Green Oxidation of Amines to Imines Based on the Development of Novel Catalytic Systems Using Molecular Oxygen or Hydrogen Peroxide

Article abstract of DOI:10.1055/s-0035-1560363

Amines are transformed into the corresponding imines by environmentally benign catalytic oxidation reactions. Gaseous oxygen or hydrogen peroxide is used as the oxidant, and water is the only byproduct. When a vanadium complex is used as the catalyst in an ionic liquid, the amine oxidation successfully proceeds with recycling of the catalyst. Amine oxidation with hydrogen peroxide as an oxidant in water is also attained by using copper(II) sulfate as catalyst. In addition, photoinduced oxidation of amines to imines is conducted by using oxygen as the oxidant in the presence of a zinc-chlorin complex as catalyst.

Full text of DOI:10.1055/s-0035-1560363

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, 31–42
feature
31
K. Marui et al.
Feature
Synthesis
Green Oxidation of Amines to Imines Based on the Development
of Novel Catalytic Systems Using Molecular Oxygen or Hydrogen
Peroxide
O
O
Kuniaki Maruia
Akihiro Nomotoa
Haruo Akashib
Akiya Ogawa*a
H
HO
catalyst
2 or air or H2O2
N
O
O
O
O
R
NH2
N
H2O
R
N
R
V
O
solvent
VO(Hhpic)2
(R = aryl or alkyl or H)
Me
N
ArF
Zn(TFPC)
ArF
a Department of Applied Chemistry, Graduate School of
Engineering, Osaka Prefecture University, 1-1 Gakuen-cho,
Nakaku, Sakai, Osaka 599-8531, Japan
three green oxidation methods
N
N
N
1. catalyst: VO(Hhpic)2, O2, solvent: ionic liquid
2. catalyst: CuSO4, H2O2, solvent: H2O
ArF
ogawa@chem.osakafu-u.ac.jp
Zn
b Research Institute of Natural Sciences, Okayama University
of Science, Ridai-cho, Okayama 700-0005, Japan
akashi@rins.ous.ac.jp
N
3. catalyst: Zn(TFPC), O2 or air, solvent: BTF
ArF = C6F5
ArF
(BTF = benzotrifluoride)
Received: 10.10.2015
Accepted: 14.10.2015
Published online: 04.11.2015
DOI: 10.1055/s-0035-1560363; Art ID: ss-2015-z0593-fa
ular oxygen (or H2O2) in water as the only solvent are still
rare. Precious metals (e.g., Au, Ru, Pd), high-pressure oxy-
gen or air, and stoichiometric amounts of bases are often
required.5
Abstract Amines are transformed into the corresponding imines by
environmentally benign catalytic oxidation reactions. Gaseous oxygen
or hydrogen peroxide is used as the oxidant, and water is the only by-
product. When a vanadium complex is used as the catalyst in an ionic
liquid, the amine oxidation successfully proceeds with recycling of the
catalyst. Amine oxidation with hydrogen peroxide as an oxidant in wa-
ter is also attained by using copper(II) sulfate as catalyst. In addition,
photoinduced oxidation of amines to imines is conducted by using oxy-
gen as the oxidant in the presence of a zinc–chlorin complex as catalyst.
Judging from the Clarke numbers (V: 0.015, Cu: 0.0055,
Zn: 0.007, Pd: 1 × 10–6, Ru: 5 × 10–7), vanadium, copper, and
zinc are relatively abundant elements. In addition, vanadi-
um and copper have excellent oxidizing potentials
[Zn(II)/Zn(0): –0.76 V; Cu(II)/Cu(I): 0.16 V; Fe(III)/Fe(II):
