Baeckvall J.-E. (ed.) Modern Oxidation Methods
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toluene, reflux
OH
NHPh
2
N
H
O
Ph
H
2
N
P
N
CORu
t
-Bu
t
-Bu
Et
Et
H
+
+
96%
ð7:37Þ
By regenerating the hydrogen acceptor in the presence of co-catalyst and oxygen,
the hydrogen transfer reaction can be extended to the catalytic aerobic oxidation.
B
€
ackvall et al. found that the ruthenium hydride formed during the hydrogen transfer
can be converted to ruthenium by a multistep electron transfer process including
hydroquinone, the metal complex, and molecular oxygen (Scheme 7.3). On the basis
of this process, aerobic oxidation of alcohols to aldehydes and ketones can be
performed at ambient pressure of O
2
in the presence of a ruthenium-cobalt bimetallic
catalyst and hydroquinone [84]. Typically, cycloheptanol is oxidized to cycloheptanone
under O
2
atmosphere with a catalytic system consisting of ruthenium complex 29,
cobalt complex 30, and 1,4-benzoquinone (Eq. (7.38)) [85].
Ru
Ru
air
Ph
Ph
Ph
O
Ph
Ph
Ph
Ph
O
Ph
H
H
OCCO
OC
CO
N
O
N
N
O
Co
OOH
29 (cat.)
30 (cat.)
29
2,6-dimethoxy-1,4-benzoquinone (cat.)
toluene, 100 °C
92%
30
ð7:38Þ
OH
OH
O
O
[Ru]
[Ru]-H
R
1
R
2
OH
R
1
R
2
O
H
+
+
[ML
m
]
ox
ML
m
1/2 O
2
H
2
O
Scheme 7.3
7.3 Oxidation with Low-Valent Ruthenium Catalysts and Oxidants
j
253
Sheldon and Arends found that the combination RuCl
2
(PPh
3
)
3
-TEMPO affords an
efficient catalytic system for the aerobic oxidation of a broad range of primary and
secondary alcohols at 100
C, giving the corresponding aldehydes and ketones,
respectively, in >99% selectivity in all cases [86]. The reoxidation of the ruthenium
hydride species with TEMPO was proposed in the latter system [86c]. Allylic alcohols
can be converted into a,b-unsaturated aldehydes with 1 atm of molecular oxygen in
the presence of RuO
2
catalyst [87].
TPAP [69] can be used as an effective catalyst for the aerobic oxidation of alcohols to
give the corresponding carbonyl compounds (Eq. (7.39)) [88]. A polymer-supported
perruthenate (PSP) and a perruthenate immobilized within MCM-41 can be used
for heterogeneous oxidation of alcohols [89]. Water-soluble diruthenium complex
[Ru
2
(OAc)
3
(CO
3
)] is effective for aerobic oxidation of alcohols in water [90].
C
9
H
19
OH
C
9
H
19
O
88%
O
2
(1 atm)
MS4A
PhCH
3
70 °C
Bu
4
N
+
RuO
4
–
(cat.)
ð7:39Þ
Heterogeneous catalysts such as Ru-Al-Mg-hydrotalcite, Ru-Co-Al-hydrotalcite,
Ru-hydroxyapatite (RuHAP) (Eq. (7.40)) [91], Ru-Al
2
O
3
[92a,b], and Ru/AlO(OH)
[92c] are highly efficient catalysts for aerobic oxidation of alcohols. In these oxidation
reactions, the key step is postulated as the reaction of Ru-H with O
2
to form Ru-OOH,
in analogy to Pd-OOH, which has been shown to operate in the palladium-catalyzed
Wacker-type asymmetric oxidation reaction [93]. It is noteworthy that ruthenium on
carbon is simple and efficient for the oxidation of alcohols (Eq. (7.41)) [92d].
C
7
H
15
OH
C
7
H
15
O
96%
O
2
(1 atm)
PhCH
3
80 °C
RuHAP (cat.)
ð7:40Þ
99%
Me
OH
Me
O
10% Ru/C (cat.)
