Copper-mediated direct alkoxylation of arenes using an N, O -bidentate directing system

Article abstract of DOI:10.1021/jo502005j

Highly effective CuCl-mediated C-H alkoxylation of arenes and heteroarenes has been developed by using a 2-aminopyridine 1-oxide moiety as an N,O-bidentate directing group. The reaction proceeds smoothly using a broad range of substrates to afford o-alkox

Full text of DOI:10.1021/jo502005j

Article
pubs.acs.org/joc
Copper-Mediated Direct Alkoxylation of Arenes Using an
N,O‑Bidentate Directing System
Lin-Bao Zhang,† Xin-Qi Hao,† Shou-Kun Zhang,† Ke Liu,† Baozeng Ren,‡ Jun-Fang Gong,†
Jun-Long Niu,*,† and Mao-Ping Song*,†
†The College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry,
Zhengzhou University, Zhengzhou 450001, People’s Republic of China
‡School of Chemical Engineering and Energy, Zhengzhou University, Zhengzhou 450001, People’s Republic of China
S
* Supporting Information
ABSTRACT: Highly effective CuCl-mediated CH alkoxylation of arenes
and heteroarenes has been developed by using a 2-aminopyridine 1-oxide
moiety as an N,O-bidentate directing group. The reaction proceeds smoothly
using a broad range of substrates to afford o-alkoxylated benzoic and hetero-
aromatic amide products. Moreover, the reaction system shows remarkable
compatibility when hexafluoroisopropanol is used as a coupling parter;
halogen, nitro, ether, alkoxy, ester, and sulfonyl functional groups are all tolerated. The directing group can be easily removed by
base hydrolysis, affording o-alkoxylated benzoic acids.
mechanistic study on Cu(II)-mediated methoxylation of
8-aminoquinoline benzamide using 2 equiv of Cu(OAc)2.
In 2005, Daugulis and co-workers employed picolinamide
and 8-aminoquinoline as N,N-bidentate directing groups for
palladium-catalyzed CH bond functionalization.22 Recently,
methods for chelating-assisted CH bond functionalization by
employing a bidentate directing group have been developed by
the groups of Daugulis,23 Miura,8b,c Nakamura,24 Chatani,25
Chen,26 and others.27 The noteworthy advantage of these
transformations is that abundant, relatively cheap first-row
transition metals, including copper, iron, and nickel, are used.28
Moreover, our laboratory was the first to report the
2-aminopyridine 1-oxide moiety as an N,O-bidentate directing
group for selective mono- or diaryloxylation of benzamides by
applying a stoichiometric copper acetate.29 Encouraged by the
notable progress in CH bond functionalization method-
ologies mentioned above, we studied the alkoxylation of CH
bonds as a complementary alternative for the synthesis of
o-alkoxylated benzoic acids.
INTRODUCTION
■
Diverse CH bond functionalization methodologies have
been developed in the past two decades.1 Compared to tradi-
tional methods, direct CH functionalization offers more
efficient ways of constructing complex chemical frameworks
without prefunctionalization of the starting materials. Recently,
tremendous CC,2 CN,3 and CO4 bond-forming reac-
tions have proven the practical utility and feasibility of direct
functionalization protocols. However, most examples of direct
functionalization of CH bonds have been performed by
applying expensive metal catalysts such as palladium,5
rhodium,6 or ruthenium.7 On the other hand, copper salts are
abundant and inexpensive alternatives to the rare metals
described above and have been reported in Cu-catalyzed or
Cu-mediated cross-dehydrogenative coupling reactions by
Miura8 and other groups9 recently.
Aryl ethers are common structural motifs in many natural
products, pharmaceuticals, and functional materials.10 From a
synthetic perspective, dehydrogenative cross coupling between
arenes and alcohols compares favorably with classical methods
such as Pd-catalyzed Buchwald−Harting couplings,11 and
Cu-catalyzed Ullmann,12 Chan−Evans−Lam,13 Williamson,14
and Mitsunobu15 reactions. Considering the fact that fruitful
strategies for direct hydroxylations,16 acetoxylations,17 and
even phenoxylations4a−d have been developed, the alkoxyla-
tion of arenes remains a challenging topic because alkanols are
easily oxidized to their corresponding aldehydes, ketones, or
carboxylic acids.18 In general, palladium salt is a highly active
catalyst for this type of transformation.19 Recently, pioneering
copper-catalyzed dehydrogenative alkoxylation of arenes has
been reported by Gooßen.20 Moreover, Stahl and co-workers21
have observed the etherification of a macrocyclic copper ligand
on the addition of alkanols and have performed a fundamental
RESULTS AND DISCUSSION
■
We first investigated the reaction of 2-benzamidopyridine
1-oxide (1a) with ethanol (2a). The results are summarized in
Table 1.
When 1a was treated with stoichiometric Cu(OAc)2 in
ethanol (2a) at 130 °C, desired ethoxylated product 3aa was
obtained in 21% yield (entry 1). As we had previously observed
a beneficial effect of base composition on the aryloxylation of
benzamide substrates,29 we next tested various bases (entries
2−9). Among them, K2CO3 proved to be effective and led to an
increase in the yield to 49% (entry 9). Subsequently, a series of
Received: August 31, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of Reaction Conditions
yield
c
b
b
entry
Cu salt
base
additive
solvent
EtOH
(%)
1
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(acac)2
CuBr2
21
38
33
25
20
36
44
45
49
trace
trace
22
nr
2
KO-tBu
NaOEt
KOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Figure 1. Varieties of directing groups.
3
4
copper-catalyzed alkoxylation.23d Structurally similar mono-
dentate directing groups (Figure 1D−F) failed to promote this
reaction either, indicating that the N,O-bidentate coordinating
group is essential for transformation.
With the optimized reaction conditions for ethoxylation in
hand, we tested the reactions of a series of 2-benzamidopyridine
1-oxide derivatives bearing different functional groups with
ethanol. The results are listed in Scheme 1. A wide range of aryl
5
DBU
6
TMG
7
Cs2CO3
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
CuCl2
Cu(ClO4)2
Cu(OTf)2
CuF2
a
Scheme 1. Reaction Scope with Respect to Amides
nr
57
53
61
49
51
54
77
84
66
60
nr
CuI
CuCl
CuCl
DMAP
bpy
CuCl
CuCl
TMEDA EtOH
Py EtOH
CuCl
CuCl
EtOH/Py (1:1)
EtOH/Py (1:1)
EtOH/Py (1:1)
EtOH/Py (1:1)
EtOH/Py (1:1)
d
23
CuCl
e
24
CuCl
25
f
26
CuCl
trace
a
Reaction conditions: [Cu] (0.2 mmol), additive (0.2 mmol), base
(0.1 mmol), 1a (0.2 mmol), solvent (1.5 mL), air atmosphere, 130 °C,
b
c
12 h, unless otherwise noted. Py = pyridine. Isolated yields; nr = no
reaction. CuCl (0.1 mmol). Run at 110 °C. Under argon
atmosphere.
d
e
f
copper salts were investigated in the reaction, including
Cu(acac)2 (acac = acetylacetonate), CuBr2, CuCl2, Cu(ClO4)2,
Cu(OTf)2, CuF2, CuI, and CuCl (entries 10−17, respectively).
The use of CuCl resulted in a significant increase in yield
(entry 17). The addition of N donor ligands to stabilize the
copper salts resulted in slightly decreased yields (entries
18−20). However, the use of pyridine as an additive substantially
influenced the yields to give a superior result (entry 21), similar
to the observation of Daugulis in copper-catalyzed fluorination
reactions.23a When pyridine was used as a cosolvent, and the
ratio of pyridine to ethanol was changed to 1:1 (v/v), the yield
increased to 84% (entry 22). Unfortunately, decreasing the
amount of CuCl or lowering the reaction temperature reduced
the yields (entries 23 and 24). Control experiments revealed
that no reaction took place without copper salts and that air
atmosphere was crucial (entries 25 and 26). Furthermore, the
2-aminopyridine 1-oxide motif appeared to be more effective
under the current identical conditions compared to other
bidentate coordinating groups (Figure 1A−C). Noteworthily,
8-aminoquinoline benzamide A was inefficient during the
dehydrogenative ethoxylation process (yield <5%) regardless of
the optimized reaction conditions that Daugulis employed for
a
Reaction conditions: CuCl (0.20 mmol), amide (0.20 mmol), K2CO3
(0.1 mmol), EtOH (0.75 mL), pyridine (0.75 mL), at 130 °C, under
air, for 12 h. Isolated yield.
substrates bearing electron-withdrawing or -donating groups
underwent monoethoxylation smoothly to afford their corre-
sponding products (3ba−3la) in 50−87% yields. Diethoxylated
products were not observed in all cases. The o-substituted
substrates, such as o-methylbenzamide 1q and o-chlorobenz-
amide 1r, did not work. Furthermore, 2-benzamidopyridine
1-oxide derivatives possessing electron-donating functional
groups in the p-position gave good yields (3ba, 3ca, and
3la). Electron-withdrawing functional groups such as chloro
(1g), bromo (1h), and iodo (1i) also provided the desired
products (3ga−3ia), albeit in moderate yields. Significantly, the
B
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 2. Reaction Scope with Respect to Alcohols
a
Reaction conditions: CuCl (0.20 mmol), 1a (0.20 mmol), K2CO3 (0.1 mmol), alcohols (0.75 mL), pyridine (0.75 mL), at 130 °C, under air, for
b
c
12 h. Pyridine solvent. Alcohols (2 mmol). The configuration is determined on a Daicel Chiralpak AD-H column with hexane/2-propanol (90:10).
Flow rate = 0.1 mL/min, UV wavelength = 254 nm, and retention time = 6.0 min (one signal).
halo-substituted benzamide moiety remained intact. Strong electron-
withdrawing functional groups, such as NO2, inhibited the reaction
and could not yield the target product under the optimized reaction
conditions. These results add to the growing evidence that the
electron density of substrates plays a more important role than steric
hindrance factors. For m-substituted substrates (1d, 1e, and 1k),
selective ethoxylation occurred at the less-hindered position to give a
good yield and excellent regioselectivity.
We next explored a variety of alcohols in copper-mediated,
direct alkoxylation of 1a (Scheme 2) and found that the
strategy of direct dehydrogenative alkoxylation coupling has
broad applications. Both primary and secondary alcohols could
proceed smoothly, affording their corresponding alkoxylated
products in moderate to good yields (3ab−3ah). The reaction
system tolerated a range of functional groups, such as
heteroaromatic (2c), branched (2d), and olefin (2e) alcohols.
The chiral alcohol menthol (2i) could react while retaining its
configuration. The benzylic alcohols did not give the desired
products because they were easily oxidized at high temperature.30
Long-chain alcohols (2j and 2k) also provided the corresponding
ethers 3aj and 3ak in moderate yields when pyridine was used as
the solvent. To our surprise, hexafluoroisopropanol (HFIP) also
underwent alkoxylation to give monoalkoxylated product 3al and
dialkoxylated product 3'al in a 2.8:1 ratio and 93% combined yield.
In light of the extraordinary potential for fluorine-containing
molecules in medicinal chemistry and chemical biology,31 we
examined the use of HFIP as the coupling partner (Scheme 3).
