Regioselective Pd-Catalyzed Synthesis of 2,3,6-Trisubstituted Pyridines from Isoxazolinones

Article abstract of DOI:10.1021/acs.joc.5b01065

Substituted pyridines are prevalent heterocycles of fundamental importance. Their efficient regioselective preparation is often still a challenge despite a large number of reported synthetic methodologies. In this letter we report an operationally simple approach that makes use of readily accessible isoxazolinones. The protocol involves a Pd(II)-catalyzed C-regioselective 1,4-addition to vinylketones, followed by a Pd(0)-catalyzed transformation, which is assumed to proceed via vinylnitrene-Pd intermediates. Both hydrogen and air are necessary for the pyridine formation step and could be employed at ratios above the upper explosive limit thus avoiding a safety issue. This new strategy allows an effective, scalable and practical access to various previously unknown 2,3,6-trisubstituted pyridines.

Full text of DOI:10.1021/acs.joc.5b01065

Article
pubs.acs.org/joc
Regioselective Pd-Catalyzed Synthesis of 2,3,6-Trisubstituted
Pyridines from Isoxazolinones
Stefan Rieckhoff, Tina Hellmuth, and Rene Peters*
́
Institut fur Organische Chemie, Universitat Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
̈
̈
S
* Supporting Information
ABSTRACT: Substituted pyridines are prevalent heterocycles of
fundamental importance. Their efficient regioselective preparation is
often still a challenge despite a large number of reported synthetic
methodologies. In this letter we report an operationally simple approach
that makes use of readily accessible isoxazolinones. The protocol
involves a Pd(II)-catalyzed C-regioselective 1,4-addition to vinylketones,
followed by a Pd(0)-catalyzed transformation, which is assumed to
proceed via vinylnitrene-Pd intermediates. Both hydrogen and air are
necessary for the pyridine formation step and could be employed at
ratios above the upper explosive limit thus avoiding a safety issue. This
new strategy allows an effective, scalable and practical access to various previously unknown 2,3,6-trisubstituted pyridines.
toward 2,3,6-trisubstituted pyridines (Scheme 1). It involves a
regioselective Pd(II)-catalyzed 1,4-addition of isoxazolinones
INTRODUCTION
■
On account of their wide range of applications in very different
fields, pyridines are among the most important aromatic
heterocycles.1 They are present as a structural motif in many
bioactive compounds2 including active pharmaceutical ingre-
dients or drug candidates,3 as well as agrochemicals.4 They are
also frequently utilized as synthetic building blocks,1,5 as ligands
in metal complexes6 or in supramolecular chemistry,7 polymer
chemistry and materials science.8 In addition they are useful as
nucleophilic/basic catalysts9 or for the development of
cooperative Lewis acid/onium salt catalysts.10
Scheme 1. Two-Step Synthesis of 2,3,6-Trisubstituted
Pyridines 3 from Isoxazolinones 1
Because of the significance of pyridines, much effort has been
devoted toward their synthesis.1,11 A very attractive strategy is
the metal-catalyzed [2 + 2 + 2] cycloaddition of a nitrile and
two alkyne molecules.12 Unfortunately, the intermolecular
version of this methodology often suffers from regioselectivity
problems. The condensation of dicarbonyl substrates with
ammonia also plays a prominent role,1,13 but only certain
substitution patterns are efficiently accessible. Several methods
which make use of substrates containing a relatively labile N−O
bond have also been reported, often avoiding the oxidation step
of a dihydropyridine intermediate, which is usually necessary
for the traditional condensation of dicarbonyl substrates with
ammonia.14 Various recently developed methodologies for the
de novo construction of substituted pyridines have efficiently
addressed the issues of regioselectivity, diversity and step
economy.11,14d−j In this context, and as a consequence of the
great importance of substituted pyridine derivatives,2−10 we
found that there is still a demand for practical, atom-economic,
catalytic routes for a rapid, cost-efficient, regioselective access of
2,3,6-trisubstituted pyridines starting from readily available
precursors.
(systematic name: 4H-isoxazol-5-ones), which are readily
prepared from β-ketoesters and hydroxylamine,15 to enones.
The 1,4-adducts are subsequently transformed into pyridines
catalyzed by Pd(0) in the presence of H2 and air. This latter
reaction is assumed to take place via vinylnitrene intermediates,
which have recently been proposed to be generated on
exposure of isoxazolinones to Pd(0) via oxidative addition of
the reactive N−O bond followed by a decarboxylation.16
RESULTS AND DISCUSSION
■
Conjugate additions of isoxazolinones are known to typically
suffer from regioselectivity problems.17,18 It has been reported
that C-alkylations are usually accompanied by formation of
significant amounts of N-alkylation products. Very recently we
have reported the first enantio- and regioselective Michael
addition of isoxazolinones to vinylketones forming quaternary
carbons.19 This reaction is efficiently catalyzed by a planar
chiral pentaphenylferrocenyl palladacycle. However, as achiral
aromatic products were targeted in the present investigation,
Herein, we report an operationally simple, divergent
methodology for a step-economic regioselective synthesis
Received: May 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.5b01065
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The Journal of Organic Chemistry
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we have reinvestigated the 1,4-addition of isoxazolinones to
develop an operationally simple and nonenantioselective
catalytic method (Table 1) still offering high levels of
regioselectivity, which is more cost-efficient than using the
above-mentioned palladacycle.20
of the isoxazolinone is supposed to coordinate to the Lewis-
acidic Pd(II), thus facilitating the substrate enolization in I by
the basic acetate ligand to form the heteroaromatic nucleophile
II (Scheme 2).22 Protonation of the initial 1,4-adduct III would
close the catalytic cycle and release the product.
Table 1. Optimization of the 1,4-Addition of Isoxazolinones
to Vinylketones
Scheme 2. Possible Simplified Mechanistic Scenario for the
Pd(OAc)2-Catalyzed 1,4-Addition
X
T
ratio
yield 4aA
a
b
#
catalyst
KOtBu
mol % solvent
(°C) 4aA:5aA
(%)
1
10
10
10
10
10
360
10
120
1
THF
25
25
−78
25
25
25
25
25
25
25
25
25
25
25
25
47:53
31:69
50:50
23:77
23:77
−
43
24
46
20
15
0
2
NaOMe
NaOMe
Cs2CO3
NaOAc
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
3
4
5
6
HOAc
7
NEt3
MeOH
MeOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
28:72
71:29
89:11
87:13
84:16
78:22
32:68
23:77
−
22
65
89
87
80
71
27
16
8
NEt3
With the 1,4-adduct 4aA the pyridine formation was
investigated under various conditions using Pd(0) catalysts
(Table 2).
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ni(OAc)2
Mn(OAc)2
10
11
12
13
14
15
0.5
0.1
0.05
10
10
−
Table 2. Optimization of the Pyridine Formation
c
c
−
−
a
b
1
1
Determined by H NMR of the crude product. Determined by H
NMR analysis of the crude product using mesitylene as an internal
c
standard. The corresponding tetrahydrate complex was used as
catalyst.
a
#
catalyst
Pd/C
X mol %
solvent
yield (%)
1
b
5
MeOH
THF
73
0
Promoting the 1,4-addition by catalytic amounts of alkoxide
bases (10 mol %) provided mainly the undesired N-alkylation
regioisomer 5aA for the model reaction of isoxazolinone 1a and
methylvinylketone (2A, MVK, entries 1−3). A similar
preference was found for inorganic bases like Cs2CO3 (entry
4) or simple alkaline acetate salts like NaOAc (entry 5). With
an excess of acetic acid (entry 6) no product was formed,
whereas catalytic amounts of NEt3 in MeOH gave mainly the
N-alkylation product (entry 7). With an excess of NEt3 the C-
alkylation product became the dominant product,17b but still
with a moderate regioselectivity (entry 8). Because of the
above-mentioned efficiency of a neutral palladacycle in the
asymmetric version of this reaction,19 Pd(OAc)2 (1 mol %) was
investigated and provided the targeted C-alkylation regioisomer
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
5
b
5
dioxane
THF
0
5
94
89
84
68
98
0
5
dioxane
MeCN
toluene
dioxane
dioxane
5
5
0.5
0.1
a
Determined by 1H NMR analysis of the crude product using
mesitylene as internal standard. This reaction was performed in the
b
absence of H2.
