Aerobic oxidative amidation of aromatic and cinnamic aldehydes with secondary amines by CuI/2-pyridonate catalytic system

Article abstract of DOI:10.1021/jo301553v

A simple and convenient CuI/2-pyridonate catalytic system for the oxidative amidation of aldehydes with secondary amines has been developed. With this system, a variety of useful arylamides have been synthesized in moderate to good yields in the presence of small amount of copper catalyst and the pyridonate ligand, generating only water as a coproduct. Synthesis of cinnamamides was also achieved by the reactions of cinnamaldehydes with secondary amines in moderate yields. Air was successfully employed as a green oxidant in this catalytic system, achieving a safe and atom-efficient system for the synthesis of amides.

Full text of DOI:10.1021/jo301553v

Article
pubs.acs.org/joc
Aerobic Oxidative Amidation of Aromatic and Cinnamic Aldehydes
with Secondary Amines by CuI/2-Pyridonate Catalytic System
Mingwen Zhu, Ken-ichi Fujita,* and Ryohei Yamaguchi*
Graduate School of Human and Environmental Studies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
S
* Supporting Information
ABSTRACT: A simple and convenient CuI/2-pyridonate
catalytic system for the oxidative amidation of aldehydes
with secondary amines has been developed. With this system, a
variety of useful arylamides have been synthesized in moderate
to good yields in the presence of small amount of copper
catalyst and the pyridonate ligand, generating only water as a coproduct. Synthesis of cinnamamides was also achieved by the
reactions of cinnamaldehydes with secondary amines in moderate yields. Air was successfully employed as a green oxidant in this
catalytic system, achieving a safe and atom-efficient system for the synthesis of amides.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
First, we examined the oxidative coupling of benzaldehyde (1a)
with piperidine (2a) to give 1-benzoylpiperidine (3a) under
various conditions in order to find optimal conditions (Table
1). When the reaction of 1a with 2a was carried out in toluene
under reflux (110 °C) in the presence of CuI (2.0 mol %),
sodium 5-methyl-2-pyridonate (L1) (4.0 mol %), and
molecular sieves 4A for 20 h under air, the formation of the
desired amide product 3a was isolated in 82% yield (entry 1).
Employment of other Cu(I) and Cu(II) salts as the catalyst
instead of CuI resulted in lower yields (entries 2−7). We also
attempted the oxidative amidation of 1a in other solvents such
as p-xylene, mesitylene, diglyme, 1,4-dioxane and water.
However, all of these reactions gave lower yields than that in
toluene.15
Next, we examined the effect of ligand added to the reaction
(entries 8−14). Sodium 2-pyridonate ligands having an
electron-donating substituent on the pyridine ring gave better
yields (entries 1, 8−11) than those having an electron-
withdrawing substituent (entries 12 and 13). When sodium
phenoxide (L8) was used instead of L1, the oxidative amidation
of 1a with 2a proceeded in extremely low yield (entry 14),
suggesting that the copper complex bearing a 2-pyridonate
ligand would act as an important catalytically active species,
which was first proposed in our previous report.14
Amides are a basic and highly important class of compounds
with a variety of biological activities. Amide moiety can be
found in a number of agrochemicals, pharmaceuticals, and
polymeric materials.1 One of the general methods for the
synthesis of amides is the condensation of carboxylic acids with
amines.2 Such reactions usually require a high reaction
temperature to avoid the formation of stable ammonium salts
by the acid−base reaction.2 The carbodiimide-mediated
amidation is another general method for the synthesis of
amides.3 However, generation of a stoichiometric amount of
urea derivatives as coproduct leads to the decrease of atom
efficiency. Other methods for the synthesis of amides include
the aminocarbonylation of haloarenes,4 the Staudinger ligation,5
the Schmidt reaction,6 the Beckmann rearrangement,7 and the
cross-coupling of formamides with aryl/alkyl halides.8 How-
ever, most of these methods generate a large amount of
wasteful byproduct and suffer from low atom efficiency. Thus, a
more environmentally friendly, safe and highly atom-efficient
method for the synthesis of amides is still needed.
In recent years, transition metal (Ru, Rh, La, Pd, and Cu)
catalyzed synthesis of amides by the oxidative coupling of
alcohols9 or aldehydes9d,10−13 with amines have been reported.
Although these catalytic systems provide a new route for the
synthesis of amides, there are still some problems, such as the
use of expensive noble transition metal,9,10,12 the use of a large
excess amount of a substrate,11 or the need of explosive oxidant
(hydrogen peroxide or TBHP),12,13 remaining to be solved.
Meanwhile, we have recently reported the aerobic dehydro-
genative oxidative homocoupling of azoles affording biazoles
catalyzed by a copper(I)/2-pyridonate catalytic system.14 In
this system, air could be employed as a green oxidant for the
oxidative homocoupling. Here, we report a simple and
convenient aerobic oxidative amidation of aldehydes with
secondary amines by a CuI/2-pyridonate catalytic system.
When the reaction was carried out under an argon
atmosphere, only a trace amount of 3a could be obtained
(entry 15). On the contrary, when the reaction was carried out
under an oxygen atmosphere, 86% yield of 3a was observed
(entry 16), indicating that the oxygen in the air must be an
important terminal oxidant. The reaction did not proceed well
in the absence of CuI or 2-pyridonate ligand (entries 17 and
18). Reaction without the addition of molecular sieves resulted
in low yield (entry 19). From the results shown above, we
Received: August 2, 2012
© XXXX American Chemical Society
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bromo, trifluoromethyl, methoxycarbonyl, cyano, and nitro
groups) at the aromatic ring proceeded to give corresponding
amide products in better yields (entries 8−15) than those
bearing an electron-donating substituent. Since the present
reactions were performed in the absence of strong base,
reactions of 4-fluoro, 4-chloro and 4-bromo benzaldehydes
(1h−1j) with 2a gave the corresponding amides (3h−3j)
selectively, remaining halogen substituents intact (entries 8−
10).16
Table 1. Optimization of the Reaction Conditions in the
Aerobic Oxidative Amidation of Benzaldehyde (1a) with
Piperidine (2a)
a
b
entry
catalyst (mol %)
additive ligand (mol %)
yield (%)
The oxidative amidation of 2-naphthaldehyde (1p) with 2a
proceeded in moderate yield (entry 16). Reactions of
heteroaromatic aldehydes required relatively higher catalyst
loadings (10 mol %) to obtain good yields (entries 17−19).
Reaction of terephthaldehyde (1t) bearing two formyl groups
was also examined. As a result, the oxidative amidation took
place only at one formyl group giving a monoamide product 3t
in 70% isolated yield.
We have also carried out the reactions of aliphatic aldehydes
such as 1-octanal and pivalaldehyde with 2a. However, the
corresponding amides were not produced in spite of complete
consumption of the aldehydes.