0.77 V; V(V)/V(IV): 0.96 V].
With these considerations in mind, we recently devel-
oped a novel system for the aerobic oxidation of benzylic al-
cohols to the corresponding aldehydes or ketones catalyzed
by vanadium–bipyridyl complexes in water as the sole sol-
vent (Equation 1).6
Key words green oxidation, imine synthesis, molecular oxygen, hy-
drogen peroxide, ionic liquid, water, photocatalysis
Oxidation is one of the most important and fundamen-
tal organic reactions, and about 30% of industrial processes
involve oxidation reactions.1 Nonetheless, stoichiometric or
excess amounts of heavy metal oxidants, such as chromi-
um(VI) oxide, explosive peroxides, and nitric acid are con-
ventionally used as oxidants in industrial processes.2 These
oxidants pose serious risks to the environment and human
safety; therefore, the development of eco-friendly oxidation
methods using catalytic amounts of safe metal complexes is
strongly desired.3 From the viewpoint of green chemistry,
green oxidation reactions require the following characteris-
tics: (1) the use of sustainable and inexpensive earth-abun-
dant transition metals; (2) the use of molecular oxygen or
hydrogen peroxide as the terminal oxidant, where water is
the only byproduct; (3) the use of eco-friendly solvents
such as water, ionic liquids, and fluorous solvents in place
of flammable organic solvents; in particular, water is the
most desirable solvent, due to its low cost, safety, and great
abundance;4 and/or (4) the use of inexhaustible sunlight
(visible light) and mild reaction conditions. However, ex-
amples of metal-complex-catalyzed oxidations with molec-
tBu
tBu
VOSO4 (5 mol%)
t-Bubpy (10 mol%)
OH
R2
O
O2 or air (0.1 MPa)
H2O (0.5 mL), 90 °C
N
N
R1
R1
R2
t-Bubpy
R
1 = aryl, R2 = aryl, alkyl, H
24–98%
Equation 1 Oxidation of benzylic alcohols catalyzed by vanadium–
bipyridyl complexes in water under oxygen or air (0.1 MPa)
Furthermore, we extended the developed reactions to
the oxidation of amines to imines. Imines are very import-
ant for the synthesis of industrial materials, biologically ac-
tive compounds (e.g., amides, chiral amines), nitrogen-
containing heterocycles (e.g., oxazolidines), and other ni-
trogen-containing compounds (e.g., hydroxyamines and ni-
trones).7 Numerous methodologies have been developed to
synthesize imines, including the oxidation of primary or
secondary amines, the condensation of amines with alde-
hydes, and the oxidative condensation of amines with alco-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

32
K. Marui et al.
Feature
Synthesis
hols.8 In particular, extensive efforts have concentrated on
developing efficient methods for the highly selective syn-
thesis of imines from primary amines without the concom-
itant formation of other undesired nitrogen-containing
compounds.9
In this article, we wish to report three novel eco-friend-
ly oxidation reactions of amines to imines, by using new
catalytic oxidation systems. The first is a vanadium-cata-
lyzed green oxidation of amines to imines under a molecu-
lar oxygen atmosphere and by using an ionic liquid as an
eco-friendly solvent. The vanadium catalyst can be effi-
ciently recycled in this system. As the second process, we
have developed a copper-catalyzed green oxidation of
amines to imines with hydrogen peroxide in water under
very mild reaction conditions (r.t., 1.5 h). The third system
is a photoinduced (visible light-irradiated) oxidation of
amines to imines under the atmosphere of molecular oxy-
gen in benzotrifluoride (BTF) as an eco-friendly, organic/
fluorous hybrid solvent10 in the presence of a zinc–chlorin
complex. These eco-friendly oxidation reactions are useful
for the synthesis of imines, and will further the develop-
ment of green oxidation reactions in organic synthesis.
Biographical Sketches
Kuniaki Marui was born in
Oita (Japan) in 1987. He gradu-
ated from Osaka Prefecture Uni-
versity in 2012 and obtained his
master degree in synthetic or-
ganic chemistry at Osaka Pre-
fecture University under the di-
rection of Prof. Akiya Ogawa.
Since then, he has been a Ph.D.
student focusing on the devel-
opment of environmentally be-
nign oxidation reactions.
Akihiro Nomoto was born in
Osaka (Japan) in 1969 and
earned his B.S. and Ph.D. de-
grees from Osaka University un-
der the supervision of Professor
Toshikazu Hirao. He held a post-
doctoral fellowship with Profes-
sor Yoshiaki Kobuke at Nara
Institute of Science and Tech-
nology, Professor Yoshito Tobe
at Osaka University, and Profes-
sor Minoru Inaba at Doshisha
University. He then joined Prof.
Akiya Ogawa’s group as an as-
sistant professor in 2005 and
lecturer in 2014 at Osaka Pre-
fecture University. His research
interests include metal complex
catalysts, bioactive complexes,
and
heteroatom-containing
conjugated chemistry.
