Selective synthesis of primary anilines from cyclohexanone oximes by the concerted catalysis of a Mg-Al layered double hydroxide supported Pd catalyst

Article abstract of DOI:10.1021/jacs.7b07347

Although the selective conversion of cyclohexanone oximes to primary anilines would be a good complement to the classical synthetic methods for primary anilines, which utilize arenes as the starting materials, there have been no general and efficient methods for the conversion of cyclohexanone oximes to primary anilines until now. In this study, we have successfully realized the efficient conversion of cyclohexanone oximes to primary anilines by utilizing a Mg-Al layered double hydroxide supported Pd catalyst (Pd(OH)_x/LDH) under ligand-, additive-, and hydrogen-acceptor-free conditions. The substrate scope was very broad with respect to both cyclohexanone oximes and cyclohexenone oximes, which gave the corresponding primary anilines in high yields with high selectivities (17 examples, 75% to >99% yields). The reaction could be scaled up (gram-scale) with a reduced amount of the catalyst (0.2 mol %). Furthermore, the one-pot synthesis of primary anilines directly from cyclohexanones and hydroxylamine was also successful (five examples, 66-99% yields). The catalysis was intrinsically heterogeneous, and the catalyst could be reused for the conversion of cyclohexanone oxime to aniline at least five times with keeping its high catalytic performance. Kinetic studies and several control experiments showed that the high activity and selectivity of the present catalyst system were attributed to the concerted catalysis of the basic LDH support and the active Pd species on LDH. The present transformation of cyclohexanone oximes to primary anilines proceeds through a dehydration/dehydrogenation sequence, and herein the plausible reaction mechanism is proposed on the basis of several pieces of experimental evidence.

Full text of DOI:10.1021/jacs.7b07347

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Article
Selective Synthesis of Primary Anilines from Cyclohexanone
Oximes by the Concerted Catalysis of a Mg#Al
Layered Double Hydroxide Supported Pd Catalyst
Xiongjie Jin, Yu Koizumi, Kazuya Yamaguchi, Kyoko Nozaki, and Noritaka Mizuno
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b07347 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 14, 2017
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Selective Synthesis of Primary Anilines from Cyclohexanone
Oximes by the Concerted Catalysis of a Mg‒Al Layered
Double Hydroxide Supported Pd Catalyst
Xiongjie Jin,*,† Yu Koizumi,‡ Kazuya Yamaguchi,*,‡ Kyoko Nozaki,†
and Noritaka Mizuno*,‡
†Department of Chemistry and Biotechnology, School of Engineering, The University of
Tokyo, 7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ8656, Japan
‡Department of Applied Chemistry, School of Engineering, The University of Tokyo,
7ꢀ3ꢀ1 Hongo, Bunkyoꢀku, Tokyo 113ꢀ8656, Japan
Fax: +81ꢀ3ꢀ5841ꢀ7220
Eꢀmail: tꢀjin@mail.ecc.uꢀtokyo.ac.jp; kyama@appchem.t.uꢀtokyo.ac.jp;
tmizuno@mail.ecc.uꢀtokyo.ac.jp
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ABSTRACT
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Although the selective conversion of cyclohexanone oximes to primary anilines would be a good
complement to the classical synthetic methods for primary anilines which utilize arenes as the
starting materials, there have been no general and efficient methods for the conversion of
cyclohexanone oximes to primary anilines until now. In this study, we have successfully realized the
efficient conversion of cyclohexanone oximes to primary anilines by utilizing a Mg‒Al layered
double hydroxide supported Pd catalyst (Pd(OH)x/LDH) under ligandꢀ, additiveꢀ, and
hydrogenꢀacceptorꢀfree conditions. The substrate scope was very broad with respect to both
cyclohexanone oximes and cyclohexenone oximes, which gave the corresponding primary anilines
in high yields with high selectivities (17 examples, 75‒>99% yields). The reaction could be scaled
up (gramꢀscale) with a reduced amount of the catalyst (0.2 mol%). Furthermore, the oneꢀpot
synthesis of primary anilines directly from cyclohexanones and hydroxylamine was also successful
(5 examples, 66‒99% yields). The catalysis was intrinsically heterogeneous, and the catalyst could
be reused for the conversion of cyclohexanone oxime to aniline at least five times with keeping its
high catalytic performance. Kinetic studies and several control experiments showed that the high
activity and selectivity of the present catalyst system was attributed to the concerted catalysis of the
basic LDH support and the active Pd species on LDH. The present transformation of cyclohexanone
oximes to primary anilines proceeds through a dehydration/dehydrogenation sequence, and herein
the plausible reaction mechanism is proposed based on several pieces of experimental evidence.
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INTRODUCTION
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Primary anilines are very important compounds which have been widely utilized for the synthesis of
a large variety of pharmaceuticals, agrochemicals, dyes, electronic materials, plastics, and resins.1
To date, various synthetic methods for primary anilines have been developed, for example, nitration
of arenes followed by reduction (Scheme 1a),1,2 nucleophilic3a or electrophilic3b,c aromatic
substitutions (Scheme 1b), and transition metalꢀcatalyzed crossꢀcoupling of aryl halides or aryl
boronic acids with ammonia (Scheme 1c).4 Despite their high synthetic efficiencies, these methods
using arenes as the starting materials sometimes have shortcomings; that is, the low
ortho/meta/para selectivities to the desired primary anilines and/or utilizing preꢀfunctionalized
substrates, such as aryl halides or aryl boronic acids (Schemes 1a, 1b and 1c). Thus, the
development of efficient synthetic protocols for primary anilines using more diverse starting
materials other than arenes is highly desirable from the retrosynthetic point of view.