Next, the scope of amines was surveyed. The results are
summarized in Table 3. A good yield of amide product 4b was
obtained in the reaction of 1a with 4-phenylpiperidine (2b)
(entry 1). Piperazine derivatives are important building blocks
for the synthesis of biologically active compounds.17 The
reactions of 1a with N-methyl-, N-benzyl-, and N-Boc-
piperazines (2c, 2d, and 2e) afforded the corresponding
amides (4c, 4d, and 4d) in good to moderate yields (entries 2−
4).18 Reaction of 1a with morpholine (2f) also proceeded
smoothly, giving the corresponding amide 4f in good yield
(entry 5). Seven-membered cyclic amine 2g reacted with 1a to
give the corresponding amide product 4g in 74% yield (entry
6). Amidation of 1a with secondary acyclic amines was also
examined. As shown in entries 7 and 8, the reaction of 1a with
N-methylbenzylamine (2h) and N-ethylbenzylamine (2i)
afforded the corresponding amide products 4h and 4i in
moderate yields, respectively. Furthermore, 1a reacted with
dibutylamine (2j) smoothly to give N,N′-dibutylbenzamide
(4j) in 71% yield (entry 9).
c
1
CuI (2.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
L2 (4.0)
L3 (4.0)
L4 (4.0)
L5 (4.0)
L6 (4.0)
L7 (4.0)
L8 (4.0)
L1 (4.0)
L1 (4.0)
L1 (4.0)
85 (82 )
44
31
12
8
2
CuBr (2.0)
CuCl (2.0)
CuOAc (2.0)
Cu2O (1.0)
Cu(OAc)2 (2.0)
CuCl2 (2.0)
CuI (2.0)
3
4
5
6
18
36
72
68
67
85
23
15
6
7
8
9
CuI (2.0)
10
11
12
13
14
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
CuI (2.0)
d
15
CuI (2.0)
5
e
16
CuI (2.0)
86
0
17
18
CuI (2.0)
CuI (2.0)
10
40
f
19
L1 (4.0)
a
Reactions were carried out with 1a (1.5 mmol), 2a (1.0 mmol), Cu-
catalysts (2.0 mol %), additive ligands (4.0 mol %) and molecular
sieves 4A (400 mg) in toluene (4 mL) reflux at 110 °C under air for 20
b
h. Yields were determined by 1H NMR using 1,3,5-trimethox-
c
d
ybenzene as an internal standard. Isolated yield. The reaction was
carried out under argon atmosphere in a sealed reactor. The reaction
was carried out under oxygen atmosphere (1 atm). The reaction was
e
f
carried out without addition of molecular sieves 4A.
The reactions of benzaldehyde with primary amines such as
benzylamine and aniline were also examined. However,
condensation reaction of aldehydes and amines occurred
preferentially affording undesired imines as the products.
Cinnamamides are very important and useful compounds,
which can be used as an herbicide,1a insecticide1b,c and
antioxidant.1f Thus, we intended to extend our aerobic
oxidative catalytic system to the synthesis of cinnamamides.
The results are summarized in Table 4. At first, we carried out
the oxidative amidation of cinnamaldehyde (1u) with
piperidine (2a) under the optimal conditions determined in
Table 1. Unfortunately, the desired amide product 5a was not
formed, although the complete consumption of 1u was
observed, probably because of the oxidative decomposition of
1u at relatively high temperature. Then, we tried to carry out
the oxidative coupling at a lower temperature (100 °C) with
increasing the amount of 1u to 2.0 mmol and the catalyst
loading to 20 mol %. As a result, 77% yield of the
corresponding cinnamamide 5a was successfully obtained
(entry 1). Reaction of 4-fluorocinnamaldehyde (1v) with 2a
proceeded at a relatively lower temperature (90 °C), affording
5b in lower yield (entry 2).19 Reaction of 4-methoxycinna-
maldehyde (1w) with 2a was carried out with the addition of
chose the reaction performed in the presence of CuI (2.0 mol
%) and L1 (4.0 mol %) in toluene reflux under air as the
optimal conditions (entry 1).
Next, the oxidative couplings of various aldehydes with 2a
were conducted under the optimal conditions. The results are
summarized in Table 2. The reaction of 1a with 2a gave 3a in
82% isolated yield (entry 1). 4-phenylbenzaldehyde (1b)
reacted with 2a to give the amide product 3b in 67% yield
(entry 2). Introduction of electron-donating groups to the
aromatic ring of the benzaldehyde resulted in relatively low
yields (entries 3−7). Compared with the reactions of 4-
methylbenzaldehyde (1e) and 3-methylbenzaldehyde (1f), the
reaction of 2-methylbenzaldehyde (1g) resulted in a slightly
lower yield, probably due to steric hindrance (entries 5−7).
On the other hand, reactions of benzaldehyde derivatives
bearing an electron-withdrawing substituent (fluoro, chloro,
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Table 2. Cu(I)-catalyzed Aerobic Oxidative Amidation of Aromatic and Heteroaromatic Aldehydes with Piperidine (2a)
a
The reactions were carried out with various aldehydes (1a−1t) (1.5 mmol), 2a (1.0 mmol), CuI (2.0 mol %), L1 (4.0 mol %) and molecular sieves
b
c
(400 mg) in toluene (4 mL) reflux at 110 °C under air for 20 h. Isolated yield. The reactions were carried out with CuI (10.0 mol %) and L1 (10.0
mol %).
ligand L5 instead of L1 to give 5c in 66% yield (entry 3).
Reaction of 1u with morpholine (2f) proceeded smoothly at
100 °C to give the corresponding cinnamamide 5d in 67% yield
(entry 4).
CuI/2-pyridonate catalytic system is proposed in the
Supporting Information).
To isolate and characterize the catalytically active copper
species, a stoichiometric reaction of CuI with 2a was carried
out. When an excess amount of 2a was added to a suspension
of CuI in THF at room temperature, a soluble copper(I)
complex was formed immediately. The structure of this
copper(I) complex was determined by X-ray diffraction
analysis, revealing that the copper(I) complex is a tetranuclear
structure of [Cu4(μ3-I)4(Pip)4] (6) in which copper centers are
bridged by iodine atoms.20,21 Catalytic reaction of 1a with 2a by
using 6 as a catalyst in the presence of additive ligand L1 gave
3a in 83% yield (eq 1), suggesting that the copper complex 6
would be a precatalyst (a plausible mechanism for the present
CONCLUSION
■
In conclusion, we have developed a simple and convenient
method for the synthesis of amides. A variety of amides, which
have useful applications in the areas of agrochemicals,
pharmaceuticals and polymetric materials, were synthesized in
moderate to good yields generating only water as a coproduct
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Table 3. Cu(I)-catalyzed Aerobic Oxidative Amidation of
Benzaldehyde (1a) with Various Secondary Amines
Table 4. Cu(I)-catalyzed Aerobic Oxidative Amidation of
Cinnamaldehydes with Secondary Amines
a
a
a
The reactions were carried out with cinnamaldehydes (1u−1w) (2.0
mmol), secondary amines (2a or 2f) (1.0 mmol), CuI (20.0 mol %),
L1 (20.0 mol %) and molecular sieves 4A (400 mg) in toluene (4 mL)
at 100 °C under air for 20 h. Isolated yield. The reaction was carried
b
c
d
out in toluene at 90 °C. The reaction was carried out with 1w (3.0
mmol), 2a (1.0 mmol), CuI (20.0 mmol %) and L5 (20.0 mmol %)
and molecular sieves 4A (400 mg) in toluene (4 mL) at 100 °C under
air for 20 h.
