Palladium-catalyzed acylation of sp2 C-H bond: Direct access to ketones from aldehydes

Article abstract of DOI:10.1021/ol900934g

A palladium-catalyzed direct access to ketones from aldehydes via C-H cleavage of arenes is described. The procedure utilizes air as a clean and free terminal oxidant.

Full text of DOI:10.1021/ol900934g

ORGANIC
LETTERS
Palladium-Catalyzed Acylation of sp2
C-H bond: Direct Access to Ketones
from Aldehydes
2009
Vol. 11, No. 14
3120-3123
Xiaofei Jia,† Shouhui Zhang,† Wenhui Wang,† Fang Luo,† and Jiang Cheng*,†,‡
College of Chemistry & Materials Engineering, Wenzhou UniVersity, Wenzhou 325027,
P. R. China, and State Key Laboratory of Coordination Chemistry, Nanjing UniVersity,
Nanjing 210093, P. R. China
jiangcheng@wzu.edu.cn
Received April 29, 2009
ABSTRACT
A palladium-catalyzed direct access to ketones from aldehydes via C-H cleavage of arenes is described. The procedure utilizes air as a clean
and free terminal oxidant.
Selective C-H bond functionalization has been a longstand-
ing goal in organic synthesis since it obviates the prefunc-
tionalization of substrates.1,2 The combination of transition
metals and directing groups is a useful strategy to facilitate
C-H bond cleavage, which affords valuable transformations
of C-H bonds to C-C,3 C-X,4 C-O5 and C-N bonds.6
Although the reaction of C-H bond with unsaturated bond
should be highly valuable, such transformations are only
limited to C-C double bonds7 and triple bonds.8 To the best
of our knowledge, the reaction of a C-H bond with the
C-hetero unsaturated bonds, such as CdO bonds, remains
rare. Moreover, from the synthetic point of view, the direct
and catalytic introduction of carbonyl functional groups into
the phenyl via C-H bond cleavage is attractive in organic
chemistry. For example, in 1996, Murai described a Ru3(CO)12-
catalyzed acylation of imidazoles with CO and olefins.9 In
2004, Orito reported Pd(OAc)2-catalyzed direct aromatic
carbonylation, providing benzolactams.10 In 2008, Yu de-
† Wenzhou University.
‡ Nanjing University.
(1) For selected examples, see: (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.;
Maleczka, R. E., Jr.; Smith, M. R., III Science 2002, 295, 305. (b) Chen,
H. Y.; Schlecht, S.; Semple, T. C.; Hartwig, J. F. Science 2000, 287, 1995.
(c) Shi, L.; Tu, Y.-Q.; Wang, M.; Zhang, F.-M.; Fan, C.-A.; Zhao, Y.-M.;
Xia, W.-J. J. Am. Chem. Soc. 2005, 127, 10836. (d) Lu, J.; Tan, X.; Chen,
C. J. Am. Chem. Soc. 2007, 129, 7768. (e) Chen, H. Y.; Schlecht, S.; Semple,
T. C.; Hartwig, J. F. Science 2000, 287, 1995. (f) Lin, M.; Shen, C.; Garcia-
Zayas, E. A.; Sen, A. J. Am. Chem. Soc. 2001, 123, 1000. (g) Dangel, B. D.;
Johnson, J. A.; Sames, D. J. Am. Chem. Soc. 2001, 123, 8149. (h) Li, Z.;
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Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2004, 126, 15034. (k)
Chen, M. S.; White, M. C. Science 2007, 318, 783. (l) Collman, J. P.;
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(2) For representative reviews on C-H functionalization, see: (a) Dyker,
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and Organic Synthesis; Springer: Berlin, 1999; pp 48-78. (c) Chatani, N.
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Soc. 1982, 104, 3723
.