When changing the ratio of pyridine and HFIP to 1:4 (v/v), we
found that a variety of aryl amide substrates 1 with electron-
withdrawing or -donating groups were hexafluoroisopropoxy-
lated to give good to excellent yields. Doubly alkoxylated
products 3' were detected for substrates that bear functional
groups at the para position of the aromatic ring (3il and
3ll−3ol). Similar to ethoxylation, excellent regioselectivity was
obtained for m-substituted substrates, and alkoxylation only
occurred at the less-congested site (3el, 3kl, and 3ul−3wl). For
o-substituted substrates, single monoalkoxylated products
(3ql−3tl) were isolated with 54−93% yields. It is worth noting
that substrate 1s, which bears the strong electron-withdrawing
NO2 functional group, also underwent alkoxylation smoothly
and transformed into its corresponding product in a syntheti-
cally useful yield (3sl). The naphthyl substrate (1x) could be
successfully reacted with HFIP with regioselectively at the
2-position in 81% yield. We were pleased to find that heteroaryl
substrates (1o, 1y, and 1z) proceeded smoothly to give their
corresponding products in good yields (75, 74, and 38%,
respectively).
To obtain more insight into the mechanism, some con-
trolled experiments were performed. The addition of 2,2,6,6-
tetramethylpiperidine-N-oxyl (TEMPO) as a radical quencher
completely inhibited the reaction (Scheme 4, eq 1), suggesting
that the reaction involved a radical pathway. TEMPOH rather
C
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Scheme 3. Exceptional Compatibility with HFIP
a
b
Reaction conditions: CuCl (0.20 mmol), 1 (0.20 mmol), K2CO3 (0.1 mmol), pyridine (0.3 mL), HFIP (1.2 mL). The combined isolated yield of
3 and 3' is given. The ratio of 3/3' is in parentheses and is determined by 1H NMR analysis of the crude reaction mixture; 3 and 3' were separated by
silica gel column chromatography.
than TEMPOOEt was detected by LC-MS, which is in
agreement with findings by Stahl and co-workers.18a Next,
treatment of a 1:1 mixture of [D5]-1a and 1a with ethanol
resulted in a kinetic isotope effect (KIE) of 2.5 (Scheme 4,
eq 2). This finding indicated that the CH activation of the
arene is rate limiting. The single-electron-transfer (SET)
mechanism proposed by Yu in copper-mediated chlorination
reactions, in which a low kinetic isotope effect had been found,
could be ruled out.4a A hydroxyarene intermediate resulting
from an attack of H2O on the benzamide was excluded based
on the fact that 2-(2-hydroxybenzamido)pyridine 1-oxide (1A)
was not transformed into 3aa under the standard reaction
conditions (Scheme 4, eq 3). Moreover, 2-(thiophen-2-yl)-
acetaldehyde 4 was obtained from 2-thiopheneethanol under
the reaction conditions in the absence of substrate 1a, which
can be used as indirect evidence of alkoxy radical formation
(Scheme 4, eq 4). However, when TEMPO was added to the
reaction mixture under the optimized conditions using HFIP as
the coupling partner, it did not inhibit the reaction. Moreover,
treatment of a 1:1 mixture of [D5]-1a and 1a with HFIP
provided a KIE of 2.1. HFIP (pKa = 9.3) is more acidic, which
differs from ethanol (pKa = 15.9), and is actually more similar
D
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Scheme 4. Controlled Experiments
Figure 2. Plausible mechanism for o-alkoxylation.
complex 9. Finally, intermediate 9 furnishes desired product
3aa by reductive elimination.
Scheme 5. Removal of the Directing Group
The 2-aminopyridine 1-oxide directing group can be easily
removed by base hydrolysis. For example, treatment of 3aa with
NaOH in EtOH at 80 °C for 8 h affords 2-ethoxybenzoic acid
10 in high yield (Scheme 5).
CONCLUSIONS
■
In summary, we have developed a copper-mediated coupling of
benzamides and alcohols with the aid of an N,O-bidentate
directing group derived from 2-aminopyridine 1-oxide. This
new-fashioned strategy is operationally simple and possesses a
broad substrate scope, thus providing a convenient synthetic
route to o-alkoxylated benzoic and heteroaromatic acids. More-
over, the exceptional compatibility of the alkoxylation reaction
with HFIP renders this reaction highly valuable for the syn-
thesis of medicinal fluorine-containing compounds. Further ex-
ploration extending this strategy to sp3 CH groups of
aliphatic substrates through a detailed mechanistic study is
currently in progress.
to phenol (pKa = 9.9). It seems that the reaction proceeds via a
CNO-pincer Cu(III) intermediate, which we have clarified in
the aryloxylation of benzamides.29
On the basis of these investigations, we searched the litera-
ture8b,20b,21 and developed a plausible reaction mechanism (Figure 2).
First, CuCl is oxidated via the formation of Cu(II)-superoxo
species 5,32 which could be easily reduced to produce
hydroperoxo form 7 after protonation while alkoxy radical 6
is simultaneously formed in the process.33 Then, ligand ex-
change with 1a occurs to form N,O-chelated complex 8. The
alkoxy radical is transferred to Cu(II) species 8 to give Cu(III)
E
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
2-(Thiophene-2-carboxamido)pyridine 1-Oxide (1y). Purified
by column chromatography on silica gel with CH2Cl2/acetone (4:1)
as an eluent (Rf = 0.35) to afford a white solid (924 mg, 70%, mp
142−143 °C from 1:3 hexane/dichloromethane). 1H NMR (400
MHz, CDCl3): δ 10.90 (s, 1H), 8.55 (d, J = 8.4 Hz, 1H), 8.30 (d, J =
6.5 Hz, 1H), 7.62−7.61 (m, 1H), 7.40−7.36 (m, 1H), 7.34−7.33 (m,
1H), 7.05−7.01 (m, 1H), 6.61−6.60 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 159.0, 146.9, 145.7, 144.1, 137.3, 128.1, 118.9, 117.0, 114.9,
112.9. HRMS (positive ESI): calcd for C10H9N2O2S [M + H], 221.0385;
found, 221.0379.
2-(Furan-2-carboxamido)pyridine 1-Oxide (1z). Purified by
column chromatography on silica gel with CH2Cl2/acetone (4:1) as an
eluent (Rf = 0.40) to afford a white solid (881 mg, 72%, mp 137−
138 °C from 1:3 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 10.79 (s, 1H), 8.53 (dd, J = 8.5, 1.7 Hz, 1H), 8.30 (dd, J =
6.5, 1.1 Hz, 1H), 7.80 (dd, J = 3.8, 1.0 Hz, 1H), 7.66 (dd, J = 5.0, 1.0
Hz, 1H), 7.41−7.37 (m, 1H), 7.19−7.17 (m, 1H), 7.05−7.01 (m, 1H).
13C NMR (100 MHz, CDCl3): δ 159.8, 144.2, 138.0, 137.0, 132.7,
EXPERIMENTAL SECTION
■
General. Unless otherwise noted, all solvents and reagents were
purchased commercially and used directly. H NMR, 13C NMR, and
1
19F NMR spectra were recorded at 400, 100, and 376 MHz, respec-
tively, using tetramethylsilane as an internal standard. Chemical shift
multiplicities are represented as follows: s = singlet, d = doublet,
t = triplet, q = quartet, p = pentalet, m = multiplet, dd = double
doublet, bs = broad singlet. HRMS spectra were obtained on a Q-TOF
mass spectrometer using the ESI technique.
Amide substrates 1a−1z were prepared according to published
procedures.29
2-(4-(tert-Butyl)benzamido)pyridine 1-Oxide (1c). Purified by
column chromatography on silica gel with CH2Cl2/acetone (5:1) as an
eluent (Rf = 0.37) to afford a white solid (1.20 g, 74%, mp 123−124 °C
1
from 1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3):
δ 10.91 (s, 1H), 8.63 (dd, J = 8.5, 1.7 Hz, 1H), 8.32 (dd, J = 6.5, 1.1
Hz, 1H), 7.97−7.94 (m, 2H), 7.56−7.53 (m, 2H), 7.42−7.38 (m, 1H),
7.04−7.00 (m, 1H), 1.36 (s, 9H). 13C NMR (100 MHz, CDCl3): δ
167.3, 160.5, 159.7, 137.5, 129.4, 128.1, 118.6, 117.3, 115.5, 115.0,
35.2, 30.9. HRMS (positive ESI): calcd for C16H19N2O2 [M + H],
271.1447; found, 271.1442.
130.1, 128.3, 128.2, 118.6, 114.7. HRMS (positive ESI): calcd for
C10H9N2O3 [M + H], 205.0613; found, 205.0608.
Typical Procedure for Copper-Mediated Dehydrogenative
Alkoxylated Coupling. A screw cap vial was equipped with a
magnetic stir bar and charged with benzamide substrate 1 (0.2 mmol),
CuCl (19.8 mg, 0.2 mmol), freshly distilled anhydrous alcohol
(0.75 mL), and freshly distilled pyridine (0.75 mL). The resulting
mixture was stirred at 35 °C for 30 min followed by the addition of
K2CO3 (13.8 mg, 0.1 mmol) and stirring for an additional 5 min at
35 °C. Then, the suspension was kept stirring for 12 h at 130 °C. The
resulting crude mixture was allowed to cool to room temperature and
quenched with 2 M HCl aqueous solution (5 mL). The mixture was
extracted with ethyl acetate (3 × 15 mL). The combined organic layers
were dried over anhydrous MgSO4, filtered, and concentrated in a
vacuum. The resulting residue was purified by column chromatog-
raphy with eluent to give corresponding alkyl-aryl ether 3.
2-(4-Bromobenzamido)pyridine 1-Oxide (1h). Purified by
column chromatography on silica gel with CH2Cl2/acetone (5:1) as
an eluent (Rf = 0.37) to afford a white solid (1.32 g, 75%, mp 188−189 °C
1
from 1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
10.92 (s, 1H), 8.58 (dd, J = 8.5, 1.7 Hz, 1H), 8.30 (dd, J = 6.5, 1.0 Hz,
1H), 7.90−7.88 (m, 2H), 7.74−7.71 (m, 2H), 7.42−7.38 (m, 1H),
7.07−7.03 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 164.5, 144.4,
137.2, 132.4, 132.0, 129.3, 128.6, 128.1, 119.0, 115.0. HRMS (positive
ESI): calcd for C12H10BrN2O2 [M + H], 292.9926; found, 292.9919.
2-(4-Iodobenzamido)pyridine 1-Oxide (1i). Purified by column
chromatography on silica gel with CH2Cl2/acetone (5:1) as an eluent
(Rf = 0.39) to afford a white solid (1.55 g, 76%, mp 198−199 °C from
1
1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 10.92
2-(2-Ethoxybenzamido)pyridine 1-Oxide (3aa). Purified by
analytical TLC on silica gel with CH2Cl2/acetone (6:1) as an eluent
(Rf = 0.35) to afford a white solid (43 mg, 84%, mp 140−141 °C from
(s, 1H), 8.58 (dd, J = 8.5, 1.6 Hz, 1H), 8.30 (dd, J = 6.5, 1.0 Hz, 1H),
7.89−7.85 (m, 2H), 7.68−7.65 (m, 2H), 7.42−7.38 (m, 1H), 7.06−
7.02 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 164.6, 144.3, 138.2,
137.1, 132.5, 129.1, 128.3, 118.9, 114.8, 100.5. HRMS (positive ESI):
calcd for C12H10IN2O2 [M + H], 340.9787; found, 340.9781.
2-(4-(Methoxycarbonyl)benzamido)pyridine 1-Oxide (1n).
