Gold-catalyzed oxidative acyloxylation of arenes

Article abstract of DOI:10.1021/ol202577c

A variety of nonactivated hindered aromatic rings are acyloxylated (22 examples, up to 83% yield) in the presence of PPh₃AuCl as the catalyst and di(acetoxy)iodobenzene as the oxidant. The reaction proceeds at 110 °C in an acid media and allows the formation of both hindered acetoxy and acyloxy derivatives. This methodology nicely complements the Pd-catalyzed arene acyloxylation reaction, which is not operating on hindered substrates and allows the Au-catalyzed unprecedented acyloxylation reaction of arenes, implying various carboxylic acids.

Full text of DOI:10.1021/ol202577c

ORGANIC
LETTERS
2011
Vol. 13, No. 22
6086–6089
Gold-Catalyzed Oxidative Acyloxylation of
Arenes§
ꢀ
Alexandre Pradal, Patrick Y. Toullec,* and Veronique Michelet*
Chimie ParisTech, Laboratoire Charles Friedel, UMR 7223 11 rue P. et M. Curie, 75231
Paris Cedex 05, France
patrick-toullec@chimie-paristech.fr; veronique-michelet@chimie-paristech.fr
Received September 23, 2011
ABSTRACT
A variety of nonactivated hindered aromatic rings are acyloxylated (22 examples, up to 83% yield) in the presence of PPh3AuCl as the catalyst and
di(acetoxy)iodobenzene as the oxidant. The reaction proceeds at 110 °C in an acid media and allows the formation of both hindered acetoxy and
acyloxy derivatives. This methodology nicely complements the Pd-catalyzed arene acyloxylation reaction, which is not operating on hindered
substrates and allows the Au-catalyzed unprecedented acyloxylation reaction of arenes, implying various carboxylic acids.
Homogeneous gold catalysis has emerged in the past few
years as a very exciting area of research due to its unique
Lewis acid carbophilic properties.1 More recently, the
electrophilicity of gold has been exploited in Csp2-H
activation of arenes. Since the initial works of Kharasch
and Isbell,2 and later on Braustein,3 it is well established
that auration of nonactivated aromatic rings occurs under
mild conditions in the presence of Au(III) complexes.
Subsequent reductive elimination liberates the functiona-
lized aryl compound and a Au(I) species. This transforma-
tion can be made catalytically by the regeneration of the
Au(III) species inthe presenceofanexternaloxidant. After
a long period of underutilization of this concept, in the past
decade, a number of synthetic functionalizations of aromatic
substrates including CꢀC,4 CꢀN5 and CꢀX6 bond forming
reactions have been described (Scheme 1).7 In line with our
research program initiated on gold-catalyzed carbonꢀ
oxygen bond-forming reactions,8 we decided to investigate
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2011, 17, 8248. (e) de Haro, T.; Nevado, C. Synthesis 2011, 2530.
§ Dedicated to Dr. C. Bruneau on the occasion of his 60th birthday.
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2006, 45, 7896. (b) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395. (c)
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Chianese, A. R.; Lee, S. J.; Gagne, M. R. Angew. Chem., Int. Ed. 2007,
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^
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^
Genet, J.-P. J. Am. Chem. Soc. 2005, 127, 9976. (c) Genin, E.; Toullec,
^
P. Y.; Antoniotti, S.; Brancour, C.; Genet, J.-P.; Michelet, V. J. Am.
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Michelet, V. Synlett 2008, 707. (g) Toullec, P. Y.; Blarre, T.; Michelet, V.
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Tetrahedron 2011, 67, 4371.
r
10.1021/ol202577c
Published on Web 10/27/2011
2011 American Chemical Society