Haruo Akashi was born in Fu-
kuoka (Japan) in 1963 and
earned his B.S. and Ph.D. de-
grees from the Okayama Uni-
versity of Science under the
supervision of Professor Takashi
Shibahara. He held a postdoc-
toral fellowship with Professor
Kiyoshi Isobe at the Institute for
Molecular Science, and he then
became an assistant professor
in 1991, lecturer in 1997, asso-
ciate professor in 2003, and
professor in 2008 at the Okaya-
ma University of Science. He
also held a postdoctoral fellow-
ship with Richard H. Holm at
Harvard University in 1995. His
research interests include metal
complexes, crystal structure
chemistry, and bioactive com-
plexes.
Akiya Ogawa was born in Osa-
ka (Japan) in 1957 and received
his Ph.D. degree from Osaka
University (1985) under the su-
pervision of Professor Noboru
Sonoda. He worked as postdoc-
toral researcher of the Japan So-
ciety for the Promotion of
Science (1985–1987), as assis-
tant professor at Osaka Univer-
sity (1987–1995, Professor
Noboru Sonoda group), as asso-
ciate professor at Osaka Univer-
sity (1995–2000, Professor
Toshikazu Hirao group), and as
visiting professor at the Univer-
sity of Pittsburgh (1996, Profes-
sor Dennis P. Curran group). In
2000, he joined the Depart-
ment of Chemistry at Nara
Women’s University, where he
is full professor. In 2004, he
moved as full professor to the
Department of Applied Chemis-
try at Osaka Prefecture Universi-
ty. His research interests are
organic synthesis, heteroatom
chemistry,
organometallic
chemistry, and green chemistry.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

33
K. Marui et al.
Feature
Synthesis
In our initial study directed at green oxidation, 3-hy-
droxypicolinic acid (H2hpic) was used as a ligand for oxova-
nadium in the catalytic oxidation of benzylic alcohols
(Equation 2).11 3-Hydroxypicolinic acid contains polar enti-
ties, such as hydroxy, hydroxycarbonyl, and pyridyl groups,
and, therefore, was expected to have a good affinity toward
water. The vanadium–3-hydroxypicolinic acid complex
[VO(Hhpic)2] can be easily synthesized from vanadium(IV)
oxide sulfate (VOSO4) and 3-hydroxypicolinic acid.12
the best results (entry 10). In the absence of a catalyst, no
reaction was observed (entry 19).
Table 1 Screening of Various Vanadium Catalysts for the Oxidation of
Benzylamine (1a)a
cat. (2.0 mol%), O2
MeCN (6.0 mL)
NH2
N
1a (1.5 mmol)
2a
VO(Hhpic)2 (2.0 mol%)
OH
Entry Catalyst
O2
Temp
(°C)
Time
(h)
Yieldb
(%)
OH
O
O2 (1.0 MPa)
Ph
Ph
MeCN (6.0 mL), 120 °C, 40 h
Ph
71%
Ph
N
CO2H
1
2
[VO(Hhpic)2]
1.0 MPa
120
100
120
120
120
120
100
70
6
3
80
79
67
60
48
NR
26
NR
NR
86
trace
34
13
30
7
1.5 mmol
H2hpic
1.0 MPa
0.5 MPa
0.3 MPa
0.1 MPa
air (0.1 MPa)
0.1 MPa
0.1 MPa
O2 bubbling
0.1 MPa
1.0 MPa
0.1 MPa
1.0 MPa
0.1 MPa
1.0 MPa
0.1 MPa
1.0 MPa
1.0 MPa
0.1 MPa
Equation 2 Oxidation of a benzylic alcohol catalyzed by the oxovana-
dium complex [VO(Hhpic)2]
3
6
4
6
5
6
As seen in Equation 2, the oxidation reaction required
the use of pressurized oxygen and the organic solvent ace-
tonitrile, with heating at high temperatures. To accomplish
the catalytic oxidation under an atmosphere of oxygen (or
air), and in water, detailed investigations regarding the op-
timization of the vanadium catalyst were conducted, and,
finally, the aerobic oxidation of benzyl alcohols in water
was developed, using 4,4′-di-tert-butylbipyridyl (t-Bubpy)
as the ligand for oxovanadium, as shown in Equation 1.6
Since we could develop a good example of green oxida-
tion of benzylic alcohols by using the vanadium catalyst
[VO(t-Bubpy)2], we next investigated the eco-friendly oxi-
dation of amines to imines (Table 1). At first, oxidation of
benzylamine (1a) was examined using the vanadium–3-hy-
droxypicolinic acid complex [VO(Hhpic)2].13 Under molecu-
lar oxygen (1.0 MPa), in acetonitrile, and at 120 °C for 6 h in
a stainless steel autoclave, N-benzylbenzylideneamine (2a)
was obtained successfully in 80% yield (entry 1). The forma-
tion of 2a can be reasonably explained by the oxidative de-
hydrogenation of benzylamine (1a) to generate benzyliden-
eamine (PhCH=NH), followed by amino group exchange be-
tween benzylideneamine and benzylamine (1a) (Scheme
1). Decreasing the oxygen pressure resulted in a decrease in
the yield of imine 2a (entries 3–5); interestingly, however,
even under 0.1 MPa of oxygen, the oxidation proceeded to
afford 2a in 48% yield (entry 5). The oxidation did not take
place under air (entry 6). Decreasing the temperature re-
sulted in decreased yields of 2a, indicating that the oxida-
tion required heating over 100 °C (entries 7 and 8). Bub-
bling with oxygen was not effective for the oxidation (entry
9). Prolonging the reaction time successfully facilitated at-
mospheric oxidation of benzylamine (1a) to afford 2a in
86% yield (entry 10). Next, other vanadium catalysts were
examined for the oxidation of amines under pressurized or
atmospheric oxygen (entries 11–18). Among the catalysts
examined, the vanadium complex [VO(Hhpic)2] exhibited
6
6
7
6
8
6
9
70
6
10
11
12
13
14
15
16
17
18
19
120
100
120
100
120
100
120
100
100
120
18
3
[VO(acac)2]
V2O5 (1 mol%)
VOSO4
18
3
18
3
18
3
30
50
25
NR
[VO{OCO(CH2)16Me}2]
[VO(OEt)3]
3
none
18
a Reactions were carried out in a stainless autoclave with magnetic stirring
under O2 (0.1 MPa).
b Yields were determined by 1H NMR; NR = no reaction.
1/2 O2
cat. VO(Hhpic)2
Ph
NH2
– NH3
Ph
NH2
Ph
N
Ph
Ph
NH
1a
2a
H2O
Scheme 1 A possible reaction pathway for the oxidation of amine 1a
to imine 2a
With the optimized conditions (Table 1, entry 10) in
hand, the catalytic oxidation of various benzylamine deriv-
atives 1 was examined using the vanadium complex
[VO(Hhpic)2] as the catalyst, and these results are shown in
Table 2. Oxidation of p-substituted benzylamines 1b–d af-
forded the corresponding imines 2b–d in good yields (en-
tries 1–3). Although benzylic primary amines 1 underwent
dehydrogenative condensation to give N-benzylbenzylidene-
amine derivatives 2, secondary amines such as dibenzyl-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

34
K. Marui et al.
Feature
Synthesis
amine (1e) underwent oxidative dehydrogenation to afford
the corresponding imines. For example, catalytic oxidation
of dibenzylamine (1e) gave N-benzylbenzylideneamine
(2a) in moderate yield (entry 4). In the case of 1,2,3,4-tetra-
hydroisoquinoline (1f), 3,4-dihydroisoquinoline (2f) was
successfully obtained in good yield (entry 5). Interestingly,
the oxidation of tertiary amine 1g afforded N-benzylidene-
aniline (2g) in good yield via the elimination of a benzyl
group (entry 6). In this reaction, the eliminated benzyl
group was converted into benzaldehyde (75%, 1H NMR
yield) via oxidation.
vaporize over 120 °C. Therefore, the oxidation could be con-
ducted in a normal glass vessel when an ionic liquid is used
as the solvent. Thus, we examined the oxidation of benzyl-
amines 1 in ionic liquids under oxygen, catalyzed by the va-
nadium complex [VO(Hhpic)2] (Table 3).
Table 3 Oxidation of Benzylamines 1 in Various Ionic Liquidsa
VO(Hhpic)2 (2 mol%), O2 (0.1 MPa)
Ar
N
Ar
Ar
NH2
ionic liquid (2.0 mL), 120 °C, 6.0 h
2
1 (1.5 mmol)
Entry
Ionic Liquid
Substrate 1 Product 2
Yieldb (%)
75
Table 2 Oxidation of p-Substituted Benzylamines 1a
nHex
Me
VO(Hhpic)2 (2 mol%)
O2 (0.1 MPa)
N
N
1
1a
2a
PF6
[hmim]PF6
Ar
NH2
Ar
N
Ar
MeCN (6.0 mL), 120 °C, 6.0 h
1 (1.5 mmol)
2c
1b
1d
1e
2b
2d
2a
73
51
33
2
3c
Entry
Substrate 1
Product Time
(h)
Yieldb
(%)
4c,d
2
nBu
Me
Me
Me
NH2
NH2
N
N
N
N
N
N
5
6
1a
1a
2a
2a
46
43
1
2
1b
1c
2b
2c
18
70
PF6
nBu
BF4
Cl
24
72c
Me
NH2
Et
BF4
3
4
5
1d
1e
1f
2d
2a
2f
18
42
18
71
7
8
9
1a
1a
1a
2a
2a
2a
18
12
10
MeO
37c,d
78
Ph
Ph
N
H
Ph
Me
Me
Et
Cl
N
N
N
N
NH
Et
Tf2N
N
Ph
6
1g
2g
24
75
Ph
a Reactions were carried out in a glass vessel under O2 (0.1 MPa).
b Yields were determined by 1H NMR.
O
O
N
c Substrate (1.0 mmol).
HO
H
d After a reaction time of 20 h, 1e was recovered (53%).
N
O
O
O
N
N
V
O
The yields of 2a were influenced by both the cation and
the anion of the tested ionic liquids. Among the ionic liq-
uids employed, 1-hexyl-3-methylimidazolium hexafluoro-
phosphate {[hmim]PF6} was found to be the most suitable
for the oxidation of 1a, and it was possible to conduct the
oxidation in a glass vessel (entry 1). Oxidation of p-substi-
tuted benzylamines 1b and 1d was also successful, and the
corresponding imines 2b and 2d were obtained in 73% and
51% yields, respectively (entries 2 and 3). In the case of
dibenzylamine (1e), oxidative dehydrogenation took place
to give imine 2a in 33% yield.
Next, we investigated the recyclability of the catalyst in
the ionic liquid [hmim]PF6 (see Figure 1); the results are
shown in Table 4. Both the substrate and catalyst easily dis-
solved in the ionic liquid, and the oxidation (Ox.) could be
performed as a homogeneous reaction. After the reaction
H2O
VO(Hhpic)2
2g
2f
a Reactions were carried out in a stainless autoclave with magnetic stirring
under O2 (0.1 MPa).
b Isolated yield.
c Yields were determined by 1H NMR.
d Amine 1e was recovered (58%).
The oxidation in acetonitrile catalyzed by the vanadium
complex [VO(Hhpic)2] required the use of a stainless steel
autoclave, because of heating at 120 °C, even though the ox-
ygen pressure was only 0.1 MPa.
Ionic liquids are useful eco-friendly solvents and suit-
able for recycling of both the ionic liquid itself and the cata-
lyst.14 Furthermore, various organic and inorganic com-
pounds have good solubility in ionic liquids, which do not
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

35
K. Marui et al.
Feature
Synthesis
(entry 1, 1st run), the product was easily extracted with di-
ethyl ether, and the ionic liquid layer, which contained the
vanadium complex [VO(Hhpic)2], was used for the next run
(Figure 1). The result showed that the ionic liquid solvent
[hmim]PF6 containing the vanadium complex [VO(Hhpic)2]
was successfully reused (entry 1, 2nd run). In the third run
(entry 1, run 3), we attempted the oxidation under air, and
the desired imine 2a was obtained in moderate yield. In the
fourth run (entry 1, run 4), the oxidation was performed
again under an oxygen atmosphere, and 2a was obtained in
good yield without any detectable loss in catalytic activity.
of the most suitable solvents. The use of water instead of
organic solvents is advantageous, as it is inexpensive, non-
toxic, and nonflammable. Furthermore, to achieve a low-
carbon society, it is necessary to reduce the use of organic
solvents. Thus, we investigated the catalytic oxidation of
amines with hydrogen peroxide in water.15
At first, the vanadium(IV) oxide sulfate catalyzed oxida-
tion of amine 1a with hydrogen peroxide in water at room
temperature was investigated. However, product 2a was ob-
tained in only 2% yield (Table 5, entry 1). Oxovanadium
bearing 3-hydroxypicolinic acid or 4,4′-di-tert-butylbipyr-
idyl were also ineffective in this oxidation (entries 2 and 3).
Thus, we examined the catalytic oxidation of benzylamine
(1a) in the presence of various metal sulfates [MSO4, M = Fe,
Co, Ni, Cu, Zn and Ce(SO4)2] as catalysts. Although most
metal sulfates exhibited minimal catalytic activities in the
oxidation (the yields of 2a were 1–3%), copper(II) sulfate
catalyzed the reaction efficiently, and 2a was obtained in a
high yield (entry 4).16,17
start
end
collect
recycle
Et2O
Ox.
Et2O
product
substrate
catalyst
IL
product
catalyst
IL
catalyst
IL
catalyst
IL
substrate
Figure 1 Reuse of ionic liquid (IL) and catalyst
Table 5 Oxidation of Benzylamine (1a) in the Presence of Various Met-
al Catalystsa
catalyst (0.2 mol%)
Table 4 Recycling Study of Vanadium Complex [VO(Hhpic)2] in Ionic
NH2
N
Liquid
H2O2 (2.0 mmol)
H2O (2.0 mL), r.t., 2.0 h
VO(Hhpic)2 (2 mol%)
N
NH2
O2 (0.1 MPa)
1a (2.0 mmol)
2a
[hmim]PF6 (2.0 mL)
120 °C, 6.0 h
Entry
Catalyst
Yieldb (%)
1a (1.5 mmol)
2a
2a
1a (recovery)
Entry
Run Recycling run
1
2
VOSO4·5H2O
VO(Hhpic)2
VO(t-Bubpy)2
CuSO4·5H2O
none
2
2
63
96
95
4
Entry 1
Yield (%)a,b 75
Entry 2
Yield (%)a,b 69
1
2
66
2
3
48c
3
4
69
4
3
2
4
88
1
1
5
6
7
8
9
5c
6
89
36
46
24
20
23
14
93
70
64
67 68
66
56
58
68 (67)
a Yields were determined by 1H NMR (isolated yield given in parentheses).
b Starting benzylamine still remained, but no byproduct was detected.
c The oxidation was carried out under air.
CuCl
38
30
49
52
54
63
trace
7
CuBr
8
CuI
9
Cu(CH3COO)2·H2O
Cu(NO3)2·6H2O
Cu(CF3SO3)2·H2O
CuSO4·5H2O
The oxidation of 1a under oxygen was examined (Table
4, entry 2), and the catalyst could be successfully recycled
more than nine times. Conceivably, coating the catalyst
with ionic liquid may prevent aggregation of the catalyst,
making it possible to maintain the catalytic activity over
several reaction cycles. Overall, the vanadium complex
[VO(Hhpic)2] is a highly effective and recyclable catalyst for
the oxidation of benzylamines to the corresponding imines
with molecular oxygen in ionic liquids such as [hmim]PF6.
In addition to molecular oxygen, hydrogen peroxide is
an alternative eco-friendly oxidant that is used in organic
synthesis and industrial chemistry, because it is inexpen-
sive, safe at low concentrations (<30% aqueous H2O2), and
affords water as the only byproduct after oxidation. When
hydrogen peroxide is employed as an oxidant, water is one
10
11
12d
a Aqueous solution of H2O2 (10%) was used.
b Yields were determined by 1H NMR; yield of imine 2a is based on sub-
strate 1a.
c Reaction time 3 h.
d Amine 1a (1.0 mmol), CuSO4 (0.01 mmol, 1.0 mol%), H2O (1.0 mL), 24 h,
O2 balloon, in the absence of H2O2.