With catalytic amounts of Pd/C (5 mol %) in MeOH at 25
°C the product was formed in a promising yield of 73% under
an atmosphere of H2 provided by a balloon (entry 1). H2 was
initially just employed in order to activate an old batch of Pd/
C. However, the investigation of Pd(PPh3)4 as catalyst revealed,
that the presence of H2 is−in contrast to our initial
expectations−essential for the product formation. Neither in
THF nor in 1,4-dioxane there was any product formation in the
absence of H2 (entries 2 and 3). In contrast, under 1 bar of H2
the product was formed in good yields in both solvents (entries
4 and 5). A similar result was obtained in MeCN (entry 6) and
toluene (entry 7). Gratifyingly, when the catalyst loading was
4aA with a significant excess and in good yield (entry 9).21
A
useful reaction outcome was still noticed with Pd(OAc)2 loads
of 0.5, 0.1, 0.05 mol % (entries 10−12). Other divalent acetate
salts like Ni(OAc)2 or Mn(OAc)2 were not efficient for the C-
alkylation even with loadings of 10 mol % (entry 13 and 14)
and the N-alkylation was dominating. In the absence of a
catalyst, no alkylation product was formed (entry 15).
We assume that the mechanism of the Pd(OAc)2 catalyzed
1,4-addition is related to the above-mentioned enantioselective
reaction catalyzed by a planar chiral palladacycle.19 The N atom
B
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Table 3. Investigation of the Scope
a
entry
3
R1
R2
R3
X mol %
Y mol %
yield step 1/2 (%)
1
2
3
4
5
6
7
3aA
3bA
3cA
3dA
3eA
3fA
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Bn
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
5
5
0.5
0.5
1
89/98
89/97
92/96
71/94
50/95
95/92
69/93
69/99
44/99
33/89
69/91
60/87
87/89
88/93
95/97
50/85
64/95
68/82
99/88
Me
nPr
5
CH2C6H4-4-Me
5
0.5
0.5
1
CH2C6H4-4-OMe
5
CH2-2-naphthyl
5
3gA
3gA*
3hA
3iA
CH2C6H4-4-NO2
5
1
b
8
CH2C6H4-4-NO2
5
5
9
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
5
1
10
C6H4-4-OMe
5
1
b
11
3jA*
3kA
3lA
C6H4-4-NO2
5
1
12
13
14
15
16
17
18
C6H4-3-OMe
5
1
Me
Ph
Ph
Ph
Ph
5
1
3aB
3aC
3aD
3aE
3mA
3n′A
5
1
(CH2)2Ph
Ph
10
5
1
1
C6H4-4-OMe
Me
10
5
1
(CH2)4
CH2CH2C(O)Me
5
c
19
Ph
Me
5
1
a
b
c
Yield of isolated product. The nitro group was reduced to a primary amino function. R2 = H in the starting isoxazolinone 1n, which was applied to
a double alkylation with MVK.
reduced to 0.5 mol % the reaction in 1,4-dioxane resulted in
nearly quantitative product formation. A further decrease to 0.1
mol % gave no product, possibly due to catalyst inhibition by
small amounts of substrate impurities below the detection level
amino function, even with 1 mol % of Pd(PPh3)4 (entry 11).
Isoxazolinones with an alkyl residue R1 (entry 13) and
vinylketones with alkyl and aryl groups R3 can be employed,
too (entries 14−17). Moreover, it is possible to form bicyclic
pyridine derivatives as entry 18 shows in which a tetrahy-
droquinoline 3mA was obtained in good overall yields starting
from a [4.3.0]-bicyclic isoxazolidinone 1n. Variation of the ring
size of the second ring would in principle allow access to other
bicyclic pyridine skeletons.23 Entry 19 describes a double
alkylation of an isoxazolinone, in which R2 = H. The efficiency
of the subsequent pyridine generation demonstrates the
compatibility with an additional keto group in the product.24
In addition we have shown for both reactions described in
entry 1 that the pyridine formation is scalable. In the first step
the Pd(OAc)2 loading was reduced to 0.1 mol % (0.4 mg
Pd(OAc)2 for 449.0 mg starting material 1a) resulting in a yield
of 76% of the isolated pure C-alkylation isomer 4aA (C/N-
alkylation ratio of the crude product: 84/16). The second step
was repeated using 621 mg of 4aA to provide 500 mg of 3aA (1
mol % catalyst, quantitative yield).
Mechanistically the pyridine formation might be explained by
the intermediacy of a vinylnitrene-Pd species 7 formed by
oxidative addition of Pd(0) to the N−O bond of 4 followed by
a decarboxylation of 6. Vinylnitrene-Pd intermediates have
recently been proposed by Ohe.16,25 The vinylnitrene might
then undergo an intramolecular [2 + 2] cycloaddition with the
ketone moiety to give the bicyclic [4.2.0] oxazapalladetidine 8,
which would then undergo a cycloreversion to give
dihydropyridine 9 and a Pd(II)-species (Scheme 3).26
1
of H NMR.
As both steps require the use of a Pd catalyst, the possibility
of a one-pot procedure using only one catalyst portion was also
considered, in which CH2Cl2 was exchanged by 1,4-dioxane and
PPh3 was added as a ligand. However, in this case using 5 mol
% of the Pd source there was nearly no conversion of the 1,4-
adduct 4aA to the pyridine 3aA. Purification of 4aA might be
mandatory to avoid catalyst inhibition.
The 2-step sequence was then applied to different
isoxazolinones and vinylketones (Table 3). Various types of
residues R2 at the CH-acidic isoxazolinone position were well
tolerated. With alkyl residues such as methyl and n-propyl
(entries 2 and 3) similarly high yields were obtained as with a
benzyl residue (entry 1). A range of isoxazolinones carrying
electron withdrawing (p-NO2) or donating (p-Me, p-OMe)
substituents at a benzylic residue or a 2-naphthylmethylene
group R2 furnished useful results (entries 4−7). Surprisingly,
the p-NO2-group was not reduced during the second step when
1 mol % of catalyst was employed (entry 7). In contrast, using 5
mol % of Pd(PPh3)4 the corresponding aniline was obtained in
high yield (entry 8). An aromatic substituent directly bound to
the isoxazolinone 4-position led to a decreased yield for the 1,4-
addition step (44%), but the subsequent pyridine generation
proceeded almost quantitatively (entry 9).
Variation of the R1-residue at the 3-position is also possible
(entries 10−13). An electron rich aryl moiety somewhat
hampered the 1,4-addition, but again the following step
furnished high yields of the aromatic heterocycles (entry 10).
Also in this case the p-NO2-group was reduced to a primary
The existence of intermediate 9 is supported by ESI-MS
measurements performed after a reaction time of 1.5 h, which
showed next to the starting material 4c a prominent species
with m/z = 214.1583 (calculated: 214.1596, R3 = Me). Initially
C
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Pd-catalyzed reaction sequence that possibly involves vinyl-
nitrene intermediates. The synthetic utility of the new method
is underscored by the fact that only two out of 19 pyridines
described in Table 3 are to our knowledge currently known
compounds. We thus anticipate that the operationally simple
route will help to contribute to new developments using
pyridines.
Scheme 3. Possible Mechanism of the Pyridine Formation
from Isoxazolinone 4
EXPERIMENTAL SECTION
■
General Procedure for the 1,4-Additions Using Palladium(II)
Acetate as Catalyst (GP1). To a solution of the corresponding
isoxazol-5(4H)-one (1 equiv, recrystallized from EtOH prior to use)19
in CH2Cl2 (0.6 M) was added palladium(II) acetate (1−10 mol %)
and subsequently the corresponding vinyl ketone (4 equiv). After 1 h
of stirring at room temperature, the solvent was removed and the
crude product was subjected to column chromatography (silica, petrol
ether/ethyl acetate: 4/1).
General Procedure for the Pyridine Formation (GP2). To a
solution of the 1,4-adduct (1 equiv) in 1,4-dioxane was added
tetrakis(triphenylphosphine)palladium(0) (0.5−5 mol %) as stock
solution, so that a substrate concentration of 0.1 M was achieved.
Hydrogen (over a balloon) was bubbled through the solution for 10
min. Thereafter the solution was set under a hydrogen atmosphere and
it was stirred for 24 h at room temperature. The solvent was
evaporated and the crude product was subjected to column
chromatography (silica, petrol ether/ethyl acetate: 4/1) to give the
respective pyridine.
we were hoping that 9 might be aromatized by the generated
Pd(II) species to close the catalytic cycle in a redox-neutral
pathway. The observation though that hydrogen is required
points to a different scenario in which hydrogen is essential to
turnover the catalytic cycle by regeneration of a catalytically
active Pd(0) species.
1,4-Additions of Isoxazolinones to Vinyl Ketones. 4-Benzyl-4-
(3-oxobutyl)-3-phenylisoxazol-5(4H)-one (4aA). According to GP1,
to 1a (50.0 mg, 0.20 mmol, 1.0 equiv) was added palladium(II) acetate
(2.2 mg, 9.80 μmol, 5 mol %). Subsequently, 2A (67 μL, 0.79 mmol, 4
equiv) was added to yield 4aA (57.0 mg, 0.18 mmol, 89%) as a
colorless solid.