Procedure for the Cu(I)-catalyzed Aerobic Oxidative
Amidation of Benzaldehyde (1a) with Piperidine (2a) Shown
in Table 1. To an oven-dried, argon purged two-necked flask were
added additive ligands (L1−L8) (0.04 mmol, 4.0 mol %), Cu-catalysts
(0.02 mmol, 2.0 mol %), molecular sieves 4A (400 mg), 1a (1.5
mmol), toluene (4 mL), and 2a (1.0 mmol). The flask was sealed and
preheated at 110 °C under argon for about 1 min and then the mixture
was stirred at 110 °C under open air for 20 h. The mixture was cooled
to room temperature. After the solvent was removed in vacuo, the
residue was diluted with dichloromethane (10 mL) and filtered
through a pad of Celite. Dichloromethane was removed in vacuo and
1,3,5-trimethoxybenzene was added as an internal standard for 1H
NMR analysis. The yield of 1-benzoyl-piperidine (3a) was calculated
a
The reactions were carried out with 1a (1.5 mmol), secondary amines
(2b−2j) (1.0 mmol), CuI (2.0 mol %), L1 (4.0 mol %) and molecular
sieves 4A (400 mg) in toluene (4 mL) reflux at 110 °C under air for 20
h. Isolated yield.
b
1
by H NMR analysis in chloroform-d.
Procedure for the Cu(I)-catalyzed Aerobic Oxidative
Amidation of Various Aldehydes with Secondary Amines
Shown in Tables 2 and 3. To an oven-dried, argon purged flask
were added sodium 5-methyl-2-pyridonate (L1) (0.04 mmol, 2.0 mol
%), CuI (0.02 mmol, 2.0 mol %), molecular sieves 4A (400 mg),
aldehydes (1a−1t) (1.5 mmol), toluene (4 mL), and secondary
amines (2a−2j) (1.0 mmol). The flask was sealed and preheated at
110 °C under argon for about 1 min and then the mixture was stirred
at 110 °C under open air for 20 h. The mixture was cooled to room
temperature. After the solvent was removed in vacuo, the residue was
diluted with dichloromethane (10 mL) and filtered through a pad of
Celite. The filtrate was concentrated by evaporation and purified by a
silica gel column chromatography (eluent: ethyl acetate/hexane).
Procedure for the Cu(I)-catalyzed aerobic oxidative amida-
tion of cinnamaldehydes with secondary amines shown in
Table 4. To an oven-dried, argon purged flask were added sodium 5-
methyl-2-pyridonate (L1) (0.2 mmol, 20.0 mol %), CuI (0.2 mmol,
20.0 mol %), molecular sieves 4A (400 mg), cinnamaldehydes (1u -
1w) (2.0 mmol), toluene (4 mL), and secondary amines (2a or 2f)
(1.0 mmol). The flask was sealed and preheated under argon for about
1 min and then the mixture was stirred at 100 °C under open air for 20
h. The mixture was cooled to room temperature. After the solvent was
by a new catalytic system composed of CuI/2-pyridonate. Air
was successfully employed as a green oxidant in this catalytic
system, which greatly improved the safety of the synthesis and
is beneficial from an atom-economical viewpoint.
EXPERIMENTAL SECTION
■
General. All reactions and manipulations were carried out by
means of standard Schlenk techniques. The column chromatography
was carried out by using silica gel. 1H NMR (500 MHz) and 13C (125
MHz) were performed on a 500 MHz spectrometer. Solvents were
dried by standard procedures and distilled prior to use. N-
Benzylpiperazine (2d)22 and N-tert-butoxycarbonylpiperazine (2e)23
were prepared according to the literature method. All other reagents
are commercially available and were used without further purification.
Preparation of 2-Pyridonate Ligands. To an oven-dried, argon
purged flask were added hydroxypyridine derivatives (1.0 mmol),
sodium ethoxide (1.0 mmol), and ethanol (2.5 mL). The mixture was
stirred at room temperature for 2 h. Then the solvent was removed
and the residue was dried in vacuo to give L1−L8 as a colorless or
pale-yellow powder.
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removed in vacuo, the residue was diluted with dichloromethane (10
mL) and filtered through a pad of Celite. The filtrate was concentrated
by evaporation and purified by a silica gel column chromatography
(eluent: ethyl acetate/hexane). Evaporation of the collected product
followed by the Kugelrohr distillation gave the pure product.
yield. 1H NMR (CDCl3, 500 MHz) δ 7.26 (t, J = 7.5 Hz, 1H), 7.2 (s,
1H), 7.19 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 3.70 (br s,
2H), 3.33 (br s, 2H), 2.36 (s, 3H), 1.67 (br s, 4H), 1.50 (br s, 2H). 13C
NMR (CDCl3, 125 MHz) δ 170.5, 138.3, 136.5, 130.1, 128.2, 127.4,
123.7, 48.8, 43.1, 26.6, 25.7, 24.6, 21.4.
1-(2-Methylbenzoyl)piperidine (3g).26 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
Preparation of Copper Complex [Cu4(μ3-I)4(Pip)4] (6):20 To an
oven-dried, argon purged flask were added CuI (1.0 mmol) and THF
(5 mL). Then, an excess of 2a (1.0 mL) was added dropwise to the
suspension. The mixture was stirred at room temperature for 1 h. The
suspension turned clear and the color of the solution turned light
violet. Concentration of the solution in vacuo to 2.5 mL followed by
the slow diffusion of hexane into the concentrated solution in a glass
tube gave colorless single crystals of 6, which are suitable for X-ray
diffraction analysis (193.3 mg, 70% yield). 1H NMR (500 MHz,
CDCl3): δ 3.00 (br, 16H), 1.85−1.60 (br, 24H). 13C NMR (CDCl3,
125 MHz) δ 49.4 (br), 27.5 (br), 24.3. Anal.Calcd. for C20H44Cu4N4I4:
C, 21.79; H, 4.02; N, 5.08. Found: C, 21.71; H, 3.90; N, 5.15.
Procedure for the [Cu4(μ3-I)4(Pip)4]-catalyzed Aerboic Oxi-
dative Amidation of Benzaldehyde with Piperidine Shown in
eq 1. To an oven-dried, argon purged two-necked flask were added
additive ligand L1 (0.04 mmol, 4.0 mol %), the complex 6 (0.005
mmol, 0.5 mol %), molecular sieves 4A (400 mg), 1a (1.5 mmol),
toluene (4 mL), and 2a (1.0 mmol). The flask was sealed and
preheated at 110 °C under argon for about 1 min and then the mixture
was stirred at 110 °C under open air for 20 h. The mixture was cooled
to room temperature. After the solvent was removed in vacuo, the
residue was diluted with dichloromethane (10 mL) and filtered
through a pad of Celite. Dichloromethane was removed in vacuo and
1,3,5-trimethoxybenzene was then added as an internal standard for 1H
NMR analysis. The yield of 1-benzoyl-piperidine (3a) was calculated
1
Hexane = 1:3 to give 3g as a pale yellow oil, 80.1 mg, 39% yield. H
NMR (CDCl3, 500 MHz) δ 7.26−7.14 (m, 4H), 3.80 (br s, 1H), 3.70
(br s, 1H), 3.17 (br s, 2H), 2.31 (s, 3H), 1.66 (br s, 1H), 1.45 (br s,
1H). 13C NMR (CDCl3, 125 MHz) δ 170.0, 136.9, 134.1, 130.4, 128.7,
125.9, 125.7, 48.0, 42.5, 26.7, 25.8, 24.7, 19.1.
