicable for cyanation, amination, etherification, and thioetherification of aryl C-H bonds. Mechanistic investigations are carried out to gain insights into the Cu(II)-catalyzed C-H functionalization reactions. Copyright

Full text of DOI:10.1021/ja061715q

Published on Web 05/06/2006
Cu(II)-Catalyzed Functionalizations of Aryl C-H Bonds Using O
2
as an
Oxidant
Xiao Chen, Xue-Shi Hao, Charles E. Goodhue, and Jin-Quan Yu*
Department of Chemistry MS015, Brandeis UniVersity, Waltham, Massachusetts 02454-9110
Received March 12, 2006; E-mail: yu200@brandeis.edu
The development of transition-metal-catalyzed C-H activation
Scheme 1. Formation of Monohydroxylated Products
reactions directed by functional groups has witnessed substantial
progress in the past three decades.1 A wide range of metal catalysts,
including Ru, Rh, Pt, and Pd, has been exploited with varying
degrees of success. From the viewpoint of the practicality of these
types of reactions in laboratory synthesis and industrial applications,
tremendous challenges lie ahead in controlling selectivity and
identifying inexpensive oxidants and metal catalysts. In light of
the remarkable progress made in the development of Cu-catalyzed
C-heteroatom bond forming reactions that were previously cata-
,2
Scheme 2. Cu(II)-Catalyzed Acetoxylation of Aryl C-H Bonds
II
3
lyzed predominantly by Pd catalysts, we turned our attention to
Cu-catalyzed C-H functionalization reactions. H-abstraction of
allylic C-H bonds using Cu(I)/tert-butyl hydroperoxide has been
4
5
successfully exploited in peroxidation and alkylation reactions.
Since the pyridyl group has been extensively used to direct C-H
activation reactions,1 we launched our effort to develop C-H
functionalization reactions directed by a pyridyl group (Py) using
Cu(II) catalysts. Herein, we report a Cu(II)-catalyzed acetoxylation
and halogenation of aryl C-H bonds. This newly discovered
reaction is also shown to be applicable to cyanation, amination,
etherification, and thioetherification of C-H bonds.
,6
Table 1. Cu(II)-Catalyzed Chlorination of Aryl C-H Bondsa
We initiated our investigations by examining whether pyridyl
can direct Cu-catalyzed ortho-selective C-H functionalizations. We
discovered that the reaction of 2-phenylpyridine with 1 equiv of
Cu(OAc)
2
2 2
and 1 equiv of H O in MeCN under O (1 atm) at 130
°
1
C for 36 h gave hydroxylated product 1b in 67% yield (Scheme
7
18
). Labeling experiments using H
2
O in the absence of O
was incorporated into product
b. The rapid hydrolysis of the corresponding acetate 1a under
2
showed
that the oxygen atom from Cu(OAc)
1
2
8
the reaction conditions led us to propose that the first step involves
the formation of the acetoxylated product, which undergoes
hydrolysis catalyzed by the intramolecular pyridyl group.9
We were delighted to find that reactions of 2-arylpyridines 2-5
give the monohydroxylated products 2a-5a in moderate yields
under the same conditions (Scheme 1). The high monoselectivity
is most likely due to the binding of the hydroxyl group and the
nitrogen in the product to Cu(II), which prevents further reaction.
In particular, the tolerance of the double bond and carbonyl
2
functional groups and the use of O as the oxidant are significant
advantages compared to our recently reported Pd-catalyzed C-H
a
With 20 mol % of CuCl2, Cl2CHCHCl2, O2 (1 atm), 130 °C, 24 h.
functionalization reactions.10
b
At 100 °C; 23% dichlorinated product was also obtained.
While the selective formation of the monohydroxylated product
is a synthetically useful feature, this product inhibits the reaction
and prevents catalytic turnover. This problem was circumvented
-
verted to Cl
2
CdCHCl and HCl that provided the Cl anion source
(see Supporting Information). The reaction of a wide range of 2-aryl-
pyridines (1-13) with 20 mol % of CuCl in Cl CHCHCl afforded
by adding Ac
2
O to the reaction to acetylate 1b. As a result, the Cu
2
2
2
loading was reduced to 10 mol % in the presence of O
resulting in significant diacetoxylation (Scheme 2).