the gold-catalyzed acyloxylation of aromatic systems.
Selective oxidation of nonactivated aromatic rings9 indeed
represents a highly interesting and challenging organic
transformation as aryl esters10,11 and phenols12 are extre-
mely frequent synthetic building molecules found in phar-
maceuticals, polymers or natural products.
Table 1. Gold- versus Transition Metal-catalyzed Acetoxyla-
tion of Mesitylene in the Presence of DAIBa
Scheme 1. Selected Examples of Au(I)/Au(III)-catalyzed CꢀH
entry
catalyst
solvent
CH3CN
temp (°C) t (h) yield (%)b
Functionalization of Arenes
1
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
(PPh3)AuCl
60
100
80
1
<5
<5
2
CH2ClCH2Cl
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
16
3
2.5
10
4
110
110
110
110
110
110
110
110
110
110
110
110
2.5
2.5
51
5c
6
40
12
62d
trace
29
7
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
8
AuCl
9
(PPh3)AuNTf2 CH3CO2H
42
10
11
12
13
14
15
AuCl3
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
CH3CO2H
49
HAuCl4
Au2O3
29
21
Ag(OAc)
PtCl2
trace
trace
6
Pd(OAc)2
Considering the recent work from Nevado,4e,13 Tse4b,d
and co-workers on gold-catalyzed CꢀC coupling reac-
tions, we selected DAIB14,15 (di(acetoxy)iodobenzene) as
a suitable oxidant for gold(I) complexes, the main issue
being to drive the reaction toward acyloxylation versus
CꢀC bond formation. We therefore wish to report our
preliminary investigations allowing the acetoxylation and
acyloxylation reactions of nonactivated hindered arenes.16
At the outset of our studies, the model substrate mesi-
tylene 2a was reacted with 1.3 equiv of DAIB 1 in the
presence of 2 mol % of a variety of gold salts (Table 1). We
initially used (PPh3)AuCl, as a stable, easy to handle gold
precursor. Whereas the reactivity in acetonitrile and di-
chloroethane was particularly disappointing (Table 1,
a Conditions: 0.5 mmol of mesitylene 2a and 1.3 equiv of di(acetoxy)-
iodobenzene 1 in 1 mL of solvent. n.d. not determined. b Yields have
been determined by GC analysis using n-octadecane as internal stan-
dard. c Reaction perfomed with 2 equivalents of di(acetoxy)iodobenzene
1. d Isolated yield.
entries 1 and 2), we were pleased to find that the use of
acetic acid led to the desired product 3a, despite in a low
yield (Table 1, entry 3). Increasing the temperature to
110 °C afforded 3ain moderate 51% yield (table 1, entry 4).
The use of an excess of DAIB 1 (Table 1, entry 5) did not
give better results, whereas prolonged reaction time af-
forded the arylacetate 3a in 62% isolated yield (Table 1,
entry 6). The importance of the gold catalyst was checked
and the reaction does not proceed in the absence of
(PPh3)AuCl (Table 1, entry 7).
ꢀ
(9) Alonso, D. A.; Najera, C.; Pastor, I. S.; Yus, M. Chem.;Eur. J.
We then evaluated the efficiency of the gold precursor
catalyst in the acetoxylation reaction and checked the
conversion and yield after 2.5 h (Table 1, entries 8ꢀ12).
The use of polymeric gold(I) chloride and cationic
2010, 16, 5274.
(10) Olah, G. A.; Molnar, A. In Hydrocarbon Chemistry, 2nd ed.; John
Wiley & Sons: New-York, 2003.
(11) For selected publications highlighting aryl esters substrates in
asymmetric homogeneous catalysis, see: (a) Heathcock, C. H.; Pirrung,
€
17
M. C.; Young, S. D.; Hagen, J. P.; Jarvi, E. T.; Badertscher, U.; Marki,
PPh3AuNTf2 gave lower yields of the desired product
H.-P.; Montgomery, S. H. J. Am. Chem. Soc. 1984, 106, 8161. (b)
Toullec, P. Y.; Bonaccorsi, C.; Mezzetti, A.; Togni, A. Proc. Natl. Acad.
Sci. 2004, 101, 5810. (c) Mori, T.; Weiss, R. G.; Inoue, Y. J. Am. Chem.
(Table 1, entries 8ꢀ9). Interestingly,16 gold trichloride
(Table 1, entry 10) had a similar activity to (PPh3)AuCl
but its hygroscopicity and hazardous manipulation drove us
to prefer (PPh3)AuCl. Other gold(III) salts such as HAuCl4
or Au2O38f were tested in the reaction process, but both led
to low yields (Table 1, entries 11ꢀ12). We finally compared
the activity of (PPh3)AuCl with other metallic salts such as
silver, platinum and palladium catalysts (Table 1, entries
13ꢀ15), none of them leading to a significant amount of 3a.
The case of the use of Pd(OAc)2 is particularly remarkable
as palladium catalysts represent a milestone in selective
€
Soc. 2004, 126, 8961. (d) Mazet, C.; Kohler, V.; Pfaltz, A. Angew. Chem.,
Int. Ed. 2005, 44, 4888. (e) Jereb, M.; Togni, A. Chem.;Eur. J. 2007, 13,
9384. (f) Harmata, M.; Chen, Y.; Barnes, C. L. Org. Lett. 2007, 9, 4701.
(g) Pautigny, C.; Jeulin, S.; Ayad, T.; Zhang, Z. G.; Genet, J.-P.; Vidal,
V. Adv. Synth. Catal. 2008, 350, 2525.
(12) Rappoport, Z. The Chemistry of Phenols; Wiley-Interscience-
VCH: Weinheim, 2003.
(13) 3-Acetoxylation of 1-benzylindole was a side reaction (12%
yield) in the Au-catalyzed ethynylation of arenes, see 4e.
(14) For the first use of DAIB in Pd-catalyzed acetoxylation of benzene,
see: Yoneyama, T.; Crabtree, R. H. J. Mol. Catal., A: Chem. 1996, 108, 35.
(15) For selected recent reviews regarding the chemistry of hyperva-
lent iodine reagents, see: (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev.
2008, 108, 5299. (b) Merritt, E. A.; Olofsson, B. Angew. Chem., Int. Ed.
2009, 48, 9052. (c) Merritt, E. A.; Olofsson, B. Synthesis 2011, 517.
(16) During the preparation of this manuscript, the AuCl3-catalyzed
acetoxylation of arenes has been reported: Qiu, D.; Zheng, Z.; Mo, F.;
Xiao, Q.; Tian, Y.; Zhang, Y.; Wang, J. Org. Lett. 2011, 13, 4988.
ꢀ
(17) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
(18) (a) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (b)
Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
Org. Lett., Vol. 13, No. 22, 2011
6087