The stoichiometric oxidant for the aromatization step is most
likely air, which apparently entered the reaction vessel via the
H2-balloon used.27 This is supported by the fact that in an
autoclave in the absence of oxygen using otherwise identical
conditions there is almost no conversion. Dihydropyridine 9 is
then also not generated in significant quantities, which might be
explained by inhibition of the catalyst by, e.g., 9 or the
corresponding 1,4-dihydropyridine tautomer or follow-up
products of these species forming relatively inert complexes,
if oxidation is not taking place.
As the amount of oxygen inside will depend on the quality of
the balloon type used, we also investigated a different setup to
ensure reproducibility on the one hand and avoiding safety
issues on the other hand caused by potentially explosive H2/O2
mixtures. For that reason we have repeated the reaction using
4aA in a sealed tube and added a calculated amount of air to
generate a H2/air mixture with a ratio 79.7/20.3% (Scheme 4).
C20H19NO3: MW 321.38 g/mol; 1H NMR (CDCl3, 500 MHz) δ =
7.81−7.75 (m, 2H), 7.62−7.46 (m, 3H), 7.22−7.09 (m, 3H), 6.87−
6.80 (m, 2H), 3.32 (d, J = 13.7, 1H), 3.29 (d, J = 13.7, 1H), 2.67−2.16
(m, 4H), 2.08 (s, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Methyl-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one (4bA). Ac-
cording to GP1, to 1b (50.0 mg, 0.29 mmol, 1.0 equiv) was added
palladium(II) acetate (3.2 mg, 14.27 μmol, 5 mol %). Subsequently,
2A (96 μL, 1.14 mmol, 4 equiv) was added to yield 4bA (63.3 mg,
0.26 mmol, 89%) as a colorless oil.
C14H15NO3: MW 245.28 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.78−7.22 (m, 2H), 7.58−7.44 (m, 3H), 7.49−2.10 (m, 4H), 2.06 (s,
3H), 1.62 (s, 3H).
The analytical data are in accordance with literature data for
Scheme 4. Use of a Nonexplosive H2/Air Mixture for the
Pyridine Generation Step
enantioenriched material.19
4-(3-Oxobutyl)-3-phenyl-4-propylisoxazol-5(4H)-one (4cA). Ac-
cording to GP1, to 1c (50.0 mg, 0.25 mmol, 1.0 equiv) was added
palladium(II) acetate (2.8 mg, 12.30 μmol, 5 mol %). Subsequently,
2A (83 μL, 0.98 mmol, 4 equiv) was added to yield 4cA (61.2 mg, 0.22
mmol, 91%) as a colorless solid.
C16H19NO3: MW 273.33 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.79−7.73 (m, 2H), 7.58−7.44 (m, 3H), 2.46−2.15 (m, 4H), 2.06 (s,
3H), 2.05−1.95 (m, 2H), 1.30−1.06 (m, 2H), 0.85 (t, J = 7.8 Hz, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
This ratio is above the upper explosive limit and should thus
avoid a risk of explosion.28 The data obtained under these
conditions are comparable to the data obtained using a balloon.
4-(4-Methylbenzyl)-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one
(4dA). According to GP1, to 1d (50.0 mg, 0.19 mmol, 1.0 equiv) was
added palladium(II) acetate (2.1 mg, 9.42 μmol, 5 mol %).
Subsequently, 2A (64 μL, 0.75 mmol, 4 equiv) was added to yield
4dA (44.9 mg, 0.13 mmol, 71%) as a colorless solid.
CONCLUSION
■
C21H21NO3: MW 335.40 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.81−7.75 (m, 2H), 7.58−7.45 (m, 3H), 6.91 (d, J = 7.9 Hz, 2H), 6.71
(d, J = 7.9 Hz, 2H), 3.30 (d, J = 13.8, 1H), 3.23 (d, J = 13.8, 1H),
2.62−2.25 (m, 4H), 2.21 (s, 3H), 2.05 (s, 3H).
In conclusion, we have reported a straightforward methodology
that allows a rapid and regioselective entry to substituted
pyridines starting from readily accessible isoxazolinones. In this
synthetic sequence a C-regioselective alkylation is followed by a
D
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The analytical data are in accordance with literature data for
enantioenriched material.19
Subsequently, 2A (60 μL, 0.71 mmol, 4 equiv) was added to yield
4kA (37.5 mg, 0.11 mmol, 60%) as a colorless solid.
C21H21NO4: MW 351.40 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.43 (t, J = 7.4 Hz, 1H), 7.37−7.29 (m, 2H), 7.19−7.08 (m, 4H),
6.89−6.84 (m, 2H), 3.85 (s, 3H), 3.35 (d, J = 13.7, 1H), 3.28 (d, J =
13.8, 1H), 2.64−2.15 (m, 4H), 2.08 (s, 3H).
4-(4-Methoxybenzyl)-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one
(4eA). According to GP1, to 1e (50.0 mg, 0.18 mmol, 1.0 equiv) was
added palladium(II) acetate (2.0 mg, 8.88 μmol, 5 mol %).
Subsequently, 2A (60 μL, 0.71 mmol, 4 equiv) was added to yield
4eA (31.2 mg, 0.09 mmol, 50%) as a colorless solid.
The analytical data are in accordance with literature data for
C21H21NO4: MW 351.40 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.81−7.76 (m, 2H), 7.61−7.47 (m, 3H), 6.77−6.73 (m, 2H), 6.68−
6.63 (m, 2H), 3.72 (s, 3H), 3.29 (d, J = 13.9, 1H), 3.23 (d, J = 13.9,
1H), 2.63−2.14 (m, 4H), 2.08 (s, 3H, COCH3).
enantioenriched material.19
4-Benzyl-3-methyl-4-(3-oxobutyl)isoxazol-5(4H)-one (4lA). Ac-
cording to GP1, to 1l (50.0 mg, 0.26 mmol, 1.0 equiv) was added
palladium(II) acetate (3.0 mg, 13.21 μmol, 5 mol %). Subsequently,
2A (90 μL, 1.06 mmol, 4 equiv) was added to yield 4lA (61.0 mg, 0.24
mmol, 87%) as colorless solid.
The analytical data are in accordance with literature data for
enantioenriched material.19
C15H17NO3: MW 259.12 g/mol; 1H NMR (CDCl3, 500 MHz) δ =
7.32−7.22 (m, 3H), 7.13−7.04 (m, 2H), 3.21 (d, J = 13.6, 1H), 2.91
(d, J = 14.5, 1H), 2.55−2.41 (m, 1H), 2.29−2.09 (m, 3H), 2.15 (s,
3H), 2.04 (s, 3H).
4-(Naphthalen-2-ylmethyl)-4-(3-oxobutyl)-3-phenylisoxazol-
5(4H)-one (4fA). According to GP1, to 1f (50.0 mg, 0.17 mmol, 1.0
equiv) was added palladium(II) acetate (1.9 mg, 8.30 μmol, 5 mol %).
Subsequently, 2A (56 μL, 0.66 mmol, 4 equiv) was added to yield 4fA
(58.5 mg, 0.16 mmol, 95%) as colorless solid.
The analytical data are in accordance with literature data for
C24H21NO3: MW 371.44 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.81−7.70 (m, 3H), 7.64−7.48 (m, 5H), 7.47−7.37 (m, 2H), 7.30−
7.24 (m, 1H), 6.99−6.91 (m, 1H), 3.36 (s, 2H), 2.75−2.20 (m, 4H),
2.09 (s, 3H).
enantioenriched material.19
4-Benzyl-4-(3-oxopentyl)-3-phenylisoxazol-5(4H)-one (4aB). Ac-
cording to GP1, to 1a (50.0 mg, 0.20 mmol, 1.0 equiv) was added
palladium(II) acetate (2.2 mg, 9.95 μmol, 5 mol %). Subsequently, 2B
(67.0 mg, 0.80 mmol, 4 equiv) was added to yield 4aB (58.7 mg, 0.18
mmol, 88%) as a colorless solid.
The analytical data are in accordance with literature data for
enantioenriched material.19
4-(4-Nitrobenzyl)-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one
(4gA). According to GP1, to 1g (50.0 mg, 0.17 mmol, 1.0 equiv) was
added palladium(II) acetate (1.9 mg, 8.43 μmol, 5 mol %).
Subsequently, 2A (57 μL, 0.68 mmol, 4 equiv) was added to yield
4gA (42.7 mg, 0.12 mmol, 69%) as a colorless solid.
