Palladium-catalyzed decarboxylative arylation of C-H bonds by aryl acylperoxides

Article abstract of DOI:10.1021/ol900756g

A Pd(OAc)₂-catalyzed protocol for decarboxylative arylation of aromatic C-H bond was developed using aryl acylperoxides as inexpensive aryl sources. Substrates containing pyridyl, oxime, and oxazoline groups undergo effectively ortho-selective C-H arylation with excellent functional group tolerance. This arylation should begin by directing-group-assisted cyclopalladation, followed by the reaction of the palladacycle with aryl radicals generated in situ by thermal decomposition of the peroxides.

Full text of DOI:10.1021/ol900756g

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3174-3177
Palladium-Catalyzed Decarboxylative
Arylation of C-H Bonds by Aryl
Acylperoxides
Wing-Yiu Yu,* Wing Nga Sit, Zhongyuan Zhou, and Albert S.-C. Chan
Open Laboratory of Chirotechnology of the Institute of Molecular Technology for
Drug DiscoVery and Synthesis and the Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic UniVersity, Hung Hom, Kowloon, Hong Kong
bcwyyu@inet.polyu.edu.hk
Received April 7, 2009
ABSTRACT
A Pd(OAc)2-catalyzed protocol for decarboxylative arylation of aromatic C-H bond was developed using aryl acylperoxides as inexpensive
aryl sources. Substrates containing pyridyl, oxime, and oxazoline groups undergo effectively ortho-selective C-H arylation with excellent
functional group tolerance. This arylation should begin by directing-group-assisted cyclopalladation, followed by the reaction of the palladacycle
with aryl radicals generated in situ by thermal decomposition of the peroxides.
Transition-metal-catalyzed biaryl cross-coupling reactions
involving C-H activation are attracting current interest.1
Without using prefunctionalized substrates, direct arylation
of C-H bonds would streamline the synthetic process and
reduce formation of byproduct. Extensive studies showed
that Rh,2 Ru,3 Pd,4 and Cu5 are effective catalysts for
direct arylation of aromatic C-H bonds using diaryliodo-
nium(III) salts,4o organoboron compounds,4a,c,k and aryl
halides.4b,d,g,j,n,5b However, the relatively high price and
limited availability of the organoboron/iodonium reagents
would hamper the general uses of the protocols for practical
synthesis. With aryl halides as coupling partners, problems
of functional group compatibility arise if substrates or the
aryl halides contain pre-installed halogen substituents de-
signed for later coupling reactions.
The use of carboxylic acids for decarboxylative arylation
reactions constitutes a new development in catalytic cross-
coupling reactions.6 Notable examples are the Heck-type
coupling reaction developed by Myers and co-workers7 and
the coupling reactions of benzoic acids with aryl halides
developed by Goossen and co-workers.8 Recently, an in-
tramolecular direct C-H arylation reaction by tandem
decarboxylation/C-H activation has been reported in the
literature.9 This process involves the use of readily available
and inexpensive benzoic acids as aryl sources, and handling
of sensitive organometallic coupling reagents is avoided.
However, high reaction temperature (140-170 °C) and long
reaction time (14-20 h) remain major shortcomings for the
decarboxylative coupling reactions. As part of our program
to explore new cross-coupling reactions via C-H activa-
tion,10 we described earlier direct C-H ethoxycarbonylation
of 2-arylpyridines by coupling of the palladacycle intermedi-
ate with the ethoxyacyl [EtOC(O)•] radical.10b Inspired by
this discovery, we envisaged that direct C-H arylation
(1) (a) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731.
(c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
10.1021/ol900756g CCC: $40.75
Published on Web 07/07/2009
 2009 American Chemical Society