10.1021/ol900934g CCC: $40.75
Published on Web 06/24/2009
 2009 American Chemical Society

scribed a palladium-catalyzed oxidative ethoxycarbonylation
of an aromatic C-H bond with diethyl azodicarboxylate for
ortho-selective ethoxycarbonylation of aromatic C-H
bonds.11 Recently, Yu also reported the synthesis of 1,2- and
1,3-dicarboxylic acids via Pd(II)-catalyzed carboxylation of
aryl and vinyl C-H bonds.12 Very recently, Kakiuchi
reported ruthenium-catalyzed amino- and alkoxycarbonyla-
tions with carbamoyl chlorides and alkyl chloroformates via
aromatic C-H bond cleavage.13 However, the generality of
the applicable carbonyl functional groups via C-H bond
cleavage is still limited. It occurred to us that the com-
mercially available, inexpensive aldehydes could serve as
the acylation reagents for C-H bond functionalization.
Herein, we report palladium-catalyzed regioselective acy-
lations of aromatic C-H bonds using aldehydes in the
presence of air as the ideal oxidant, affording the aromatic
ketones in moderate to good yields.
Our initial investigations focused on the acylation of
2-phenylpyridine with benzaldehyde, and the results outlined
in Table 1. Disappointingly, no desired product was obtained
Table 1. Screening for the Optimal Conditionsa
(3) (a) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (b) Tan, K. L.; Bergman,
R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 2685. (c) Pastine, S. J.;
Gribkov, D. V.; Sames, D. J. Am. Chem. Soc. 2006, 128, 14220. (d) Chiong,
H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (e) Xia, J.-B.; You, S.-L.
Organometallics 2007, 26, 4869. (f) Wakui, H.; Kawasaki, S.; Satoh, T.;
Miura, M.; Nomura, M. J. Am. Chem. Soc. 2004, 126, 8658. (g) Hennessy,
E. J.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 12084. (h) Ueda, S.;
Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411. (i) Roy, A. H.;
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I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (k)
entry
palladium
oxidant
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(OCOCF3)2
PdCl2
Cu(OAc)2
CuBr2
benzoquinone
toluene
toluene
toluene
toluene
dioxane
xylene
DMF
<5b
<5b
<5b
10b
42b
78
<5
<5
60
49
¨
Ozdemir, I.; Demir, S.; Cetinkaya, B.; Gourlaouen, C.; Maseras, F.; Bruneau,
C.; Dixneuf, P. H. J. Am. Chem. Soc. 2008, 130, 1156. (l) Reddy, B. V. S.;
Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391. (m) Lane, B. S.; Sames,
D. Org. Lett. 2004, 6, 2897. (n) Wang, D.; Wasa, M.; Giri, R.; Yu, J.-Q.
J. Am. Chem. Soc. 2008, 130, 7190. (o) Lie´gault, B.; Fagnou, K.
Organometallics 2008, 27, 4841. (p) Oi, S.; Fukita, S.; Inoue, Y. Chem.
Commun. 1998, 2439. (q) Ko, S.; Kang, B.; Chang, S. Angew. Chem., Int.
Ed. 2005, 44, 455. (r) Rueping, M.; Sugiono, E.; Azap, C. Angew. Chem.,
Int. Ed. 2006, 45, 2619. (s) Ackermann, L.; Vicente, R.; Althammer, A.
Org. Lett. 2008, 10, 2299.
NMP
xylene
xylene
xylene
xylene
xylene
(4) (a) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z.
J. Am. Chem. Soc. 2006, 128, 7416. (b) Giri, R.; Chen, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2005, 44, 2112. (c) Hull, K. L.; Anani, W. Q.; Sanford,
M. S. J. Am. Chem. Soc. 2006, 128, 7134.
53
<5
<5
Pd2(dba)3
(5) (a) Desai, L. V.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 9542. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem.
Soc. 2004, 126, 2300. (c) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org.
Lett. 2006, 8, 1141. (d) Desai, L. V.; Stowers, K. J.; Sanford, M. S. J. Am.