C21H21NO3: MW 335.40 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.80−7.73 (m, 2H), 7.60−7.45 (m, 3H), 7.21−7.08 (m, 3H), 6.87−
6.80 (m, 2H), 3.33 (d, J = 13.8, 1H), 3.28 (d, J = 14.1, 1H), 2.67−2.54
(m, 1H), 2.48−2.28 (m, 4H), 2.26−2.12 (m, 1H), 0.98 (t, J = 7.6 Hz,
3H).
C20H18N2O5: MW 366.37 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.93 (d, J = 11.4, 2H), 7.71 (d, J = 6.9, 2H), 7.59−7.43 (m, 3H), 6.93
(d, J = 8.4, 2H), 3.36 (d, J = 13.5, 1H), 3.30 (d, J = 13.5, 1H), 2.65−
2.11 (m, 4H), 2.03 (s, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Benzyl-4-(3-oxo-5-phenylpentyl)-3-phenylisoxazol-5(4H)-one
(4aC). According to GP1, to 1a (50.0 mg, 0.20 mmol, 1.0 equiv) was
added palladium(II) acetate (4.4 mg, 19.90 μmol, 10 mol %).
Subsequently, 2C (127.5 mg, 0.80 mmol, 4 equiv) was added to yield
4aC (77.8 mg, 0.19 mmol, 95%) as a colorless solid.
The analytical data are in accordance with literature data for
enantioenriched material.19
4-(3-Oxobutyl)-3,4-diphenylisoxazol-5(4H)-one (4hA). According
to GP1, to 1h (50.0 mg, 0.21 mmol, 1.0 equiv) was added
palladium(II) acetate (2.4 mg, 10.53 μmol, 5 mol %). Subsequently,
2A (71 μL, 0.84 mmol, 4 equiv) was added to yield 4hA (28.5 mg,
0.09 mmol, 44%) as a colorless oil.
C27H25NO3: MW 411.50 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.76 (d, J = 7.7, 2H), 7.61−7.47 (m, 3H), 7.24−7.05 (m, 8H), 6.83 (d,
J = 8.3, 2H), 3.32 (d, J = 13.8, 1H), 3.29 (d, J = 13.8, 1H), 2.89−2.77
(m, 2H), 2.70−2.51 (m, 3H), 2.48−2.32 (m, 2H), 2.25−2.10 (m, 1H).
The analytical data are in accordance with literature data for
enantioenriched material.19
C19H17NO3: MW 307.35 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.53−7.48 (m, 2H), 7.46−7.29 (m, 8H), 2.92−2.79 (m, 1H), 2.66−
1.37 (m, 2H), 2.31−2.16 (m, 1H), 2.09 (s, 3H).
4-Benzyl-4-(3-oxo-3-phenylpropyl)-3-phenylisoxazol-5(4H)-one
(4aD). According to GP1, to 1a (50.0 mg, 0.20 mmol, 1.0 equiv) was
added palladium(II) acetate (2.2 mg, 9.95 μmol, 5 mol %).
Subsequently, 2D (105.7 mg, 0.80 mmol, 4 equiv) was added to
yield 4aD (38.3 mg, 0.10 mmol, 50%) as a colorless solid.
C25H21NO3: MW 383.45 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.88−7.79 (m, 4H), 7.59−7.48 (m, 4H), 7.21−7.11 (m, 3H), 6.90−
6.85 (m, 2H), 3.41 (d, J = 13.4, 1H), 3.35 (d, J = 13.8, 1H), 3.12−2.97
(m, 1H), 2.86−2.55 (m, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Benzyl-3-(4-methoxyphenyl)-4-(3-oxobutyl)isoxazol-5(4H)-one
(4iA). According to GP1, to 1i (50.0 mg, 0.18 mmol, 1.0 equiv) was
added palladium(II) acetate (2.0 mg, 8.89 μmol, 5 mol %).
Subsequently, 2A (60 μL, 0.71 mmol, 4 equiv) was added to yield
4iA (20.6 mg, 0.06 mmol, 33%) as colorless solid.
C21H21NO4: MW 351.40 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.78−7.71 (m, 2H), 7.21−7.09 (m, 3H), 7.03−6.98 (m, 2H), 6.88−
6.83 (m, 2H), 3.89 (s, 3H), 3.32 (d, J = 13.6, 1H), 3.26 (d, J = 13.6,
1H), 2.63−2.12 (m, 4H), 2.07 (s, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Benzyl-4-(3-(4-methoxyphenyl)-3-oxopropyl)-3-phenylisoxa-
zol-5(4H)-one (4aE). According to GP1, to 1a (50.0 mg, 0.20 mmol,
1.0 equiv) was added palladium(II) acetate (2.2 mg, 9.95 μmol, 5 mol
%). Subsequently, 2E (129.8 mg, 0.80 mmol, 4 equiv) was added to
yield 4aE (52.7 mg, 0.13 mmol, 64%) as a colorless solid.
C26H23NO4: MW 413.47 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
7.87−7.77 (m, 4H), 7.62−7.44 (m, 3H), 7.24−7.09 (m, 3H), 6.93−
6.83 (m, 4H), 3.85 (s, 3H), 3.40 (d, J = 14.2, 1H), 3.35 (d, J = 14.2,
1H), 3.06−2.53 (m, 4H).
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Benzyl-3-(4-nitrophenyl)-4-(3-oxobutyl)isoxazol-5(4H)-one
(4jA). According to GP1, to 1j (50.0 mg, 0.17 mmol, 1.0 equiv) was
added palladium(II) acetate (1.9 mg, 8.44 μmol, 5 mol %).
Subsequently, 2A (57 μL, 0.68 mmol, 4 equiv) was added to yield
4jA (42.7 mg, 0.12 mmol, 69%) as a colorless solid.
C20H18N2O5: MW 366.37 g/mol; 1H NMR (CDCl3, 300 MHz) δ =
8.34 (d, J = 9.7, 2H), 7.93 (d, J = 10.3, 2H), 7.22−7.06 (m, 3H), 6.77
(d, J = 8.0, 2H), 3.35 (d, J = 14.0, 1H), 3.25 (d, J = 14.0, 1H), 2.66−
2.36 (m, 3H), 2.26−2.11 (m, 1H), 2.07 (s, 3H).
The analytical data are in accordance with literature data for
enantioenriched material.19
3a-(2-Oxopropyl)-4,5,6,7-tetrahydrobenzo[c]isoxazol-3(3aH)-one
(4mA). According to GP1, to 1m (50.0 mg, 0.36 mmol, 1.0 equiv) was
added palladium(II) acetate (4.0 mg, 18.00 μmol, 5 mol %).
Subsequently, 2A (121 μL, 1.44 mmol, 4 equiv) was added to yield
4mA (51.1 mg, 0.24 mmol, 68%) as a colorless oil.
The analytical data are in accordance with literature data for
enantioenriched material.19
4-Benzyl-3-(3-methoxyphenyl)-4-(3-oxobutyl)isoxazol-5(4H)-one
(4kA). According to GP1, to 1k (50.0 mg, 0.18 mmol, 1.0 equiv) was
added palladium(II) acetate (2.0 mg, 8.89 μmol, 5 mol %).
E
DOI: 10.1021/acs.joc.5b01065
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
C11H15NO3: MW 209.25 g/mol; 1H NMR (CDCl3, 500 MHz) δ =
2.68−1.34 (m, 12H), 2.11 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ =
206.2, 180.8, 172.2, 49.8, 37.6, 34.2, 30.1, 27.3, 25.6, 25.2, 20.5; IR
698, 632, 609, 578, 535; MS (ESI) m/z 274.16 (100%, [M + H]+);
HRMS (ESI) m/z calcd. for [C20H19N + H]+ 274.1590, found
274.1593.
(ATR) v = 2944, 2867, 2254, 1781, 1714, 1621, 1448, 1366, 1315,
4-(4-Methoxybenzyl)-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one
(3eA). According to GP2, to a solution of 4eA (50.0 mg, 0.14 mmol, 1
equiv) was added tetrakis(triphenylphosphine)palladium(0) (0.8 mg,
0.71 μmol, 0.5 mol %), and the reaction was set under hydrogen to
yield 3eA (39.1 mg, 0.14 mmol, 95%) as a colorless oil.
̃
1279, 1213, 1166, 1144, 1079, 1043, 1014, 986, 941, 912, 861, 838,
727, 647, 592, 566, 552; MS (ESI) m/z 232.10 (100%, [M + Na]+);
HRMS (ESI) m/z calcd. for [C11H15NO3 + Na]+ 232.0944, found
232.0958.
1
C20H19NO: MW 289.37 g/mol; H NMR (CDCl3, 500 MHz) δ =
4,4′-(5-Oxo-3-phenyl-4,5-dihydroisoxazole-4,4-diyl)bis(butan-2-
one) (4n′A). To a suspension of 1n (50.0 mg, 0.31 mmol, 1.0 equiv) in
DCM (0.4 mL) was added palladium(II) acetate (3.4 mg, 15.00 μmol,
5 mol %). Subsequently, 2A (105 μL, 1.24 mmol, 4 equiv) was added
to yield 4n′A (92.6 mg, 0.31 mmol, 99%) as a colorless oil.