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The dehydrative aromatization of cyclohexenone oximes to primary anilines, known as the
Semmler‒Wolff reaction,5 is another attractive method for the synthesis of substituted primary
anilines with high ortho/meta/para selectivities because of the easy availability of cyclohexenone
oximes with various substituted patterns on cyclohexenyl rings through dehydrative condensation of
cyclohexenones and hydroxylamine.6 Despite its great potential for the synthesis of substituted
primary anilines, the Semmler‒Wolff reaction has rarely been utilized in organic synthesis due to its
harsh reaction conditions (e.g., refluxing in AcOH/Ac2O with HCl gas), which leads to the narrow
substrate scope and generally low yields and selectivities (Scheme 1d).5 A heterogeneous Pd/C
catalyst has been reported to promote the Semmler‒Wolff reaction under high reaction temperatures
(e.g., 188 °C) with the substrate scope limited to cyclohexenone oximes (Scheme 1d).7 More
recently, Stahl and coꢀworkers have reported an elegant homogeneous Pdꢀcatalyzed conversion of
cyclohexenone oxime esters to primary anilines (Scheme 1d); however, the substrate scope is
limited to cyclohexenone oxime esters, thus, preꢀfunctionalization of cyclohexenone oximes to the
corresponding oxime esters should be required.8 Overall, as far as we know, there are virtually no
general and efficient catalytic systems for the direct conversion of cyclohexanone oximes and
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cyclohexenone oximes to the desired primary anilines.9
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Herein, we successfully realized the efficient and selective conversion of various kinds of
structurally diverse cyclohexanone oximes and cyclohexenone oximes to the corresponding primary
anilines by a basic Mg‒Al layered double hydroxide (LDH, Mg/Al = 3:1)10 supported Pd catalyst
(Pd(OH)x/LDH) under ligandꢀ, additiveꢀ, and hydrogenꢀacceptorꢀfree conditions (Scheme 1e). This
unprecedented selective conversion is a highly challenging reaction, because of the potential side
reactions, such as the Beckmann rearrangement11a and condensation of the substrates and primary
aniline products.11b Recently, we have successfully developed supported Pd or Au‒Pd catalysts for
the synthesis of phenols and Nꢀsubstituted anilines from sixꢀmembered carbocyclic compounds by
employing the dehydrogenative aromatization strategy.12,13 For these reactions, a basic LDH support
was found to significantly accelerate the dehydrogenative aromatization by promoting
deprotonative coordination of the substrates to the active metal (Pd) centers.12d,e Thus, we
envisioned that the concerted catalysis of supported metal species and the basic LDH support could
selectively promote the conversion of cyclohexanone oximes to primary anilines. The key points to
realize the present Pd(OH)x/LDHꢀcatalyzed selective conversion of cyclohexanone oximes and
cyclohexenone oximes to primary anilines turned out to be (1) the promoting effect of LDH for the
desired Pdꢀcatalyzed aromatization as revealed by our previous works12d,e and (2) the suppression of
the aboveꢀmentioned undesirable condensation, which are typically promoted by acids,11 by using
the basic LDH support.
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Scheme 1. Synthetic Methods for Primary Anilines
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2
3
(a) Nitration/reduction
NO2
NH2
4
5
6
nitration
R
reduction
R
R
7
8
(b) Nucleophilic or electrophilic aromatic substitution
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X
NH2
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+
KNH2
R
R
R
X = halogen atoms
NH2
H2N SO4H
or
Lewis acid
+
R
MsONH3OTf
(c) Cross-coupling
X
NH2
halogenation
NH3
R
R
borylation
B(OH)2
R
[Pd] or [Cu]
NH3
borylation
X = halogen atom
[Cu]
R
(d) Semmler−Wolff reaction: cyclohexenone oximes to anilines
R = H
OR
classical: HCl (g), Ac2O/AcOH, reflux
Matsumoto et al.: Pd/C, Diglyme, 188 °C
R = Pivaloyl
N
NH2
R'
R'
Stahl et al.: Pd(OAc)2/tricyclopentylphosphine,
PivOH, K2CO3, toluene, 95
(e) This work: cyclohexanone oximes to anilines
°
C
Beckmann
rearrangement
O
R
NH
(undesired)
OH
N
NH2
Pd(OH)x/LDH
+ H2O + H2
R
desired but
unknown
R
selective formation!
Condensation
(undesired)
N
R
R
ꢀ
Wide substrate scope
High selectivity
Ligandꢀ, additiveꢀ, and hydrogenꢀacceptorꢀfree
Reusable heterogeneous catalyst
ꢀ
ꢀ
ꢀ
ꢀ
Water and molecular hydrogen as the byꢀproducts
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RESULTS AND DISCUSSION
Effect of Catalysts. Initially, we prepared the Pd(OH)x/LDH catalyst by
a
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depositionꢀprecipitation method. Then, the catalyst was directly applied to the conversion of
cyclohexanone oxime (1a) to aniline (2a) in N,Nꢀdimethylacetamide (DMA) at 130 °C under 1 atm
of Ar. To our delight, the reaction gave 2a in 81% yield with only 10% of Nꢀcyclohexylaniline (3a)
formed due to the undesired dimerization of 1a, and the Beckmann rearrangement product was not
detected at all (Table 1, entry 1). We also confirmed that ca. one equivalent of hydrogen gas (H2)
with respect to 1a was formed during the Pd(OH)x/LDHꢀcatalyzed reaction. Other supports, such as
Al2O3, TiO2, and carbon, were less effective than LDH; the conversions of 1a with these catalysts
were lower than that with Pd(OH)x/LDH, and the selectivities to the desired 2a were also not
satisfactory due to the significant undesirable formation of 3a and diphenylamine (4a) (Table 1,
entries 2‒4). In the presence of other supported metal catalysts, such as Cu(OH)x/Al2O3,
Rh(OH)x/Al2O3, Au/Al2O3, and Ru(OH)x/Al2O3, 2a was not produced at all (Table 1, entries 5‒8).
The desired reaction did not proceed at all when employing the reported conditions for the
conversion of cyclohexenone oxime esters to primary anilines using Pd acetate
(Pd(OAc)2)/tricyclopentylphosphine (Pcyp3)/pivalic acid (PivOH) as the catalyst (Table 1, entry
9).8,14 The LDH support alone could not promote the reaction (Table 1, entry 10). Among various
solvents examined, such as DMA, N,Nꢀdimethylformamide (DMF), dimethylsulfoxide (DMSO),
oꢀdichlorobenzene, pꢀxylene, and diethylene glycol dimethyl ether (diglyme), DMA was the most
suitable solvent for the present reaction (Table S1).