During the screening of reaction conditions for this acetoxylation
2
, albeit
chlorinated products in excellent yields (Table 1). In the presence
of an ortho-substituent on the pyridine (entry 11), the monochlori-
nated product was obtained as a major product, which indicates
that the steric hindrance around the N atom of the pyridyl group pre-
vents further chlorination. It is also observed that electron-with-
drawing groups attached to the aryl ring resulted in lower conversion
(entry 7). Pleasingly, monoselectivity was also improved by carrying
reaction, we found that the reaction of 1 with 20 mol % of Cu-
(
OAc)
lated yield.
pH measurements indicated that Cl
2 2 2
in Cl CHCHCl gave dichlorinated product 1d in 92% iso-
11,12
1
Analysis of the reaction mixture using H NMR and
CHCHCl was partially con-
2
2
6790
9
J. AM. CHEM. SOC. 2006, 128, 6790-6791
10.1021/ja061715q CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Cu(II)-Mediated Diverse C-H Functionalizationsa
2
first order in both substrate 1 and CuCl . Third, electron-withdraw-
ing groups decrease the reaction rates (see Supporting Information).
On the basis of Kochi’s seminal work on Co(TFA) -mediated
3
oxidation of aryl C-H bonds,15 we invoked a radical-cation
pathway to explain the data obtained from our mechanistic studies
(Scheme 5). A single electron transfer (SET) from the aryl ring to
anion
entry
source
solvent
product (X)
yield
the coordinated Cu(II) leading to the cation-radical intermediate
15 is the rate-limiting step. The lack of reactivity of biphenyl
suggests that the coordination of Cu(II) to the pyridine is necessary
for the SET process. The observed ortho-selectivity is explained
by an intramolecular anion transfer from a nitrogen-bound Cu(I)
“ate” complex 15.16
In summary, we have discovered Cu(II)-catalyzed diverse C-H
functionalization reactions. The use of inexpensive Cu catalysts and
2
O as the stoichiometric oxidant is a significant practical advantage.
The tolerance of alkene, alkoxy, and aldehyde functionality is a
synthetically useful feature. Identification of new conditions to
achieve catalytic turnover for the amination, cyanation, etherifica-
tion, and thioetherification reactions is underway.
65%d
1
2
3
4
5
6
7
8
9
-
Br2CHCHBr2
ClCH2CH2Cl
MeCN
Br, 1f
I, 1g
CN, 1h
CN, 1h
TsNH, 1i
p-CN-PhO, 1j
PhS, 1k
MeS, 1l
OH, 1b
b,d
I2
61%
42%
67%
74%
35%
40%d
TMSCN
-
TsNH2
p-CN-PhOH
PhSH
MeSSMe
H2O
MeNO2
MeCN
MeCN
DMSO
DMSO
51%
22%c
DMSO
a
b
With 1 equiv of Cu(OAc)2, air, solvent, 130 °C, 24 h. At 100 °C, 8
h. c With 1 equiv of CuF2. Difunctionalized products (10-20%) were also
obtained.
d
Scheme 3. Dimerization
Acknowledgment. We thank Brandeis University for financial
support, and the Camille and Henry Dreyfus Foundation for a New
Faculty Award. We thank Professor Peter Beak (University of
Illinois, UrbanasChampaign) for helpful discussions about the
mechanism.
Supporting Information Available: Experimental procedure and
characterization of all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 4. Isotope Effect
References
(
1) For reviews on directed C-H activation reactions, see: (a) Dyker, G.
Angew. Chem., Int. Ed. 1999, 38, 1698. (b) Ritleng, V.; Sirlin, C.; Pfeffer,
M. Chem. ReV. 2002, 102, 1731 and references therein.
Scheme 5. Possible Mechanism
(
2) (a) Murai, S.; Kakiuchi, F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda,
M.; Chatani, N. Nature 1993, 366, 529. (b) Jun, C. H.; Lee, H.; Hong, J.
B. J. Org. Chem. 1997, 62, 1200. (c) Lenges, C. P.; Brookhart, M. J. Am.
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(
3) (a) Marcoux, J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
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19, 10539. (b) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem.
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J. G.; van Koten, G. Org. Lett. 2005, 7, 5241.
out the reaction at a lower temperature (100 °C, entry 2).
