Palladium-catalyzed direct C(sp2)-H alkoxylation of 2-aryloxypyridines using 2-pyridyloxyl as the directing group

Article abstract of DOI:10.1021/jo5014146

An efficient and highly regioselective palladium-catalyzed ortho-C(sp²)-H bond alkoxylation of 2-aryloxypyridines was developed using 2-pyridyloxyl as the directing group and alcohols as alkoxylation reagents. Under an air atmosphere and in the presence of PhI(OAc)₂, the reaction gave the corresponding products in moderate to good yields, and a series of functional groups could be tolerated.

Full text of DOI:10.1021/jo5014146

Note
pubs.acs.org/joc
Palladium-Catalyzed Direct C(sp2)−H Alkoxylation of
2‑Aryloxypyridines Using 2‑Pyridyloxyl as the Directing Group
Chun Zhang† and Peipei Sun*,†,‡
†Jiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and Materials Science, Nanjing Normal University, Nanjing
210097, China
‡Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, Nanjing Normal University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: An efficient and highly regioselective palladium-
catalyzed ortho-C(sp2)−H bond alkoxylation of 2-aryloxypyridines
was developed using 2-pyridyloxyl as the directing group and
alcohols as alkoxylation reagents. Under an air atmosphere and in
the presence of PhI(OAc)2, the reaction gave the corresponding
products in moderate to good yields, and a series of functional
groups could be tolerated.
ransition-metal-catalyzed direct C−H bond functionaliza-
purpose, in this note, we describe a Pd-catalyzed ortho-
Ttion has been used in the construction of a variety of alkoxylation of C(sp2)−H bonds on benzene ring using 2-
pyridyloxyl as the directing group and alcohols as alkoxylation
reagents.
carbon−carbon and carbon−heteroatom bonds with features of
step-economics and green chemistry primarily.1 By this
strategy, a series of valuable polyfunctional compounds can
be synthesized expediently. Among numerous functional
groups used as the directing groups in C−H bond
functionalization, 2-pyridyl has been thoroughly investigated
because of its moderate coordination ability to transition metals
and transformation ability. The alkenylation,2 arylation,3
acetoxylation,4 acylation,5 alkylation,6 and halogenation7 on
the ortho-C(sp2)−H bond of 2-arylpyridines were intensively
studied. Pyridyl-directed C(sp3)−H bond activations were also
developed.8 To expand the directing function of the pyridyl
group is still necessary and valuable. Very recently, a number of
C−C bond formation reactions directed by 2-pyridyloxyl were
developed, e.g., Pd9- or Ru10-catalyzed ortho-arylation of 2-
phenoxypyridines, Pd11- or Ru12-catalyzed oxidative alkenyla-
tion of 2-phenoxypyridines, Pd-catalyzed oxidative C(sp2)−H
acylation,13 and Pd-catalyzed oxidative alkoxycarbonylation.14
In these transition-metal-catalyzed C−C bond formation
reactions, the six-membered cyclopalladated intermediates
were generated by the coordination of the pyridyl group to
metals. It is well-known that alkoxyl is an important functional
group in organic chemistry; the aryl ethers are also a common
motif in pharmaceuticals, functional materials, and many other
fine chemicals.15 Though a few transition-metal-catalyzed direct
alkoxylation of arenes to form aryl ethers were developed,
compared with the transition-metal-catalyzed direct aromatic
C−C bond formation reaction, the alkoxylation of inert C−H is
more difficult and still needed to be studied more adequately.16
On the other hand, 2-phenoxypyridine series compounds have
interesting bioactivities and have aroused much attention in the
pharmaceutical field.17 Therefore, to develop the simple and
efficient route for the structural modification of these
compounds should be significant and valuable. For this
Optimization studies were performed with 2-(3-
methoxyphenoxy)pyridine and methanol in the presence of
palladium catalyst and oxidant; the results are summarized in
Table 1. The oxidant was very important to the transition-
metal-catalyzed alkoxylation reaction.16 Thus, using Pd(OAc)2
(10 mol %) as the catalyst and methanol as both methoxylation
reagent and the solvent, a series of oxidants were first tested for
this transformation. Unfortunately, in the presence of AgOAc,
BQ (benzoquinone), or O2, no conversion was observed at 90
°C for 24 h (entries 1−3). We tried other oxidants including
K2S2O8, Na2S2O8, (NH4)2S2O8, and Cu(OAc)2 again, yet only a
trace of alkoxylation product was found (entries 4−7).
