Palladium-Catalyzed Regioselective C–H Acetoxylation of 2-Aryloxypyridines with 2-Pyridyloxy as a Removable Directing Group

Article abstract of DOI:10.1002/ejoc.201600508

A simple and regioselective palladium-catalyzed ortho-C(sp²)–H acetoxylation of 2-aryloxypyridines with PhI(OAc)₂as both the oxidant and acetate source has been developed. The mono- and di-acetoxylated products can be achieved by tuning the equivalents of PhI(OAc)₂and the reaction temperature. A wide range of 2-aryloxypyridines is tolerated. Moreover, 2-pyridyloxyl and acetyl groups can be easily removed, which provides straightforward access to poly-substituted phenols.

Full text of DOI:10.1002/ejoc.201600508

DOI: 10.1002/ejoc.201600508
Full Paper
C–H Acetoxylation
Palladium-Catalyzed Regioselective C–H Acetoxylation of 2-
Aryloxypyridines with 2-Pyridyloxy as a Removable Directing
Group
[
a]
[a]
[b]
[a]
[a]
Liang Wang,* Liang Pan, Yibo Huang, Qun Chen, and Mingyang He*
Abstract: A simple and regioselective palladium-catalyzed or- tuning the equivalents of PhI(OAc) and the reaction tempera-
2
2
tho-C(sp )–H acetoxylation of 2-aryloxypyridines with PhI(OAc)
ture. A wide range of 2-aryloxypyridines is tolerated. Moreover,
2
as both the oxidant and acetate source has been developed. 2-pyridyloxyl and acetyl groups can be easily removed, which
The mono- and di-acetoxylated products can be achieved by provides straightforward access to poly-substituted phenols.
Introduction
sioned that ortho-C–H acetoxylation may be achieved by intro-
duction of 2-pyridinyloxy as a removable directing group. If that
reaction was possible, then substituted catechols or pyrogallols
could be obtained after removal of DG as well as the acetyl
groups (Scheme 1). To the best of our knowledge, regioselective
The direct acetoxylation of inert C–H bonds into C–O bond pro-
vides a powerful and atom-economic approach to generate
complex and highly valued phenols or esters. Particularly, util-
ization of transition-metal catalysts together with directing
groups (DGs) significantly facilitates C–H bond cleavage and
controls regioselectivity. Pioneer work in this filed includes
the palladium-catalyzed acetoxylation reactions of aryl C–H
bonds reported by Sanford's group and Cu-mediated ortho-
[
1]
C–H acetoxylation reaction of 2-pyridyloxyarenes have not been
[16l]
fully explored.
Given that substituted catechol or pyrogallols
[
2]
are of great importance owing to their wide applications in
[20]
pharmaceutical chemistry and organic chemistry, and in con-
[
3]
[21]
tinuation of our interest in C–H activation, herein, we report
acetoxylation reactions of aryl C–H bonds reported by Yu's
2
a simple and regioselective palladium-catalyzed ortho-C(sp )–H
[
4]
group. Thereafter, various directing groups, such as pyr-
acetoxylation reaction of 2-aryloxypyridines with PhI(OAc) as
2
[
5]
[6]
[7]
[8]
[9]
idines, amides, pyrimidines, oxime, carbonyl, 1,2,3-tri-
oxidant and acetate source.
[
10]
sulfoximines,[11] organophosphate,[12] and thio-
azoles,
[
13]
ether have been employed successfully as DGs for acetoxyla-
tion reactions. Despite promising progress, long reaction times,
high reaction temperatures, and the need for extra additives
remain the most common issues to be addressed. Some of
these reactions also suffer from poor regioselectivity (mono/di
ratio). In addition, most of the reported DGs are difficult to re-
move, which is a big drawback for their practical application in
organic synthesis.
Recently, research reports have disclosed that DGs, which
[
14]
[15]
[16]
include benzyl pyridines,
oxazolines,
2-pyridinyloxy,
2-
[
17]
[18]
pyridylmethyl ether, and pyridyldiisopropylsilyl group
could be easily removed after C–H bond functionalizations.
[
19]
Scheme 1. Working plan.
Among them, the 2-pyridinyloxy group has attracted much
more attention and a series of functionalization reactions have
[
16]
been realized.
Encouraged by the reported results, we envi-
Results and Discussion
[
[
a] School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced
Catalytic Materials & Technology, Changzhou University, Gehu Raod 1,
Wujin, Changzhou, 213164, P. R. China
Initially, 2-phenoxypyridine 1a was selected as the model sub-
strate to optimize the reaction conditions (Table 1). A variety
of reaction conditions, which included catalyst, solvent, acetate
source, and reaction temperature, were screened. Pleasingly,
the reaction afforded trace amounts of mono-acetoxylated
product 2a and 78 % yield of di-acetoxylated product 2a′ by
treating 1a with iodobenzene diacetate (3 equiv.) in the pres-
E-mail: lwcczu@126.com
hemingyangjpu@yahoo.com
b] Department of Pharmacy, Changzhou Institute of Engineering and
Technology, Changzhou, 213164, P. R. China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600508.
