Palladium-Catalyzed Directed Halogenation of Bipyridine N-Oxides

Article abstract of DOI:10.1021/acs.joc.7b00444

The palladium-catalyzed directed C-H halogenation of bipyridine N-oxides was investigated. Using NCS or NBS (N-chloro- or N-bromosuccinimide) and 5 mol % Pd(OAc)₂ in chlorobenzene (0.10 molar) at 110 °C, pyridine-directed functionalization took place and 3-chloro- or 3-bromobipyridine N-oxides were obtained in high yields. The reaction is sensitive to steric hindrance by 4- and 6′-substituents. Only in the latter case, where coordination of palladium by the pyridine is hindered, 3′-halogenation directed by the N-oxide function was observed. The halogenated products were deoxygenated by PCl₃ or PBr₃.

Full text of DOI:10.1021/acs.joc.7b00444

Article
pubs.acs.org/joc
Palladium-Catalyzed Directed Halogenation of Bipyridine N‑Oxides
Sina P. Zucker, Friedrich Wossidlo, Manuela Weber, Dieter Lentz, and C. Christoph Tzschucke*
Freie Universitat Berlin, Institut fur Chemie und Biochemie, Takustrasse 3, 14195 Berlin, Germany
̈
̈
S
* Supporting Information
ABSTRACT: The palladium-catalyzed directed C−H halogenation of
bipyridine N-oxides was investigated. Using NCS or NBS (N-chloro- or
N-bromosuccinimide) and 5 mol % Pd(OAc)2 in chlorobenzene (0.10
molar) at 110 °C, pyridine-directed functionalization took place and 3-
chloro- or 3-bromobipyridine N-oxides were obtained in high yields. The
reaction is sensitive to steric hindrance by 4- and 6′-substituents. Only in
the latter case, where coordination of palladium by the pyridine is
hindered, 3′-halogenation directed by the N-oxide function was observed. The halogenated products were deoxygenated by PCl3
or PBr3.
bind as a bidentate chelating ligand and form a stable,
catalytically inactive N,N-chelate complex with the transition
metal. C−H activation would require energetically unfavorable
decomplexation of one of the nitrogen atoms and formation of
a C,N-chelate, a so-called “roll-over” complex (cf. Scheme 1C),
which is usually not feasible under catalytic conditions.17 Only a
few examples of roll-over complexes have been reported with
iridium,18 rhodium,19 platinum,20 gold,21 and palladium22
formed from stoichiometric reactions. As examples for catalytic
directed functionalizations of 2,2′-bipyridines, solely rhodium-
catalyzed C3-alkylations and alkenylations with terminal
olefins,23 and silylacetylenes have been reported.24
Recently, Puddephatt and co-workers reported the synthesis
of bipyridine and phenanthroline N-oxide N,O-chelate
platinum(II) complexes and investigated their reactivity under
stoichiometric conditions.25 While a phenanthroline N-oxide
complex underwent oxidative addition with the N−O bond to
give an N,N-chelate phenanthroline platinum(IV) complex, the
analogous bipyridine N-oxide formed a roll-over C,N-chelate
platinum(II) complex (cf. Scheme 1C). C−H bond activation
requires decoordination of the N-oxide oxygen and rotation of
both aromatic planes, which is not possible with metal-bound
phenanthroline N-oxide due to its rigid structure. Since
bipyridine N-oxide is able to form roll-over complexes, we
envisaged applying them as N-protected surrogates for
bipyridines in directed halogenations. Here, we demonstrate
that bipyridine N-oxides undergo catalytic roll-over C−H bond
activation to give 3-chloro- and 3-bromobipyridine N-oxides in
the presence of NXS (N-halosuccinimide). The halogenated
products were deoxygenated with PX3 (X = Cl, Br) to the
corresponding 3-chloro- and 3-bromobipyridines. Potential
palladium intermediates were isolated, and their reactivity
investigated.
INTRODUCTION
■
Halogenated heterocycles are versatile synthetic intermediates,
however, 3-halo-2,2′-bipyridines have been underutilized,
because they are difficult to access by known methods. Of
the three reported preparations (Scheme 1), two involve the
ortho-directed lithiation of 2,2′-bipyridine under kinetic control
at low temperatures followed by halogenation. Thus,
intercepting lithiated bipyridine with iodine as an electrophile
gave 3-iodo-2,2′-bipyridine in only 11% yield.1 Using similar
conditions, lithiation of 5,5′-bis(trimethylsilyl)bipyridine fol-
lowed by bromination with C2Br4Cl2 occurred in slightly higher
yield of 52% (Scheme 1A).2 A drawback of these reported
procedures for the synthesis of 3-halobipyridines is the use of
lithiation/quenching sequences. In a different approach, 3-
chlorobipyridines were prepared by a palladium-catalyzed
Hiyama cross-coupling of 2-trimethylsilyl-3-chloropyridine
with 2-bromoypyridine (Scheme 1B).3 The coupled product
was obtained in a good yield of 65% considering that the
synthesis of 2,2′-bipyridines by transition-metal catalyzed cross-
coupling reactions are generally complicated,4 because the
product is a good chelating ligand and binds to the catalyst,
which results in catalyst inhibition or deactivation.
We envisaged transition-metal-catalyzed directed functional-
ization reactions, which have been demonstrated for substrates
with numerous directing groups in the ortho-position,5 might be
more efficient for the synthesis of 3-halo-2,2′-bipyridines since
the pyridyl ring is a good directing group. Transition-metal-
catalyzed pyridyl- or, more general, azine-directed halogen-
ations of 2-arylpyridines, benzo[h]quinolines, and related
substrates have been achieved with N-halosuccinimides,6 but
also with main group metal halides,7 copper halides,8 acid
chlorides,9 benzyl chloride,10 1,2-DCE (1,2-dichloroethane),11
or electrochemically with elemental iodine12 or HBr as a
halogen source.13 Typically palladium catalysts,6a,b,9a,c,12−14 but
also copper(II) salts6f,h,7a,b,9b and cobalt,15 gold,16 and rhodium
catalysts,6e,7c,11 catalyze directed halogenation reactions.
However, 2,2′-bipyridines are not suitable for such transition-
metal-catalyzed directed functionalizations, because they can
Received: February 24, 2017
© XXXX American Chemical Society
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Scheme 1. Approaches for Preparation of 3-Halo-2,2′-
Table 1. Optimization of Reaction Conditions
bipyridines
a
entry
solvent(s)
AcOH
remarks
yield (%)
1
2
3
4
120 °C, cond. ref 14a
10
35
37
42
DCE
CH3CN
AcOH/benzene
(1:1)
5
DMA
14
16
0
6
2-butanone
b
7
ethers
c
8
alcohols
0
9
benzene
77
d
10
11
12
13
14
Ac2O
0 (27)
e
toluene
0 (22)
benzotrifluoride
chlorobenzene
chlorobenzene
56
f
77 (22)
f
0 (52)
g
150 °C
(19)
h
15
16
17
chlorobenzene
chlorobenzene
chlorobenzene
w/o catalyst, 150 °C, w/o NBS
w/o catalyst, 110 °C
w/o catalyst, 150 °C, 0.2 equiv of
NBS
0 (>99)
h
0 (>99)
g
0 (20)
h
(80)
h
18
chlorobenzene
w/o catalyst, 150 °C, succinimide
instead of NBS
0 (>99)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
benzene
Pd(OTf)2
65
63
68
62
56
23
69
56
21
23
99
90
80
59
47
benzene
Pd(OBz)2
benzene
Pd(OPiv)2
benzene
PdCl2
benzene
[Pd(OAc)(tBu2PCMe2CH2)]2
[Pd(Br)(tBu2PCMe2CH2)]2
[Pd(OAc)(o-tol2PC6H4CH2)]2
[Pd(Br)(o-tol2PC6H4CH2)]2
0.37 M in 1a
RESULTS AND DISCUSSION
■
benzene
Initially, we tested the conditions previously reported by
Sanford and co-workers for directed halogenations of 2-
phenylpyridines6b,14a and attempted the bromination of
bipyridine N-oxide 1a with NBS in AcOH at 120 °C (Table
1, entry 1). However, with the reported conditions only a low
yield of the desired product 2a was observed. When we
screened different solvents, the reaction in benzene gave the
best yield (entry 9); lower yields were obtained with DCE,
CH3CN, or an AcOH/benzene mixture, DMA, and 2-butanone
(entries 2−6), while ethers and alcohols (entries 7, 8) were not
suitable. The reaction in Ac2O did not lead to the brominated
product 2a, but 6-succinimidylbipyridine 3 was found instead
(entry 10). This product could arise from a Reissert−Henze-
type activation of the N-oxide as N-acetoxybipyridinium acetate
followed by nucleophilic attack of succinimidate (Scheme 2).26
Indeed, control reactions in the absence of a catalyst with either
NBS or succinimide resulted in the same product in 39% and
62% yield, respectively.
Because of the toxicity of benzene and the fact that its
atmospheric boiling point is lower than the reaction temper-
ature, we sought a replacement. Toluene, which is often used as
a substitute for benzene, proved unsuitable, because, instead of
the desired product, only N′-benzylated compound 4 was
obtained (Table 1, entry 11). Probably, NBS halogenated
toluene converted to benzyl bromide,27 which in turn alkylated
the starting material. A control reaction with 1a and benzyl
bromide in CH3CN provided 94% of a substance with
matching spectroscopic properties (Scheme 3). The structural
benzene
benzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
chlorobenzene
0.25 M in 1a
0.06 M in 1a
1.2 equiv of NBS
1.0 equiv of NBS
2.5 mol % Pd(OAc)2
1.0 mol % Pd(OAc)2
a
Determined by 1H NMR vs 1,3,5-trimethoxybenzene as internal
b
c
standard. Ethers = THF, DME, dioxane, MTBE. Alcohols = EtOH,
d
iPrOH, ethylene glycol. Yield of 6-succinimidyl-2,2′-bipyridine (3).
e
f
Yield of N′-oxo-N-benzylbipyridinium bromide (4). Yield of 3-
g
h
bromo-2,2′-bipyridine (5a). 2,2′-Bipyridine. Yield of recovered 1a.
assignment of 4 is further supported by 2D NMR spectroscopy
(COESY, HMBC, and HMQC).
Benzotrifluoride as solvent, which is resistant to radical
reactions, resulted in a 56% yield, somewhat lower than in the
case of benzene (Table 1, entry 12). Finally, chlorobenzene
(entry 13), which in contrast to benzene is not carcinogenic or
mutagenic, was found to be a suitable replacement for benzene
and provided a 77% yield of the desired product 2a besides
22% of deoxygenated product 5a. At 150 °C, deoxygenated
product 5a became the main product in 52% yield together
with 19% of 2,2′-bipyridine, which results from deoxygenation
of the starting material (entry 14). Control experiments
(entries 15−18) in the absence of Pd(OAc)2 showed that
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Scheme 2. Formation of 6-Succinimidylbipyridine 3 with Ac2O
Scheme 3. Formation of N-Benzylbipyridinium Bromide 4
Simple palladium(II) compounds, such as Pd(OTf)2, Pd-
(OBz)2, Pd(OPiv)2, and PdCl2, also catalyzed the directed
halogenation (Table 1, entries 19−22), albeit in lower yields
than Pd(OAc)2. Cyclometalated complexes [Pd(X)-
(tBu2PCMe2CH2)]2 and [Pd(X)(o-tol2PC6H4CH2)]2 (X = Br,
OAc), which are known to be active catalysts in C−H bond
arylations of pyridine N-oxides,28 also formed active catalysts,
possibly by thermal decomposition of the complex under the
reaction conditions, to give the brominated product 2a (entries
23−26). Some other palladium ([(tmeda)PdCl2], [(dppf)-
PdCl2], [(CH3CN)2Pd(BF4)2], [(2,2′-bipyridine)Pd(OAc)2],
Buchwald’s precatalyst G1) and ruthenium complexes (RuCl3·
H2O, [(η6-arene)RuX2] with arene = p-cymene or benzene, and
X = Cl or OAc) either were completely unreactive or produced
NBS and not succinimide is responsible for the deoxygenation.
Bipyridine N-oxide 1a on its own is stable at that temperature
and was recovered quantitatively after 17 h at 150 °C
(entry15).
Table 2. Preparation of Bipyridine N-Oxides 1 by Direct Arylation
a
a
entry
R1
R2
yield of 1 (%)
yield of 6 (%)
b
1
2
3
4
5
6
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1a
1b
1c
1d
1e
1f
44 (lit. 23)
6a
6b
6c
6d
6e
6f
0
c
6-Me
6-CO2Et
6-CF3
6-CN
5-OMe
5-Me
8, 22
−
−
−
−
16
0
b
59 (lit. 10)
49
b
8 (lit. 58)
35
20
c
7
1g
1h
1i
6g
6h
6i
b
8
9
5-CO2Me
72 (lit. 25)
0
5-NO2
13
15
3
c
10
4-OMe
1j
6j
0
b
b
11
12
13
4-Cl
1k
1l
41 (lit. 35)
6k
6l
12 (lit. 8)
b
b
4-CO2Et
67 (lit. 67)
15 (lit. 13)
b
b
4-CF3
1m
1n
1p
1q
1r
87 (lit. 65)
6m
6n
6p
6q
6r
10 (lit. 18)
c
b
b
14
4-CN
27 (lit. 56)
5 (lit. 15)
c
15
H
6′-OMe
6′-Me
6′-CF3
5′-Me
4′-OMe
4′-Me
4′-F
4′-CO2Et
4′-CF3
H
64
41
65
13
44
31
8
13
5
c
16
H
17
18
19
20
H
11
0
H
1s
1t
6s
6t
H
7
H
1u
1v
1w
1x
1y
1z
6u
6v
6w
6x
6y
6z
4
d
21
H
0
22
H
44
15
21
19
11
0
d
23
H
24
25
2-pyrazine N-oxide
2-quinoline N-oxide
0
H
−
a
b
c
Isolated yields. Yields in parentheses reported in ref 28d with Pd(OAc)2/PtBu3 as catalyst and K2CO3 as base. Pd(OAc)2 (5 mol %) and PtBu3 (6
d
mol %) were used. 2-Chloropyridine derivative was used.
C
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a
Scheme 4. Scope of Direct Halogenation of 1 with Substituted N-Oxide Ring
a
b
c
Isolated yields. Obtained as mixture of 1o and 8o. Reaction without Pd(OAc)2. c.m. = complex product mixture.
exclusively deoxygenated starting material in approximately
50% yield. The combination of NXS with stoichiometric
copper(I) chloride or bromide, which has been reported for the
halogenation of phenylpyridine,8c proved to be unreactive and
the starting material was reisolated. We briefly tried other
bromine sources (Br2, Br2 + PhI(OAc)2, LiBr + oxone, KBr +
oxone, CuBr2), but these resulted only in decomposition of the
starting material.
The influence of concentration, equivalents of NBS, and
catalyst loading was tested (Table 1, entries 27−33). Increasing
the concentration of bipyridine N-oxide 1a to more than 0.125
mol/L led to a precipitous drop in the yield (entries 27−29).
This observation is in contrast to the arylation of pyridine N-
oxides, where higher substrate concentrations resulted in higher
yields. Adjusting the amount of NBS to 1.2 equiv led to a 90%
yield of the desired product 2a (entry 30). Lowering the
catalyst loading unsurprisingly resulted in lower yields (entries
32 and 33). No reaction occurred in the absence of Pd(OAc)2,
and the starting material 1a was quantitatively recovered (entry
16).
starting materials, most of which have not been reported before,
by palladium-catalyzed direct arylation of pyridine N-oxides
with 2-bromopyridines.28d,e We used slightly modified con-
ditions (K3PO4 instead of K2CO3, and cyclometalated dimer
[Pd(OAc)(tBu2PCMe2CH2)]2 as the catalyst instead of Pd-
(OAc)2/PtBu3) and obtained bipyridine N-oxides 1 in good to
moderate yields (Table 2). With the exception of the cyano
(1e, 1n) and nitro (1i) substituents, electron-poorer pyridine
N-oxides (1a, 1c, 1d, 1h, 1k, 1l, 1m) were arylated in higher
yields (41−87%) than more electron-rich pyridine N-oxides
(1b, 1f, 1g, 1j, 15−35%). This reactivity trend has been
previously observed and can be explained by the more polarized
C−H undergoing faster C−H bond activation via a concerted
metalation−deprotonation (CMD) mechanism.28a−c
With respect to the substituent at the bromopyridine, the
arylation does not follow an obvious electronic trend. Thus,
arylation with the most electron-rich 4-methoxybromopyridine
gave the same yield as with the most electron-poor 4-
esterbromopyridine (cf. Table 2, entry 19 vs 22). However,
the position of the substituent apparently has a stronger
influence on the yield, since 6-substituted bromopyridines
To examine the substrate scope of the directed halogenation
of bipyridine N-oxides 1, we had to prepare the functionalized
D
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resulted in typically higher yields than the corresponding 4-
substituted derivatives (Table 2, entries 15−17 vs 19−23).
With a number of substituted bipyridine N-oxides 1 in hand,
the scope of the directed halogenation with Pd(OAc)2 as
catalyst in chlorobenzene at 110 °C was tested (Schemes 4 and
5). The directed halogenation occurred exclusively in the 3-
provided 7i in a low yield of 31%. 4-Substituted bipyridine N-
oxides 1j−o were generally unreactive, probably because steric
hindrance by the substituent prevented cyclometalation, except
for 4-cyano bipyridine N-oxide 1n, which was brominated in
37% yield. Here, the linear cyano group is just small enough to
allow C−H activation. With the 4-trifluoromethyl derivative
1m, coupling with succinimide in the 6-position, instead of the
desired C-3 halogenation, occurred and provided 8m in 36%
yield (53% starting material recovered). Similarly, succinimide-
coupled products 8 were observed with 4-nitrobipyridine N-
oxide 1o and 2-pyridylquinoline N-oxide 1z. The structures of
brominated products 2a, 2f, and 2n were confirmed by single
crystal X-ray diffraction.
Scheme 5. Scope of Direct Halogenation of 1 with
a
Substituted Pyridyl Ring
For comparison with the conditions developed by Sanford
and co-workers, we carried out the bromination of 2-
phenylpyridine 9 (Scheme 4). The mono- (10) and
dibrominated product (11) were isolated in 49% and 13%
yield, respectively, which corresponds to the expected mixture if
the rate constant of the first functionalization is approximately
2.3 times larger than that of the second functionalization (for a
derivation of this value, see end of the Experimental Section).
From reaction at 120 °C in CH3CN under otherwise identical
conditions, Sanford and co-workers obtained 63% of
monobrominated product 10,14a which requires that the rate
constant of the first functionalization is at least 4 times larger
than that of the second one.
Substitution of the 6′-position remarkably changed the
regioselectivity of the reaction to give exclusively 3′-
halogenation (Scheme 5, with 1p−r). This observation can
be explained by the steric hindrance imposed by the
substituent, which prevents coordination of the palladium
catalyst to the pyridine moiety and hence prevents activation in
the 3-position. Instead, C−H activation directed by the usually
less coordinating N-oxide takes place, which otherwise cannot
compete with coordination by the more donating pyridine
nitrogen.30 To test this hypothesis we subjected 2-phenyl-
pyridine N-oxide (12) to the catalytic bromination conditions
(Scheme 4). Indeed, only ortho-brominated product 13 was
obtained in 66% yield (besides 10% dibrominated product 14),
which is consistent with N-oxide directed functionalization. In a
control experiment without Pd(OAc)2 no brominated products
were observed.
a
Isolated yields.
Substitutions in the 4′-position (CH3, F, CO2Et, CF3) led to
the expected pyridine-directed halogenation in the 3-position in
high yields (Scheme 5, with 1u−x). However, bromination of
5′-methylbipyridine N-oxide 1s gave only a 7% yield together
with the deoxygenated product 5s in 8% yield. Deoxygenation
of products was observed solely in brominations (cf. 2g, 2z
Scheme 4 and 2r Scheme 5), but not in chlorination reactions.
Although speculatory at this point, this particular result might
be explained by a palladium-catalyzed pyridyl-directed deoxy-
genation (as opposed to uncatalyzed deoxygenation at higher
temperatures; cf. Table 1, entry 17) and subsequent inhibition
by the bipyridine product.
The halogenated products were easily deoxygenated by
treatment with PCl3 or PBr3 (Scheme 6).28d,31 We used PCl3
for the deoxygenations of the chlorinated products and PBr3 for
the brominated products to exclude any conceivable halogen
exchange reactions. Generally, the reductions with PCl3 gave
better yields than the ones with PBr3, and the latter reactions
usually required purification by flash column chromatography,
while reductions with PCl3 mostly provided pure products
directly after extraction. In the case of the halogenated 5-
position of the pyridine N-oxide ring where cyclometalation,
directed by the pyridine ring, is expected. Functionalization of
the 6-position, which might conceivably result from activation
of the polarized C−H bond neighboring the N-oxide in analogy
to the arylations of pyridine N-oxides,28a,d,e,29 was not observed.
Likewise, no functionalization of the 3′-position, by a possible
N-oxide directed C−H bond activation,30 was observed (see
however Scheme 5, with 1p−r). Gratifyingly, N-chlorosuccini-
mide (NCS) was also a suitable halogenating reagent, which in
several cases gave even better yields than NBS, possibly because
of the higher stability of chlorinated compounds compared to
their brominated analogues. The same trend had already been
observed by Sanford and co-workers.6b Substitutions in the 5-
or 6-position (CH3, OCH3, CF3, CO2R) were well tolerated,
and the corresponding halogenation products 2 and 7 were
obtained in high yields. However, the cyano and nitro
substituents were found to be problematic. 6-Cyanobipyridine
N-oxide 1e was brominated in only 17% yield, while
chlorination did not occur. Bromination of 5-nitro derivative
1i resulted in an inseparable complex mixture, and chlorination
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a
Scheme 6. Deoxygenation of Halogenated Bipyridine N-Oxides 2 and 7
a
Isolated yields.
