COMMUNICATION
Palladium-catalyzed acetoxylation of sp3 C–H bonds using molecular
oxygenw
Huanfeng Jiang,* Huoji Chen, Azhong Wang and Xiaohang Liu
Received 9th April 2010, Accepted 1st July 2010
DOI: 10.1039/c0cc00841a
Molecular oxygen as oxidant to promote palladium-catalyzed
acetoxylation of sp3 C–H bonds to afford a-oxygenated products
is reported.
Table 1 Optimization of reaction conditions for the palladium-
catalyzed acetoxylation of 2-ethylpyridinea
Transition metal-catalyzed C–H bond functionalization has
attracted much interest in recent years.1 A particularly appealing
aspect of this area is the Pd-catalyzed reactions of sp3 C–H
bonds, such as acetoxylation,2 halogenation,3 amination,4
sulfonylation,5 and arylation.1e These reactions are usually
performed using PhI(OAc)2, IOAc, MeCO3t-Bu or t-BuO2H
as oxidant. Still, the development of such reactions with safe
and environmentally friendly oxidants remains challenging.
Oxygen would be environmentally preferred due to its
abundance and ultimate ‘‘greenness’’, and is emerging as an
effective oxidant in palladium catalysis.6,7 More recently, we
have described a new Pd-catalyzed selective difunctionalization
of alkenes.8 The results prompted us to investigate the reactivity
and selectivity of unactivated sp3 C–H bonds by using
molecular oxygen as the sole oxidant, which represents a
central challenge in the field. In this communication, we will
report our preliminary results.
O2
Entry (atm) Cat.
Conversion Yieldb
Additive
T/1C (%)
(%)
1
8
8
8
8
8
8
8
8
8
8
8
8
8
8
1
Pd(OAc)2 KI
Pd(OAc)2
100
100
120
140
120
140
120
120
10
10
2
—
0
30
0
30
3
4
5
6
7
8
Pd(OAc)2 KI
Pd(OAc)2 KI
Pd(OAc)2 CuI
Pd(OAc)2 CuI
Pd(OAc)2 CuCl
Pd(OAc)2 CuCl2
50
71
31
25
17
71 (63)
31
25
Trace
Trace
0
Trace
Trace
0
9
Pd(OAc)2 Cu(OAc)2 120
10
11
12
13
14
15
—
—
PdCl2
Pd2(dba)3 CuI
Pd/C CuI
Pd(OAc)2 CuI
CuI
—
CuI
120
120
120
120
120
120
0
37
0
37
Trace
Trace
Trace
Trace
Trace
Trace
Treatment of 2-ethylpyridine (1a) using
5 mol% of
Pd(OAc)2, 1 equiv. of KI in 3 mL HOAc under 8 atm of O2
at 100 1C for 24 h afforded a-oxygenated product (2a) in only
10% GC yield and the b-oxygenated product was not detected
in this process.2b This result made us very interested in screening
suitable reaction conditions for the a-oxygenated product. On
examining the additive KI, we noted that it is essential to
promote this catalytic oxidation although inferior results were
obtained at different temperature (Table 1, entries 1–4).
Inspired by this finding, we searched for another additive to
replace KI, and we were pleased to find that the breakthrough
was achieved when CuI was employed, and 1a underwent
acetoxylation smoothly to give 2a in 71% GC and 63%
isolated yield (Table 1, entry 5). Further investigation on other
Cu salts led to inferior results, which indicated that the
selection of CuI is crucial to this reaction (Table 1, entries
7–9). The presence of Pd is also critical for the success of this
reaction (Table 1, entry 10). Pd(OAc)2 is superior to any other
Pd catalysts so far tested (Table 1, entry 5 vs. entries 12–14).
Moreover, a lower yield of 2a was obtained when the reaction
was run under 1 atm of pressure of O2 (Table 1, entry 15).
Under the optimized conditions, various substrates were
examined, and the results are summarized in Table 2. The
a
Reaction conditions: All reactions were performed with 1a (1 mmol),
Pd catalyst (5 mol%), and additive (1 equiv.) in 3 mL of HOAc for
b
24 h. Determined by GC. Number in parentheses is isolated yield.
substrate scope was tested by using a variety of pyridines
and pyrazines; the acetoxylation afforded the a-oxygenated
products in modest to excellent yields. Reactions of substrates
1b, 1d, 1f and 1h could produce a-oxygenated products at
lower temperature, however high temperature produced the
a-oxidized by-products [2-formylpyridine, 2-benzoylpyridine,
2-(4-chlorobenzoyl)pyridine and 2-formylpyrazine] (Table 2,
entries 2, 4, 6, 8). Substrate 1k, which contains multiple
possible sites for directed C–H activation, showed high
selectivity for functionalization of 21 a-C–H bonds in lieu of
those at 11 carbon centers (Table 2, entry 11). A small amount
of diacetate (2lb) was obtained by the reaction of substrate 1l
(Table 2, entry 12). Notably, all employed substrates revealed
extremely high selectivity for acetoxylation at the a-C–H
bonds. In this system, we also detected the a-iodinated and
a-oxidized by-products.
The exact mechanism for the product formation is not clear
at the present stage. To clarify whether or not the reaction
involves b-hydride elimination to produce 1-hetaryl olefin with
subsequent addition of AcOH across the olefin double bond a
control reaction (Scheme 1, A) was carried out with 2-vinyl-
pyridine under the optimized conditions; no acetate product
College of Chemistry, South China University of Technology,
Guangzhou City, Guangdong Province 510640, China.
E-mail: jianghf@scut.edu.cn
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c0cc00841a
c
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 7259–7261 7259
Jiang, Huanfeng