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Full Paper
ence of Pd(OAc) (5 mol-%) in acetonitrile at 100 °C (Table 1, the reaction conditions to deliver corresponding products in
2
Entry 1). The yield of 2a′ decreased to 62 % when the catalyst moderate to good yields. Substrates that bore strong electron-
loading was decreased to 2.5 mol-% (Table 1, Entry 2). Other withdrawing groups, such as nitro and cyano at the para posi-
catalysts, such as Pd(PPh ) Cl , Pd(acac) , and Pd(CH CN) Cl , tion, gave poor yields (2h: 0 % and 2i: 25 %). o-Nitro-substi-
3
2
2
2
3
2
2
provided poor yields (Table 1, Entries 3–5). The choice of sol- tuted phenoxypyridine, however, afforded desired product 2l in
vent had a significant impact on the reaction. Trace amounts 36 % yield at elevated temperatures for 24 h. Steric hindrance
of desired products were observed in N,N-dimethylformamide influence was observed for meta-substituted phenoxypyridines,
(DMF) and dioxane. Reactions in toluene, 1,2-dichloroethane and the reaction occurred exclusively at the ortho position (2m:
(DCE), and acetic acid gave products 2a and 2a′ in lower yields 55 % and 2n: 44 %). This protocol was extended to naphthol-
(Table 1, Entries 6, 7, and 10). Other acetate sources, such as derived 2-aryloxypyridines, which gave ꢀ-acetoxylated product
Cu(OAc)2 and AcOH/Ac O (1:2) were investigated, however, in 51 % yield (2o). For 2-(naphthalen-2-yloxy)pyridine 1p, a mix-
2
poor results were obtained (Table 1, Entries 11 and 12). The ture of α- and ꢀ-acetoxylated products was observed in a 1.2:1
reaction did not give better yields even in the presence of iodo- ratio (2p).
benzene diacetate and AcOH/Ac O simultaneously (Table 1, En-
2
try 13). It is noteworthy that the amount of iodobenzene diacet-
ate and temperature significantly affected the regioselectivity
of this reaction. The results clearly showed that relatively less
iodobenzene diacetate and lower temperatures favored the for-
mation of mono-acetoxylated product 2a. A 68 % yield of prod-
uct 2a together with excellent regioselectivity were obtained
when the reaction proceeded in the presence of iodobenzene
diacetate (1.5 equiv.) at 80 °C (Table 1, Entry 18).
Table 2. Pd-catalyzed mono-acetoxylation reaction of 2-aryloxypyridines.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry Catalyst
Solvent AcO source
equiv.]
Temp. Yield [%][b]
[°C] 2a 2a′
[
1
2
3
4
5
6
7
8
9
Pd(OAc)
Pd(OAc)
Pd(PPh
Pd(acac)
Pd(CH CN)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
CH
CH
CH
CH
CH
3
CN PhI(OAc)
CN PhI(OAc)
CN PhI(OAc)
CN PhI(OAc)
CN PhI(OAc)
toluene PhI(OAc)
2
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
(3)
100 trace 78
100 trace 80, 62,[d] 75[e]
[c]
2
3
2
3
)
2
Cl
2
3
2
100 trace 12
100 trace 23
100 trace 25
2
3
2
3
2
Cl
2
3
2
2
2
100 43
100 12
27
34
2
DCE
DMF
PhI(OAc)
PhI(OAc)
2
2
2
100 trace trace
100 trace trace
2
dioxane PhI(OAc)
AcOH PhI(OAc)
CH CN Cu(OAc)
CH CN AcOH/Ac
CH CN PhI(OAc)
CH CN PhI(OAc)
CH CN PhI(OAc)
CH CN PhI(OAc)
CH CN PhI(OAc)
CH CN PhI(OAc)
CH CN PhI(OAc)
2
1
0
2
2
100 32
100 n.r.
38
n.r.
1
1
2
3
2
1
2
2
3
2
O (3) 100 trace trace
(3)
(2)
(1.5) 100 62
(1.2) 100 45
(1.5)
(1.5)
(1.5)
[
f]
1
3
2
3
2
100 15
100 31
76
1
4
2
3
2
45
13
1
5
2
3
2
[
(
a] Reaction conditions: 1 (0.3 mmol), Pd(OAc)
2 2
(5 mol-%), and PhI(OAc)
1
6
2
3
2
trace
10
trace
trace
1.5 equiv.) in CH CN (2 mL) was stirred at 80 °C for 16 h in a sealed tube.
3
1
7
2
3
2
90 66
80 68
70 42
Isolated yields are reported. [b] Reaction was carried out at 100 °C for 24 h.