Scheme 7. Syntheses of Putative Catalyst Intermediates
methoxybipyridine N-oxide 2f and 7f, additional halogenation
in the 6-position by an electrophilic aromatic substitution was
observed to give the corresponding dihalogenated bipyridines.
Similarly, additional chlorination in the 4-position occurred
while deoxygenating chlorinated quinoline N-oxide 7z. In an
initial attempt to deoxygenate 3-bromobipyridine N-oxide 2a
using Pd/C (10 mol %), NH4HCO2 in MeOH,28a quantitative
dehalogenation was observed and only bipyridine was
recovered (see Experimental Section). Using the same
conditions, no reaction was observed with chlorinated
bipyridine N-oxide 7a.
Recent mechanistic investigations of the azine-directed
chlorination by Ritter and co-workers support a catalytic
cycle consisting of (i) cyclopalladation of the substrate forming
a dimeric palladium(II) succinimidate-bridged complex, (ii)
rate-determining acetate-assisted bimetallic oxidation, and (iii)
bimetallic reductive elimination.32 To probe the mechanism of
the directed halogenation of bipyridine N-oxides 1, we
F
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independently prepared two cyclometalated putative catalytic
intermediates A and B. Initially, Pd(OAc)2 and 1a form a
monomeric 1:2 complex C, in which the pyridine rings bind
trans to each other (Scheme 7, crystal structure was obtained
for analogous complex with 1l; for crystal structure, see
Supporting Information). Upon heating to 50 °C in the
presence of HOAc, the monomeric complex C is converted to
cyclometalated complex A,33 which has a dimeric structure with
bridging acetate ligands and closely resembles the structures of
the benzo[h]quinoline-derived complexes reported previous-
ly.32b The acetate ligands were easily exchanged in the presence
of succinimide to give analogous dimer B with succinimidate as
the bridging ligand.
Scheme 9. Stoichiometric Reactions of Cyclometalated
Palladium(II) Dimers
a
We performed catalytic reactions using Pd(OAc)2, dimer A,
or dimer B as the catalyst (Scheme 8). After 1 h of reaction
a
1
Yields were determined by H NMR vs 1,3,5-trichlorobenzene as
b
internal standard. Recovered dimer B.
Scheme 8. Mechanistic Investigations under Catalytic
a
Conditions
succinimidate dimer B resulted in a yield of 20%, which
increased to 51% in the presence of added HOAc, and further
increased to 81%, when NBu4OAc was added. These
observations are essentially consistent with the acetate-assisted
bimetallic oxidation outlined in Scheme 10, which was
proposed by Ritter for the directed halogenation of 2-
phenylpyridine and benzo[h]quinoline:32d (i) Coordination
and cyclopalladation of bipyridine N-oxide 1 forms a
succinimidate-bridged dimeric palladium(II) complex B. This
step is probably rate-limiting in the present reaction. (ii)
Acetate-assisted bimetallic oxidation leads to a dimeric
palladium(III) complex, which (iii) undergoes bimetallic
reductive elimination forming the new carbon−halogen bond.
Exchange of the palladium-bound product for a molecule of
starting material finally closes the catalytic cycle.
a
1
Yields are based on the ratio 1a:2a in the crude H NMR.
time, Pd(OAc)2 provided 66% yield of 2a, while acetate dimer
A gave a 93% yield. In contrast, succinimidate dimer B, which
corresponds to the previously reported catalyst resting state in
analogous reactions,32d resulted in only 41% yield, which shows
B itself is not kinetically competent and acetate is required.
Indeed, the yield increased to 95% when 10 mol % of HOAc
was added; however, it decreased to 25% when 10 mol % of
NBu4OAc was added. Obviously, the rate-determining step
either changes or is inhibited in the presence of free acetate
anions, but is accelerated with HOAc. This result is in contrast
to the reports by Ritter and co-workers, who observed that the
directed chlorination of benzo[h]quinoline becomes faster in
both cases, with HOAc and NBu4OAc. They concluded that
the oxidation step is rate-limiting and mediated by acetate. In
the directed bromination of bipyridine N-oxide 1a, the
retardation of the reaction by added acetate might be explained
by a rate-determining cyclopalladation. Conceivably, excess
acetate inhibits the cyclometalation by blocking a free
coordination site at the palladium(II) center, which is required
for the C−H bond cleavage.34 The requirement for a free
coordination site at the palladium(II) center is further
supported by the observation that added pyridine (Scheme
8f), as well as higher substrate concentrations (Table 1, entries
27−29), inhibit the catalytic reaction. The higher yield of 2a,
obtained with added HOAc, might be due to protonation of the
N-oxide oxygen of 1a to prevent N,O-chelate complex
formation and to facilitate the desired C,N coordination mode.
Stoichiometric reactions of dimers A and B with NBS were
performed in the presence of pyridine at 110 °C for 10 min
(Scheme 9).35 Brominated product 2a was obtained in 66%
yield in the reaction with acetate dimer A. The reaction with
CONCLUSION
■
In conclusion, we described the efficient synthesis of 3-bromo-
and 3-chlorobipyridines, which are difficult to access by other
methods, via the palladium-catalyzed directed halogenation of
bipyridine N-oxides followed by deoxygenation of the products
with PX3. The reactivities of isolated dinuclear cyclometalated
complexes are consistent with a Pd(II)/Pd(III) mechanism
previously proposed for related palladium-catalyzed directed
halogenations. Ongoing work on subsequent conversion of the
3-halobipyridines into other functional groups, as well as the
extension of the scope for other directed functionalizations of
bipyridine N-oxides, will be reported in due course.
EXPERIMENTAL SECTION
■
General Experimental Methods. Unless otherwise noted, direct
halogenation reactions were set up in Teflon-lined screw-cap reaction
vials (8 or 20 mL) under an air atmosphere and heated in a preheated
aluminum block placed on a heater with digital temperature control.
The syntheses of bipyridine N-oxide starting materials by palladium-
catalyzed direct arylation are air and moisture sensitive and were
carried out using oven-dried glassware under an argon atmosphere.
The reactions were set up in an argon-filled glovebox and heated under
stirring outside the glovebox in a preheated oil bath. Commercial and
noncommercial pyridine N-oxides, which were prepared by literature
procedures28d and have been described earlier,28d,36 were dried by
azeotropic distillations by means of Dean−Stark distillation from
toluene prior to use. Toluene was dried and distilled over sodium/
benzophenone and degassed using the freeze−pump−thaw technique.
K3PO4 was heat-dried at 300−400 °C under vacuum and stored in the
glovebox. All other solvents and reagents were used as received from
G
DOI: 10.1021/acs.joc.7b00444
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The Journal of Organic Chemistry
Article
Scheme 10. Mechanism of Palladium-Catalyzed Directed Halogenation of Bipyridine N-Oxides 1
commercial suppliers. Cyclometalated catalysts [Pd(tBu2PCMe2CH2)-
OAc]2,28e [Pd(tBu2PCMe2CH2)Br]2,37 Herrmann−Beller catalyst,38
Pd(OTf)2,39 Pd(OBz)2,40 and Pd(OPiv)2,41 were prepared by
reported procedures. Column chromatography was performed on
silica gel (230−400 mesh) and monitored by TLC on silica gel using a
UV lamb (254 nm) to visualize spots. NMR chemical shifts (δ) are
reported in parts per million (ppm) and referenced to residual solvent
HMQC. Mp 140−150 °C; 1H NMR (500 MHz, CDCl3): δ 8.67 (dd, J
= 4.8, 1.7 Hz, 1H, ArH-3′), 8.47 (d, J = 7.9 Hz, 1H, ArH-3), 8.34 (d, J
= 7.9 Hz, 1H, ArH-5), 7.97 (td, J = 7.9, 0.6 Hz, 1H, ArH-4), 7.78 (td, J
= 7.8, 1.8 Hz, 1H, ArH-5′), 7.36−7.26 (m, 2H, ArH-4′, ArH-6′), 2.93
(s, 2H, −CH2−); 13C{1H} NMR (126 MHz, CDCl3): δ 175.8, 156.8,
155.1, 149.3, 145.8, 139.4, 137.1, 124.2, 122.0, 121.7, 121.3, 28.8; IR
(v/cm−1): 1704, 1583, 1558, 1452, 1427, 1381, 1173, 993, 774, 743;
HRMS (ESI-TOF): [M + Na]+ calcd for C14H11N3O2Na 276.0743;
found 276.0757.
1
1
peak (CDCl3: H δ = 7.26 ppm, 13C δ = 77.16 ppm; C6D6: H δ =
1
7.16 ppm, 13C δ = 128.06 ppm; CD2Cl2: H δ = 5.32 ppm, 13C δ =
53.84 ppm; 19F: frequency calibrated log with 1 ppm deviation).
Multiplicities are given as follows: s = singlet, d = doublet, t = triplet, q
= quartet, and m = multiplet. Coupling constants (J) are reported in
hertz (Hz). High resolution mass spectra were recorded on an ESI-
TOF (electrospray ionization-time-of-flight) instrument. IR spectra
were recorded on an FT/IR with a ZnSe optical window. The
absorption bands are given in wave numbers (cm−1). Melting points
(mp) are uncorrected. Elemental analyses for contents of carbon,
nitrogen, and hydrogen are reported in percentage (%).
General Procedure for Optimization of Palladium-Catalyzed
Bromination. A Teflon-lined screw cap vial was charged with
bipyridine N-oxide 1a (0.25 mmol), NBS, catalyst, and solvent. After
stirring at 110 °C for 17 h, the reaction mixtures were cooled to room
temperature, diluted with DCM, and extracted with a 1 M NaOH
solution. The combined organic layers were dried with Na2SO4 and
filtered, and the solvent was removed from the filtrate. The crude
products were redissolved in a stock solution of TMB in CDCl3 and
transferred into an NMR vial. Yields were calculated by integration of
the isolated and fitted signals relative to the aromatic protons of 1,3,5-
trimethoxybenzene.
Independent Syntheses of Observed Side Products. 6-(2,5-
Pyrrolindion-1-yl)-2,2′-bipyridine (3). Bipyridine N-oxide 1a (86.3
mg, 0.50 mmol) and succinimide (74.8 mg, 0.76 mmol) were dissolved
in Ac2O (4.00 mL). The reaction solution was heated at 110 °C for 9 h
before MeOH (4.00 mL) was added. The volatiles were removed in
vacuum, and the crude product was purified by column chromatog-
raphy (SiO2, MeOH in DCM: 3%) providing 3 (82.8 mg, 0.31 mmol,
62%) as a tan solid. Alternatively, the reaction of bipyridine N-oxide 1a
(87.7 mg, 0.51 mmol) and NBS (136.1 mg, 0.77 mmol) in Ac2O (4.00
mL) provided 3 (49.9 mg, 0.20 mmol, 39%) following the same
procedure. The structure was confirmed by COESY, HMBC, and
N′-Benzyl-N-oxo-2,2′-bipyridinium Bromide (4). Reaction of
bipyridine N-oxide 1a (173 mg, 1.00 mmol) and benzyl bromide
(0.13 mL, 1.09 mmol) in MeCN (1.00 mL) at 60° for 4 h provided 4
(325 mg, 0.95 mmol, 94%) as a tan oil after removal of the solvent,
washing the residue with Et2O and drying in vacuum. Structure was
1
confirmed by COESY, HMBC, and HMQC. H NMR (500 MHz,
CDCl3): δ 9.35 (d, J = 5.2 Hz, 1H, ArH-3′), 8.67 (t, J = 7.7 Hz, 1H,
ArH-5′), 8.34 (d, J = 6.4 Hz, 1H, ArH-3), 8.15 (t, J = 6.8 Hz, 1H, ArH-
4′), 8.06 (d, J = 7.4 Hz, 1H, ArH-6′), 7.97 (d, J = 6.9 Hz, 1H, ArH-6),
7.56 (t, J = 7.1 Hz, 1H, ArH-4), 7.42 (t, J = 7.8 Hz, 1H, ArH-5), 7.32−
7.23 (m, 5H, Ph-H), 5.97 (d, J = 14.5 Hz, 1H, −CH2−), 5.92 (d, J =
14.7 Hz, 1H, −CH2−); 13C{1H} NMR (126 MHz, CDCl3): δ 146.9
(C-2′), 146.8 (C-5′), 146.6 (C-3′), 141.0 (C-2), 139.8 (C-3), 131.6
(C-6′), 131.5 (C-1″), 130.6 (C-6), 130.1 (C-4″), 129.7 (C-3″, C-5″),
129.6 (C-2″, C-6″), 129.0 (C-4′), 129.0 (C-4), 127.0 (C-5), 62.9
(−CH2−); IR (v/cm−1): 3390, 3044, 1621, 1480, 1455, 1422, 1244,
1154, 1031, 847, 771, 745, 725, 696; HRMS (ESI-TOF) m/z: [M −
Br]+ calcd for C17H15N2O 263.1179; found 263.1181.
General Procedure for Synthesis of Bipyridine N-Oxides.
Based on a reported procedure,28d an oven-dried Schlenk flask was
charged with pyridine N-oxide (2.0 equiv), 2-bromopyridine derivative
(1.0 equiv), K3PO4 (2.0 equiv), cyclometalated palladium complex
[Pd(tBu2PCMe2CH2)OAc]2 (2.5 mol %) or Pd(OAc)2 (5 mol %) and
PtBu3 (6 mol %), and toluene (c = 1.0 M) inside the glovebox. The
flask was brought outside the glovebox and placed in a preheated oil
bath. After stirring at 120 °C for 24−48 h, the reaction mixture was
cooled to room temperature and directly subjected to column
chromatography (MeOH in DCM mixtures: 0−10%, 1% increments;
or acetone in hexane mixtures: 0−100%, 10% increments).
2,2′-Bipyridine N-Oxide (1a). (150 mg, 44% for 2.0 mmol scale
using [Pd(tBu2PCMe2CH2)OAc]2, MeOH/DCM mixtures); 1H NMR
H
DOI: 10.1021/acs.joc.7b00444
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The Journal of Organic Chemistry
Article
(400 MHz, CDCl3): δ 8.89 (d, J = 8.1 Hz, 1H), 8.71 (ddt, J = 4.8, 1.7,
0.8 Hz, 1H), 8.30 (ddt, J = 6.5, 1.3, 0.6 Hz, 1H), 8.17 (dd, J = 8.0, 2.2
Hz, 1H), 7.82 (dddd, J = 8.3, 7.7, 1.8, 0.7 Hz, 1H), 7.40−7.29 (m,
2H), 7.30−7.21 (m, 1H). The chemical shifts are in agreement with
previous reports.28d,42 Alternatively, 1a can be prepared by N-oxidation
of 2,2′-bipyridine with H2O2 in TFA,42 or with mCPBA.31
7.27 (ddd, J = 7.7, 4.9, 1.3 Hz, 1H), 7.14 (ddd, J = 8.3, 1.7, 0.8 Hz,
1H), 2.29 (d, J = 0.8 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ
149.8, 149.3, 144.7, 140.4, 136.3, 136.1, 127.3, 127.2, 125.4, 124.0,
18.1; IR (v/cm−1): 1377, 1272, 1208, 825, 783, 742; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H11N2O 187.0866; found
187.0888, [M + Na]+ calcd for C11H10N2ONa 209.0685; found
209.0712, [M + K]+ calcd for C11H10N2OK 225.0425; found 225.0602.
5-Methoxycarbonyl-2,2′-bipyridine N-Oxide (1h). (8.14 g, 72% for
49 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2, acetone/hexane
6-Methyl-2,2′-bipyridine N-Oxide (1b). (711 mg, 8% for 50 mmol
scale using [Pd(tBu2PCMe2CH2)OAc]2, 1.02 g, 22% for 25 mmol scale
using Pd(OAc)2/PtBu3, acetone/hexane mixtures); 1H NMR (400
MHz, CDCl3): δ 8.80 (dt, J = 8.1, 1.1 Hz, 1H), 8.71 (ddd, J = 4.8, 1.8,
0.9 Hz, 1H), 7.98 (dd, J = 7.6, 2.7 Hz, 1H), 7.80 (td, J = 7.8, 1.9 Hz,
1H), 7.32 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.30−7.23 (m, 2H), 2.58 (s,
3H). The chemical shifts are in agreement with previous reports.43
6-Ethoxycarbonyl-2,2′-bipyridine N-Oxide (1c). (5.48 g, 59% for
38 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2, acetone/hexane
1
mixtures); H NMR (400 MHz, CDCl3): δ 9.00 (dt, J = 8.1, 1.1 Hz,
1H), 8.90 (dd, J = 1.6, 0.6 Hz, 1H), 8.75 (ddd, J = 4.8, 1.8, 0.9 Hz,
1H), 8.33 (dd, J = 8.4, 0.6 Hz, 1H), 7.91 (dd, J = 8.4, 1.6 Hz, 1H), 7.86
(ddd, J = 8.1, 7.6, 1.9 Hz, 1H), 7.40 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H),
3.99 (s, 3H). The chemical shifts are in agreement with previous
reports.28d
1
mixtures); H NMR (400 MHz, CDCl3): δ 8.93 (dt, J = 8.1, 1.1 Hz,
5-Nitro-2,2′-bipyridine N-Oxide (1i). Yellow solid (209 mg, 13% for
7.3 mmol scale besides 6i using [Pd(tBu2PCMe2CH2)OAc]2, acetone/
1H), 8.72 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.28 (dd, J = 8.1, 2.2 Hz,
1H), 7.81 (ddd, J = 8.1, 7.6, 1.9 Hz, 1H), 7.48 (dd, J = 7.7, 2.2 Hz,
1H), 7.38 (t, J = 7.9 Hz, 1H), 7.35 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 4.49
(q, J = 7.1 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). The chemical shifts are in
agreement with previous reports.28d
1
hexane mixtures); mp 154 °C; H NMR (500 MHz, CDCl3): δ 9.10
(d, J = 2.2 Hz, 1H), 9.01 (dt, J = 7.9, 1.0 Hz, 1H), 8.75 (dt, J = 4.8, 1.3
Hz, 1H), 8.48 (d, J = 9.0 Hz, 1H), 8.04 (dd, J = 9.0, 2.1 Hz, 1H), 7.86
(td, J = 7.8, 1.8 Hz, 1H), 7.41 (ddd, J = 7.5, 4.7, 1.2 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 151.9, 149.9, 147.8, 145.6, 137.3, 136.7,
128.0, 125.8, 125.6, 119.2; IR (v/cm−1): 1510, 1352, 1268, 820, 784,
736; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H8N3O3
218.0560; found 218.0576, [M + Na]+ calcd for C10H7N3O3Na
240.0380; found 240.0404, [M + K]+ calcd for C10H7N3O3K
256.0119; found 256.0128.
6-Trifluoromethyl-2,2′-bipyridine N-Oxide (1d). Yellow oil (518
mg, 49% for 4.4 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2,
acetone/hexane mixtures); 1H NMR (400 MHz, CDCl3): δ 8.85 (ddt,
J = 8.1, 2.1, 1.1 Hz, 1H), 8.69 (dtd, J = 4.7, 1.9, 0.9 Hz, 1H), 8.37 (dt, J
= 8.2, 2.1 Hz, 1H), 7.78 (ddt, J = 8.1, 7.5, 1.8 Hz, 1H), 7.69 (dt, J =
7.9, 1.9 Hz, 1H), 7.39 (tdd, J = 8.0, 1.7, 0.8 Hz, 1H), 7.33 (dddd, J =
7.7, 4.7, 1.8, 1.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 149.6,
148.4, 139.5 (q, J = 32.7 Hz), 136.3, 130.8, 125.7, 124.9, 124.7 (q, J =
4.1 Hz), 124.2, 120.2 (q, J = 272.1 Hz); 19F NMR (376 MHz, CDCl3):
δ − 68.6;
5′-Nitro-2,2′:6,2″-terpyridine N-Oxide (6i). Yellow oil (28.6 mg,
1
3%); H NMR (500 MHz, CDCl3): δ 8.87 (dt, J = 8.0, 1.0 Hz, 1H),
8.77 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.71 (d, J = 5.0 Hz, 1H), 8.44 (d, J
= 8.9 Hz, 1H), 7.98−7.87 (m, 3H), 7.81 (td, J = 7.8, 1.8 Hz, 1H),
7.43−7.39 (m, 2H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.2,
149.8, 148.4, 148.3, 136.5, 128.04, 128.00, 127.1, 126.2, 125.9, 125.7,
125.4, 124.7, 120.1; IR (v/cm−1): 1540, 1352, 796, 756; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C15H11N4O3 295.0826; found
295.0823, [M + Na]+ calcd for C15H10N4O3Na 317.0645; found
317.0642.