1-(4-Fluorobenzoyl)piperidine (3h).24 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give 3h as a colorless solid, 182.0 mg, 88%
1
yield. H NMR (CDCl3, 500 MHz) δ 7.41−7.39 (m, 2H), 7.10−7.07
(m, 2H), 3.70 (br s, 2H), 3.36 (br s, 2H), 1.69 (br s, 4H), 1.53 (br s,
2H). 13C NMR (CDCl3, 125 MHz) δ 169.6, 164.4, 162.4, 132.6, 132.6,
129.3, 129.2, 115.7, 115.5, 49.1, 43.5, 26.7, 25.8, 24.7.
1-(4-Chlorobenzoyl)piperidine (3i).24 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give 3i as a pale yellow solid, 178.9 mg,
1
80% yield. H NMR (CDCl3, 500 MHz) δ 7.37 (d, J = 8.5 Hz, 2H),
7.33 (d, J = 8.5 Hz, 2H), 3.70 (br s, 2H), 3.33 (br s, 2H), 1.68 (br s,
4H), 1.52 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 169.3, 135.5,
134.9, 128.8, 128.5, 48.9, 43.3, 26.6, 25.7, 24.6.
1-(4-Bromobenzoyl)piperidine (3j).28 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give p10 as a pale yellow solid, 201.8 mg,
1
75% yield. H NMR (CDCl3, 500 MHz) δ 7.54 (d, J = 8.5 Hz, 2H),
1
by H NMR analysis in chloroform-d.
7.27 (d, J = 8.5 Hz, 2H), 3.69 (br s, 2H), 3.32 (br s, 2H), 1.68 (br s,
4H), 1.52 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 169.4, 135.4,
131.8, 128.7, 123.7, 48.9, 43.3, 26.7, 25.7, 24.7.
1-Benzoylpiperidine (3a).24 Purification was performed by
column chromatography on silica gel eluting with EtOAc/Hexane =
1
1-(4-Trifluoromethylbenzoyl)piperidine (3k).27 Purification
was performed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give 3k as a pale yellow solid, 228.5 mg, 88%
yield. 1H NMR (CDCl3, 500 MHz) δ 7.67 (d, J = 8.0 Hz, 2H), 7.50 (d,
J = 8.0 Hz, 2H), 3.73 (br s, 2H), 3.30 (br s, 2H), 1.70 (br s, 4H), 1.52
(br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 168.9, 140.2, 131.4 (q, J =
32.6 Hz), 127.3, 125.7, 123.7 (q, J = 272.3 Hz), 48.8, 43.3, 26.7, 25.7,
24.6.
1:3 to give 3a as a pale yellow oil, 154.1 mg, 82% yield. H NMR
(CDCl3, 500 MHz) δ 7.39 (s, 5H), 3.71 (br s, 2H), 3.34 (br s, 2H),
1.68 (br s, 4H), 1.52 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ
170.2, 136.5, 129.3, 128.3, 126.9, 48.6, 43.0, 26.5, 25.6, 24.5.
1-(4-Phenylbenzoyl)piperidine (3b).25 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
Hexane = 1:1 to give 3b as a pale yellow solid, 178.4 mg, 67% yield. 1H
NMR (CDCl3, 500 MHz) δ 7.62−7.58 (m, 4H), 7.48−7.43 (m, 4H),
7.36 (t, J = 7.5 Hz, 1H), 3.73 (br s, 2H), 3.41 (br s, 2H), 1.69 (br s,
4H), 1.54 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 170.2, 142.4,
140.5, 135.4, 129.0, 127.8, 127.5, 127.2, 49.0, 43.3, 26.7, 25.8, 24.7.
1-(4-Methoxybenzoyl)piperidine (3c).24 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
1-(4-Methoxycarobonylbenzoyl)piperidine (3l).28 Purification
was performed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give 3l as a pale yellow solid, 211.7 mg, 86%
1
yield. H NMR (CDCl3, 500 MHz) δ 8.08 (d, J = 10.0 Hz, 2H), 7.46
(d, J = 10.0 Hz, 2H), 3.94 (s, 3H), 3.73 (br s, 2H), 3.30 (br s, 2H),
1.69 (br s, 4H), 1.52 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ
169.2, 166.4, 140.9, 130.8, 129.8, 126.8, 52.3, 48.7, 43.1, 26.5, 25.6,
24.5.
1
Hexane = 1:1 to give 3c as a pale yellow oil, 130.5 mg, 60% yield. H
NMR (CDCl3, 500 MHz) δ 7.35 (d, J = 8.0 Hz, 2H), 6.88 (d, J = 8.0
Hz, 2H), 3.81 (s, 3H), 3.67 (br s, 2H), 3.40 (br s, 2H), 1.66 (br s, 4H),
1.58 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 170.4, 160.6, 129.0,
128.7, 113.7, 55.5, 49.1, 43.5, 26.2, 24.8.
1-(4-Cyanobenzoyl)piperidine (3m). Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1:1 to give 3m as a pale yellow solid, m.p.: 95.3−96.0 °C, 171.7 mg,
1-(4-tert-Butylbenzoyl)piperidine (3d). Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
Hexane = 1:1 to give 3c as a pale yellow solid, m.p.: 75.1−75.7 °C,
1
79% yield. H NMR (CDCl3, 500 MHz) δ 7.71 (d, J = 8.5 Hz, 2H),
7.50 (d, J = 8.5 Hz, 2H), 3.72 (br s, 2H), 3.29 (br s, 2H), 1.70 (br s,
4H), 1.53 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 168.3, 141.0,
132.5, 127.6, 118.3, 113.3, 48.7, 43.3, 26.6, 25.6, 24.5. Anal. Calcd for
C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.89; H, 6.36; N,
12.99.
1
162.9 mg, 66% yield. H NMR (CDCl3, 500 MHz) δ 7.40 (d, J = 8.0
Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 3.71 (br s, 2H), 3.38 (br s, 2H),
1.68 (br s, 4H), 1.52 (br s, 2H), 1.32 (s, 9H). 13C NMR (CDCl3, 125
MHz) δ 170.6, 152.7, 133.7, 126.8, 125.4, 48.9, 43.2, 34.9, 31.5, 26.7,
25.8, 24.8. Anal. Calcd for C16H23NO: C, 78.32; H, 9.45; N, 5.71.
Found: C, 77.92; H, 9.82; N, 5.97.
1-(4-Nitrobenzoyl)piperidine (3n).29 Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1
1-(4-Methylbenzoyl)piperidine (3e).26 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:3 to give 3e as a pale yellow oil, 157.4 mg, 77%
yield. 1H NMR (CDCl3, 500 MHz) δ 7.29 (d, J = 8.0 Hz, 2H), 7.19 (d,
J = 8.0 Hz, 2H), 3.70 (br s, 2H), 3.36 (br s, 2H), 2.37 (s, 3H), 1.67 (br
s, 4H), 1.52 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 170.6, 139.5,
133.7, 129.1, 127.0, 48.9, 43.3, 26.7, 25.9, 24.8, 21.5.