1
8
2
3
2
19
2
3
2
[
a] Reaction conditions: 1a (0.3 mmol), acetate source, catalyst (5 mol-%) in
solvent (2 mL) was stirred at a given temperature for 16 h in a sealed tube.
b] Isolated yields. [c] Catalyst (10 mol-%) was used. [d] Catalyst (2.5 mol-%)
The di-acetoxylation reaction of 2-aryloxypyridines was also
investigated. The results are summarized in Table 3. Generally,
[
2
-aryloxypyridines with different substituents survived well un-
was used. [e] Reaction at undertaken at 110 °C. [f] AcOH/Ac
was used as additive.
2
O = 1:2 (1 equiv.)
der the improved reaction conditions to give the di-acetoxy-
lated products in moderate to good yields (trace amounts of
A series of 2-aryloxypyridines were then employed to explore mono-acetoxylated compounds were determined as byprod-
the generality of this protocol (Table 2). As shown from Table 2, ucts). Similarly, substrates with strong electron-withdrawing
the reactions proceeded smoothly to afford mono-acetoxylated groups led to failure of the reaction (see 2h′ and 2i′). For meta-
2
-aryloxypyridines in the presence of PhI(OAc) (1.5 equiv.) at substituted phenoxypyridines only trace amounts of desired
2
80 °C. Diverse functional groups, which include methyl, products was obtained as a result of steric hindrance (2m′ and
methoxyl, tert-butyl, fluoro, chloro, bromo, and cyano, survived 2n′). Moreover, no di-acetoxylated product was observed for
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substrate 2-(naphthalen-1-yloxy)pyridine (1o), whereas sub-
strate 2-(naphthalen-2-yloxy)pyridine (1p) provided corre-
sponding product 2p′ in 38 % yield.
Table 3. Pd-catalyzed di-acetoxylation of 2-aryloxypyridines.[a]
Scheme 3. Kinetic isotope experiment.
Palladacycle A was prepared by the stoichiometric reaction
[
16e,16i,22]
of 1a with Pd(OAc)2,
and was employed to test its activ-
ity towards the present transformation. As shown in Scheme 4,
the mono-acetoxylation reaction of 1a proceeded smoothly un-
der standard conditions to provide corresponding product 2a
in 53 % yield, which suggests palladacycle A might be a reac-
tion intermediate.
Scheme 4. Study on the catalytic activity of palladacycle A.
Based on the above results and previous reports,[3,23] a plau-
sible mechanism was proposed. Initially, electrophilic pallada-
II
tion between 1a and Pd generates six-membered palladacycle
[
16e]
intermediate A,
which is oxidized to form intermediate B
in the presence of PhI(OAc) . Then intermediate B undergoes
reductive elimination to afford product 2a and Pd (Scheme 5).
2
[
(
a] Reaction conditions: 1 (0.3 mmol), Pd(OAc)
2 2
(5 mol-%), and PhI(OAc)
II
3 equiv.) in CH CN (2 mL) was stirred at 100 °C for 16 h in a sealed tube.
3
Isolated yields are reported.
Similarly, another catalytic cycle that starts from 2a provides di-
acetoxylated product 2a′.
A series of experiments were conducted to obtain a better
understanding of the mechanism of the present transformation.
Initially, an intermolecular competition experiment between 1b
and 1e under standard conditions showed that electron-rich
substrate 1b reacted preferentially, which was consistent with
an electrophilic palladation pathway (Scheme 2). Next, intra-
molecular kinetic isotope effects of 2-phenylpyridine were in-
vestigated by reaction of ortho-monodeuterio-2-phenoxypyr-
[
16e] 1
idine 1a-D under standard Condition A (vide supra).
H NMR
spectroscopic analysis gave k /k = 2.3, which indicates that
H
D
cleavage of the C–H bond might be the rate-determining step
Scheme 3).
(
Scheme 5. Plausible mechanism.
The synthetic utility of this methodology lies in the easy re-
moval of the 2-pyridinyloxy and acetyl groups. By using 2a as
example, the 2-pyridinyloxy group could be removed by treat-
ment of 2a with MeOTf in dry toluene, followed by heating to
[
16c,16i]
reflux in a Na/MeOH system.
Further hydrolysis in acidic
solution facilitated removal of the acetyl group (Scheme 6).
Thus, this protocol may provide a feasible approach for the syn-
thesis of substituted catechols or pyrogallols.
Scheme 2. Competitive experiment [Condition A: Pd(OAc)
PhI(OAc) (1.5 equiv.), 80 °C, 16 h; Condition B: Pd(OAc) (5 mol-%), PhI(OAc)
3 equiv.), 100 °C, 16 h].
2
(5 mol-%),
2
2
2
(
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(dd, J = 7.0, 5.1 Hz, 1 H), 6.89 (d, J = 8.3 Hz, 1 H), 6.81 (dd, J = 8.9,
2
.9 Hz, 1 H), 6.75 (d, J = 2.9 Hz, 1 H), 3.79 (s, 3 H), 2.05 (s, 3 H) ppm.