4-Methoxy-2,2′-bipyridine N-Oxide (1j). (1.46 g, 15% for 50 mmol
scale using Pd(OAc)2/PtBu3, MeOH/DCM mixtures); 1H NMR (400
MHz, CDCl3): δ 8.97 (dq, J = 8.1, 1.2 Hz, 1H), 8.68 (ddd, J = 4.8, 1.9,
1.0 Hz, 1H), 8.19 (dd, J = 7.3, 1.0 Hz, 1H), 7.80 (ddt, J = 8.1, 7.5, 1.5
Hz, 1H), 7.69 (dd, J = 3.6, 1.2 Hz, 1H), 7.33 (ddt, J = 7.3, 4.8, 1.2 Hz,
1H), 6.82 (ddd, J = 7.2, 3.6, 1.1 Hz, 1H), 3.90 (s, 3H). The chemical
shifts are in agreement with previous reports.31 Alternatively, 1j can be
prepared by a two-step sequence from 1a. First nitration with KNO3/
H2SO4 to give 4-nitro-2,2′-bipyridine N-oxide (1o), followed by
methoxylation with NaOMe in MeOH.31
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H8F3N2O
241.0583; found 241.0597, [M + Na]+ calcd for C11H7F3N2ONa
263.0403; found 263.0442.
6-Cyano-2,2′-bipyridine N-Oxide (1e). (640 mg, 8% for 40 mmol
scale using [Pd(tBu2PCMe2CH2)OAc]2, acetone/hexane mixtures);
1H NMR (400 MHz, CDCl3): δ 8.91 (dt, J = 8.1, 1.1 Hz, 1H), 8.73
(ddt, J = 4.8, 2.1, 1.0 Hz, 1H), 8.49 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.86
(td, J = 8.1, 1.8 Hz, 1H), 7.69 (ddd, J = 7.8, 2.1, 0.8 Hz, 1H), 7.46−
7.36 (m, 2H). The chemical shifts are in agreement with previous
reports.28d
5-Methoxy-2,2′-bipyridine N-Oxide (1f). Brown solid (1.42 g, 35%
for 20 mmol scale besides 6f using [Pd(tBu2PCMe2CH2)OAc]2,
acetone/hexane mixtures); mp 67 °C; 1H NMR (500 MHz, CDCl3): δ
8.81 (dt, J = 8.2, 1.1 Hz, 1H), 8.65 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 8.07
(d, J = 9.1 Hz, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.76 (td, J = 7.8, 1.9 Hz,
1H), 7.26 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H), 6.97 (dd, J = 9.1, 2.4 Hz,
1H), 3.85 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 157.4, 149.7,
149.3, 141.1, 136.3, 127.9, 127.6, 125.2, 123.8, 114.1, 56.3; IR (v/
cm−1): 1514, 1462, 1440, 1388, 1312, 1292, 1206, 776; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H11N2O2 203.0815; found
203.0841, [M + Na]+ C11H10N2O2Na 225.0634; found 225.0666, [M
+ K]+ calcd for C11H10N2O2K 241.0374; found 241.0401.
5′-Methoxy-2,2′:6,2″-terpyridine N-Oxide (6f). Brown solid (459
mg, 16%); mp 143 °C; 1H NMR (500 MHz, CDCl3): δ 8.83−8.77 (m,
2H), 8.67 (d, J = 3.9 Hz, 1H), 8.23 (d, J = 9.1 Hz, 1H), 7.83 (td, J =
7.7, 1.8 Hz, 1H), 7.71 (td, J = 7.8, 1.9 Hz, 1H), 7.51 (dt, J = 7.8, 1.1
Hz, 1H), 7.35 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H), 7.30−7.21 (m, 1H), 7.11
(d, J = 9.2 Hz, 1H), 3.83 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3):
δ 156.0, 150.2, 150.0, 149.2, 141.6, 141.5, 136.6, 136.1, 127.1, 126.2,
125.5, 123.7, 123.6, 120.7, 109.9, 56.7; IR (v/cm−1): 1425, 1360, 1082,
779, 745; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C16H14N3O2
280.1081; found 280.1089, [M + Na]+ calcd for C16H13N3O2Na
302.0900; found 302.0912, [M + K]+ calcd for C16H13N3O2K
318.0639; found 318.0661.
4-Chloro-2,2′-bipyridine N-Oxide (1k). (1.27 g, 41% for 15 mmol
scale besides 6k using [Pd(tBu2PCMe2CH2)OAc]2, acetone/hexane
1
mixtures); H NMR (400 MHz, CDCl3): δ 8.96 (dt, J = 8.1, 1.1 Hz,
1H), 8.72 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.26 (d, J = 3.1 Hz, 1H), 8.22
(d, J = 7.0 Hz, 1H), 7.84 (td, J = 7.8, 1.8 Hz, 1H), 7.37 (ddd, J = 7.6,
4.8, 1.2 Hz, 1H), 7.23 (dd, J = 7.0, 3.1 Hz, 1H). The chemical shifts are
in agreement with previous reports.28d
1
4′-Chloro-2,2′:6,2″-terpyridine N-Oxide (6k). (246 mg, 12%); H
NMR (400 MHz, CDCl3): δ 8.77−8.74 (m, 4H), 8.13 (s, 2H), 7.84
(td, J = 7.9, 1.6 Hz, 2H), 7.39 (ddd, J = 7.6, 4.6, 1.3 Hz, 2H). The
chemical shifts are in agreement with previous reports.28d
4-Ethoxycarbonyl-2,2′-bipyridine N-Oxide (1l). (326 mg, 67% for
2.0 mmol scale besides 6l using [Pd(tBu2PCMe2CH2)OAc]2, acetone/
1
hexane mixtures); H NMR (400 MHz, CDCl3): δ 8.82 (dd, J = 8.1,
1.0 Hz, 1H), 8.82−8.73 (m, 2H), 8.35 (d, J = 6.8 Hz, 1H), 7.92−7.79
(m, 2H), 7.38 (ddt, J = 7.0, 4.8, 1.1 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H),
1.42 (t, J = 7.1 Hz, 3H). The chemical shifts are in agreement with
previous reports.28d
5-Methyl-2,2′-bipyridine N-Oxide (1g). Off-white solid (1.85 g,
4′-Ethoxycarbonyl-2,2′:6,2″-terpyridine N-Oxide (6l). (47.0 mg,
15%); 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 4.8 Hz, 2H), 8.62
(s, 2H), 8.58 (d, J = 8.1 Hz, 2H), 7.80 (td, J = 7.7, 1.5 Hz, 2H), 7.35
(dd, J = 7.5, 4.8, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz,
3H). The chemical shifts are in agreement with previous reports.28d
20% for 50 mmol scale using Pd(OAc)2/PtBu3, acetone/hexane
1
mixtures); mp 65 °C; H NMR (500 MHz, CDCl3): δ 8.84 (dt, J =
8.1, 1.1 Hz, 1H), 8.66 (ddd, J = 4.8, 1.9, 1.0 Hz, 1H), 8.13 (dt, J = 1.7,
0.8 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.76 (td, J = 7.8, 1.9 Hz, 1H),
I
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
4-Trifluoromethyl-2,2′-bipyridine N-Oxide (1m). (420 mg, 87% for
2.0 mmol scale besides 6m using [Pd(tBu2PCMe2CH2)OAc]2,
acetone/hexane mixtures); 1H NMR (400 MHz, CDCl3): δ 8.90
(dt, J = 8.1, 1.0 Hz, 1H), 8.73 (ddd, J = 4.7, 1.7, 0.8 Hz, 1H), 8.52 (d, J
= 2.7 Hz, 1H), 8.35 (d, J = 6.9 Hz, 1H), 7.83 (td, J = 7.8, 1.8 Hz, 1H),
7.44 (dd, J = 6.8, 2.8 Hz, 1H), 7.37 (ddd, J = 7.6, 4.7, 1.1 Hz, 1H). The
chemical shifts are in agreement with previous reports.28d
J = 7.1, 2.2, 0.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 150.1,
148.0 (q, J = 35.2 Hz), 146.1, 140.9, 138.0, 128.3, 128.1, 126.1, 126.0,
121.5 (q, J = 274.3 Hz), 120.8 (q, J = 2.7 Hz); 19F NMR (376 MHz,
CDCl3): δ −68.0; HRMS (ESI-TOF) m/z: [M + Na]+ calcd for
C11H7F3N2ONa 263.0403; found 263.0426.
6,6″-Bis(trifluoromethyl)-2,2′:6′,2″-terpyridine N-Oxide (6r). Pale
1
yellow solid (111 mg, 11%); mp 188−190 °C; H NMR (400 MHz,
4′-Trifluoromethyl-2,2′:6,2″-terpyridine N-Oxide (6m). (32.0 mg,
10%); 1H NMR (400 MHz, CDCl3): δ 8.77 (dd, J = 4.8, 0.9 Hz, 2H),
8.72 (d, J = 8.0 Hz, 2H), 8.38 (s, 2H), 7.85 (td, J = 7.8, 1.8 Hz, 2H),
7.40 (ddd, J = 7.6, 4.8, 1.2 Hz, 2H). The chemical shifts are in
agreement with previous reports.28d
CDCl3): δ 8.97 (d, J = 8.1 Hz, 2H), 8.23 (d, J = 8.0 Hz, 2H), 8.01 (t, J
= 7.9 Hz, 2H), 7.75 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3): δ 150.7, 148.1 (q, J = 35.1 Hz),
147.1, 137.7, 128.9, 128.3, 126.0, 121.5 (q, J = 274.4 Hz), 120.8 (q, J =
2.8 Hz); 19F NMR (376 MHz, CDCl3): δ −67.9; IR (v/cm−1): 1338,
1239, 1212, 1173, 1111, 1059, 790, 743, 668 (m); HRMS (ESI-TOF)
m/z: [M + H]+ C17H10F6N3O 386.0723; found 386.0719, [M + Na]+
calcd for C17H9F6N3ONa 408.0542; found 408.0547, [M + K]+ calcd
for C17H9F6N3OK 424.0281; found 424.0274.
5′-Methyl-2,2′-bipyridine N-Oxide (1s). Brown solid (438 mg, 13%
for 17 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2, MeOH/DCM
mixtures); mp 44−45 °C; 1H NMR (500 MHz, CDCl3): δ 8.78 (d, J =
8.2 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.27 (dd, J = 6.5, 0.8 Hz, 1H),
8.14 (dd, J = 8.1, 2.1 Hz, 1H), 7.61 (ddd, J = 8.2, 2.3, 0.7 Hz, 1H), 7.32
(td, J = 7.8, 1.2 Hz, 1H), 7.22 (ddd, J = 7.4, 6.6, 2.2 Hz, 1H), 2.37 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.0, 147.5, 147.0, 140.8,
136.8, 134.4, 127.7, 125.8, 125.0, 18.5; IR (v/cm−1): 1466, 1424, 1246,
1226, 1026, 846, 767, 716; HRMS (ESI-TOF) m/z: [M + H]+ cald for
C11H11N2O 187.0866; found 187.0873, [M + Na]+ cald for
C11H10N2ONa 209.0691; found 209.0685.
4-Cyano-2,2′-bipyridine N-Oxide (1n). (2.62 g, 27% for 50 mmol
scale besides 6n using Pd(OAc)2/PtBu3, acetone/hexane mixtures);
1H NMR (400 MHz, CDCl3): δ 8.88 (dt, J = 8.1, 1.1 Hz, 1H), 8.76
(ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.61 (dd, J = 2.6, 0.6 Hz, 1H), 8.32 (dd,
J = 6.8, 0.6 Hz, 1H), 7.87 (ddd, J = 8.2, 7.6, 1.8 Hz, 1H), 7.47 (dd, J =
6.9, 2.6 Hz, 1H), 7.42 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H). The chemical
shifts are in agreement with previous reports.28d
1
4′-Cyano-2,2′:6,2″-terpyridine N-Oxide (6n). (310 mg, 5%); H
NMR (400 MHz, CDCl3): δ 8.78 (ddd, J = 4.8, 1.8, 1.0 Hz, 2H), 8.70
(dt, J = 8.1, 1.1 Hz, 2H), 8.42 (s, 2H), 7.86 (td, J = 7.8, 1.8 Hz, 2H),
7.42 (ddd, J = 7.6, 4.8, 1.2 Hz, 2H). The chemical shifts are in
agreement with previous reports.28d
6′-Methoxy-2,2′-bipyridine N-Oxide (1p). Colorless solid (3.05 g,
64% for 23 mmol scale besides 6p using Pd(OAc)2/PtBu3, MeOH/
1
DCM mixtures; mp 90−91 °C; H NMR (400 MHz, CDCl3): δ 8.76
(dd, J = 7.6, 0.8 Hz, 1H), 8.35 (dd, J = 8.1, 2.2 Hz, 1H), 8.31 (dt, J =
6.5, 1.1 Hz, 1H), 7.72 (ddd, J = 8.3, 7.5, 0.8 Hz, 1H), 7.35 (ddt, J = 8.0,
7.3, 1.4 Hz, 1H), 7.23 (dddd, J = 7.5, 6.5, 2.3, 1.1 Hz, 1H), 6.83 (dt, J =
8.3, 0.8 Hz, 1H), 3.99 (d, J = 0.8 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3): δ 163.3, 147.2 146.1, 141.2, 139.4, 127.7, 125.6, 124.8, 118.9,
112.5, 53.5: IR (v/cm−1): 1583, 1576, 1466, 1424, 1396, 1335, 1263,
1229, 1208, 1154, 1017, 828, 805, 770, 740; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C11H11N2O2 203.0815; found 203.0803, [M +
Na]+ C11H10N2O2Na 225.0634; found 225.0647.
4′-Methoxy-2,2′-bipyridine N-Oxide (1t). Brown solid (573 mg,
44% for 5.0 mmol scale besides 6t using [Pd(tBu2PCMe2CH2)OAc]2,
acetone/hexane mixtures); mp 64 °C, 1H NMR (500 MHz, CDCl3): δ
8.55 (d, J = 2.6 Hz, 1H), 8.47 (d, J = 5.7 Hz, 1H), 8.26 (ddd, J = 6.5,
1.3, 0.6 Hz, 1H), 8.17 (dd, J = 8.0, 2.2 Hz, 1H), 7.32 (ddd, J = 8.1, 7.5,
1.3 Hz, 1H), 7.23 (ddd, J = 7.5, 6.5, 2.2 Hz, 1H), 6.83 (dd, J = 5.7, 2.6
Hz, 1H), 3.87 (s, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.9,
151.1, 150.3, 147.3, 140.8, 128.1, 125.8, 125.3, 111.22, 111.16, 55.4; IR
(v/cm−1): 1585, 1565, 1467, 1442, 1405, 1311, 1273, 1241, 1025, 866,
827, 766, 731; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H11N2O2 203.0815; found 203.0841, [M + Na]+ C11H10N2O2Na
225.0634; found 225.0666.
4,4″-Dimethoxy-2,2′:6′,2″-terpyridine N-Oxide (6t). Brown solid
(52.8 mg, 7%); mp 167 °C; 1H NMR (500 MHz, CDCl3): δ 8.51 (d, J
= 5.7 Hz, 2H), 8.27 (d, J = 2.5 Hz, 2H), 8.04 (d, J = 7.9 Hz, 2H), 7.42
(t, J = 7.9 Hz, 1H), 6.86 (dd, J = 5.7, 2.5 Hz, 2H), 3.87 (s, 6H);
13C{1H} NMR (126 MHz, CDCl3): δ 165.8, 152.1, 150.4, 148.3,
127.9, 125.5, 111.3, 55.5; IR (v/cm−1): 2923, 1584, 1561, 1461, 1373,
1292, 1239, 1030, 852, 811; HRMS (ESI-TOF) m/z: calcd for
C17H16N3O3 310.1186; found 310.1185, [M + Na]+ calcd for
C17H15N3O3Na 332.1006; found 332.1005, [M + K]+ C17H15N3O3K
348.0745; found 348.0741.
6,6″-Dimethoxy-2,2′:6′,2″-terpyridine N-Oxide (6p). Colorless
1
solid (482 mg, 13%); mp 141 °C; H NMR (400 MHz, CDCl3): δ
8.53 (dt, J = 7.6, 0.8 Hz, 2H), 8.19 (dd, J = 8.0, 0.7 Hz, 2H), 7.71 (ddd,
J = 8.3, 7.5, 0.7 Hz, 2H), 7.44 (td, J = 8.0, 0.7 Hz, 1H), 6.83 (dt, J =
8.3, 0.8 Hz, 2H), 4.01 (d, J = 0.7 Hz, 6H); 13C{1H} NMR (101 MHz,
CDCl3): δ 163.5, 148.3, 147.2, 139.1, 127.2, 125.0, 119.0, 111.9, 53.5;
IR (v/cm−1): 1577, 1459, 1422, 1407, 1256, 1237, 1020, 778, 729 (s);
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C17H16N3O3 310.1186;
found 310.1169, [M + Na]+ calcd for C17H15N3O3Na 332.1006; found
332.1037, [M + K]+ C17H15N3O3K 348.0745; found 348.0723.
6′-Methyl-2,2′-bipyridine N-Oxide (1q). Reddish oil (1.90 g, 41%
for 25 mmol scale besides 6q using Pd(OAc)2/PtBu3, MeOH/DCM
1
mixtures); H NMR (400 MHz, CDCl3): δ 8.65 (dt, J = 7.9, 0.8 Hz,
1H), 8.30 (ddd, J = 6.5, 1.2, 0.6 Hz, 1H), 8.17 (dd, J = 8.0, 2.2 Hz,
1H), 7.71 (t, J = 7.8 Hz, 1H), 7.35 (ddd, J = 8.1, 7.5, 1.3 Hz, 1H),
7.27−7.22 (m, 1H), 7.20 (ddd, J = 7.8, 1.1, 0.6 Hz, 1H), 2.61 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 158.3, 149.0, 147.8, 140.8,
136.6, 128.1, 125.8, 125.1, 124.0, 122.6, 24.7; IR (v/cm−1): 1584,
1572, 1453, 1424, 1247, 1221, 880, 825, 800, 764; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C11H11N2O 187.0866; found 187.0885.
6,6″-Dimethyl-2,2′:6′,2″-terpyridine N-Oxide (6q). Tan solid (176
mg, 5%); mp 151−155 °C; 1H NMR (400 MHz, CDCl3): δ 8.44 (ddd,
J = 7.9, 1.1, 0.6 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.69 (t, J = 7.8 Hz,
1H), 7.44 (t, J = 7.9 Hz, 1H), 7.21 (ddd, J = 7.6, 1.1, 0.5 Hz, 1H), 2.64
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 158.3, 150.0, 148.6,
136.4, 127.7, 125.6, 123.8, 122.9, 24.7; IR (v/cm−1): 1584, 1573, 1446,
1369, 1242, 1218, 810, 772, 733; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C17H16N3O 278.1288; found 278.1303.
4′-Methyl-2,2′-bipyridine N-Oxide (1u). Brown solid (1.46 g, 31%
for 25 mmol scale besides 6u using [Pd(tBu2PCMe2CH2)OAc]2,
acetone/hexane mixtures); mp 72 °C; 1H NMR (500 MHz, CDCl3): δ
8.66 (s, 1H), 8.53 (dd, J = 4.9, 1.2 Hz, 1H), 8.27 (dt, J = 6.4, 1.4 Hz,
1H), 8.09 (dt, J = 8.1, 1.7 Hz, 1H), 7.31 (tt, J = 7.8, 1.3 Hz, 1H), 7.22
(ddt, J = 6.6, 4.4, 1.3 Hz, 1H), 7.12 (d, J = 4.0 Hz, 1H), 2.39 (s, 3H);
13C{1H} NMR (126 MHz, CDCl3): δ 149.5, 149.2, 147.5, 140.7,
128.0, 126.3, 125.8, 125.3, 125.2, 21.3; IR (v/cm−1): 1613, 1597, 1429,
1249, 1184, 876, 835, 754, 722; HRMS (ESI-TOF) m/z: [M + H]+
cald for C11H11N2O 187.0866; found 187.0881, [M + Na]+ calcd for
C11H10N2ONa 209.0691; found 209.0703, [M + K]+ cald for
C11H10N2OK 225.0425; found 225.0437.
4,4″-Dimethyl-2,2′:6′,2″-terpyridine N-Oxide (6u). Off-white solid
(135 mg, 4%); mp 135 °C; 1H NMR (500 MHz, CDCl3): δ 8.57 (dd, J
= 5.0, 0.8 Hz, 2H), 8.48 (dt, J = 1.7, 0.8 Hz, 2H), 7.99 (d, J = 7.9 Hz,
2H), 7.42 (t, J = 7.9 Hz, 1H), 7.14 (ddt, J = 4.4, 1.7, 0.8 Hz, 2H), 2.39
(t, J = 0.7 Hz, 6H); 13C{1H} NMR (126 MHz, CDCl3): δ 150.4,
149.3, 148.4, 147.3, 127.7, 126.5, 125.6, 125.1, 21.3; IR (v/cm−1):
1592, 1366, 1248, 863, 829, 796, 761; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C17H16N3O 278.1288; found 278.1273, [M + Na]+ calcd
6′-Trifluoromethyl-2,2′-bipyridine N-Oxide (1r). Pale yellow solid
(838 mg, 65% for 5.4 mmol scale besides 6r using [Pd-
1
(tBu2PCMe2CH2)OAc]2, acetone/hexane mixtures); H NMR (400
MHz, CDCl3): δ 9.18 (dt, J = 8.2, 0.8 Hz, 1H), 8.30 (ddd, J = 6.4, 1.3,
0.6 Hz, 2H), 8.27 (dd, J = 8.1, 2.2 Hz, 1H), 7.99 (ddt, J = 8.4, 7.8, 0.7
Hz, 1H), 7.71 (dt, J = 7.7, 0.7 Hz, 1H), 7.43−7.34 (m, 1H), 7.30 (tdd,
J
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
for C17H15N3ONa 300.1107; found 300.1087, [M + K]+ calcd for
C17H15N3OK 316.0847; found 316.0823.
736; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H11N2O
223.0871; found 223.0898, [M + Na]+ calcd for C14H10N2ONa
245.0691; found 245.0724.
4′-Fluoro-2,2′-bipyridine N-Oxide (1v). Brown solid (276 mg, 8%
for 19 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2 and 4-fluoro-2-
General Procedure for Palladium-Catalyzed Directed Halo-
genations. A reaction vial was charged with bipyridine N-oxide 1 (1.0
equiv), Pd(OAc)2 (5 mol %), NXS (1.2 equiv), and chlorobenzene
(0.10 M). After stirring at 110 °C for 24 h, the reaction mixture was
cooled to room temperature, diluted with DCM, and extracted with an
aqueous NaOH solution (1.0 M). The aqueous layer was extracted
with DCM, the combined organic layers were dried with Na2SO4 and
filtered, and the solvent was removed from the filtrate. In cases of
incomplete conversion of the starting material additional purification
by column chromatography (MeOH in DCM: 0−10%, 1% incre-
ments) was performed. All structures were confirmed by COSEY,
HMBC, and HMQC.
3-Bromo-2,2′-bipyridine N-Oxide (2a). Colorless solid (1.95 g,
87% for 8.9 mmol scale, after extraction); mp 142 °C; 1H NMR (500
MHz, CDCl3): δ 8.78 (d, J = 4.7 Hz, 1H, ArH-3′), 8.27 (d, J = 6.5 Hz,
1H, ArH-4), 7.86 (td, J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.56 (d, J = 8.3 Hz,
1H, ArH-6), 7.50 (d, J = 7.8 Hz, 1H, ArH-6′), 7.39 (ddd, J = 7.6, 4.9,
0.9 Hz, 1H, ArH-4′), 7.17 (dd, J = 8.2, 6.6 Hz, 1H, ArH-5); 13C{1H}
NMR (126 MHz, CDCl3): δ 151.3 (C-2′), 150.3 (C-3′), 148.7 (C-2),
139.2 (C-4), 136.9 (C-5′), 129.9 (C-6), 125.43 (C-5), 125.35 (C-6′),
124.4 (C-4′), 122.1 (C-3′); IR (v/cm−1): 1597, 1565, 1454, 1426,
1412, 1282, 1253, 1029, 991, 900, 791, 779, 745, 731; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C10H8BrN2O 250.9815; found
250.9830, [M + Na]+ calcd for C10H7BrN2ONa 272.9634; found
272.9650; Elemental analysis (%): Anal. calcd for C10H7BrN2O: C,
47.8; H, 2.81; N, 11.2. Found: C, 47.9; H, 2.85; N, 11.2. Single crystals
for X-ray diffraction were grown by slow diffusion of pentane into a
concentrated solution of 2a in DCM. CCDC-1476436 contains the
crystallographic data for 2a.
3-Bromo-6-mtehyl-2,2′-bipyridine N-Oxide (2b). Brown oil (73.5
mg, 50% for 0.56 mmol scale, 2.57 g, 60% for 16.2 mmol scale, after
column chromatography with MeOH/DCM mixtures); 1H NMR
(500 MHz, CDCl3): δ 8.79 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H, ArH-3′),
7.86 (td, J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.49−7.46 (m, 2H, ArH-4, ArH-
6′), 7.38 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H, ArH-4′), 7.20 (dd, J = 8.4, 0.8
Hz, 1H, ArH-5), 2.48 (d, J = 0.6 Hz, 3H, −CH3); 13C{1H} NMR (126
MHz, CDCl3): δ 152.0 (C-2′), 150.2 (C-3′), 149.0 (C-2), 148.4 (C-
6), 137.0 (C-5′), 129.0 (C-4), 125.9 (C-5), 125.2 (C-6′), 124.1 (C-4′),
118.7 (C-3), 18.0 (−CH3); IR (v/cm−1): 1601, 1585, 1567, 1458,
1443, 1426, 1344, 1256, 1146, 1001, 903, 871, 781, 745; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H10BrN2O 264.9971; found
264.9966, [M + Na]+ calcd for C11H9BrN2ONa 286.9790; found
286.9794, [M + K]+ calcd for C11H9BrN2OK 302.9530; found
302.9534.
3-Bromo-6-ethoxycarbonyl-2,2′-bipyridine N-Oxide (2c). Brown
oil (271 mg, 82% for 1.02 mmol scale, after extraction); 1H NMR (500
MHz, CDCl3): δ 8.78 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, ArH-3′), 7.86 (td,
J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.58 (d, J = 8.5 Hz, 1H, ArH-4), 7.51 (dt,
J = 7.8, 1.1 Hz, 1H, ArH-6′), 7.48 (d, J = 8.6 Hz, 1H, ArH-5), 7.39
(ddd, J = 7.7, 4.9, 1.2 Hz, 1H ArH-4′), 4.42 (q, J = 7.1 Hz, 2H,
−CH2−), 1.37 (t, J = 7.1 Hz, 3H, −CH3); 13C{1H} NMR (126 MHz,
CDCl3): δ 161.3 (CO), 150.7 (C-2′), 150.2 (C-3′), 149.7 (C-2),
141.6 (C-6), 137.0 (C-5′), 128.8 (C-4), 125.8 (C-5), 125.6 (C-6′),
124.5 (C-4′), 123.8 (C-3), 62.9 (−CH2−), 14.2 (−CH3); IR (v/
cm−1): 1736, 1581, 1369, 1351, 1316, 1247, 1150, 1082, 1011, 992,
917, 780; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H12BrN2O3
323.0028; found 323.0042, [M + Na]+ calcd for C13H11BrN2O3Na
344.9845; found 344.9851.
1
chloropyridine, acetone/hexane mixtures); mp 94 °C; H NMR (500
MHz, CDCl3): δ 8.82 (dd, J = 11.0, 2.5 Hz, 1H), 8.64 (dd, J = 8.6, 5.5
Hz, 1H), 8.29 (dd, J = 6.5, 1.3 Hz, 1H), 8.25 (dd, J = 8.0, 2.2 Hz, 1H),
7.34 (td, J = 7.8, 1.3 Hz, 1H), 7.27 (ddd, J = 7.5, 6.5, 2.2 Hz, 1H), 7.07
(ddd, J = 7.9, 5.5, 2.5 Hz, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ
169.7, 167.7, 152.3 (d, J = 9.1 Hz), 151.3 (d, J = 7.4 Hz), 146.2, 140.9,
128.0, 125.8 (d, J = 2.2 Hz), 113.8 (d, J = 21 Hz), 112.2 (d, J = 17
Hz); 19F NMR (471 MHz, CDCl3): δ − 101.2 (q, J = 8.3 Hz); IR (v/
cm−1): 1594, 1575, 1468, 1431, 1389, 1255, 1176, 894, 841, 768, 729,
719; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H8FN2O
191.0615; found 191.0623, [M + Na]+ calcd for C10H7FN2ONa
213.0435; found 213.0447, [M + K]+ calcd for C10H7FN2OK
229.0174; found 229.0161.
4′-Ethoxycarbonyl-2,2′-bipyridine N-Oxide (1w). Brown solid
(573 mg, 44% for 5.3 mmol scale besides 6w using [Pd-
1
(tBu2PCMe2CH2)OAc]2, acetone/hexane mixtures); mp 68 °C; H
NMR (500 MHz, CDCl3): δ 9.37 (dd, J = 1.6, 0.9 Hz, 1H), 8.82 (dd, J
= 4.9, 0.9 Hz, 1H), 8.30 (ddd, J = 6.5, 1.3, 0.6 Hz, 1H), 8.13 (dd, J =
8.0, 2.2 Hz, 1H), 7.88 (dd, J = 4.9, 1.6 Hz, 1H), 7.34 (td, J = 7.7, 1.3
Hz, 1H), 7.27 (ddd, J = 7.4, 6.4, 2.3 Hz, 1H), 4.40 (q, J = 7.2 Hz, 3H),
1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (126 MHz, CDCl3): δ 165.0,
150.9, 150.0, 146.8, 140.8, 138.3, 128.0, 125.7, 124.8, 123.6, 62.0, 14.3;
IR (v/cm−1): 1716, 1426, 1385, 1280, 1219, 1202, 1123, 1024, 897,
887, 781, 765, 715, 682; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H13N2O3 245.0921; found 245.0916, [M + Na]+ calcd for
C13H12N2O3Na 267.0740; found 267.0744.
4,4″-Bis(ethoxycarbonyl)-2,2′:6′,2″-terpyridine N-Oxide (6w).
Brown solid (114 mg, 11%); mp 108 °C; 1H NMR (500 MHz,
CDCl3): δ 9.18 (dd, J = 1.6, 0.9 Hz, 2H), 8.88 (dd, J = 5.0, 0.9 Hz,
2H), 8.07 (d, J = 7.9 Hz, 2H), 7.92 (dd, J = 5.0, 1.6 Hz, 2H), 7.48 (t, J
= 7.9 Hz, 1H), 4.41 (q, J = 7.1 Hz, 4H), 1.38 (t, J = 7.1 Hz, 6H);
13C{1H} NMR (126 MHz, CDCl3): δ 165.1, 151.6, 150.2, 147.8,
138.2, 128.3, 125.5, 125.0, 123.6, 62.0, 14.4; IR (v/cm−1): 1718, 1662,
1590, 1380, 1364, 1260, 1243, 1018, 760; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C21H20N3O5 394.1397; found 394.1424, [M + Na]+
calcd for C21H19N3O5Na 416.1217; found 416.1246, [M + K]+ calcd
for C21H19N3O5K 432.0956; found 432.0979.
4′-Trifluoromethyl-2,2′-bipyridine N-Oxide (1x). Brown oil (204
mg, 15% for 5.7 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2 and 4-
trifluoromethyl-2-chloropyridine, acetone/hexane mixtures); 1H NMR
(500 MHz, CDCl3): δ 9.28 (dt, J = 1.7, 0.8 Hz, 1H), 8.88 (d, J = 5.0
Hz, 1H), 8.34 (dd, J = 6.5, 1.2 Hz, 1H), 8.24 (dd, J = 8.0, 2.2 Hz, 1H),
7.55 (ddd, J = 5.0, 1.7, 0.8 Hz, 1H), 7.39 (ddd, J = 8.0, 7.6, 1.3 Hz,
1H), 7.32 (ddd, J = 7.5, 6.5, 2.2 Hz, 1H); 13C{1H} NMR (126 MHz,
CDCl3): δ 151.0, 150.2, 146.1, 140.9, 138.8 (q, J = 35 Hz), 136.4,
128.1, 126.09, 126.06, 122.9 (q, J = 273 Hz), 121.5 (q, J = 4.1 Hz),
120.0 (q, J = 3.5 Hz); 19F NMR (471 MHz, CDCl3): δ −64.6; IR (v/
cm−1): 1433, 1394, 1333, 1283, 1227, 1169, 1129, 1085, 851, 766, 666;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H8N2O 241.0583;
found 241.0592, [M + Na]+ calcd for C11H7N2ONa 263.0403; found
263.0410.
2-(Pyridin-2-yl)pyrazine N-Oxide (1y). (794 mg, 21% for 22 mmol
scale using [Pd(tBu2PCMe2CH2)OAc]2, acetone/hexane mixtures);
1H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.76 (d, J = 4.1 Hz,
1H), 8.57 (d, J = 8.0 Hz, 1H), 8.52 (d, J = 4.2 Hz, 1H), 8.44 (d, J = 4.1
Hz, 1H), 7.96 (td, J = 7.9, 1.8 Hz, 1H), 7.52 (ddd, J = 7.5, 4.8, 0.9 Hz,
1H). The chemical shifts are in agreement with previous reports.43
2-(Pyridin-2-yl)quinoline N-Oxide (1z). Yellow solid (896 mg, 19%
for 21 mmol scale using [Pd(tBu2PCMe2CH2)OAc]2, MeOH/DCM
mixtures); mp 92−93 °C; 1H NMR (500 MHz, CDCl3): δ 9.12 (d, J =
8.1 Hz, 1H), 8.82 (d, J = 8.8 Hz, 1H), 8.73 (d, J = 4.1 Hz, 1H), 8.23
(d, J = 8.9 Hz, 1H), 7.86−7.77 (m, 2H), 7.77−7.69 (m, 2H), 7.61−
7.56 (m, 1H), 7.31 (ddd, J = 7.4, 4.8, 0.9 Hz, 1H); 13C{1H} NMR
(126 MHz, CDCl3): δ 150.3, 149.4, 143.3, 142.4, 136.3, 130.4, 130.0,
128.8, 128.0, 126.0, 125.1, 124.2, 123.2, 120.2; IR (v/cm−1): 1584,
1563, 1466, 1427, 1348, 1254, 1209, 1065, 992, 922, 892, 822, 773,
3-Bromo-6-trifluoromethyl-2,2′-bipyridine N-Oxide (2d). Color-
less solid (111 mg, quant. for 0.33 mmol scale, after extraction); mp
148 °C; 1H NMR (500 MHz, CDCl3): δ 8.80 (d, J = 4.8 Hz, 1H, ArH-
3′), 7.88 (td, J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.64 (d, J = 8.7 Hz, 1H,
ArH-4), 7.59 (d, J = 8.7 Hz, 1H, ArH-5), 7.52 (dt, J = 7.8, 1.2 Hz, 1H,
ArH-6′), 7.42 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H, ArH-4′); 13C{1H} NMR
(126 MHz, CDCl3): δ 150.7 (C-2), 150.4 (C-3′), 150.1 (C-2′), 137.0
(C-5′), 128.5 (C-4), 125.7 (C-6), 125.6 (C-6′), 124.7 (C-4′), 124.3 (q,
J = 3.8 Hz, C-5), 123.1 (C-3), 119.8 (q, J = 273 Hz, −CF3); 19F NMR
K
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(376 MHz, CDCl3): δ −68.8; IR (v/cm−1): 1362, 1339, 1270, 1253,
1148, 1120, 1066, 915, 838, 783; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H8BrF3N2O 318.9688; found 318.9713, [M + Na]+ calcd
for C11H7BrF3N2ONa 340.9508; found 340.9517, [M + K]+ calcd for
C11H7BrF3N2OK 358.9247; found 356.9234.
[M + H]+ calcd for C12H10BrN2O3 308.9869; found 308.9878, [M +
Na]+ calcd for C12H9BrN2O3Na 330.9689; found 330.9701.
3-Bromo-5-nitro-2,2′-bipyridine N-Oxide (2i). (101 mg of a
complex product mixture for 0.53 mmol scale, after extraction).
3-Bromo-4-methoxy-2,2′-bipyridine N-Oxide (2j). (0% for 1.02
mmol scale, but 83% of recovered 1j, after extraction).
3-Bromo-6-cyano-2,2′-bipyridine N-Oxide (2e). Colorless solid
3,4-Dichloro-2,2′-bipyridine N-Oxide (2k). (154 mg of a complex
(48.4 mg, 17% for 1.04 mmol scale besides 14% of 1e, after column
1
product mixture for 1.00 mmol scale, after extraction).
chromatography); mp 178−181 °C; H NMR (500 MHz, CDCl3): δ
3-Bromo-4-ethoxycarbonly-2,2′-bipyridine N-Oxide (2l). (0% for
0.36 mmol scale, but 1l was quantitatively recovered, after extraction).
3-Bromo-4-trifluoromethyl-2,2′-bipyridine N-Oxide (2m). (0% for
1.03 mmol scale, but 8m and 53% of recovered 1m, after column
chromatography).
8.78 (ddd, J = 4.9, 1.5, 1.0 Hz, 1H, ArH-3′), 7.88 (td, J = 7.8, 1.8 Hz,
1H, ArH-5′), 7.62 (d, J = 8.7 Hz, 1H, ArH-4), 7.55 (d, J = 8.7 Hz, 1H,
ArH-5), 7.49 (dt, J = 7.8, 0.9 Hz, 1H, ArH-6′), 7.43 (ddd, J = 7.7, 4.8,
1.0 Hz, 1H, ArH-4′); 13C{1H} NMR (126 MHz, CDCl3): δ 150.5 (C-
3′), 149.9 (C-2), 149.6 (C-2′), 137.1 (C-5′), 130.0 (C-5), 129.0 (C-4),
126.6 (C-6), 125.7 (C-3), 125.4 (C-6′), 125.0 (C-4′), 111.5 (−CN);
IR (v/cm−1): 1579, 1446, 1428, 1347, 1257, 1210, 996, 918, 828, 780,
746, 697; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H8BrN3O
275.9767; found 275.9766, [M + Na]+ calcd for C11H7BrN3ONa
297.9586; found 297.9586.
4-Trifluoromethyl-6-dioxopyrrolidinyl-2,2′-bipyridine N-Oxide
(8m). Brown solid (125 mg, 36%); mp 122 °C; 1H NMR (500
MHz, CDCl3): δ 8.82 (dt, J = 8.1, 1.1 Hz, 1H, ArH-6′), 8.75 (ddd, J =
4.8, 1.8, 1.0 Hz, 1H, ArH-3′), 8.65 (dd, J = 2.8, 0.8 Hz, 1H, ArH-5),
7.82 (td, J = 7.8, 1.9 Hz, 1H, ArH-5′), 7.60 (dd, J = 2.8, 0.7 Hz, 1H,
ArH-3), 7.39 (ddd, J = 7.6, 4.7, 1.2 Hz, 1H, ArH-4′), 3.12−2.92 (m,
4H, −CH2CH2−); 13C{1H} NMR (126 MHz, CDCl3): δ 174.3 (C
O), 149.8 (C-3), 148.9 (C-2′), 147.9 (C-2), 140.6 (C-6), 136.6 (C-5′),
126.1 (q, J = 36.0 Hz, C-4), 125.5 (C-6′), 125.4 (C-4′), 125.2 (q, J =
4.0 Hz, C-5), 122.7 (q, J = 3.9 Hz, C-3), 122.3 (q, J = 272 Hz, CF3),
29.1 (−CH2CH2−); 19F NMR (471 MHz, CDCl3): δ −63.3; IR (v/
cm−1): 1715, 1388, 1327, 1272, 1150, 1134, 1116, 787, 737; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C15H11F3N3O3 338.0747; found
338.0749, [M + Na]+ calcd for C15H10F3N3O3Na 360.0566; found
360.0573, [M + K]+ calcd for C15H10F3N3O3K 376.0306; found
376.0270.
3-Bromo-4-cyano-2,2′-bipyridine N-Oxide (2n). Red solid (102
mg, 37% for 1.00 mmol scale besides 32% of recovered 1n, after
column chromatography); mp 157 °C; 1H NMR (500 MHz, CDCl3):
δ 8.80 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H, ArH-3′), 8.28 (d, J = 7.0 Hz, 1H,
ArH-5), 7.91 (td, J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.53 (d, J = 6.9 Hz, 1H,
ArH-6), 7.48−7.43 (m, 2H, ArH-4′, ArH-6′); 13C{1H} NMR (126
MHz, CDCl3): δ 150.6 (C-3′), 150.5 (C-2′), 150.0 (C-2), 139.7 (C-
5), 137.3 (C-5′), 128.3 (C-6), 125.4 (C-3), 125.3 (C-6′), 125.0 (C-4′),
115.2 (C-4), 112.2 (−CN); IR (v/cm−1): 2228, 1428, 1403, 1288,
1267, 1080, 821, 738, 727; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C11H7BrN3O 275.9767; found 275.9788, [M + Na]+ calcd for
C11H6BrN3ONa 297.9586; found 297.9609. Single crystals for X-ray
diffraction were grown by slow diffusion of pentane into a
concentrated solution of 2n in DCM. CCDC-1476429 contains the
crystallographic data for 2n.
3-Bromo-5-methoxy-2,2′-bipyridine N-Oxide (2f). Brown solid
1
(281 mg, 99% for 1.01 mmol scale, after extraction); mp 122 °C; H
NMR (500 MHz, CDCl3): δ 8.77 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H, ArH-
3′), 8.04 (d, J = 2.3 Hz, 1H, ArH-4), 7.83 (td, J = 7.7, 1.7 Hz, 1H,
ArH-5′), 7.48 (dt, J = 7.8, 1.1 Hz, 1H, ArH-6′), 7.36 (ddd, J = 7.6, 4.9,
1.2 Hz, 1H, ArH-4′), 7.20 (d, J = 2.2 Hz, 1H, ArH-6), 3.86 (s, 3H,
-OCH3); 13C{1H} NMR (126 MHz, CDCl3): δ 156.9 (C-2), 151.2
(C-2′), 150.1 (C-3′), 142.2 (C-5), 136.8 (C-5′), 127.6 (C-4), 125.9
(C-6′), 124.1 (C-4′), 121.5 (C-3), 117.5 (C-6), 56.6 (−OCH3); IR
(v/cm−1): 1594, 1539, 1451, 1422, 1384, 1313, 1233, 1214, 1159,
1139, 1020, 891, 853, 821, 790; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H10BrN2O2 280.9920; found 280.9913, [M + Na]+ calcd
for C11H9BrN2O2Na 302.9740; found 302.9727. Single crystals for X-
ray diffraction were grown by slow diffusion of pentane into a
concentrated solution of 2f in DCM. CCDC-1476430 contains the
crystallographic data for 2f.