Chem. Soc. 2008, 130, 13285.
a 2-Phenylpyridine (0.2 mmol), benzaldehyde (0.3 mmol), Pd (10 mol
%), indicated oxidant, air, dry solvent (2 mL), 120 °C, 24 h. Isolated yield.
b At 110 °C.
(6) (a) Thu, H. Y.; Yu, W. Y.; Che, C. M. J. Am. Chem. Soc. 2006,
128, 9048. (b) Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya,
K. Org. Lett. 2007, 9, 2931.
(7) (a) Tsukada, N.; Mitsuboshi, T.; Setoguchi, H.; Inoue, Y. J. Am.
Chem. Soc. 2003, 125, 12102. (b) Halbritter, G.; Knoch, F.; Wolski, A.;
Kisch, H. Angew. Chem., Int. Ed. Engl. 1994, 33, 1603. (c) Jun, C.-H.;
Hwang, D.-C.; Na, S.-J. Chem. Commun. 1998, 1405. (d) Chatani, N.; Ie,
Y.; Kakiuchi, F.; Murai, S. J. Org. Chem. 1997, 62, 2604.
in the reaction of 2-phenylpyridine with 1.5 equiv of ben-
zaldehyde under the combined system of Pd(OAc)2 (10 mol
%) and Cu(OAc)2 (2 equiv) at 110 °C in air for 24 h.
Benzoquinone was also ineffective for this transformation.
Since aldehydes are sensitive to some oxidants, the choice
of oxidants is crucial for this transformation. Gratifyingly,
employing air as the sole oxidant resulted in the sp2 C-H
acylation of 2-phenylpyridine to afford the desired product
phenyl(2-(pyridin-2-yl)phenyl)methanone 3aa, albeit in only
10% yield (Table 1, entry 4). The reaction temperature and
solvent were also crucial for the reaction, and the yield
sharply improved to 78% under air by replacing toluene with
xylene as the solvent at 120 °C (Table 1, entry 6). Under an
O2 atmosphere, part of benzaldehyde was oxidized into
benzoic acid and the yield decreased to 47%, while only 12%
of the desired product was isolated when the reaction was
performed under N2 atmosphere. Among the Pd(II) catalysts
tested, Pd(OAc)2 turned out to be the best, while no product
could be detected in the absence of Pd(II). Pd(0) was totally
ineffective for the reaction.
(8) (a) Lail, M.; Arrowood, B. N.; Gunnoe, T. B. J. Am. Chem. Soc.
2003, 125, 7506. (b) Chatani, N.; Asaumi, T.; Ikeda, T.; Yorimitsu, S.;
Ishii, Y.; Kakiuchi, F.; Murai, S. J. Am. Chem. Soc. 2000, 122, 12882. (c)
Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer,
P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc.
2002, 124, 1586. (d) Kakiuchi, F.; Yamauchi, M.; Chatani, N.; Murai, S.
Chem. Lett. 1996, 2, 111. (e) Lenges, C. P.; Brookhart, M. J. Am. Chem.
Soc. 1999, 121, 6616. (f) Lim, Y. G.; Kim, Y. H.; Kang, J. B. J. Chem.
Soc., Chem. Commun. 1994, 2267. (g) Thalji, R. K.; Ahrendt, K. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692. (h) Jun,
C. H.; Moon, C. W.; Hong, J. B.; Lim, S. G.; Chung, K. Y.; Kim, Y. H.
Chem.sEur. J. 2002, 8, 485. (i) Thalji, R. K.; Ellman, J. A.; Bergman,
R. G. J. Am. Chem. Soc. 2004, 126, 7192. (j) Mikami, K.; Hatano, M.;
Terada, M. Chem. Lett. 1999, 1, 55. (k) Jun, C.-H.; Hong, J.-B.; Kim, Y.-
H.; Chung, K.-Y. Angew. Chem., Int. Ed. 2000, 41, 3440. (l) Guari, Y.;
Sabo-Etienne, S.; Chaudret, B. J. Am. Chem. Soc. 1998, 120, 4228.