Purified by column chromatography on silica gel with CH2Cl2/
acetone (5:1) as an eluent (Rf = 0.44) to afford a white solid (1.22 g,
1
1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.30
(s, 1H), 8.74 (dd, J = 8.5, 1.8 Hz, 1H), 8.31−8.28 (m, 2H), 7.55−7.51
(m, 1H), 7.38−7.34 (m, 1H), 7.13−7.09 (m, 1H), 7.07 (d, J = 8.4 Hz,
1H), 7.02−6.98 (m, 1H), 4.35 (q, J = 7.0 Hz, 2H), 1.72 (t, J = 7.0 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 164.0, 157.5, 145.4, 137.4,
134.3, 132.7, 127.8, 121.1, 120.5, 118.5, 115.9, 112.4, 65.4, 14.8. HRMS
(positive ESI): calcd for C14H15N2O3 [M + H], 259.1083; found,
259.1081.
2-(4-Methyl-2-ethoxybenzamido)pyridine 1-Oxide (3ba).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1)
as an eluent (Rf = 0.32) to afford a white solid (46 mg, 85%, mp 162−
163 °C from 1:5 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.16 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 8.20−8.18 (m, 1H),
8.09−8.07 (d, J = 8.0 Hz, 1H), 7.26−7.23 (m, 1H), 6.91−6.88 (m,
1H), 6.83 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H),
2.32 (s, 3H), 1.63 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
164.0, 157.4, 145.5, 137.4, 132.5, 127.9, 122.0, 118.3, 117.8, 115.7,
113.0, 65.2, 21.9, 14.8. HRMS (positive ESI): calcd for C15H17N2O3
[M + H], 273.1239; found, 273.1234.
1
75%, mp 131−132 °C from 1:3 hexane/dichloromethane). H NMR
(400 MHz, CDCl3): δ 10.99 (s, 1H), 8.61 (dd, J = 8.5, 1.7 Hz, 1H),
8.32 (dd, J = 6.5, 1.0 Hz, 1H), 8.21−8.19 (m, 2H), 8.09−8.06 (m,
2H), 7.45−7.40 (m, 1H), 7.09−7.05 (m, 1H), 3.97 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 166.0, 164.4, 144.3, 137.1, 136.8, 134.0, 130.2,
128.4, 127.7, 119.1, 114.9, 52.6. HRMS (positive ESI): calcd for
C14H13N2O4 [M + H], 273.0875; found, 273.0871.
2-(2-Chlorobenzamido)pyridine 1-Oxide (1r). Purified by
column chromatography on silica gel with CH2Cl2/acetone (5:1) as
an eluent (Rf = 0.38) to afford a white solid (1.07 g, 72%, mp 151−152 °C
1
from 1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
10.82 (s, 1H), 8.63 (dd, J = 8.4, 1.7 Hz, 1H), 8.30 (dd, J = 6.5, 1.0 Hz,
1H), 7.79 (dd, J = 7.6, 1.4 Hz, 1H), 7.52−7.45 (m, 2H), 7.44−7.38
(m, 2H), 7.08−7.04 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 164.7,
144.2, 137.3, 133.7, 132.5, 131.4, 130.8, 130.3, 128.3, 127.3, 119.2,
115.2. HRMS (positive ESI): calcd for C12H10ClN2O2 [M + H],
249.0431; found, 249.0426.
2-(4-tert-Butyl-2-ethoxybenzamido)pyridine 1-Oxide (3ca).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1) as
an eluent (Rf = 0.42) to afford a white solid (52 mg, 83%, mp 127−128 °C
1
from 1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
2-(2-Nitrobenzamido)pyridine 1-Oxide (1s). Purified by
column chromatography on silica gel with CH2Cl2/acetone (4:1) as
an eluent (Rf = 0.30) to afford a yellow solid (780 mg, 51%, mp 203−
204 °C from 1:3 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 10.50 (s, 1H), 8.54 (dd, J = 8.4, 1.2 Hz, 1H), 8.19 (d, J =
5.8 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.76−7.72 (m, 1H), 7.67−7.64
(m, 2H), 7.42−7.38 (m, 1H), 7.07−7.03 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 164.6, 146.4, 143.9, 137.2, 134.0, 131.6, 131.5, 128.5,
128.3, 124.8, 119.5, 115.3. HRMS (positive ESI): calcd for C12H10N3O4
[M + H], 260.0671; found, 260.0667.
12.27 (s, 1H), 8.75 (dd, J = 8.5, 1.7 Hz, 1H), 8.29 (dd, J = 6.5, 1.0 Hz,
1H), 8.20 (d, J = 8.3 Hz, 1H), 7.37−7.33 (m, 1H), 7.14 (dd, J = 8.4,
1.7 Hz, 1H), 7.05 (d, J = 1.6 Hz, 1H), 7.00−6.96 (m, 1H), 4.37 (q, J =
7.0 Hz, 2H), 1.73 (t, J = 7.0 Hz, 3H). 1.36 (s, 9H). 13C NMR (100
MHz, CDCl3): δ 164.0, 158.6, 157.3, 145.5, 137.3, 132.3, 127.8, 118.4,
118.3, 117.8, 115.8, 109.4, 65.1, 35.4, 31.1, 14.8. HRMS (positive ESI):
calcd for C18H23N2O3 [M + H], 315.1709; found, 315.1705.
2-(5-Methoxy-2-ethoxybenzamido)pyridine 1-Oxide (3da).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1) as
an eluent (Rf = 0.31) to afford a white solid (35 mg, 61%, mp 179−180 °C
F
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
from 1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
1H), 4.37 (q, J = 7.0 Hz, 2H), 4.00 (s, 3H), 3.94 (s, 3H), 3.93 (s, 3H),
1.58 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 163.4,
149.3, 147.5, 146.8, 146.4, 145.2, 137.4, 127.7, 119.5, 118.6, 115.7,
107.9, 71.3, 61.4, 61.3, 56.1, 15.5. HRMS (positive ESI): calcd for
C17H21N2O6 [M + H], 349.1400; found, 349.1392.
2-(2-Ethoxy-5-(trifluoromethyl)benzamido)pyridine 1-Oxide
(3ka). Purified by analytical TLC on silica gel with CH2Cl2/acetone
(3:1) as an eluent (Rf = 0.41) to afford a white solid (38 mg, 59%, mp
190−191 °C from 1:5 hexane/dichloromethane). 1H NMR (400
MHz, CDCl3): δ 12.25 (s, 1H), 8.73−8.71 (m, 1H), 8.59−8.58 (m,
1H), 8.30−8.29 (m, 1H), 7.77 (dd, J = 8.7, 2.2 Hz, 1H), 7.40−7.36
(m, 1H), 7.17 (d, J = 8.7 Hz, 1H), 7.05−7.02 (m, 1H), 4.41 (q, J = 7.0
Hz, 2H), 1.75 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
12.40 (s, 1H), 8.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.30−8.29 (m, 1H), 7.81
(d, J = 3.2 Hz, 1H), 7.38−7.34 (m, 1H), 7.11−7.08 (m, 1H), 7.02−
7.00 (m, 2H), 4.31 (q, J = 7.0 Hz, 2H), 3.85 (s, 3H), 1.69 (t, J = 7.0
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 163.8, 153.6, 151.9, 145.4,
137.4, 127.8, 121.3, 120.8, 118.6, 115.8, 115.4, 114.0, 65.8, 55.9, 14.8.
HRMS (positive ESI): calcd for C15H17N2O4 [M + H], 289.1188;
found, 289.1185.
2-(5-Methyl-2-ethoxybenzamido)pyridine 1-Oxide (3ea).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1)
as an eluent (Rf = 0.33) to afford a white solid (35 mg, 64%, mp 191−
192 °C from 1:5 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.32 (s, 1H), 8.74 (dd, J = 8.5, 1.8 Hz, 1H), 8.30−8.28 (m,
1H), 8.08 (d, J = 2.2 Hz, 1H), 7.38−7.31 (m, 2H), 7.01−6.97 (m,
1H), 6.96 (d, J = 8.6 Hz, 1H), 4.31 (q, J = 7.0 Hz, 2H), 2.36 (s, 3H),
1.70 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.2, 155.5,
145.5, 137.3, 134.9, 132.7, 130.4, 127.8, 120.0, 118.4, 115.9, 112.4,
65.3, 20.4, 14.8. HRMS (positive ESI): calcd for C15H17N2O3 [M + H],
273.1239; found, 273.1236.
2-(3-Ethoxy-[1,1′-biphenyl]-4-ylcarboxamido)pyridine 1-Oxide
(3fa). Purified by analytical TLC on silica gel with CH2Cl2/acetone
(3:1) as an eluent (Rf = 0.36) to afford a white solid (39 mg, 59%, mp
174−175 °C from 1:3 hexane/dichloromethane). 1H NMR (400
MHz, CDCl3): δ 12.32 (s, 1H), 8.76 (dd, J = 8.6, 1.7 Hz, 1H), 8.34 (d,
J = 8.2 Hz, 1H), 8.31−8.29 (m, 1H), 7.64−7.62 (m, 2H), 7.50−7.46
(m, 2H), 7.43−7.41 (m, 1H), 7.36−7.32 (m, 2H), 7.25−7.24 (m, 1H),
7.02−6.98 (m, 1H), 4.43 (q, J = 7.0 Hz, 2H), 1.75 (t, J = 7.0 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 163.8, 157.7, 147.4, 145.4, 139.9,
161.5, 158.5, 144.0, 136.3, 130.0 (q, JC−F = 3.4 Hz), 129.3 (q, JC−F
=
3.7 Hz), 127.0, 122.8 (q, JC−F = 269.9 Hz), 122.5 (q, JC−F = 33.3 Hz),
119.8, 117.9, 114.9, 111.8, 65.1, 13.6. 19F NMR (376 MHz, CDCl3): δ
−61.92. HRMS (positive ESI): calcd for C15H14F3N2O3 [M + H],
327.0957; found, 327.0953.
2-(2-Ethoxy-4-methoxybenzamido)pyridine 1-Oxide (3la).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (2:1)
as an eluent (Rf = 0.29) to afford a white solid (50 mg, 87%, mp 196−
197 °C from 1:5 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.16 (s, 1H), 8.74 (dd, J = 8.5, 1.3 Hz, 1H), 8.29−8.27 (m,
1H), 8.24 (d, J = 8.9 Hz, 1H), 7.36−7.32 (m, 1H), 6.99−6.96 (m,
1H), 6.63 (dd, J = 8.8, 2.2 Hz, 1H), 6.54 (d, J = 2.2 Hz, 1H), 4.31 (q,
J = 7.0 Hz, 2H), 3.83 (s, 3H), 1.72 (t, J = 7.0 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 164.6, 163.7, 159.0, 145.6, 137.3, 134.4, 128.1, 118.1,
115.7, 113.5, 105.7, 99.1, 65.4, 55.6, 14.7. HRMS (positive ESI): calcd
for C15H17N2O4 [M + H], 289.1188; found, 289.1185.
137.3, 133.2, 129.0, 128.4, 127.9, 127.3, 119.9, 119.2, 118.5, 115.9,
111.1, 65.5, 14.8. HRMS (positive ESI): calcd for C20H19N2O3 [M + H],
335.1396; found, 335.1392.
