Palladium-catalyzed aryl C-H bonds activation/acetoxylation utilizing a bidentate system

Article abstract of DOI:10.1021/ol902497k

[Chemical Equation Presented] A palladium-catalyzed aryl C-H bonds activation/acetoxylation reaction utilizing a bidentate system has been explored. This transformation has been applied to a wide array of pyridine and 8-aminoquinoline derivatives and it exhibits excellent functional group tolerance.

Full text of DOI:10.1021/ol902497k

ORGANIC
LETTERS
2009
Vol. 11, No. 24
5726-5729
Palladium-Catalyzed Aryl C-H Bonds
Activation/Acetoxylation Utilizing a
Bidentate System
Fa-Rong Gou,† Xiang-Chuan Wang,† Peng-Fei Huo,† Hai-Peng Bi,†
Zheng-Hui Guan,† and Yong-Min Liang*,†,‡
State Key Laboratory of Applied Organic Chemistry, Lanzhou UniVersity,
Lanzhou 730000, People’s Republic of China, and State Key Laboratory of Solid
Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of Science,
Lanzhou 730000, People’s Republic of China
liangym@lzu.edu.cn
Received October 29, 2009
ABSTRACT
A palladium-catalyzed aryl C-H bonds activation/acetoxylation reaction utilizing a bidentate system has been explored. This transformation
has been applied to a wide array of pyridine and 8-aminoquinoline derivatives and it exhibits excellent functional group tolerance.
The development of transition metal-catalyzed C-H activa-
tion reactions directed by directing functional groups has seen
substantial progress in recent years.1,2 These reactions allow
for the highly site-selective transformations of a C-H bond
proximal to a coordinating directing group (DG) into a new
C-X bond (X ) O,3 C,4 N,5 X,6 S7). A wide range of metal
catalysts, including Ru, Rh, and Pd, have been exploited with
varying degrees of success.1 And a wide variety of directing
groups, such as ketone, ester, amide, pyridine, oxazoline, imine,
cyano groups, etc., have been reported to function as directing
groups.1,2 In most cases reported to date, a monodentate
system has been utilized. However, rare examples of such
transformations utilizing a bidentate system have been
described (Scheme 1). Recent elegant work has begun to
Scheme 1. Monodentate and Bidentate Systems
† Lanzhou University.
‡ Chinese Academy of Science.
(1) For reviews, see: (a) Shilov, A. E.; Shul’pin, G. B. Chem. ReV. 1997,
97, 2879. (b) Dyker, G. Angew. Chem., Int. Ed. 1999, 38, 1698. (c) Ritleng,
V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (d) Daugulis, O.;
Zaitsev, V. G.; Shabashov, D.; Pham, Q. N.; Lazareva, A. Synlett 2006,
3382. (e) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107,
174. (f) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem.,
Int. Ed. 2009, 48, 5094
.
10.1021/ol902497k  2009 American Chemical Society
Published on Web 11/19/2009