1:1 to give 3n as a pale yellow solid, 192.1 mg, 82% yield. H NMR
(CDCl3, 500 MHz) δ 8.27 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz,
2H), 3.73 (br s, 2H), 3.29 (br s, 2H), 1.71 (br s, 4H), 1.54 (br s, 2H).
13C NMR (CDCl3, 125 MHz) δ 168.0, 148.3, 142.8, 127.9, 124.0, 48.8,
43.3, 26.6, 25.6, 24.5.
1-(3-Nitrobenzoyl)piperidine (3o). Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1:1 to give 3o as a pale yellow solid, m.p.: 81.0−81.7 °C, 179.6 mg,
1-(3-Methylbenzoyl)piperidine (3f).27 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:1 to give 3f as a pale yellow oil, 119.1 mg, 60%
1
74% yield. H NMR (CDCl3, 500 MHz) δ 8.29−8.27 (m, 2H), 7.74
(d, J = 8.0 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 3.74 (br s, 2H), 3.34 (br
E
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The Journal of Organic Chemistry
Article
s, 2H), 1.72 (br s, 4H), 1.56 (br s, 2H). 13C NMR (CDCl3, 125 MHz)
δ 167.7, 148.2, 138.2, 133.1, 129.9, 124.4, 122.2, 49.0, 43.5, 26.7, 25.6,
24.6. Anal. Calcd for C12H14N2O3: C, 61.53; H, 6.02; N, 11.96. Found:
C, 61.35; H, 5.99; N, 11.92.
80.1, 47.7, 43.9 (br), 42.2, 28.5. Anal. Calcd for C16H22N2O3: C, 66.18;
H, 7.64; N, 9.65. Found: C, 65.91; H, 7.74; N, 9.85
1-Benzoylmorpholine (4f).24 Purification was performed by
column chromatography on silica gel eluting with EtOAc/Hexane =
1-(2-Naphthalenecarbonyl)piperidine (3p).28 Purification was
performed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:1 to give 3p as a pale yellow solid, 148.3 mg, 61%
1:1 to give 4f as a pale yellow solid, 136.3 mg, 75% yield. H NMR
1
(CDCl3, 500 MHz) δ 7.42 (s, 5H), 3.76−3.46 (br, 8H). 13C NMR
(CDCl3, 125 MHz) δ 170.5, 135.5, 130.0, 128.7, 127.2, 67.0, 48.4,
42.8.
1
yield. H NMR (CDCl3, 500 MHz) δ 7.89−7.86 (m, 4H), 7.53−7.48
(m, 3H), 3.76 (br s, 2H), 3.39 (br s, 2H), 1.70 (br s, 4H), 1.53 (br s,
2H). 13C NMR (CDCl3, 125 MHz) δ 170.5, 134.0, 133.7, 132.9, 128.5,
128.3, 127.9, 127.0, 126.7, 126.6, 124.4, 49.0, 43.4, 26.7, 25.8, 24.8.
1-(4-Pyridinecarbonyl)piperidine (3q).30 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc
1-Benzoylhexahydroazepine (4g). Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1
1:3 to give 4f as a pale yellow oil, 143.6 mg, 74% yield. H NMR
(CDCl3, 500 MHz) δ 7.37 (s, 5H), 3.68 (t, J = 5.8 Hz, 2H), 3.36 (t, J =
5.8 Hz, 2H), 1.85−1.81 (m, 2H), 1.65 - 1.58 (m, 6H). 13C NMR
(CDCl3, 125 MHz) δ 171.6, 137.4, 129.1, 128.4, 126.4, 49.7, 46.3,
29.5, 27.9, 27.3, 26.5. Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N,
6.89. Found: C, 76.55; H, 8.56; N, 6.86
1
100% to give 3q as a pale yellow oil, 158.5 mg, 83% yield. H NMR
(CDCl3, 500 MHz) δ 8.70 (s, 2H), 7.29 (d, J = 5.0 Hz, 2H), 3.71 (t, J
= 5.0 Hz, 2H), 3.29 (t, J = 5.0 Hz, 2H), 1.69 (br s, 4H), 1.52 (br s,
2H). 13C NMR (CDCl3, 125 MHz) δ 167.4, 150.1, 144.0, 121.0, 48.3,
42.8, 26.3, 25.3, 24.2.
N-Benzyl-N-methyl-benzamide (4h).24 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
1-(3-Pyridinecarbonyl)piperidine (3r).30 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc
Hexane = 1:3 to give 4i as a pale yellow oil, 157.3 mg, 68% yield. H
1
NMR (CDCl3, 500 MHz) δ 7.46−7.29 (m, 9H), 7.17 (s, 1H), 4.76 (br
s, 1H), 4.51 (br s, 1H), 3.03 (br s, 1.5H), 2.86 (br s, 1.5H). 13C NMR
(CDCl3, 125 MHz) δ 172.5, 171.7, 137.2, 136.7, 136.4, 129.7, 129.0,
128.8, 128.5, 128.3, 127.6, 127.1, 126.9, 55.3, 50.9, 37.1, 33.3.
N-Benzyl-N-ethyl-benzamide (4i).36 Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1
100% to give 3r as a pale yellow oil, 155.1 mg, 80% yield. H NMR
(CDCl3, 500 MHz) δ 8.66 (s, 2H), 7.75 (d, J = 9.5 Hz, 2H), 7.37−
7.34 (m, 2H), 3.73 (br s, 2H), 3.36 (br s, 2H), 1.70 (br s, 4H), 1.55
(br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 167.8, 150.6, 147.8, 134.9,
132.3, 123.6, 48.9, 43.3, 26.7, 25.6, 24.5.
1-(2-Pyridinecarbonyl)piperidine (3s).31 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc
1:3 to give 4j as a pale yellow oil, 101.0 mg, 42% yield. H NMR
1
(CDCl3, 500 MHz) δ 7.43−7.19 (m, 10H), 4.78 (br s, 1H), 4.51 (br s,
1H), 3.52 (br s, 1H), 3.21 (br s, 1H), 1.21 (br s, 1.5H), 1.07 (br s,
1.5H). 13C NMR (CDCl3, 125 MHz) δ 172.1, 137.6, 137.1, 136.9,
136.7, 129.5, 128.8, 128.6, 128.2, 128.0, 127.5, 126.9, 126.7, 126.5,
52.2, 47.0, 42.9, 39.7, 13.8, 12.3.
1
100% to give 3s as a pale yellow oil, 146.1 mg, 76% yield. H NMR
(CDCl3, 500 MHz) δ 8.60 (d, J = 4.5 Hz, 1H), 7.80−7.77 (m, 1H),
7.57 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 6.0 Hz, 1H), 3.75 (s, 2H), 3.43 (t,
J = 5.5 Hz, 2H), 1.69 (br s, 4H), 1.57 (br s, 2H). 13C NMR (CDCl3,
125 MHz) δ 167.8, 154.9, 148.6, 137.1, 124.3, 123.4, 48.4, 43.4, 26.6,
25.7, 24.7.
