Chelation-assisted palladium-catalyzed acyloxylation of benzyl sp3 C-H bonds using PhI(OAc)2 as oxidant

Article abstract of DOI:10.1016/j.tetlet.2010.04.075

A chelation-assisted palladium-catalyzed acyloxylation of the sp³ C-H bond of benzyl by carboxylic acid is described, which employs PhI(OAc)₂ as a stoichiometric oxidant. The procedure tolerates a series of functional groups, such as

Full text of DOI:10.1016/j.tetlet.2010.04.075

Tetrahedron Letters 51 (2010) 3317–3319
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Chelation-assisted palladium-catalyzed acyloxylation of benzyl sp3 C–H
bonds using PhI(OAc)2 as oxidant
a,b,
Shouhui Zhang a, Fang Luo a, Wenhui Wang a, Xiaofei Jia a, Maolin Hu a, , Jiang Cheng
*
*
a College of Chemistry and Materials Science, Wenzhou University, Wenzhou 325027, PR China
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, PR China
a r t i c l e i n f o
a b s t r a c t
A chelation-assisted palladium-catalyzed acyloxylation of the sp3 C–H bond of benzyl by carboxylic acid
is described, which employs PhI(OAc)2 as a stoichiometric oxidant. The procedure tolerates a series of
functional groups, such as methoxyl, chloro, bromo, iodo, vinyl, formyl, phenolic hydroxyl, nitro, and
cyano groups, providing the acyloxylation products in moderate to good yields.
Ó 2010 Elsevier Ltd. All rights reserved.
Article history:
Received 22 February 2010
Revised 13 April 2010
Accepted 20 April 2010
Available online 24 April 2010
Transition-metal-catalyzed direct C–H bond functionalization
has become a versatile synthetic method for the regional oxidation
of organic molecules.1 Recently, much attention has been paid to
the development of regioselective C–O bond formation via C–H
cleavage.2 In 2006, Yu reported Cu(OAc)2-catalyzed oxidative acet-
oxylation of arene C–H bonds using oxygen as terminal oxidant.3
Recently, Sanford reported a detailed study of C–O reductive elim-
ination from palladium(IV) complexes via arene C–H bond functi-
naliztion.4 Very recently, we also developed an efficient
chelation-assisted rhodium-catalyzed ortho-acyloxylation of the
sp2 C–H bond.5 However, examples of C–O bond-forming reaction
through sp3 C–H bond cleavage were rarely reported before and
were almost limited to acetoxylation.6 Furthermore, from the syn-
thetic point of view, it is more cost-efficient to directly employ the
inexpensive carboxylic acid as reaction partner in sp3 C–H acyloxy-
lation reaction. Herein, we wish to report a chelation-assisted pal-
ladium-catalyzed acyloxylation of benzyl sp3 C–H bond employing
PhI(OAc)2 as a stoichiometric oxidant.
catalysts were inferior to Pd(OAc)2 (Table 1, entries 12–14), and no
product was observed in the absence of Pd(II) (Table 1, entry 15).
The reaction conducted on a 5 mmol scale could gain the acyloxy-
lation product 3aa in 82% yield. Moreover, this transformation is
very practical, for it does not need the strong bases or expensive li-
gands and the rigorous exclusion of air and moisture was also not
required.
Table 1
Selected results of screening the optimal conditions
NO2
NO2
O
O
O
Pd source
+
Oxidant, solvent
N
N
HO
1a
2a
3aa
Initially, we investigated the reaction of 3-nitrobenzoic acid and
8-methyl quinoline using Pd(OAc)2 as the catalyst (Table 1). The
oxidant had a dramatic effect on the reaction. Among the oxidant
tested, Oxone, BQ, and O2 were totally ineffective for this transfor-
mation (Table 1, entries 1–3), and Cu(OAc)2 and CuBr2 also showed
less reactivity (Table 1, entries 4 and 6). On the contrary, the yield
of 3aa could increase to 50% using K2S2O8 (Table 1, entry 5). To our
delight, PhI(OAc)2 which was a versatile oxidant in Pd(IV)-medi-
ated C–H functionalization7,8 turned out to be the best (Table1, en-
try 7), and the yield of 3aa was sharply increased to 90% with the
same condition. Moreover, the mono-acyloxylation product was
mainly obtained. Replacing toluene with other solvents such as
1,4-dioxane, DMF, NMP, and xylene decreased the yield (Table 1,
entries 8–11). Further studies revealed that other Pd(II) and Pd(0)
Entry
Pd source
Oxidant
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
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(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Oxone
BQ
O2
Cu(OAc)2
K2S2O8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Dioxane
DMF
<5
<5
<5
15
50
15
90
40
40
55
45
78
77
70
<5
CuBr2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
NMP
Xylene
Toluene
Toluene
Toluene
Toluene
Pd2(dba)3
Pd(OCOCF3)2
a
All reactions were run with 8-methylquinoline (0.2 mmol), 3-nitrobenzoic acid
(0.4 mmol), Pd source (10 mol %), oxidant (0.2 mmol), dry solvent (2 mL), air,
120 °C, 24 h. Isolated yield.
* Corresponding authors. Tel.: +86 18957768407; fax: +86 577 56998939.
E-mail addresses: maolin@wzu.edu.cn(M. Hu),jiangcheng@wzu.edu.cn(J. Cheng).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.04.075