reactions could be achieved by coupling of aryl radicals with
organopalladium complexes (Scheme 1). Here we describe
As a proof-of-concept study, we were gratified that
treatment of a 2-phenylpyridine-derived palladacyclic com-
plex with benzoyl peroxide (2 equiv) in a MeCN/AcOH (1:1
v/v) mixture at 100 °C for 2 h afforded 2a in 78% yield
(Scheme 1). With this favorable result, we turned to develop
a catalytic direct C-H arylation protocol using 2-phenylpy-
ridine (1a) as model substrate. When 1a reacted with benzoyl
peroxide (4 × 0.5 equiv/0.5 h) and Pd(OAc)2 (5 mol %) in
a MeCN/AcOH mixture (1:1 v/v) at 100 °C for 2 h, 2a was
formed in 80% yield [Table 1, entry 1 (method A)].13 Slower
Scheme 1. Reaction of Palladacycle with Benzoyl Peroxide
Table 1. Optimization of Reaction Conditionsa
the Pd(OAc)2-catalyzed decarboxylative arylation of arene
C-H bonds using aryl acylperoxides. During the course of
our investigation, Li and co-workers reported direct arene
C-H methylation using cumyl peroxide.11 It is accepted that
aryl radicals can be generated by decarboxylation of aryl-
carboxyl radicals, produced by the homolytic O-O cleavage
of the peroxides.12 In this work, the decarboxylative direct
arylation can be achieved in good yield and selectivity in
10 min to 2 h.
entry
solvent
% convn % yielda
1
AcOH/CH3CN ) 1:1
AcOH/CH3CN ) 1:1
DCE
92
92
43
46
68
43
56
86
80
80
38
64
77
56
61
80
2b
3c
4
CH3CN
5
6
CH3CN (2 mL) + AcOH (0.1 mL)
AcOH/DMF ) 1:1
AcOH/DMSO ) 1:1
AcOH/CH3CN ) 1:1
7
(2) (a) Jin, W.; Yu, Z.; He, W.; Ye, W.; Xiao, W.-J. Org. Lett. 2009,
11, 1317. (b) Wang, X.; Lane, B. S.; Sames, D. J. Am. Chem. Soc. 2005,
127, 4996. (c) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2005, 7, 2229.
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Ed. 2006, 45, 2619. (b) Kakiuchi, F.; Matsuura, Y.; Kan, S.; Chatani, N.
J. Am. Chem. Soc. 2005, 127, 5936. (c) Oi, S.; Aizawa, E.; Ogino, Y.;
Inoue, Y. J. Org. Chem. 2005, 70, 3113.
8d
a The reactions were carried out on a 0.5-mmol scale of 1a. Conversion
and yield were determined by GC/FID. The percentage yield is based on
conversion. b Reaction at 100 °C for 4 h, peroxide (4 × 0.5 equiv/1 h).
c Dimer of 1a (yield 12%) and chlorinated product (trace) were detected
by GC-MS. d Method B.
(4) (a) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008,
130, 17676. (b) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem.
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J. Am. Chem. Soc. 2008, 130, 7190. (d) Lebrasseur, N.; Larrosa, I. J. Am.
Chem. Soc. 2008, 130, 2926. (e) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J.
Angew. Chem., Int. Ed. 2008, 47, 1115. (f) Brasche, G.; Garc´ıa-Fortanet,
J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. (g) Shabashov, D.;
Maldonado, J. R. M.; Daugulis, O. J. Org. Chem. 2008, 73, 7818. (h) Stuart,
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J. Am. Chem. Soc. 2007, 129, 11904. (j) Chiong, H. A.; Pham, Q.-N.;
Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (k) Shi, Z.; Li, B.; Wan,
X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem., Int.
Ed. 2007, 46, 5554. (l) Yang, S.; Li, B.; Wan, X.; Shi, Z. J. Am. Chem.
Soc. 2007, 129, 6066. (m) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn,
R.; DeBoef, B. Org. Lett. 2007, 9, 3137. (n) Becht, J.-M.; Catala, C.; Drian,
C. L.; Wagner, A. Org. Lett. 2007, 9, 1781. (o) Kalyani, D.; Deprez, N. R.;
Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330.
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H.-Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(6) For reviews, see: (a) Goossen, L. J.; Rodriguez, N.; Goossen, K.
Angew. Chem., Int. Ed. 2008, 47, 3100. (b) Bonesi, S. M.; Fagnoni, M.;
Albini, A. Angew. Chem., Int. Ed 2008, 47, 10022. For recent examples:
(c) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int. Ed. 2009,
48, 792. (d) Becht, J.-M.; Drian, C. L. Org. Lett. 2008, 10, 3161.
(7) (a) Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc.
2005, 127, 10323. (b) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am.
Chem. Soc. 2002, 124, 11250.
addition rate of the peroxide (4 × 0.5 equiv/1 h) gave similar
results (entry 2). In the absence of Pd(OAc)2, only a trace
amount of 2a was formed.14 Performing the Pd-catalyzed
reaction in MeCN or DCE alone (i.e., without AcOH)
resulted in lower product yield and substrate conversion
(entries 3 and 4). Furthermore, using a MeCN/AcOH (20:1
v/v) mixture as solvent for the arylation reaction also gave
less satisfactory results (entry 5). Employing DMF or DMSO
as co-solvent failed to produce better results (entries 6 and
7). Notably, when 1a reacted with benzoyl peroxide (2 equiv)
and Pd(OAc)2 (5 mol %) at 160 °C in MeCN/AcOH (1:1
(12) (a) Moad, G.; Solomon, D. H. The Chemistry of Free Radical
Polymerization; Elsevier: Boston, 2006. (b) Moody, C. J.; Whitham, G. H.
ReactiVe Intermediates; Oxford University Press: New York, 1992.
(13) Experimental Procedure. Method A: A mixture of substrate (0.5
mmol), Pd(OAc)2 (0.025 mmol, 5 mol %), and benzoyl peroxide (1 mmol;
addition interval 4 × 0.5 equiv/0.5 h) in acetonitrile (1 mL) and acetic acid
(1 mL) was sealed in a 8 mL vial with a Teflon-lined cap. The mixture was
heated at 100 °C (oil bath temperature) for 2 h. Method B: A mixture of
substrate (0.5 mmol), Pd(OAc)2 (0.025 mmol, 5 mol %), and benzoyl
peroxide (1 mmol) in acetonitrile (1 mL) and acetic acid (1 mL) was sealed
in a 8 mL vial with a Teflon-lined cap. The mixture was heated at 160 °C
(oil bath temperature) for 10 min. Method C: A mixture of substrate (0.5
mmol), Pd(OAc)2 (0.05 mmol, 10 mol %), and benzoyl peroxide (1 mmol)
in acetonitrile (2 mL) was sealed in a 8 mL vial with a Teflon-lined cap.
The mixture was heated at 160 °C (oil bath temperature) for 10 min.
Caution: Aryl acylperoxides are potentially explosive and should be handled
with care and in small quantities.
(8) (a) Goossen, L. J.; Rodriguez, N.; Linder, C. J. Am. Chem. Soc.
2008, 130, 15248. (b) Goossen, L. J.; Zimmermann, B.; Knauber, T. Angew
Chem. Int. Ed. 2008, 47, 7103. (c) Goossen, L. J.; Rodriguez, N.; Melzer,
B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824.
(d) Goossen, L. J.; Deng, G.; Lavy, L. M. Science 2006, 313, 662.
(9) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194.
(10) (a) Yu, W.-Y.; Tsoi, Y.-T.; Zhou, Z.; Chan, A. S. C. Org. Lett.
2009, 11, 469. (b) Yu, W.-Y.; Sit, W. N.; Lai, K.-M.; Zhou, Z.; Chan,
A. S. C. J. Am. Chem. Soc. 2008, 130, 3304. (c) Thu, H.-Y.; Yu, W.-Y.;
Che, C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (d) Choi, M. K.-W.; Yu,
W.-Y.; Che, C.-M. Org. Lett. 2005, 7, 1081. (e) Cheung, W.-H.; Zheng,
S.-L.; Yu, W.-Y.; Zhou, G.-C.; Che, C.-M. Org. Lett. 2003, 5, 2535.
(11) Zhang, Y.; Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008, 130, 2900.
(14) Without Pd(OAc)2 catalyst, 1a (87%) was recovered with trace
quantities of isomeric o-, m-, and p-arylated products being observed by
GC-MS.
Org. Lett., Vol. 11, No. 15, 2009
3175