C17H19NO4: MW 301.34 g/mol; 1H NMR (CDCl3, 500 MHz) δ =
7.76 (d, 2H), 7.58−7.45 (m, 3H), 2.44−2.15 (m, 8H); 13C NMR
(CDCl3, 75 MHz) δ = 205.5, 180.1, 166.7, 132.3, 129.6, 127.1, 126.5,
7.48−7.31 (m, 6H), 7.07 (d, J = 7.9, 1H), 6.92 (d, J = 9.0, 2H), 6.79 (d,
J = 8.9, 2H), 3.90 (s, 2H), 3.78 (s, 3H), 2.59 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ = 158.3, 158.0, 155.8, 140.7, 138.6, 132.8, 131.1,
129.8, 129.0, 128.3, 127.9, 122.0, 113.9, 55.3, 37.3, 24.4; IR (ATR) v =
̃
3000, 2932, 2834, 1610, 1588, 1565, 1510, 1461, 1440, 1384, 1301,
1247, 1176, 1119, 1034, 910, 820, 798, 748, 700, 633, 536; MS (EI)
m/z 289.20 (100%, [M]+); HRMS (EI) m/z calcd. for [C20H19NO]+
289.1467, found 289.1458.
53.5, 38.0, 29.9, 29.7; IR (ATR) v = 2929, 1789, 1714, 1551, 1499,
̃
6-Methyl-3-(naphthalen-2-ylmethyl)-2-phenylpyridine (3fA). Ac-
cording to GP3, to a solution of 4fA (50.0 mg, 0.13 mmol, 1 equiv)
was added tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 1.35
μmol, 1.0 mol %), and the reaction was set under hydrogen to yield
3fA (38.3 mg, 0.12 mmol, 92%) as a colorless oil.
1447, 1420, 1366, 1264, 1231, 1162, 1119, 1087, 949, 883, 804, 775,
693, 634, 590, 569; MS (ESI) m/z 324.12 (100%, [M + Na]+); HRMS
(ESI) m/z calcd. for [C17H19NO4 + Na]+ 324.1206, found 324.1207.
Pyridine Synthesis. 3-Benzyl-6-methyl-2-phenylpyridine (3aA).
According to GP2, to a solution of 4aA (50.0 mg, 0.16 mmol, 1 equiv)
was added tetrakis(triphenylphosphine)palladium(0) (0.9 mg, 0.78
μmol, 0.5 mol %), and the reaction was set under hydrogen to yield
3aA (40.6 mg, 0.16 mmol, 98%) as a colorless oil.
1
C23H19NO: MW 309.40 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.84−7.48 (m, 1H), 7.77−7.70 (m, 2H), 7.53−7.36 (m, 8H), 7.18−
7.14 (m, 1H), 7.09 (d, J = 7.7, 1H), 4.15 (s, 2H), 2.63 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ = 158.5, 156.1, 140.7, 138.8, 128.3, 133.6,
132.1, 130.5, 129.1, 128.3, 128.2, 128.0, 127.6, 127.5, 127.4, 127.2,
1
C19H17N: MW 259.35 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.48−7.43 (m, 2H), 7.43−7.34 (m, 4H), 7.28−7.15 (m, 3H), 7.08 (d, J
= 7.6, 1H), 7.01 (d, J = 7.6, 2H), 3.98 (s, 2H), 2.61 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ = 158.5, 155.9, 140.69, 140.67, 138.7, 130.7,
129.0, 128.8, 128.5, 128.3, 127.9, 126.2, 122.0, 38.1, 24.3; IR (ATR) v
= 3082, 3058, 3026, 2920, 2846, 1589, 1565, 1493, 1451, 1439, 1384,
1372 1294, 1244, 1169, 1119, 1074, 1057, 1028, 1001, 968, 908, 841,
802, 772, 725, 695, 643, 633, 618, 596, 541, 524; MS (ESI) m/z
260.14 (100%, [M + H]+); HRMS (ESI) m/z calcd. for [C19H17N +
H]+ 260.1434, found 260.1424.
126.1, 125.5, 122.1, 38.4, 24.4; IR (ATR) v = 3051, 2919, 1632, 1590,
̃
1565, 1507, 1495, 1458, 1438, 1371, 1285, 1271, 1243, 1169, 1149,
1120, 1075, 1057, 1027, 956, 928, 858, 813, 799, 756, 741, 699, 633,
620, 608, 580, 538; MS (ESI) m/z 310.16 (100%, [M + H]+); HRMS
(ESI) m/z calcd. for [C23H19N + H]+ 310.1590, found 310.1595.
6-Methyl-3-(4-nitrobenzyl)-2-phenylpyridine (3gA). According to
GP2, to a solution of 4gA (50.0 mg, 0.14 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 1.36 μmol, 1.0 mol
%), and the reaction was set under hydrogen to yield 3gA (38.6 mg,
0.13 mmol, 92%) as a colorless oil.
̃
3,6-Dimethyl-2-phenylpyridine (3bA). According to GP2, to a
solution of 4bA (50.0 mg, 0.20 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.2 mg, 1.01 μmol, 0.5
mol %), and the reaction was set under hydrogen to yield 3bA (35.6
mg, 0.19 mmol, 97%) as a colorless oil.
C19H16N2O2: MW 304.34 g/mol; 1H NMR (CDCl3, 500 MHz) δ =
8.05 (d, J = 7.84, 2H), 7.43−7.30 (m, 6H), 7.11 (d, J = 7.6, 1H), 7.07
(d, J = 8.5, 2H), 4.06 (s, 2H), 2.59 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ = 158.7, 156.8, 148.3, 146.5, 140.3, 138.6, 129.5, 129.1, 128.8,
1
C13H13N: MW 183.25 g/mol; H NMR (CDCl3, 500 MHz) δ =
128.4, 128.1, 123.7, 122.3, 38.2, 24.4; IR (ATR) v = 3056, 2922, 2852,
̃
7.55−7.48 (m, 2H), 7.48−7.41(m, 3H), 7.41−7.33 (m, 1H), 7.03 (d, J
1596, 1566, 1513, 1492, 1459, 1439, 1372, 1342, 1245, 1179, 1109,
1075, 1057, 1027, 1015, 919, 858, 826, 803, 775, 754, 733, 700, 632,
606, 566, 534; MS (ESI) m/z 305.13 (100%, [M + H]+); HRMS (ESI)
m/z calcd. for [C19H16N2O2 + H]+ 305.1285, found 305.1291.
4-((6-Methyl-2-phenylpyridin-3-yl)methyl)aniline (3gA*). Accord-
ing to GP2, to a solution of 4gA (50.0 mg, 0.14 mmol, 1 equiv) was
added tetrakis(triphenylphosphine)palladium(0) (7.9 mg, 6.8 μmol,
5.0 mol %), and the reaction was set under hydrogen to yield 3gA*
(37.1 mg, 0.14 mmol, 99%) as a colorless oil.
= 7.5 Hz, 1H), 2.59 (s, 3H), 2.29 (s, 3H).
The analytical data are in accordance with the literature.29
6-Methyl-2-phenyl-3-propylpyridine (3cA). According to GP2, to a
solution of 4cA (50.0 mg, 0.18 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (2.1 mg, 1.83 μmol, 1.0
mol %), and the reaction was set under hydrogen to yield 3cA (36.5
mg, 0.17 mmol, 96%) as a colorless oil.
1
C15H17N: MW 211.30 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.49 (d, J = 7.9, 1H), 7.46−739 (m, 4H), 7.39−7.32 (m, 1H), 7.08 (d, J
= 7.7, 1H), 2.57 (s, 3H), 2.56 (t, J = 7.7, 2H), 1.50 (m, 2H), 0.83 (t, J =
7.6, 3H); 13C NMR (CDCl3, 75 MHz) δ = 158.2, 155.2, 141.0, 137.6,
1
C19H18N2: MW 274.37 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.48−7.32 (m, 6H), 7.05 (d, J = 7.6, 1H), 6.78 (d, J = 8.1, 2H), 6.58 (d,
J = 8.1, 2H), 3.84 (s, 2H), 2.58 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
= 158.3, 155.7, 144.5, 140.8, 138.5, 131.5, 130.7, 129.7, 129.0, 128.2,
132.3, 128.9, 128.2, 127.6, 121.8, 34.1, 24.2, 24.1, 13.9; IR (ATR) v =
̃
3056, 2958, 2928, 2870, 1590, 1566, 1494, 1459, 1440, 1375, 1293,
1245, 1179, 1128, 1073, 1054, 1027, 916, 828, 806, 778, 751, 735, 699,
633, 609, 568, 535; MS (ESI) m/z 212.14 (100%, [M + H]+); HRMS
(ESI) m/z calcd. for [C15H17N + H]+ 212.1434, found 212.1423.