O
2
(1 atm)
PhCH
3
70 °C
ð7:41Þ
Polystyrene-based immobilized ruthenium catalysts can be used in oxidation of
alcohols with NMO, TEMPO/O
2
,orO
2
[94]. Catalytic oxidative cleavage of vicinal
diols to aldehydes with dioxygen was reported with RuCl
2
(PPh
3
)
3
on active car-
bon [95]. Ionic liquids such as tetramethyl ammonium hydroxide and Aliquat
336
can be used as the solvent for the RuCl
2
(PPh
3
)
3
-catalyzed aerobic oxidation of
alcohols [96].
254
j
7 Ruthenium-Catalyzed Oxidation for Organic Synthesis
Kinetic resolution of secondary alcohols and desymmetrization of diols were
reported by asymmetric oxidation using chiral (nitrosyl)Ru(salen) chloride (31)
(Eq. (7.42)) [97] in addition to the aerobic oxidation reaction [97d].
OH
Ph
OH
Ph
O
Ph
k
rel
= 20
N
O
N
O
PhPh
Ru
NO
Cl
+
air, h
ν
C
6
H
5
Cl, rt
35%
99.5%
ee
65%
31 (cat.)
ð7:42Þ
7.3.3
Oxidation of Amines
Selective oxidative demethylation of tertiary methyl amines is one of the specific and
important functions of cytochrome P-450. Novel cytochrome P-450-type oxidation
behavior with tertiary amines has been found in the catalytic systems of low-valent
ruthenium complexes with peroxides. These systems exhibit specific reactivity
toward oxidations of nitrogen compounds such as amines and amides, differing
from that with RuO
4
. Low-valent ruthenium complex-catalyzed oxidation of tertiary
methylamines with t-BuOOH gives the corresponding a-(tert-butyldioxy)alkylamines
efficiently (Eq. (7.43)) [98]. The hemiaminal-type product has a similar structure to
that of the a-hydroxymethylamine intermediate derived from the oxidation with
cytochrome P-450.
R
1
N
R
2
CH
3
R
1
N
R
2
CH
2
OO-
t
-Bu
RuCl
2
(PPh
3
)
3
t
-BuOOH
(cat.)
ð7:43Þ
As shown in Scheme 7.4, the catalytic oxidation reactions can be rationalized by
assuming the formation of oxo-ruthenium species by the reaction of low-valent
Ru
n+2
O
Ru
n
– Ru
n
R
1
C
R
2
OO-
t
-Bu
N
R
3
R
4
– H
2
O
Ru
n
OO-
t-
Bu
NC
R
1
R
2
R
4
R
3
R
1
C
R
2
H
N
R
3
R
4
Ru
n
(OH)
t
-BuOOH
– t
-BuOH
+
32
t
-BuOOH
Scheme 7.4
7.3 Oxidation with Low-Valent Ruthenium Catalysts and Oxidants
j
255
ruthenium complexes with peroxides. a-Hydrogen abstraction from amines and the
subsequent electron transfer gives the iminium ion ruthenium complex 32. Trap-
ping 32 with t-BuOOH would afford the corresponding a-tert-butyldioxyamine,
water, and low-valent ruthenium complex to complete the catalytic cycle.
The oxidation of N-methylamines provides various useful methods for organic
synthesis. Selective demethylation of tertiary methylamines can be performed by
ruthenium-catalyzed oxidation and subsequent hydrolysis (Eq. (7.44)) [98]. This is
the first practical synthetic method for the N-demethylation of tertiary amines. The
methyl group is removed chemo-selectively in the presence of various alkyl groups.
N
CH
3
CH
2
CH
3
NCH
2
CH
3
2M HCl
RuCl
2
(PPh
3
)
3
(cat.)
N
CH
2
OO-
t
-Bu
CH
2
CH
3
t
-BuOOH
H
61%
ð7:44Þ
Biomimetic construction of piperidine skeletons from N-methylhomoallylamines
is performed by means of the ruthenium-catalyzed oxidation and subsequent alkene-
iminium ion cyclization reaction. trans-1-Phenyl-3-propyl-4-chloropiperidine (34)
was obtained from N-methyl-N-(3-heptenyl)aniline stereoselectively via 33 (55%)
upon treatment with a 2 M HCl solution (Eq. (7.45)).