N,N-Dibutylbenzamide (4j).7 Purification was performed by
column chromatography on silica gel eluting with EtOAc/Hexane =
1-(4-Formylcarbonyl)piperidine (3t).32 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
1:3 to give 4j as a pale yellow oil, 161.4 mg, 71% yield. H NMR
1
(CDCl3, 500 MHz) δ 7.36 (m, 5H), 3.49 (br s, 2H), 3.18 (br s, 2H),
1.65 (br s, 2H), 1.48 (br s, 2H), 1.41 (br s, 2H), 1.14 (br s, 2H), 0.98
(br s, 3H), 0.78 (br s, 3H) . 13C NMR (CDCl3, 125 MHz) δ 171.8,
137.5, 129.1, 128.4, 126.6, 48.9, 44.6, 30.9, 29.8, 20.4, 19.8, 14.1, 13.7.
1-Cinnamoylpiperidine (5a).28 Purification was performed by
column chromatography on silica gel eluting with EtOAc/Hexane =
1:1. Evaporation of the collected product followed by the Kugelrohr
distillation (200 °C, 1.0 mmHg) gave the pure product 5a as a pale
yellow solid, 167.0 mg, 77% yield. 1H NMR (CDCl3, 500 MHz) δ 7.45
(d, J = 15.5 Hz, 2H), 7.52 (d, J = 6.0 Hz, 2H), 7.39−7.34 (m, 3H),
6.91 (d, J = 15.5 Hz, 2H), 3.67 (brs, 2H), 3.59 (brs, 2H), 1.69−1.62
(br, 6H). 13C NMR (CDCl3, 125 MHz) δ 165.5, 142.3, 135.6, 129.5,
128.9, 127.8, 117.9, 47.2, 43.5, 26.9, 25.8, 24.8.
1
Hexane = 1:1 to give 3t as a pale yellow oil, 152.8 mg, 70% yield. H
NMR (CDCl3, 500 MHz) δ 10.05 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H),
7.50 (d, J = 8.5 Hz, 2H), 3.73 (br s, 2H), 3.43 (br s, 2H), 1.70 (br s,
4H), 1.53 (br s, 2H). 13C NMR (CDCl3, 125 MHz) δ 191.7, 169.0,
142.4, 136.8, 130.1, 127.5, 48.8, 43.2, 26.7, 25.7, 24.6.
1-Benzoyl-4-phenylpiperidine (4b). Purification was performed
by column chromatography on silica gel eluting with EtOAc/Hexane =
1:1 to give 4b as a pale yellow solid, m.p.: 80.0−80.8 °C, 217.7 mg,
1
82% yield. H NMR (CDCl3, 500 MHz) δ 7.42 (m, 5H), 7.32 (t, J =
7.5 Hz, 2H), 7.20 (d, J = 7.0 Hz, 3H), 4.89 (br s, 1H), 3.88 (br s, 1H),
3.13 (br s, 1H), 2.86 (br s, 1H), 2.78 (br t, J = 8.5 Hz, 1H), 1.98 (br s,
1H), 1.79 (br s, 2H), 1.64 (br s, 1H). 13C NMR (CDCl3, 125 MHz) δ
170.5, 145.2, 136.4, 129.6, 128.7, 128.6, 127.0, 126.8, 126.6, 48.5, 42.9,
34.1, 33.0. Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28.
Found: C, 81.18; H, 7.24; N, 5.23.
1-(p-Fluoro-cinnamoyl)piperidine (5b).36 Purification was
performed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:1. Evaporation of the collected product followed
by the Kugelrohr distillation (200 °C, 1.0 mmHg) gave the pure
1-Benzoyl-4-methylpiperazine (4c).33 Purification was per-
formed by column chromatography on silica gel eluting with
EtOAc/Hexane = 5:1 to give 4c as pale yellow oil, 143.0 mg, 70%
1
product 5b as a pale yellow solid, 102.8 mg, 44% yield. H NMR
(CDCl3, 500 MHz) δ 7.60 (d, J = 15.5 Hz, 2H), 7.51 (t, J = 7.0 Hz,
2H), 7.08−7.03 (t, J = 7.3 Hz, 2H), 3.67(brs, 2H), 3.58 (brs, 2H),
1.69−1.60 (br, 6H). 13C NMR (CDCl3, 125 MHz) δ 165.3, 164.5,
162.5, 141.0, 131.8, 129.6, 129.5, 117.6, 116.0, 115.8, 47.1, 43.5, 26.9,
25.7, 24.7.
1
yield. H NMR (CDCl3, 500 MHz) δ 7.41 (s, 5H), 3.83 (br s, 2H),
3.48 (br s, 2H), 2.53 (br s, 2H), 2.40 (br s, 2H), 2.35 (s, 3H). 13C
NMR (CDCl3, 125 MHz) δ 170.4, 135.9, 129.7, 128.5, 127.1, 55.4,
54.8, 47.7, 46.1, 42.1.
1-Benzoyl-4-benzylpiperazine (4d).34 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc
1-Methoxycinnamoylpiperidine (5c).37 Purification was per-
formed by column chromatography on silica gel eluting with EtOAc/
1
1
(100%) to give 4d as pale yellow oil, 182.2 mg, 63% yield. H NMR
Hexane = 1:1 gave 5c as a pale yellow oil, 169.1 mg, 66% yield. H
(CDCl3, 500 MHz) δ 7.39 (s, 5H), 7.33−7.31 (m, 5H), 3.80 (brs,
2H), 3.54 (s, 2H), 3.42 (brs, 2H), 2.54 (brs, 2H), 2.38 (brs, 2H). 13C
NMR (CDCl3, 125 MHz) δ 170.4, 137.7, 136.0, 129.7, 129.2, 128.6,
128.5, 127.4, 127.2, 63.0, 53.5, 52.9, 47.9, 42.3.
NMR (CDCl3, 500 MHz) δ 7.60 (d, J = 15.5 Hz, 2H), 7.48 (m, 2H),
7.08−6.88 (m, 2H), 6.77 (d, J = 15.5 Hz, 2H), 3.83 (s, 3H), 3.66 (brs,
2H), 3.58 (brs, 2H), 1.69−1.58 (br, 6H). 13C NMR (CDCl3, 125
MHz) δ 165.7, 160.8, 141.9, 129.3, 128.4, 115.4, 114.3, 55.4, 47.1,
43.4, 26.8, 25.7, 24.8.
1-Benzoyl-4-tert-butoxylcarbonylpiperazine (4e). Purification
was performed by column chromatography on silica gel eluting with
EtOAc/Hexane = 1:1 to give 4e as pale yellow solid, mp 107.0−107.6
1-Cinnamoylmorpholine (5d).38 Purification was performed by
column chromatography on silica gel eluting with EtOAc/Hexane =
1
1
°C, 146.8 mg, 51% yield. H NMR (CDCl3, 500 MHz) δ 7.44−7.39
1:1 gave 5d as a pale yellow solid, 154.3 mg, 71% yield. H NMR
(m, 5H), 3.75 (br, 2H), 3.52 (br, 2H), 3.40 (br, 2H), 1.47 (s, 9H). 13C
(CDCl3, 500 MHz) δ 7.70 (d, J = 15.5 Hz, 2H), 7.53−7.51 (m, 2H),
7.40−7.33 (m, 2H), 6.85 (d, J = 15.5 Hz, 2H), 3.73−3.67 (br, 8H).
