Aerobic ruthenium-catalyzed oxidative transformation of secondary amines to imines

Article abstract of DOI:10.1055/s-2007-984515

Aerobic, catalytic oxidation of secondary amines is performed efficiently in the presence of a diruthenium complex catalyst Ru₂(OAc) ₄Cl to give the corresponding imines. The catalytic system is characterized by its high selectivity, activity, and operational simplicity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-984515

LETTER
1675
Aerobic Ruthenium-Catalyzed Oxidative Transformation of Secondary
Amines to Imines
mines Ichi Murahashi,*a,b Yuriko Okano, Hideomi Sato, Takahiro Nakae, Naruyoshi Komiya
a
a
a
a
O
S
xidative Tra
n
h
sformationo
u
f
Secondary
n
Amines toI
-
a
Department of Chemistry, Graduate School of Engineering Science, Osaka University, 1-3 Machikaneyama, Toyonaka, Osaka 560-8531,
Japan
b
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science, 1-1 Ridaicho, Okayama 700-0005, Japan
Fax +81(86)2564292; E-mail: murahashi@high.ous.ac.jp
Received 10 April 2007
This work is dedicated to the memory of Professor Yoshihiko Ito.
excellent catalyst for the oxidative transformation of sec-
ondary amines to imines using molecular oxygen (1 atm,
balloon) under mild conditions (50 °C, Equation 1).19
Abstract: Aerobic, catalytic oxidation of secondary amines is
performed efficiently in the presence of a diruthenium complex
catalyst Ru (OAc) Cl to give the corresponding imines. The cata-
2
4
lytic system is characterized by its high selectivity, activity, and
operational simplicity.
H
Ru2(OAc)4Cl (cat.)
R1
R1
N
N
+
1/2 O2
R2
+
H2O
Key words: ruthenium, oxidations, molecular oxygen, amines,
imines
R2
toluene, 50 °C
(1 atm)
Equation 1
Metal-catalyzed oxidation of secondary amines is one of
the most important functional transformations in organic
synthesis, because the oxidation products such as imines
and nitrones are highly useful intermediates for synthesis
First of all, we examined the catalytic activity of various
ruthenium complexes for the aerobic oxidation of 1,2,3,4-
tetrahydroisoquinoline (1, Table 1). The oxidation of 1
was carried out under molecular oxygen (1 atm, balloon)
in the presence of a catalytic amount of a ruthenium com-
plex (2 mol%) in toluene at 50 °C. The conversions of 1
and the yields of 3,4-dihydroisoquinoline (2) and isoquin-
oline (3) were determined by GLC analyses. It is notewor-
thy that only dinuclear ruthenium complex, Ru (OAc) Cl,
1
,2
of biologically active nitrogen compounds. In 1985, we
reported the first catalytic and general method for oxida-
tive transformation of secondary amines to the corre-
sponding imines using RuCl (PPh ) catalyst and t-
2
3 3
3
BuOOH. After this finding, many methods for metal-cat-
alyzed oxidations of secondary amines with oxidants such
as RuCl (PPh ) /PhIO, Pr NRuO /N-methyl morpholine
N-oxide, [{Ph (h -C CO)}Ru(CO) ]/Co(salen)/MnO ,
NiSO /K S O , and Rh (cap) /t-BuOOH were reported.
2
4
4
was found to be effective among the ruthenium catalysts
2
5
3 3
4
4
4
6
4
4
3
2
7
8
4
2
2
8
2
4
Table 1 Catalytic Activity of Various Ruthenium Complexes for
the Oxidation of 1,2,3,4-Tetrahydroisoquinoline with Molecular
Oxygena
Recently, aerobic oxidation is recognized to be very
9
important in view of green chemistry. Many methods for
metal-catalyzed aerobic oxidative transformation of
primary amines to the corresponding nitriles have been
Ru2(OAc)4Cl (4 mol%)
+
NH
N
N
O2 (1 atm)
1
0–17
explored;
however, the methods for catalytic aerobic
toluene, 50 °C, 10 h
1
2
3
oxidative transformation of secondary amines to the
corresponding imines are limited to a few systems, which Entry
include Ru/Co/benzoquinone-based coupled redox sys-
Catalyst
Conv. (%)b
Yield (%)b
2
3
1
8
15
tem, heterogeneous Ru/Al O catalyst, and CuCl cata-
2
3
1
7
lyst in the presence of MS 3 Å. The difficulty of the
aerobic oxidation of secondary amines is due to the unsta-
bleness of the product imines under the oxidation condi-
tions and easy hydrolysis to carbonyl compounds.
1
2
3
4
5
6
Ru
2
(OAc)
4
Cl
98
18
15
6
77
10
14
5
6
1
1
1
RuCl3
RuO2
We wish to report diruthenium complex catalyzed aerobic
oxidative transformation of secondary amines to imines,19
which are highly useful intermediates for synthesis of
RuCl (PPh )
3 3
2
Ru(bpy) Cl
2
2
Trace
Trace
Trace
2
2
2
0
biologically important nitrogen compounds. We found
Ru(bpy) Cl
4
3
3
2
21
that dinuclear ruthenium complex, Ru (OAc) Cl is an
2
4
7
Ru(TPP)(CO)
5
4
a
Reaction conditions: Ru (OAc) Cl (0.015 mmol), 1,2,3,4-tetra-
2
4
SYNLETT 2007, No. 11, pp 1675–1678
0
3
.0
7
.2
0
0
7
hydroisoquinoline (0.75 mmol), toluene (1 mL), O (1 atm), 50 °C.
Determined by GLC analysis using an internal standard.
2
Advanced online publication: 25.06.2007
DOI: 10.1055/s-2007-984515; Art ID: U03107ST
Georg Thieme Verlag Stuttgart · New York
b
©