The initial success prompted us to test whether the use of other
copper sources, CuX , or a combination of Cu(OAc) and nucleo-
2 2
philic anions could be equally effective, thereby introducing differ-
ent types of functionality onto the aryl ring. Remarkably, this re-
activity was extended to cyanation, amination, etherification, and
(
4) For a review on Cu-catalyzed allylic oxidation, see: Eames, J.; Watkinson,
M. Angew. Chem., Int. Ed. 2001, 40, 3567.
(
(
5) Li, Z.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 56.
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(
7) For a stoichiometric hydroxylation reaction of N-benzoyl-2-methylalanine
using Cu(0)/trimethylamine N-oxide, see: Reinaud, O.; Capdevielle, P.;
Maumy, M. J. Chem. Soc., Chem. Commun. 1990, 566.
thioetherification reactions by using a combination of Cu(OAc)
2
(8) For oxygen insertions into aryl C-H bonds involving bis(µ-oxo)dicopper
complexes, see: Holland, P. L.; Rodgers, K. R.; Tolman, W. B. Angew.
Chem., Int. Ed. 1999, 38, 1139.
and various nucleophilic anions (Table 2). The monofunctionalized
products are obtained as major products. Direct cyanation is a valu-
able transformation in heterocycle synthesis since the conversion
of CN into tetrazole is frequently used in drug syntheses.13 The
(9) For a stoichiometric acetoxylation reaction of p-methoxyphenol using Cu-
2
(OAc) under argon, see: Takizawa, Y.; Tateishi, A.; Sugiyama, J.;
Yoshida, H.; Yoshihara, N. J. Chem. Soc., Chem. Commun. 1991, 104.
(10) (a) Giri, R.; Chen, X.; Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44, 2112.
(
b) Giri, R.; Liang, J.; Lei, J. G.; Li, J. J.; Wang, D. H.; Chen, X.; Naggar,
use of MeNO
ient (entry 4).14 We also identified TsNH
to achieve the first direct amination of aryl C-H bonds (entry 5).
The formation of the hydroxylated product using CuF and H O is
2
as a CN source for cyanation is practically conven-
I. C.; Guo, C.; Foxman, B. M.; Yu, J. Q. Angew. Chem., Int. Ed. 2005,
7420. (c) Chen, X.; Li, J. J.; Hao, X. S.; Goodhue, C. E.; Yu, J. Q. J. Am.
Chem. Soc. 2006, 128, 78.
2
as a nitrogen anion source
(
11) For a stoichiometric chlorination reaction of enolates, see: (a) Kochi, J.
K. J. Am. Chem. Soc. 1955, 77, 5274. (b) Shi, X. X.; Dai, L.-X. J. Org.
Chem. 1993, 58, 4596.
2
2
practically attractive if the yield can be further improved (entry 9).
By running the iodination reaction (entry 2) at 130 °C using PhI
as a solvent, the dimerized product 1m was obtained in 67% yield
(
(
(
(
2
12) For CuCl -catalyzed para-chlorination of phenols, see: Menini, L.;
Gusevskaya, E. V. Chem. Commun. 2006, 209.
13) Amantini, D.; Beleggia, R.; Fringuelli, F.; Pizzo, F.; Vaccaro, L. J. Org.
Chem. 2004, 69, 2896.
(Scheme 3). Presumably, the initially formed iodinated product 1g
14) The mechanism of the formation of the cyanation product in the absence
of CN- remains to be elucidated.
underwent Ullmann coupling to give 1m.
15) (a) Kochi, J. K.; Tang, R. T.; Bernath, T. J. Am. Chem. Soc. 1973, 95,
To achieve catalytic turnover in these reactions, we carried out
mechanistic investigations and obtained a number of insights. First,
no isotope effect was observed in an intramolecular competition
experiment using substrate 14 (Scheme 4). This result suggests that
the reaction mechanism is different from the Pd-catalyzed func-
tionalization reactions, in which substantial isotope effects are usu-
ally observed.1 Second, the chlorination reaction was found to be
7
114-7123. (b) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations
of Organic Compounds; Academic Press: New York, 1981; pp 7-8.
16) An alternative mechanism: an electrophilic attack of the pyridyl-
coordinated Cu(II) on the aryl ring could take place in a manner similar
(
1
5
4
to that of the Pb(TFA) -mediated oxidation of aryl C-H bonds. The
subsequent loss of a proton would give an unusual cyclometalated aryl
Cu(II) complex that could undergo reductive elimination to give the
functionalized products and Cu(0).
0a
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