2-(2-Butoxybenzamido)pyridine 1-Oxide (3ab). Purified by
analytical TLC on silica gel with CH2Cl2/acetone (10:1) as an eluent
(Rf = 0.40) to afford a white solid (50 mg, 87%, mp 90−91 °C from
2-(4-Chloro-2-ethoxybenzamido)pyridine 1-Oxide (3ga).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1)
as an eluent (Rf = 0.36) to afford a white solid (29 mg, 50%, mp 210−
211 °C from 1:3 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.19 (s, 1H), 8.71 (dd, J = 8.5, 1.4 Hz, 1H), 8.30−8.28 (m,
1H), 8.23 (d, J = 8.5 Hz, 1H), 7.38−7.34 (m, 1H), 7.10 (dd, J = 8.5,
1.8 Hz, 1H), 7.06 (d, J = 1.8 Hz, 1H), 7.03−6.99 (m, 1H), 4.34 (q, J =
7.0 Hz, 2H), 1.73 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
163.0, 157.8, 145.2, 140.2, 137.4, 133.8, 128.0, 121.5, 119.1, 118.7,
115.9, 113.1, 66.0, 14.6. HRMS (positive ESI): calcd for C14H14ClN2O3
[M + H], 293.0693; found, 293.0690.
2-(4-Bromo-2-ethoxybenzamido)pyridine 1-Oxide (3ha).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (3:1)
as an eluent (Rf = 0.39) to afford a white solid (36 mg, 53%, mp 195−
196 °C from 1:3 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.18 (s, 1H), 8.72−8.70 (m, 1H), 8.30−8.28 (m, 1H),
8.14 (d, J = 8.5 Hz, 1H), 7.38−7.34 (m, 1H), 7.26 (dd, J = 8.5, 1.7 Hz,
1H), 7.22 (d, J = 1.6 Hz, 1H), 7.03−6.99 (m, 1H), 4.34 (q, J = 7.0 Hz,
2H), 1.73 (t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 163.1,
157.7, 145.2, 137.4, 133.9, 128.6, 128.0, 124.5, 119.5, 118.7, 116.0,
115.8, 66.0, 14.6. HRMS (positive ESI): calcd for C14H14BrN2O3
[M + H], 337.0188; found, 337.0184.
1
1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.26
(s, 1H), 8.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.30−8.27 (m, 2H), 7.55−7.51
(m, 1H), 7.37−7.33 (m, 1H), 7.13−7.07 (m, 2H), 7.01−6.97 (m, 1H),
4.29 (t, J = 7.1 Hz, 2H), 2.14−2.07 (m, 2H), 1.60−1.50 (m, 2H), 1.02
(t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.0, 157.6,
145.4, 137.4, 134.3, 132.7, 127.7, 121.0, 120.6, 118.5, 115.8, 112.5,
69.6, 30.6, 19.3, 13.8. HRMS (positive ESI): calcd for C16H19N2O3
[M + H], 287.1396; found, 287.1401.
2-(2-(2-(Thiophen-2-yl)ethoxy)benzamido)pyridine 1-Oxide
(3ac). Purified by analytical TLC on silica gel with CH2Cl2/acetone
(5:1) as an eluent (Rf = 0.30) to afford a white solid (50 mg, 73%, mp
123−124 °C from 1:5 hexane/dichloromethane). 1H NMR (400
MHz, CDCl3): δ 12.26 (s, 1H), 8.74 (dd, J = 8.4, 1.1 Hz, 1H), 8.30−
8.26 (m, 2H), 7.53−7.49 (m, 1H), 7.38−7.34 (m, 1H), 7.14−7.10 (m,
2H), 7.04−6.99 (m, 2H), 6.97−6.96 (m, 1H), 6.93−6.91 (m, 1H),
4.45 (t, J = 7.3 Hz, 2H), 3.70 (t, J = 7.2 Hz, 2H). 13C NMR (100 MHz,
CDCl3): δ 163.8, 157.1, 145.3, 139.7, 137.3, 134.3, 132.7, 127.8, 126.9,
126.1, 124.1, 121.5, 120.7, 118.5, 115.8, 112.5, 70.4, 29.6. HRMS
(positive ESI): calcd for C18H17N2O3S [M + H], 341.0960; found,
341.0955.
2-(2-(2-Methylbutoxy)benzamido)pyridine 1-Oxide (3ad).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (6:1)
as an eluent (Rf = 0.30) to afford a white solid (45 mg, 75%, mp 117−
118 °C from 1:5 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.19 (s, 1H), 8.73 (dd, J = 8.5, 1.8 Hz, 1H), 8.30−8.25 (m,
2H), 7.54−7.50 (m, 1H), 7.36−7.32 (m, 1H), 7.12−7.06 (m, 2H),
7.01−6.97 (m, 1H), 4.19−4.15 (m, 1H), 4.04−3.99 (m, 1H), 2.39−
2.31 (m, 1H), 1.66−1.56 (m, 1H), 1.40−1.29 (m, 1H), 1.09 (d, J = 6.7
Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
164.1, 157.7, 145.3, 137.4, 134.2, 132.6, 127.5, 121.0, 120.7, 118.5,
115.8, 112.6, 74.9, 33.7, 26.3, 16.8, 11.0. HRMS (positive ESI): calcd
for C17H21N2O3 [M + H], 301.1552; found, 301.1547.
2-(2-Ethoxy-4-iodobenzamido)pyridine 1-Oxide (3ia). Puri-
fied by analytical TLC on silica gel with CH2Cl2/acetone (3:1) as an
eluent (Rf = 0.39) to afford a white solid (45 mg, 58%, mp 163−164 °C
1
from 1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
12.17 (s, 1H), 8.72−8.69 (m, 1H), 8.29−8.28 (m, 1H), 7.96 (d, J =
8.3 Hz, 1H), 7.47 (dd, J = 8.3, 1.3 Hz, 1H), 7.40 (d, J = 1.1 Hz, 1H),
7.37−7.33 (m, 1H), 7.03−6.99 (m, 1H), 4.33 (q, J = 7.0 Hz, 2H), 1.72
(t, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 163.3, 157.3,
145.2, 137.4, 133.8, 130.6, 127.9, 121.9, 120.2, 118.7, 115.8, 101.1,
66.0, 14.7. HRMS (positive ESI): calcd for C14H14IN2O3 [M + H],
385.0049; found, 385.0044.
2-(2-(But-3-en-1-yloxy)benzamido)pyridine 1-Oxide (3ae).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (10:1)
as an eluent (Rf = 0.29) to afford a white solid (42 mg, 74%, mp 107−
108 °C from 1:5 hexane/dichloromethane). 1H NMR (400 MHz,
CDCl3): δ 12.23 (s, 1H), 8.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.30−8.27 (m,
2H), 7.55−7.51 (m, 1H), 7.37−7.33 (m, 1H), 7.14−7.06 (m, 2H),
2-(2-Ethoxy-3,4,5-trimethoxybenzamido)pyridine 1-Oxide
(3ja). Purified by analytical TLC on silica gel with CH2Cl2/acetone
(3:1) as an eluent (Rf = 0.45) to afford a white solid (48 mg, 69%, mp
98−99 °C from 1:5 hexane/dichloromethane). H NMR (400 MHz,
CDCl3): δ 12.58 (s, 1H), 8.69 (dd, J = 8.5, 1.7 Hz, 1H), 8.30 (dd, J =
6.5, 1.1 Hz, 1H), 7.53 (s, 1H), 7.39−7.34 (m, 1H), 7.03−6.99 (m,
1
G
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.01−6.98 (m, 1H), 6.02−5.92 (m, 1H), 5.24−5.19 (m, 1H), 5.13−
5.10 (m, 1H), 4.31 (t, J = 7.2 Hz, 2H), 2.93−2.88 (m, 2H). 13C NMR
(100 MHz, CDCl3): δ 163.9, 157.3, 145.4, 137.3, 134.3, 133.8, 132.7,
127.7, 121.2, 120.6, 118.5, 117.6, 115.8, 112.5, 69.0, 33.1. HRMS
(positive ESI): calcd for C16H17N2O3 [M + H], 285.1239; found,
285.1237.
4.27 (t, J = 7.2 Hz, 2H), 2.15−2.08 (m, 2H), 1.51−1.45 (m, 2H),
1.42−1.35 (m, 2H), 1.29−1.24 (m, 14H), 0.88 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 164.1, 157.6, 145.4, 137.3, 134.3, 132.6,
127.6, 121.0, 120.6, 118.5, 115.8, 112.5, 69.9, 31.9, 29.6, 29.4, 29.2,
28.6, 26.0, 22.7, 14.1. HRMS (positive ESI): calcd for C24H35N2O3
[M + H], 399.2648; found, 399.2645.
2-(2-Phenethoxybenzamido)pyridine 1-Oxide (3af). Purified
by analytical TLC on silica gel with CH2Cl2/acetone (5:1) as an eluent
(Rf = 0.33) to afford a white solid (44 mg, 66%, mp 153−154 °C from
2-(2-((Hexafluoropropan-2-yl)oxy)benzamido)pyridine 1-Oxide
(3al). Purified by analytical TLC on silica gel with petroleum ether/
ethyl acetate (1:1) as an eluent (Rf = 0.30 and 0.38 for 3al and 3′al,
respectively) to afford a white solid (52 mg, 68%, and mp 138−139 °C
from 1:2 hexane/dichloromethane for 3al; 26 mg, 24%, and mp 196−
1
1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.28
(s, 1H), 8.74 (dd, J = 8.5, 1.6 Hz, 1H), 8.32−8.26 (m, 2H), 7.52−7.48
(m, 1H), 7.39−7.27 (m, 5H), 7.24−7.20 (m, 1H), 7.13−7.10 (m, 1H),
7.03−6.99 (m, 2H), 4.42 (t, J = 7.8 Hz, 2H), 3.47 (t, J = 7.9 Hz, 2H).
13C NMR (100 MHz, CDCl3): δ 163.9, 157.3, 145.3, 137.5, 137.4,
134.3, 132.7, 129.2, 129.0, 128.5, 127.9, 126.6, 126.4, 121.3, 120.7,
118.6, 115.8, 112.6, 70.7, 35.5. HRMS (positive ESI): calcd for
C20H19N2O3 [M + H], 335.1396; found, 335.1392.
1
197 °C from 1:2 hexane/dichloromethane for 3'al). H NMR (400
MHz, CDCl3): δ 11.22 (s, 1H), 8.63 (dd, J = 8.5, 1.8 Hz, 1H), 8.32−
8.30 (m, 1H), 8.09−8.06 (m, 1H), 7.62−7.58 (m, 1H), 7.39−7.31 (m,
2H), 7.17 (d, J = 8.4 Hz, 1H), 7.05−7.01 (m, 1H), 5.14−5.08 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 163.1, 154.7, 144.5, 137.3,
134.0, 132.3, 127.6, 125.1, 125.0, 120.7 (q, JC−F = 285.8 Hz), 119.0,
115.4, 115.3, 76.4 (p, JC−F = 33.8 Hz). 19F NMR (376 MHz, CDCl3):
δ −72.78. HRMS (positive ESI): calcd for C15H11F6N2O3 [M + H],
381.0674; found, 381.0672.
2-(2-(2-Methoxyethoxy)benzamido)pyridine 1-Oxide (3ag).
Purified by analytical TLC on silica gel with CH2Cl2/acetone (2:1) as
an eluent (Rf = 0.44) to afford a white solid (40 mg, 70%, mp 114−115 °C
1
2-(2,6-(Bis(hexafluoropropan-2-yl)oxy)benzamido)pyridine
from 1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ
1
1-Oxide (3′al). H NMR (400 MHz, DMSO-d6): δ 8.41−8.37 (m,
12.24 (s, 1H), 8.72 (dd, J = 8.5, 1.8 Hz, 1H), 8.30−8.27 (m, 2H),
7.56−7.51 (m, 1H), 7.37−7.33 (m, 1H), 7.15−7.10 (m, 2H), 7.01−
6.97 (m, 1H), 4.42 (t, J = 4.7 Hz, 2H), 4.10 (t, J = 4.9 Hz, 2H), 3.48
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 163.8, 157.4, 145.4, 137.3,
134.3, 132.7, 127.6, 121.5, 120.8, 118.5, 115.8, 112.8, 70.4, 69.0, 59.1.