PhN
ClPhN
C
3
H
7
C
3
H
7
CH
2
OO-
t
-Bu
PhN
C
3
H
7
Cl
34
H
3
O
+
+
35
33
PhN
C
3
H
7
CH
3
RuCl
2
(PPh
3
)
3
3
(cat.)
t
-BuOOH
87%
55%
ð7:45Þ
This cyclization can be rationalized by assuming the formation of iminium ion 35
by protonation of the oxidation product 33, subsequent elimination of t-BuOOH, and
nucleophilic attack of an alkene, giving a carbonium ion, which is trapped with the
Cl
nucleophile from the less hindered side. Similar treatment using CF
3
CO
2
Hin
place of HCl gave the corresponding hydroxy derivative (Eq. (7.46)).
N
H
3
PhC
N
Ph
OH
H
Ru cat.
H
3
O
+
t
-BuOOH
ð7:46Þ
a-Methoxylation of tertiary amines can be carried out upon treatment with
hydrogen peroxide in the presence of RuCl
3
catalyst in MeOH [99]. Thus, the
oxidation of tertiary amine 36 gave the corresponding a-methoxyamine 37 in
60% yield (Eq. (7.47)).
256
j
7 Ruthenium-Catalyzed Oxidation for Organic Synthesis
N
Ph
N
Ph
OMe
H
2
O
2
MeOH, rt
RuCl
3
•nH
2
O
3736
(cat.)
ð7:47Þ
Oxidation with molecular oxygen and direct carbon-carbon bond formation by
trapping the iminium ion intermediate with a carbon nucleophile can be performed
under oxidative conditions. Thus, RuCl
3
-catalyzed oxidative cyanation of tertiary
amines with NaCN gives the corresponding a-aminonitriles, which are useful inter-
mediates for the synthesis of various compounds such as a-amino acids and 1,2-
diamines (Eq. (7.48)) [100]. Oxidative cyanation of pyrrolidine derivatives with H
2
O
2
gives the corresponding a-cyanated products in good yields (Eq. (7.49)) [101].
Aminonitriles thus obtained are versatile synthetic intermediates for the construction
of quinoline skeletons. For example, TiCl
4
-promoted reaction of N-cyanomethyl-N-
methylaniline (38) with allyltrimethylsilane gave 1-methyl-4-[(trimethylsilyl)methyl]-
1,2,3,4-tetrahydroisoquinoline (39), which is an important precursor of isoquinoline
alkaloids (Eq. (7.50)).
N
CH
3
CH
3
N
CH
2
CN
CH
3
O
2
(1 atm)
(cat.)
RuCl
3
NaCN
MeOH, AcOH
60
o
C
88%
38
ð7:48Þ
NCH
3
O
(cat.)
RuCl
3
NaCN
MeOH, AcOH
rt
H
2
O
2
NCH
3
O
NC
80%
ð7:49Þ
N
CH
3
CH
2
CN
+
Si(CH
3
)
3
TiCl
4
CH
2
Cl
2
N
CH
3
Si(CH
3
)
3
75%
38
39
ð7:50Þ
Tertiary amine N-oxides can be prepared from the corresponding tertiary amines
by RuCl
3
-catalyzed oxidation with molecular oxygen [102].
Secondary amines can be converted into the corresponding imines in a single step
highly efficiently through treatment with 2 equiv. of t-BuOOH in benzene in the
presence of RuCl
2
(PPh
3
)
3
catalyst at room temperature [103]. This is the first catalytic
oxidative transformation of secondary amines to imines. The oxidations of tetra-
hydroisoquinoline 40 and allylamine 42 gave the corresponding cyclic imine 41 and
azadiene 43 in 93% and 69% yields, respectively (Eqs. (7.51) and (7.52)).