1
3
C NMR (75 MHz, CDCl ): δ = 168.4, 163.3, 156.9, 147.5, 143.0, 139.3,
3
1
38.5, 123.6, 118.3, 112.1, 110.5, 109.2, 55.6, 20.4 ppm. HRMS (ESI):
+
calcd. for C H NNaO [M + Na] 282.0737; found 282.0746.
14
13
4
Scheme 6. Removal of the 2-pyridinyloxy and acetyl groups.
5
-(tert-Butyl)-2-(pyridin-2-yloxy)phenyl Acetate (2d): White
1
solid, m.p. 51–53 °C. H NMR (300 MHz, CDCl ): δ = 8.17 (dd, J =
3
5.0, 1.4 Hz, 1 H), 7.66 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.28 (dd, J =
Conclusions
8.5, 2.3 Hz, 1 H), 7.16 (dd, J = 8.6, 5.4 Hz, 2 H), 7.00–6.89 (m, 2 H),
2
.07 (s, 3 H), 1.32 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 168.6,
3
In summary, a simple and regioselective palladium-catalyzed
163.1, 148.7, 147.6, 142.7, 141.8, 139.3, 123.8, 122.2, 120.6, 118.4,
2
ortho-C(sp )–H acetoxylation reaction of 2-aryloxypyridines 110.8, 34.5, 31.2, 20.4 ppm. HRMS (ESI): calcd. for C H NNaO [M
17
19
3
+
with PhI(OAc) as both the oxidant and acetate source has been + Na] 308.1257; found 308.1268.
2
developed. Mono- and di-acetoxylated products could be
5
-Fluoro-2-(pyridin-2-yloxy)phenyl Acetate (2e): White solid,
achieved by varying the amount of PhI(OAc) and the tempera-
1
2
m.p. 45–46 °C. H NMR (300 MHz, CDCl ): δ = 8.17–8.11 (m, 1 H),
3
ture. A series of functional groups survived the reaction condi-
tions to afford the corresponding products in moderate to good 4 H), 2.05 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ = 168.0, 162.9,
7.70 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.24–7.16 (m, 1 H), 7.04–6.89 (m,
13
3
yields. Importantly, the 2-pyridyloxyl and acetyl groups can be 159.3 (d, J = 245.2 Hz), 147.5, 143.1 (d, J = 11.4 Hz), 141.4 (d, J =
easily removed, thereby providing straightforward access to 3.7 Hz), 139.5, 123.9 (d, J = 9.5 Hz), 118.7, 113.4 (d, J = 22.9 Hz),
1
11.5 (d, J = 25.8 Hz), 110.7, 20.4 ppm. HRMS (ESI): calcd. for
poly-substituted phenols.
+
C H FNNaO [M + Na] 270.0537; found 270.0544.
13
10
3
5
-Chloro-2-(pyridin-2-yloxy)phenyl Acetate (2f): White solid, m.p.
1
66–68 °C. H NMR (300 MHz, CDCl ): δ = 8.15–8.13 (m, 1 H), 7.69
Experimental Section
3
(
ddd, J = 8.3, 7.3, 2.0 Hz, 1 H), 7.26–7.15 (m, 3 H), 7.03–6.98 (m, 1
General Methods: Chemicals were used as received without special
13
H), 6.94 (d, J = 8.3 Hz, 1 H), 2.05 (s, 3 H) ppm. C NMR (75 MHz,
CDCl ): δ = 168.1, 162.7, 147.5, 144.0, 143.0, 139.6, 130.1, 126.9,
124.4, 124.0, 118.9, 111.0, 20.4 ppm. HRMS (ESI): calcd. for
C H ClNNaO [M + Na] 286.0241; found 286.0250.
1
13
purification. H and C NMR spectra were recorded with a Bruker
3
Advance 300 instrument in CDCl with tetramethylsilane as internal
standard. Melting points were determined with an Optimelt MPA
3
+
13
10
3
1
00 apparatus. High-resolution mass spectrometry (HRMS) was per-
5
-Bromo-2-(pyridin-2-yloxy)phenyl Acetate (2g): White solid,
formed with an Agilent 6540 Q-TOF MS instrument with an ESI
1
m.p. 75–77 °C. H NMR (300 MHz, CDCl ): δ = 8.14 (ddd, J = 5.0, 2.0,
0.7 Hz, 1 H), 7.70 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.40–7.36 (m, 2 H),
7
source. 2-Phenoxypyridines (1a–1o) were prepared in accordance
3
with reported literature.[
16e,16i,24]
1
3
.14–7.09 (m, 1 H), 7.03–6.93 (m, 2 H), 2.05 (s, 3 H) ppm. C NMR
Typical Procedure for Acetoxylation of 2-Aryloxypyridines: A re-
action vial (10 mL) equipped with a stirrer bar was charged with 1a
(75 MHz, CDCl ): δ = 168.1, 162.5, 147.5, 144.6, 143.1, 139.6, 129.8,
3
1
26.9, 124.4, 118.9, 117.3, 110.9, 20.3 ppm. HRMS (ESI): calcd. for
(51.3 mg, 0.3 mmol), Pd(OAc)2 (3.4 mg, 5 mol-%), PhI(OAc)2
+
C H BrNNaO [M + Na] 329.9736; found 329.9744.