HRMS (positive ESI): calcd for C15H17N2O4 [M + H], 289.1188;
found, 289.1185.
2H), 7.70−7.66 (m, 1H), 7.52−7.49 (m, 1H), 7.29 (d, J = 8.6 Hz,
2H), 7.24−7.21 (m, 1H), 6.67−6.63 (m, 2H). 13C NMR (100 MHz,
DMSO-d6): δ 161.0, 153.4, 142.9, 137.6, 132.0, 127.4, 121.0 (q, JC−F
=
285.8 Hz), 120.1, 118.0, 114.2, 109.8, 72.6 (p, JC−F = 32.4 Hz). 19F
NMR (376 MHz, DMSO-d6): δ −72.90. HRMS (positive ESI): calcd
for C18H11F12N2O4 [M + H], 547.0527; found, 547.0526.
2-(2-((Hexafluoropropan-2-yl)oxy)-5-methylbenzamido)-
pyridine 1-Oxide (3el). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.33) to afford a white solid
(69 mg, 88%, mp 159−160 °C from 1:4 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 11.20 (s, 1H), 8.63 (dd, J = 8.5, 1.8 Hz,
1H), 8.30 (d, J = 6.2 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.38−7.34 (m,
2H), 7.07−7.01 (m, 2H), 5.09−5.04 (m, 1H), 2.39 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 163.3, 152.7, 144.6, 137.3, 135.0, 134.5, 132.4,
127.6, 124.6, 120.8 (q, JC−F = 285.2 Hz), 118.9, 115.5, 115.3, 76.7 (p,
JC−F = 34.0 Hz), 20.5. 19F NMR (376 MHz, CDCl3): δ −72.84.
HRMS (positive ESI): calcd for C16H13F6N2O3 [M + H], 395.0830;
found, 395.0828.
2-(2-((Hexafluoropropan-2-yl)oxy)-4-iodobenzamido)-
pyridine 1-Oxide (3il). Purified by analytical TLC on silica gel with
petroleum ether/ethyl acetate (1:1) as an eluent (Rf = 0.28 and 0.60
for 3al and 3′al, respectively) to afford a white solid (54 mg, 53%,
and mp 99−100 °C from 1:4 hexane/dichloromethane for 3il; 38 mg,
28%, and mp 138−139 °C from 1:4 hexane/dichloromethane for 3'il).
1H NMR (400 MHz, CDCl3): δ 11.21 (s, 1H), 8.60 (dd, J = 8.5, 1.5
2-(2-Isopropoxybenzamido)pyridine 1-Oxide (3ah). Purified
by analytical TLC on silica gel with CH2Cl2/acetone (5:1) as an eluent
(Rf = 0.40) to afford a white solid (39 mg, 71%, mp 138−139 °C from
1
1:5 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.28
(s, 1H), 8.75 (dd, J = 8.5, 1.8 Hz, 1H), 8.31−8.28 (m, 2H), 7.54−7.50
(m, 1H), 7.37−7.33 (m, 1H), 7.11−7.07 (m, 2H), 7.01−6.97 (m, 1H),
4.96−4.90 (m, 1H), 1.60 (d, J = 6.1 Hz, 6H). 13C NMR (100 MHz,
CDCl3): δ 164.1, 156.5, 145.4, 137.4, 134.2, 132.8, 127.7, 121.2, 120.9,
118.5, 115.9, 113.6, 72.3, 21.9. HRMS (positive ESI): calcd for
C15H17N2O3 [M + H], 273.1239; found, 273.1237.
2-(2-(((1R,2R,5R)-2-Isopropyl-5-methylcyclohexyl)oxy)-
benzamido)pyridine 1-Oxide (3ai). Purified by analytical TLC on
silica gel with CH2Cl2/acetone (10:1) as an eluent (Rf = 0.49) to
afford a white solid (28 mg, 38%, mp 133−134 °C from 1:2 hexane/
1
dichloromethane). H NMR (400 MHz, CDCl3): δ 12.29 (s, 1H),
8.74 (dd, J = 8.5, 1.7 Hz, 1H), 8.31−8.28 (m, 2H), 7.53−7.49 (m,
1H), 7.34−7.30 (m, 1H), 7.13−7.06 (m, 2H), 6.99−6.95 (m, 1H),
4.45−4.39 (m, 1H), 2.25−2.16 (m, 3H), 1.83−1.79 (m, 1H), 1.73−
1.72 (m, 1H), 1.52−1.49 (m, 1H), 1.44−1.38 (m, 1H), 1.15−1.10 (m,
2H), 0.95 (d, J = 3.0 Hz, 3H), 0.93 (d, J = 2.5 Hz, 3H), 0.76 (d, J = 6.9
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 164.2, 157.1, 145.4, 137.4,
134.3, 132.9, 127.3, 121.2, 120.7, 118.4, 115.8, 113.3, 79.7, 46.4, 39.9,
34.0, 31.7, 26.3, 23.6, 22.0, 20.6, 16.5. HRMS (positive ESI): calcd for
C22H29N2O3 [M + H], 369.2178; found, 369.2178.
Hz, 1H), 8.31−8.30 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.70−7.68 (m,
1H), 7.50 (s, 1H), 7.39−7.35 (m, 1H), 7.06−7.02 (m, 1H), 5.13−5.09
(m, 1H). 13C NMR (100 MHz, CDCl3): δ 162.4, 154.4, 144.3, 137.3,
134.6, 133.4, 127.6, 124.7, 124.5, 120.7 (q, JC−F = 280.0 Hz), 119.2,
115.4, 99.6, 76.5 (p, JC−F = 33.4 Hz). 19F NMR (376 MHz, CDCl3):
δ −72.66. HRMS (positive ESI): calcd for C15H10F6IN2O3 [M + H],
506.9640; found, 506.9644.
2-(2-n-Decoxybenzamido)pyridine 1-Oxide (3aj). Purified by
analytical TLC on silica gel with CH2Cl2/acetone (10:1) as an eluent
(Rf = 0.45) to afford a white solid (42 mg, 57%, mp 83−84 °C from
2-(2,6-Bis((hexafluoropropan-2-yl)oxy)-4-iodobenzamido)-
1
1
1:3 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.27
pyridine 1-Oxide (3′il). H NMR (400 MHz, DMSO-d6): δ 8.39−
(s, 1H), 8.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.30−8.26 (m, 2H), 7.55−7.50
(m, 1H), 7.37−7.32 (m, 1H), 7.12−7.06 (m, 2H), 7.01−6.97 (m, 1H),
4.27 (t, J = 7.2 Hz, 2H), 2.15−2.08 (m, 2H), 1.52−1.49 (m, 2H),
1.42−1.35 (m, 2H), 1.28−1.24 (m, 10H), 0.87 (t, J = 7.0 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 164.1, 157.6, 145.4, 137.3, 134.3, 132.6,
127.6, 121.0, 120.6, 118.5, 115.8, 112.5, 69.9, 31.9, 29.6, 29.5, 29.3,
29.2, 28.6, 26.0, 22.7, 14.1. HRMS (positive ESI): calcd for C22H31N2O3
[M + H], 371.2335; found, 371.2332.
8.33 (m, 2H), 7.72 (s, 2H), 7.50−7.46 (m, 1H), 7.24−7.20 (m, 1H),
6.72−6.66 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 160.7, 153.4,
143.0, 137.7, 127.2, 120.8 (q, JC−F = 282.4 Hz), 120.2, 118.5, 118.0,
114.6, 96.7, 72.5 (p, JC−F = 32.8 Hz). 19F NMR (376 MHz, DMSO-
d6): δ −72.91. HRMS (positive ESI): calcd for C18H10F12IN2O4
[M + H], 672.9499; found, 672.9493.
2-(2-((Hexafluoropropan-2-yl)oxy)-5-(trifluoromethyl)-
benzamido)pyridine 1-Oxide (3kl). Purified by analytical TLC
on silica gel with CH2Cl2/acetone (6:1) as an eluent (Rf = 0.45) to
afford a white solid (84 mg, 94%, mp 110−111 °C from 1:4 hexane/
2-(2-Dodecoxybenzamido)pyridine 1-Oxide (3ak). Purified by
analytical TLC on silica gel with CH2Cl2/acetone (10:1) as an eluent
(Rf = 0.45) to afford a white solid (48 mg, 60%, mp 78−79 °C from
1
dichloromethane). H NMR (400 MHz, CDCl3): δ 11.30 (s, 1H),
1
8.62 (dd, J = 8.5, 1.7 Hz, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.32−8.30 (m,
1H), 7.86 (dd, J = 8.8, 2.2 Hz, 1H), 7.41−7.37 (m, 1H), 7.30 (d, J =
8.8 Hz, 1H), 7.09−7.05 (m, 1H), 5.25−5.20 (m, 1H). 13C NMR
1:2 hexane/dichloromethane). H NMR (400 MHz, CDCl3): δ 12.27
(s, 1H), 8.73 (dd, J = 8.5, 1.7 Hz, 1H), 8.30−8.26 (m, 2H), 7.55−7.50
(m, 1H), 7.37−7.32 (m, 1H), 7.13−7.06 (m, 2H), 7.01−6.97 (m, 1H),
H
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(100 MHz, CDCl3): δ 161.6, 156.4, 144.1, 137.2, 130.9 (q, JC−F
=
154.6, 143.5, 137.2, 134.2, 128.1, 123.2, 120.5 (q, JC−F = 282.7 Hz), 119.6,
114.9, 111.5, 75.6 (p, JC−F = 33.9 Hz), 53.3. 19F NMR (376 MHz,
CDCl3): δ −73.04. HRMS (positive ESI): calcd for C20H13F12N2O6
[M + H], 605.0582; found, 605.0583.
3.4 Hz), 130.1 (q, JC−F = 3.4 Hz), 127.7, 127.4 (q, JC−F = 33.7 Hz),
125.2, 123.1 (q, JC−F = 270.7 Hz), 120.5 (q, JC−F = 282.4 Hz), 119.5,
115.5, 115.4, 75.8 (p, JC−F = 34.1 Hz). 19F NMR (376 MHz, CDCl3):
δ −62.45, −72.62. HRMS (positive ESI): calcd for C16H10F9N2O3
[M + H], 449.0548; found, 449.0553.
2-(2-((Hexafluoropropan-2-yl)oxy)-4-methoxybenzamido)-
pyridine 1-Oxide (3ll). Purified by analytical TLC on silica gel with
petroleum ether/ethyl acetate (1:1) as an eluent (Rf = 0.23 and
0.50 for 3ll and 3'll, respectively) to afford a white solid (23 mg, 28%,
and mp 157−158 °C from 1:4 hexane/dichloromethane for 3ll; 69 mg,
60%, and mp 182−183 °C from 1:4 hexane/dichloromethane for 3'll).
1H NMR (400 MHz, CDCl3): δ 11.28 (s, 1H), 8.63 (dd, J = 8.4, 1.4
Hz, 1H), 8.31−8.29 (m, 1H), 8.12 (d, J = 8.8 Hz, 1H), 7.34−7.32 (m,
1H), 7.02−6.99 (m, 1H), 6.83−6.81 (m, 1H), 6.65 (d, J = 2.1 Hz,
1H), 5.21−5.15 (m, 1H), 3.89 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 164.3, 162.7, 156.1, 144.8, 137.3, 134.5, 127.6, 120.7 (q, JC−F = 285.3
Hz), 118.7, 116.8, 115.4, 109.2, 101.9, 76.1 (p, JC−F = 34.0 Hz), 55.9.