4-(4-Methylbenzyl)-4-(3-oxobutyl)-3-phenylisoxazol-5(4H)-one
(3dA). According to GP2, to a solution of 4dA (50.0 mg, 0.15 mmol, 1
equiv) was added tetrakis(triphenylphosphine)palladium(0) (0.9 mg,
0.75 μmol, 0.5 mol %), and the reaction was set under hydrogen to
yield 3dA (38.3 mg, 0.14 mmol, 94%) as a colorless oil.
127.8, 122.0, 115.3, 37.2, 24.3; IR (ATR) v = 3445, 3336, 3214, 3054,
̃
3026, 2919, 2848, 2210, 1886, 1621, 1589, 1565, 1513, 1458, 1438,
1373, 1275, 1244, 1177, 1122, 1075, 1057, 1027, 909, 883, 816, 797,
757, 731, 699, 633, 609, 579, 537, 500; MS (ESI) m/z 275.15 (100%,
[M + H]+); HRMS (ESI) m/z calcd. for [C19H18N2 + H]+ 275.1543,
found 275.1530.
6-Methyl-2,3-diphenylpyridine (3hA). According to GP2, to a
solution of 4hA (50.0 mg, 0.16 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.9 mg, 1.63 μmol, 1.0
mol %), and the reaction was set under hydrogen to yield 3hA (39.5
mg, 0.16 mmol, 99%) as a colorless oil.
1
C20H19N: MW 273.37 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.48−7.44 (m, 2H), 7.43−7.33 (m, 4H), 7.09−7.03 (m, 3H), 6.94−
6.88 (m, 2H), 3.94 (s, 2H), 2.60 (s, 3H), 2.32 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ = 158.4, 155.8, 140.7, 138.7, 137.6, 135.6, 130.9,
1
C18H15N: MW 245.32 g/mol; H NMR (CDCl3, 500 MHz) δ =
129.2, 129.0, 128.7, 128.2, 127.8, 122.0, 37.6, 24.3, 21.0; IR (ATR) v =
3050, 3020, 2919, 1590, 1564, 1511, 1494, 1458, 1438, 1380, 1293,
1243, 1180, 1119, 1075, 1056, 1027, 948, 913, 883, 847, 812, 785, 749,
7.60 (d, J = 7.6 Hz, 1H), 7.34−7.32 (m, 1H), 7.23−7.12 (m, 10H),
̃
2.65 (s, 3H).
The analytical data are in accordance with the literature.30
F
DOI: 10.1021/acs.joc.5b01065
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
3-Benzyl-2-(4-methoxyphenyl)-6-methylpyridine (3iA). According
to GP2, to a solution of 4iA (50.0 mg, 0.14 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 1.42 μmol, 1.0 mol
%), and the reaction was set under hydrogen to yield 3iA (36.6 mg,
0.13 mmol, 89%) as a colorless oil.
140.7, 138.8, 130.8, 129.1, 128.9, 128.5, 128.2, 127.9, 126.1, 120.6,
38.1, 31.2, 14.2; IR (ATR) v = 3059, 3026, 2966, 2932, 2872, 1588,
̃
1562, 1494, 1463, 1452, 1438, 1393, 1288, 1222, 1168, 1121, 1074,
1060, 1026, 1001, 973, 918, 872, 843, 819, 770, 725, 698, 632, 546;
MS (ESI) m/z 274.16 (100%, [M + H]+); HRMS (ESI) m/z calcd. for
[C20H19N + H]+ 274.1590, found 274.1591.
1
C20H19NO: MW 289.37 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.34−7.26 (m, 3H), 7.20−7.13 (m, 2H), 7.13−7.06 (m, 1H), 6.96 (d, J
= 7.9, 1H), 6.93 (d, J = 7.5, 2H), 6.85 (d, J = 8.9, 2H), 3.91 (s, 2H),
3.76 (s, 3H), 2.50 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ = 159.5,
158.1, 155.9, 140.8, 138.9, 133.2, 130.6, 130.3, 128.9, 128.5, 126.2,
3-Benzyl-6-phenethyl-2-phenylpyridine (3aC). According to GP2,
to a solution of 4aC (50.0 mg, 0.12 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 1.22 μmol, 1.0 mol
%), and the reaction was set under hydrogen to yield 3aC (41.2 mg,
0.12 mmol, 97%) as a colorless oil.
121.8, 113.7, 55.4, 38.2, 24.3; IR (ATR) v = 3025, 3000, 2930, 2835,
̃
1
1737, 1608, 1590, 1574, 1512, 1493, 1450, 1413, 1382, 1295, 1243,
1174, 1119, 1108, 1074, 1058, 1029, 937, 890, 835, 797, 763, 731, 721,
697, 642, 618, 584, 549, 527; MS (ESI) m/z 290.15 (100%, [M +
H]+); HRMS (ESI) m/z calcd. for [C20H19NO + H]+ 290.1539, found
290.1550.
C26H23N: MW 349.47 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.49−7.33 (m, 6H), 7.32−7.15 (m, 8H), 7.05−6.99 (m, 3H), 3.99 (s,
2H), 3.13 (m, 4H); 13C NMR (CDCl3, 75 MHz) δ = 158.9, 158.5,
141.7, 140.7, 138.7, 131.1, 129.1, 128.8, 128.6, 128.5, 128.3, 128.2,
127.9, 126.2, 125.9, 121.6, 39.8, 38.2, 36.2; IR (ATR) v = 3083, 3059,
̃
4-(3-Benzyl-6-methylpyridin-2-yl)aniline (3jA*). According to
GP2, to a solution of 4jA (50.0 mg, 0.14 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 1.36 μmol, 1.0 mol
%), and the reaction was set under hydrogen to yield 3jA* (34.0 mg,
0.12 mmol, 91%) as a colorless oil.
3025, 2923, 2856, 1601, 1587, 1565, 1494, 1452, 1439, 1393, 1290,
1178, 1116, 1074, 1056, 1028, 918, 843, 809, 751, 728, 698, 670, 632,
542; MS (ESI) m/z 350.19 (100%, [M + H]+); HRMS (ESI) m/z
calcd. for [C26H23N + H]+ 350.1903, found 350.1907.
3-Benzyl-2,6-diphenylpyridine (3aD). According to GP2, to a
solution of 4aD (50.0 mg, 0.13 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.5 mg, 1.30 μmol, 1.0
mol %), and the reaction was set under hydrogen to yield 3aD (35.7
mg, 0.11 mmol, 85%) as a colorless oil.
1
C19H18N2: MW 274.36 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.35 (d, J = 7.6, 1H), 7.29−7.21 (m, 4H), 7.20−7.12 (m, 1H), 7.05−
6.97 (m, 3H), 6.70 (d, J = 8.2, 2H), 4.0 (s, 2H), 2.57 (s, 3H); 13C
NMR (CDCl3, 75 MHz) δ = 158.4, 155.8, 146.2, 140.9, 138.7, 130.9,
130.4, 130.2, 128.9, 128.5, 126.1, 121.4, 114.8, 38.2, 24.3; IR (ATR) v
= 3365, 3218, 3058, 3026, 2922, 1762, 1714, 1611, 1589, 1518, 1493,
1450, 1377, 1288, 1243, 1178, 1118, 1074, 1057, 1029, 910, 835, 794,
764, 729, 698, 645, 619, 580, 545; MS (ESI) m/z 275.15 (100%, [M +
H]+); HRMS (ESI) m/z calcd. for [C19H18N2 + H]+ 275.1543, found
275.1542.
1
̃
C24H19N: MW 321.41 g/mol; H NMR (CDCl3, 500 MHz) δ =
8.11−8.03 (m, 2H), 7.66 (d, J = 8.2, 1H), 7.62−7.54 (m, 3H), 7.50−
7.35 (m, 6H), 7.32−7.16 (m, 3H), 7.07 (d, J = 7.4, 2H), 4.10 (s, 2H);
13C NMR (CDCl3, 75 MHz) δ = 158.7, 154.9, 140.7, 140.6, 139.3,
132.2, 129.3, 128.9, 128.8, 128.7, 128.6, 128.0, 126.9, 126.2, 119.0,
38.3; IR (ATR) v = 3058, 3025, 2930, 2852, 1601, 1584, 1573, 1559,
̃
3-Benzyl-2-(3-methoxyphenyl)-6-methylpyridine (3kA). Accord-
ing to GP2, to a solution of 4kA (50.0 mg, 0.14 mmol, 1 equiv) was
added tetrakis(triphenylphosphine)palladium(0) (1.6 mg, 1.42 μmol,
1.0 mol %), and the reaction was set under hydrogen to yield 3kA
(35.8 mg, 0.12 mmol, 87%) as a colorless oil.