13
10
3
(1.5 equiv. or 3 equiv.), and CH CN (2 mL). The reaction mixture
3
5
-Cyano-2-(pyridin-2-yloxy)phenyl Acetate (2i): White solid, m.p.
was heated at 80 or 100 °C for 16 h. After having cooled to room
temperature, the mixture was diluted with ethyl acetate, filtered
through a plug of Celite, and the solvent was removed under re-
duced pressure. The residue was purified by flash column chroma-
tography with silica gel with ethyl acetate/petroleum ether to afford
desired product 2a or 2a′.
7
0
7
3–75 °C. 1H NMR (300 MHz, CDCl ): δ = 8.16 (ddd, J = 5.0, 1.9,
3
.6 Hz, 1 H), 7.76 (ddd, J = 8.3, 7.3, 2.0 Hz, 1 H), 7.58–7.52 (m, 2 H),
.33 (d, J = 8.4 Hz, 1 H), 7.09 (ddd, J = 7.2, 5.0, 0.8 Hz, 1 H), 7.01 (d,
13
J = 8.3 Hz, 1 H), 2.10 (s, 3 H) ppm. C NMR (75 MHz, CDCl ): δ =
1
1
3
67.8, 161.9, 149.7, 147.6, 142.6, 140.0, 130.9, 127.7, 123.6, 119.7,
17.8, 111.6, 108.6, 20.3 ppm. HRMS (ESI): calcd. for C H N NaO
14
10
2
3
2
-(Pyridin-2-yloxy)phenyl Acetate (2a): White solid, m.p. 67–
+
[
M + Na] 277.0584; found 277.0587.
1
6
9 °C. H NMR (300 MHz, CDCl ): δ = 8.17 (ddd, J = 5.0, 2.0, 0.7 Hz,
3
1
H), 7.68 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.29–7.19 (m, 4 H), 6.99
3-Methyl-2-(pyridin-2-yloxy)phenyl Acetate (2j): White solid, m.p.
58–59 °C. H NMR (300 MHz, CDCl
(ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.20–7.13 (m, 2 H), 7.06–7.01 (m, 1
H), 7.00–6.89 (m, 2 H), 2.20 (s, 3 H), 2.02 (s, 3 H) ppm. C NMR
): δ = 168.7, 162.8, 147.7, 143.4, 143.1, 139.4, 133.1,
1
(
ddd, J = 7.2, 5.0, 0.9 Hz, 1 H), 6.93 (dd, J = 8.3, 0.8 Hz, 1 H), 2.06 (s,
): δ = 8.15–8.13 (m, 1 H), 7.68
3
3
1
H) ppm. 13C NMR (75 MHz, CDCl ): δ = 168.5, 163.0, 147.6, 145.3,
3
1
3
42.6, 139.4, 126.8, 125.8, 123.7, 123.1, 118.6, 110.9, 20.4 ppm.
HRMS (ESI): calcd. for C H NNaO [M + Na]+ 252.0631; found (75 MHz, CDCl
1
3
11
3
3
2
52.0640.
128.5, 125.4, 120.9, 118.2, 110.0, 20.5, 16.3 ppm. HRMS (ESI): calcd.
for C H NNaO [M + Na] 266.0788; found 266.0795.
+
14
13
3
5
-Methyl-2-(pyridin-2-yloxy)phenyl Acetate (2b): White solid,
1
m.p. 93–95 °C. H NMR (300 MHz, CDCl ): δ = 8.16 (ddd, J = 5.0, 1.9, 3-Bromo-2-(pyridin-2-yloxy)phenyl Acetate (2k): White solid,
3
1
0
7
.6 Hz, 1 H), 7.67 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.14–7.05 (m, 2 H),
.01–6.90 (m, 3 H), 2.36 (s, 3 H), 2.05 (s, 3 H) ppm. C NMR (75 MHz,
m.p. 76–78 °C. H NMR (300 MHz, CDCl
7.72 (ddd, J = 8.0, 7.4, 2.0 Hz, 1 H), 7.53 (dd, J = 7.3, 2.3 Hz, 1 H),
7.21–7.12 (m, 2 H), 7.03–6.99 (m, 2 H), 2.03 (s, 3 H) ppm. C NMR
3
): δ = 8.13–8.10 (m, 1 H),
1
3
1
3
CDCl ): δ = 168.6, 163.2, 147.6, 142.7, 142.2, 139.3, 135.6, 127.5,
3
1
24.1, 122.8, 118.4, 110.7, 20.9, 20.4 ppm. HRMS (ESI): calcd. for (75 MHz, CDCl
3
): δ = 168.2, 162.1, 147.5, 144.3, 143.2, 139.6, 130.7,
+
C H NNaO [M + Na] 266.0788; found 266.0784.