successfully address some of these challenges,8 but the C-H
activation/acetoxylation reaction that utilizes this bidentate
system has thus far remained elusive. As part of our ongoing
interest in developing methods for C-H activation reactions9
via organometallic catalysis, we herein wish to report the
details of this Pd-catalyzed aryl C-H bond activation
reaction.
We initiated our investigations by examining whether the
analogous pyridine derivatives can direct this Pd-catalyzed
C-H activation/acetoxylation reaction. We discovered that
the combination of 1.0 equiv of substrate N-benzylpicolina-
mide 1a with 5 mol % of Pd(OAc)2 and PhI(OAc)2 (1.5
equiv) in toluene at 110 °C for 12 h produced a 3:4 ratio of
the expected monoacetoxylated product 2a and diacetoxy-
lated product 2b in 63% isolated yield (Table 1, entry 1).
of catalyst resulted in complete recovery of 1a, and no
reaction was observed in the absence of PhI(OAc)2 (Table
1, entries 2 and 3). Compared with other solvents, such as
HOAc and HOAc/Ac2O (1:1) (entries 4 and 5), toluene was
more effective. During a survey of the effect of various
oxidants, it was determined that PhI(OAc)2 was superior to
others (entries 6-8). We envisioned that PhI(OAc)2 might
be playing other roles than just a simple oxidant; it might
also serve as an acetate source.
Significant improvement was achieved by the use of 2.0
equiv of PhI(OAc)2 and 1.0 equiv of HOAc/Ac2O (1:1)
resulting in clean formation of the diacetoxylated product
2b in 70% yield (entry 9). Furthermore, conducting the above
reaction at 150 °C for 6 h furnished 77% yield of the product
2b (entry 10). This meant that higher temperatures were
beneficial for both the rate and the yield of the reaction.
Herein, the optimum reaction conditions thus far developed
employ 1.0 equiv of substrate, 5 mol % of Pd(OAc)2, 2.0
equiv of PhI(OAc)2, and 1.0 equiv of HOAc/Ac2O (1:1) in
toluene at 150 °C. It should be noted that the rigorous
exclusion of air/moisture is not required in any of these
transformations, and comparable results are obtained in the
presence and absence of air, as well as in freshly distilled
versus commercial solvents. As such, this represents an
exceedingly convenient method for functional group-directed
functionalization of C-H bonds.
Table 1. Optimization of the Pd-Catalyzed Acetoxylation of
Pyridine 1aa
isolated
ratio
With the optimized conditions in hand, the reaction
generality was investigated with various pyridines. The
results are summarized in Table 2. Our initial attempt to
acetoxylate the unactivated sp3 C-H bond of substrate 1b
failed to provide any product (entry 2, Table 2). When the
benzylic position of amine was substituted with a methyl
entry oxidant
solvent
time (h) yield (%) 2a/2bb
1
PhI(OAc)2 toluene
PhI(OAc)2 toluene
toluene
PhI(OAc)2 HOAc
12
6
6
3
3
6
6
12
10
6
63
3:4
2c
3
n.r.d
n.r.d
e
4
5
6
7
-
-
e
PhI(OAc)2 HOAc/Ac2O (1:1)
TBHP
AgOAc
Oxone
toluene
toluene
toluene
n.r.d
n.r.d
tracef
70
(3) For selected recent examples, see: (a) Dick, A. R.; Hull, K. L.;
Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. (b) Desai, L. V.; Stowers,
K. J.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 13285. (c) Kalyani, D.;
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Sanford, M. S. Org. Lett. 2006, 8, 1141. (e) Giri, R.; Liang, J.; Lei, J. G.;
Li, J. J.; Wang, D. H.; Chen, X.; Naggar, I. C.; Guo, C.; Foxman, B. M.;
Yu, J. Q. Angew. Chem., Int. Ed. 2005, 44, 7420. (f) Chen, X.; Hao, X.-S.;
Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (g) Gu,
S. J.; Chen, C.; Chen, W. Z. J. Org. Chem. 2009, 74, 7203. (h) Wang,
G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem. 2008, 73, 4717.
(4) For selected references, see: (a) Dipannita, K.; Deprez, N. R.; Deprez,
L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (b) Chiong,
H. A.; Pham, Q.-N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879. (c)
Deng, G. J.; Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 6278. (d)
Zhao, X. D.; Yu, Z. K. J. Am. Chem. Soc. 2008, 130, 8136. (e) Tsai, A. S.;
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R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082.
8
9g
PhI(OAc)2 toluene
<1:99
<1:99
10h PhI(OAc)2 toluene
77
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of solvent
with 1.0 equiv of 1a, 1.5 equiv of oxidant, and 0.05 equiv of [Pd] at 110
°C. b The ratio was determined by the isolated yields of the products. c No
catalyst. d n.r. ) no reaction. e Decomposed. f A trace amount of 2b was
isolated. g With 2.0 equiv of PhI(OAc)2 and 1.0 equiv of HOAc/Ac2O (1:1).
h The reaction was conducted with 2.0 equiv of PhI(OAc)2 and 1.0 equiv
of HOAc/Ac2O (1:1) at 150 °C.
Although the NMR spectroscopic data support the formation
of acetoxylated products 2, the structure was unambiguously
confirmed through an X-ray crystal structure analysis of 2b.10
Encouraged by the promising results, we attempted to
optimize the reaction conditions. Utilizing 1a as a reactant,
the reaction parameters (i.e., oxidants, solvents, additives,
and temperature) were varied to achieve this goal. Key results
are shown in Table 1. The control experiment in the absence
(5) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048.
(6) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org.
Lett. 2006, 8, 2523. (b) Wan, X. B.; Ma, Z. X.; Li, B. J.; Zhang, K. Y.;
Cao, S. K.; Zhang, S. W.; Shi, Z. J. J. Am. Chem. Soc. 2006, 128, 7416. (c)
Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
128, 6790. (d) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem.,
Int. Ed. 2008, 47, 5215.
(7) Zhao, X. D.; Dimitrijevic’, E.; Dong, V. M. J. Am. Chem. Soc. 2009,
131, 3466.
(8) (a) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154. (b) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N.
J. Am. Chem. Soc. 2009, 131, 6898. (c) Reddy, B. V. S.; Reddy, L. R.;
Corey, E. J. Org. Lett. 2006, 8, 3391.
(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. Chem. Soc. 1999, 121, 6616. (d) Thalji, R. K.; Ahrendt, K. A.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 9692. (e)
Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Tetrahedron 2006,
62, 11483.
(9) (a) Guan, Z.-H.; Ren, Z.-H.; Spinella, S. M.; Yu, S.; Liang, Y.-M.;
Zhang, X. J. Am. Chem. Soc. 2009, 131, 729. (b) Shu, X.-Z.; Xia, X.-F.;
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7464.
(10) Structure of 2b is listed in the Supporting Information.
Org. Lett., Vol. 11, No. 24, 2009
5727

