Palladium-catalyzed aerobic oxidation of amines

Article abstract of DOI:10.1016/j.tetlet.2006.09.088

Pd-Catalyzed aerobic oxidation of different amines was systematically examined for the first time. A PdCl₂/PPh₃ system was successfully developed to catalyze the aerobic oxidation of several types of amines including Ar-CH₂NHPh, Ar-CH₂NHOMe, and Ar-CH₂NHMs with high yields. Theoretical studies showed a remarkable difference in the energy barriers of β-hydride elimination between an alcohol and various amines.

Full text of DOI:10.1016/j.tetlet.2006.09.088

Tetrahedron Letters 47 (2006) 8293–8297
Palladium-catalyzed aerobic oxidation of amines
Jia-Rui Wang, Yao Fu, Bei-Bei Zhang, Xin Cui, Lei Liu* and Qing-Xiang Guo*
Department of Chemistry, University of Science and Technology of China, Hefei 230026, PR China
Received 26 July 2006; revised 18 September 2006; accepted 19 September 2006
Available online 10 October 2006
Abstract—Pd-Catalyzed aerobic oxidation of different amines was systematically examined for the first time. A PdCl2/PPh3 system
was successfully developed to catalyze the aerobic oxidation of several types of amines including Ar–CH2NHPh, Ar–CH2NHOMe,
and Ar–CH2NHMs with high yields. Theoretical studies showed a remarkable difference in the energy barriers of b-hydride elim-
ination between an alcohol and various amines.
Ó 2006 Elsevier Ltd. All rights reserved.
Selective oxidation of organic compounds with O2 as a
sole oxidant is valuable from both environmental and
economic points of view.1 For this reason, considerable
efforts have been devoted in recent years to develop
transition metal-catalyzed aerobic oxidation reactions.
Among the transition metals used, Pd is the most attrac-
tive because one Pd-catalyzed aerobic oxidation reaction
(i.e., the Wacker process) has already received an indus-
trial success.2 Many recent studies have also shown that
Pd2+ can catalyze other oxidative transformations
including alcohol oxidation, dehydrosilylation of sily
enol ethers, and oxidative C–O, C–N, and C–C coupling
reactions with olefins.3 Despite these successes, there
remain some important oxidative transformations for
which it has been extremely difficult to find an effective
Pd catalyst system. One such example is the aerobic
oxidation of amines to yield nitriles or imines.
quinone.6 Some Cu salts have also been reported to be
able to mediate aerobic oxidation of amines.7 Nonethe-
less, no Pd catalyst system has ever been reported for the
aerobic oxidation of amines.
Herein we report our recent success in finding some Pd
catalyst systems that can catalyze aerobic oxidation of
amines. Initially, we examined the oxidation of benzyl
alcohol and a number of substituted benzyl amines with
˚
Uemura’s (Pd(OAc)2/pyridine/MS3 A/O2) catalyst sys-
tem (Table 1).8 Although benzyl alcohol (entry 1) was
smoothly oxidized to benzaldehyde, benzylamine, and
N-methyl benzyl amine (entries 2 and 3) were unreactive.
Gratefully, N-phenyl benzylamine could be oxidized to
the corresponding imine by the procedure, although
the yield (43%) was only modest (entry 4). Next, we
examined N-benzylacetamide but found it completely
unreactive (entry 5). N-Benzylmethanesulfonamide and
N-benzyl-toluenesulfonamide, on the other hand, were
found to be oxidized to sulfoximines by the procedure
(entries 6 and 7). It was also found that N-methoxylbenz-
ylamine could be successfully oxidized to the corre-
sponding oxime (entry 8) with a satisfactory yield (89%).
The importance of the aerobic amine oxidation is at
least twofold: (1) the products of the reaction, that is,
imines or nitriles, are valuable intermediates in organic
synthesis; (2) on the basis of catalytic amine oxidation
it is possible to develop kinetic resolution methods to
access enantiomerically enriched secondary amines.
Previously James and Bailey reported a Ru–porphyrin
catalyzed aerobic procedure for the oxidation of amines
to imines.4 Mizuno and Yamaguchi reported a Ru-cata-
lyzed heterogeneous aerobic oxidation of primary
amines to nitriles.5 More recently, Ba¨ckvall and
co-workers reported biomimetic aerobic oxidation of
secondary amines to imines catalyzed by Ru and hydro-
The above results indicated that Pd-catalyzed aerobic
oxidation of amines was not something forbidden by
nature. However, it was also found that the chemical
structures of the amines exerted significant effects on
the efficiency of oxidation. To improve the yields and
thereby the practicability of the transformation, we next
examined a number of reaction conditions as shown in
Table 2. Briefly, by extending the reaction time from
2 h to 14 h, the yield increased dramatically from 43%
to 70% (entry 1). Using pyridine as the ligand we tried
*
Corresponding authors. Tel.: +86 5513607466; fax: +86 5513606689
(L.L.); e-mail: leiliu@ustc.edu
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.09.088