(9) Chatani, N.; Fukuyama, T.; Kakiuchi, F.; Murai, S. J. Am. Chem.
Soc. 1996, 118, 493.
(10) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004, 126,
14342.
(11) Yu, W.-Y.; Sit, W.; Lai, K.-M.; Zhou, Z.; Chan, A. S. C. J. Am.
Chem. Soc. 2008, 130, 3304.
(12) Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
(13) Kochi, T.; Urano, S.; Seki, H.; Muzushima, E.; Sato, M.; Kakiuchi,
F. J. Am. Chem. Soc. 2009, 131, 2792.
From these preliminary explorations, the optimized condi-
tions for this sp2 C-H acylation were found as following:
Org. Lett., Vol. 11, No. 14, 2009
3121

10 mol % of Pd(OAc)2 as the catalyst, and a 1:2 mol ratio
of 2-phenylpyridine and aldehyde substrates in dry xylene
(2 mL) at 120 °C under air. Notably, neither strong bases/
acids nor expensive ligands were required for this transfor-
mation. Moreover, the employment of air as the terminal
oxidant significantly improved the practicality of this C-H
functionalization reaction.
With the optimized conditions in hand, the acylations of
2-arylpyridines by benzaldehyde were tested, as shown in
Table 2.
acylation products were isolated in moderate to good yields
(Table 2, entries 2-6). Generally, the reaction efficiency was
not sensitive to the electronic property of the substituents,
as both electron-donating groups (Table 2, entries 2, 3 and
5) and electron-withdrawing groups could be employed in
the reaction (e.g., Table 2, entry 6). However, the acylation
of highly electron-deficient 2-(4-nitrophenyl)pyridine failed.
We reasoned that this reaction may be blocked by the
electrophilic attack of the Pd(II) center to the phenyl ring.
The hindrance on the aryl group of 2-arylpyridine had a quite
limited effect on the yield of the reaction. For example, the
ortho-substituted substrate 1c delivered a 79% yield of 3ca
(Table 2, entry 3). When benzo[h]quinoline 1h was subjected
to the procedure, a 90% yield of the acylation product was
isolated (Table 2, entry 8). Interestingly, while 2-(naphthalen-
1-yl)pyridine failed to undergo the acylation reaction,
2-(naphthalen-2-yl)pyridine ran smoothly under the standard
conditions and produced the ꢀ-acylation product 3ga in 50%
yield (Table 2, entry 7).14 Evidently, the regioselectivity in
the acylation of meta-substituted substrates was dominated
by steric effects, and only the less hindered ortho position
of 2-arylpyridine was acylated. No regioisomeric products
were observed by GC-MS and 1H NMR spectroscopy (Table
2, entries 2 and 12).15 It is also worth noting that phenyl(py-
ridin-2-yl)methanone 1i, 2-aryloxypyridine 1j and 1-phenyl-
1H-pyrazole 1k substrates could also provide the acylation
products in moderate yields at an elevated temperature with
prolonged reaction time (Table 2, entries 9-14). Disappoint-
ingly, the alkyl aldehydes did not work under the current
condition.
Table 2. Acylation Reaction with Benzaldehydea
Next, the acylations of 1a and 1j by various aldehydes
were investigated (Table 3). In general, aldehydes possessing
electron-withdrawing groups on the phenyl ring gave higher
yields than those with electron-donating groups. While
4-methoxybenzaldehyde failed to deliver the acylation
product under this procedure, the reaction of 4-formylben-
zonitrile 2e could lead to a 79% yield of 3ae (Table 3, entry
4).16 The procedure tolerated functional groups such as CN,
Cl, COOMe, and NO2. Importantly, aryl bromides were also
applicable, albeit only moderate yields of the acylation
products 3ad and 3jd were isolated (Table 3, entries 3 and
9). This is notable as on one hand the aryl bromide substrates
are often very reactive in Pd0/II catalytic cycles, and on the
other hand the bromo products could be easily further
modifiable.