of 8-aminoquinoline derivatives. In this regard substrate 3a
was surveyed under the optimized reaction conditions. To
our delight, the results exceeded our expectations, and were
somewhat better than those for the pyridines. Although a
longer reaction time was needed, the desired diacetoxylated
product 4a formed in 81% yield (Table 3, entry 1). We found
Table 2. Pd-Catalyzed Acetoxylation of Pyridines 1a
Table 3. Pd-Catalyzed Acetoxylation of 8-Aminoquinolines 3a
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of toluene
with 1.0 equiv of 1, 2.0 equiv of PhI(OAc)2, 1.0 equiv of HOAc/Ac2O
(1:1), and 0.05 equiv of [Pd] at 150 °C. b n.r. ) no reaction. c Conversions
are indicated in parentheses.
group, surprisingly no reaction occurred, leading to 93%
recovery of starting material (entry 3). This might be due to
the steric effect. The additional functional groups such as
methoxy, chloro, and even bromo substituents did not
interfere with the palladium-catalyzed C-H activation reac-
tion, showing good group tolerance. However, a significant
influence of the substituents on the reactions was observed.
The use of the substrates containing electron-donating
substituents afforded moderate yields of the diacetoxylated
products (entries 4 and 5). But the efficiency of these
transformations was much lower in the presence of an
electron-withdrawing substituent, affording comparatively
low yields of monoacetoxylated products after longer
reaction times (entries 6 and 7). Perhaps the low electron
density on the phenyl ring reduces the tendency for C-H
activation.
a Reactions were carried out on a 0.2 mmol scale in 2.0 mL of toluene
with 1.0 equiv of 3, 2.0 equiv of PhI(OAc)2, 1.0 equiv of HOAc/Ac2O
(1:1), and 0.05 equiv of [Pd] at 150 °C. b Conversions are indicated in
parentheses. c n.r. ) no reaction.
The results encouraged us to extend our protocol to
investigate this new C-H activation reaction. We envisioned
that a similar approach might be applied to the acetoxylation
5728
Org. Lett., Vol. 11, No. 24, 2009

that this methodology was broadly applicable to a variety
of amides, affording acetoxylated products in synthetically
valuable yields. All of the substrates bearing either an
electron-donating group or an electron-withdrawing group
at the ortho-, meta-, and the para-positions of the phenyl
groups formed the desired products. Generally, the reac-
tions of substrates with methyl groups at the ortho- and
meta-positions afforded much better results than the para-
substituted ones (entries 2-5). The substrate with a
stronger electron-donating group at the ortho-position also
worked well and afforded product 4f in 65% yield after
8 h (entry 6). Excitingly, an extremely fast and efficient
reaction was observed in the case of 2,3-dimethoxy-
substituted amide 3g, product 4g being obtained in high
yield after 3 h (92%, entry 7). It is not surprising that the
2-chloro-substituted substrate 3h exhibited a similar effect
to pyridines 1f and 1g. The presence of an electron-
withdrawing substituent was no benefit in this transforma-
tion (entry 8). Comparing 1-naphthyl-substituted substrate
3i with the less sterically hindered substrate 3a, the
efficiency of the reaction was reduced dramatically, only
52% yield of product was formed (entry 9). With the
purpose of acetoxylation of heteroaromatic compound,
pyridine 3j was tested. Rewardingly, the reaction furnished
the desired product in 55% yield (entry 10). An additional
attempt to acetoxylate the sp3 C-H bond of substrate 3k
failed (entry 11).
Figure 1. The exploration of the analogous pyridines.
palladacyles,8 followed by an unstable Pd(IV) specie3 that
decompose via a reductive elimination pathway. Subsequent
functionalization would be possible (Scheme 2).
Scheme 2. Possible Reaction Mechanism
In conclusion, a new and highly regioselective C-H
activation/acetoxylation of amides possessing a directing
pyridine and 8-aminoquinoline group was developed. This
kind of bidentate system has large potential for the explora-
tion of new reactions that have not been achieved by general
monodentate-assisted systems. Current studies are focused
on further exploration of the substrate scope and synthetic
utility of this bidentate system.
Then we proposed the mechanism of this Pd-catalyzed
C-H bond activation with a series of pyridine derivatives.
Pyridines having shorter or longer carbon chains, as in 5,
6, and 7, did not give any desired products. Furthermore,
no reaction was observed when the corresponding N-
methyl-substituted substrate 8 was employed (Figure 1).
Acknowledgment. We thank the NSF (NSF-20621091,
The above results indicate that the coordination in an N,N
fashion is a key step, and substrates having shorter or longer
carbon chains were not effective. Furthermore, a free NH is
necessary for the process. The C-H activation of the
resulting acetoxylated products could be easily realized due
to the selective coordination of substrate bearing a N,N donor
with the palladium catalyst, formation of two five-membered
NSF-20672049) for financial support.
Supporting Information Available: Typical experimental
procedure, characterization data for all products, and X-ray
data for 2b, in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL902497K
Org. Lett., Vol. 11, No. 24, 2009
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