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J.-R. Wang et al. / Tetrahedron Letters 47 (2006) 8293–8297
Table 1. Aerobic oxidation of benzyl alcohol and benzylic amines catalyzed by the Pd(II)/pyridine catalyst systema
Entry
Reactant
Product
GC yield (%)
1
2
3
4
5
6
7
8
PhCH2OH
PhCH2NH2
PhCHO
99
0
0
43
0
23
16
89
No reaction
No reaction
PhCH@NPh
No reaction
PhCH@NMs
PhCH@NTs
PhCH@NOMe
PhCH2NHCH3
PhCH2NHPh
PhCH2NHAc
PhCH2NHMs
PhCH2NHTs
PhCH2NHOMe
a
˚
Conditions: reactant = 0.5 mmol, Pd(OAc)2 = 5 mol %, pyridine = 20 mol %, toluene = 5 mL, MS3 A = 0.25 g, O2 = 1 atm, 80 °C, 2 h.
Table 2. Aerobic oxidation of N-phenyl benzylaminea
Ph
Ph
Pd/air
N
H
N
conditions
Entry
Catalyst
Ligand
Base
Solvent
GC yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Pd(OAc)2
PdCl2
Pyridine
Pyridine
Pyridine
Pyridine
—
NEt3
NEt3
NEt3
Phen
Bipyridine
i-Pr2NEt
TMEDA
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
—
—
—
—
Toluene
Toluene
DMSO
DMF
DMSO
CH2Cl2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
DMSO
DMA
NMP
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
70
0
25
65
68
3
15
74
0
1
10
2
96
10
98
97
97
7
88
29
64
50
0
99
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
NaHCO3
—
—
NaOAc
NaOAc
NaOAc
—
—
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
—
NaOAc
t-BuOK
K2CO3
NaOH
i-Pr2NEt
NaOAc
NaOAc
PPh3
PPh3
PPh3
PPh3
—
PPh3
PdCl2
PdCl2(PPh3)2
PdCl2
95 (in air)
a
˚
Conditions: reactant = 0.5 mmol, Pd salt = 5 mol %, ligand = 10 (for PPh3) or 20 mol % (for others), solvent = 5 mL, MS3 A = 0.25 g, O2 = 1 atm
(except for entry 25), base = 0.5 mmol, 80 °C, 14 h.
several solvent systems such as DMSO and DMF which
were previously reported to be favorable for Pd-cata-
lyzed aerobic oxidations9 (entries 2–4). The results re-
vealed that toluene provided the highest yield. Next,
we tried some other ligands including no ligand,10 trieth-
ylamine,11 bipyridine, diisopropylethylamine, 1,10-phen-
anthroline (Phen), and tetramethylethylene-diamine
(TMEDA) (entries 5–12). Triethylamine was found
to provide the highest yield (74%) when NaOAc was
present (entry 8).12
were always high (96–98%) in a few different solvents
(DMF, DMSO, DMA, and NMP) except for toluene
(entries 13–17). NaOAc was found to be essential to
the reaction (entry 18) when PdCl2 was used as the cat-
alyst. However, Pd(OAc)2 was less effective than the
combination of PdCl2 and NaOAc (entry 19). Com-
pared to NaOAc, other bases including t-BuOK,
K2CO3, NaOH, and i-Pr2NEt gave much lower yields
(entries 20–23). It was also found that the commercially
available PdCl2(PPh3)2 complex was as effective as the
combination of PdCl2 and PPh3 (entry 24). Further-
more, we were pleased to find that the aerobic oxidation
could also be performed with a high yield (95%) in air
(entry 25).
An interesting breakthrough was then made when we
used triphenylphosphine as the ligand (entry 13). This
finding was quite counterintuitive because phosphines
are oxygen sensitive and therefore, not expected to be
useful in oxidation reactions.13 Nonetheless, the yields
of the phosphine-mediated amine oxidation reaction
Having confirmed that PdCl2/PPh3/NaOAc/DMF pro-
vided excellent conditions for the aerobic oxidation of