Table 2. Substrate Scope of the Gold-catalyzed Acetoxylation
of Arenes in the Presence of DAIBa
Table 3. Acid Scope of the Gold-catalyzed Acyloxylation of
Arenes in the Presence of DAIBa
a Reaction conditions: 0.5 mmol of arene and 1.3 equiv of di(acetoxy)-
iodobenzene 1 in 1 mL of acetic acid. b Isolated yields. c Ratio and struc-
tures determined by 2D NMR experiments.
CꢀH activation by transition metals18 and were subse-
quently investigated in depth in the acetoxylation of aro-
matic rings.19 This lack of reactivity may be accounted for
by the steric hindrance of the mesitylene, which has been
previously observed by Crabtree and co-workers.14,20 Using
the optimized system consisting of 2 mol % of (PPh3)AuCl
and 1.3 equiv of 1 at 110 °C in acetic acid, the arene scope of
a Reaction conditions: 0.5 mmol of arene 2aꢀg and 1.3 equiv of
di(acetoxy)iodobenzene 1 in 1 mL of carboxylic acid. b Isolated yields
after column chromatography. c the corresponding diacyloxy derivative
was also isolated (17 40% entry 10, 18 12% entry 11).
(19) For selected key contributions regarding the Pd-catalyzed acet-
oxylation of aromatic rings, see: (a) Dick, A. R.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 2300. (b) Dick, A. R.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790. (c) Desai, L. V.;
Stowers, K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285. (d)
Stowers, K. J.; Sanford, M. S. Org. Lett. 2009, 11, 4584. (e) Mutule, I.;
Suna, E.; Olofsson, K.; Pelcman, B. J. Org. Chem. 2009, 74, 7195. (f)
Powers, D. C.; Xiao, D. Y.; Geibel, M. A. L.; Ritter, T. J. Am. Chem.
Soc. 2010, 132, 14530. (g) Liu, Q.; Li, G.; Yi, H.; Wu, P.; Liu, J.; Lei, A.
Chem.;Eur. J. 2011, 17, 2353. (h) Sun, C.-L.; Liu, J.; Wang; Zhou, X.;
Li, B.-J.; Shi, Z.-J Synlett 2011, 844.
the reaction was explored. We selected aryl derivatives that
do not present two adjacent nonsubstituted carbons to
avoid the competitive formation of biphenyl derivatives
(21) For the reactions of anisole, 1,3-dimethoxybenzene, 1,4-di-
methylbenzene and 1-acetyl-4-methylbenzene, see Supporting Informa-
tion for other examples.
(20) For a more general discussion, see: Kaliany, D.; Sanford, M. S.
Org. Lett. 2005, 7, 4149.
6088
Org. Lett., Vol. 13, No. 22, 2011