19F NMR (376 MHz, CDCl3): δ −72.67. HRMS (positive ESI): calcd
for C16H13F6N2O4 [M + H], 411.0780; found, 411.0784.
2-(3-((Hexafluoropropan-2-yl)oxy)isonicotinamido)pyridine
1-Oxide (3ol). Purified by analytical TLC on silica gel with petroleum
ether/ethyl acetate (1:1) as an eluent (Rf = 0.22 and 0.60 for 3ol and
3'ol, respectively) to afford a white solid (41 mg, 54%, and mp
138−139 °C from 1:4 hexane/dichloromethane for 3ol; 23 mg, 21%,
1
and mp 250−251 °C from 1:4 hexane/dichloromethane for 3'ol). H
NMR (400 MHz, CDCl3): δ 11.24 (s, 1H), 8.68−8.65 (m, 2H), 8.59
(dd, J = 8.4, 1.6 Hz, 1H), 8.32−8.31 (m, 1H), 7.90 (d, J = 4.7 Hz, 1H),
7.42−7.38 (m, 1H), 7.11−7.07 (m, 1H), 5.31−5.25 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 161.1, 149.9, 147.0, 143.9, 139.1, 137.3,
131.7, 127.7, 124.3, 120.5 (q, JC−F = 280.0 Hz), 119.7, 115.5, 76.9 (p,
JC−F = 34.1 Hz). 19F NMR (376 MHz, CDCl3): δ −72.77. HRMS
(positive ESI): calcd for C14H10F6N3O3 [M + H], 382.0626; found,
382.0623.
2-(2,6-Bis((hexafluoropropan-2-yl)oxy)isonicotinamido)-
pyridine 1-Oxide (3′ol). 1H NMR (400 MHz, DMSO-d6): δ 8.62 (s,
2H), 8.39−8.35 (m, 2H), 7.50−7.46 (m, 1H), 7.26−7.22 (m, 1H),
6.82−6.76 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 159.6, 149.0,
143.0, 138.0, 127.0, 125.3, 120.8 (q, JC−F = 279.8 Hz), 120.6, 115.2,
73.3 (p, JC−F = 32.8 Hz). 19F NMR (376 MHz, DMSO-d6): δ −72.85.
HRMS (positive ESI): calcd for C17H10F12N3O4 [M + H], 548.0480;
found, 548.0473.
2-(2,6-Bis((hexafluoropropan-2-yl)oxy)-4-methoxybenzamido)-
1
pyridine 1-Oxide (3′ll). H NMR (400 MHz, DMSO-d6): δ 8.42−
8.34 (m, 2H), 7.52−7.48 (m, 1H), 7.23−7.20 (m, 1H), 6.91 (s, 2H),
6.71−6.65 (m, 2H), 3.90 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ
162.2, 160.7, 154.4, 143.0, 137.4, 127.5, 120.9 (q, JC−F = 281.7 Hz),
119.8, 113.9, 110.5, 96.2, 72.3 (p, JC−F = 32.5 Hz), 56.3. 19F NMR
(376 MHz, DMSO-d6): δ −72.94. HRMS (positive ESI): calcd for
C19H13F12N2O5 [M + H], 577.0633; found, 577.0638.
2-(2-((Hexafluoropropan-2-yl)oxy)-4-(trifluoromethyl)-
benzamido)pyridine 1-Oxide (3pl). Purified by analytical TLC on
silica gel with CH2Cl2/acetone (10:1) as an eluent (Rf = 0.40) to
afford a white solid (69 mg, 77%, mp 119−120 °C from 1:1 hexane/
2-(2-((Hexafluoropropan-2-yl)oxy)-4-(methylsulfonyl)-
benzamido)pyridine 1-Oxide (3ml). Purified by analytical TLC on
silica gel with petroleum ether/ethyl acetate (1:1) as an eluent (Rf =
0.25 and 0.55 for 3ml and 3'ml, respectively) to afford a white solid
(64 mg, 70%, and mp 206−207 °C from 1:4 hexane/dichloromethane
for 3ml; 27 mg, 22%, and mp 291−292 °C from 1:4 hexane/dichloro-
methane for 3'ml). 1H NMR (400 MHz, DMSO-d6): δ 8.45−8.41 (m,
2H), 8.08 (d, J = 8.0 Hz, 1H), 8.04 (d, J = 1.0 Hz, 1H), 7.90−7.88 (m,
1H), 7.53−7.48 (m, 1H), 7.26−7.22 (m, 1H), 6.95−6.89 (m, 1H),
3.35 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ 162.2, 153.2, 144.6,
143.1, 137.5, 132.0, 129.6, 127.3, 122.9, 120.9 (q, JC−F = 282.3 Hz),
120.3, 114.9, 114.2, 73.5 (p, JC−F = 33.0 Hz), 43.2. 19F NMR (376
MHz, DMSO-d6): δ −72.44. HRMS (positive ESI): calcd for
C16H13F6N2O5S [M + H], 459.0449; found, 459.0456.
1
dichloromethane). H NMR (400 MHz, CDCl3): δ 11.19 (s, 1H),
8.62−8.60 (m, 1H), 8.30−8.29 (m, 1H), 8.18−8.16 (m, 1H), 7.60−
7.58 (m, 1H), 7.42−7.38 (m, 2H), 7.09−7.05 (m, 1H), 5.26−5.20 (m,
1H). 13C NMR (100 MHz, CDCl3): δ 161.9, 154.4, 144.1, 137.2,
135.6 (q, JC−F = 33.5 Hz), 133.1, 128.4, 127.7, 122.7 (q, JC−F = 271.6
Hz), 121.9 (q, JC−F = 3.5 Hz), 120.5 (q, JC−F = 280.9 Hz), 119.5,
115.4, 112.6, 76.3 (p, JC−F = 34.1 Hz). 19F NMR (376 MHz, CDCl3):
δ −63.23, −72.76. HRMS (positive ESI): calcd for C16H10F9N2O3
[M + H], 449.0548; found, 449.0550.
2-(2-((Hexafluoropropan-2-yl)oxy)-6-methylbenzamido)-
pyridine 1-Oxide (3ql). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.35) to afford a white solid
1
(73 mg, 93%, mp 95−96 °C from 1:4 hexane/dichloromethane). H
2-(2,6-Bis((hexafluoropropan-2-yl)oxy)-4-(methylsulfonyl)-
benzamido)pyridine 1-Oxide (3′ml). 1H NMR (400 MHz,
DMSO-d6): δ 8.38−8.36 (m, 2H), 7.82 (s, 2H), 7.50−7.46 (m,
1H), 7.25−7.21 (m, 1H), 6.89−6.83 (m, 2H), 3.35 (s, 3H). 13C NMR
(100 MHz, DMSO-d6): δ 160.4, 153.7, 143.7, 143.1, 137.9, 127.1,
NMR (400 MHz, CDCl3): δ 10.20 (s, 1H), 8.63−8.61 (m, 1H), 8.25−
8.24 (m, 1H), 7.42−7.35 (m, 2H), 7.09−7.04 (m, 2H), 6.93 (d, J = 8.4
Hz, 1H), 4.97−4.91 (m, 1H), 2.41 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 164.9, 153.6, 144.0, 138.1, 137.3, 131.1, 128.2, 127.8, 126.7,
120.8 (q, JC−F = 284.9 Hz), 119.1, 114.9, 112.2, 76.0 (p, JC−F = 33.5
Hz), 19.2. 19F NMR (376 MHz, CDCl3): δ −73.20. HRMS (positive
ESI): calcd for C16H13F6N2O3 [M + H], 395.0830; found, 395.0828.
2-(2-Chloro-6-((hexafluoropropan-2-yl)oxy)benzamido)-
pyridine 1-Oxide (3rl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.40) to afford a white solid
(59 mg, 71%, mp 141−142 °C from 1:4 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 10.28 (s, 1H), 8.60 (dd, J = 8.4, 1.6 Hz,
1H), 8.27−8.26 (m, 1H), 7.46−7.39 (m, 2H), 7.30−7.28 (m, 1H),
7.10−7.04 (m, 2H), 5.02−4.96 (m, 1H). 13C NMR (100 MHz,
CDCl3): δ 161.8, 154.3, 143.7, 137.3, 132.8, 131.2, 128.1, 127.7, 126.0,
120.6 (q, JC−F = 285.4 Hz), 119.5, 115.0, 113.7, 76.1 (p, JC−F = 33.7
Hz). 19F NMR (376 MHz, CDCl3): δ −73.09. HRMS (positive ESI):
calcd for C15H10ClF6N2O3 [M + H], 415.0284; found, 415.0281.
2-(2-((Hexafluoropropan-2-yl)oxy)-6-nitrobenzamido)-
pyridine 1-Oxide (3sl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (6:1) as an eluent (Rf = 0.35) to afford a yellow solid
(46 mg, 54%, mp 162−163 °C from 1:4 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 10.42 (s, 1H), 8.56 (dd, J = 8.4, 1.2 Hz,
1H), 8.24−8.22 (m, 1H), 8.06 (d, J = 8.2 Hz, 1H), 7.71−7.67 (m,
1H), 7.50−7.41 (m, 2H), 7.10−7.06 (m, 1H), 5.13−5.08 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 160.8, 154.2, 146.6, 143.7, 137.2, 131.9,
128.4, 123.7, 121.2, 120.5, 120.5 (q, JC−F = 282.4 Hz), 119.5, 115.1,
122.7, 120.8 (q, JC−F = 281.0 Hz), 114.9, 110.5, 108.6, 72.8 (p, JC−F
=
33.0 Hz), 43.2. 19F NMR (376 MHz, DMSO-d6 ): δ −72.77. HRMS
(positive ESI): calcd for C19H13F12N2O6S [M + H], 625.0303; found,
625.0305.
2-(2-((Hexafluoropropan-2-yl)oxy)-4-(methoxycarbonyl)-
benzamido)pyridine 1-Oxide (3nl). Purified by analytical TLC on
silica gel with petroleum ether/ethyl acetate (1:1) as an eluent (Rf =
0.22 and 0.46 for 3nl and 3'nl, respectively) to afford a white solid
(49 mg, 56%, and mp 173−174 °C from 1:4 hexane/dichloromethane
for 3nl; 28 mg, 23%, and mp 163−164 °C from 1:4 hexane/dichloro-
methane for 3'nl). 1H NMR (400 MHz, CDCl3): δ 11.24 (s, 1H), 8.62
(dd, J = 8.5, 1.6 Hz, 1H), 8.33−8.31 (m, 1H), 8.14 (d, J = 8.1 Hz, 1H),
7.97−7.95 (m, 1H), 7.83 (s, 1H), 7.40−7.36 (m, 1H), 7.08−7.04 (m,
1H), 5.29−5.24 (m, 1H), 3.98 (s, 3H). 13C NMR (100 MHz, CDCl3):
δ 165.0, 162.3, 154.2, 144.2, 137.3, 135.2, 132.6, 128.6, 127.6, 125.7,
120.6 (q, JC−F = 282.0 Hz), 119.3, 115.8, 115.4, 75.9 (p, JC−F = 34.0
Hz), 52.9. 19F NMR (376 MHz, CDCl3): δ −72.72. HRMS (positive
ESI): calcd for C17H13F6N2O5 [M + H], 439.0729; found, 439.0727.