126.4, 122.9, 118.7, 118.2, 110.4, 20.4 ppm. HRMS (ESI): calcd. for
14
13
3
+
C H BrNNaO [M + Na] 329.9736; found 329.9741.
13
10
3
5
-Methoxy-2-(pyridin-2-yloxy)phenyl Acetate (2c): Light yellow
1
solid, m.p. 55–57 °C. H NMR (300 MHz, CDCl ): δ = 8.15 (dd, J =
3-Nitro-2-(pyridin-2-yloxy)phenyl Acetate (2l): White solid, m.p.
3
1
4
.9, 1.7 Hz, 1 H), 7.69–7.62 (m, 1 H), 7.15 (d, J = 8.9 Hz, 1 H), 6.96
100–102 °C. H NMR (300 MHz, CDCl ): δ = 8.05–8.03 (m, 1 H), 7.96
3
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(
(
dd, J = 8.3, 1.7 Hz, 1 H), 7.75 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.50
dd, J = 8.2, 1.7 Hz, 1 H), 7.39 (t, J = 8.2 Hz, 1 H), 7.08–7.00 (m, 2 H),
5-(tert-Butyl)-2-(pyridin-2-yloxy)phenyl Acetate (2d′): Light yel-
1
low solid, m.p. 94–95 °C. H NMR (300 MHz, CDCl ): δ = 8.14 (dd,
3
2
1
.09 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 168.0, 161.7, 147.1,
J = 5.0, 1.4 Hz, 1 H), 7.65 (ddd, J = 8.4, 7.2, 2.0 Hz, 1 H), 7.08 (s, 2
3
1
3
44.9, 143.9, 139.9, 139.5, 128.7, 125.1, 122.8, 119.2, 110.7, 20.3 ppm.
H), 7.00–6.89 (m, 2 H), 2.01 (s, 6 H), 1.31 (s, 9 H) ppm. C NMR
HRMS (ESI): calcd. for C H N NaO [M + Na]+ 297.0482; found
(75 MHz, CDCl ): δ = 168.1, 162.3, 148.4, 147.5, 143.2, 139.3, 134.8,
1
3
10
2
5
3
2
97.0488.
118.6, 118.0, 110.1, 34.6, 31.0, 20.3 ppm. HRMS (ESI): calcd. for
+
C H NNaO [M + Na] 366.1312; found 366.1317.
19
21
5
4
-Methyl-2-(pyridin-2-yloxy)phenyl Acetate (2m): White solid,
1
5-Fluoro-2-(pyridin-2-yloxy)-1,3-phenylene Diacetate (2e′):
m.p. 83–85 °C. H NMR (300 MHz, CDCl ): δ = 8.18–8.16 (m, 1 H),
3
Light yellow solid, m.p. 93–95 °C. 1H NMR (300 MHz, CDCl ): δ =
7
8
.68 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.10–6.96 (m, 4 H), 6.92 (d, J =
3
.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 168.7, 163.0, 147.6,
8.15–8.08 (m, 1 H), 7.72–7.66 (m, 1 H), 7.03–6.89 (m, 4 H), 2.03 (s, 6
3
H) ppm. 13C NMR (75 MHz, CDCl ): δ = 167.7, 162.2, 158.4 (d, J =
1
2
44.8, 140.1, 139.4, 137.0, 126.1, 123.5, 123.2, 118.5, 110.8, 21.0,
0.4 ppm. HRMS (ESI): calcd. for C H NNaO [M + Na] 266.0788;
3
+
246.1 Hz), 147.4, 144.2 (d, J = 13.3 Hz), 139.6 (2 C), 134.01 (d, J =
1
4
13
3
4
.8 Hz), 118.9, 110.1, 108.8 (d, J = 25.8 Hz), 20.3 ppm. HRMS (ESI):
found 266.0790.
+
calcd. for C H FNNaO [M + Na] 328.0592; found 328.0599.