1493, 1452, 1436, 1377, 1315, 1266, 1178, 1156, 1126, 1074, 1027,
1018, 1001, 918, 844, 792, 750, 724, 693, 635, 615, 581, 549, 529, 508;
MS (ESI) m/z 322.16 (100%, [M + H]+); HRMS (ESI) m/z calcd. for
[C24H19N + H]+ 322.1590, found 322.1589.
3-Benzyl-6-(4-methoxyphenyl)-2-phenylpyridine (3aE). According
to GP2, to a solution of 4aE (50.0 mg, 0.12 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 1.21 μmol, 1.0 mol
%), and the reaction was set under hydrogen to yield 3aE (40.4 mg,
0.11 mmol, 95%) as a colorless oil.
1
C20H19NO: MW 289.37 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.33 (d, J = 7.2, 1H), 7.26−7.20 (m, 1H), 7.20−7.13 (m, 2H), 7.13−
7.06 (m, 1H), 7.00 (d, J = 8.1, 1H), 6.96−6.90 (m, 3H), 6.87−6.80 (m,
2H), 3.88 (s, 2H), 3.65 (s, 3H), 2.51 (s, 3H); 13C NMR (CDCl3, 75
MHz) δ = 159.4, 158.3, 155.9, 141.9, 140.8, 138.8, 130.6, 129.3, 128.8,
1
C25H21NO: MW 351.45 g/mol; H NMR (CDCl3, 500 MHz) δ =
128.5, 126.1, 122.1, 121.3, 114.2, 114.1, 55.2, 38.2, 24.3; IR (ATR) v =
̃
8.03 (d, J = 8.8, 2H), 7.63−7.51 (m, 4H), 7.50−7.34 (m, 3H), 7.32−
7.15 (m, 3H), 7.06 (d, J = 7.3, 2H), 6.98 (d, J = 8.7, 2H), 4.08 (s, 2H),
3.86 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ = 160.4, 158.5, 154.6,
140.8, 140.7, 139.2, 131.9, 131.4, 129.3, 129.0, 128.9, 128.5, 128.2,
3059, 3026, 3001, 2935, 2834, 1715, 1679, 1599, 1579, 1492, 1452,
1427, 1382, 1318, 1286, 1246, 1231, 1165, 1119, 1074, 1041, 995, 918,
875, 845, 825, 782, 759, 729, 700, 635, 620, 558, 527; MS (ESI) m/z
290.16 (100%, [M + H]+); HRMS (ESI) m/z calcd. for [C20H19NO +
H]+ 290.1515, found 290.1523.
128.1, 127.9, 126.2, 118.3, 114.1, 113.8, 55.4, 38.3; IR (ATR) v = 3059,
̃
3026, 2931, 2835, 1607, 1584, 1560, 1512, 1494, 1453, 1437, 1376,
1304, 1288, 1250, 1172, 1110, 1074, 1059, 1044, 1029, 919, 833, 815,
784, 766, 725, 699, 669, 638, 565, 526; MS (ESI) m/z 352.17 (100%,
[M + H]+); HRMS (ESI) m/z calcd. for [C25H21NO + H]+ 352.1696,
found 352.1689.
3-Benzyl-2,6-dimethylpyridine (3lA). According to GP2, to a
solution of 4lA (50.0 mg, 0.19 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (2.2 mg, 1.93 μmol, 1.0
mol %), and the reaction was set under hydrogen to yield 3lA (33.9
mg, 0.17 mmol, 89%) as a colorless oil.
1
2-Methyl-5,6,7,8-tetrahydroquinoline (3mA). According to GP2,
to a solution of 4mA (50.0 mg, 0.24 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (13.8 mg, 11.9 μmol, 5.0
mol %), and the reaction was set under hydrogen to yield 3mA (28.8
mg, 0.20 mmol, 82%) as a colorless oil.
C14H15N: MW 197.28 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.25−7.08 (m, 4H), 7.01 (d, J = 6.8, 2H), 6.84 (d, J = 7.6, 1H), 3.85 (s,
2H), 2.42 (s, 3H), 2.37 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ =
156.4, 155.5, 139.5, 137.8, 130.9, 128.7, 128.6, 126.3, 120.8, 38.4, 24.1,
22.6; IR (ATR) v = 3060, 3026, 2919, 1713, 1593, 1576, 1493, 1463,
̃
1
C10H13N: MW 147.22 g/mol; H NMR (CDCl3, 500 MHz) δ =
1450, 1392, 1370, 1263, 1245, 1158, 1114, 1074, 1028, 971, 911, 838,
813, 786, 724, 696, 642, 613, 570, 549, 521; MS (ESI) m/z 198.13
(100%, [M + H]+); HRMS (ESI) m/z calcd. for [C14H15N + H]+
198.1277, found 198.1255.
7.22 (d, J = 8.3, 1H), 6.86 (d, J = 7.3, 1H), 2.87 (t, J = 6.4, 2H), 2.69 (t,
J = 6.2, 2H), 2.47 (s, 3H), 1.90−1.73 (m, 4H); 13C NMR (CDCl3, 300
MHz) δ = 156.4, 155.0, 137.1, 129.0, 120.5, 32.6, 28.4, 24.1, 23.2, 22.8;
IR (ATR) v = 2928, 2858, 2836, 1713, 1594, 1573, 1469, 1438, 1425,
̃
3-Benzyl-6-ethyl-2-phenylpyridine (3aB). According to GP2, to a
solution of 4aB (50.0 mg, 0.15 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (1.7 mg, 1.49 μmol, 1.0
mol %), and the reaction was set under hydrogen to yield 3aB (37.9
mg, 0.14 mmol, 93%) as a colorless oil.
1401, 1372, 1309, 1263, 1243, 1158, 1116, 1034, 985, 936, 898, 862,
831, 806, 732, 710, 607, 562, 535; MS (EI) m/z 147.10 (100%, [M]+);
HRMS (EI) m/z calcd. for [C10H13N]+ 147.1048, found 147.1042.
4-(6-Methyl-2-phenylpyridin-3-yl)butan-2-one (3n′A). According
to GP2, to a solution of 4n′A (50.0 mg, 0.17 mmol, 1 equiv) was
added tetrakis(triphenylphosphine)palladium(0) (9.6 mg, 8.3 μmol,
5.0 mol %), and the reaction was set under hydrogen to yield 3n′A
(34.9 mg, 0.15 mmol, 88%) as a colorless oil.
1
C20H19N: MW 273.38 g/mol; H NMR (CDCl3, 500 MHz) δ =
7.40−7.24 (m, 5H), 7.19−7.12 (m, 2H), 7.12−7.06 (m, 1H), 7.00 (d, J
= 7.9, 1H), 6.92 (d, J = 7.4, 2H), 3.89 (s, 2H), 2.78 (q, J = 7.6, 2H),
1.24 (t, J = 7.6, 3H); 13C NMR (CDCl3, 75 MHz) δ = 161.2, 158.3,
G
DOI: 10.1021/acs.joc.5b01065
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
C16H17NO: MW 239.32 g/mol; H NMR (CDCl3, 500 MHz) δ =
(5) Selected examples: (a) Peters, R.; Althaus, M.; Diolez, C.;
Rolland, A.; Manginot, E.; Veyrat, M. J. Org. Chem. 2006, 71, 5783.
(b) Peters, R.; Diolez, C.; Rolland, A.; Manginot, E.; Veyrat, M.
Heterocycles 2007, 72, 255.
(6) Selected examples: (a) Chan, Y. T.; Moorefield, C. N.; Soler, M.;
Newkome, G. R. Chem.Eur. J. 2010, 16, 1768. (b) Smejkal, T.; Breit,
B. Angew. Chem., Int. Ed. 2008, 47, 311. (c) Kwong, H.-L.; Yeung, H.-
L.; Yeung, C.-T.; Lee, W.-S.; Lee, C.-S.; Wong, W.-L. Coord. Chem.
Rev. 2007, 251, 2188.
7.45 (d, J = 7.7, 1H), 7.43 (d, J = 3.8, 4H), 7.40−7.33 (m, 1H), 7.07 (d,
J = 8.2, 1H), 2.88 (t, J = 7.5, 2H), 2.56 (s, 3H), 2.51 (t, J = 7.6, 2H),
2.00 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ = 207.5, 158.1, 155.9,
140.7, 137.9, 130.7, 128.7, 128.4, 127.9, 122.0, 44.2, 29.8, 26.2, 24.2; IR
(ATR) v = 3056, 2923, 1712, 1591, 1566, 1495, 1460, 1440, 1363,
̃
1287, 1160, 1123, 1063, 1027, 967, 918, 820, 790, 748, 701, 634, 609,
596, 550; MS (ESI) m/z 240.14 (100%, [M + H]+); HRMS (ESI) m/z
calcd. for [C16H17NO + H]+ 240.1377, found 240.1383.