through direct oxidative coupling of the aromatic rings.4b,d,21
The results are summarized in Table 2. Yields are good
for a variety of methyl-substituted benzenes (Table 2, entries
1ꢀ4). Halogen-containing arenes are also acetoxylated in
moderate to good yields (Table 2, entries 5ꢀ6). In the case of
1-iodo-3,5-dimethylbenzene, the reaction led to a mixture of
regioisomers 3f and 3f0 in a 1:3 ratio (Table 2, entry 5). The
presence of an electron-withdrawing group on the aromatic
ring was not deleterious to the acetylation reaction but also
gave a mixture of nonseparable regioisomers 3h and 3h0 in
50% yield (Table 2, entry 7). The reaction of the electron-
rich nitrogen heterocycle 1,2-dimethylindole 2i was also
tried but gave the acetylated derivative 3i in low yield
(Table 2, entry 8), which is in full agreement with Nevado’s
group’s results.4e
elimination occurs from complex C leading to the for-
mation of the acyloxylated arene product and the re-
generation of Au(I) complex A. In the case of nonhin-
dered arene substrates (Scheme 1, eq 1),4b,d the arylation
of a second arene molecule leads to the formation of the
diarylated complex D. Reductive elimination then oc-
curs to liberate the biphenyl product and regenerates
precatalyst A.
Scheme 2. Proposed Mechanism
We further challenged this methodology by investigating
the unprecedented acyloxylation reaction of arenes in the
presence of the same catalytic system. Considering that the
formation of bis(acyloxy)iodoarenes could be achieved by
ligand metathesis between DAIB and carboxylic acids,22 we
postulated that the replacement of acetic acid by other acids
would result in the direct incorporation of the latter in the
product. The acyloxylation reactions were therefore carried
out in a carboxylic acid as solvent, and rewardingly pro-
ceeded efficiently for a variety of carboxylic acids (Table 3).
Mesitylene 2a was engaged in acyloxylation reactions in
the presence of several carboxylic acids (Table 3, entries 1ꢀ6)
and led to the corresponding esters 4ꢀ8 in good yields
(62ꢀ80%) except in the case of 2-methoxyethanoic acid,
which was unstable under the reaction conditions. Note-
worthy that the steric hindrance of the carboxylic acid moiety
does not seem to hamper the reaction. The esters 10ꢀ12
derived from propanoic, undecanoic and pivalic acids
(Table 3, entries 7ꢀ9) and 1,2,3,4,5-pentamethylbenzene
were obtained in 59ꢀ68% isolated yields. Interestingly, the
reaction of 1,2,4,5-tetramethylbenzene 2d gave rise to the
desired esters 13ꢀ15 accompanied with variable amount of
the corresponding diesters 17ꢀ18, depending on the steric
hindrance of the carboxylic acid (Table 3, entries 10ꢀ12).
The reaction conditions were compatible with the bromoaro-
matic ring (Table 3, entry 13), and 3-bromo-2,4,6-trimethyl-
phenyl propionate 16 was obtained in 55% isolated yield.
The mechanism of this transformation based on a Au(I)
precatalyst A may involve an initial oxidation upon reac-
tion with 1 to give an Au(III) intermediate B (Scheme 2).7
The second step involves the arylation of the gold center
to give complex C and the liberation of one equivalent of
acetic acid. In the case of hindered arenes, reductive
In conclusion, we have developed a gold-catalyzed
oxidative acyloxylation reaction of nonactivated hindered
arenes associating (PPh3)AuCl as a simple and easy to
handle precursor and DAIB as oxidant. We could demon-
strate that this association allows the formation of hin-
dered acetyl-functionalized aromatic rings and more
remarkably acyloxyderivatives in moderate to good iso-
lated yields. This methodology opens new perspectives in
the selective oxidation of nonactivated aromatic rings for
the synthesis of arylesters and phenols. Further studies will
be dedicated to improve the efficiency of this gold catalytic
system.
Acknowledgment. This work was supported by the
Centre National de la Recherche Scientifique and the
0
ꢁ
Ministere de l Education et de la Recherche. A.P. is grate-
ful to National Research Agency (ANR-09-JCJC-0078)
for a grant (2009-2012). We thank Dr. M.-N. Rager and S.
Walme (Chimie ParisTech) for 2D NMR experiments of
3hꢀ3h0. Johnson-Matthey is acknowledged for generous
loans of PtCl2 and HAuCl4.
Supporting Information Available. Experimental pro-
cedures and characterization data of acyloxylated pro-
ducts 3aꢀi and 4ꢀ18. This material is available free of
charge via the Internet at http://pubs.acs.org.
(22) Stang, P. J.; Boehshar, M.; Wingert, H.; Kitamura, T. J. Am.
Chem. Soc. 1988, 110, 3272.
Org. Lett., Vol. 13, No. 22, 2011
6089