2-(2,6-Bis((hexafluoropropan-2-yl)oxy)-4-(methoxycarbonyl)-
1
benzamido)pyridine 1-Oxide (3′nl). H NMR (400 MHz, CDCl3):
δ 10.30 (s, 1H), 8.57 (dd, J = 8.4, 1.4 Hz, 1H), 8.29−8.27 (m, 1H),
7.58 (s, 2H), 7.44−7.39 (m, 1H), 7.10−7.06 (m, 1H), 5.11−5.05 (m,
2H), 4.01 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 164.2, 159.8,
I
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
76.2 (p, JC−F = 33.7 Hz). 19F NMR (376 MHz, CDCl3): δ −72.95.
HRMS (positive ESI): calcd for C15H10F6N3O5 [M + H], 426.0525;
found, 426.0524.
NMR (100 MHz, CDCl3): δ 158.6, 152.6, 144.5, 137.3, 132.2, 127.7,
120.6, 120.5 (q, JC−F = 280.0 Hz), 118.9, 115.8, 115.3, 76.8 (p, JC−F
=
34.2 Hz). 19F NMR (376 MHz, CDCl3): δ −72.81. HRMS (positive
ESI): calcd for C13H9F6N2O3S [M + H], 387.0238; found, 387.0235.
2-(3-((Hexafluoropropan-2-yl)oxy)furan-2-carboxamido)-
pyridine 1-Oxide (3zl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (6:1) as an eluent (Rf = 0.44) to afford a white solid
(28 mg, 38%, mp 153−154 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 10.94 (s, 1H), 8.55 (d, J = 7.8 Hz, 1H),
8.31−8.30 (m, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.38−7.34 (m, 1H),
7.06−7.03 (m, 1H), 6.51 (d, J = 2.0 Hz, 1H), 6.09−6.03 (m, 1H). 13C
NMR (100 MHz, CDCl3): δ 155.6, 151.0, 144.7, 144.0, 137.3, 131.2,
2-(2-((Hexafluoropropan-2-yl)oxy)-4,6-dimethylbenzamido)-
pyridine 1-Oxide (3tl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.39) to afford a white solid
(74 mg, 91%, mp 105−106 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 10.17 (s, 1H), 8.62−8.60 (m, 1H), 8.26−
8.25 (m, 1H), 7.40−7.36 (m, 1H), 7.06−7.03 (m, 1H), 6.89 (s, 1H),
6.72 (s, 1H), 4.97−4.91 (m, 1H), 2.37 (s, 6H). 13C NMR (100 MHz,
CDCl3): δ 165.1, 153.7, 144.1, 141.9, 137.9, 137.3, 128.1, 127.5, 125.0,
120.8 (q, JC−F = 285.1 Hz), 119.0, 114.8, 112.9, 76.0 (p, JC−F = 33.4
Hz), 21.6, 19.3. 19F NMR (376 MHz, CDCl3): δ −73.22. HRMS
(positive ESI): calcd for C17H15F6N2O3 [M + H], 409.0987; found,
409.0986.
2-(5-Chloro-2-((hexafluoropropan-2-yl)oxy)benzamido)-
pyridine 1-Oxide (3ul). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.41) to afford a white solid
(77 mg, 93%, mp 127−128 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 11.24 (s, 1H), 8.60 (dd, J = 8.6, 1.7 Hz,
1H), 8.31−8.29 (m, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.54 (dd, J = 8.9,
2.7 Hz, 1H), 7.40−7.36 (m, 1H), 7.15 (d, J = 8.9 Hz, 1H), 7.08−7.04
(m, 1H), 5.15−5.09 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 161.7,
128.2, 120.8 (q, JC−F = 284.6 Hz), 119.0, 114.9, 107.2, 76.5 (p, JC−F
=
33.6 Hz). 19F NMR (376 MHz, CDCl3): δ −73.32. HRMS (positive
ESI): calcd for C13H9F6N2O4 [M + H], 371.0467; found, 371.0462.
General Procedure for Removal of the Directing Group. A
mixture of 2-(2-ethoxybenzamido)pyridine 1-oxide (51.6 mg,
0.2 mmol) and NaOH (120 mg, 3 mmol) in EtOH (2 mL) was
stirred at 80 °C for 8 h. After completion of the reaction, the resulting
dark red solution was cooled to room temperature and quenched with
2 M HCl aqueous solution (15 mL). The mixture was extracted with
CH2Cl2 (3 × 15 mL). The organic layers were combined, dried over
MgSO4, and filtered, and the solvent was evaporated under a vacuum.
Purification by silica gel column chromatography (CH2Cl2/methanol,
20:1) afforded 2-ethoxybenzoic acid 10 as a light yellow oil (27 mg,
80%, CAS: 134-11-2). 1H NMR (400 MHz, CDCl3): δ 10.97 (bs, 1H),
8.18 (dd, J = 7.8, 1.8 Hz, 1H), 7.58−7.54 (m, 1H), 7.15−7.11 (m,
1H), 7.05 (d, J = 8.3 Hz, 1H), 4.34 (q, J = 7.0 Hz, 2H), 1.57 (t, J = 7.0
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 165.6, 157.4, 135.1, 133.7,
122.2, 117.7, 112.6, 66.0, 14.7.
153.1, 144.2, 137.2, 133.7, 132.1, 130.7, 127.7, 126.3, 120.6 (q, JC−F
=
285.3 Hz), 119.3, 117.0, 115.4, 76.6 (p, JC−F = 33.9 Hz). 19F NMR
(376 MHz, CDCl3): δ −72.77. HRMS (positive ESI): calcd for
C15H10ClF6N2O3 [M + H], 415.0284; found, 415.0283.
2-(4,5-Dichloro-2-((hexafluoropropan-2-yl)oxy)benzamido)-
pyridine 1-Oxide (3vl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (10:1) as an eluent (Rf = 0.49) to afford a white solid
(75 mg, 84%, mp 137−138 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 11.26 (s, 1H), 8.60−8.58 (m, 1H), 8.31−
8.29 (m, 1H), 8.20 (s, 1H), 7.40−7.36 (m, 1H), 7.32 (s, 1H), 7.08−
7.05 (m, 1H), 5.17−5.12 (m, 1H). 13C NMR (100 MHz, CDCl3): δ
160.9, 152.9, 144.2, 137.9, 137.3, 133.7, 129.6, 127.7, 124.5, 120.4 (q,
JC−F = 282.6 Hz), 119.4, 117.8, 115.5, 76.7 (p, JC−F = 34.3 Hz). 19F
NMR (376 MHz, CDCl3): δ −72.64. HRMS (positive ESI): calcd for
C15H9Cl2F6N2O3 [M + H], 448.9894; found, 448.9889.
2-(2-((Hexafluoropropan-2-yl)oxy)-4,5-dimethoxybenzamido)-
pyridine 1-Oxide (3wl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (5:1) as an eluent (Rf = 0.32) to afford a white solid
(71 mg, 80%, mp 170−171 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 11.36 (s, 1H), 8.62 (dd, J = 8.5, 1.6 Hz,
1H), 8.31−8.29 (m, 1H), 7.58 (s, 1H), 7.37−7.33 (m, 1H), 7.03−7.00
(m, 1H), 6.62 (s, 1H), 5.04−4.99 (m, 1H), 3.97 (s, 3H), 3.95 (s, 3H).
13C NMR (100 MHz, CDCl3): δ 162.8, 153.5, 149.7, 146.2, 144.7,
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: niujunlong@zzu.edu.cn.
*E-mail: mpsong@zzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
137.3, 127.5, 120.7 (q, JC−F = 283.0 Hz), 118.8, 116.6, 115.2, 113.1,
100.0, 77.7 (p, JC−F = 33.5 Hz), 56.4, 56.3. 19F NMR (376 MHz,
CDCl3): δ −72.67. HRMS (positive ESI): calcd for C17H15F6N2O5
[M + H], 441.0885; found, 441.0886.
We are grateful to the National Natural Science Foundation of
China (Grants 21072177 and 21272217) for financial support
of this work.
2-(2-((Hexafluoropropan-2-yl)oxy)-1-naphthamido)pyridine
1-Oxide (3xl). Purified by analytical TLC on silica gel with CH2Cl2/
acetone (10:1) as an eluent (Rf = 0.47) to afford a white solid (70 mg,
REFERENCES
■
1
(1) For recent reviews, see: (a) Alberico, D.; Scott, M. E.; Lautens,
M. Chem. Rev. 2007, 107, 174. (b) Gevorgyan, V. Chem. Soc. Rev.
2007, 36, 1173. (c) Park, Y. J.; Park, J.-W.; Jun, C.-H. Acc. Chem. Res.
2008, 41, 222. (d) Lewis, L. C.; Bergman, R. G.; Ellman, J. A. Acc.
Chem. Res. 2008, 41, 1013. (e) Yeung, C. S.; Dong, V. M. Chem. Rev.
2011, 111, 1215. (f) Baudoin, O. Chem. Soc. Rev. 2011, 40, 4902.
(g) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236. (h) Bellina, F.; Rossi, R. Chem. Rev.
2010, 110, 1082. (i) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew.
Chem., Int. Ed. 2011, 50, 11062. (j) Cho, S. H.; Kim, J. Y.; Kwak, J.;
Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (k) Bras, J. L.; Muzart, J.
Chem. Rev. 2011, 111, 1170. (l) Yamaguchi, J.; Yamaguchi, A. D.;
Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960. (m) Liu, C.; Zhang,
H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (n) Li, B.-J.; Shi, Z.-J.
Chem. Soc. Rev. 2012, 41, 5588.
81%, mp 106−107 °C from 1:5 hexane/dichloromethane). H NMR
(400 MHz, CDCl3): δ 10.41 (s, 1H), 8.73−8.71 (m, 1H), 8.25−8.23
(m, 1H), 7.98 (d, J = 9.2 Hz, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.87 (d,
J = 8.0 Hz, 1H), 7.59−7.50 (m, 2H), 7.44−7.40 (m, 1H), 7.30 (d, J =
9.1 Hz, 1H), 7.07−7.04 (m, 1H), 5.14−5.08 (m, 1H). 13C NMR (100
MHz, CDCl3): δ 164.5, 150.8, 144.0, 137.3, 132.9, 130.7, 130.5, 128.7,
128.3, 128.1, 126.4, 124.5, 123.2, 120.8 (q, JC−F = 285.1 Hz), 119.3,
115.2, 115.0, 76.6 (p, JC−F = 33.4 Hz). 19F NMR (376 MHz, CDCl3):
δ −73.08. HRMS (positive ESI): calcd for C19H13F6N2O3 [M + H],
431.0830; found, 431.0826.
2-(3-((Hexafluoropropan-2-yl)oxy)thiophene-2-carboxamido)-
pyridine 1-Oxide (3yl). Purified by analytical TLC on silica gel with
CH2Cl2/acetone (6:1) as an eluent (Rf = 0.37) to afford a white solid
(57 mg, 74%, mp 161−162 °C from 1:5 hexane/dichloromethane). 1H
NMR (400 MHz, CDCl3): δ 11.29 (s, 1H), 8.57 (d, J = 7.5 Hz, 1H),
8.31−8.30 (m, 1H), 7.63 (d, J = 5.6 Hz, 1H), 7.35−7.31 (m, 1H),
7.04−7.00 (m, 1H), 6.97 (d, J = 5.6 Hz, 1H), 5.18−5.13 (m, 1H). 13C
(2) For recent reviews, see: (a) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Colby,
J
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624.