7.3 Oxidation with Low-Valent Ruthenium Catalysts and Oxidants
j
257
NH
PhCH
2
O
MeO
N
PhCH
2
O
MeO
C
6
H
6
t
-BuOOH
40
RuCl
2
(PPh
3
)
3
(cat.)
93%
41
ð7:51Þ
NPh
Cl
NPh
Cl
42 43
H
69%
ð7:52Þ
Aromatization takes place when an excess amount of t-BuOOH is used. For
example, tetrahydroquinoline (44) can be converted into quinoline (45) (73%)
(Eq. (7.53)).
N
H
N
4544
RuCl
2
(PPh
3
)
3
t
-BuOOH
C
6
H
6
(cat.)
ð7:53Þ
It is worth noting that tungstate-catalyzed oxidation of the secondary amine with
hydrogen peroxide gives nitrone (46) (Eq. (7.54)) [104]. These two catalytic transfor-
mations of secondary amines (Eqs. (7.51) and (7.54)) are particularly useful for the
introduction of a substituent at the a-position of the amines, because either imines or
nitrones undergo diastereo and enantioselective reactions with nucleophiles to give
chiral a-substituted amines highly efficiently [105].
CHNHR
3
R
1
R
2
NC
R
1
R
2
R
3
O
46
H
2
O
2
+
Na
2
WO
4
-
(cat.)
ð7:54Þ
The catalytic system consisting of (n-Pr
4
N)(RuO
4
) and N-methylmorpholine N-
oxide (NMO) can be also used for oxidative transformation of secondary amines to
imines (Eq. (7.55)) [106].
NPh
H
PhNPhPh
(Bu
4
N)(RuO
4
)
(cat.)
MS4A
CH
3
CN
88%
NO
O
Me
-
+
ð7:55Þ
The ruthenium-catalyzed oxidation of diphenylmethylamine with t-BuOOH gave
benzophenone (88%), which was formed by hydrolysis of the imine intermediate
(Eq. (7.56)) [103].
CHNH
2
Ph
Ph
C
Ph
Ph
OC
Ph
Ph
NH
H
2
O
Ru cat.
t
-BuOOH
ð7:56Þ
258
j
7 Ruthenium-Catalyzed Oxidation for Organic Synthesis
Murahashi et al. found that aerobic oxidative transformation of secondary amines
to the corresponding imines can be carried out highly efficiently using the bimetallic
ruthenium catalyst Ru
2
(OAc)
4
Cl (Eq. (7.57)) [107].
NH
CH
3
O
CH
3
O
O
2
(1 atm)
(cat.)
Ru
2
(OAc)
4
Cl
toluene
50
o
C
N
CH
3
O
CH
3
O
80%
ð7:57Þ
B
€
ackvall et al. found that the oxidation of secondary amines to imines can be
performed by a hydrogen transfer reaction under mild conditions in the presence of
2,6-dimethoxybenzoquinone and the ruthenium catalyst 29 (Eq. (7.58)) [108].
Ru
Ru
Ph
Ph
Ph
O
Ph
Ph
Ph
Ph
O
Ph
H
H
OCCO
OC
CO
29 (cat.)
29
2,6-dimethoxy-1,4-benzoquinone
toluene, 110
o
C
97%
NPh
H
OMeNPhOMe
ð7:58Þ
Potassium ruthenate (K
2
RuO
4
) was used as a catalyst for the oxidation of benzy-
lamine with K
2
S
2
O
8
[109]. Primary amines can be converted to nitriles readily by
aerobic oxidation reactions. James and coworkers reported that aerobic oxidative
transformation of primary amines to nitriles can be carried out in the presence of
a ruthenium porphyrin complex Ru(TMP)(O)
2
(1) (100%) (Eq. (7.59)) [110].
NH
2
CN
Air, C
6
H
6
, 50 °C
Ru(TMP)(O)
2
(1)
(cat.)
ð7:59Þ
Heterogeneous catalysts such as hydroxyapatite-bound Ru [111] (Eq. (7.60)) and
Ru/Al
2
O
3
can be also used for the aerobic oxidation of primary amines to nitriles
(Eq. (7.61)) [112, 113].