More experiments were carried out to gain a better
understanding the mechanism. Following the reported pro-
cedure, palladacycle A was obtained in 80% yield.11
(14) Oi, S.; Fukita, S.; Hirata, N.; Watanuki, N.; Miyano, S.; Inoue, Y.
Org. Lett. 2001, 3, 2579.
(15) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Matsuura, Y.; Tamura, M.; Kochi, T.;
Sato, M.; Chatani, N.; Kakiuchi, F. J. Am. Chem. Soc. 2007, 129, 9858. (c)
Zhang, Y.; Feng, J.; Li, C.-J. J. Am. Chem. Soc. 2008, 130, 2900. (d)
Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am. Chem.
Soc. 2008, 130, 5858. (e) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7,
4149.
a 2-Arylpyridine (0.2 mmol), benzaldehyde (0.3 mmol), Pd(OAc)2 (10
mol %), dry xylene (2 mL), air, 120 °C, 24 h. Isolated yield. b At 130 °C,
48 h.
(16) The electronic effect observed in our reaction was consistent with
the previously reported rhodium-catalyzed arylation reaction, which involved
the insertion of an aryl rhodium species to the CdO bond in the catalytic
cycle, see: Pucheault, M.; Darses, S.; Genet, J. P. J. Am. Chem. Soc. 2004,
126, 15356.
As expected, a series of functional groups on the phenyl
ring of the 2-arylpyridines, such as methyl, methoxy, fluoro
and COOMe, were compatible under this procedure, and the
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Org. Lett., Vol. 11, No. 14, 2009

Table 3. Reaction of 2-Phenylpyridine with Aldehydesa
Scheme 1. Plausible Mechanism
cyclopalladated intermediate A. The high regioselectivity as
well as the high catalytic activity of the isolated cyclopal-
ladated complex A provides strong evidence to support this
step. In step (ii), insertion of the CdO bond of the aldehyde
into the C-Pd bond of cyclopalladated intermediate A
produces intermediate B. The final step (iii) consists the ꢀ-H
elimination of intermediate B to release the product along
with a Pd(II) species. Then the Pd(II) species undergoes
reductive elimination to produce a Pd(0) species, which is
oxidized by air to regenerate the Pd(II) catalyst.
In conclusion, we have demonstrated an efficient pal-
ladium-catalyzed acylation of arene C-H bonds. The reac-
tion provides a very convenient and atom-economic method
for the synthesis of aromatic ketones directly from aldehydes.
Ongoing work seeks to gain further insights into the
mechanism of this reaction and to expand the scope to the
acylation of unactivated sp3 C-H bonds.
a 2-Phenylpyridine (0.2 mmol), aldehyde (0.4 mmol), Pd(OAc)2 (10 mol
%), dry xylene (2 mL), air, 120 °C, 24 h. Isolated yield. b Aldehyde (0.2
mmol). c Aldehyde (0.3 mmol). d At 130 °C, 48 h.
Complex A catalyzed the formation of 3aa in 81% isolated
yield in xylene under air at 120 °C (see Supporting
Information). This result indicated that palladacycle A may
be an active species during this catalytic cycle. The kinetic
isotope effects of 2-phenylpyridine were studied. The kH/kD
was found to be 3.6 (see Supporting Information). The
observed intramolecular kinetic isotope effect indicates slow
C-H bond activation.
Acknowledgment. We thank the Key Project of Chinese
Ministry of Education (No. 209054) and State Key Labora-
tory of Coordination Chemistry of Nanjing University for
financial support.
Supporting Information Available: Experimental pro-
cedures along with copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
Based upon the experimental results, a plausible mecha-
nism is outlined in Scheme 1. Step (i) involves the chelate-
directed C-H activation of 2-phenylpyridine to afford a
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