(c) McGlacken, G. P.; Bateman, L. M. Chem. Soc. Rev. 2009, 38, 2447.
(3) For selected references, see: (a) John, A.; Nicholas, K. M. J. Org.
Chem. 2011, 76, 4158. (b) Pan, J.; Su, M.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2011, 50, 8647. (c) Wang, H.; Yu, Y.; Hong, X.; Tan,
Q.; Xu, B. J. Org. Chem. 2014, 79, 3279. (d) Xu, H.; Qiao, X.; Yang, S.;
Shen, Z. J. Org. Chem. 2014, 79, 4414.
(4) For selected references, see: (a) Chen, X.; Hao, X.-S.; Goodhue,
C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (b) Xiao, B.; Gong,
T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu, J.; Liu, L. J. Am. Chem. Soc.
2011, 133, 9250. (c) Wei, Y.; Yoshikai, N. Org. Lett. 2011, 13, 5504.
(d) Zhao, J.; Wang, Y.; He, Y.; Liu, L.; Zhu, Q. Org. Lett. 2012, 14,
1078. (e) Zhang, C.; Feng, P.; Jiao, N. J. Am. Chem. Soc. 2013, 135,
15257. (f) Takemura, N.; Kuninobu, Y.; Kanai, M. Org. Lett. 2013, 15,
844. (g) Shan, G.; Yang, X.; Zong, Y.; Rao, Y. Angew. Chem., Int. Ed.
2013, 52, 13606.
(5) For some recent reviews, see: (a) Musaev, D. G.; Figg, T. M.;
Kaledin, A. L. Chem. Soc. Rev. 2014, 43, 5009. (b) Wu, Y.; Wang, J.;
Mao, F.; Kwong, F. Y. Chem.Asian J. 2014, 9, 26. (c) Franzoni, I.;
Mazet, C. Org. Biomol. Chem. 2014, 12, 233.
(6) (a) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651.
(b) Jayakumar, J.; Parthasarathy, K.; Chen, Y.-H.; Lee, T.-H.; Chuang,
S.-C.; Cheng, C.-H. Angew. Chem., Int. Ed. 2014, 53, 9889 and
references therein.
(7) For recent reviews, see: (a) Ackermann, L. Chem. Rev. 2011, 111,
1315. (b) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (c) Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
(8) (a) Kitahara, M.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J.
Am. Chem. Soc. 2011, 133, 2160. (b) Nishino, M.; Hirano, K.; Satoh,
T.; Miura, M. Angew. Chem., Int. Ed. 2013, 52, 4457. (c) Odani, R.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2013, 78, 11045.
(9) For related studies, see: (a) Mao, Z.; Wang, Z.; Xu, Z.; Huang, F.;
Yu, Z.; Wang, R. Org. Lett. 2012, 14, 3854. (b) Fan, S.; Chen, Z.;
Zhang, X. Org. Lett. 2012, 14, 4950. (c) Qin, X.; Feng, B.; Dong, J.; Li,
X.; Xue, Y.; Lan, J.; You, J. J. Org. Chem. 2012, 77, 7677.
(10) Enthaler, S.; Company, A. Chem. Soc. Rev. 2011, 40, 4912.
(11) (a) Altman, R. A.; Shafir, A.; Lichtor, P. A.; Buchwald, S. L. J.
Org. Chem. 2008, 73, 284. (b) Hartwig, J. F. Nature 2008, 455, 314.
(12) For a review of Ullmann-type coupling reactions, see: Monnier,
F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954.
(i) Chen, F.-J.; Zhao, S.; Hu, F.; Chen, K.; Zhang, Q.; Zhang, S.-Q.;
Shi, B.-F. Chem. Sci. 2013, 4, 4187. (j) Gao, T.; Sun, P. J. Org. Chem.
2014, 79, 9888.
(20) (a) Bhadra, S.; Dzik, W. I.; Gooßen, L. J. Angew. Chem., Int. Ed.
2013, 52, 2959. (b) Bhadra, S.; Matheis, C.; Katayev, D.; Gooßen, L. J.
Angew. Chem., Int. Ed. 2013, 52, 9279.
(21) (a) Huffman, L. M.; Casitas, A.; Font, M.; Canta, M.; Costas,
M.; Ribas, X.; Stahl, S. S. Chem.Eur. J. 2011, 17, 10643. (b) King, A.
E.; Huffman, L. M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am.
Chem. Soc. 2010, 132, 12068. (c) Suess, A. M.; Ertem, M. Z.; Cramer,
C. J.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 9797.
(22) Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc.
2005, 127, 13154.
(23) (a) Truong, T.; Klimovica, K.; Daugulis, O. J. Am. Chem. Soc.
2013, 135, 9342. (b) Tran, L. D.; Roane, J.; Daugulis, O. Angew.
Chem., Int. Ed. 2013, 52, 6043. (c) Tran, L. D.; Popov, I.; Daugulis, O.
J. Am. Chem. Soc. 2012, 134, 18237. (d) Roane, J.; Daugulis, O. Org.
Lett. 2013, 15, 5842. (e) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int.
Ed. 2014, 53, 10209.
(24) Shang, R.; Ilies, L.; Matsumoto, A.; Nakamura, E. J. Am. Chem.
Soc. 2013, 135, 6030.
(25) (a) Inoue, S.; Shiota, H.; Fukumoto, Y.; Chatani, N. J. Am.
Chem. Soc. 2009, 131, 6898. (b) Aihara, Y.; Chatani, N. Chem. Sci.
2013, 4, 664. (c) Aihara, Y.; Chatani, N. J. Am. Chem. Soc. 2013, 135,
5308.
(26) (a) He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192.
(b) Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2012, 134, 7313. (c) Zhang, S.-Y.; He, G.; Nack, W.
A.; Zhao, Y.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124.
(d) Li, Q.; Zhang, S.-Y.; He, G.; Ai, Z.; Nack, W. A.; Chen, G. Org.
Lett. 2014, 16, 1764.
(27) (a) Li, X.; Liu, Y.-H.; Gu, W.-J.; Li, B.; Chen, F.-J.; Shi, B.-F. Org.
Lett. 2014, 16, 3904. (b) Dong, J.; Wang, F.; You, J. Org. Lett. 2014,
16, 2884. (c) Wu, X.; Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem., Int.
Ed. 2014, 53, 3706. (d) Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.-
L.; Wu, B. Org. Lett. 2014, 16, 480. (e) Zhang, L.-S.; Chen, G.; Wang,
X.; Guo, Q.-Y.; Zhang, X.-S.; Pan, F.; Chen, K.; Shi, Z.-J. Angew. Chem.,
Int. Ed. 2014, 53, 3899. (f) Rit, R. K.; Yadav, M. R.; Sahoo, A. K. Org.
Lett. 2012, 14, 3724. (g) Rodríguez, N.; Romero-Revilla, J. A.;
́
́ ́
Fernandez-Ibanez, M. A.; Carretero, J. C. Chem. Sci. 2013, 4, 175.
̃
(h) Ye, X.; He, Z.; Ahmed, T.; Weise, K.; Akhmedov, N. G.; Petersen,
J. L.; Shi, X. Chem. Sci. 2013, 4, 3712. (i) Gu, Q.; Al Mamari, H. H.;
Graczyk, K.; Diers, E.; Ackermann, L. Angew. Chem., Int. Ed. 2014, 53,
3868. (j) Huang, L.; Sun, X.; Li, Q.; Qi, C. J. Org. Chem. 2014, 79,
6720.
(13) For a review, see: Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829.
(14) For a book, see: Li, J. J. Name Reactions; Springer: New York,
2014; p 628.
(15) For a review, see: Kumara Swamy, K. C.; Bhuvan Kumar, N. N.;
Balaraman, E.; Pavan Kumar, K. V. P. Chem. Rev. 2009, 109, 2551.
(16) (a) Zou, Y.-Q.; Chen, J.-R.; Liu, X.-P.; Lu, L.-Q.; Davis, R. L.;
Jørgensen, K. A.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51, 784.
(b) Yan, Y.; Feng, P.; Zheng, Q.-Z.; Liang, Y.-F.; Lu, J.-F.; Cui, Y.; Jiao,
N. Angew. Chem., Int. Ed. 2013, 52, 5827. (c) Zhang, Y.-H.; Yu, J.-Q. J.
Am. Chem. Soc. 2009, 131, 14654. (d) Shan, G.; Yang, X.; Ma, L.; Rao,
Y. Angew. Chem., Int. Ed. 2012, 51, 13070. (e) Mo, F.; Trzepkowski, L.
J.; Dong, G. Angew. Chem., Int. Ed. 2012, 51, 13075.
(17) (a) Emmert, M. H.; Cook, A. K.; Xie, Y. J.; Sanford, M. S.
Angew. Chem., Int. Ed. 2011, 50, 9409. (b) Cheng, X.-F.; Li, Y.; Su, Y.-
M.; Yin, F.; Wang, J.-Y.; Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J.
Am. Chem. Soc. 2013, 135, 1236. (c) Wang, W.; Luo, F.; Zhang, S.;
Cheng, J. J. Org. Chem. 2010, 75, 2415.
(28) For a recent review of direct CH functionalization aided by a
bidentate directing group, see: Rouquet, G.; Chatani, N. Angew. Chem.,
Int. Ed. 2013, 52, 11726.
(29) Hao, X.-Q.; Chen, L.-J.; Ren, B.; Li, L.-Y.; Yang, X.-Y.; Gong, J.-
F.; Niu, J.-L.; Song, M.-P. Org. Lett. 2014, 16, 1104.
(30) (a) Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133,
16901. (b) Gamez, P.; Reedijk, I. W. C. E. J.; Sheldon, R. A. Chem.
Commun. 2003, 2414.
(31) (a) Sun, R.; Liu, Y.; Zhang, Y.; Xiong, Li.; Wang, Q. J. Agric.
Food Chem. 2011, 59, 2471. (b) Xu, X. Y.; Qian, X. H.; Li, Z.; Huang,
Q. C. J. Fluorine Chem. 2003, 121, 51.
(32) Mirica, L. M.; Ottenwaelder, X.; Stack, D. P. Chem. Rev. 2004,
104, 1013.
(18) (a) Hoover, J. M.; Ryland, B. L.; Stahl, S. S. J. Am. Chem. Soc.
2013, 135, 2357. (b) Kumpulainen, E. T. T.; Koskinen, A. M. P.
Chem.Eur. J. 2009, 15, 10901. (c) Okada, T.; Awasa, T.; Sugiyama,
Y.; Kirihara, M.; Iwai, T.; Kimura, Y. Synlett 2014, 25, 596.
(19) (a) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc.
2010, 132, 12203. (b) Jiang, T.-S.; Wang, G.-W. J. Org. Chem. 2012,
77, 9504. (c) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (d) Li, W.; Sun, P. J. Org. Chem. 2012, 77, 8362.
(e) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
(f) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476. (g) Wang,
H.; Li, G.; Engle, K. M.; Yu, J.-Q.; Davies, H. M. L. J. Am. Chem. Soc.
2013, 135, 6774. (h) Shi, S.; Kuang, C. J. Org. Chem. 2014, 79, 6105.
(33) (a) Chen, P.; Root, D. E.; Campochiaro, C.; Fujisawa, K.;
Solomon, E. I. J. Am. Chem. Soc. 2003, 125, 466. (b) Klinman, J. P.
Chem. Rev. 1996, 96, 2541. (c) Whittaker, J. W. Chem. Rev. 2003, 103,
2347.
K
dx.doi.org/10.1021/jo502005j | J. Org. Chem. XXXX, XXX, XXX−XXX