1
676
S.-I. Murahashi et al.
LETTER
examined (entry 1). RuCl and RuO showed moderate matography on Al O (eluent: hexane–EtOAc = 2:1 to
3
2
2
3
catalytic activity (entries 2 and 3), while RuCl (PPh ) , 1:1) gave 6,7-dimethoxy-3,4-dihydroisoquinoline (5) and
2
3 3
Ru(bpy) Cl , Ru(bpy) Cl , Ru(TPP)(CO) (TPPH = tetra- 6,7-dimethoxyisoquinoline in 80% and 4% yields, respec-
2
2
3
2
2
phenylporphyrin) showed almost no catalytic activity tively.
under these conditions (entries 4–7).
The representative results of the ruthenium-catalyzed ox-
Typical procedure for the oxidation of 6,7-dimethoxy- idative transformation of secondary amines are summa-
,2,3,4-tetrahydroisoquinoline (4) is as follows. In a flask rized in Table 2. The Ru (OAc) Cl-catalyzed oxidation of
1
2
4
were placed amine 4 (0.75 mmol) and Ru (OAc) Cl 1,2,3,4-tetrahydroisoquinolines 1 and 4 gave efficiently
2
4
(
0.030 mmol). After the flask was flushed with molecular the corresponding imines 2 and 5, which are important
oxygen, toluene (1 mL) was added, and the mixture was precursors for synthesis of isoquinoline alkaloids (entries
stirred under oxygen atmosphere (1 atm) at 50 °C for 12 1 and 2). 1,2,3,4-Tetrahydroquinoline (6) was converted
hours. Removal of the solvent followed by column chro- into the imine, which subsequently underwent dehydro-
Table 2 Ruthenium-Catalyzed Oxidation of Various Amines with Molecular Oxygena
Entry
1
Substrate
Product
Time (h)
3
Conv. (%)b
100
Yield (%)b
77f
NH
N
1
MeO
2
2
MeO
12
72
100
86
80g,h
NH
N
MeO
MeO
4
5
3c
55
N
N
H
7
6
8
4
5
1
100
100
83
79
N
N
H
H
9
48
N
H
N
H
1
1
0
2
11
6d
7e
18
48
97
38
72i
27
N
H
N
N
1
3
N
H
1
1
4
6
15
8
CN
7
100
66
NH2
1
7
a
Reaction conditions: Ru (OAc) Cl (0.03 mmol), amine (0.75 mmol), toluene (1 mL), O (1 atm), 50 °C.
Determined by GLC analysis using an internal standard.
Reaction was carried out at 80 °C.
Reaction was carried out with oxygen bubbling.
In the presence of nitrogen ligands 1 (0.06 mmol).
Quinoline 3 was also formed in 6% yield.
Isolated yield.
2
4
2
b
c
d
e
f
g
h
i
6
,7-Dimethoxyquinoline was also formed in 4% yield.
Benzaldehyde was also formed in 17% yield.
Synlett 2007, No. 11, 1675–1678 © Thieme Stuttgart · New York