15
12
5
4
-Chloro-2-(pyridin-2-yloxy)phenyl Acetate (2n): Light yellow
1
5-Chloro-2-(pyridin-2-yloxy)-1,3-phenylene Diacetate (2f′): Light
solid, m.p. 86–87 °C. H NMR (300 MHz, CDCl ): δ = 8.17 (dd, J =
3
1
yellow solid, m.p. 103–105 °C. H NMR (300 MHz, CDCl ): δ = 8.13
3
5
2
6
.0, 1.3 Hz, 1 H), 7.71 (ddd, J = 8.3, 7.3, 2.0 Hz, 1 H), 7.25–7.18 (m,
H), 7.13 (d, J = 8.6 Hz, 1 H), 7.03 (ddd, J = 7.2, 5.0, 0.7 Hz, 1 H),
.96 (d, J = 8.3 Hz, 1 H), 2.06 (s, 3 H) ppm. C NMR (75 MHz, CDCl3):
(
ddd, J = 5.0, 1.9, 0.7 Hz, 1 H), 7.70 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H),
13
1
3
7.16 (s, 2 H), 7.04–6.95 (m, 2 H), 2.04 (s, 6 H) ppm. C NMR (75 MHz,
CDCl ): δ = 167.7, 162.0, 147.5, 144.2, 139.6, 136.5, 129.8, 121.6,
3
δ = 168.3, 162.4, 147.6, 145.8, 141.2, 139.7, 131.6, 125.4, 124.4, 123.4,
19.1, 111.1, 20.4 ppm. HRMS (ESI): calcd. for C H ClNNaO [M +
1
19.0, 110.2, 20.4 ppm. HRMS (ESI): calcd. for C H ClNNaO [M +
15 12 5
1
1
3
10
3
+
+
Na] 344.0296; found 344.0301.
Na] 286.0241; found 286.0247.
5
-Bromo-2-(pyridin-2-yloxy)-1,3-phenylene Diacetate (2g′):
1
-(Pyridin-2-yloxy)naphthalen-2-yl Acetate (2o): Light yellow
1
Light yellow solid, m.p. 111–112 °C. H NMR (300 MHz, CDCl ): δ =
1
3
solid, m.p. 124–126 °C. H NMR (300 MHz, CDCl ): δ = 8.14–8.11 (m,
3
8.12 (ddd, J = 5.0, 1.9, 0.7 Hz, 1 H), 7.70 (ddd, J = 8.3, 7.2, 2.0 Hz, 1
1
7
8
H), 8.00–7.95 (m, 1 H), 7.92–7.86 (m, 1 H), 7.78 (d, J = 8.9 Hz, 1 H),
1
3
H), 7.29 (s, 2 H), 7.05–6.92 (m, 2 H), 2.03 (s, 6 H) ppm. C NMR
75 MHz, CDCl ): δ = 167.7, 161.9, 147.5, 144.4, 139.6, 137.0, 124.4,
.70 (ddd, J = 8.4, 7.2, 2.0 Hz, 1 H), 7.52–7.44 (m, 2 H), 7.37 (d, J =
.9 Hz, 1 H), 7.01–6.97 (m, 2 H), 2.08 (s, 3 H) ppm. C NMR (75 MHz,
(
1
3
3
119.0, 116.7, 110.2, 20.3 ppm. HRMS (ESI): calcd. for C H BrNNaO
15 12 5
CDCl ): δ = 168.6, 163.3, 147.7, 139.6, 139.5, 139.4, 132.6, 128.5,
3
+
[
M + Na] 387.9791; found 387.9796.
1
27.9, 126.6, 126.1, 125.8, 122.0, 121.9, 118.4, 110.0, 20.5 ppm.
HRMS (ESI): calcd. for C H NNaO [M + Na]+ 302.0788; found 2-(Pyridin-2-yloxy)naphthalene-1,3-diyl Diacetate (2p′): Yellow
1
7
13
3
1
3
02.0796.
solid, m.p. 140–142 °C. H NMR (300 MHz, CDCl
1
1
3
): δ = 8.16–8.13 (m,
H), 7.85–7.79 (m, 2 H), 7.71 (ddd, J = 8.2, 7.3, 2.0 Hz, 1 H), 7.65 (s,
H), 7.53–7.47 (m, 2 H), 7.08–7.00 (m, 2 H), 2.30 (s, 3 H), 2.00 (s, 3
2
-(Pyridin-2-yloxy)naphthalen-1-yl Acetate and 3-(Pyridin-2-yl-
1
oxy)naphthalen-2-yl Acetate (2p): H NMR (300 MHz, CDCl ): δ =
13
3
H) ppm. C NMR (75 MHz, CDCl ): δ = 168.2 (2 H), 162.5, 147.7,
3
8
.20–8.17 (m, 2 H), 7.89–7.68 (m, 9 H), 7.56–7.36 (m, 5 H), 7.04–6.98
1
1
42.0, 139.5, 139.1, 135.8, 130.7, 127.8, 126.8, 126.6, 126.5, 126.1,
21.2, 118.9, 110.2, 20.5, 20.4 ppm. HRMS (ESI): calcd. for
1
3
(m, 4 H), 2.33 (s, 3 H), 2.09 (s, 3 H) ppm. C NMR (75 MHz, CDCl3):
δ = 168.7, 168.5, 163.2, 163.1, 147.7, 147.6, 144.2, 142.1, 141.7, 139.5,
+
C H NNaO [M + Na] 360.0842; found 360.0850.