3-Bromo-5-methyl-2,2′-bipyridine N-Oxide (2g). Tan solid (107
mg, 40% for 1.01 mmol scale besides 3-bromo-5-methyl-2,2′-
1
bipyridine 5g, after column chromatography): mp 109−112 °C; H
NMR (500 MHz, CDCl3): δ 8.73 (d, J = 4.9 Hz, 1H, ArH-3′), 8.09 (s,
1H, ArH-4), 7.79 (td, J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.44 (d, J = 7.8 Hz,
1H, ArH-6′), 7.37 (s, 1H, ArH-6), 7.32 (ddd, J = 7.6, 4.9, 1.1 Hz, 1H,
ArH-4′), 2.27 (s, 3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3): δ
151.2 (C-2′), 150.0 (C-3′), 145.8 (C-2), 138.9 (C-4), 136.6 (C-5′),
136.2 (C-5), 130.9 (C-6), 125.4 (C-6′), 124.0 (C-4′), 121.1 (C-3),
18.0 (−CH3); IR (v/cm−1): 1598, 1537, 1428, 1371, 1280, 1212, 1146,
1020, 986, 854, 789; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H10BrN2O 264.9971; found 264.9991, [M + Na]+ calcd for
C11H9BrN2ONa 286.9790; found 286.9813, [M + K]+ calcd for
C11H9BrN2OK 302.9530; found 302.9560.
3-Bromo-4-nitro-2,2′-bipyridine N-Oxide (2o). (0% for 1.00 mmol
scale, but 75.3 mg of an 1:1.4 mixture of 8o and 1o, besides 55% of
pure 1o, after column chromatography).
4-Nitro-6-dioxopyrrolidinyl-2,2′-bipyridine N-Oxide (8o). (12%);
1H NMR (500 MHz, CDCl3): δ 9.23 (d, J = 3.3 Hz, 1H), 8.80−8.73
3-Bromo-5-methyl-2,2′-bipyridine (5g). Red oil (88.9 mg, 35%);
1H NMR (500 MHz, CDCl3): δ 8.69 (s, 1H, ArH-3′), 8.43 (s, 1H,
ArH-4), 7.79 (dd, J = 1.8, 0.7 Hz, 1H, ArH-6), 7.75 (td, J = 7.7, 1.8 Hz,
1H, ArH-5′), 7.67 (d, J = 7.8 Hz, 1H, ArH-6′), 7.27 (ddd, J = 7.4, 4.8,
1.1 Hz, 1H, ArH-4′), 2.32 (s, 3H, −CH3); 13C{1H} NMR (126 MHz,
CDCl3): δ 157.1 (C-2′), 153.7 (C-2), 149.1 (C-3′), 148.5 (C-4), 141.8
(C-6), 136.2 (C-5′), 134.5 (C-5), 124.3 (C-6), 123.2 (C-4′), 119.0 (C-
3), 17.7 (−CH3); IR (v/cm−1): 1584, 1568, 1445, 1424, 1377, 1099,
1086, 1030, 991, 872, 797, 744; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H10BrN2 249.0022; found 249.0040, [M + Na]+ calcd for
C11H9BrN2Na 270.9841; found 270.9863.
(m, 2H), 8.20 (d, J = 3.3 Hz, 1H), 7.82 (td, J = 7.8, 2.0 Hz, 1H), 7.41
(ddd, J = 7.4, 4.7, 1.1 Hz, 1H), 3.16−2.92 (m, 4H).
3′-Bromo-6′-methoxy-2,2′-bipyridine N-Oxide (2p). Brown solid
1
(276 mg, 98% for 1.00 mmol scale, after extraction); mp 142 °C; H
NMR (500 MHz, CDCl3): δ 8.32−8.28 (m, 1H, ArH-3), 7.78 (d, J =
8.8 Hz, 1H, ArH-5′), 7.37 (dd, J = 5.5, 4.4 Hz, 1H, ArH-4), 7.34−7.30
(m, 2H, ArH-5, ArH-6), 6.72 (d, J = 8.8 Hz, 1H, ArH-4′), 3.87 (s, 3H,
−OCH3); 13C{1H} NMR (126 MHz, CDCl3): δ 163.1 (C-5′), 148.5
(C-2), 148.2 (C-2′), 142.8 (C-6′), 139.9 (C-3), 127.5 (C-4), 126.0
and 125.1 (C-5, C-6), 113.4 (C-4′), 113.1 (C-3′), 54.1 (−CH3); IR
(v/cm−1): 1579, 1456, 1423, 1408, 1320, 1247, 1219, 1128, 1119,
1020, 1011, 893, 835, 823, 783, 764; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C11H10BrN2O2 280.9920; found 280.9930, [M + Na]+
calcd for C11H9BrN2O2Na 302.9740; found 302.9755, [M + K]+ calcd
for C11H9BrN2O2K 318.9479; found 318.9490.
3-Bromo-5-methoxycarbonyl-2,2′-bipyridine N-Oxide (2h). As
reddish oil (9.3 mg, 3% for 1.01 mmol scale, after column
1
chromatography); H NMR (500 MHz, CDCl3): δ 8.85−8.81 (m,
2H, ArH-4, ArH-3′), 8.13 (d, J = 1.1 Hz, 1H, ArH-6), 7.89 (td, J = 7.8,
1.5 Hz, 1H, ArH-5′), 7.53 (d, J = 7.6 Hz, 1H, ArH-6′), 7.45−7.40 (m,
1H, ArH-4′), 3.99 (s, 3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3):
δ 162.6 (CO), 151.6 (C-2), 150.7 (C-3′), 150.4 (C-2′), 140.2 (C-
4), 137.0 (C-5′), 130.2 (C-6), 128.9 (C-5), 125.4 (C-6′), 124.8 (C-4′),
122.1 (C-3), 53.5 (−CH3); IR (v/cm−1): 1727, 1581, 1538, 1426,
1364, 1301, 1235, 1192, 1106, 928, 850, 786; HRMS (ESI-TOF) m/z:
3′-Bromo-6′-methyl-2,2′-bipyridine N-Oxide (2q). (0% for 0.95
mmol scale, but 5b, after column chromatography).
3-Bromo-6-methyl-2,2′-bipyridine (5b). Orange oil (30.9 mg,
1
13%); H NMR (500 MHz, CDCl3): δ 8.74 (d, J = 4.8 Hz, 1H,
ArH-3′), 7.86 (d, J = 8.2 Hz, 1H, ArH-4), 7.79 (td, J = 7.7, 1.8 Hz, 1H,
ArH-5′), 7.67 (d, J = 7.8 Hz, 1H, ArH-6′), 7.32 (ddd, J = 7.6, 4.9, 1.2
L
DOI: 10.1021/acs.joc.7b00444
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The Journal of Organic Chemistry
Article
Hz, 1H, ArH-4′), 7.06 (d, J = 8.2 Hz, 1H, ArH-5), 2.57 (s, 3H,
−CH3); 13C{1H} NMR (126 MHz, CDCl3): δ 157.5 and 157.4 (C-6,
C2′), 155.8 (C-2), 149.3 (C-3′), 141.6 (C-4), 136.4 (C-5′), 124.5 (C-
5), 124.4 (C-6′), 123.4 (C-4′), 116.5 (C-3), 24.2 (−CH3); IR (v/
cm−1): 1561, 1417, 1014, 820, 796, 757; HRMS (ESI-TOF) m/z: [M
+ H]+ calcd for C11H10BrN2 249.0022; found 249.0042, [M + Na]+
calcd for C11H9BrN2Na 270.9841; found 270.9863.
3′-Bromo-6′-trifluoromethyl-2,2′-bipyridine N-Oxide (2r). Tan
solid (23.4 mg, 7% for 1.00 mmol scale, besides 5d, after column
chromatography); 1H NMR (500 MHz, CDCl3): δ 8.31 (d, J = 5.7 Hz,
1H, ArH-3), 8.19 (dt, J = 8.2, 0.7 Hz, 1H, ArH-4′), 7.65 (d, J = 8.3 Hz,
1H, ArH-5′), 7.47 (dd, J = 7.0, 2.8 Hz, 1H, ArH-5), 7.43−7.36 (m, 2H,
ArH-4, ArH-6); 13C{1H} NMR (126 MHz, CDCl3): δ 152.5 (C-2′),
147.3 (q, J = 36 Hz, C-6′), 146.9 (C-2), 142.1 (C-4′), 139.9 (C-3),
127.6 (C-5), 126.8 (C-4), 126.1 (C-3′), 125.7 (C-6), 122.0 (q, J = 3.0
Hz, C-5′), 121.2 (q, J = 274 Hz, −CF3); 19F NMR (376 MHz,
CDCl3): δ −67.5; IR (v/cm−1): 1337, 1258, 1106, 1022, 795, 772;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H7BrF3N2O
318.9688; found 318.9697, [M + Na]+ calcd for C11H6BrF3N2ONa
340.9508; found 340.9520.
302.9757, [M + K]+ calcd for C11H9BrN2O2K 318.9479; found
318.9489.
3-Bromo-4′-methyl-2,2′-bipyridine N-Oxide (2u). Brown solid
(282 mg, quant. for 1.01 mmol scale, after extraction); mp 79 °C;
1H NMR (500 MHz, CDCl3): δ 8.63 (dd, J = 5.1, 0.8 Hz, 1H, ArH-
6′), 8.26 (dd, J = 6.5, 1.0 Hz, 1H, ArH-4), 7.55 (dd, J = 8.3, 1.0 Hz,
1H, ArH-6), 7.31 (d, J = 0.8 Hz, 1H, ArH-3′), 7.20 (d, J = 5.0 Hz, 1H,
ArH-5′), 7.15 (dd, J = 8.3, 6.5 Hz, 1H, ArH-5), 2.42 (s, 3H, −CH3);
13C{1H} NMR (126 MHz, CDCl3): δ 151.1 (C-2), 150.0 (C-6′),
148.3 (C-2′), 139.2 (C-4), 129.8 (C-6), 128.7 (C-4′), 126.0 (C-3′),
125.4 (C-5′), 125.3 (C-5), 122.1 (C-3), 21.3 (−CH3); IR (v/cm−1):
1711, 1605, 1407, 1256, 1182, 904, 829, 779, 720; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C11H10BrN2O 264.9971; found 264.9991, [M
+ Na]+ calcd for C11H9BrN2ONa 286.9790; found 286.9813, [M + K]+
calcd for C11H9BrN2OK 302.9530; found 302.9556.
3-Bromo-4′-ethoxycarbonyl-2,2′-bipyridine N-Oxide (2w). Brown
1
solid (272, 83% for 1.01 mmol scale, after extraction); mp 68 °C; H
NMR (500 MHz, CDCl3): δ 8.94 (dd, J = 5.0, 0.9 Hz, 1H, ArH-6′),
8.29 (dd, J = 6.6, 1.0 Hz, 1H, ArH-4), 8.07 (dd, J = 1.6, 0.9 Hz, 1H,
ArH-3′), 7.96 (dd, J = 5.1, 1.6 Hz, 1H, ArH-5′), 7.59 (dd, J = 8.3, 1.0
Hz, 1H, ArH-6), 7.21 (dd, J = 8.3, 6.6 Hz, 1H, ArH-5), 4.42 (q, J = 7.2
Hz, 2H, −CH2−), 1.40 (t, J = 7.1 Hz, 3H, −CH3); 13C{1H} NMR
(126 MHz, CDCl3): δ 164.6 (CO), 152.2 (C-2′), 151.1 (C-6′),
148.2 (C-2), 139.2 (C-4), 138.9 (C-4′), 129.9 (C-6), 125.7 (C-5),
124.9 (C-3′), 123.6 (C-5′), 122.1 (C-3), 62.2 (−CH2−), 14.3
(−CH3); IR (v/cm−1): 1722, 1408, 1303, 1289, 1236, 1116, 1101,
1014, 896, 784, 760; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C13H12BrN2O3 323.0028; found 323.0057, [M + Na]+ calcd for
C13H11BrN2O3Na 344.9845; found 344.9882.
3-Bromo-6-trifluoromethyl-2,2′-bipyridine (5d). Colorless solid
1
(75.8 mg, 25%); mp 54 °C; H NMR (400 MHz, CDCl3): δ 8.75
(d, J = 4.8 Hz, 1H, ArH-3′), 8.21 (d, J = 8.2 Hz, 1H, ArH-4), 7.86 (td,
J = 7.7, 1.7 Hz, 1H, ArH-5′), 7.77 (d, J = 7.8 Hz, 1H, ArH-6′), 7.58 (d,
J = 8.3 Hz, 1H, ArH-5), 7.40 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H, ArH-4′);
13C{1H} NMR (126 MHz, CDCl3): δ 155.5, 155.2, 149.2, 146.1 (q, J =
35.6 Hz), 140.0, 136.9, 133.8, 124.8, 124.1, 121.3 (d, J = 274.3 Hz)
121.0 (q, J = 2.3 Hz); 19F NMR (376 MHz, CDCl3): δ − 67.5; IR (v/
cm−1): 1394, 1335, 1185, 1121, 1097, 1082, 1032, 1019, 845, 797, 742;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H7BrF3N2 302.9739;
found 302.9769, [M + Na]+ calcd for C11H6BrF3N2Na 324.9559;
found 324.9588.
3-Bromo-5′-methyl-2,2′-bipyridine N-Oxide (2s). Brown solid
(11.6 mg, 7% for 0.60 mmol scale besides 5s and 15% of recovered
1s, after extraction); mp 138 °C; 1H NMR (500 MHz, CDCl3): δ 8.62
(dt, J = 1.9, 0.8 Hz, 1H, ArH-6′), 8.27 (dd, J = 6.6, 1.1 Hz, 1H, ArH-
4), 7.67 (ddd, J = 7.9, 2.2, 0.9 Hz, 1H, ArH-4′), 7.56 (dd, J = 8.3, 1.0
Hz, 1H, ArH-6), 7.41 (dd, J = 7.9, 0.8 Hz, 1H, ArH-3′), 7.15 (dd, J =
8.3, 6.6 Hz, 1H, ArH-5), 2.42 (s, 3H, −CH3); 13C{1H} NMR (126
MHz, CDCl3): δ 150.8 (C-6′), 148.5 (C-2), 139.2 (C-4), 137.4 (C-
4′), 134.3 (C-5′), 129.8 (C-6), 125.3 (C-5), 124.8 (C-3′), 122.3 (C-3),
18.7 (−CH3); IR (v/cm−1): 1451, 1408, 1252, 1026, 903, 828, 797;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10BrN2O 264.9971;
found 264.9977, [M + Na]+ calcd for C11H9BrN2ONa 286.9790;
found 286.9801, [M + K]+ calcd for C11H9BrN2OK 302.9530; found
302.9540.
3-Bromo-5′-methyl-2,2′-bipyridine (5s). Brown oil (11.1 mg, 8%);
1H NMR (500 MHz, CDCl3): δ 8.64 (dd, J = 4.5, 1.5 Hz, 1H, ArH-4),
8.58 (s, 1H, ArH-6′), 8.01 (dd, J = 8.1, 1.5 Hz, 1H, ArH-6), 7.66−7.61
(m, 2H, ArH-3′, ArH-4′), 7.19 (dd, J = 8.1, 4.6 Hz, 1H, ArH-5), 2.41
(s, 3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3): δ 156.7 (C-2),
154.6 (C-2′), 149.7 (C-6′), 148.1 (C-4), 141.7 (C-6), 136.9 (C-3′),
132.2 (C-5′), 124.2 (C-5), 124.0 (C-4′), 119.8 (C-3), 18.5 (−CH3);
IR (v/cm−1): 1567, 1459, 1429, 1374, 1093, 1015, 838, 791, 743;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10BrN2 249.0022;
found 249.0030, [M + Na]+ calcd for C11H9BrN2Na 270.9841; found
270.9852.
3-Bromo-4′-methoxy-2,2′-bipyridine N-oxide (2t). Yellow oil
(94.2 mg, 54% for 1.01 mmol scale, after column chromatography);
1H NMR (500 MHz, CDCl3): δ 8.57 (d, J = 5.8 Hz, 1H, ArH-4), 8.24
(dd, J = 6.6, 1.1 Hz, 1H, ArH-6), 7.53 (dd, J = 8.3, 1.0 Hz, 1H, ArH-
6′), 7.15 (dd, J = 8.3, 6.5 Hz, 1H, ArH-5), 6.99 (d, J = 2.5 Hz, 1H,
ArH-5′), 6.89 (dd, J = 5.7, 2.5 Hz, 1H, ArH-3′), 3.86 (s, 3H, -OCH3);
13C{1H} NMR (126 MHz, CDCl3): δ 166.3 (C-2′), 152.6 (C-2),
151.5 (C-6′), 148.8 (C-4′), 139.1 (C-4), 129.7 (C-6), 125.3 (C-5),
122.0 (C-3′), 111.4 (C-3), 110.6 (C-5′), 55.5 (−OCH3); IR (v/cm−1):
1602, 1563, 1473, 1410, 1312, 1256, 1029, 903, 862, 845, 783; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H10BrN2O2 280.9920; found
280.9934, [M + Na]+ calcd for C11H9BrN2O2Na 302.9740; found
3-Bromo-2-(pyridin-2-yl)pyrazine N-Oxide (2y). (0% for 1.02
mmol scale, but 78% recovered 1y, after extraction).
3-Bromo-2-(pyridin-2-yl)quinoline N-Oxide (2z). Brown solid (143
mg, 49% for 0.96 mmol scale besides 5z and 8z, after column
1
chromatography); mp 158 °C; H NMR (500 MHz, CDCl3): δ 8.82
(d, J = 4.4 Hz, 1H, ArH-6′), 8.66 (d, J = 8.9 Hz, 1H, ArH-9), 8.06 (s,
1H, ArH-4), 7.89 (td, J = 7.8, 1.7 Hz, 1H, ArH-4′), 7.80 (d, J = 8.0 Hz,
1H, ArH-6), 7.75 (ddd, J = 8.6, 7.0, 1.4 Hz, 1H, ArH-8), 7.66 (ddd, J =
8.2, 6.9, 1.2 Hz, 1H, ArH-7), 7.58 (d, J = 7.8 Hz, 1H, ArH-3′), 7.42
(ddd, J = 7.6, 4.9, 1.2 Hz, 1H, ArH-5′); 13C{1H} NMR (126 MHz,
CDCl3): δ 152.2 (C-2′), 150.2 (C-6′), 144.4 (C-2), 141.3 (C-10),
136.9 (C-4′), 130.8 (C-8), 129.9 (C-7), 129.7 (C-5), 128.5 (C-4),
127.3 (C-6), 125.4 (C-3′), 124.2 (C-5′), 120.4 (C-9), 116.2 (C-3); IR
(v/cm−1): 1324, 1205, 918, 846, 768, 750, 742; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C14H10BrN2O 300.9971; found 300.9979, [M +
Na]+ calcd for C14H9BrN2ONa 322.9790; found 322.9803, [M + K]+
calcd for C14H9BrN2OK 338.9530; found 338.9535.
3-Bromo-2-(pyridin-2-yl)quinoline (5z). Brown solid (23.6 mg,
1
9%); mp 86−88 °C; H NMR (500 MHz, CDCl3): δ 8.79 (d, J = 4.8
Hz, 1H, ArH-6′), 8.52 (s, 1H ArH-4), 8.15 (d, J = 8.5 Hz, 1H ArH-9),
7.86 (td, J = 7.7, 1.7 Hz, 1H, ArH-4′), 7.29 (d, J = 7.9 Hz, 2H, ArH-6,
ArH-3′), 7.74 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, ArH-8), 7.59 (t, J = 7.5
Hz, 1H, ArH-7), 7.39 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H, ArH-5′); 13C{1H}
NMR (126 MHz, CDCl3): δ 157.6 (C-2′), 156.4 (C-2), 149.2 (C-6′),
146.5 (C-10), 140.4 (C-4), 136.6 (C-4′), 130.3 (C-8), 129.8 (C-6),
128.8 (C-5), 128.0 (C-7), 126.7 (C-6), 124.5 (C-3′), 123.6 (C-5′),
116.2 (C-3′); IR (v/cm−1): 1476, 1434, 1396, 1085, 857, 900, 775,
752, 742; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H10BrN2
285.0022; found 285.0044, [M + Na]+ calcd for C14H9BrN2Na
306.9841; found 306.9865.
3-Bromo-4-dioxopyrrolidinyl-2-(pyridin-2-yl)quinoline N-Oxide
1
(8z). Brown solid (29.4 mg, 8%); mp 116−120 °C; H NMR (500
MHz, CDCl3): δ 8.83 (d, J = 3.8 Hz, 1H, ArH-6′), 8.72 (d, J = 8.5 Hz,
1H, ArH-6), 7.90 (td, J = 7.7, 1.6 Hz, 1H, ArH-4′), 7.80 (ddd, J = 8.6,
7.0, 1.3 Hz, 1H, ArH-7), 7.69 (ddd, J = 8.2, 6.9, 1.2 Hz, 1H, ArH-8),
7.61−7.54 (m, 2H, ArH-9, ArH-3′), 7.42 (t, J = 6.3 Hz, 1H, ArH-5′),
3.15−3.02 (m, 4H, −CH2CH2−); 13C{1H} NMR (126 MHz, CDCl3):
δ 174.8 (CO), 151.9 (C-2′), 150.4 (C-6′), 144.9 (C-2), 142.2 (C-
4), 137.0 (C-4′), 131.3 (C-7), 130.9 (C-8), 126.8 (C-10), 126.6 (C-5),
125.5 (C-3′), 124.5 (C-5′), 123.1 (C-9), 121.2 (C-6), 118.9 (C-3),
29.1 (−CH2CH2−); IR (v/cm−1): 1716, 1411, 1320, 1169, 1150,
M
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1079, 771, 762; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C18H13BrN3O3 398.0135; found 398.0165, [M + Na]+ calcd for
C18H12BrN3O3Na 419.9954; found 419.9985.