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The color of Pd(OH)x/LDH was changed from light brown to black in less than 2 min (Figure
1a). The XPS spectrum of the freshly prepared Pd(OH)x/LDH catalyst showed the binding energies
of Pd 3d3/2 and 3d5/2 at 341.8 eV and 336.5 eV, respectively, indicating the oxidation state of the Pd
species is +2 (Figure 1b). After the reaction, the binding energies of Pd 3d3/2 and 3d5/2 were changed
to 339.9 eV and 334.6 eV, respectively, suggesting that most of the Pd2+ species in the freshly
prepared Pd(OH)x/LDH were reduced by 1a to Pd0 species during the reaction (Figure 1b). By
comparison of the XRD patterns of Pd(OH)x/LDH before and after the reaction, it was revealed that
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the layered structure of LDH was maintained well during the reaction (Figure 1c). Furthermore, it
was revealed from the transmission electron microscopy (TEM) analysis of Pd(OH)x/LDH after the
reaction that Pd nanoparticles were formed on the surface of LDH (average size of the nanoparticles
= 2.8 nm, Figure 1d). Also, it was confirmed from the N2 adsorptionꢀdesorption isotherms that the
BET surface area and the total pore volume of the used catalyst were almost unchanged compared
to the fresh catalyst (BET surface area: the fresh vs used catalyst: 48 vs 51 m2 g–1; the total pore
volume: the fresh vs used catalyst: 0.17 vs 0.15 cm3 g–1) (Figure S1).
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Table 1. Acceptorless Dehydrogenation of Cyclohexanone Oxime
(1a) to Aniline (2a) with Various Catalystsa
OH
N
NH2
O
H
N
H
N
catalyst (1 mol%)
+
+
+
DMA (2 mL), Ar (1 atm)
130 oC, 3 h
1a
2a
3a
4a
5a
Yield (%)
Entry Catalyst
Conv. (%)
97
2a
81
40
37
34
nd
nd
nd
nd
nd
nd
3a
4a
nd
8
5a
nd
6
1
Pd(OH)x/LDH
10
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30
nd
nd
nd
nd
nd
nd
2
Pd(OH)x/Al2O3 82
3
Pd(OH)x/TiO2
Pd/C
76
75
6
3
4
8
3
5
Cu(OH)x/Al2O3 17
nd
nd
nd
nd
nd
nd
11
nd
2
6
Rh(OH)x/Al2O3
Au/Al2O3
4
2
7
8
Ru(OH)x/Al2O3 18
13
3
9b
Pd(OAc)2
9
10
LDH
<1
nd
aReaction conditions: 1a (0.5 mmol), catalyst (metal: 1 mol%), DMA (2
mL), 130 °C, Ar (1 atm), 3 h. Conversion and yields were determined by
GC analysis. DMA = N,Nꢀdimethylacetamide. nd = not detected.
bReaction conditions reported in ref. 8: Pd(OAc)2 (10 mol%), PCyp3 (20
mol%), PivOH (30 mol%), K2CO3 (2 mmol), toluene (3 mL), 95 °C, Ar
(1 atm).
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Figure 1. Characterization of the catalysts: (a) Pictures of (i) the initial reaction mixture and (ii) that
after the reaction for 2 min. (b) XPS spectra of (i) the fresh Pd(OH)x/LDH and (ii) Pd(OH)x/LDH
after the 1st use; the blue dots indicate the data points; the red solid and black broken lines indicate
the deconvoluted signals and the sum of the deconvoluted signals, respectively. (c) XRD patterns of
(i) LDH, (ii) the fresh Pd(OH)x/LDH, and (iii) Pd(OH)x/LDH after the 1st use. (d) TEM image of
the Pd(OH)x/LDH catalyst after the first use (average: 2.8 nm, σ: 0.6 nm), inset: Pd nanoparticle
size distribution (n = 222).
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Substrate Scope and Catalyst Reuse. We next investigated the substrate scope of the present
Pd(OH)x/LDHꢀcatalyzed system. Cyclohexanone oxime and its derivatives with alkyl and phenyl
substituents on 2ꢀ, 3ꢀ, or 4ꢀpositions were all efficiently converted to the corresponding primary
anilines in high yields with high selectivities (Table 2, entries 1‒8). A gramꢀscale (10 mmolꢀscale)
synthesis of aniline was also successful; the high yield of aniline was still obtained upon reducing
the amount of the catalyst to 0.2 mol% (Table 2, entry 1). An allylꢀgroupꢀsubstituted cyclohexanone
oxime was quantitatively converted to the primary aniline product with the hydrogenation of the
allyl group (Table 2, entry 9). Cyclohexanone oximes possessing an alkoxy or ester group were well
tolerated without hydrolysis of these functional groups (Table 2, entries 10‒12). A hydroxy or
trifluoromethyl substituted cyclohexanone oximes were also good substrates for the present reaction
(Table 2, entries 13 and 14). In addition to cyclohexanone oximes, cyclohexenone oxime (Table 2,
entry 15) and tetralone oximes (Table 2, entries 16 and 17) were also efficiently reacted to give the
corresponding primary anilines in high yields. Interestingly, the oneꢀpot synthesis of primary
anilines directly from cyclohexanones and hydroxylamine was also successful; generally high
yields of primary anilines were obtained with the tolerance of ether and ester groups under the
present reaction conditions (Table 3).
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To verify whether the observed catalysis was intrinsically heterogeneous or not, the
Pd(OH)x/LDH catalyst was removed by hot filtration when the conversion of 1a was about 50%,
then the reaction was again carried out with the filtrate. In this case, the reaction was completely
stopped (Figure 2a). In addition, the analysis of the filtrate after the reaction by the inductively
coupled plasma atomic emission spectroscopy (ICPꢀAES) showed that Pd species were not present
in the filtrate (below the detection limit, Pd: <0.2%). These results indicated that the observed
catalysis was truly heterogeneous.15 The Pd(OH)x/LDH catalyst could be easily retrieved from the
reaction mixture by simple filtration with >90% recovery, and could be reused at least five times
with keeping its high catalytic performance (Figure 2b). Even at the fifth reuse experiment, 80%
yield of 2a was still obtained, although a slight decrease in the reaction rate was observed (Figure
S2). The XRD and TEM analyses of the Pd(OH)x/LDH catalyst after the 5th reuse experiment
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revealed that the layered structure of LDH and the average size of the Pd nanoparticles were almost
unchanged compared to the catalyst after the 1st use (after the 1st use: 2.8 nm, after the 5th reuse
experiment: 2.9 nm) (Figures S3 and S4).