v/v) solvent, 2a was obtained in 80% yield in 10 min.
Prolonged reaction (30 min) at 160 °C had little effect on
the product yield (76%). However, addition of further
equivalents of the peroxide led to lower product yield (41%).
Table 2 depicts the scope of the decarboxylative arylation
reaction; the arylpyridines were converted to their biaryls in
However, when the analogous reaction was conducted at 160
°C for 10 min (method B), 2j was produced in 78% yield
(entry 10). Yet, the arylations of oxazoline (1k) and oximes
(3a, 3b) with benzoyl peroxide (2 equiv) and Pd(OAc)2 (10
mol %) were best performed at 160 °C in MeCN for 10 min
(method C), and the expected biaryls were formed in ca.
80% yield (entries 11-14).15
Various aryl acylperoxides have been examined for the
Pd-catalyzed direct C-H arylations. The acylperoxides were
prepared from their carboxylic acid precursors. As shown
in Table 3, the halongenated (Cl, Br, F) and other function-
Table 2. Pd-Catalyzed Decarboxylative Arylation of Aromatic
C-H Bondsa
Table 3. Reaction with Various Aryl Acylperoxidesa
entry
Ar
% convn
% yieldb
1
2
3
4
5
6
7
8
2-Cl-C6H4
3-Cl-C6H4
4-Cl-C6H4
4-F-C6H4
4-Br-C6H4
2-Me-C6H4
4-Me-C6H4
4-CF3-C6H4
4-tBu-C6H4
4-CN-C6H4
4-NO2-C6H4
2,4,6-(Me)3-C6H2
70
87
85
78
84
65
76
88
70
63
90
84
83
83
84
75
82
81
84
81
80
54
9
10
11
12c
a Reaction conditions: 1a (0.5 mmol), Pd(OAc)2 (5 mol %), 100 °C for
2 h in CH3CN (1 mL), AcOH (1 mL), peroxide (4 × 0.5 equiv/0.5 h).
b Isolated yield based on conversion. c Methods A and B were employed,
but no arylation products were detected.
t
alized (Me, Bu, CF3, CN, and NO2) peroxides can effect
the biaryl formation (6a-6k) regioselectively.16 Yet, the
coupling reaction with sterically crowded 2,3,6-trimethyl-
benzene acylperoxide was unsuccessful (entry 12). Neverthe-
less, our results are comparable to other reported protocols
using diaryliodonium salts, organoborons, and aryl halides
as reagents.
However, the methoxy-substituted aryl acylperoxides were
found to be poor reagents for the decarboxylative C-H
arylations. When 1a was treated with the methoxy-substituted
peroxides using either method A or B, no arylation products
were formed with 90% substrate recovery. When method C
was employed, arylcarboxylation products were obtained ex-
clusively in ca. 85% yield (Scheme 2). We hypothesized that
the electron-releasing OMe group may stabilize the aryl
carboxyl radicals, thereby retarding the decarboxylation reaction.
The observed carboxylation should be mediated by the reaction
of the aryl carboxyl radical with the palladacycle.18
a Reaction conditions: substrate (0.5 mmol), peroxide (2 equiv),
Pd(OAc)2 [5 mol % (for entries 1-10); 10 mol % (for entries 11-14)].
b Isolated yield based on conversion.
good yields with excellent functional group (F, OMe, CF3,
CHO) tolerance (entries 1-8). Using our Pd-catalyzed
protocol, 8-methylquinoline (1i) would undergo facile ary-
lation at the sp3 C-H bond, and 2i was furnished in 81%
yield (entry 9). For 1j as substrate, our initial catalytic
protocol [i.e., method A, Pd(OAc)2 (5 mol %), benzoyl
peroxide (4 × 0.5 equiv/0.5 h), 100 °C, MeCN/AcOH (1:1)
mixture] failed to effect any conversion of the substrate.
(15) Performing the arylation of oximes in MeCN/AcOH medium
produced a complicated mixture, and extensive hydrolysis of the oximes
was observed (see Table S10 in Supporting Information for results).
(16) See Supporting Information for details.
3176
Org. Lett., Vol. 11, No. 15, 2009