3-Chloro-6-ethoxycarbonyl-2,2′-bipyridine N-Oxide (7c). Brown
oil (252 mg, 91% for 0.99 mmol scale, after extraction); 1H NMR (500
MHz, CDCl3): δ 8.78 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, ArH-6′), 7.85 (td,
J = 7.7, 1.8 Hz, 1H, ArH-4′), 7.57−7.51 (m, 2H, ArH-5, ArH-3′), 7.40
(d, J = 8.7 Hz, 1H, ArH-4), 7.38 (dd, J = 4.9, 1.1 Hz, 1H, ArH-5′), 4.42
(q, J = 7.1 Hz, 2H, −CH2−), 1.37 (t, J = 7.1 Hz, 3H, −CH3); 13C{1H}
NMR (126 MHz, CDCl3): δ 161.3 (CO), 150.3 (C-6′), 149.3 (C-
2′), 148.7 (C-2), 141.3 (C-6), 136.8 (C-4′), 135.2 (C-3), 125.89 (C-
3′), 125.85 (C-4), 125.5 (C-5), 124.5 (C-5′), 62.9 (−CH2−), 14.2
(−CH3); IR (v/cm−1): 1736, 1583, 1383, 1318, 1248, 1158, 1099,
1084, 1012, 940, 782, 745; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C13H12ClN2O3 279.0531; found 279.0532, [M + Na]+ calcd for
C13H11ClN2O3Na 301.0350; found 301.0356, [M + K]+ calcd for
C13H11ClN2O3K 317.0090; found 317.0088.
2-(2-Bromophenyl)pyridine N-Oxide (13). Colorless solid (165 mg,
66% for 1.00 mmol scale besides 2-(3,6-dibromophenyl)pyridine N-
oxide 14, after column chromatography with acetone in hexane
mixtures 0−100%; 10% increments); mp 113 °C; 1H NMR (500
MHz, CDCl3): δ 8.31 (dp, J = 6.9, 2.3 Hz, 1H), 7.67 (dd, J = 8.1, 1.2
Hz, 1H), 7.42−7.39 (m, 1H), 7.37 (dd, J = 7.6, 2.0 Hz, 1H), 7.33−
7.27 (m, 4H); 13C{1H} NMR (126 MHz, CDCl3): δ 149.3, 140.1,
134.5, 133.0, 131.1, 130.9, 128.1, 127.6, 125.6, 125.2, 123.6; IR (v/
cm−1): 1458, 1411, 1254, 1241, 1230, 1007, 841, 756, 737; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H9BrNO 249.9862; found
249.9870, [M + Na]+ calcd for C11H8BrNONa 271.9681; found
271.9691, [M + K]+ calcd for C11H8BrNOK 287.9421; found
287.9454. Uncatalyzed reaction: Similar to the general procedure, the
reaction of 2-phenylpyridine N-oxide (175 mg, 1.02 mmol), and NBS
(220 mg, 1.24 mmol) in chlorobenzene (10.0 mL) provided only
recovered starting material (79.6 mg, 0.46 mmol, 45%) after column
chromatography.
2-(3,6-dibromophenyl)pyridine N-Oxide (14). Brown solid (32.1
mg, 10%); mp 154 °C; 1H NMR (500 MHz, CDCl3): δ 8.37 (dd, J =
5.2, 2.4 Hz, 1H, ArH-3), 7.64 (d, J = 8.0 Hz, 2H, ArH-3′, ArH-5′),
7.36−7.32 (m, 2H, ArH-4, ArH-5), 7.30−7.26 (m, 1H, ArH-6), 7.19
(t, J = 8.1 Hz, 1H, ArH-4′); 13C{1H} NMR (126 MHz, CDCl3): δ
149.2 (C-2), 140.1 (C-3), 135.5 (C-1′), 132.0 (C-4′, C-5′), 131.8 (C-
4′), 128.2 (C-6), 126.1 and 125.2 (C-4, C-5), 124.6 (C-2′); IR (v/
cm−1): 1419, 1245, 1186, 847, 783, 764, 718; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C11H8Br2NO 327.8967; found 327.8975, [M +
Na]+ calcd for C11H7Br2NONa 349.8787; found 349.8797, [M + K]+
calcd for C11H7Br2NOK 365.8526; found 365.8583.
3-Chloro-6-cyano-2,2′-bipyridine N-Oxide (7e). (0% for 0.99
mmol scale, but 85% recovered 1e, after column chromatography).
3-Chloro-5-methoxy-2,2′-bipyridine N-Oxide (7f). Brown solid
1
(230 mg, 97% for 1.01 mmol scale, after extraction); mp 145 °C; H
NMR (500 MHz, CDCl3): δ 8.76 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H, ArH-
6′), 8.01 (d, J = 2.2 Hz, 1H, ArH-4), 7.82 (td, J = 7.7, 1.8 Hz, 1H,
ArH-4′), 7.50 (dt, J = 7.8, 1.1 Hz, 1H, ArH-3′), 7.35 (ddd, J = 7.7, 4.9,
1.2 Hz, 1H, ArH-5′), 7.02 (d, J = 2.2 Hz, 1H, ArH-6), 3.85 (s, 3H,
−CH3); 13C{1H} NMR (126 MHz, CDCl3): δ 156.7 (C-5), 150.1 (C-
6′), 149.8 (C-2′), 141.1 (C-2), 136.7 (C-4′), 133.3 (C-3), 127.1 (C-4),
126.1 (C-3′), 124.1 (C-5′), 114.5 (C-6), 56.6 (−CH3); IR (v/cm−1):
1603, 1545, 1460, 1449, 1427, 1376, 1165, 1018, 893, 865, 836, 787,
748; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10ClN2O2
237.0425; found 237.0449, [M + Na]+ calcd for C11H9ClN2O2Na
259.0245; found 259.0274, [M + K]+ calcd for C11H9ClN2O2K
274.9984; found 275.0009.
3-Chloro-5-methyl-2,2′-bipyridine N-Oxide (7g). Brown solid (198
mg, 90% for 1.00 mmol scale, after extraction); mp 113 °C; 1H NMR
(500 MHz, CDCl3): δ 8.78 (d, J = 4.6 Hz, 1H, ArH-6′), 8.11 (s, 1H,
ArH-4), 7.85 (td, J = 7.7, 1.7 Hz, 1H, ArH-4′), 7.52 (dt, J = 7.9, 1.1
Hz, 1H, ArH-3′), 7.38 (ddd, J = 7.5, 4.9, 1.2 Hz, 1H, ArH-5′), 7.24 (s,
1H, ArH-6), 2.33 (s, 3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3):
δ 150.2 (C-6′), 149.9 (C-2′), 144.9 (C-2), 138.7 (C-4), 136.8 (C-4′),
136.0 (C-5), 132.9 (C-3), 128.1 (C-6), 125.9 (C-3′), 124.2 (C-5′),
18.3 (−CH3); IR (v/cm−1): 1710, 1599, 1566, 1539, 1427, 1374, 1283,
1217, 1146, 1022, 991, 892, 845, 789, 750; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C11H10ClN2O 221.0476; found 221.0488, [M +
Na]+ calcd for C11H9ClN2ONa 243.0296; found 243.0313, [M + K]+
calcd for C11H9ClN2OK 259.0035; found 259.0319.
3-Chloro-5-methoxycarbonyl-2,2′-bipyridine N-Oxide (7h).
Brown solid (170 mg, 64% for 1.00 mmol scale, after extraction);
mp 96 °C; 1H NMR (500 MHz, CDCl3): δ 8.80 (dd, J = 5.8, 1.1 Hz,
1H, ArH-6′), 8.79 (s, J = 1.3 Hz, 1H, ArH-4), 7.95 (d, J = 1.4 Hz, 1H,
ArH-6), 7.88 (td, J = 7.8, 1.8 Hz, 1H, ArH-4′), 7.55 (dt, J = 7.8, 1.1
Hz, 1H, ArH-3′), 7.42 (ddd, J = 7.7, 4.9, 1.2 Hz, 1H, ArH-5′), 3.98 (s,
3H, −OCH3); 13C{1H} NMR (126 MHz, CDCl3): δ 162.6 (CO),
150.3 (C-2), 149.1 (C-2′), 139.7 (C-4), 137.0 (C-4′), 133.8 (C-3),
128.7 (C-5), 128.6 (C-6′), 127.1 (C-6), 125.6 (C-3′), 124.7 (C-5′),
53.5 (−OCH3); IR (v/cm−1): 1724, 1427, 1372, 1318, 1231, 1110,
1008, 958, 879, 757, 744, 728; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C12H10ClN2O3 265.0374; found 265.0379, [M + Na]+ calcd
for C12H9ClN2O3Na 287.0194; found 287.0199, [M + K]+ calcd for
C12H9ClN2O3K 302.9933; found 302.9945.
3-Chloro-5-nitro-2,2′-bipyridine N-Oxide (7i). Yellow solid (26.0
mg, 31% for 0.33 mmol scale besides 33% of recovered 1i, after
column chromatography); mp 165−168 °C (decomp.); 1H NMR
(400 MHz, CDCl3): δ 9.05 (d, J = 2.0 Hz, 1H, ArH-4), 8.83 (d, J = 4.5
Hz, 1H, ArH-3′), 8.15 (d, J = 2.0 Hz, 1H, ArH-6), 7.92 (td, J = 7.8, 1.7
Hz, 1H, ArH-5′), 7.56 (d, J = 7.8 Hz, 1H, ArH-6′), 7.47 (ddd, J = 7.7,
4.9, 1.1 Hz, 1H, ArH-4′); 13C{1H} NMR (126 MHz, CDCl3): δ 152.2
(C-2), 150.6 (C-3′), 148.1 (C-2′), 145.2 (C-5), 137.1 (C-5′), 135.1
(C-4), 134.4 (C-3), 125.6 (C-6′), 125.2 (C-4′), 120.9 (C-6); IR (v/
cm−1): 1514, 1424, 1374, 1351, 1268, 1186, 1101, 994, 778, 743;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H7ClN3O3 252.0170;
found 252.0166, [M + Na]+ calcd for C10H6ClN3O3Na 273.9990;
found 273.9990.
2-(2-Bromophenyl)pyridine (10). Pale yellow oil (119 mg, 49% for
1.03 mmol scale besides 2-(3,6-dibromophenyl)pyridine 11, after
column chromatography with EtOAc in hexane mixtures 0−100%;
10% increments); 1H NMR (500 MHz, CDCl3): δ 8.71 (ddd, J = 4.9,
1.8, 1.0 Hz, 1H), 7.75 (td, J = 7.7, 1.8 Hz, 1H), 7.67 (dd, J = 8.0, 1.2
Hz, 1H), 7.59 (dt, J = 7.9, 1.1 Hz, 1H), 7.53 (dd, J = 7.6, 1.7 Hz, 1H),
7.40 (td, J = 7.5, 1.2 Hz, 1H), 7.30−7.22 (m, 2H). The chemical shifts
are in agreement with previous reports.44
2-(2,6-Dibromophenyl)pyridine (11). Pale yellow solid (41.2 mg,
13%); 1H NMR (500 MHz, CDCl3): δ 8.75 (ddd, J = 4.9, 1.8, 1.0 Hz,
1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.34 (ddd,
J = 7.6, 4.9, 1.2 Hz, 1H), 7.30 (dt, J = 7.8, 1.1 Hz, 1H), 7.12 (t, J = 8.1
Hz, 1H). The chemical shifts are in agreement with previous reports.44
3-Chloro-2,2′-bipyridine N-Oxide (7a). Brown solid (3.93 g, 95%
1
for 20.0 mmol scale, after extraction); mp 105 °C; H NMR (500
MHz, CDCl3): δ 8.79 (ddd, J = 4.9, 1.7, 1.0 Hz, 1H, ArH-6′), 8.24 (dd,
J = 6.6, 1.0 Hz, 1H, ArH-4), 7.87 (td, J = 7.8, 1.7 Hz, 1H, ArH-4′),
7.53 (dd, J = 8.5, 1.0 Hz, 1H, ArH-6), 7.42−7.38 (m, 2H, ArH-3′,
ArH-5′), 7.23 (dd, J = 8.4, 6.5 Hz, 1H, ArH-5); 13C{1H} NMR (126
MHz, CDCl3): δ 149.6 (C-6′), 148.8 (C-2), 146.8 (C-2′), 138.4 (C-
4), 137.4 (C-3), 133.7 (C-4′), 128.5 (C-6), 125.6 (C-5), 125.5 (C-3′),
124.6 (C-5′); IR (v/cm−1): 1415, 1266, 1247, 1031, 926, 792, 780,
725; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H8ClN2O
207.0320; found 207.0325, [M + Na]+ calcd for C10H7ClN2ONa
229.0139; found 229.0147, [M + K]+ calcd for C10H7ClN2OK
244.9878; found 244.9869.
3-Chloro-6-methyl-2,2′-bipyridine N-Oxide (7b). Tan oil (75.1 mg,
1
68% for 0.49 mmol scale, after column chromatography); H NMR
(500 MHz, CDCl3): δ 8.77 (d, J = 4.8 Hz, 1H, ArH-6′), 7.83 (td, J =
7.8, 1.8 Hz, 1H, ArH-4′), 7.47 (d, J = 7.8 Hz, 1H, ArH-3′), 7.36 (ddd, J
= 7.7, 4.9, 1.1 Hz, 1H, ArH-5′), 7.30 (d, J = 8.5 Hz, 1H, ArH-4), 7.24
(d, J = 8.5 Hz, 1H, ArH-5), 2.47 (s, 3H, −CH3); 13C{1H} NMR (126
MHz, CDCl3): δ 150.5 (C-2′), 150.2 (C-6′), 148.5 (C-2), 147.2 (C-
6), 136.8 (C-4′), 130.5 (C-3), 126.0 (C-4), 125.41 (C-5), 125.36 (C-
3′), 124.0 (C-5′), 17.8 (−CH3); IR (v/cm−1): 1459, 1443, 1426, 1347,
1260, 1002, 928, 782, 745, 708; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H10ClN2O 221.0476; found 221.0491, [M + Na]+ calcd
for C11H9ClN2ONa 243.0296; found 243.0319.
N
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-Chloro-4-cyano-2,2′-bipyridine N-Oxide (7n). (0% for 0.82
mmol scale, but 91% recovered 1n, after extraction).
3-Chloro-4′-trifluoromethyl-2,2′-bipyridine N-Oxide (7x). Brown
oil (155 mg, 97% for 0.58 mmol scale, after extraction); 1H NMR (500
MHz, CDCl3): δ 8.98 (d, J = 5.3 Hz, 1H, ArH-6), 8.27 (dd, J = 6.6, 1.1
Hz, 1H, ArH-4), 7.81 (s, 1H, ArH-3′), 7.62 (dd, J = 5.1, 0.9 Hz, 1H,
ArH-5′), 7.44 (dd, J = 8.4, 1.1 Hz, 1H, ArH-6), 7.30 (dd, J = 8.4, 6.5
Hz, 1H, ArH-5); 13C{1H} NMR (126 MHz, CDCl3): δ 151.3 (C-6′),
151.1 (C-2′), 146.4 (C-2), 139.2 (q, J = 35 Hz, C-4′), 138.8 (C-4),
133.7 (C-3), 127.0 (C-6), 125.5 (C-5), 122.7 (q, J = 274 Hz, −CF3),
121.9 (q, J = 3.7 Hz, C-3′), 120.1 (q, J = 3.5 Hz, C-5′); 19F NMR (376
MHz, CDCl3): δ −64.6; IR (v/cm−1): 1414, 1395, 1333, 1244, 1169,
1133, 1083, 1046, 931, 850, 833, 787; HRMS (ESI-TOF) m/z: [M +
H]+ calcd for C11H7ClF3N2O 275.0194; found 275.0192, [M + Na]+
calcd for C11H6ClF3N2ONa 297.0013; found 297.0013, [M + K]+
calcd for C11H6ClF3N2OK 312.9752; found 312.9748.
3′-Chloro-6′-methoxy-2,2′-bipyridine N-Oxide (7p). Yellow solid
1
(227 mg, 96% for 1.00 mmol scale, after extraction); mp 134 °C; H
NMR (500 MHz, CDCl3): δ 8.29 (dd, J = 4.9, 2.8 Hz, 1H, ArH-3),
7.78 (d, J = 8.7 Hz, 1H, ArH-5′), 7.37 (dd, J = 5.5, 4.4 Hz, 1H, ArH-5),
7.32−7.28 (m, 2H, ArH-4, ArH-6), 6.72 (d, J = 8.7 Hz, 1H, ArH−),
3.88 (s, 3H, −OCH3); 13C{1H} NMR (126 MHz, CDCl3): δ 163.1
(C-6′), 148.5 (C-2′), 148.2 (C-2), 142.8 (C-5′), 139.9 (C-3), 127.5
(C-5), 126.0 and 125.10 (C-4, C-6), 113.4 (C-3′), 113.1 (C-4′), 54.1
(−OCH3); IR (v/cm−1): 1584, 1460, 1410, 1324, 1251, 1226, 1023,
930, 893, 831, 766; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H10ClN2O2 237.0425; found 237.0451, [M + Na]+ calcd for
C11H9ClN2O2Na 259.0245; found 259.0276.
3′-Chloro-6′-methyl-2,2′-bipyridine N-Oxide (7q). (0% for 1.01
3-Chloro-2-(pyridin-2-yl)pyrazine N-Oxide (7y). (0% for 1.00
mmol scale, but 92% recovered 1y, after extraction).
mmol scale, but quant. recovered 1q, after extraction).
3′-Chloro-6′-trifluoromethyl-2,2′-bipyridine N-Oxide (7r). Color-
less solid (234 mg, 90% for 0.95 mmol scale, after extraction); mp 146
°C; 1H NMR (500 MHz, CDCl3): δ 8.32 (dd, J = 5.6, 2.0, 1H, ArH-3),
8.01 (dt, J = 8.3, 0.7 Hz, 1H, ArH-4′), 7.74 (d, J = 8.4 Hz, 1H, ArH-
5′), 7.50 (dd, J = 7.3, 2.6 Hz, 1H, ArH-6), 7.43−7.36 (m, 2H, ArH-4,
ArH-5); 13C{1H} NMR (126 MHz, CDCl3): δ 150.8 (C-2), 146.5 (q, J
= 36 Hz, C-6′), 146.6 (C-2′), 139.9 (C-3), 138.8 (C-4′), 136.5 (C-3′),
127.8 (C-6), 126.8 and 125.4 (C-4, C-5), 122.0 (q, J = 2.4 Hz, C-5′),
121.2 (q, J = 275 Hz, −CF3); 19F NMR (471 MHz, CDCl3): δ −67.4;
IR (v/cm−1): 1422, 1336, 1251, 1173, 1160, 1135, 1119, 1105, 1033,
850, 823, 770; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H7ClF3N2O 275.0194; found 275.0198, [M + Na]+ calcd for
C11H6ClF3N2ONa 297.0013; found 297.0025.
3-Chloro-4′-methyl-2,2′-bipyridine N-Oxide (7u). Brown solid
(216 mg, 98% for 0.98 mmol scale, after extraction); mp 129 °C;
1H NMR (500 MHz, CDCl3): δ 8.63 (dd, J = 5.0, 0.8 Hz, 1H, ArH-4),
8.23 (dd, J = 6.6, 1.1 Hz, 1H, ArH-6), 7.38 (dd, J = 8.4, 1.1 Hz, 1H,
ArH-6′), 7.33 (dt, J = 1.7, 0.8 Hz, 1H, ArH-3′), 7.21 (dd, J = 8.3, 6.6
Hz, 1H, ArH-5′), 7.20 (ddd, J = 5.0, 1.6, 0.7 Hz, 1H, ArH-5), 2.42 (s,
3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3): δ 150.0 (C-2), 149.6
(C-2′), 148.2 (C-4), 147.8 (C-4′), 138.7 (C-6), 133.7 (C-3), 126.8 (C-
6′), 126.2 (C-3′), 125.4 (C-5), 124.9 (C-5′), 21.2 (−CH3); IR (v/
cm−1): 1605, 1404, 1252, 927, 835, 788, 723; HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C11H10ClN2O 221.0476; found 221.0473, [M +
Na]+ calcd for C11H9ClN2ONa 243.0296; found 243.0317, [M + K]+
calcd for C11H9ClN2OK 259.0035; found 259.0030.
3-Chloro-4′-fluoro-2,2′-bipyridine N-Oxide (7v). Brown solid (204
mg, 90% for 1.01 mmol scale, after extraction); mp 125 °C; 1H NMR
(500 MHz, CDCl3): δ 8.77 (dd, J = 8.3, 5.7 Hz, 1H), 8.26 (dd, J = 6.6,
1.0 Hz, 1H), 7.42 (dd, J = 8.4, 1.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.4 Hz,
1H), 7.27 (dd, J = 8.4, 6.6 Hz, 1H), 7.15 (ddd, J = 8.2, 5.7, 2.5 Hz,
1H); 13C{H} NMR (126 MHz, CDCl3): δ 169.0 (d, J = 264 Hz, C-
4′), 152.8 (d, J = 7.5 Hz, C-6′), 152.4 (d, J = 8.0 Hz, C-2′), 146.7 (C-
2), 138.8 (C-4), 133.7 (C-3), 126.9 (C-6), 125.4 (C-5), 114.2 (d, J =
18 Hz, C-3′), 112.5 (d, J = 16 Hz, C-5′); 19F NMR (471 MHz,
CDCl3): δ −100.7; IR (v/cm−1): 1600, 1575, 1467, 1414, 1395, 1267,
1184, 1046, 900, 932, 894, 839, 829, 783, 724; HRMS (ESI-TOF) m/
z: [M + H]+ calcd for C10H7ClFN2O 225.0225; found 225.0259, [M +
Na]+ calcd for C10H6ClFN2ONa 247.0045; found 247.0051, [M + K]+
calcd for C10H6ClFN2OK 262.9784; found 262.9766.