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Table 2.
Substrate Scopea
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3
Entry
Substrate
Product
Entry
10
Substrate
Product
OH
N
1
OH
4
5
NH2
NH2
N
OMe
OMe
6
7
8
9
12 h, 82%
0.5 mmol scale: 3 h, 81%
10 mmol scale: 8 h, 91(85)%b
11
OH
N
NH2
2c
OH
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N
N
N
NH2
1 h, 78%
OH
OH
O
O
O
O
3
NH2
3 h, 82(75)%
OH
12
N
NH2
7 h, 82%
4
NH2
COOEt
COOEt
7 h, 75%
13c
OH
N
NH2
5 h, 76%
5c
OH
OH
N
N
NH2
1 h, 95%
OH
OH
1 h, (80)%
6
NH2
14c
OH
N
NH2
11 h, 91%
CF3
CF3
7c
OH
NH2
N
1 h, 85(71)%
15c
OH
N
NH2
2 h, 95(83)%
OH
8
1 h, 90%
N
NH2
OH
16c
N
NH2
Ph
Ph
3 h, 93(90)%
6 h, >99%
9c
17c
OH
OH
N
NH2
N
NH2
MeO
MeO
2 h, 97(84)%
1 h, >99(92)%
aReaction conditions: Substrate (0.5 mmol), Pd(OH)x/LDH (Pd: 1 mol%), DMA (2 mL), 130 °C, Ar
b
(1 atm). Yields were determined by GC analysis. Substrate (10 mmol), Pd(OH)x/LDH (Pd:
c
0.2 mol%), DMA (20 mL), 150 °C, Ar (1 atm). Pd(OH)x/LDH (Pd: 5 mol%), 150 °C. The isolated
yields are shown in the parentheses.
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Table 3. Oneꢀpot Synthesis of Primary Anilines from Cyclohexanones and Hydroxylaminea
1
2
3
4
Entry
1
Substrate
Product
Entry
4
Substrate
Product
NH2
O
NH2
O
5
6
7
8
9
2 h, 75%
2b
O
NH2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
O
O
O
O
2 h, 66%
5 h, 72%
5b
O
NH2
3
O
NH2
Ph
Ph
COOEt
COOEt
1 h, 99%
1 h, 74%
aReaction conditions: Cyclohexanone (0.5 mmol), NH2OH
·HCl (0.5 mmol), K2CO3 (0.5 mmol),
Pd(OH)x/LDH (Pd: 5 mol%), DMA (2 mL), 130 °C, Ar (1 atm). Yields were determined by GC
analysis. b150 °C.
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OH
N
NH2
1
2
H
N
Pd(OH)x/LDH (1 mol%)
+
3
4
5
DMA (2 mL), Ar (1 atm)
130 oC
1a
2a
3a
6
7
(a)
100
80
60
40
20
0
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Removalof the catalyst
0
1
2
3
4
5
6
Time (h)
1a conv.
2a yield
3a yield
(b)
97
fresh
81
10
89
90
1streuse
80
78
6
2nd reuse
3rd reuse
4th reuse
5th reuse
5
92
79
8
94
79
10
97
80
14
0
20
40
60
80
100
Conv.& Yield (%)
Figure 2. (a) Effect of removal of the Pd(OH)x/LDH catalyst on the dehydrogenation of 1a. The
closed squares and circles indicate the yields of 2a and 3a, respectively, without removal of the
catalyst; the open squares and circles indicate the yields of 2a and 3a, respectively, after removal of
the catalyst. (b) Pd(OH)x/LDH reuse experiments. The reaction conditions were the same as those
described in Table 1. Conversion and yields were determined by GC analysis.
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1
2
3
4
5
6
7
8
Mechanistic Studies. The present reaction likely proceeds through either (1) dehydrogenation
of cyclohexanone oximes to cyclohexenone oximes followed by dehydration (Scheme 2, path (a))
or alternatively (2) dehydration of cyclohexanone oximes to cyclohexenylimines followed by
dehydrogenation (Scheme 2, path (b)). To identify the reaction pathway active in the present
Pd(OH)x/LDHꢀcatalyzed conversion of cyclohexanone oximes to primary anilines, we carried out
the following kinetic studies. For the Pd(OH)x/LDHꢀcatalyzed conversion of 1a to 2a and
conversion of cyclohexenone oxime (6a) to 2a, both of the reaction rates showed the firstꢀorder
dependence on the substrate concentrations, and the rate constants for the conversion of 1a (k1) and
6a (k2) were determined to be 0.023 min‒1 and 0.078 min‒1, respectively (Figures 3a, 3b, and S5). In
addition, it was revealed from the reaction profile for the conversion of 1a to 2a that 6a was not
detected during the reaction (Figure 3c). Therefore, if the reaction proceeds through path (a), the
dehydration of 6a to 2a should be much faster than the dehydrogenation of 1a to 6a, and the rate
constant for the conversion of 1a to 6a should be approximately equal to k1. Additionally, assuming
that path (a) is active in the present reaction, we simulated the reaction profile using the determined
rate constants k1 = 0.023 min‒1 and k2 = 0.078 min‒1 (Figure 3d). The simulation result indicates that
at least ca. 20% yield of 6a should be observed at the initial stage of the reaction, which is in sharp
contradiction with the actual reaction profile (Figure 3c vs 3d). All the above results suggest that the
conversion of 1a to 2a likely proceeds through path (b) for which the dehydrogenation step is much
faster than the dehydration step.