NMR (CDCl3, 125 MHz) δ 170.8, 154.7, 135.7, 130.1, 128.7, 127.2,
F
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Article
13C NMR (CDCl3, 125 MHz) δ 165.7, 143.3, 135.2, 129.9, 128.9,
127.9, 116.7, 67.0, 46.3, 42.6.
Marion, N.; Nolan, S. P. J. Org. Chem. 2010, 75, 1197. (e) Martínez-
́
Asencio, A.; Yus, M.; Ramon, D. J. Tetrahedron 2012, 68, 3948.
(8) Sawant, D. N.; Wagh, Y. S.; Bhatte, K. D.; Bhanage, B. M. J. Org.
Chem. 2011, 76, 5489.
X-ray Structure Analysis of Copper Complex 6. Diffraction
data for 6 were obtained with a Rigaku RAXIS RAPID instrument.
Reflection data were corrected for Lorentz and polarization effects.
Empirical absorption corrections were applied. The structures was
solved by direct method39,40 and refined anisotropically for non-
hydrogen atoms by full-matrix least-squares calculations. Atomic
scattering factors and anomalous dispersion terms were taken from the
literature.41 Hydrogen atoms were located on the idealized positions.
The calculations were performed using the program system
CrystalStructure.42,43 ORTEP drawing of 6 is shown in Figure S1
(Supporting Information). The crystal data and details are shown in a
CIF file.
(9) (a) Naota, T.; Murahashi, S.-I. Synlett 1991, 693. (b) Fujita, K.;
Takahashi, Y.; Owaki, M.; Yamamoto, K.; Yamaguchi, R. Org. Lett.
2004, 6, 2785. (c) Nordstrøm, L. U.; Vogt, H.; Madsen., R. J. Am.
Chem. Soc. 2008, 130, 17672. (d) Muthaiah, S.; Ghosh, S. C.; Jee, J.-E.;
Chen, C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002.
(e) Zhang, Y.; Chen., C.; Ghosh, S. C.; Li, Y.; Hong, S. H.
Organometallics 2010, 29, 1374.
(10) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 523.
(11) (a) Seo, S.-Y.; Marks, T. J. Org. Lett. 2008, 10, 317. (b) Li, J.;
Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575. (c) Qian, C.;
Zhang, X.; Li, J.; Xu, F.; Zhang, Y.; Shen, Q. Organometallics 2009, 28,
3856. (d) Cai, C.; Li, L.; Xu, F.; Shen, Q. Chi. Sci. Bull. 2010, 55, 3641.
(e) Xu, B.; Huang, L.; Yang, Z.; Yao, Y.; Zhang, Y.; Shen, Q.
Organometallics 2011, 30, 3588.
ASSOCIATED CONTENT
■
S
* Supporting Information
Table of optimization of reaction solvent, copies of 1H and 13
C
(12) Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008, 49,
NMR spectra of all products, X-ray structural details of 6. This
material is available free of charge via the Internet at http://
pubs.acs.org.
5732.
(13) Yoo, W.-J.; Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.
(14) Zhu, M.; Fujita, K.; Yamaguchi, R. Chem. Commun. 2011, 47,
12876.
(15) The optimization of reaction solvent is summarized in Table S1
in Supporting Information.
AUTHOR INFORMATION
■
Corresponding Author
*yamaguchi.ryohei.75s@st.kyoto-u.ac.jp; fujita.kenichi.6a@
kyoto-u.ac.jp
(16) Amination of aryl halides usually occurs by the reaction of aryl
halides with amines when Cu(I) salts were employed as the catalyst in
the presence of a strong base. See: (a) Gajare, A. S.; Toyota, K.;
Yoshifuji, M.; Ozawa, F. Chem. Commun. 2004, 40, 1994. (b) Zhang,
H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70, 5164. (c) de Lange, B.;
Lambers-Verstappen, M. H.; S.-van de Vondervoort, L.; Sereinig, N.;
de Rijk, R.; de Vries, A. H. M.; de Vries, J. G. Synlett 2006, 18, 3105.
(d) Zhu, D.; Wang, R.; Mao, J.; Xu, L.; Wu, F.; Wan, B. J. Mol. Catal. A
Chem. 2006, 256, 256. (e) Wang, D.; Ding, K. Chem. Commun. 2009,
45, 1891.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) For recent articles of amide compounds used in agriculture, see:
(a) Vishnoi, S.; Agrawal, V.; Kasana, V. K. J. Agric. Food Chem. 2009,
57, 3261. (b) Yang, Y.-C.; Lee, S.-G.; Lee, H.-K.; Kim, M. K.; Lee, S.
H.; Lee, H. S. J. Agric. Food Chem. 2002, 50, 3765. (c) Castral, T. C.;
Matos, A. P.; Monteiro, J. L.; Araujo, F. M.; Bondancia, T. M.; Batista-
Pereira, L. G.; Fernandes, J. B.; Vieira, P. C.; da Silva, M. F. G. F.;
(17) (a) Kwie, F. H. A; Briet, M.; Soupaya, D.; Hoffmann, P.;
Maturano, M.; Rodriguez, F.; Blonski, C.; Lherbet, C.; Baudoin-
Dehoux, C. Chem. Biol. Drug Des. 2011, 77, 86. (b) Byrtus, H.;
́
Obniska, J.; Czopek, A.; Kaminski, K.; Pawlowski, M. Bioorg. Med.
Chem. 2011, 19, 6149. (c) Huang, W.; Huang, R.; Attene-Ramos, M.
S.; Sakamuru, S.; Englund, E. E.; Inglese, J.; Austin, C. P.; Xia, M.
Bioorg. Med. Chem. Lett. 2011, 21, 5239. (d) Lin, S.-W.; Sun, Q.; Ge,
Z.-M.; Wang, X.; Ye, J.; Li, R.-T. Bioorg. Med. Chem. Lett. 2011, 21,
940.
̂
Correa, A. G. J. Agric. Food Chem. 2011, 59, 4822. For recent articles
of amide compounds used in pharmacy, see: (d) Sood, A.;
Panchagnula, R. Chem. Rev. 2001, 101, 3275. (e) Punkvang, A.;
Saparpakorn, P.; Hannongbua, S.; Wolschann, P.; Berner, H.; Pungpo,
P. Monatsh. Chem. 2010, 141, 1029. For recent articles of amide
compounds used in organic synthesis, see: (f) Son, S.; Lewis, B. A. J.
Agric. Food Chem. 2002, 50, 468. (g) Cho, S. J.; Roh, J. S.; Sun, W. S.;
Kim, S. H.; Park, K. D. Bioorg. Med. Chem. Lett. 2006, 16, 2682.
(2) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827
and references cited therein.