J.-R. Wang et al. / Tetrahedron Letters 47 (2006) 8293–8297
8295
Table 3. Aerobic oxidation of different amines or amides catalyzed by the PdCl2/PPh3/NaOAc/DMF procedurea
Entry
Reactant
Product
Isolated yield (%)
Ph
Ph
N
H
N
1
95
Ph
Ph
N
H
N
2
3
48b
Ph
Ph
Ph
N
H
N
58b
95
98
63
95
MeO
MeO
H
N
N
Ph
Ph
4
5
6
7
H
N
N
Ph
MeO
MeO
H
N
N
N
Ph
Ph
H3COC
H3COC
OMe
OMe
N
H
MeO
MeO
8
56b
N
N
H
9
56
HN
N
H
N
N
Ph
Ph
10
25b
OMe
N
OMe
OMe
OMe
N
N
H
11
12
91
92
OMe
OMe
N
H
Br
Br
O
H
SO2Me
N
H
13
14
15
76
82
95
O
SO2Me
N
H
H
O
SO2Me
N
H
H
MeO
MeO
O
16
17
No reaction
0
0
N
H
H
N
No reaction
Me
Ph
N
H
18
19
No reaction
No reaction
0
0
N
H
a
˚
Conditions: reactant = 1 mmol, PdCl2 = 5 mol %, PPh3 = 10 mol %, DMF = 10 mL, MS3 A = 0.5 g, O2 = 1 atm, NaOAc = 1 mmol, 80 °C, 14 h.
b Determined by 1H NMR.