However, to our delight, when 1 equiv of PhI(OAc)2 was
added, the desired product was obtained in 44% yield (entry 8).
When the amount of PhI(OAc)2 was increased to 2 equiv, a
yield of 83% was afforded (entry 9). We then tested the effect
of additive. The result showed that the addition of AcOH did
not improve the present reaction significantly (entry 11),
whereas TFA, TsOH, or MeSO3H had an evident inhibition to
the reaction (entries 12−14). At 90 °C, the reaction gave the
highest yield. Raising the reaction temperature to 100 °C could
not improve the yield obviously, but reducing it to 70 °C led to
the decrease of the reaction activity (entry 9). The appropriate
amount of catalyst was 10 mol %. To decrease the amount of
Pd(OAc)2 to 5 mol % brought a lower yield of 58% (entry 10).
Furthermore, we explored other palladium catalysts, such as
PdCl2, PdCl2(MeCN)2, and Pd(PPh3)4; the results revealed
that they were substantially less effective to the reaction (entries
15−17). Additionally, if mixed solvent MeOH/MeCN (1:1) or
Received: June 25, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5014146 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
Pd(OAc)2
oxidant (equiv)
additive (equiv)
yield (%)
1
2
3
4
5
6
7
8
9
AgOAc (1)
none
0
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
Pd(OAc)2
Pd(OAc)2
PdCl2
BQ (1)
none
0
O2 (1 atm)
none
0
K2S2O8 (1)
none
<5
<5
<5
<5
44
Na2S2O8 (1)
(NH4)2S2O8 (1)
Cu(OAc)2 (1)
PhI(OAc)2 (1)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
PhI(OAc)2 (2)
none
none
none
none
c
none
83 (53, 85)
d
10
none
58
81
<10
0
11
12
13
14
15
16
17
AcOH (5)
TFA (5)
TsOH (5)
MeSO3H (5)
none
0
<5
16
27
<10
PdCl2(CH3CN)2
Pd(PPh3)4
Pd(OAc)2
none
none
e
18
none
a
Unless otherwise specified, the reactions were carried out in a sealed tube in the presence of 2-(3-methoxyphenoxy)pyridine (0.5 mmol), methanol
b
c
(2 mL), catalyst (10 mol %), and oxidant (1 mmol) under an air atmosphere at 90 °C for 24 h. Isolated yields. At 70 and 100 °C, respectively.
d
e
Pd(OAc)2 (5 mol %) was used. Mixed solvent MeOH/MeCN (1:1, 2 mL) or MeOH/dioxane (1:1, 2 mL) was used.
MeOH/dioxane (1:1) was used, very low yields were obtained
(entry 18).
moderate to good yields (3ab−3fd). Significantly, an electron-
donating group methoxyl substituted on the meta-position of
the benzene ring increased the reactivity of these trans-
formations similarly as above (3fb, 3fc, 3fd). It should be
pointed out that, in some cases, the presence of 10 equiv of
AcOH was helpful to improve the yields.
In summary, we have developed a new palladium-catalyzed
direct C(sp2)−H alkoxylation using 2-pyridyloxyl as the
directing group and obtained ortho-alkoxylation products on
the benzene ring selectively in moderate to good yields. This
technology was available for both primary and secondary
alcohols. The reaction could proceed smoothly in an air
atmosphere under mild reaction conditions, making the
method highly applicable.
We then assessed the scope of the reaction between 2-
phenoxypyridine derivatives 1(a−n) and several alcohols 2(a−
d) under the optimized reaction conditions (Table 2). Using
methanol as the coupling partner, various 2-aryloxypyridines
were first examined and the corresponding ortho-monomethox-
ylation products were obtained selectively. The presence of a
substituent group on the benzene ring affected the yield of the
reaction obviously. It seemed that an electron-rich benzene ring
was favorable to this alkoxylation reaction. When the electron-
donating group such as methoxyl and methyl substituted on the
benzene ring (1a−j), the higher yields could be obtained. In
particular, the reactants with a strong electron-donating group
alkoxyl gave the best results (3ea, 3fa, 3ja). However, when a
methyl existed on the ortho-position, a low yield of 38% was
obtained, which could be attributed to the steric hindrance
(3da). It is interesting that, when 2-(3-methylphenoxy)pyridine
(1c) or 2-(3-methoxyphenoxy)pyridine (1f) was employed as
the reaction substrate, only the product 3ca or 3fa was found,
but when 2-(benzo[d][1,3]dioxol-5-yloxy)pyridine (1j) was
used, a mixture of 3ja and 3ja′ was produced with a ratio of
1.2:1, which suggested that the steric hindrance in 1j was
weaker than other 3-substituted reactants. Another reason
might be the strong electron-donating property of the
substituent group in 1j bringing about the decrease of the
regioselectivity. In contrast, the presence of electron-with-
drawing groups, including Cl, Br, and COOMe, led to the lower
yields (3ka−3na).
EXPERIMENTAL SECTION
■
General. All reactions were run in oven-dried flasks under air.
Alcohols were dried using a general method; other reagents were
commercially available and were used without purification. NMR
spectra were recorded at 400 MHz (1H) and 100 MHz (13C) using
TMS as an internal standard. Chemical shifts are given relative to
1
CDCl3 (7.28 ppm for H NMR, 77.16 ppm for 13C NMR).. The
following abbreviations were used to explain the multiplicities: s =
singlet, d = doublet, t = triplet, dd = doublet of doublet, m = multiplet.
Melting points are uncorrected. For the HRMS measurements, Q-
TOF was used.
General Experimental Procedures and Characterizations. 2-
Aryloxypyridine (0.5 mmol), PhI(OAc)2 (1 mmol), Pd(OAc)2 (0.05
mmol), and alcohol (2 mL) were added in a 25 mL sealed tube with a
Teflon-lined cap. The mixture was heated at 90 °C (oil bath
temperature) for 24 h. After cooling to room temperature, the volatiles
were removed under reduced pressure, and the residue was purified by
flash column chromatography on silica gel using hexane/ethyl acetate
(10:1, v/v) as eluent to give the corresponding product. For the solid
Some other alcohols, such as ethanol (2b), propanol (2c),
and a secondary alcohol isopropanol (2d), were also used as the
coupling partners for this Pd-catalyzed alkoxylation reaction,
and the desired ortho-alkoxylation products were obtained in
B
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The Journal of Organic Chemistry
Note
a b
,
Table 2. ortho-Alkoxylation of 2-Phenoxypyridine Derivatives with Alcohols
a
Unless otherwise specified, all reactions were carried out with 2-phenoxypyridine derivatives (1, 0.5 mmol), alcohol (2, 2 mL), Pd(OAc)2 (10 mol
b
%), and PhI(OAc)2 (1.0 mmol) under air atmosphere at 90 °C for 24 h. All listed yields are isolated ones. 10 equiv of AcOH was used as the
additive.
products, the melting points were obtained after further recrystalliza-
tion from this mixed solvent.
123.1, 121.1, 118.0, 112.9, 110.7, 55.9. HRMS-ESI (m/z): calcd for
C12H12NO2 [M + H]+ 202.0863, found 202.0859.
2-(2-Methoxyphenoxy)pyridine (3aa). Yield: 46% (46 mg). Rf
0.46. White solid, mp: 69−71 °C. H NMR (CDCl3, 400 MHz): δ
2-(2-Methoxy-4-methylphenoxy)pyridine (3ba). Yield: 58% (62
mg). Rf 0.42. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−8.16
1
1
8.18−8.16 (m, 1H), 7.70−7.66 (m, 1H), 7.25−7.21 (m, 1H), 7.16 (dd,
J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.05−6.93 (m, 4H), 3.79 (s, 3H). 13C
NMR (CDCl3, 100 MHz): δ 163.7, 151.8, 147.6, 142.6, 139.2, 126.0,
(m, 1H), 7.68−7.64 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.97−6.91 (m,
2H), 6.85−6.80 (m, 2H), 3.77 (s, 3H), 2.39 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 163.9, 151.4, 147.5, 140.2, 139.1, 135.9, 122.8,
C
dx.doi.org/10.1021/jo5014146 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
121.5, 117.8, 113.8, 110.6, 55.9, 21.5. HRMS-ESI (m/z): calcd for
C13H14NO2 [M + H]+ 216.1019, found 216.1013.
MHz): δ 8.16−8.14 (m, 1H), 7.72−7.67 (m, 1H), 7.09 (d, J = 8.0 Hz,
1H), 7.01−6.95 (m, 4H), 3.78 (s, 3H). 13C NMR (CDCl3, 100 MHz):
δ 163.4, 152.4, 147.5, 141.2, 139.3, 130.9, 123.9, 120.9, 118.3, 113.5,
110.8, 56.1. HRMS-ESI (m/z): calcd for C12H11NO2Cl [M + H]+
236.0473, found 236.0484.
2-(2-Methoxy-5-methylphenoxy)pyridine (3ca). Yield: 62% (66
1
mg). Rf 0.43. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.18−8.17
(m, 1H), 7.69−7.65 (m, 1H), 7.02−6.91 (m, 5H), 3.75 (s, 3H), 2.32
(s, 3H). 13C NMR (CDCl3, 100 MHz): δ 163.8, 149.6, 147.6, 142.3,
139.1, 130.8, 126.3, 123.7, 117.9, 113.0, 110.7, 56.1, 20.6. HRMS-ESI
(m/z): calcd for C13H14NO2 [M + H]+ 216.1019, found 216.1014.
2-(2-Methoxy-6-methylphenoxy)pyridine (3da). Yield: 38% (41
2-(4-Bromo-2-methoxyphenoxy)pyridine (3la). Yield: 47% (65
1
mg). Rf 0.40. White solid, mp: 63−65 °C. H NMR (CDCl3, 400
MHz): δ 8.16−8.14 (m, 1H), 7.72−7.67 (m, 1H), 7.13 (dd, J1 = 8.4
Hz, J2 = 2.0 Hz, 2H), 7.03 (dd, J1 = 8.0 Hz, J2 = 2.0 Hz, 1H), 7.00−
6.95 (m, 2H), 3.77 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 163.3,
152.5, 147.4, 141.8, 139.3, 124.4, 124.0, 118.4, 118.3, 116.4, 110.8,
56.1. HRMS-ESI (m/z): calcd for C12H11NO2Br [M + H]+ 279.9968,
found 279.9980.
1
mg). Rf 0.43. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−8.15
(m, 1H), 7.69−7.64 (m, 1H), 7.13 (t, J = 8.0 Hz, 1H), 6.96−6.86 (m,
4H), 3.75 (s, 3H), 2.20 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
163.4, 152.1, 147.6, 139.2, 132.5, 130.9, 125.6, 122.9, 117.7, 110.2,
109.9, 56.0, 16.2. HRMS-ESI (m/z): calcd for C13H14NO2 [M + H]+
216.1019, found 216.1013.
2-(5-Bromo-2-methoxyphenoxy)pyridine (3ma). Yield: 39% (54
1
mg). Rf 0.42. White solid, mp: 81−83 °C. H NMR (CDCl3, 400
2-(2,4-Dimethoxyphenoxy)pyridine (3ea). Yield: 67% (77 mg). Rf
0.40. Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.17−8.15 (m, 1H),
7.67−7.63 (m, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.95−6.89 (m, 2H), 6.60
(d, J = 2.8 Hz, 1H), 6.51 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 3.82 (s,
3H), 3.75 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.1, 157.8,
152.5, 147.5, 139.1, 136.2, 123.2, 117.8, 110.4, 104.2, 100.7, 55.9, 55.6.
HRMS-ESI (m/z): calcd for C13H14NO3 [M + H]+ 232.0968, found
232.0978.
2-(2,5-Dimethoxyphenoxy)pyridine (3fa). Yield: 83% (96 mg). Rf
0.38. Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.18 (dd, J1 = 5.2 Hz,
J2 = 1.6 Hz, 1H), 7.69−7.65 (m, 1H), 6.98−6.92 (m, 3H), 6.78−6.73
(m, 2H), 3.77 (s, 3H), 3.72 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
163.6, 154.1, 147.6, 146.0, 143.3, 139.2, 118.1, 114.2, 110.7, 110.5,
109.6, 56.8, 55.7. HRMS-ESI (m/z): calcd for C13H14NO3 [M + H]+
232.0968, found 232.0979.
MHz): δ 8.17−8.15 (m, 1H), 7.72−7.67 (m, 1H), 7.31 (dd, J1 = 9.6
Hz, J2 = 1.6 Hz, 2H), 7.01−6.95 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H),
3.75 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 163.2, 151.2, 147.5,
143.3, 139.4, 128.7, 126.2, 118.5, 114.1, 112.4, 110.9, 56.1. HRMS-ESI
(m/z): calcd for C12H11NO2Br [M + H]+ 279.9968, found 279.9978.
Methyl 3-Methoxy-4-(pyridin-2-yloxy)benzoate (3na). Yield: 35%
1
(45 mg). Rf 0.34. White solid, mp: 95−97 °C. H NMR (CDCl3, 400
MHz): δ 8.16−8.14 (m, 1H), 7.74−7.69 (m, 3H), 7.19 (d, J = 8.0 Hz,
1H), 7.02−6.98 (m, 2H), 3.93 (s, 3H), 3.84 (s, 3H). 13C NMR
(CDCl3, 100 MHz): δ 166.6, 163.2, 151.5, 147.5, 146.8, 139.4, 127.6,
123.0, 122.6, 118.6, 113.8, 111.2, 56.1, 52.2. HRMS-ESI (m/z): calcd
for C14H14NO4 [M + H]+ 260.0917, found 260.0924.
2-(2-Ethoxyphenoxy)pyridine (3ab). Yield: 42% (45 mg). Rf 0.45.
Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.16 (dd, J1 = 4.8 Hz, J2 =
1.6 Hz, 1H), 7.69−7.65 (m, 1H), 7.18 (d, J = 7.6 Hz, 2H), 7.02−6.98
(m, 2H), 6.97−6.91 (m, 2H), 4.00 (q, J = 6.8 Hz, 2H), 1.17 (t, J = 7.2
Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 163.9, 151.0, 147.4, 139.0,
129.7, 125.9, 123.0, 121.2, 117.9, 114.4, 110.7, 64.4, 14.6. HRMS-ESI
(m/z): calcd for C13H14NO2 [M + H]+ 216.1019, found 216.1016.
2-(2-Ethoxy-4-methylphenoxy)pyridine (3bb). Yield: 55% (63
2-(4-Ethyl-2-methoxyphenoxy)pyridine (3ga). Yield: 59% (67
1
mg). Rf 0.45. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17 (dd,
J1 = 5.2 Hz, J2 = 1.6 Hz, 1H), 7.68−7.64 (m, 1H), 7.06 (d, J = 8.0 Hz,
1H), 6.96−6.91 (m, 2H), 6.87−6.83 (m, 2H), 3.78 (s, 3H), 2.68 (q, J
= 7.6 Hz, 2H), 1.29 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δ 163.9, 151.0, 147.6, 142.1, 140.4, 139.1, 122.7, 120.2, 117.9, 112.7,
110.6, 55.9, 28.8, 15.4. HRMS-ESI (m/z): calcd for C14H16NO2 [M +
H]+ 230.1176, found 230.1184.
1
mg). Rf 0.43. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.16 (d, J
= 4.0 Hz, 1H), 7.68−7.63 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.96−
6.92 (m, 2H), 6.83−6.80 (m, 2H), 3.99 (q, J = 7.2 Hz, 2H), 2.37 (s,
3H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.1,
150.7, 147.4, 140.7, 139.0, 135.7, 122.7, 121.6, 117.7, 115.3, 110.6,
64.4, 21.4, 14.7. HRMS-ESI (m/z): calcd for C14H16NO2 [M + H]+
230.1176, found 230.1170.
2-((3-Methoxy-[1,1′-biphenyl]-4-yl)oxy)pyridine (3ha). Yield: 66%
1
(91 mg). Rf 0.35. White solid, mp: 115−117 °C. H NMR (CDCl3,
400 MHz): δ 8.22−8.20 (m, 1H), 7.73−7.69 (m, 1H), 7.64−7.61 (m,
2H), 7.49−7.45 (m, 2H), 7.40−7.36 (m, 1H), 7.24 (d, J = 0.8 Hz,
3H), 7.01−6.98 (m, 2H), 3.86 (s, 3H). 13C NMR (CDCl3, 100 MHz):
δ 163.7, 151.9, 147.6, 142.1, 141.0, 139.4, 139.3, 128.8, 127.3, 127.2,
123.2, 119.9, 118.1, 112.0, 110.9, 56.0. HRMS-ESI (m/z): calcd for
C18H16NO2 [M + H]+ 278.1176, found 278.1178.
2-(2-Ethoxy-5-methoxyphenoxy)pyridine (3fb). Yield: 75% (92
1
mg). Rf 0.38. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−8.15
(m, 1H), 7.67−7.63 (m, 1H), 6.97−6.91 (m, 3H), 6.77 (d, J = 2.8 Hz,
1H), 6.71 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 3.91 (q, J = 7.2 Hz, 2H),
3.76 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ
163.8, 154.3, 147.4, 145.1, 144.0, 139.1, 118.1, 116.1, 110.7, 110.5,
109.4, 65.5, 55.6, 14.8. HRMS-ESI (m/z): calcd for C14H16NO3 [M +
H]+ 246.1125, found 246.1134.
2-(2-Methoxy-4,5-dimethylphenoxy)pyridine (3ia). Yield: 62% (71
1
mg). Rf 0.42. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.18−8.17
(m, 1H), 7.68−7.64 (m, 1H), 6.96−6.92 (m, 3H), 6.83 (s, 1H), 3.75
(s, 3H), 2.28 (s, 3H), 2.22 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ
164.0, 149.4, 147.6, 140.0, 139.1, 134.0, 129.1, 124.1, 117.8, 114.8,
110.6, 56.2, 19.8, 19.0. HRMS-ESI (m/z): calcd for C14H16NO2 [M +
H]+ 230.1176, found 230.1183.
2-(2-Ethoxy-4-ethylphenoxy)pyridine (3gb). Yield: 45% (54 mg).
1
Rf 0.42. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.18−8.16 (m,
1H), 7.67−7.63 (m, 1H), 7.08 (d, J = 7.6 Hz, 1H), 6.96−6.91 (m,
2H), 6.86−6.82 (m, 2H), 4.00 (q, J = 7.2 Hz, 2H), 2.67 (q, J = 7.6 Hz,
2H), 1.28 (t, J = 7.6 Hz, 3H), 1.17 (t, J = 7.2 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): δ 164.1, 150.7, 147.4, 142.0, 140.9, 139.0, 122.6,
120.4, 117.8, 114.2, 110.6, 64.4, 28.7, 15.5, 14.7. HRMS-ESI (m/z):
calcd for C15H18NO2 [M + H]+ 244.1332, found 244.1340.
2-((4-Methoxybenzo[d][1,3]dioxol-5-yl)oxy)pyridine (3ja). Yield:
40% (49 mg). Rf 0.43. White solid, mp: 103−105 °C. 1H NMR
(CDCl3, 400 MHz): δ 8.19−8.17 (m, 1H), 7.70−7.66 (m, 1H), 6.98−
6.92 (m, 2H), 6.63 (d, J = 8.8 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 6.00
(s, 2H), 3.88 (s, 3H). 13C NMR (CDCl3, 100 MHz): δ 164.0, 147.5,
146.4, 139.9, 139.2, 138.1, 137.0, 118.0, 115.1, 110.5, 102.0, 101.6,
59.9. HRMS-ESI (m/z): calcd for C13H12NO4 [M + H]+ 246.0761,
found 246.0772.
2-(4-Bromo-2-ethoxyphenoxy)pyridine (3lb). Yield: 35% (52 mg).
1
Rf 0.40. White solid, mp: 89−91 °C. H NMR (CDCl3, 400 MHz): δ
8.13 (dd, J1 = 5.2 Hz, J2 = 1.2 Hz, 1H), 7.70−7.66 (m, 1H), 7.13−7.11
(m, 2H), 7.05 (d, J = 8.8 Hz, 1H), 6.99−6.94 (m, 2H), 3.97 (q, J = 7.2
Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). 13C NMR (CDCl3, 100 MHz): δ
163.5, 151.8, 147.3, 142.2, 139.2, 124.2, 124.0, 118.2, 117.5, 110.9,
64.7, 14.4. HRMS-ESI (m/z): calcd for C13H13NO2Br [M + H]+
294.0124, found 294.0127.
2-((6-Methoxybenzo[d][1,3]dioxol-5-yl)oxy)pyridine (3ja′). Yield:
1
33% (40 mg). Rf 0.38. Yellow oil. H NMR (CDCl3, 400 MHz): δ
8.18−8.16 (m, 1H), 7.69−7.65 (m, 1H), 6.98−6.92 (m, 2H), 6.72 (s,
1H), 6.67 (s, 1H), 5.97 (s, 2H), 3.71 (s, 3H). 13C NMR (CDCl3, 100
MHz): δ 163.9, 147.5, 146.6, 144.9, 141.1, 139.2, 136.1, 118.0, 110.6,
104.8, 101.5, 96.7, 57.2. HRMS-ESI (m/z): calcd for C13H12NO4 [M +
H]+ 246.0761, found 246.0772.
2-(2-Propoxyphenoxy)pyridine (3ac). Yield: 41% (47 mg). Rf 0.44.
Yellow oil. 1H NMR (CDCl3, 400 MHz): δ 8.17−8.15 (m, 1H), 7.68−
7.64 (m, 1H), 7.22−7.18 (m, 2H), 7.03−6.98 (m, 2H), 6.96−6.92 (m,
2H), 3.89 (t, J = 6.4 Hz, 2H), 1.61−1.53 (m, 2H), 0.74 (t, J = 7.6 Hz,
2-(4-Chloro-2-methoxyphenoxy)pyridine (3ka). Yield: 36% (42
1
mg). Rf 0.37. White solid, mp: 60−62 °C. H NMR (CDCl3, 400
D
dx.doi.org/10.1021/jo5014146 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3H). 13C NMR (CDCl3, 100 MHz): δ 163.9, 151.2, 147.4, 142.9,
139.0, 125.9, 123.1, 121.0, 117.8, 114.0, 110.6, 70.1, 22.4, 10.2. HRMS-
ESI (m/z): calcd for C14H16NO2 [M + H]+ 230.1176, found 230.1169.
2-(4-Methyl-2-propoxyphenoxy)pyridine (3bc). Yield: 48% (58
Topics in Current Chemistry; Daugulis, O., Ed.; Springer-Verlag: Berlin,
2010; Vol. 292, pp 57−84. (e) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (f) Sun, C. L.; Li, B. J.; Shi, Z. J. Chem. Rev. 2011,
111, 1293. (g) Liu, C.; Zhang, H.; Shi, W.; Lei, A. W. Chem. Rev. 2011,
111, 1780. (h) Davies, H. L.; Bois, J. D.; Yu, J. Q. Chem. Soc. Rev. 2011,
40, 1855 and other reviews in this themed issue. (i) Li, B. J.; Shi, Z. J.
Chem. Soc. Rev. 2012, 41, 5588. (j) Neufeldt, S. R.; Sanford, M. S. Acc.
Chem. Res. 2012, 45, 936. (k) Li, B.; Dixneuf, P. H. Chem. Soc. Rev.
2013, 42, 5744. (l) Wu, Y. N.; Wang, J.; Mao, F.; Kwong, F. Y.
Chem.Asian J. 2014, 9, 26.
1
mg). Rf 0.42. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−8.15
(m, 1H), 7.67−7.63 (m, 1H), 7.07 (d, J = 7.6 Hz, 1H), 6.95−6.91 (m,
2H), 6.83−6.79 (m, 2H), 3.88 (t, J = 6.4 Hz, 2H), 2.38 (s, 3H), 1.62−
1.53 (m, 2H), 0.74 (t, J = 7.6 Hz, 3H). 13C NMR (CDCl3, 100 MHz):
δ 164.1, 150.8, 147.4, 140.6, 139.0, 135.8, 122.7, 121.5, 117.7, 114.9,
110.5, 70.1, 22.5, 21.5, 10.2. HRMS-ESI (m/z): calcd for C15H18NO2
[M + H]+ 244.1332, found 244.1339.
(2) Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009,
74, 7094.
2-(5-Methoxy-2-propoxyphenoxy)pyridine (3fc). Yield: 80% (103
1
mg). Rf 0.38. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−8.15
(3) (a) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Sanford, M. S. J. Am.
Chem. Soc. 2005, 127, 7330. (b) Deprez, N. R.; Sanford, M. S. J. Am.
Chem. Soc. 2009, 131, 11234. (c) Li, W.; Yin, Z. W.; Jiang, X. Q.; Sun,
P. P. J. Org. Chem. 2011, 76, 8543.
(4) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300.
(m, 1H), 7.68−7.64 (m, 1H), 6.97−6.91 (m, 3H), 6.80 (d, J = 2.8 Hz,
1H), 6.72 (dd, J1 = 8.8 Hz, J2 = 2.8 Hz, 1H), 3.82 (t, J = 6.4 Hz, 2H),
3.78 (s, 3H), 1.56−1.48 (m, 2H), 0.72 (t, J = 7.6 Hz, 3H). 13C NMR
(CDCl3, 100 MHz): δ 163.8, 154.2, 147.5, 145.3, 143.8, 139.1, 118.0,
115.6, 110.6, 110.5, 109.4, 71.2, 55.7, 22.6, 10.2. HRMS-ESI (m/z):
calcd for C15H18NO3 [M + H]+ 260.1281, found 260.1285.
(5) (a) Zhou, W.; Li, H. J.; Wang, L. Org. Lett. 2012, 14, 4594.
2-(2-Isopropoxy-5-methylphenoxy)pyridine (3cd). Yield: 55% (67
(b) Basle,
́
O.; Bidange, J.; Shuai, Q.; Li, C. J. Adv. Synth. Catal. 2010,
O.; Deng, G. J.;
1
mg). Rf 0.42. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.18−8.17
352, 1145. (c) Xiao, F. H.; Shuai, Q.; Zhao, F.; Basle,
Li, C. J. Org. Lett. 2011, 13, 1614. (d) Li, M.; Ge, H. B. Org. Lett. 2010,
12, 3464.
́
(m, 1H), 7.68−7.64 (m, 1H), 7.01−6.98 (m, 3H), 6.97−6.89 (m, 2H),
4.45−4.36 (m, 1H), 2.33 (s, 3H), 1.13 (d, J = 6.4 Hz, 6H). 13C NMR
(CDCl3, 100 MHz): δ 164.0, 147.6, 147.4, 144.0, 139.0, 131.3, 126.2,
123.8, 117.8, 117.1, 110.7, 71.8, 22.0, 20.7. HRMS-ESI (m/z): calcd
for C15H18NO2 [M + H]+ 244.1332, found 244.1334.
(6) Chen, X.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128,
12634.
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S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009, 131,
11310. (b) Whitfield, S. R.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
15142. (c) Stowers, K. J.; Sanford, M. S. Org. Lett. 2009, 11, 4584.
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50, 5192. (c) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52,
11726. (d) Li, B.; Darcel, C.; Dixneuf, P. H. Chem. Commun. 2014, 50,
5970.
(9) Chu, J. H.; Lin, P. S.; Wu, M. J. Organometallics 2010, 29, 4058.
(10) Ackermann, L.; Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154.
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Lett. 2012, 14, 5294.
2-(2-Isopropoxy-4-methoxyphenoxy)pyridine (3ed). Yield: 42%
1
(54 mg). Rf 0.40. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.17−
8.15 (m, 1H), 7.67−7.62 (m, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.95−6.92
(m, 1H), 6.88 (dd, J1 = 8.0 Hz, J2 = 0.8 Hz, 1H), 6.59 (d, J = 2.8 Hz,
1H), 6.52 (dd, J1 = 8.8 Hz, J2 = 3.2 Hz, 1H), 4.49−4.40 (m, 1H), 3.82
(s, 3H), 1.15 (d, J = 6.0 Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ
164.2, 157.5, 150.6, 147.4, 138.9, 137.7, 123.3, 117.7, 110.5, 104.8,
103.6, 71.5, 55.6, 21.9. HRMS-ESI (m/z): calcd for C15H18NO3 [M +
H]+ 260.1281, found 260.1282.
2-(2-Isopropoxy-5-methoxyphenoxy)pyridine (3fd). Yield: 78%
1
(101 mg). Rf 0.39. Yellow oil. H NMR (CDCl3, 400 MHz): δ 8.18−
8.16 (m, 1H), 7.67−7.62 (m, 1H), 6.96−6.93 (m, 2H), 6.88 (dd, J1 =
8.4 Hz, J2 = 0.8 Hz, 1H), 6.77 (d, J = 3.2 Hz, 1H), 6.70 (dd, J1 = 8.8
Hz, J2 = 3.2 Hz, 1H), 4.34−4.28 (m, 1H), 3.76 (s, 3H), 1.11 (d, J = 6.0
Hz, 6H). 13C NMR (CDCl3, 100 MHz): δ 163.7, 154.7, 147.5, 145.3,
143.8, 139.1, 119.1, 118.1, 110.7, 110.6, 109.3, 72.8, 55.6, 22.1. HRMS-
ESI (m/z): calcd for C15H18NO3 [M + H]+ 260.1281, found 260.1287.
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ASSOCIATED CONTENT
(16) (a) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912.
(b) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
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Z. W.; Jiang, X. Q.; Sun, P. P. J. Org. Chem. 2013, 78, 10002. (h) Chen,
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Chem. Sci. 2013, 4, 4187.
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D.; Duckett, D. R.; Kamenecka, T. M. Bioorg. Med. Chem. Lett. 2011,
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A.; Abell, L. M.; Schumacher, W. A.; Bostwick, J. S.; Steinbacher, T. E.;
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■
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sunpeipei@njnu.edu.cn (P.S.).
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Projects 21272117 and 20972068) and
the Priority Academic Program Development of Jiangsu Higher
Education Institutions.
REFERENCES
■
(1) For partial recent reviews, see: (a) Chen, X.; Engle, K. M.; Wang,
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W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Sun, C. L.; Li, B. J.;
Shi, Z. J. Chem. Commun. 2010, 46, 677. (d) Yu, J. Q.; Shi, Z. J. In
E
dx.doi.org/10.1021/jo5014146 | J. Org. Chem. XXXX, XXX, XXX−XXX