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Scheme 2. Possible Reaction Pathways
OH
N
H2O
H2
OH
(a)
(b)
6a
N
NH2
1a
2a
H2
H2O
NH
main path
7a
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(a) R0 vs [1a]0
(b) R0 vs [6a]0
1
2
60
7
3
4
5
6
7
8
9
6
5
4
3
2
1
50
40
30
20
10
0
10
11
12
13
14
15
16
17
18
19
20
21
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30
31
32
33
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42
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44
45
46
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48
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50
51
52
53
54
55
56
57
58
59
60
0
0
100
200
300
0
200
400
600
800
[1a]0 (mM)
[6a]0 (mM)
(c) Experimental reaction profile
(d) Simulation of the reaction profile
250
300
[2a]
[2a]
250
[6a]
[6a]
200
200
150
150
OH
OH
OH
100
H2
H2O
N
N
NH2
N
NH2
100
50
0
Pd(OH)x/LDH (1 mol%)
DMA (2 mL), Ar (1 atm)
k1 = 0.023 min−1
k1 = 0.078 min−1
130 °C
50
0
1a (250 mM)
2a
1a
6a
2a
0
1
2
3
4
5
0
1
2
3
4
5
Time (h)
Time (h)
Figure 3. Kinetic studies. (a) Dependence of initial reaction rates on [1a]0, line fit: R0 = 0.023[1a]0
(r2 = 0.993). (b) Dependence of initial reaction rates on [6a]0, line fit: R0 = 0.078[6a]0 (r2 = 0.996).
(c) Experimental reaction profile for the conversion of 1a to 2a. (d) Simulation of the reaction
profile using k1 = 0.023 min‒1 and k2 = 0.078 min‒1 for the conversion of 1a to 2a by assuming that
path (a) is active in the present reaction. Reaction conditions: (a) 1a (50‒250 mM), Pd(OH)x/LDH
(Pd: 1 mol%), DMA (2 mL), 130 °C, Ar (1 atm); (b) 6a (257‒631 mM), Pd(OH)x/LDH (Pd: 1
mol%), DMA (2 mL), 130 °C, Ar (1 atm); (c) the reaction conditions are the same as that shown in
Table 1, entry 1. Conversion and yields were determined by GC analysis.
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1
2
3
4
5
6
7
8
Based on the aforementioned results, we here propose a plausible reaction mechanism for the
present reaction which is illustrated in Scheme 3.14 For the dehydration of 1a to cyclohexenylimine
(7a), the deprotonative coordination of 1a to Pd species with the assistance of basic LDH initially
gives an intermediate A (Scheme 3, step 1), which is followed by the isomerization to afford B
(Scheme 3, step 2). Then, the βꢀhydride elimination from B gives an intermediate C (Scheme 3, step
3), followed by the dehydration to afford 7a (Scheme 3, step 4).16 For the dehydrogenation of 7a to
2a, an intermediate D is initially generated by the deprotonative coordination of αꢀcarbon of 7a to
Pd species with the assistance of basic LDH (Scheme 3, step 5), or by the isomerization of D’
generated by the deprotonative coordination of nitrogen atom of 7a to Pd species, or even by the
direct oxidative addition of Pd species to the αꢀCꢀH bond of 7a. Then, the βꢀhydride elimination
from D gives the final product 2a with the concomitant formation of a Pd‒H species E (Scheme 3,
step 6), which is followed by protonation to liberate H2 (Scheme 3, step 7). Also, the dehydrative
aromatization of 6a likely proceeds through the steps 1‒4 in Scheme 3.
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60
Scheme 3. A Plausible Reaction Mechanism
NH
NH
+ B:
B:H
OH
N
B:H
+ B: + H2O
7a
7a
Pd
Pd
NH
N
step 5
H
Pd
C
step 3
step 4
D
D’
NH2
OH
Dehydration
(slow)
Dehydrogenation
N
[Pd]
OH
(fast)
Pd
step 6
2a
B
step 1
step 2
O
N
Pd
H
N
Pd
step 7
7a
E
+ B:
B:H
NH2
H
N
A
1a
1a or 7a
H2
B:H
[Pd] = Pd nanoparticle
B: = LDH
3a
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Journal of the American Chemical Society
1
2
3
4
5
6
7
8
To gain further insights into the reaction mechanism, the following several control experiments
were conducted. Firstly, the reaction of 1a with 4ꢀtertꢀbutylaniline was carried out, which
selectively gave 2a without the formation of the crossꢀcoupled products 8 and 8’ (Scheme 4a). On
the other hand, for the reaction of 1a with 4ꢀtertꢀbutylcyclohexylamine, the selectivity to 2a
significantly decreased with the concomitant formation of the crossꢀcoupled product 9 (Scheme 4a).
These results indicate that the formation of byꢀproducts, such as 3a and 4a, during the reaction of
1a was not derived from the coupling of 2a and 1a, rather, likely from the condensation of 1a or 7a
with cyclohexylamine formed through the undesirable hydrogenation of 7a by the Pd‒H species E
(Scheme 3). Next, the Pd(OH)x/Al2O3ꢀcatalyzed conversion of 1a to 2a was carried out in the
presence of K2CO3 or LDH (Scheme 4b). In these cases, both the conversion of 1a and the
selectivity to 2a were significantly improved in comparison with the reaction without these bases
(Scheme 4b). Therefore, the LDH support works as a base to accelerate the desired reaction, thus, to
improve the selectivity likely via the concerted catalysis of the LDH support and Pd species to
accelerate the baseꢀrelevant steps 1, 2, 4, 5 and 7 shown in Scheme 3. The improved selectivity
when using LDH as the support could also be attributed to the suppression of the condensation of
1a or 7a with cyclohexylamine because of the stronger basicity of the LDH support compared to the
other supports utilized in this study (Table 1). Notably, the yield of and selectivity to 2a for the
conversion of 1a with Pd(OH)x/LDH were significantly higher than those with a physical mixture of
Pd(OH)x/Al2O3 and LDH, indicating that the Pd species supported on the LDH surface is crucial for
the concerted catalysis (Table 1, entry 1 vs Scheme 4b, entry 3). Finally, the hydrogenation of 6a by
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60
Pd/LDH (prepared by the treatment of Pd(OH)x/LDH in 1 atm of H2 at 130 °C for 15 min) using 1
atm of H2 gave 1a in a high selectivity even under room temperature (Scheme 4c), suggesting an
equilibrium also exists between species B and C (Scheme 3, step 3).