(18) Further deprotection of the Boc group can be easily conducted
to obtain N-benzoyl piperazine, which can be subjected to other
chemical transformations. See: (a) Jacquemard, U.; Ben
́ ́
eteau, V.;
Lefoix, M.; Routier, S.; Merour, J.-Y.; Coudert, G. Tetrahedron 2004,
́
60, 10039. (b) Li, B.; Berliner, M.; Buzon, R.; Chiu, C. K.-F.; Colgan,
S. T.; Kaneko, T.; Keene, N.; Kissel, W.; Le, T.; Leeman, K. R.;
Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.; Witt, M.;
Weaver, J.; Zhang, Z.; Zhang, Z. J. Org. Chem. 2006, 71, 9045.
(19) Reaction of 1v with 2a at 100 °C was also carried out. However,
no formation of the corresponding amide product was observed with
complete consumption of 1v, probably due to the oxidative
decomposition.
(3) (a) Sehgal, D.; Vijay, I. K. Anal. Biochem. 1994, 218, 87. (b) Ho,
G.-J.; Emerson, K. M.; Mathre, D. J.; Shuman, R. F.; Grobowski, E. J. J.
J. Org. Chem. 1995, 60, 3569. (c) Vovk, M. V.; Kraitor, V. A.;
Mel’nichenko, N. V. Chem. Heterocycl. Com. 1998, 34, 1096.
(4) (a) Lin, Y.-S.; Alper, H. Angew. Chem. Int. Ed. 2001, 40, 779.
(b) Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara, H.; Ryu, I.
Angew. Chem. Int. Ed. 2005, 44, 1075.
(20) Preparation of the complex of CuI having piperidine ligand was
first reported by A. U. Malik in 1967. However, the crystal structure
and the catalytic property of the complex have never been reported.
See: Malik, A. U. J. Inorg. Nucl. Chem. 1967, 29, 2106.
(21) Detailed X-ray crystallographic data and ORTEP drawings for
the tetranuclear copper(I) complex 6 is summarized in a CIF file and
Supporting Information.
(5) (a) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Org. Chem.
2002, 67, 4993. (b) Nillson, B. L.; Kiessling, L. L.; Raines, R. T. Org.
Lett. 2000, 2, 1939. (c) Shangguan, N.; Katukojvala, S.; Greenberg, R.;
Williams, L. J. J. Am. Chem. Soc. 2003, 125, 7754. (d) Merkx, R.;
Brouwer, A. J.; Rijkers, D. T. S.; Liskamp, R. M. J. Org. Lett. 2005, 7,
1125.
(6) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc.
(22) Peterson, Q. P.; Hsu, D. C.; Goode, D. R.; Novotny, C. J.;
Totten, R. K.; Hergenrother, P. J. J. Med. Chem. 2009, 52, 5721.
(23) Wertz, S.; Kodama, S.; Studer, A. Angew. Chem., Int. Ed. 2011,
50, 11511.
2005, 127, 16046. (b) Yao, L.; Aube,
2766.
(7) (a) Park, S.; Choi, Y.-A.; Han, H.; Yang, S. H.; Chang, S. Chem.
Commun. 2003, 39, 1936. (b) Owston, N. A.; Parker, A. J.; Williams, J.
M. J. Org. Lett. 2007, 9, 3599. (c) Ramalingan, C.; Park, Y.-T. J. Org.
́
J. J. Am. Chem. Soc. 2007, 129,
(24) Wang, J.; Li, J.; Xu, F.; Shen, Q. Adv. Synth. Catal. 2009, 351,
́ ́
Chem. 2007, 72, 4536. (d) Ramon, R. S.; Bosson, J.; Díez-Gonzalez, S.;
1363.
G
dx.doi.org/10.1021/jo301553v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(25) DiBlasi, C. M.; Macks, D. E.; Tan, D. S. Org. Lett. 2005, 7, 1777.
(26) Jo, Y.; Ju, J.; Choe, J.; Song, K. H.; Lee, S.-W. J. Org. Chem.
2009, 74, 6358.
(27) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D. A.;
Buchwald, S. L. Science 2010, 328, 1679.
(28) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2010, 132, 1770.
(29) Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
(30) Deguest, G.; Devineau, A.; Bischoff, L.; Fruit, C.; Marsais, F.
Org. Lett. 2006, 8, 5889.
(31) Takac
10372.
́ ́
s, A.; Jakab, B.; Petz, A.; Kollar, L. Tetrahedron 2007, 63,
(32) Dimmock, J. R.; Padmanilayam, M. P.; Das, U.; Zello, G. A.;
Sharma, R. K.; Shrivastav, A.; Selvakumar, P.; Pasha, M. K.; Nienaber,
K. H.; Lee, J. S.; Allen, T. M.; Santos, C. L.; Balzarini, J.; de Clercq, E.
J. Enzyme Inhib. Med. Chem. 2003, 18, 313.
(33) Iriepa, I.; Madrid, A. I.; Gal
2006, 787, 8.
́
vez, E.; Bellanato, J. J. Mol. Struct.
(34) Petride, H.; Drag
Chem. 2006, 4, 674.
̆
hici, C.; Florea, C.; Petride, A. Cent. Eur. J.
(35) Koziara, A.; Zawadzki, S.; Zwierzak, A. Synthesis 1979, 7, 527.
(36) Xiao, W.-J.; Shi, L.-L.; Chen, Z.-Q. Heteroatom Chem. 1990, 1,
245.
(37) Fang, F.; Li, Y.; Tian, S.-K. Eur. J. Org. Chem. 2011, 1084.
(38) Concellon, J. M.; Rodríguez-Solla, H.; Díaz, P. J. Org. Chem.
2007, 72, 7974.
́
(39) Beurskens, P. T.; Admiraal, G.; Beurskens, G.; Bosman, W. P.;
R. de Gelder, Israel, R.; Smits, J. M. M. The DIRDIF-99 program
system, Technical Report of the Crystallography Laboratory; University
of Nijmegen: Nijmegen, The Netherlands, 1999.
(40) Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi, A.;
Burla, M.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27, 435.
(41) (a) Cromer, D. T.; Waber, G. T. International Table for X-Ray
Crystallography; The Kynoch Press: Birmingham, U.K., 1974; Vol. IV,
table 2.2 A. (b) Ibers, J. A.; Hamilton, W. C. Acta Crystallogr. 1964, 17,
871. (c) Creagh, D. C.; McAuley, W. J. In International Tables for X-
Ray Crystallography; Wilson, A. J. C., Ed.; Kluwer Academic
Publishers: Boston, 1992; Vol. C, pp 219−222, table 4.2.6.8.
(d) Creagh, D. C.; Hubbell, J. H. In International Tables for X-Ray
Crystallography; Wilson, A. J. C., Ed.; Kluwer Academic Publishers:
Boston, MA, 1992; Vol. C, pp 200−206, table 4.2.4.3.
(42) CrystalStructure 3.8, Crystal Structure Analysis Package; Rigaku
and Rigaku/Molecular Structure Corp.: The Woodlands, TX, 2000−
2006.
(43) Carruthers, J. R.; Rollett, J. S.; Betteridge, P.W.; Kinna, D.;
Pearce, L.; Larsen, A.; Gabe, E. CRYSTALS Issue 11; Chemical
Crystallography Laboratory: Oxford, 1999.
H
dx.doi.org/10.1021/jo301553v | J. Org. Chem. XXXX, XXX, XXX−XXX