3-Chloro-4′-ethoxycarbonyl-2,2′-bipyridine N-Oxide (7w). Brown
oil (124 mg, 90% for 0.59 mmol scale, after extraction); 1H NMR (500
MHz, CDCl3): δ 8.94 (d, J = 5.0 Hz, 1H, ArH-6), 8.28 (d, J = 6.5 Hz,
1H, ArH-4), 8.11 (t, J = 1.2 Hz, 1H, ArH-3′), 7.97 (dd, J = 5.0, 1.6 Hz,
1H, ArH-5′), 7.43 (d, J = 8.3 Hz, 1H, ArH-6), 7281 (dd, J = 8.6, 6.7
Hz, 1H, ArH-5), 4.43 (q, J = 7.1 Hz, 2H, −CH2−), 1.41 (t, J = 7.1 Hz,
3H, −CH3); 13C{1H} NMR (126 MHz, CDCl3): δ 164.6 (CO),
151.1 (C-6′), 150.7 (C-2′), 139.0 (C-4), 138.8 (C-4′), 133.8 (C-3),
127.1 (C-6), 125.3 (C-5), 125.2 (C-3′), 123.7 (C-5′), 119.9 (C-2),
62.2 (−CH2−), 14.3 (−CH3); IR (v/cm−1): 1412, 1303, 1236, 1116,
1100, 1014, 930, 787, 762; HRMS (ESI-TOF) m/z: [M + H]+ calcd
for C13H12ClN2O3 279.0531; found 279.0537, [M + Na]+ calcd for
C13H11ClN2O3Na 301.0350; found 301.0359, [M + K]+ calcd for
C13H11ClN2O3K 317.0090; found 317.0094.
3-Chloro-2-(pyridin-2-yl)quinoline N-Oxide (7z). Brown solid (236
mg, 87% for 1.05 mmol scale, after extraction); mp 127−130 °C; H
1
NMR (500 MHz, CDCl3): δ 8.83 (ddd, J = 4.9, 1.6, 0.9 Hz, 1H, ArH-
6′), 8.69 (d, J = 8.7 Hz, 1H, ArH-9), 7.89 (td, J = 7.8, 1.8 Hz, 1H,
ArH-4′), 7.87 (s, 1H, ArH-4), 7.81 (dd, J = 8.1, 1.2 Hz, 1H, ArH-6),
7.75 (ddd, J = 8.6, 7.0, 1.4 Hz, 1H, ArH-8), 7.67 (ddd, J = 8.1, 7.0, 1.2
Hz, 1H, ArH-7), 7.61 (dt, J = 7.8, 1.0 Hz, 1H, ArH-3′), 7.42 (ddd, J =
7.7, 4.9, 1.1 Hz, 1H, ArH-5′); 13C{1H} NMR (126 MHz, CDCl3): δ
150.8 (C-2), 150.3 (C-6′), 143.7 (C-2′), 141.2 (C-10), 136.8 (C-4′),
130.6 (C-8), 129.9 (C-7), 129.1 (C-3), 128.2 (C-5), 127.5 (C-6),
125.7 (C-3′), 125.1 (C-4), 124.2 (C-5′, 120.5 (C-9); IR (v/cm−1):
1713, 1589, 1556, 1472, 1428, 1328, 938, 847, 821, 769; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C14H10ClN2O 257.0476; found
257.0499, [M + Na]+ calcd for C14H9ClN2ONa 279.0296; found
279.0326.
General Procedure for Deoxygenation of Halogenated
Bipyridine N-Oxides. A reaction vial was loaded with halogenated
bipyridine N-oxide 2 or 7 (1.0 equiv) and CHCl3 (0.10 M). The
solution was cooled to 0 °C, and PX3 (4.0 equiv, X = Br for 2 and X =
Cl for 7) was added. After stirring at 80 °C for 3 h, the reaction
mixture was cooled to room temperature, quenched, and neutralized
with sat. NaHCO3. The aqueous layer was extracted with DCM, and
the combined organic layers were dried with Na2SO4, and filtered, and
the volatiles were removed from the filtrate. If necessary, flash column
chromatography (acetone/hexane 1:9) was performed.
3-Bromo-2,2′-bipyridine (5a). Pale yellow oil (44.3 mg, 76% for
1
0.25 mmol scale, after extraction); H NMR (500 MHz, CDCl3): δ
8.74 (d, J = 4.4 Hz, 1H), 8.64 (d, J = 3.7 Hz, 1H), 8.01 (dd, J = 8.1, 1.5
Hz, 1H), 7.81 (td, J = 7.7, 1.8 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.34
(ddd, J = 7.5, 4.9, 1.2 Hz, 1H), 7.20 (dd, J = 8.1, 4.6 Hz, 1H); 13C{1H}
NMR (126 MHz, CDCl3): δ 157.3, 156.7, 149.3, 148.1, 141.7, 136.4,
124.4, 124.3, 123.5, 119.7; IR (v/cm−1): 1567, 1410, 1101, 1014, 991,
792, 744; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C10H8BrN2
234.9865; found 234.9890, [M + Na]+ calcd for C10H7BrN2Na
256.9685; found 256.9713. Attempted deoxygenation with Pd/C and
NH4CO2H: 2a (63.6 mg, 0.25 mmol) was dissolved in MeOH (1.30
mL), and NH4CO2H (188 mg, 2.99 mmol) and Pd/C (w = 10%, 26.5
mg, 0.025 mmol) were added as solids. The reaction mixture was
stirred at room temperature for 5 h, the volatiles were removed, and
the residue was extracted with DCM. After removal of the solvent
from the extracted solution, 2,2′-bipyridine (35.5 mg, 0.25 mmol,
quant.) was obtained.
3-Bromo-6-methyl-2,2′-bipyridine (5b). Orange oil (38.3 mg, 79%
for 0.19 mmol scale, after extraction). NMR data are identical to those
of the previous obtained sample (s.a.).
3-Bromo-6-ethoxycarbonyl-2,2′-bipyridine (5c). Colorless oil
(58.8 mg, 61% for 0.31 mmol scale, after extraction); 1H NMR
(400 MHz, CDCl3): δ 8.72 (d, J = 4.6 Hz, 1H), 8.15 (d, J = 8.3 Hz,
1H), 7.98 (d, J = 8.3 Hz, 1H), 7.84 (td, J = 7.7, 1.7 Hz, 1H), 7.76 (d, J
= 7.7 Hz, 1H), 7.36 (ddd, J = 7.4, 4.9, 1.2 Hz, 1H), 4.45 (q, J = 7.1 Hz,
2H), 1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
164.7, 156.7, 149.0, 146.9, 142.7, 136.7, 125.5, 124.7, 123.8, 123.7,
62.3, 14.4; IR (v/cm−1): 1739, 1715, 1562, 1417, 1392, 1367, 1311,
1281, 1136, 1105, 1015, 992, 856, 798, 785, 744; HRMS (ESI-TOF)
O
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
m/z: [M + H]+ calcd for C13H12BrN2O2 307.007; found 307.0107, [M
+ Na]+ calcd for C13H11BrN2O2Na 328.9896; found 328.9937, [M +
K]+ calcd for C13H11BrN2O2K 344.9635; found 344.9666.
J = 7.5, 4.9, 1.2 Hz, 1H), 7.11 (d, J = 8.2 Hz, 1H), 2.57 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 156.8, 156.3, 154.2, 149.4,
138.4, 136.3, 127.5, 124.6, 124.0, 123.3, 24.1; IR (v/cm−1): 1562,
1448, 1418, 1474, 1234, 1141, 1118, 1027, 992, 821, 797, 745; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H10ClN2 205.0527; found
205.0549.
3-Bromo-6-trifluoromethyl-2,2′-bipyridine (5d). Colorless solid
(34.8 mg, 43% for 0.27 mmol scale, after column chromatography).
NMR data are identical to those of the previous obtained sample (v.s.).
3,6-Dibromo-5-methoxy-2,2′-bipyridine (16f). Pale yellow solid
(83.4 mg, 45% for 0.53 mmol scale, after column chromatography);
3-Chloro-6-ethoxycarbonyl-2,2′-bipyridine (15c). Orange oil (104
1
mg, 82% for 0.48 mmol scale, after extraction); H NMR (400 MHz,
1
mp 93−96 °C; H NMR (400 MHz, CDCl3): δ 8.72 (d, J = 4.8 Hz,
CDCl3): δ 8.71 (d, J = 4.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.93 (d, J
= 8.3 Hz, 1H), 7.83−7.75 (m, 2H), 7.33 (ddd, J = 6.7, 4.8, 1.8 Hz,
1H), 4.43 (q, J = 7.1 Hz, 1H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3): δ 164.4, 155.6, 155.2, 149.1, 146.2, 139.4, 136.6,
134.2, 125.4, 124.8, 123.8, 62.2, 14.3; IR (v/cm−1): 1739, 1716, 1568,
1418, 1392, 1368, 1313, 1282, 1221, 1140, 1109, 1030, 857, 800, 787,
745; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H12ClN2O2
263.0582; found 263.0588, [M + Na]+ calcd for C13H11ClN2O2Na
285.0401; found 285.0409.
1H), 7.80 (td, J = 7.8, 1.7 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.43 (s,
1H), 7.32 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 3.98 (s, 3 H); 13C{1H} NMR
(101 MHz, CDCl3): δ 155.9, 152.9, 149.1, 148.3, 136.6, 130.7, 124.6,
123.9, 123.5, 118.5, 56.9; IR (v/cm−1): 1562, 1460, 1410, 1316, 1211,
1119, 1065, 1011, 873, 797, 744; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H9Br2N2O 344.9056; found 344.9078, [M + Na]+ calcd
for C11H8Br2N2ONa 366.8875; found 366.8899.
3-Bromo-6-methoxy-2,2′-bipyridine (5p). Pale yellow oil (7.9 mg,
1
8% for 0.35 mmol scale, after column chromatography); H NMR
3-Chloro-5-methoxy-2,2′-bipyridine (15f). Colorless solid (46.4
(400 MHz, CDCl3): δ 8.74 (d, J = 4.1 Hz, 1H), 7.87−7.77 (m, 2H),
7.73 (dt, J = 7.9, 1.0 Hz, 1H), 7.34 (ddd, J = 7.6, 4.9, 1.2 Hz, 1H), 6.68
(d, J = 8.7 Hz, 1H), 3.95 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3):
δ 162.7, 157.4, 153.1, 148.9, 144.1, 136.5, 124.5, 123.4, 112.4, 110.3,
77.2, 54.0; IR (v/cm−1): 1564, 1458, 1408, 1318, 1011, 992, 823, 795,
744; HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10BrN2O
264.9971; found 264.9979, [M + Na]+ calcd for C11H9BrN2ONa
286.9790; found 286.9791.
3-Bromo-4′-methyl-2,2′-bipyridine (5u). Pale yellow solid (65.8
mg, 45% for 0.59 mmol scale, after column chromatography); mp 50−
52 °C; 1H NMR (400 MHz, CDCl3): δ 8.59 (d, J = 4.6 Hz, 1H), 8.56
(d, J = 5.0 Hz, 1H), 7.97 (dt, J = 8.1, 1.6 Hz, 1H), 7.50 (s, 1H), 7.18−
7.11 (m, 2H), 2.39 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
157.1, 156.7, 148.9, 147.9, 147.6, 141.6, 125.1, 124.4, 124.2, 119.6,
21.2; IR (v/cm−1): 1603, 1568, 1437, 1384, 1018, 994, 797, 772, 743;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10BrN2 249.0022;
found 249.0020, [M + Na]+ calcd for C11H9BrN2Na 270.9841; found
270.9854.
3-Bromo-4′-ethoxycarbonyl-2,2′-bipyridine (5w). Brown solid
(128 mg, 86% for 0.49 mmol scale, after extraction); mp 78−80 °C;
1H NMR (400 MHz, CDCl3): δ 8.87 (d, J = 5.0 Hz, 1H), 8.65 (dd, J =
4.6, 1.3 Hz, 1H), 8.28 (s, 1H), 8.02 (dd, J = 8.1, 1.4 Hz, 1H), 7.90 (dd,
J = 5.0, 1.5 Hz, 1H), 7.22 (dd, J = 8.1, 4.6 Hz, 1H), 4.41 (q, J = 7.1 Hz,
2H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ
164.9, 158.2, 155.8, 149.9, 148.2, 141.8, 138.3, 124.6, 123.7, 122.6,
119.7, 62.0, 14.3; IR (v/cm−1): 1721, 1374, 1307, 1293, 1249, 1232,
1203, 1128, 1015, 899, 912, 750, 733; HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C13H11BrN2O2Na 328.9896; found 328.9928.
3-Bromo-2-(pyridin-2-yl)quinoline (5z). Colorless solid (39.6 mg,
38% for 0.37 mmol scale, after column chromatography). NMR data
are identical to previous obtained sample (v.s.).
mg, 58% for 0.36 mmol scale besides 3,6-dichloro-5-methoxy-2,2′-
1
bipyridine, after column chromatography); mp 63 °C; H NMR (500
MHz, CDCl3): δ 8.73 (br s, 1H), 8.33 (br s, 1H), 7.76 (td, J = 7.6, 1.6
Hz, 1H), 7.72 (br d, J = 7.0 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.30−
7.27 (m, 1H), 3.87 (s, 1H); 13C{1H} NMR (126 MHz, CDCl3): δ
156.0, 155.7, 149.2, 147.3, 136.3, 136.0, 130.5, 124.5, 123.1, 122.3,
56.1; IR (v/cm−1): 1583, 1455, 1424, 1273, 1239, 1206, 1177, 1142,
1097, 1032, 991, 871, 801, 747; HRMS (ESI-TOF) m/z: [M + H]+
calcd for C11H10ClN2O 221.0476; found 221.0485.
3,6-Dichloro-5-methoxy-2,2′-bipyridine (17f). Pale yellow solid
(12.5 mg, 14%); mp 66−68 °C; 1H NMR (500 MHz, CDCl3): δ 8.73
(d, J = 4.4 Hz, 1H), 7.80 (td, J = 7.5, 1.5 Hz, 1H), 7.75 (dt, J = 7.9, 1.1
Hz, 1H), 7.32 (ddd, J = 7.4, 4.8, 1.4 Hz, 1H), 7.33 (s, 1H), 3.98 (s,
3H); 13C{1H} NMR (126 MHz, CDCl3): δ 155.0, 151.6, 149.2, 145.9,
138.4, 136.6, 129.5, 124.7, 123.4, 121.5, 56.8; IR (v/cm−1): 1568,
1456, 1413, 1324, 1213, 1123, 1081, 1016, 867, 798, 745; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H9Cl2N2O 255.0086; found
255.0087, [M + Na]+ calcd for C11H8Cl2N2ONa 276.9906; found
276.9908.
3-Chloro-5-methyl-2,2′-bipyridine (15g). Brown oil (59.8 mg, 85%
for 0.32 mmol scale, after extraction); 1H NMR (400 MHz, CDCl3): δ
8.74 (d, J = 4.7 Hz, 1H), 8.43 (s, 1H), 7.81 (td, J = 7.6, 1.7 Hz, 1H),
7.75 (d, J = 7.8 Hz, 1H), 7.63 (s, 1H), 7.33 (ddd, J = 7.2, 4.9, 1.3 Hz,
1H), 2.37 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 155.8, 151.8,
149.0, 148.3, 138.8, 136.7, 134.7, 130.0, 124.7, 123.4, 17.9; IR (v/
cm−1): 1585, 1446, 1426, 1380, 1105, 1034, 898, 799, 746; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C11H10ClN2 205.0527; found
205.0542.
3-Chloro-5-methoxycarbonyl-2,2′-bipyridine (15h). Tan solid
1
(66.4 mg, 93% for 0.29 mmol scale, after extraction); mp 52 °C; H
NMR (400 MHz, CDCl3): δ 9.17 (d, J = 1.8 Hz, 1H), 8.79 (d, J = 4.3
Hz, 1H), 8.42 (dd, J = 1.8, 0.8 Hz, 1H), 7.88 (td, J = 7.8, 1.7 Hz, 1H),
7.83 (d, J = 7.8 Hz, 1H), 7.42 (ddd, J = 7.0, 4.9, 1.3 Hz, 1H), 3.98 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3): δ 164.5, 157.7, 154.9, 149.1,
148.4, 139.6, 137.1, 130.6, 126.7, 125.0, 124.2, 52.9; IR (v/cm−1):
1726, 1584, 1424, 1377, 1279, 1104, 1088, 1033, 992, 958, 761, 742;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C12H10ClN2O2 249.0425;
found 249.0440, [M + Na]+ calcd for C12H9ClN2O2Na 271.0245;
found 271.0261.
3-Chloro-2,2′-bipyridine (15a). Pale orange oil (34.9 mg, 37% for
1
0.49 mmol scale, after extraction); H NMR (400 MHz, CDCl3): δ
8.73 (d, J = 3.2 Hz, 1H), 8.59 (d, J = 3.9 Hz, 1H), 7.78 (dd, J = 8.0, 1.2
Hz, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.31 (ddd, J = 7.2, 4.9, 1.2 Hz, 1H),
7.25 (dd, J = 8.1, 4.6 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ
156.1, 155.0, 149.3, 147.6, 138.4, 136.4, 130.5, 124.5, 124.2, 123.5; IR
(v/cm−1): 1569, 1412, 1104, 1030, 991, 796, 746; HRMS (ESI-TOF)
m/z: [M + H]+ calcd for C10H8ClN2 191.0371; found 191.0384, [M +
Na]+ calcd for C10H7ClN2Na 213.0190; found 213.0208, [M + K]+
calcd for C10H7ClN2K 228.9929; found 228.9958. Attempted
deoxygenation with Pd/C and NH4CO2H: 7a (51.7 mg, 0.25 mmol)
was dissolved in MeOH (1.30 mL) and NH4CO2H (158 mg, 2.51
mmol) and Pd/C (w = 10%, 26.0 mg, 0.024 mmol) were added as
solids. The reaction mixture was stirred at room temperature for 5 h,
the volatiles were removed, and the residue was extracted with DCM.
After removal of the solvent from the extracted solution, only starting
material (53.4 mg, 0.26 mmol, quant.) was recovered.
3-Chloro-6-methoxy-2,2′-bipyridine (15p). Colorless oil (35.0 mg,
1
66% for 0.24 mmol scale, after column chromatography); H NMR
(400 MHz, CDCl3): δ 8.74 (d, J = 4.8 Hz, 1H), 7.80 (td, J = 7.5, 1.6
Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.32 (ddd,
J = 6.9, 4.8, 1.1 Hz, 1H), 6.74 (d, J = 8.7 Hz, 1H), 3.95 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 162.1, 156.5, 151.4, 149.0,
141.14, 141.12, 136.4, 124.6, 123.3, 122.3, 112.10, 112.08, 54.0; IR (v/
cm−1): 1583, 1567, 1460, 1408, 1322, 1252, 1129, 823, 797, 745;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10ClN2O 221.0476;
found 221.0489, [M + Na]+ calcd for C11H9ClN2ONa 243.0296;
found 243.0308.
3-Chloro-6-methyl-2,2′-bipyridine (15b). Pale yellow oil (46.4 mg,
1
58% for 0.36 mmol scale, after column chromatography); H NMR
(400 MHz, CDCl3): δ 8.73 (d, J = 4.5 Hz, 1H), 7.77 (td, J = 7.7, 1.8
Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.30 (ddd,
3-Chloro-6-trifluoromethyl-2,2′-bipyridine (15r). Yellow solid
(67.8 mg, 85% for 0.31 mmol scale, after extraction); mp 51−53
P
DOI: 10.1021/acs.joc.7b00444
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
°C; 1H NMR (400 MHz, CDCl3): δ 8.76 (d, J = 4.9 Hz, 1H), 8.01 (d,
J = 8.3 Hz, 1H), 7.86 (td, J = 7.7, 1.8 Hz, 1H), 7.81 (dt, J = 7.9, 1.0 Hz,
1H), 7.67 (d, J = 8.3 Hz, 1H), 7.40 (ddd, J = 7.3, 4.8, 1.3 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3): δ 155.6, 155.3, 149.2, 146.1 (q, J =
35.7 Hz), 140.0, 136.9, 133.8, 124.8, 124.1, 121.3 (q, J = 274.3 Hz),
121.0 (q, J = 2.6 Hz); 19F NMR (376 MHz, CDCl3): δ −67.5; IR (v/
cm−1): 1395, 1334, 1185, 1122, 1097, 1032, 845, 742; HRMS (ESI-
TOF) m/z: [M + H]+ calcd for C11H7ClF3N2 259.0244; found
259.0266, [M + Na]+ calcd for C11H6ClF3N2Na 281.0064; found
281.0083.