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Scheme 4. Control Experiments
(a)
1
2
H
N
3
4
5
6
NH2
OH
N
8
NH2
tꢀBu
tꢀBu
H
N
Pd(OH)x/LDH (1 mol%)
H
N
+
+
+
DMA (2 mL), Ar (1 atm)
130 oC, 3 h
tꢀBu
7
1a (0.5 mmol) (0.5 mmol)
2a
3a
8'
8
nd
Conv.: 99%
<1%
Yield: 75%
4%
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60
H
N
NH2
OH
N
NH2
H
N
tꢀBu
9
Pd(OH)x/LDH (1 mol%)
+
+
+
26%
DMA (2 mL), Ar (1 atm)
130 oC, 3 h
H
N
tꢀBu
1a (0.5 mmol) (0.5 mmol)
2a
3a
tꢀBu
tꢀBu
10
3%
Conv.: 93%
40%
Yield: 38%
4%
(b)
OH
N
NH2
+
O
H
N
H
N
Pd(OH)x/Al2O3 (1 mol%)
+
+
DMA (2 mL), 130 °C
Ar (1 atm), 3 h
1a (0.5 mmol)
2a
3a
4a
5a
Yield (%)
Entry Additive
Conv. of 1a (%)
2a
40
70
59
3a
27
4
4a
5a
6
1
2
3
none
82
8
K2CO3 (1 equiv) 96
LDH (20 mg) 97
nd
nd
5
4
12
(c)
OH
OH
N
N
NH2
O
Pd/LDH (1 mol%)
+
+
DMA (2 mL), rt
H2 (1 atm), 0.5 h
6a (0.5 mmol)
1a (56%)
2a (2%)
5a (7%)
In the presence of Pd(OH)x/LDH and D2O, a complete deuterium incorporation to the hydroxy
group of 1a was observed even at room temperature (Scheme 5a), indicating the deprotonation from
the hydroxy group of 1a is very fast (Scheme 3, step 1). When 1a was treated with D2O in the
presence of just LDH, no deuterium incorporation at αꢀposition of 1a was observed (Scheme 5b),
which suggests that LDH alone cannot cleave the αꢀC‒H of 1a directly. Therefore, the species B is
less likely to be formed by the LDHꢀpromoted deprotonation of the αꢀC‒H of 1a followed by
coordination to the Pd species, and the Pd species play a crucial role on the cleavage of the αꢀC‒H
bond. When the Pd(OH)x/LDHꢀcatalyzed conversion of 1a to 2a was carried out in the presence of
D2O, 20% of deuterium labeling at 2ꢀ and/or 6ꢀpositions of 2a was observed, and no deuterium was
found at the 3ꢀ and/or 5ꢀpositions (Scheme 5c). If the direct oxidative addition of the αꢀC‒H bond
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of 1a to Pd0 species takes place, the deuterium incorporation at 3ꢀ and/or 5ꢀpositions should be
observed to some extent for the reaction in Scheme 5c because the Pd‒H species formed can be
reꢀinserted to the βꢀposition according to the backward reaction of step 3 in Scheme 3. Furthermore,
in a separate experiment, we confirmed that the deuterium incorporation at 2ꢀ and/or 6ꢀpositions of
2a was not observed at all even when 2a was treated with D2O in the presence of Pd(OH)x/LDH
(Scheme 5d). From these results, we concluded that the direct oxidative addition of the αꢀC‒H bond
to Pd species is less likely to occur in the present catalytic cycle. Consequently, we assume that the
species B is probably derived from the LDHꢀassisted isomerization of the intermediate A (Scheme 3,
step 2) formed by the deprotonative coordination of 1a to Pd species (Scheme 3, step 1).17 In
addition, relatively fast equilibrium reactions likely exist between the active Pd species and the
species B and/or D (Scheme 3, steps 1, 2, and 5).
1
2
3
4
5
6
7
8
9
10
11
12
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44
45
46
47
48
49
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52
53
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57
58
59
60
Scheme 5. Deuterium Labeling Experiments
(a)
OH
OD
N
N
Pd(OH)x/LDH (1 mol%)
DMFꢀd7 (0.75 mL), D2O (0.25 mL)
air (1 atm), rt, 30 min
1a (0.5 mmol)
1a' (>99%)
OH/D(1:6)
OH
N
(b)
(c)
N
LDH (20 mg)
H/D(>99:<1)
DMA (0.9 mL), D2O (0.1 mL)
Ar (1 atm), 130 oC, 10 min
H/D(>99:<1)
H/D(>99:<1)
H/D(1/2)
1a (0.5 mmol)
1a'
OH
N
HN
Pd(OH)x/LDH (1 mol%)
H/D(4:1)
DMA (0.9 mL), D2O (0.1 mL)
Ar (1 atm), 130 oC, 10 min
H/D(>99:<1)
H/D(>99:<1)
1a (0.5 mmol)
2a (28%)
H/D(1/4)
(d)
NH2
HN
Pd/LDH (1 mol%)
H/D(>99:<1)
DMA (0.9 mL), D2O (0.1 mL)
Ar (1 atm), 130 oC, 10 min
2a (0.5 mmol)
H/D(>99:<1)
H/D(>99:<1)
2a'
The Arrhenius plot for the conversion of 1a to 2a (the pseudoꢀfirstꢀorder rate constant kobs vs 1/T
in the range of 393‒423 K) are shown in Figure S6, from which the activation energy Ea was
calculated to be 79.8 kJ·mol‒1. Also, the other activation parameters were obtained from the
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Eyring’s equation: ∆H≠403 K = 76.4 kJ mol‒1, ∆S≠
= ‒123.9 J K‒1 mol‒1, and ∆G≠
= 126.3
403 K
1
2
403 K
kJ mol‒1. The relatively large negative value of ∆S≠
indicates that the rateꢀdetermining step of
3
4
403 K
5
6
7
8
the reaction probably includes a bimolecular transition state, where two molecules (or more) are
converted into one transition state molecule.18 Thus, the LDHꢀassisted dehydration from the species
C to the cyclohexenylimine intermediate 7a is likely involved in the rateꢀdetermining step for the
present reaction (Scheme 3, step 4).