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J.-R. Wang et al. / Tetrahedron Letters 47 (2006) 8293–8297
N-phenyl benzylamine, we next examined whether the
same procedure could be used to oxidize other amines.
Instead of determining the GC yields, herein we focused
on the isolated yields to ensure the practicability of the
newly developed reaction (Table 3). Firstly we changed
the aromatic groups at both the N-phenyl site and the
benzylamine site. It was found that both electron-rich
and poor aromatic groups could be tolerated (entries
1–9). Nonetheless, it was found that an aryl group with
an ortho-substituent (entry 10) would dramatically
decrease the yield. This indicated that the reaction
was sensitive to steric crowding of the substrate. As to
N-methoxylamines, it was found that the PPh3 proce-
dure was superior to the pyridine procedure because
the yields were relatively higher (entries 11 and 12).
The PPh3 procedure also provided much higher yields
in the cases of N-methanesulfonamides, although the
major products were the corresponding aldehydes
(entries 13–15). A proposed explanation for this obser-
vation was that the sulfoximine products were rapidly
hydrolyzed under the reaction conditions (where H2O
was produced as a by-product unavoidably).
2.42
2.34
1.54
2.38
1.94
2.37
1.64
2.49
2.05
3.10
2.41
2.05
PhCH2OH, ΔG = 0.3 kcal/mol
2.38 2.42
2.35
1.55
2.37
3.10
2.49
2.05
1.94
2.41
1.64
2.11
PhCH2NH2, ΔG = 7.4 kcal/mol
2.35
1.55
2.42
2.48
2.07
2.38
2.42
2.39
1.95
1.64
2.11
PhCH2NHCH3, ΔG = 7.3 kcal/mol
Amides, N-phenylalkylamines, and N-alkyl benzylam-
ines (entries 16–19) were not oxidized by the PPh3 pro-
cedure. Evidently both the electronic and steric effects
played vital roles in the reaction. Before the aerobic oxi-
dation of more challenging amines, we decided to utilize
theoretical tools to obtain some physical insights into
the reaction. Thus we calculated the free energy barrier
of the b-hydride elimination step for various substrates
using standard B3PW91/LANL2DZ + p//B3PW91/
LANL2DZ methods.14,15 It is worth noting that in
many previous studies b-hydride elimination was pro-
posed to be the rate-determining step.16,17
2.40
2.37
1.63
2.35
1.55
2.41
2.08
2.43
1.85
2.49
2.14
2.09
PhCH2NHPh, ΔG = 1.7 kcal/mol
2.35
1.56
2.40
2.37
2.48
2.37
2.01
2.42
1.95
1.60
2.09
2.14
PhCH2NHCOCH3, ΔG = 6.7 kcal/mol
From the theoretical results (Fig. 1), it was evident
that the energy barrier of b-hydride elimination for
PhCH2NH2 was about 7 kcal/mol higher than that for
PhCH2OH (which could be translated to ca. 105-fold
difference in reactivity). The addition of a methyl group
in the case of PhCH2NHCH3 only decreased the energy
barrier by 0.1 kcal/mol. By contrast, a phenyl group in
PhCH2NHPh dramatically reduced the energy barrier
to 1.7 kcal/mol, so that the reactivity between
PhCH2OH and PhCH2NHPh differed only by about
10-fold. This explained why PhCH2NHPh could be
oxidized relatively easily. Furthermore, the energy
barriers for PhCH2NHAc and PhCH2NHMs were 6.7
and 3.6 kcal/mol, respectively. This explained why
PhCH2NHMs could be oxidized but PhCH2NHAc
could not. Finally, the energy barrier for PhCH2-
NHOMe was 1.9 kcal/mol. Thus, PhCH2NHOMe was
also a good substrate for Pd-catalyzed aerobic oxida-
tion. The energy barrier for PhCH- (CH3)NHPh was
7.6 kcal/mol, which was about 6 kcal/mol higher than
that for PhCH2NHPh. Accordingly, a secondary amine
was much more difficult to oxidize than a primary amine
because of the steric problems.
2.35
1.55
2.40
2.36
2.50
2.07
2.39
2.06
2.43
1.62
1.97
2.14
PhCH2NHSO2CH3, ΔG = 3.6 kcal/mol
2.35
1.55
2.37
2.42
2.42
2.07
2.48
2.09
2.44
1.63
1.88
2.16
PhCH2NHOMe, ΔG = 1.9 kcal/mol
2.40
1.85
2.37
2.35
1.55
2.41
2.06
2.43
2.14
1.63
2.49
2.09
PhCHCH3NHPh, ΔG = 7.6 kcal/mol
Figure 1. Structures of the starting material (left), transition state
(middle), and product of b-hydride elimination (right).
To conclude, in the present study we reported the first
examples of Pd-catalyzed aerobic oxidation of amines.
An interesting PdCl2/PPh3 procedure was developed
and it was successfully utilized to catalyze the aerobic
oxidations of several different types of amines including

J.-R. Wang et al. / Tetrahedron Letters 47 (2006) 8293–8297
8297
8. (a) Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S.
Tetrahedron Lett. 1998, 39, 6011; (b) Nishimura, T.; Onoue,
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Ar–CH2NHAr, Ar–CH2NHOMe, and Ar–CH2NHMs
with high yields. Further theoretical studies showed a
remarkable difference in the free energy barrier of the
b-hydride elimination step for different amines. Thus,
in order to oxidize those ‘more difficult’ amines we need
to find more powerful solutions to reduce their energy
barriers for b-hydride elimination. Given the fact that
many phosphine ligands are available and many of them
have been known to exhibit extraordinary effects in Pd
catalysis, we are optimistic that some Pd/phosphine sys-
tem could be developed in the near future to catalyze the
aerobic oxidations of more general amines under milder
conditions.
Acknowledgment
This research was supported by the NSFC (No.
20332020 and 20472079).
14. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G.
E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A.,
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R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
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Hratchian, H. P.; Cross, J. B.; Adamo, C.; Jaramillo, J.;
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Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2006.09.088.
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