NH
2
HO
CN
HO
RuHAP (cat.)
O
2
, toluene
90 ºC
(RuHAP = hydroxyapatite-bound Ru)
ð7:60Þ
O
2
(1 atm)
Ru/Al
2
O
3
(cat.)
PhCF
3
, 100 ºC
97%
NH
2
CN
OMeOMe
ð7:61Þ
7.3 Oxidation with Low-Valent Ruthenium Catalysts and Oxidants
j
259
7.3.4
Oxidation of Amides and b-Lactams
The oxidation of the a-CH bond of amides is an attractive strategy for the synthesis
of biologically active nitrogen compounds. Selective oxidation of amides is difficult
because of low reactivity. The RuCl
2
(PPh
3
)
3
-catalyzed oxidation of amides with
t-BuOOH proceeds under mild conditions to give the corresponding a-(tert-butyl-
dioxy)amides 47 highly efficiently (Eq. (7.62)) [114].
NC
R
3
t
-BuOO
O
R
2
R
1
CR
4
NC
R
3
H
O
R
2
R
1
CR
4
t
-BuOOH
47
Ru cat.
ð7:62Þ
The ruthenium-catalyzed oxidation of 1-(methoxycarbonyl)pyrrolidine with t-
BuOOH gives 2-(t-butyldioxy)-1-(methoxycarbonyl)pyrrolidine (48) in 60% yield
(Eq. (7.63)).
N
CO
2
Me
N
CO
2
Me
OO-
t
-Bu
48
C
6
H
6
, rt
t
-BuOOH
RuCl
2
(PPh
3
)
3
(cat.)
ð7:63Þ
The tert-butyldioxy amides of the isoquinoline 49 and the indole 50, which are
important synthetic intermediates for the synthesis of natural products, were
obtained in excellent yields (Eqs. (7.64) and (7.65)). Since the Lewis acid-promoted
reactions of these oxidized products with nucleophiles give the corresponding
N-acyl-a-substituted amines efficiently, the present reactions provide versatile
methods for selective carbon-carbon bond formation at the a-position of
amides [115].
N
PhCH
2
O
COMeMeO
N
PhCH
2
O
COMeMeO
OO-
t
-Bu
49
t
-BuOOH
RuCl
2
(PPh
3
)
3
C
6
H
6
(cat.)
98%
ð7:64Þ
N
H
N
CO
2
NMe
H
N
CO
2
Me
OO-
t
-Bu
50
92%
ð7:65Þ
Typically, the TiCl
4
-promoted reaction of a-t-butyldioxypyrrolidine (48) with a silyl
enol ether gave the keto amide 51 (81%), while a similar reaction with a less reactive
1,3-diene gave the a-substituted amide 52 (Eq. (7.66)).
260
j
7 Ruthenium-Catalyzed Oxidation for Organic Synthesis
OSiMe
3
N
CO
2
Me
O
N
CO
2
Me
Cl
52
51
TiCl
4
, -78 °C
48
99%
TiCl
4
81%
ð7:66Þ
Oxidative modification of peptides has been performed by ruthenium-catalyzed
oxidation with peracetic acid. For example, the reaction of N,C-protected peptides
containing glycine residues with peracetic acid in the presence of RuCl
3
catalyst gives
a-ketoamides derived from the selective oxidation at the C
a
position of the glycine
residue (81%, conv. 70%) (Eq. (7.67)) [116]. Direct conversion of N-acylproline to
N-acylglutamate was achieved by Ru(TMP)Cl
2
and 2,6-dichloropyridine N-oxide
(Eq. (7.68)) [117].
Ac-Gly-Ala-OEt
!
RuCl
3
ðcat:Þ
CH
3
CO
3
H
AcOH
AcNHCOCO-Ala-OEt ð7:67Þ
N
OPh
CO
2
H
Ru(TMP)Cl
2
(cat.)