3-Chloro-4′-methyl-2,2′-bipyridine (15u). Tan solid (110 mg, 95%
for 0.57 mmol scale, after extraction); mp 61 °C; 1H NMR (400 MHz,
CDCl3): δ 8.57 (br s, 2H), 7.78 (dd, J = 8.1, 1.4 Hz, 1H), 7.54 (s, 1H),
7.24 (dd, J = 8.1, 4.6 Hz, 1H), 7.14 (d, J = 5.0 Hz, 1H), 2.38 (s, 3H);
13C{1H} NMR (101 MHz, CDCl3): δ 155.8, 155.0, 148.8, 147.9,
147.5, 138.4, 130.5, 125.3, 124.5, 124.1, 21.2; IR (v/cm−1): 1604,
1568, 1433, 1385, 1141, 1117, 1099, 1035, 993, 835, 800, 774, 762;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C11H10ClN2 205.0527;
found 205.0532, [M + Na]+ calcd for C11H9ClN2Na 227.0346; found
227.0355.
found 241.0532, [M + Na]+ calcd for C14H9ClN2Na 263.0346; found
263.0350.
3,4-Dichloro-2-(pyridin-2-yl)quinoline (17z). Pale yellow solid
1
(17.2 mg, 13%); mp 101−103 °C; H NMR (400 MHz, CDCl3): δ
8.80 (d, J = 4.1 Hz, 1H), 8.25 (dd, J = 8.4, 0.7 Hz, 1H), 8.18 (d, J = 8.4
Hz, 1H), 7.88 (td, J = 7.7, 1.8 Hz, 1H), 7.81−7.76 (m, 2H), 7.70 (ddd,
J = 7.9, 7.0, 0.8 Hz, 1H), 7.42 (dd, J = 7.6, 4.9 Hz, 1H, ArH-4′);
13C{1H} NMR (101 MHz, CDCl3): δ 156.7, 156.0, 149.4, 146.2,
141.4, 136.7, 130.7, 130.3, 128.9, 126.8, 126.4, 124.6, 124.5, 123.9; IR
(v/cm−1): 1564, 1476, 1380, 1351, 1335, 1310, 1285, 1111, 905, 851,
792, 760, 736, 711; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C14H9Cl2N2 275.0137; found 275.0144, [M + Na]+ calcd for
C14H8Cl2N2Na 296.9957; found 296.9959.
Syntheses of Catalyst Intermediates. (2,2′-Bipyridin-3-yl-N-
oxide)palladium Acetate Dimer (Dimer A). An argon-purged Schlenk
flask was charged with Pd2dba3·CHCl3 (1.01 g, 0.98 mmol), 3-
bromobipyridine N-oxide 2a (508 mg, 2.02 mmol), and dry toluene
(20.0 mL). The mixture was stirred at 50 °C for 1 h and then cooled
to room temperature before the flask was opened to air. The volatiles
were removed in vacuum, and the solid residue was redissolved in
DCM (20.0 mL). AgOAc (1.01 g, 6.06 mmol) was added as a solid,
and the resulting mixture was stirred at room temperature for 2.5 h.
The reaction mixture was filtered through Celite, the filtrate was
concentrated in vacuum, and Et2O was added, which resulted in the
formation of a yellow solid. The clear yellow supernatant solution was
decanted, and the solid was washed with Et2O and dried in vacuum
providing dimer A (624 mg, 0.93 mmol, 95%) as a yellow solid. Single
crystals for X-ray diffraction were grown by slow diffusion of Et2O into
a concentrated solution of A in DCM. CCDC-1476427 contains the
3-Chloro-4′-fluoro-2,2′-bipyridine (15v). Colorless solid (42.7 mg,
62% for 0.33 mmol scale, after column chromatography); mp 74−76
1
°C; H NMR (400 MHz, CDCl3): δ 8.72 (dd, J = 8.5, 5.7 Hz, 1H),
8.62 (d, J = 4.6 Hz, 1H), 7.84 (dd, J = 8.1, 1.4 Hz, 1H), 7.53 (dd, J =
9.6, 2.5 Hz, 1H), 7.32 (dd, J = 8.1, 4.6 Hz, 1H), 7.10 (ddd, J = 8.2, 5.6,
2.5 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ 168.8 (d, J = 263
Hz), 159.2 (d, J = 7.1 Hz), 153.9 (d, J = 3.7 Hz), 151.7 (d, J = 7.1 Hz),
147.7, 138.8, 130.7, 124.7, 112.7 (d, J = 18.0 Hz), 111.5 (d, J = 16.2
Hz); 19F NMR (376 MHz, CDCl3): δ −101.7 (q, J = 8.8 Hz); IR (v/
cm−1): 1579, 1448, 1388, 1188, 1038, 905, 874, 845, 812, 766; HRMS
(ESI-TOF) m/z: [M + H]+ calcd for C10H7ClFN2 209.0276; found
209.0293, [M + Na]+ calcd for C10H6ClFN2Na 231.0096; found
231.0113, [M + K]+ calcd for C10H6ClFN2K 246.9817; found
246.9817.
3-Chloro-4′-ethoxycarbonyl-2,2′-bipyridine (15w). Orange solid
(61.2 mg, 70% for 0.34 mmol scale, after extraction); mp 99−102 °C;
1H NMR (400 MHz, CDCl3): δ 8.91 (br s, 1H), 8.65 (br s, 1H), 8.34
(s, 1H), 7.92 (dd, J = 5.0, 1.3 Hz, 1H), 7.86 (dd, J = 8.1, 1.4 Hz, 1H),
7.33 (dd, J = 8.1, 4.6 Hz, 1H), 4.43 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3): δ 164.9, 157.1, 154.2,
150.0, 147.8, 138.7, 138.5, 124.6, 124.0, 122.8, 62.1, 14.3; IR (v/cm−1):
1720, 1442, 1376, 1308, 1295, 1251, 1228, 1129, 1020, 813, 750;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C13H12ClN2O2 263.0582;
found 263.0598, [M + Na]+ calcd for C13H11ClN2O2Na 285.0401;
found 285.0432.
1
crystallographic data for dimer A. Mp 204 °C (decomp.); H NMR
(400 MHz, CDCl3, major isomer): δ 9.07 (ddd, J = 8.3, 1.6, 0.7 Hz,
2H), 7.99 (ddd, J = 5.6, 1.7, 0.7 Hz, 2H), 7.75−7.69 (m, 4H), 6.83
(dd, J = 7.7, 1.2 Hz, 2H), 6.76 (ddd, J = 7.4, 5.5, 1.5 Hz, 2H), 6.74 (dd,
J = 7.7, 6.4 Hz, 2H), 2.24 (s, 8H); 13C{1H} NMR (126 MHz, CDCl3):
δ 182.6, 157.6, 149.7, 148.7, 147.6, 139.6, 136.8, 125.5, 123.3, 122.4,
24.8; IR (v/cm−1): 1559, 1524, 1401, 1253, 1244, 1205, 902, 782, 746,
+
706; HRMS (ESI-TOF) m/z: [M-OAc]+ calcd for C22H17N4O4Pd2+
614.9324; found 614.9368, [M + Na]+ calcd for C24H20N4NaO6Pd2
696.9354; found 696.9401. Elemental analysis (%): Anal. calcd for
C24H20N4O6Pd2: C, 42.8; H, 2.99; N, 8.32. Found: C, 42.8; H, 3.34; N,
8.36.
(2,2′-Bipyridin-3-yl-N-oxide)palladium Succinimidate (Dimer B).
A mixture of palladium acetate dimer A (336 mg, 0.5 mmol) and
succinimide (101 mg, 1.02 mmol) in MeCN (20.0 mL) was stirred at
40 °C for 1.5 h. The volatiles were removed, the residue was
redissolved in CHCl3 (20.0 mL), and the resulting solution was stirred
at 40 °C for an additional 1.5 h. The reaction solution was
concentrated in vacuum, and Et2O was added, which resulted in
formation of a yellow precipitation. The supernatant liquid was
decanted, and the solid was washed with Et2O and dried in vacuum.
The dimer B (372 mg, 0.50 mmol, quant.) was obtained as a yellow
3-Chloro-4′-trifluoromethyl-2,2′-bipyridine (15x). Colorless solid
(22.3 mg, 37% for 0.23 mmol scale, after column chromatography);
1
mp 49−50 °C; H NMR (400 MHz, CDCl3): δ 8.94 (d, J = 5.0 Hz,
1H), 8.65 (d, J = 4.6 Hz, 1H), 8.05 (s, 1H), 7.87 (dd, J = 8.1, 1.5 Hz,
1H), 7.58 (dd, J = 5.1, 1.0 Hz, 1H), 7.35 (dd, J = 8.1, 4.6 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3): δ 157.6, 153.7, 150.2, 147.8, 139.0
(q, J = 34.3 Hz), 138.9, 130.8, 124.9, 122.9 (q, J = 273.4 Hz) 120.5 (d,
J = 3.6 Hz), 119.1 (d, J = 3.4 Hz); 19F NMR (376 MHz, CDCl3): δ
−64.6; IR (v/cm−1): 1397, 1334, 1277, 1164, 1131, 1086, 1033, 870,
838, 798, 779; HRMS (ESI-TOF) m/z: [M + H]+ calcd for
C11H7ClF3N2 259.0244; found 259.0248, [M + Na]+ calcd for
C11H6ClF3N2Na 281.0064; found 281.0057.
1
solid. Mp >250 °C (decomp.); H NMR (400 MHz, CDCl3): δ 9.21
(d, J = 8.3 Hz, 2H), 7.94 (d, J = 5.4 Hz, 2H), 7.78−7.70 (m, 4H), 6.83
(t, J = 6.6 Hz, 2H), 6.61 (dd, J = 7.6, 6.6 Hz, 2H), 6.43 (d, J = 7.7 Hz,
2H), 2.91−2.79 (m, 8H); 13C{1H} NMR (126 MHz, CDCl3): δ 195.7,
188.2, 157.1, 149.3, 148.4, 146.7, 140.0, 136.9, 130.5, 125.6, 123.8,
122.8, 32.2, 32.1; IR (v/cm−1): 1589, 1379, 1244, 1215, 897, 789, 747,
706; HRMS (ESI-TOF) m/z: [M
+
Na]+ calcd for
+
C28H22N6NaO6Pd2 774.9563; found 774.9609, [0.5 M + Na]+ calcd
for C14H11N3NaO3Pd+ 397.9727; found 397.9751.
3-Chloro-2-(pyridin-2-yl)quinoline (15z). Pale yellow solid (64.9
mg, 57% for 0.47 mmol scale besides 3,4-dichloro-2-(pyridin-2-
yl)quinoline, after column chromatography); mp 87−88 °C; 1H NMR
(400 MHz, CDCl3): δ 8.78 (d, J = 4.7 Hz, 1H), 8.28 (s, 1H), 8.16 (d, J
= 8.3 Hz, 1H), 7.87−7.78 (m, 2H), 7.76 (d, J = 8.2 Hz, 1H), 7.71
(ddd, J = 8.4, 7.0, 1.4 Hz, 1H), 7.56 (td, J = 7.6, 7.1, 1.0 Hz, 1H), 7.37
(ddd, J = 6.8, 4.9, 1.7 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3): δ
156.5, 155.4, 149.3, 146.1, 136.7, 136.5, 130.0, 129.8, 128.3, 128.0,
127.2, 126.6, 124.7, 123.6; IR (v/cm−1): 1582, 1568, 1479, 1434, 1400,
1370, 1310, 1092, 1047, 994, 971, 952, 900, 860, 772, 750, 734, 711;
HRMS (ESI-TOF) m/z: [M + H]+ calcd for C14H10ClN2 241.0527;
(4-Ethoxycarbonyl-2,2′-bipyridine-N-oxide)palladium(II) Acetate
(Monomer C). Pd(OAc)2 (56.3 mg, 0.25 mmol) and 4-ethoxycarbon-
yl-2,2′-bipyridine N-oxide (122 mg, 0.50 mmol) were dissolved in
DCM (3.00 mL) under vigorous stirring. Precipitation occurred within
the first 2 min. The mixture was additionally stirred at room
temperature for 12 h, before Et2O (3.00 mL) was added. The
supernatant liquid was decanted, the remaining solid was washed with
Et2O, and dried in vacuum. The title complex was obtained as a 2:1
mixture with 4-ethoxycarbonyl-2,2′-bipyridine N-oxide (190 mg).
Single crystals for X-ray diffraction were grown by slow diffusion of
Q
DOI: 10.1021/acs.joc.7b00444
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The Journal of Organic Chemistry
Article
Et2O into a concentrated solution in CDCl3. CCDC-1476437 contains
the crystallographic data for monomer C. Mp 154 °C; 1H NMR (400
MHz, CDCl3): δ 10.57 (d, J = 1.9 Hz, 2H), 8.71 (d, J = 5.2 Hz, 2H),
8.25 (d, J = 6.8 Hz, 2H), 8.02 (dd, J = 6.8, 2.5 Hz, 2H), 7.89 (dd, J =
8.0, 0.9 Hz, 2H), 7.87−7.79 (m, 2H, overlapping with free
noncoordinated N-oxide), 7.30 (ddd, J = 7.5, 5.8, 1.6 Hz, 2H), 4.49
(q, J = 7.1 Hz, 4H), 1.57 (s, 6H), 1.46−1.37 (m, 6H, overlapping with
noncoordinated N-oxide); IR (v/cm−1): 1718, 1624, 1361, 1304, 1246,
1206, 776; HRMS (ESI-TOF) m/z: [M-OAc]+ calcd for
C28H27N4O8Pd+ 653.0858; found 653.0964, [M − (OAc)2 + OMe]+
calcd for C27H27N4O7Pd+ 625.0909; found 625.1013.
General Procedure for Mechanistic Experiments under
Catalytic Conditions. 8 mL reaction vials were charged with 1a
(0.25 mmol), NBS (0.30 mmol), a palladium source (5 mol % based
on [Pd]), chlorobenzene (2.50 mL), and if applicable the additive.
NBu4OAc (0.025 mmol, 10 mol %) was directly weighted out together
with the substrate, and the liquids were added using Hamilton syringe.
Pyridine (20 μL, 0.25 mmol) was added neat, and HOAc was added as
stock solution in chlorobenzene (0.25 M, 100 μL, 0.025 mmol, 10 mol
%). After stirring at 110 °C for 1 h, the vials were cooled to room
temperature, the reaction mixtures were transferred into round-bottom
flasks, and the solvent was removed by rotary evaporation. The solid
residues were additionally dried in high vacuum for several hours,
before being redissolved in CDCl3. The solutions were directly filtered
through a short plug of Celite (pipet), and the filtrate was transferred
into NMR tubes and analyzed by 1H NMR. Only isolated peaks of the
starting material 1a and brominated product 2a were used for
integration. The average of 3−4 integrals for each compound was used
to calculate the ratio 2a to 1a.
Scheme 11. Bromination of phenylpyridine
[10]t
[9]0
k1
k2 − k1
b =
c =
=
(e−k t − e−k t
)
1
2
(2)
[11]t
[9]0
1
(k2e−k t − k1e−k t
)
1
2
= 1 −
k2 − k1
(3)
The product fractions b and c can be expressed independent of time by
inserting eq 1 into eqs 2 and 3, respectively, where s is the ratio of the
rate constants according to eq 4.
k2
k1
s =
(4)
(5)
a − as
s − 1
b =
sa − as
s − 1
c = 1 −
(6)
(7)
a + b + c = 1
The values of a, b, and c are obtained directly from the yields of 9,
10, and 11. If the starting material is not reisolated, a can be calculated
by eq 7. The ratio of the rate constants s can in principle be obtained
from eq 5. However, eq 5 cannot be solved for s by using elementary
functions. Therefore, it is easier to find the solution for s numerically
by a simple iterative search. In the case of the bromination of 9 under
our conditions, b = 0.49 and c = 0.13 are found experimentally, from
which a = 0.38 is calculated. For these values, s = 0.4323 solves eq 5,
meaning that k1 is approximately 2.3 times larger than k2 (Figure 1).
General Procedure for Mechanistic Experiments under
Stoichiometric Conditions. 20 mL reaction vials were charged
with dimer A or B (0.075 mmol), NBS (0.17 mmol), pyridine (120
μL, 1.50 mmol), and chlorobenzene (7.5 mM, based on palladium
dimer). NBu4OAc (22.9 mg, 0.075 mmol) was directly weighted out
together with the palladium dimer and NBS. HOAc was added as
stock solution in chlorobenzene (0.25 M, 1.20 mL, 0.30 mmol). After
stirring at 110 °C for 10 min, the vials were cooled to room
temperature, the reaction mixtures were transferred into round-bottom
flasks, and the solvent was removed by rotary evaporation. The solid
residues were additionally dried in high vacuum for several hours,
before a stock solution of 1,3,5-trichlorobenzene (TCB) in CDCl3
(0.17 M, 0.25 mL, 0.042 mmol) was added. The mixtures were directly
filtered through a short plug of Celite (pipet), and the filtrate was
1
transferred into NMR tubes and analyzed by H NMR. Only isolated
peaks were used for quantification. The average values of several
integrals for each compound were used to calculate the yields.
Detection of Monomer C and Dimer A. A reaction vial was
charged with 1a (51.5 mg, 0.30 mmol), Pd(OAc)2 (68.4 mg, 0.30
mmol), and CDCl3 (0.60 mL) and sealed. After stirring at room
temperature for 3 h a precipitation was formed, which was allowed to
settle, and the supernatant solution was transferred into an NMR tube
and measured by 1H NMR. 1H NMR (400 MHz, CDCl3): δ 9.13 (dd,
J = 8.1, 1.6 Hz, 2H), 8.79 (td, J = 7.9, 1.3 Hz, 2H), 8.54 (dd, J = 6.4,
1.2 Hz, 2H), 8.43 (dd, J = 5.7, 1.1 Hz, 2H), 8.12 (d, J = 7.3 Hz, 2H),
7.87 (td, J = 7.8, 1.6 Hz, 2H), 7.65 (ddd, J = 8.0, 6.4, 1.7 Hz, 2H), 7.48
(ddd, J = 7.6, 5.7, 1.4 Hz, 2H), 1.98 (s, 6H); then, the reaction mixture
was treated with one drop of HOAc resulting in formation of a clear
solution. The solution was stirred under heating at 50 °C for an
additional 3 h before again being measured by 1H NMR. The
spectrum showed besides the formation of dimer A an additional set of
signals.
Figure 1. Plot of b as a function of s according to eq 5 for a = 0.38.
The literature14a reports the yield of 10, but not the conversion or the
amount of 11; only b = 0.63 is known, which is not sufficient to
calculate s. However, the concentration of 10 passes through a
maximum during the course of the reaction. By treating b as a function
of a, the maximum is easily found and the respective values for a and b
are given in eqs 8 and 9.
Estimation of Relative Rate Constants for Formation of 10
and 11. The bromination of 9 to 10 and 11 (Scheme 11) is a
sequential reaction. Hence, the molar fractions a, b, and c of the three
components can be derived from the integrated rate laws and are given
by eqs 1, 2, and 3, respectively.45
amax = s1/(1−s)
(8)
1
bmax
=
(s1/(1−s) − ss/(1−s)
)
(9)
1 − s
[9]t
[9]0
1
a =
= e−k t
With bmax = 0.63, s = 0.2499 (i.e., k1 is at least 4.0 times larger than
k2) can be numerically found as a solution of eq 9 (Figure 2). This
(1)
R
DOI: 10.1021/acs.joc.7b00444
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The Journal of Organic Chemistry
Article
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Figure 2. Plot of bmax as a function of s according to eq 9.
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value for s is the upper limit for the ratio of the rate constants under
the assumption that the concentration of monobrominated product 10
passed the maximum in the moment, when the reaction was stopped.
If the same approach is applied to our result with bmax = 0.48, one
obtains s = 0.5265 (i.e., k1 is at least 1.9 times larger than k2) as the
upper limit for s, which is close to the value obtained above.
Clearly, eq 5 is not applicable for s = 1. In this case, b is given by eq
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b = −a·ln a
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amax = e−1
(8a)
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bmax = e−1
(9a)
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00444.
■
(14) (a) Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S.
Tetrahedron 2006, 62, 11483−11498. (b) Song, B.; Zheng, X.; Mo, J.;
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S
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1657−1712.
́ ́
quez-Cespedes, S.;
1H, 13C, and 19F NMR spectra for all new compounds
(PDF)
Compounds 2a, 2f, 2n, dimer A, and monomer C (CIF)
́
(17) (a) Butschke, B.; Schwarz, H. Chem. Sci. 2012, 3, 308−326.
(b) Lersch, M.; Tilset, M. Chem. Rev. 2005, 105, 2471−2526.
(18) (a) Young, K. J. H.; Mironov, O. A.; Periana, R. A.
Organometallics 2007, 26, 2137−2140. (b) Young, K. J. H.;
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AUTHOR INFORMATION
Corresponding Author
*E-mail: tzschucke@chemie.fu-berlin.de.
■
ORCID
C. Christoph Tzschucke: 0000-0003-1489-6330
Notes
The authors declare no competing financial interest.
(19) Zuber, M.; Pruchnik, F. P. Polyhedron 2006, 25, 2773−2777.
(20) (a) Minghetti, G.; Stoccoro, S.; Cinellu, M. A.; Soro, B.; Zucca,
A. Organometallics 2003, 22, 4770−4777. (b) Butschke, B.; Schlangen,
ACKNOWLEDGMENTS
M.; Schroder, D.; Schwarz, H. Chem. - Eur. J. 2008, 14, 11050−11060.
̈
■
(c) Crosby, S. H.; Clarkson, G. J.; Rourke, J. P. Organometallics 2011,
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Chem. Soc., Chem. Commun. 1985, 0, 609−611. (h) Zucca, A.;
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We thank Prof. Rainer Haag for continuing generous support of
our work. Funding by the Deutsche Forschungsgemeinschsft
(DFG, Grant Tz 68/3-1 to C.C.T.) is gratefully acknowledged.
S.P.Z. thanks the Fonds der Chemischen Industrie (FCI) for
support by a scholarship.
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