LETTER
Oxidative Transformation of Secondary Amines to Imines
1677
genation under the reaction conditions to give quinoline 7 cies was demonstrated for the first time in the asymmetric
entry 3). The treatment of indolines gave the correspond- oxypalladation of allylphenols,22 and later palladium-
(
2
3
ing indoles in good yields (entries 4 and 5). Linear sec- catalyzed aerobic oxidation of alcohols, and ruthenium-
ondary amines such as dibenzylamine (12) were also catalyzed oxidative transformation of primary amines to
converted into the corresponding imine 13 (entry 6). The nitriles.15 The reaction of 20 with secondary amines
bulky secondary amine N-phenylbenzylamine (14) is not would give the product imine, hydrogen peroxide, and
reactive under the reaction conditions (entry 7). However, recovered the intermediate 18 to complete the catalytic
addition of a catalytic amount of external ligands such as cycle. Control experiments confirmed that hydrogen per-
1
and 2 improved the catalytic efficiency dramatically. oxide thus formed undergoes fast decomposition to give
For example, the Ru (OAc) Cl-catalyzed oxidation of 14 molecular oxygen and water under the reaction condi-
2
4
gave a trace amount of imine 15; however, 15 was ob- tions; however, hydrogen peroxide does not work as an
24
tained in 27% yield in the presence of a catalytic amount oxidant for oxidation of amines. The result of the oxy-
of 1, indicating that coordination of nitrogen ligands to the gen-uptake measurement also supports this mechanism.
ruthenium species is important for the oxidation. The One equivalent of molecular oxygen is consumed for the
green complex formed from
a 1:2 mixture of oxidation of two equivalents of 1 under the standard reac-
Ru (OAc) Cl and 1 is soluble in toluene, while tion conditions. In this scheme, we describe that the reac-
2
4
Ru (OAc) Cl alone is insoluble in toluene.
tion takes place on one ruthenium atom for simplicity;
however, it is likely the reaction uses both of the rutheni-
um atoms. High catalytic activity at low temperature is
due to the synergic effect of dinuclear structure of the
ruthenium catalyst.
2
4
It is noteworthy that the ruthenium complex formed in situ
upon treatment of Ru (OAc) Cl with amine 1 was also
2
4
found to be highly effective for the oxidation of alcohols.
Thus, the aerobic oxidation of benzyl alcohol in the pres-
ence of a catalytic amount of Ru (OAc) Cl and 1 (1:2) When substrates are primary amines (R¢ = H), the reaction
2
4
gives benzaldehyde in 97% yield, while Ru (OAc) Cl proceeds by two-step oxidation via imine intermediate as
2
4
alone shows no catalytic activity (<1%). The addition of shown in Scheme 2. The intermediate 22, which is formed
inorganic bases such as K CO and NaOAc showed nega- by b-hydride elimination of 21, undergoes reaction with
2
3
tive effect, indicating that the amine 1 plays an important molecular oxygen to give Ru–OOH species 23. The intra-
role as a ligand to the ruthenium rather than a base for molecular proton transfer from 23 would give 24 and
deprotonation. The oxidation of primary amine 16 gives hydrogen peroxide. Further b-hydride elimination of 24
the corresponding nitrile 17 in a highly efficient manner would give ruthenium hydride species 25. Insertion of
(
entry 8).
molecular oxygen to the metal hydride of 25 would give
6, and subsequent reaction with primary amine would
give the nitrile, hydrogen peroxide, and recovered 21 to
2
The oxidation of secondary amines can be rationalized by
assuming the mechanism shown in Scheme 1. The
diruthenium(II,III) core of Ru (OAc) Cl is tentatively
represented as Rn Ru , because the oxidation states of It is noteworthy that the oxidation of primary amines
the rutheniums may be electrically symmetric during the gives the corresponding nitriles rather than the dimeric
complete the catalytic cycle.
2
4
n
n
reaction.
products in the present system. This is in contrast to the
transition-metal-catalyzed alkyl group exchange reaction,
giving the dimerization products via addition of an amine
to the imine complex as shown in Scheme 3.25
Initially, secondary amines (RCH NHR¢) coordinate to
2
Ru (OAc) Cl to give 18 by ligand-exchange reaction. b-
2
4
Hydride elimination from 18 would give imine–rutheni-
um hydride species 19. Insertion of molecular oxygen to
the ruthenium hydride species 19 would afford a rutheni-
um hydroperoxide 20. Such oxidation of a metal hydride
M–H species with molecular oxygen to give M–OOH spe-
H2O2
1/2 O2 + H2O
RCH2NH
+
RC
N
RC
N
RCH NH
RCH2NR'
RCH NR'
n
n
n
n
Ru Ru
n
n
HOO Ru Ru
H
Ru Ru
22
n
n
Ru Ru
21
26
RCH NH
n
Ru Run
2
2
18
H
O2
19
O2
RCH NR'
RCH2NHR'
+
H2O2
O2
RCH
N
RCH NH
RC
N
Run Run
n
n
n
n
HOO
Ru Ru
RCH NR'
H
Ru Ru
24
23
2
5
H2O2
1
/2 O2 + H2O
HOO Ru Run
n
20
1/2 O2 + H2O
Scheme 1
Scheme 2
Synlett 2007, No. 11, 1675–1678 © Thieme Stuttgart · New York

1
678
S.-I. Murahashi et al.
LETTER
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1
R CH2NH2
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1
1
R CH NH
M
R CH2 NH
1
R CH2NH2
2
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MH
HMH
3
1
R CH NH2
1
R CH2NHCH2R1
M
+
NH3
(
10) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem.
Soc., Chem. Commun. 1978, 562.
11) Schröder, M.; Griffith, W. P. J. Chem. Soc., Chem. Commun.
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1
R CH2N
MH2
H
(
Scheme 3
(
(
12) Bailey, A. J.; James, B. R. Chem. Commun. 1996, 2343.
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Work is in progress to determine the structure of the
reactive ruthenium species and to apply this new catalytic
system to the other reactions.
(
14) Mori, K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.;
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Acknowledgment
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480.
1
This work was supported by a Grant-in-Aid for Scientific Research,
the Ministry of Education, Culture, Sports, Science, and Techno-
logy, Japan.
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(
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2
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(
(
2
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