19
15
5
1
1
1
39.4, 137.1, 132.0, 131.7, 131.0, 128.1, 128.0, 127.4, 127.3, 127.1,
26.8, 126.3, 126.1, 125.8, 125.7, 121.8, 121.2, 121.0, 119.9, 118.8,
18.7, 111.1, 110.9, 20.5, 20.4 ppm.
Procedure for Depyridinylation and Deacetylation of 2a: Under
a nitrogen atmosphere, MeOTf (0.36 mmol) was added to a solution
of 2a (0.2 mmol) in dry toluene (5 mL). The reaction mixture was
stirred at 100 °C for 2 h. After having cooled to room temperature,
the solution was evaporated under vacuum. The residue was dis-
solved in dry methanol (5 mL), and added to a solution of Na
2
-(Pyridin-2-yloxy)-1,3-phenylene Diacetate (2a′): White solid,
1
m.p. 85–86 °C. H NMR (300 MHz, CDCl ): δ = 8.16–8.11 (m, 1 H),
3
7
7
8
1
.68 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H), 7.24 (dd, J = 9.1, 7.2 Hz, 1 H),
.15–7.08 (m, 2 H), 7.00 (ddd, J = 7.2, 5.0, 0.8 Hz, 1 H), 6.94 (d, J =
.3 Hz, 1 H), 2.04 (s, 6 H) ppm. C NMR (75 MHz, CDCl ): δ =
(110.4 mg, 4.8 mmol)/MeOH (5 mL). The mixture was heated to
1
3
3
reflux for 1 h. After having cooled to room temperature, the solution
was slowly poured into ice-water (5 mL), acidified with dilute HCl,
and the mixture was stirred for 3 h. The reaction mixture was then
extracted with ethyl acetate, dried with Na SO , and filtered
68.1, 162.2, 147.5, 144.0, 139.4, 124.8, 120.9, 118.7, 110.1, 20.3 ppm.
HRMS (ESI): calcd. for C H NNaO [M + Na]+ 310.0686; found
1
5
13
5
3
10.0677.
2
4
through the pad of silica gel. The filtrate was concentrated and the
resulting residue was purified by flash column chromatography to
afford desired product 3a.
5
-Methyl-2-(pyridin-2-yloxy)-1,3-phenylene Diacetate (2b′):
1
White solid, m.p. 118–119 °C. H NMR (300 MHz, CDCl ): δ = 8.14
3
(ddd, J = 5.0, 1.9, 0.7 Hz, 1 H), 7.67 (ddd, J = 8.3, 7.2, 2.0 Hz, 1 H),
6
2
1
.99 (ddd, J = 7.2, 5.0, 0.8 Hz, 1 H), 6.94–6.92 (m, 3 H), 2.36 (s, 3 H),
.03 (s, 6 H) ppm. 1 C NMR (75 MHz, CDCl ): δ = 168.3, 162.4, 147.6,
3
3
Acknowledgments
43.5, 139.4, 135.4, 135.0, 121.6, 118.6, 110.1, 21.1, 20.4 ppm. HRMS
+
The authors gratefully acknowledge financial support from the
National Natural Science Foundation of China (NSFC) (grant
number 21302014), from the Jiangsu Province Key Laboratory
of Fine Petrochemical Engineering (open project KF1304), the
Jiangsu Key Laboratory of Advanced Catalytic Materials and
Technology (grant number BM2012110) and from the
(ESI): calcd. for C H NNaO [M + Na] 324.0842; found 324.0850.
16
15
5
5
-Methoxy-2-(pyridin-2-yloxy)-1,3-phenylene Diacetate (2c′):
1
White solid, m.p. 111–113 °C. H NMR (300 MHz, CDCl ): δ = 8.14
3
(
6
dd, J = 5.0, 1.4 Hz, 1 H), 7.66 (ddd, J = 8.4, 7.2, 2.0 Hz, 1 H), 7.00–
.90 (m, 2 H), 6.68 (s, 2 H), 3.78 (s, 3 H), 2.04 (s, 6 H) ppm. 1 C NMR
3
(
1
75 MHz, CDCl ): δ = 168.0, 162.5, 156.3, 147.7, 144.2, 139.6, 131.0,
3
18.7, 110.1, 106.9, 55.9, 20.5 ppm. HRMS (ESI): calcd. for Changzhou University, Advanced Catalysis and Green Manufac-
+
C H N NaO [M + Na] 340.0792; found 340.0794.
turing Innovation Center.
16
15
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973.
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C–H Acetoxylation
L. Wang,* L. Pan, Y. Huang,
Q. Chen, M. He* .................................. 1–7
Palladium-Catalyzed Regioselective
C–H Acetoxylation of 2-Aryloxypyr-
idines with 2-Pyridyloxy as a Re-
movable Directing Group
A simple and regioselective palladium- PhI(OAc) as both oxidant and acetate
catalyzed ortho-C(sp )–H acetoxylation source has been developed.
2
2
reaction of 2-aryloxypyridines with
DOI: 10.1002/ejoc.201600508
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim