Palladium-catalyzed direct C-H arylation of pyridine N-oxides with potassium aryl- and heteroaryltrifluoroborates

Article abstract of DOI:10.1039/c5ob02409a

An efficient ligand-free Pd(OAc)₂-catalyzed selective arylation of pyridine N-oxides using potassium (hetero)aryltrifluoroborates as coupling partners via C-H bond activation was achieved in the presence of TBAI. This approach has a broad subst

Full text of DOI:10.1039/c5ob02409a

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Palladium-catalyzed direct C–H arylation of
pyridine N-oxides with potassium aryl- and
heteroaryltrifluoroborates†
Cite this: DOI: 10.1039/c5ob02409a
Mengli Li, Xing Li,* Honghong Chang, Wenchao Gao and Wenlong Wei*
Received 23rd November 2015,
Accepted 15th January 2016
An efficient ligand-free Pd(OAc)2-catalyzed selective arylation of pyridine N-oxides using potassium
(hetero)aryltrifluoroborates as coupling partners via C–H bond activation was achieved in the presence of
TBAI. This approach has a broad substrate scope and shows moderate to high yields.
DOI: 10.1039/c5ob02409a
www.rsc.org/obc
Introduction
The heterocycle-aryl structural motif containing a 2-arylpyridyl
moiety represents an important class of molecules and is
frequently encountered in pharmacophores, natural products,
functional materials and ligands, and its corresponding
derivatives also serve as valuable synthetic building blocks.1
Consequently, the significance of this class of compounds has
inspired chemists to develop efficient synthetic methods.
Traditional cross-couplings through two alternative paths have
proven to be important methods. One path is the cross-coup-
ling of 2-pyridyl boronic acid/ester or borate with aryl halides2
and the other uses 2-halogenated pyridines as one of the coup-
ling partners.3 However, the former is limited in terms of the
accessibility and/or stability of the boron-containing reagents
and the latter requires preinstallation of reactive carbon–
halogen bonds precisely at the bond forming sites. To avoid
prefunctionalization such as metalation and halogenation,
N-activated pyridine species have emerged as a promising
alternative to synthesize 2-arylpyridines via direct C–H
functionalization of pyridine rings.4
Recently, the development of selective functionalization of
C–H bonds catalyzed by transition metals has witnessed tre-
mendous progress and attracted intensive attention because of
its economic advantages.5 Pioneered by Fagnou,6 N-oxides
have been introduced for direct arylation of inert C–H bonds.7
Subsequently, several protocols demonstrated the palladium-
catalyzed direct arylation of pyridine N-oxides for constructing
2-arylpyridines with some commonly used coupling partners
such as aryl halides,8 aryl triflates,9 aryl tosylates,10 arylboronic
Scheme 1 Direct C–H arylation of pyridine N-oxides using different
coupling partners.
acids or esters11 and aromatic carboxylic acids12 (Scheme 1,
eqn (2)). Moreover, the elegant C–H activation-based couplings
of arenes and heteroarenes have been described (Scheme 1,
eqn (2)).13 Despite significant progress in this area, the devel-
opment of novel and efficient methods using other partners
with a broader substrate scope still remains highly desirable.
Interestingly, potassium aryltrifluoroborates as coupling part-
ners for the synthesis of biaryls have provided an attractive
alternative over the past decade.14 However, to the best of our
knowledge there is no example employing the use of them to
form 2-arylpyridines via functionalization of the C–H bond.
Considering their broad applications, potassium aryltrifluoro-
borates have the potential to serve as the ideal aryl sources for
C–C bond-forming reactions via C–H bond activation. Herein,
we report a novel approach to 2-arylpyridines from pyridine
N-oxides and potassium aryltrifluoroborates via Pd-catalyzed
selective oxidative C–H bond activation of pyridine N-oxides in
the presence of Ag2O (Scheme 1, eqn (3)).
Taiyuan University of Technology, Department of Chemistry and Chemical
Engineering, 79 West Yingze Street, Taiyuan 030024, People’s Republic of China.
E-mail: lixing@tyut.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob02409a
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fully carried out with 3.3 equiv. of pyridine N-oxide when
10 mol% of Pd(OAc)2 was used in combination with Ag2O
Results and discussion
We initiated our investigations by selecting pyridine N-oxide 1a (2 equiv.), and TBAI (20 mol%) in 1,4-dioxane at 90 °C for 17 h
as a substrate model and potassium phenyltrifluoroborate 2a (Table 1, entry 11). This transformation is high in regio-
as a coupling partner to optimize various reaction parameters. selectivity and chemoselectivity, and C–H functionalization
First, various catalysts were investigated for this transform- occurs at the 2-position of pyridine N-oxide.
ation (ESI†), and Pd(OAc)2 proved to be a superior catalyst, pro-
With the optimal reaction conditions in hand, we turned
viding the highest yield (Table 1, entry 2). No reaction was our attention to explore the reactions of various potassium
detected in the absence of a catalyst (Table 1, entry 1). The aryltrifluoroborates 2 with 1a (Table 2). It was found that the
examination of oxidants demonstrated that Ag2O was essential reactions could proceed well with a series of substituents on
for the formation of the desired product 3a in the presence of the benzene ring of 2, affording the corresponding products
Pd(OAc)2 in 1,4-dioxane as a solvent (Table 1, entry 2). In con- 3a–i in moderate to good yields. Potassium phenyltrifluorobo-
trast, a trace amount of the product was detected when Ag2O rates with electron-donating groups, such as methyl or MeO
was omitted (Table 1, entry 3). 14% yield was obtained with groups substituted in the aromatic rings, proceeded smoothly
Ag2CO3 (Table 1, entry 4). In sharp contrast, Ag2SO4 gave a and provided the desired products in 68–98% yields (Table 2,
trace amount of the product and the reactions almost did not 3b–e). Electron-withdrawing groups, such as F, afforded the
take place when AgNO3 and AgBF4 were used as oxidants desired products in 92% and 91% yields, respectively (Table 2,
(Table 1, entries 5–7). To improve the yield further, tetrabutyl-
ammonium salts as additives were screened.13a While all five
tetrabutylammonium salts improved the yields, the effect was
most pronounced with addition of 20 mol% TBAI, and the
Table 2 Reactions of the pyridine N-oxide 1a with various potassium
(hetero)aryltrifluoroboratesa,b
yield was improved to 88% (Table 1, entry 11). However, the
addition of tetraethylammonium hydroxide decreased the
yield to 49% (Table 1, entry 13). Instead of TBAI, when 20 mol%
KI, I2 and AgI were examined as additives, 66%, 62% and 66%
yields were obtained, respectively (Table 1, entries 14–16).
These results also suggested that not the iodide anion but the
tetrabutylammonium cation (which might solubilise the silver
oxide) is playing a key role. Finally, the reaction was success-
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant
Additive
Yield (%)b
1
2
3
4
5
6
7
8
—
Ag2O
Ag2O
—
—
—
—
—
—
—
—
TBAF
TBAC
TBAB
TBAI
TBAOH
TEAOH
KI
n.r. c
60
Trace
14
Trace
n.r.
n.r.
81
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
Pd(OAc)2
Pd(OAc)2
Ag2CO3
Ag2SO4
AgNO3
AgBF4
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
9
79
10
11
12
13
14
15
16
78
88(95d)
80
49
66
62
66
I2
AgI
a Reactions were carried out with pyridine N-oxide 1a (0.45 mmol), a Reactions were performed using pyridine N-oxide 1a (0.5 mmol),
potassium phenyltrifluoroborate 2a (0.15 mmol), oxidant (2.0 equiv.), potassium aryltrifluoroborate 2 (0.15 mmol), Ag2O (0.3 mmol, 2
Pd(OAc)2 (10 mol%) and additive (20 mol%) in 1,4-dioxane (0.5 mL) at equiv.), Pd(OAc)2 (10 mol%) and TBAI (20 mol%) in 1,4-dioxane
90 °C for 17 h. b Isolated yield. c n.r. = no reaction. d 3.3 equiv. of (0.5 mL) at 90 °C for a specified time. b Isolated yield. c 80 °C. d 120 °C.
pyridine N-oxide 1a was used.
e 110 °C. f 100 °C.
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3f and 3g). Potassium 4-formylphenyltrifluoroborate might
give 65% yield (Table 2, 3h). Unfortunately, only 47% yield was
obtained with a NO2 group (Table 2, 3i). The product 3j could
be offered with 71% yield when this reaction system was
applied to potassium 2-naphthyltrifluoroborate.
To expand the substrate scope, we applied this catalytic
system to potassium heteroaryltrifluoroborates of a number of
oxygen- or sulphur-containing heterocycles such as furan and
thiophene. It was found that they could be employed as suit-
able substrates, giving the corresponding products 3k–q in
moderate to good yields. Disubstituted potassium 3-thienyltri-
fluoroborate can also be utilized as a coupling partner and
provided 57% yield (Table 2, 3p). In addition, 91% yield
was obtained with potassium benzofuran-2-trifluoroborate
(Table 2, 3q).
Scheme 2 Mechanistic studies.
Encouraged by the results obtained, a range of pyridine
N-oxide derivatives were next examined with 2a under the opti-
mized conditions. Pyridine N-oxides having electron-withdraw-
ing 4-nitro and 2-chloro groups underwent the reactions,
affording the desired products in 98% and 75% yields, respecti-
vely (Table 3, 3r and 3s). Pyridine N-oxides substituted with
4-methyl, 3-methyl, 2-methyl and 4-methoxy groups reacted
smoothly with 2a and provided the desired products in moder-
ate to good yields (Table 3, 3t–w). Notably, 84% yield could
be obtained when 4-nitro-3-methyl pyridine N-oxide was
employed (Table 3, 3x).
To probe the reaction mechanism, the coupling of pyridine
N-oxide with PhBF3K was carried out in the presence of a
typical radical inhibitor TEMPO (2 equiv.). The fact that the
Scheme 3 Proposed mechanism.
yield of product 3a was only slightly affected by the reagent
(87%) suggested the irrelevancy of organic radical species
(Scheme 2a).15 In addition, Ag(0) was detected by XPS in the
reaction system that utilized Ag2O as a oxidant (Table 1, entry
11). However, only a trace amount of product 3a was provided
when AgI was adopted as an oxidant and Ag(0) was not
detected (Scheme 2b). On the basis of the observations and
related precedents,16 a plausible catalytic cycle is proposed in
Scheme 3. The process begins with the electrophilic pallada-
tion at the preferential C-2 position of pyridine N-oxide
leading to the key heterocoupling intermediate A, which
undergoes transmetalation to form the arylpalladium inter-
mediate B, followed by reductive elimination to produce the
desired product with the generation of Pd(0). The active Pd(II)
catalyst is regenerated when the Pd(0) is reoxidized by Ag(I).
Table 3 Reactions of the potassium phenyltrifluoroborate 2a with
various pyridine N-oxidesa,b
Conclusions
In summary, we present the first example of Pd-catalyzed
direct arylation of pyridine N-oxide compounds with potass-
ium aryl- and heteroaryltrifluoroborates without requiring the
addition of any ligand, thus leading to the highly site-selective
synthesis of 2-arylpyridine N-oxides. This method proves to be
a very general method, applicable to both potassium (hetero)
a Reactions were performed using pyridine N-oxide 1 (0.5 mmol),
potassium aryltrifluoroborate 2a (0.15 mmol), Ag2O (0.3 mmol, 2
equiv.), Pd(OAc)2 (10 mol%) and TBAI (20 mol%) in 1,4-dioxane
(0.5 mL) at 90 °C for a specified time. b Isolated yield. c 120 °C.
d 100 °C. e 80 °C.
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aryltrifluoroborates and pyridine N-oxides. Importantly, this J = 7.9, 2.0 Hz, 1H), 7.81 (dt, J = 8.9, 2.9 Hz, 2H), 8.31 (dd, J =
method provides moderate to high yields of desired biaryl 6.6, 0.5 Hz, 1H) ppm. IR (cm−1, KBr): 3064, 2984, 1584, 1497,
products, good functional group tolerability, and high 1446, 1332, 1251, 1204, 1179, 833, 766.
regioselectivity.
2-(3-Methoxyphenyl)-pyridine N-oxide (3c). Rf = 0.6 (AcOEt/
alcohol = 6/1 v/v); white solid; m.p. = 120–122 °C; 1H NMR
(600 MHz, CDCl3): δ = 3.85 (s, 3H), 6.99 (ddd, J = 8.2, 2.6,
1.0 Hz, 1H), 7.22–7.26 (m, 1H), 7.29–7.34 (m, 2H), 7.38 (t, J =
7.7 Hz, 1H), 7.42–7.44 (m, 2H), 8.32 (dd, J = 6.5, 0.8 Hz, 1H)
ppm. IR (cm−1, KBr): 3102, 3057, 2935, 2841, 1608, 1531, 1435,
1243, 830, 761.
2-(2-Methoxyphenyl)-pyridine N-oxide (3d). Rf = 0.5 (AcOEt/
alcohol = 6/1 v/v); white solid; m.p. = 169–171 °C; 1H NMR
(600 MHz, CDCl3): δ = 3.82 (s, 3H), 7.01 (d, J = 8.3 Hz, 1H), 7.05
(td, J = 7.5, 1.0 Hz, 1H), 7.23–7.27 (m, 1H), 7.27 (dd, J = 7.6,
1.4 Hz, 1H), 7.34–7.37 (m, 1H), 7.38 (dd, J = 7.5, 1.7 Hz, 1H),
7.43–7.46 (m, 1H), 8.33–8.35 (m,1H) ppm. IR (cm−1, KBr):
3094, 3044, 2961, 2843, 1598, 1487, 1435, 1367, 1243, 961, 827,
733.
Experimental section
General information
Unless otherwise noted, all reagents were obtained from com-
mercial suppliers and used without further purification. Deut-
erated solvents were purchased from Aldrich. Purification of
the products was carried out by flash column chromatography
on silica gel (200–300 mesh) using an ethyl acetate/alcohol
gradient. In addition, all yields were referred to isolated yields
(average of two runs) of compounds unless otherwise
specified. On one hand, the known compounds were partly
characterized by melting points (for solid samples) and
1H NMR, and compared to authentic samples or the literature
data. Melting points were determined with RD-II digital
2-(4-Methylphenyl)-pyridine
N-oxide (3e). Rf
=
0.6
(petroleum ether/AcOEt = 6/1 v/v); yellowish solid; m.p. =
129–131 °C; 1H NMR (600 MHz, CDCl3): δ = 2.41 (s, 3H),
7.19–7.23 (m, 1H), 7.28–7.32 (m, 3H), 7.60–7.64 (m, 3H), 7.4
(dd, J = 7.9, 2.3 Hz, 1H), 7.71 (dt, J = 8.1, 2.0 Hz, 2H), 8.32 (dt,
J = 6.1, 1.0 Hz, 1H) ppm. IR (cm−1, KBr): 3066, 3043, 2915,
1614, 1430, 1240, 1010, 816, 760.
2-(4-Fluorophenyl)-pyridine N-oxide (3f). Rf = 0.6 (AcOEt/
alcohol = 10/1 v/v); yellowish solid; m.p. = 161–163 °C; 1H
NMR (600 MHz, CDCl3): δ = 7.15–7.20 (m, 2H), 7.23–7.26 (m,
1H), 7.30 (td, J = 7.8, 1.2 Hz, 1H), 7.41 (dd, J = 7.8, 2.0 Hz, 1H),
7.83–7.86 (m, 2H), 8.33 (dd, J = 6.4, 0.9 Hz, 1H) ppm.
IR (cm−1, KBr): 3062, 3040, 2463, 1916, 1597, 1246, 1018, 760,
572.
1
melting point apparatus and were uncorrected. H NMR data
were obtained at 300 K on a Bruker AMX-600 spectrometer.
The 1H NMR (600 MHz) chemical shifts were measured relative
to CDCl3 as the internal reference (CDCl3: δ = 7.26 ppm).
Spectra are reported as follows: chemical shift (δ = ppm), mul-
tiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constants (Hz), integration, and assign-
ment. On the other hand, the unknown compounds were
partly characterized by 13C NMR and HR-MS as well. The 13C
NMR (100 MHz) chemical shifts were given using CDCl3 as the
internal standard (CDCl3: δ = 77.16 ppm). High-resolution
mass spectra (HR-MS) were obtained with Waters-
Q-TOF-Premier (ESI).
2-(3-Fluorophenyl)-pyridine N-oxide (3g). Rf = 0.6 (AcOEt/
1
alcohol = 6/1 v/v); yellowish solid; m.p. = 106–107 °C; H NMR
General procedure for direct arylation of pyridine N-oxides
with potassium phenyltrifluoroborate
(600 MHz, CDCl3): δ = 7.14–7.18 (m, 1H), 7.25–7.29 (m, 1H),
7.31 (td, J = 7.7, 1.2 Hz, 1H), 7.43–7.48 (m, 2H), 7.55–7.58(m,
To a tube equipped with a magnetic stir bar were added the 1H), 7.61 (dt, J = 9.9, 1.7 Hz, 1H), 8.34 (dd, J = 6.4, 0.7 Hz, 1H)
catalyst Pd(OAc)2 (10 mol%), Ag2O (2 equiv.), TBAI (20 mol%), ppm; 13C NMR (150 MHz, CDCl3): δ = 119.4, 119.5, 119.7,
potassium phenyltrifluoroborate (2a, 0.15 mmol) and pyridine 127.9, 128.8, 130.2, 132.7 (d, J = 8.6 Hz), 132.8, 143.5, 164.5 (d,
N-oxide (1a, 3.3 equiv.) in turn. Subsequently, the solvent (1,4- J = 244.2 Hz) ppm; HRMS (ESI, m/z): Calcd for C11H8FNO
dioxane, 0.5 mL) was added in air. The reaction system was [M + H]+ 190.0668, found 190.0662. IR (cm−1, KBr): 3074, 3051,
then stirred at 90 °C until potassium phenyltrifluoroborate was 2421, 1603, 1497, 1332, 1263, 1007, 801, 596.
completely consumed as determined by TLC. Finally, the reac-
tion mixture was purified by silica gel column chromatography yellow solid; m.p. = 162–164 °C; 1H NMR (400 MHz, CDCl3):
to afford the desired pure coupling product 3a. δ = 7.28–7.33 (m, 1H), 7.33 (td, J = 7.6, 1.3 Hz, 1H), 7.46 (dd, J =
4-(N-Oxopyridin-2-yl)benzoic acid (3h). Rf = 0.2 (AcOEt);
2-Phenylpyridine N-oxide (3a). Rf = 0.5 (AcOEt/alcohol = 10/1 7.8, 2.0 Hz, 1H), 8.00 (s, 4H), 8.35 (dd, J = 6.2, 0.8 Hz, 1H), 10.8
1
v/v); light yellow solid; m.p. = 141–142 °C; H NMR (600 MHz, (s, 1H) ppm. IR (cm−1, KBr): 3632, 3103, 3051, 2443, 1597,
CDCl3): δ = 7.20–7.24 (m, 1H), 7.28 (td, J = 7.6, 1.1 Hz, 1H), 1497, 1348, 1203, 819, 796.
7.41 (dd, J = 8.0, 2.2 Hz, 1H), 7.44–7.47 (m, 1H), 7.46–7.50 (m,
2-(3-Nitrophenyl)-pyridine N-oxide (3i). Rf = 0.4 (AcOEt/
2H), 7.80–7.83 (m, 2H), 8.32 (dd, J = 6.6, 0.7 Hz, 1H) ppm. alcohol = 10/1 v/v); pale yellow solid; m.p. = 175–177 °C; 1H
IR (cm−1, KBr): 3063, 3044, 1477, 1418, 1240, 841, 759, 724, NMR (400 MHz, CDCl3): δ = 7.31 (td, J = 6.4, 2.2 Hz, 1H), 7.36
697.
(td, J = 7.6, 1.4 Hz, 1H), 7.50 (dd, J = 7.8, 2.2 Hz, 1H), 7.66 (t,
2-(4-Methoxyphenyl)-pyridine N-oxide (3b). Rf = 0.6 (AcOEt/ J = 8.0 Hz, 1H), 8.25 (dt, J = 8.1, 1.3 Hz, 1H), 8.31 (dq, J = 8.3,
1
alcohol = 6/1 v/v); yellowish solid; m.p. = 121–123 °C; H NMR 1.0 Hz, 1H), 8.36 (dd, J = 6.2, 0.9 Hz, 1H), 8.66 (t, J = 1.9 Hz,
(600 MHz, CDCl3): δ = 3.87 (s, 3H), 6.99 (dt, J = 8.9, 2.9 Hz, 1H) ppm. IR (cm−1, KBr): 3076, 3041, 1580, 1440, 1368, 1237,
2H), 7.17–7.21 (m, 1H), 7.27 (td, J = 7.7, 1.2 Hz, 1H), 7.41 (dd, 1108, 928, 743.
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2-(2-Naphthalenyl)-pyridine N-oxide (3j). Rf = 0.4 (AcOEt/ 8.2, 0.9 Hz, 1H), 7.37–7.42 (m, 1H), 7.52 (dd, J = 8.3, 0.7 Hz,
alcohol = 6/1 v/v); white solid; m.p. = 139–141 °C; 1H NMR 1H), 7.71–7.74 (m, 1H), 8.15 (dd, J = 8.2, 2.0 Hz, 1H), 8.34–8.36
(600 MHz, CDCl3): δ = 7.25–7.28 (m, 1H), 7.33 (td, J = 7.6, (m, 1H), 8.46 (d, J = 0.9, Hz, 1H) ppm. IR (cm−1, KBr): 3098,
1.1 Hz, 1H), 7.50–7.53 (m, 1H), 7.52–7.57 (m, 2H), 7.87 (d, J = 3059, 1558, 1494, 1307, 1298, 1109, 1047, 897, 791.
7.9 Hz, 1H), 7.91 (t, J = 5.9 Hz, 1H), 7.93–7.97 (m, 2H), 8.26 (s,
1H), 8.37–8.39 (m, 1H) ppm. IR (cm−1, KBr): 3097, 3056, 1607, yellow solid; m.p. = 135–136 °C; 1H NMR (600 MHz, CDCl3):
1529, 1430, 1368, 1137, 892, 698. δ = 7.52–7.54 (m, 3H), 7.80–7.82 (m, 2H), 8.02 (dd, J = 7.1, 3.2
4-Nitro-2-phenylpyridine N-oxide (3r). Rf = 0.5 (AcOEt); pale
2-(2-Furanyl)-pyridine N-oxide (3k). Rf = 0.4 (AcOEt); pale Hz, 1H), 8.28 (d, J = 3.2 Hz, 1H), 8.36 (d, J = 7.2 Hz, 1H) ppm.
1
yellow solid; m.p. = 94–96 °C; H NMR (600 MHz, CDCl3): δ = IR (cm−1, KBr): 3041, 1597, 1508, 1339, 1284, 1231, 1114, 895,
6.61 (q, J = 1.7 Hz, 1H), 7.11 (td, J = 7.1, 1.9 Hz, 1H), 7.29–7.33 724.
(m, 1H), 7.59 (d, J = 1.1 Hz, 1H), 7.93 (dd, J = 8.2, 1.9 Hz, 1H),
2-Chloro-6-phenylpyridine N-oxide (3s). Rf = 0.3 (petroleum
ether/AcOEt = 3/1 v/v); pale yellow solid; m.p. = 141–142 °C; 1H
NMR (600 MHz, CDCl3): δ = 7.20 (t, J = 8.0 Hz, 1H), 7.35 (dd,
8.02 (d, J = 3.4 Hz, 1H), 8.27 (d, J = 6.4 Hz, 1H) ppm. IR (cm−1
,
KBr): 3075, 1594, 1498, 1423, 1276, 1258, 898, 841, 591.
2-(3-Thienyl)-pyridine N-oxide (3l). Rf = 0.4 (AcOEt); pale J = 7.9, 2.0 Hz, 1H), 7.45–7.50 (m, 4H), 7.78–7.81 (m, 2H) ppm.
yellow solid; m.p. = 118–119 °C; 1H NMR (600 MHz, CDCl3): IR (cm−1, KBr): 3048, 1610, 1508, 1497, 1328, 1263, 1209, 1095,
δ = 7.15–7.18 (m, 1H), 7.28–7.32 (m, 1H), 7.40 (dd, J = 5.2, 3.1 747, 678.
Hz, 1H), 7.64 (dd, J = 5.2, 1.3 Hz, 1H), 7.68 (dd, J = 8.1, 1.9 Hz,
4-Methyl-2-phenylpyridine N-oxide (3t). Rf = 0.2 (AcOEt/
1H), 8.33 (dd, J = 6.2, 0.8 Hz, 1H), 8.86 (dd, J = 3.2, 1.3 Hz, 1H) alcohol = 6/1 v/v); pale yellow liquid; 1H NMR (400 MHz,
ppm. IR (cm−1, KBr): 3044, 1563, 1477, 1450, 1291, 1197, 898, CDCl3): δ = 2.39 (s, 3H), 7.04 (dd, J = 6.5, 2.3 Hz, 1H), 7.31 (t,
872, 633.
J = 8.1 Hz, 1H), 7.45–7.50 (m, 3H), 7.78–7.84 (m, 2H), 8.27 (d,
2-(2-Thienyl)-pyridine N-oxide (3m). Rf = 0.4 (AcOEt); pale J = 6.7 Hz, 1H) ppm. IR (cm−1, KBr): 3072, 2978, 1598, 1541,
1
yellow solid; m.p. = 143–146 °C; H NMR (600 MHz, CDCl3): δ 1469, 1382, 1294, 1098, 814, 716.
= 7.11 (td, J = 6.9, 1.9 Hz, 1H), 7.21–7.23 (m, 1H), 7.30–7.34 (m,
5-Methyl-2-phenylpyridine N-oxide (3u). Rf = 0.3 (AcOEt/
1H), 7.57 (dd, J = 5.2, 1.1 Hz, 1H), 7.86 (dd, J = 4.0, 1.1 Hz, 1H), alcohol = 10/1 v/v); pale yellow solid; m.p. = 168–169 °C;
7.93 (td, J = 8.3, 1.8 Hz, 1H), 8.31 (dd, J = 6.8, 0.8 Hz, 1H) ppm. 1H NMR (400 MHz, CDCl3): δ = 2.33 (s, 3H), 7.12–7.15 (m, 1H),
IR (cm−1, KBr): 3059, 1544, 1498, 1423, 1276, 1258, 898, 841, 7.30 (d, J = 8.0 Hz, 1H), 7.42–7.50 (m, 3H), 7.78 (dd, J = 8.3,
591.
2-(5-Methyl-2-thienyl)-pyridine N-oxide (3n). Rf
(AcOEt); yellow solid; m.p. = 140–142 °C; H NMR (600 MHz,
1.7 Hz, 2H), 8.20 (s, 1H) ppm. IR (cm−1, KBr): 3048, 2967,
0.4 1603, 1523, 1481, 1378, 1321, 1245, 1103, 829, 732, 699.
6-Methyl-2-phenylpyridine N-oxide (3v). Rf = 0.5 (petroleum
=
1
CDCl3): δ = 2.55 (s, 3H), 6.88 (dd, J = 4.0, 1.0 Hz, 1H), 7.06 (td, ether/AcOEt = 2/1 v/v); pale yellow solid; m.p. = 118–119 °C;
J = 7.1, 1.9 Hz, 1H), 7.28 (dd, J = 7.6, 1.3 Hz, 1H), 7.67 (d, J = 1H NMR (600 MHz, CDCl3): δ = 2.58 (s, 3H), 7.18 (t, J = 7.7 Hz,
4.0 Hz, 1H), 7.85 (dd, J = 8.3, 1.7 Hz, 1H), 8.27–8.30 (m, 1H) 1H), 7.24 (d, J = 2.2 Hz, 1H), 7.30 (dd, J = 8.0, 2.2 Hz, 1H),
ppm. IR (cm−1, KBr): 3034, 3017, 2986, 1599, 1509, 1479, 1329, 7.42–7.48 (m, 3H), 7.77 (dd, J = 8.3, 1.6 Hz, 2H) ppm. IR (cm−1
,
1276, 1128, 935, 698.
KBr): 3059, 3015, 2946, 2889, 1597, 1523, 1470, 1369, 1315,
0.4 1287, 1103, 799, 693.
4-Methoxy-2-phenylpyridine N-oxide (3w). Rf = 0.5 (AcOEt/
2-(5-Bromo-2-thienyl)-pyridine N-oxide (3o). Rf
=
(AcOEt); pale yellow solid; m.p. = 164–166 °C; 1H NMR
(600 MHz, CDCl3): δ = 7.14 (dd, J = 7.2, 1.8 Hz, 1H), 7.18 (d, J = alcohol = 4/1 v/v); pale yellow liquid; 1H NMR (400 MHz,
4.3 Hz, 1H), 7.33–7.36 (m, 1H), 7.59 (d, J = 4.3 Hz, 1H), 7.87 CDCl3): δ = 3.87 (s, 3H), 6.78 (q, J = 3.5 Hz, 1H), 6.92 (d, J =
(dd, J = 8.3, 1.7 Hz, 1H), 8.30 (d, J = 6.9 Hz, 1H) ppm; 13C NMR 3.5 Hz, 1H), 7.44–7.50 (m, 3H), 7.80 (dd, J = 9.7, 1.9 Hz, 2H),
(100 MHz, CDCl3): δ = 119.9, 121.3, 122.3, 126.1, 126.5, 128.8, 8.23 (d, J = 7.3 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ =
132.4, 139.1, 142.5 ppm; HRMS (ESI, m/z): Calcd for 56.1, 110.9, 112.4, 128.3, 129.3, 129.7, 132.8, 141.2, 149.8,
C9H6BrNOS [M + H]+ 255.9432, found 255.9442. IR (cm−1
KBr): 3071, 1603, 1508, 1329, 1307, 1258, 1124, 1085, 876, 691.
,
157.6 ppm; HRMS (ESI, m/z): Calcd for C12H11NO2[M + H]+
202.0868, found 202.0867. IR (cm−1, KBr): 3074, 2954, 2883,
2-(2,5-Dimethyl-3-thienyl)-pyridine N-oxide (3p). Rf = 0.4 1590, 1514, 1473, 1382, 1342, 1291, 1249, 1073, 832, 719.
(AcOEt/alcohol 3-Methyl-4-nitro-6-phenylpyridine N-oxide (3x). Rf = 0.3 (pet-
6/1 v/v); pale yellow liquid; 1H NMR
=
(600 MHz, CDCl3): δ = 2.38 (s, 3H), 2.42 (s, 3H), 6.89 (d, J = 0.6 roleum ether/AcOEt = 3/1 v/v); yellow solid; m.p. = 169–170 °C;
Hz, 1H), 7.18 (td, J = 6.7, 2.5 Hz, 1H), 7.23 (d, J = 8.1 Hz, 1H), 1H NMR (400 MHz, CDCl3): δ = 2.63 (d, J = 0.5 Hz, 3H),
7.26–7.29 (m, 1H), 8.31 (d, J = 6.4 Hz, 1H) ppm; 13C NMR 7.50–7.53 (m, 3H), 7.78–7.81 (m, 2H), 8.20 (s, 1H), 8.26 (s, 1H)
(100 MHz, CDCl3): δ = 14.4, 15.2, 124.2, 124.9, 126.4, 128.0, ppm. IR (cm−1, KBr): 3082, 1590, 1514, 1346, 1295, 1249, 1073,
129.1, 136.1, 138.0, 140.5, 146.0 ppm; HRMS (ESI, m/z): Calcd 827, 743.
for C11H12NOS [M + H]+ 206.0640, found 206.0643. IR (cm−1
,
KBr): 3077, 3049, 2989, 2908, 1583, 1494, 1371, 1267, 1209,
1107, 877, 806.
Acknowledgements
2-(2-Benzofuranyl)-pyridine N-oxide (3q). Rf = 0.5 (AcOEt);
pale yellow solid; m.p. = 139–141 °C; 1H NMR (600 MHz, We appreciate gratefully the Natural Science Foundation of
CDCl3): δ = 7.19–7.22 (m, 1H), 7.28–7.31 (m, 1H), 7.35 (dd, J = Shanxi Province (No. 2012021007-2) for financial support.
This journal is © The Royal Society of Chemistry 2016
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Organic & Biomolecular Chemistry
7 (a) J.-P. Leclerc and K. Fagnou, Angew. Chem., Int. Ed., 2006,
45, 7781; (b) L.-C. Campeau, M. Bertrand-Laperle,
J.-P. Leclerc, E. Villemure, S. Gorelsky and K. Fagnou, J. Am.
Chem. Soc., 2008, 130, 3276; (c) M. P. Huestis and
K. Fagnou, Org. Lett., 2009, 11, 1357; (d) D. Lapointe,
T. Markiewicz, C. J. Whipp, A. Toderian and K. Fagnou,
J. Org. Chem., 2011, 76, 749; (e) W. Liu, Y. Li, Y. Wang and
C. Kuang, Org. Lett., 2013, 15, 4682; (f) G. Yan,
A. J. Borah and M. Yang, Adv. Synth. Catal., 2014, 356,
2375.
8 (a) See ref. 6; (b) H.-Y. Sun, S. I. Gorelsky, D. R. Stuart,
L.-C. Campeau and K. Fagnou, J. Org. Chem., 2010, 75,
8180; (c) F. Gosselin, S. J. Savage, N. Blaquiere and
S. T. Staben, Org. Lett., 2012, 14, 862; (d) L.-C. Campeau,
D. R. Stuart, J.-P. Leclerc, M. Bertrand-Laperle,
E. Villemure, H.-Y. Sun, S. Lasserre, N. Guimond,
M. Lecavallier and K. Fagnou, J. Am. Chem. Soc., 2009, 131,
3291; (e) S. Duric and C. C. Tzschucke, Org. Lett., 2011, 13,
2310; (f) M. P. Huestis and K. Fagnou, Org. Lett., 2009, 11,
1357.
Notes and references
1 For selected examples, see: (a) A. G. Fang, J. V. Mello and
N. S. Finney, Org. Lett., 2003, 5, 967; (b) Y. Liu, K. Ye,
Y. Fan, W. Song, Y. Wang and Z. Hou, Chem. Commun.,
2009, 3699; (c) S. W. Thomas, K. Venkatesan, P. Müller and
T. M. Swager, J. Am. Chem. Soc., 2006, 128, 16641;
(d) A. S. Tsai, M. E. Tauchert, R. G. Bergman and
J. A. Ellman, J. Am. Chem. Soc., 2011, 133, 1248.
2 For recent selected examples, see: (a) K. L. Billingsley and
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 4695;
(b) D. X. Yang, S. L. Colletti, K. Wu, M. Song, G. Y. Li and
H. C. Shen, Org. Lett., 2009, 11, 381; (c) S. Sakashita,
M. Takizawa, J. Sugai, H. Ito and Y. Yamamoto, Org. Lett.,
2013, 15, 4308; (d) J. Z. Deng, D. V. Paone, A. T. Ginnetti,
H. Kurihara, S. D. Dreher, S. A. Weissman, S. R. Stauffer
and C. S. Burgey, Org. Lett., 2009, 11, 345;
(e) I. A. I. Mkhalid, D. N. Coventry, D. Albesa-Jove,
A. S. Batsanov, J. A. K. Howard, R. N. Perutz and
T. B. Marder, Angew. Chem., Int. Ed., 2006, 45, 489.
3 For recent selected examples, see: (a) M. Pal, V. R. Batchu,
I. Dager, N. K. Swamy and S. Padakanti, J. Org. Chem.,
9 D. J. Schipper, M. El-Salfiti, C. J. Whipp and K. Fagnou,
Tetrahedron, 2009, 65, 4977.
2005, 70, 2376; (b) C. A. Fleckenstein and H. Plenio, J. Org. 10 L. Ackermann and S. Fenner, Chem. Commun., 2011, 47,
Chem., 2008, 73, 3236; (c) C. Liu and W. Yang, Chem. 430.
Commun., 2009, 6267; (d) Y. Zou, G. Yue, J. Xu and J. Zhou, 11 (a) P. Mai, J. Yuan, Z. Li, G. Sun and L. Qu, Synlett, 2012,
Eur. J. Org. Chem., 2014, 5901; (e) C. Senter, A. Rumple,
W. Medina-Ramos, D. Houle, Z. Cheng, C. Gelbaum,
145; (b) Y. Shen, J. Chen, M. Liu, J. Ding, W. Gao, X. Huang
and H. Wu, Chem. Commun., 2014, 50, 4292.
J. Fisk, B. Holden, P. Pollet, C. A. Eckerta and C. L. Liotta, 12 R. Suresh, S. Muthusubramanian, R. S. Kumaran and
Org. Biomol. Chem., 2014, 12, 7598. G. Manickam, Asian J. Org. Chem., 2014, 3, 604.
4 (a) A. Larivée, J. J. Mousseau and A. B. Charette, J. Am. 13 (a) X. Gong, G. Song, H. Zhang and X. Li, Org. Lett., 2011,
Chem. Soc., 2007, 130, 52; (b) J. Xu, G. Cheng, D. Su, Y. Liu,
X. Wang and Y. Hu, Chem. – Eur. J., 2009, 15, 13105;
13, 1766; (b) S. H. Cho, S. J. Hwang and S. Chang, J. Am.
Chem. Soc., 2008, 130, 9254.
(c) J. A. Bull, J. J. Mousseau, G. Pelletier and A. B. Charette, 14 For recent reviews and selected examples on the coupling
Chem. Rev., 2012, 112, 2642; (d) I. B. Seiple, S. Su,
R. A. Rodriguez, R. Gianatassio, Y. Fujiwara, A. L. Sobel and
P. S. Baran, J. Am. Chem. Soc., 2010, 132, 13194.
5 (a) G. P. McGlacken and L. M. Bateman, Chem. Soc. Rev.,
2009, 38, 2447; (b) F. Bellina and R. Rossi, Tetrahedron,
2009, 65, 10269; (c) J. J. Mousseau and A. B. Charette, Acc.
Chem. Res., 2013, 46, 412; (d) A. M. Berman, J. C. Lewis,
R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2008,
130, 14926; (e) D. J. Schipper, L.-C. Campeau and
K. Fagnou, Tetrahedron, 2009, 65, 3155; (f) H. Zhao,
reactions with R-BF3K salts, see: (a) S. Darses and
J.-P. Genet, Chem. Rev., 2008, 108, 288; (b) G. A. Molander,
C.-S. Yun, M. Ribagorda and B. Biolatto, J. Org. Chem.,
2003, 68, 5534; (c) E. Alacid and C. Nájera, Org. Lett., 2008,
10, 5011; (d) V. Colombel, M. Presset, D. Oehlrich,
F. Rombouts and G. A. Molander, Org. Lett., 2012, 14, 1680;
(e) A. Joliton and E. M. Carreira, Org. Lett., 2013, 15, 5147;
(f) J.-J. Tan, Y.-G. Chen, H.-M. Li and N. Yasuda, J. Org.
Chem., 2014, 79, 8871; (g) H. Huang, K. Jia and Y. Chen,
Angew. Chem., Int. Ed., 2015, 54, 1881.
R. Wang, P. Chen, B. T. Gregg, M. M. Hsia and W. Zhang, 15 H. Wang, S. Yu, Z. Qi and X. Li, Org. Lett., 2015, 17,
Org. Lett., 2012, 14, 1872; (g) C., S. Yeung and V. M. Dong, 2812.
Chem. Rev., 2011, 111, 1215; (h) C. Liu, J. Yuan, M. Gao, 16 (a) K. M. Engle, P. S. Thuy-Boun, M. Dang and J.-Q. Yu,
S. Tang, W. Li, R. Shi and A. Lei, Chem. Rev., 2015, 115,
12138.
6 L.-C. Campeau, S. Rousseaux and K. Fagnou, J. Am. Chem.
Soc., 2005, 127, 18020.
J. Am. Chem. Soc., 2011, 133, 18183; (b) W.-H. Rao and
B.-F. Shi, Org. Lett., 2015, 17, 2784; (c) Y. Tan, F. Barrios-
Lan deros and J. F. Hartwig, J. Am. Chem. Soc., 2012, 134,
3683.
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