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60
CONCLUSION
We have successfully developed the novel efficient conversion of cyclohexanone oximes
cyclohexenone oximes to primary anilines by the heterogeneous Pd(OH)x/LDH catalyst under
ligandꢀ, additiveꢀ, and hydrogenꢀacceptorꢀfree conditions via the concerted catalysis of basic LDH
and supported Pd species. The reaction proceeded highly selectively to afford the desired primary
anilines without the formation of byꢀproducts derived from the Beckmann rearrangement. The
substrate scope was very broad with respect to both cyclohexanone oximes and cyclohexenone
oximes. In addition, the reaction theoretically produces only water and H2 as the byꢀproducts, which
features the environmentallyꢀfriendly nature of the reaction. The catalysis was truly heterogeneous,
and the Pd(OH)x/LDH catalyst could be reused for the conversion of cyclohexanone oxime to
aniline at least five times with keeping its high catalytic performance. The present catalyst system
could also be scaled up with a reduced amount of the catalyst, thus, would find broad applications
in the bulk and fine chemicals synthesis.
EXPERIMENTAL SECTION
Instruments and Reagents. Gas chromatography (GC) analyses were performed on Shimadzu
GCꢀ2014 equipped with a flame ionization detector (FID) and an InertCapꢀ5 capillary column. GC
mass spectrometry (GCꢀMS) spectra were recorded on Shimadzu GCMSꢀQP2010 equipped with an
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1
2
InertCapꢀ5 capillary column at an ionization voltage of 70 eV. Liquidꢀstate NMR spectra were
1
recorded on JEOL JNMꢀECAꢀ500 spectrometer. H and 13C NMR spectra were measured at 500.2
3
4
5
6
7
8
and 125.8 MHz, respectively, using tetramethylsilane (TMS) as an internal reference (δ = 0 ppm).
ICPꢀAES analyses were performed on a Shimadzu ICPSꢀ8100. TEM observations were performed
on JEOL JEMꢀ2010HC. XRD patterns were measured on a Rigaku SmartLab diffractometer (CuKα,
λ = 1.5405 Å, 45 kV‒200 mA). The XPS measurements were carried out on JEOL JPSꢀ9000 using
Mg Kα radiation (hν = 1253.6 eV, 8 kV, 10 mA). The binding energies were calibrated by using the
Mg 2p signal at 49.5 eV.19 Pd/C (Lot. No. 217ꢀ024030, NE CHEMCAT), LDH
(Mg6Al2(OH)16CO3·4H2O, BET surface area: 51 m2 g–1, Tomita Pharmaceutical Co., Ltd.),20 Al2O3
(BET surface area: 160 m2 g–1, Cat. No. KHSꢀ24, Sumitomo Chemical), and TiO2 (BET surface
area: 316 m2 g–1, Cat. No. STꢀ01, Ishihara Sangyo Kaisya) were commercially available. Solvents,
cyclohexanones, and cyclohexenones were obtained from Kanto Chemical, TCI, Wako, or Aldrich
(reagent grade), and purified prior to the use if required.21 Various cyclohexanone oximes and
cyclohexenone oximes in Table 2 were prepared according to the literature procedures.22
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Preparation of Pd(OH)x/LDH. First, LDH (2.0 g) was added to a 60 mL aqueous solution of
PdCl2 (0.83 mM) and KCl (2 equiv with respect to PdCl2, 1.67 mM). The mixture was vigorously
stirred at room temperature for 18 h. The solid was then filtered off, washed with water (3 L), and
dried in vacuo to afford Pd(OH)x/LDH (Pd content: 0.25 mmol g–1). Other catalysts such as
Cu(OH)x/Al2O3, Rh(OH)x/Al2O3, Au/Al2O3, Ru(OH)x/Al2O3, Pd(OH)x/Al2O3, and Pd(OH)x/TiO2
were prepared according to the literature procedures.23
Conversion of Oximes to Primary Anilines. A typical procedure for the reaction:
0.5 mmolꢀscale: Into a Schlenk tube (volume: ca. 20 mL) connected to a balloon partially filled
with Ar gas, Pd(OH)x/LDH (20 mg, Pd: 1 mol %), cyclohexanone oxime (0.5 mmol),
N,Nꢀdimethylacetamide (DMA) (2.0 mL), and a Teflonꢀcoated magnetic stir bar were successively
placed, and the reaction mixture was vigorously stirred at 130 °C. After the reaction was completed,
an internal standard (nꢀhexadecane) was added to the reaction mixture, and the conversion of
cyclohexanone oxime and the yield of aniline were determined by GC analysis. The product was
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identified by GCꢀMS analysis. The detection of hydrogen in the gasꢀphase was carried out with
gasꢀphase MS analysis. The quantification of hydrogen gas formation was performed by
measurement of the evolved gas volume.
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10 mmolꢀscale: Into a Schlenk tube (volume: ca. 50 mL) connected to a balloon partially filled
with Ar gas, Pd(OH)x/LDH (80 mg, Pd: 0.2 mol %), cyclohexanone oxime (10 mmol), DMA (20
mL), and a Teflonꢀcoated magnetic stir bar were successively placed, and the reaction mixture was
vigorously stirred at 130 °C for 8 h, in 1 atm of Ar. After the reaction, the catalyst was filtered off
(>90 % recovery). Then, EtOAc (20 mL) and nꢀhexane (5 mL) were added to the filtrate, which was
washed with brine (25 mL) 3 times. The organic phase was dried with Na2SO4, and evaporated to
remove solvents. The crude product was subjected to column chromatography on silica gel (using
nꢀhexane/EtOAc as the eluent), giving the pure product. The product was identified by GCꢀMS and
NMR (1H and 13C) analyses. The retrieved catalyst was washed with water and ethanol before being
used for the reuse experiment.
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Syntheses of Anilines from Cyclohexanones and Hydroxylamine. A typical procedure for the
reaction: Into a Schlenk tube (volume: ca. 20 mL), cyclohexanone (0.5 mmol), K2CO3 (0.5 mmol),
NH2OH·HCl (0.5 mmol), DMA (1 mL), and a Teflonꢀcoated magnetic stir bar were successively
placed, and the reaction mixture was vigorously stirred at room temperature for 0.5 h. Then,
Pd(OH)x/LDH (100 mg, Pd: 5 mol %) and DMA (1 mL) were added to the Schlenk tube, which was
connected to a balloon. The reactor was filled with Ar gas, and the reaction mixture was vigorously
stirred at 130 °C. After the reaction was completed, an internal standard (nꢀhexadecane) was added
to the reaction mixture, and the conversion of cyclohexanone and the yield of aniline were
determined by GC analysis. The product was identified by GCꢀMS analysis.