3318
S. Zhang et al. / Tetrahedron Letters 51 (2010) 3317–3319
Table 2
Finally, we found the optimized conditions for this chelation-as-
sisted sp3 C–H acyloxylation as following: 10 mol % of Pd(OAc)2 as
the catalyst, and a 1:2 mol ratio of 8-methyl quinoline and carbox-
ylic acid substrates in dry toluene in the presence of one equivalent
of PhI(OAc)2 at 120 °C for 24 h.
Acyloxylation of 8-methyl quinoline with carboxylic acids
Pd(OAc)2, PhI(OAc)2
N
RCOOH
O
N
toluene, 120 ºC, air
With the optimized conditions in hand, we explored the scope
of the reaction of carboxylic acids with 8-methyl quinoline (Ta-
ble 2). As expected, all carboxylic acids worked well under the
reaction condition. Generally, the arene carboxylic acids possessing
electron-withdrawing functional groups were found to give higher
yields than those of electron-donating groups (Table 2, entries 1,
11, 12, 14 vs 2, 3, 4, 5). A wide range of functional groups, including
methoxy, chloro, bromo, iodo, vinyl, cyano, formyl, nitro, and phe-
nolic hydroxyl groups, were well tolerated in the reaction. Steric
hindrance of the carboxylic acids had slight effect on the efficiency.
For example, 3ad and 3ae were isolated in 67% and 81%, respec-
tively (Table 2, entries 4 and 5). Importantly, the halo groups on
the phenyl ring of arene carboxylic acids survived in the procedure
(Table 2, entries 6–9). It is remarkable that the aryl halogen (Cl, Br,
and I) was a compatible substrate in this transformation, as C–Cl/
Br/I of the product could be further functionalized. Moreover, the
C–halogen bond is quite sensitive under a Pd0/II catalytic cycle. It
is also worth noting that hetero-arene, alkenyl, and alkyl carbox-
ylic acids also worked well under the standard reaction condition
(Table 2, entries 10, 15, and 16). Particularly, the formyl group
was compatible in the presence of PhI(OAc)2, and 3al was isolated
in 73% yield. 8-Benzyl quinoline 1b was subjected to the proce-
dure, delivering 3ba in 62% yield (Table 2, entry 17).
O
R'
R
R'
1
2
3
Entry
R
R0
Product
Yielda (%)
90
1
H (1a)
3aa
COOH
O2N
2a
COOH
2
3
1a
1a
3ab
3ac
76
61
2b
COOH
2c
4
5
6
1a
1a
1a
3ad
3ae
3af
67
81
70
COOH
2d
2e
OMe
COOH
COOH
Cl
Cl
Next, the acyloxylation of other substrates with carboxylic acids
was investigated (Fig. 1). To our delight, the di-acyloxylation prod-
uct 3ca was formed with excellent yield. Particularly, the product
of 3da could be gained in moderate yield. As such, it represents a
general and versatile chelation-assisted acyloxylation of benzyl
sp3 C–H bond.
The intramolecular isotope kinetic effect of benzyl was studied
(Scheme 1). The kH/kD was found to be 2.0, indicating slow C–H
bond activation.
2f
I
7
8
1a
1a
3ag
3ah
77
69
COOH
2g
COOH
COOH
2h
2i
Br
Based on the experimental and the well-established Pd(IV)-
9
10
11
1a
1a
3ai
3aj
3ak
70
58
83
mediated C–H functionalization using PhI(OAc)2 as an oxidant,7,8
Ph
NC
COOH
2j
NO2
COOH
1a
1a
OMe
N
2k
NO2
O
COOH
OHC
O
12
13
3al
73
59
O
N
O
O
2l
OH
O
N
NO2
1a
1a
3am
COOH
NO2
3ca 90%b
3da 32%c
2m
a
Figure 1. Acyloxylation of other substrates. Reaction conditions: 1 (0.2 mmol), 2
(0.4 mmol), Pd(OAc)2 (10 mol %), PhI(OAc)2 (0.2 mmol), dry toluene (2 mL), air,
120 °C, 24 h. Isolated yield. b 2 (0.8 mmol), PhI(OAc)2 (0.4 mmol). c O2, 130 °C, 36 h.
14
3an
93
COOH
O2N
2n
COOH
15
16
O
2o
1a
1a
3ao
3ap
81
65
Pd(OAc)2 (10%)
N
EtCOOH
PhI(OAc)2 (1eq)
N
+
O
O2N
COOH
NO2
toluene, 120ºc, 24 h
D
H(D)
17
Ph (1b)
3ba
62
O
3a'a
O2N
COOH
1.2 H
1a'
2a
2a
99% D
yield: 90%
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), Pd(OAc)2 (10 mol %), PhI(OAc)2
(0.2 mmol), dry toluene (2 mL), air, 120 °C, 24 h. Isolated yield.
Scheme 1. Kinetic isotope effect study.