2,6-pyridine
N
-oxide
benzene
Ph
H
CON
2
H
CO
2
HO
91%
ð7:68Þ
One of the most challenging topics among the oxidations of amides is the catalytic
oxidation of b-lactams. Oxidation of b-lactams requires specific reaction conditions
because of the high strain of the four-membered rings. Direct oxidative acyloxylation
of b-lactams was successfully carried out by ruthenium-catalyzed oxidation with
peracetic acid in acetic acid under mild conditions. The products obtained are highly
versatile and are key intermediates in the synthesis of antibiotics. Thus, the
ruthenium-catalyzed oxidation of 2-azetidinones with peracetic acid in acetic acid
in the presence of sodium acetate at room temperature gives the corresponding 4-
acetoxy-2-azetidinones 53 in 94% yield (Eq. (7.69)) [114]. One can use RuCl
2
(PPh
3
)
3
or RuCl
3
, but for practical synthesis ruthenium on charcoal can be used conveniently.
Although peracetic acid is the best oxidant, other oxidants such as m-chloroperben-
zoic acid, methyl ethyl ketone peroxide, and iodosylbenzene can be used for the
acyloxylation of b-lactams.
NH
O
NH
O
OAc
AcONa, AcOH
Ru/C (cat.)
CH
3
CO
3
H
53
rt
94%
ð7:69Þ
7.3 Oxidation with Low-Valent Ruthenium Catalysts and Oxidants
j
261
Importantly, (1
0
R,3S)-3-[1
0
-(tert-butyldimethylsilyloxy)ethyl]azetidin-2-one (54) can
be converted into the corresponding 4-acetoxyazetidinone 55 with extremely high
diastereoselectivity (94%, >99%de) (Eq. (7.70)). The product (55) is a versatile and key
intermediate for the synthesis of carbapenems of antibiotics. Now, 100 000 kg of the
compound 55 is produced per year in the industry.
NH
O
OSiMe
2
-
t
-Bu
H
NH
O
OSiMe
2
-
t
-Bu
H
OAc
Ru/C (cat.)
CH
3
CO
3
H
5554 94%, de>99%
AcOH, AcONa
ð7:70Þ
This method was applied to the stereoselective synthesis of 3-amino-4-acetoxya-
zetidinone 56 in 85% yield (Eq. (7.71)) [118].
NH
O
N
CBz
NH
O
N
CBz
OAc
CBz
CBz
AcOH, AcONa
56
Ru/C (cat.)
CH
3
CO
3
H
ð7:71Þ
Aerobic oxidation of b-lactams can be performed highly efficiently in the presence
of acetaldehyde, an acid, and sodium acetate [119]. Typically, the RuCl
3
-catalyzed
oxidation of b-lactam 54 with molecular oxygen (1 atm) in the presence of acetalde-
hyde and sodium carboxylate gave the corresponding 4-acyloxy b-lactam 55 in 91%
yields (de >99%) (Eq. (7.72)). This aerobic oxidation shows similar reactivity to the
ruthenium-catalyzed oxidation with peracetic acid.
RuCl
3
•nH
2
O (cat.)
CH
3
CHO
AcOH, AcONa
91%, de>99%
EtOAc, 40°C
NH
O
OSiMe
2
-
t
-Bu
H
NH
O
OSiMe
2
-
t
-Bu
H
OAc
54
55
O
2
(1 atm)
ð7:72Þ
7.3.5
Oxidation of Phenols
The oxidative transformation ofphenols is of importance with respect to the biological
and synthetic aspects. However, the oxidation of phenols generally lacks selectivity
because of coupling reactions caused by phenoxyl radicals [120], and selective
oxidation of phenols is limited to phenols bearing bulky substituents at the 2- and
6-positions [121]. Using ruthenium catalysts, a biomimetic and selective oxidation of
phenols can be performed. Thus, the oxidation of p-substituted phenols bearing no
substituent at the 2- and 6-positions with t-BuOOH in the presence of RuCl
2
(PPh
3
)
3
catalystgives4-(tert-butyldioxy)-4-alkylcyclohexadienonesselectively (Eq. (7.73)) [122].
262
j
7 Ruthenium-Catalyzed Oxidation for Organic Synthesis