In closing, we have developed a Pd-catalyzed protocol for
decarboxylative arene C-H arylation using aryl acylperox-
ides as reagents. While the aryl acylperoxides are an
inexpensive source of aryl groups and readily prepared from
diverse carboxylic acids, CO2 was produced as an innocuous
byproduct. Our results demonstrate a new approach for biaryl
formation based on the cross-coupling reactions of organo-
palladium complexes with aryl radicals. While pursuing a
wider application of the biaryl coupling reactions, we are
exploring coupling reactions with other carboradicals or
heteroatom radicals.
Scheme 2.
Arylcarboxylation of 1a17
In this work, the catalytic C-H arylation is probably
initiated by cyclometalation of 2-arylpyridines to form a
palladacycle, which would subsequently react with aryl
radicals to afford the biaryl products.19 The aryl radicals were
produced by the thermal decomposition of aryl acylperoxides.
Consistent with a radical mechanism, radical scavengers such
as ascorbic acid were found to reduce the substrate conver-
sion in a dose-dependent manner (Table 4).
Acknowledgment. We are thankful for financial support
from The Hong Kong Polytechnic University (ASD Fund),
the Hong Kong Research Grants Council (PolyU5017-07P),
and The Areas of Excellence Scheme (AoE/P-10-01) ad-
ministered by the Hong Kong University Grants Committee.
W.N.S. is grateful to the Hong Kong Polytechnic University
for the award of a Postgraduate Research Studentship.
Table 4. The Effect of Radical Scavengersa
Supporting Information Available: Experimental pro-
cedures, characterization data, and experimental data for
reaction optimization. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL900756G
entry
ascorbic acid (mol %)
% convn
% yield
1
2
3
4
92
82
62
44
80
78
80
78
(17) With 2-methoxylbenzoyl peroxide as reagent, no arylation but
carboxylation products formation was observed with recovery of 1a.
(18) A plausible alternative route to arylcarboxylation is via oxidative
addition of the peroxide to Pd(II) to give a reactive Pd(IV) species, which
would subsequently undergo reductive elimination; see: Canty, A. J.; Jin,
H.; Skelton, B. W.; White, A. H. Inorg. Chem. 1998, 37, 3975.
(19) Ritter and co-workers disclosed a radical mechanism for the
Pd(OAc)2-catalyzed heteroatom C-H functionalization, and formation of a
Pd(III) -Pd(III) intermediate was proposed; see: Powers, D. C.; Ritter, T.
Nat. Chem. 2009, 1, 302–309.
10
25
50
a The reactions were carried out on a 0.5-mmol scale of 1a at 100 °C
for 2 h in CH3CN (1 mL) and AcOH (1 mL), peroxide (4 × 0.5 equiv/
0.5 h). Conversion and yield were determined by GC/FID. The percentage
yield is based on conversion.
Org. Lett., Vol. 11, No. 15, 2009
3177