Scale-up Experiment: 1,4-Addition. According to GP1, to 1a
(449.0 mg, 1.79 mmol, 1.0 equiv) was added palladium(II) acetate (0.4
mg, 1.79 μmol, 0.1 mol %). Subsequently, 2A (604 μL, 7.14 mmol, 4
equiv) was added and the reaction was stirred for 24 h. Column
chromatography (silica, petrol ether/ethyl acetate: 4/1) yielded 4aA
(436.1 mg, 1.36 mmol, 76%) as a colorless solid.
Scale-up Experiment: Pyridine Formation. According to GP2,
to a solution of 4aA (621.0 mg, 1.93 mmol, 1 equiv) was added
tetrakis(triphenylphosphine)palladium(0) (35.9 mg, 19.3 μmol, 1.0
mol %), and the reaction was set under hydrogen. After 24 h the
solvent was evaporated and the crude product was subjected to
column chromatography (silica, petrol ether/ethyl acetate: 4/1) to
yield 3aA (500 mg, 1.93 mmol, 100%) as a colorless oil.
Pyridine Formation in a Sealed Tube. A 120 mL sealed tube
was charged with 4aA (30.7 mg, 0.095 mmol, 1 equiv), tetrakis-
(triphenylphosphine)palladium(0) (0.55 mg, 0.47 μmol, 0.5 mol %)
and 1,4-dioxane (1.5 mL). A constant stream of H2 was bubbled
through the solution for 10 min. Thereafter the tube was filled with H2
(94 mL) and air (24 mL) via syringes and sealed. The reaction mixture
was subsequently stirred for 24 h. Column chromatography (silica,
petrol ether/ethyl acetate: 4/1) yielded 3aA (22 mg, 0.085 mmol,
89%) as a colorless oil.
(7) (a) Lehn, J.-M. In Supramolecular ChemistryConcepts and
Perspectives; VCH: Weinheim, 1995. Selected examples: (b) Hofmeier,
H.; Schubert, U. S. Chem. Commun. 2005, 2423.
(8) Selected examples: (a) Makiura, R.; Motoyama, S.; Umemura, Y.;
Yamanaka, H.; Sakata, O.; Kitagawa, H. Nat. Mater. 2010, 9, 565.
(b) Kang, N. G.; Changez, M.; Lee, J. S. Macromolecules 2007, 40,
8553.
(9) Selected examples: (a) Coeffard, V.; Muller-Bunz, H.; Guiry, P. J.
Org. Biomol. Chem. 2009, 7, 1723. (b) Guizzetti, S.; Benaglia, M.;
Rossi, S. Org. Lett. 2009, 11, 2928. (c) Ruble, J. G.; Fu, G. C. J. Org.
Chem. 1996, 61, 7230. (d) Shaw, S. A.; Aleman, P.; Vedejs, E. J. Am.
Chem. Soc. 2003, 125, 13368. (e) Peters, R.; Fischer, D. F.; Jautze, S.
Top. Organomet. Chem. 2011, 33, 139.
(10) (a) Kull, T.; Peters, R. Angew. Chem., Int. Ed. 2008, 47, 5461.
(b) Kull, T.; Cabrera, J.; Peters, R. Chem.Eur. J. 2010, 16, 9132.
(c) Meier, P.; Broghammer, F.; Latendorf, K.; Rauhut, G.; Peters, R.
Molecules 2012, 17, 7121.
(11) Selected recent methods for de novo constructions of
substituted pyridines: (a) Li, Z.; Huang, X.; Chen, F.; Zhang, C.;
Wang, X.; Jiao, N. Org. Lett. 2015, 17, 584. (b) Yoshida, M.;
Mizuguchi, T.; Namba, K. Angew. Chem., Int. Ed. 2014, 53, 14550.
(c) Xi, L.-Y.; Zhang, R.-Y.; Liang, S.; Chen, S.-Y.; Yu, X.-Q. Org. Lett.
2014, 16, 5269. (d) Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135,
3756. (e) Wang, Y.-F.; Chiba, S. J. Am. Chem. Soc. 2009, 131, 12570.
(e) Colby, D. A.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008,
130, 3645. (f) Stark, D. G.; O’Riordan, T. J. C.; Smith, A. D. Org. Lett.
2014, 16, 6496. (g) Sha, F.; Shen, H.; Wu, X.-Y. Eur. J. Org. Chem.
2013, 2537. (h) Kim, S. H.; Kim, K. H.; Kim, H. S.; Kim, J. N.
Tetrahedron Lett. 2008, 49, 1948. (i) Michlik, S.; Kempe, R. Angew.
Chem., Int. Ed. 2013, 52, 6326. (j) Sim, Y.-K.; Lee, H.; Park, J.-W.;
Kim, D.-S.; Jun, C.-H. Chem. Commun. 2012, 48, 11787. (k) Allais, C.;
Lieby-Muller, F.; Constantieux, T.; Rodriguez, J. Adv. Synth. Catal.
2012, 354, 2537. (l) Yamamoto, S.-i.; Okamoto, K.; Murakoso, M.;
Kuninobu, Y.; Takai, K. Org. Lett. 2012, 14, 3182. (m) Sha, F.; Wu, L.;
Huang, X. J. Org. Chem. 2012, 77, 3754.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedures, NMR spectra. The Support-
ing Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.joc.5b01065.
AUTHOR INFORMATION
Corresponding Author
*E-mail: rene.peters@oc.uni-stuttgart.de.
■
Notes
The authors declare no competing financial interest.
(12) (a) Heller, B.; Hapke, M. Chem. Soc. Rev. 2007, 36, 1085.
Selected examples: (b) Suzuki, D.; Nobe, Y.; Watai, Y.; Tanaka, R.;
Takayama, Y.; Sato, F.; Urabe, H. J. Am. Chem. Soc. 2005, 127, 7474.
(c) Tanaka, R.; Yuza, A.; Watai, Y.; Suzuki, D.; Takayama, Y.; Sato, F.;
Urabe, H. J. Am. Chem. Soc. 2005, 127, 7774. (d) Satoh, Y.; Obora, Y.
J. Org. Chem. 2013, 78, 7771. Substituted arenes by [2 + 2 + 2]
cycloadditions of alkynes in general: (e) Galan, B. R.; Rovis, T. Angew.
Chem., Int. Ed. 2009, 48, 2830.
ACKNOWLEDGMENTS
■
This article is dedicated to Professor Franz Effenberger on the
occasion of his 85th birthday. This work was financially
supported by the Deutsche Forschungsgemeinschaft (DFG, PE
818/4-1 and PE 818/4-2).
(13) (a) Lieb
Chem. Commun. 2008, 4207. (b) Donohoe, T. J.; Basutto, J. A.; Bower,
J. F.; Rathi, A. Org. Lett. 2011, 13, 1036. (c) Allais, C.; Lieby-Muller,
F.; Rodriguez, J.; Constantieux, T. Eur. J. Org. Chem. 2013, 4131 and
cited literature.
(14) Selected examples: (a) From isoxazolines: Kanemasa, S.; Asai,
Y.; Tanaka, J. Bull. Chem. Soc. Jpn. 1991, 64, 375. (b) Pyridine N-
oxides from isoxazolines: Foti, F.; Risitano, F.; Grassi, G. J. Chem. Res.,
Synop. 1979, 7, 244. (c) Pyridines from isoxazoles: Ohashi, M.;
Kamachi, H.; Kakisawa, H.; Stork, G. J. Am. Chem. Soc. 1967, 89, 5460.
(d) From oximes via cycloisomerization: Trost, B. M.; Gutierrez, A. C.
Org. Lett. 2007, 9, 1473. (e) From α,β-unsaturated oxime derivatives:
Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135, 66. (f) See ref 11d.
(g) Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.; Chiba, S. Synlett 2011, 2789.
(h) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846.
(i) Chen, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2015, 17, 2567.
́
y-Muller, F.; Allais, C.; Constantieux, T.; Rodriguez, J.
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́
H
DOI: 10.1021/acs.joc.5b01065
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The Journal of Organic Chemistry
Article
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M.; Perez, M.; Pleixats, R. Tetrahedron 1994, 50, 515. (b) Alkylation
́
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(22) The different regioselectivity outcome with other, less soft
acetate salts could be explained by preferential O-coordination of the
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̈
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I
DOI: 10.1021/acs.joc.5b01065
J. Org. Chem. XXXX, XXX, XXX−XXX