S. Zhang et al. / Tetrahedron Letters 51 (2010) 3317–3319
3319
References and notes
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Pd(II)
N
O
RE
O
Ar
iii
i
O
N
Pd(II)
A
IV
Pd
2
Ar
O
N
B
AcO
ii
PhI(OCOAr)2
ArCOOH
PhI(OAc)2
ligand was omitted for clarity
Scheme 2. Plausible mechanism.
a plausible mechanism was outlined in Scheme 2. To start with,
step (i) involves the chelation-assisted sp3 C–H activation of benzyl
to form a cyclopalladated intermediate A. Secondly, the Pd(II)
intermediate A is oxidized by PhI(OCOAr)2, which derives from
the reaction of PhI(OAc)2 and ArCOOH,9 to form a Pd(IV) interme-
diate B. Finally, in step (iii), the reductive elimination of the Pd(IV)
intermediate B takes place to deliver the acyloxylation product and
regenerates Pd(II) species. It should be noted that a mechanism of
Pd(0)/Pd(II) circle could not be completely excluded.10
In summary, we have developed a general and efficient chela-
tion-assisted palladium-catalyzed acyloxylation reaction of the
benzyl sp3 C–H bond, providing the mono or di-acyloxylation prod-
ucts in moderate to good yields. Works focusing on exploring fur-
ther insights into the mechanism of the reaction and expanding the
reaction scope to unactivated sp3 C–H in more substrates are ongo-
ing in our laboratory.11
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Hypervalent Iodine In Organic Synthesis; Academic Press: Oxford, 1997. pp. 11–12.
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Commun. 2008, 31, 3625.
Acknowledgments
11. General procedure: Under air atmosphere, a reaction tube was charged with
substrates (0.2 mmol), carboxylic acid (0.4 mmol), Pd(OAc)2 (4.5 mg, 10 mol %),
PhI(OAc)2 (64.4 mg, 1 equiv), and dry toluene (2 mL). The mixture was stirred
at 120 °C for 24 h. After completion of the reaction, as monitored by TLC, the
solvent was concentrated in vacuo and the residue was purified by flash
column chromatography on silica gel to give the desired product.
We thank the National Natural Science Foundation of China
(No. 20504023) and the Key Project of Chinese Ministry of Educa-
tion (No. 209054) for financial support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.04.075.