ASSOCIATED CONTENT
Supporting Information. Spectral data of the aniline products, Table S1, Figures S1‒S6, NMR
spectra of the deuterated products shown in Scheme 5. This material is available free of charge via
the Internet at http://pubs.acs.org.
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ACKNOWLEDGMENT
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This work was supported in part by JSPS KAKENHI Grant Number 15H05797 in Precisely
Designed Catalysts with Customized Scaffolding and Grant Number 17K14860.
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(9) It has been reported that aniline is formed as the sideꢀproduct (<15% yield) during the solid
acidꢀcatalyzed Beckmann rearrangement of cyclohexanone oxime under harsh reaction
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conditions (e.g., >350 °C); see: (a) Conesa, T. D.; Mokaya, R.; Yang, Z.; Luque, R.; Campelo,
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J. M.; Romero, A. A. J. Catal. 2007, 252, 1. (b) Mandal, S.; Santra, C.; Kumar, R.; Pramanik,
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(10) For selected examples of LDH as a basic support for functional group transformations, see:
(a) Motokura, K.; Nishimura, D.; Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. J. Am.
Chem. Soc. 2004, 126, 5662. (b) Ebitani, K.; Motokura, K.; Mizugaki, T.; Kaneda, K. Angew.
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Jitsukawa, K.; Kaneda, K. Angew. Chem. Int. Ed. 2008, 47, 138. (d) Mitsudome, T.; Noujima,
A.; Mikami, Y.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Angew. Chem. Int. Ed. 2010, 49,
5545. (e) Noujima, A.; Mitsudome, T.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Angew. Chem.
Int. Ed. 2011, 50, 2986.
(11) (a) Clayden, J.; Greeves, N.; Warren, S. Organic Chemistry, 2nd ed., Oxford University Press
Inc., New York, 2012, 958. (b) de Angelis, A.; Ingallina, P.; Perego, C. Ind. Eng. Chem. Res.
2004, 43, 1169.
(12) Our recent works, see: (a) Taniguchi, K.; Jin, X.; Yamaguchi, K.; Mizuno, N. Chem. Commun.
2015, 51, 14969. (b) Taniguchi, K.; Jin, X.; Yamaguchi, K.; Mizuno, N. Catal. Sci. Technol.
2016, 6, 3929. (c) Taniguchi, K.; Jin, X.; Yamaguchi, K.; Nozaki, K.; Mizuno, N. Chem. Sci.
2017, 8, 2131. (d) Jin, X.; Taniguchi, K.; Yamaguchi, K.; Mizuno, N. Chem. Sci. 2016, 7,
5371. (e) Jin, X.; Taniguchi, K.; Yamaguchi, K.; Nozaki, K.; Mizuno, N. Chem. Commun.
2017, 53, 5267.
(13) Dehydrogenative aromatization has emerged as an attractive method for the synthesis of
various aromatic compounds from ubiquitous saturated sixꢀmembered carbocyclic compounds,
for reviews, see: (a) Girard. S. A.; Huang, H.; Zhou, F.; Deng, G.ꢀJ.; Li, C.ꢀJ. Org. Chem.
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Front. 2015, 2, 279. (b) Iosub, A. V.; Stahl, S. S. ACS Catal. 2016, 6, 8201. (c) Zeng, H.; Qiu,
Z.; DomínguezꢀHuerta, A.; Hearne, Z.; Chen, Z.; Li, C.ꢀJ. ACS. Catal. 2017, 7, 510.
(14) The inefficiency of the homogeneous Pd catalyst reported by Stahl and coꢀworkers for the
conversion of 1a (Table 1, entry 9) suggests that the Pd0 nanoparticles is crucial for the
reaction. We assume that multiꢀnuclear Pd species are responsible for the desired reaction.
(15) Sheldon, R. A.; Wallau, M.; Arends, I. W. C. E.; Schuchardt, U. Acc. Chem. Res. 1998, 31,
485.
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(16) The reduction of oximes to amines with Pd/C has been reported using organic reductants such
as ammonium formate or polymethylhydrosiloxane, see: (a) Jnaneshwara, G. K.; Sudalai, A.;
Deshpande, V. H. J. Chem. Research 1998, 160. (b) Chandrasekhar, S.; Venkat Reddy, M.;
Chandraiah, L. Synlett 2000, 1351.
(17) In this study, we propose the Pdꢀassisted deprotonative coordination mechanism for the
formation of an intermediate B (steps 1 and 2 in Scheme 3) based on several pieces of
experimental evidence. However, we cannot completely exclude the possibility of the direct
αꢀC‒H bond cleavage by the Pd species. One of the reviewers pointed out this; the reviewer
commented that the Pd enolate species is also possibly formed by the direct oxidative addition
of αꢀC‒H bond to the Pd species. Recent works on the Pdꢀcatalyzed dehydrogenations suggest
that both the Pdꢀassisted deprotonative coordination and the direct oxidative addition are
possible, see: (a) Pun, D.; Diao, T.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 8213. (b) Chen,
Y.; Romaire, J. P.; Newhouse, T. R. J. Am. Chem. Soc. 2015, 137, 5875. (c) Chen, M.; Dong,
G. J. Am. Chem. Soc. 2017, 139, 7757.
(18) Connors, K. A. Chemical Kinetics: The Study of Reaction Rates in Solution, John Wiley &
Sons, Inc., New York, 1990, 220.
(19) Cantrell, D. G.; Gillie, L. J.; Lee, A. F.; Wilson, K. Appl. Catal. A: General 2005, 287, 183.
(20) The Mg‒Al LDH could otherwise be synthesized by a simple coꢀprecipitation method, see
Cavani, F.; Trifiro, F.; Vaccari, A. Catal. Today 1991, 11,173.
(21) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory Chemicals, 3rd ed., Pergamon
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Press, Oxford, 1988.
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(22) (a) Zhao, H.; Vandenbossche, C. P.; Koenig, S. G.; Singh, S. P.; Bakale, R. P. Org. Lett. 2008,
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(23) (a) Jin, X.; Kataoka, K.; Yatabe, T.; Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2016,
55, 7212. (b) Taniguchi, K.; Itagaki, S.; Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed.
2013, 52, 8420.
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