A negligible yield of imine 2a was obtained when no
catalyst was used (Table 5, entry 5). Various copper(I) and
copper(II) salts were examined in the oxidation, giving
imine 2a in poor to high yields, with recovery of the start-
ing amine (entries 6–11). On the other hand, the desired
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

36
K. Marui et al.
Feature
Synthesis
amine oxidation did not take place under oxygen in the ab-
sence of hydrogen peroxide (entry 12). Overall, copper(II)
sulfate was the best catalyst for the oxidation of amine 1a to
imine 2a with hydrogen peroxide.
Table 6 Oxidation of Benzylamine Derivatives 1a
CuSO4
H2O2 (2.0 mmol)
Ar
NH2
Ar
N
Ar
H2O (2.0 mL), r.t., 1.5 h
The oxidation of substituted benzylamines 1 with hy-
drogen peroxide in water at room temperature was investi-
gated using copper(II) sulfate as the catalyst (Table 6). The
oxidation of benzylamine (1a) proceeded very smoothly,
and was complete within 1.5 hours (entries 1 and 2).
Chloro, methyl, methoxy, trifluoromethyl, and tert-butyl
groups were all tolerated in the catalytic oxidation, afford-
ing the corresponding imine derivatives 2 in good to high
yields (entries 3–13). In the cases of amines 1b, 1d, 1h, and
1i, the use of 0.5–1.0 mol% of the catalyst resulted in higher
yields of the imines, and the isolated yields are shown in
parentheses. In contrast, the oxidation of secondary amines
such as dibenzylamine (1e) and 1,2,3,4-tetrahydroisoquin-
oline (1f) did not proceed, probably because oxidative de-
hydrogenation of secondary amines requires the use of
higher reaction temperatures (entries 14 and 15).
In general, aliphatic amines are oxidized less efficiently
than the corresponding aromatic amines. Very interesting-
ly, this mild oxidation method could, nevertheless, be ap-
plied successfully to aliphatic amines; aliphatic primary
amines 1l, 1m, and 1n were also efficiently oxidized to the
corresponding imines 2l, 2m, and 2n (Table 6, entries 16–
18).
Since the copper(II) sulfate catalyzed oxidation proceed-
ed under very mild reaction conditions, we next investigat-
ed the cross condensation of two amines. When the oxida-
tion of equimolar amounts of benzylamine (1a) and hexyl-
amine (1l) with hydrogen peroxide was examined in the
presence of copper(II) sulfate (0.2 mol%) in water at room
temperature for 1.5 hours, two types of cross-condensed
imine derivatives 3a and 3a′ were obtained in 26% and 6%
yields, respectively, along with the homo-condensed prod-
uct 2a (30%) (Equation 3). Despite our efforts, the selective
formation of 3a could not be attained. To inhibit the forma-
tion of the regioisomer (e.g., 3a′), the oxidative cross con-
densation was performed using aromatic amines such as
aniline (PhNH2, 1o) instead of hexylamine 1l. Owing to the
decreased nucleophilicity of aniline, however, the forma-
tion of cross-condensed products such as N-phenylben-
zylideneamine (PhCH=NPh, 2g) was not observed, even
when an excess of aniline was used.
1 (2.0 mmol)
2
Entry Substrate 1
CuSO4
(mol%)
Product Yieldb (%)
2
1c
2
84
2a
NH2
1a
1b
0.2
91 (72)
3
0.2
0.5
78
NH2
NH2
2b
4
85 (84)
Cl
5
1c
1d
1h
1i
0.2
2c
2d
2h
2i
74 (71)
Me
6c
0.2
0.5
0.2
0.5
0.2
1.0
71
NH2
7
87 (76)
62
MeO
8
9
MeO
NH2
99 (90)
67
10
11
NH2
OMe
81 (66)
NH2
NH2
12
1j
0.2
2j
78 (70)
F3C
13d
14
1k
1e
1f
0.2
0.2
0.2
2k
2a
2f
82 (66)
trace
ND
tBu
Ph
N
Ph
H
15
NH
16
17
1l
0.2
0.2
2l
75
85
NH2
1m
2m
NH2
NH2
18d
1n
0.2
2n
74 (57)
a Aqueous solution of H2O2 (10%) was used.
b Yields were determined by 1H NMR yield (isolated yield in parentheses);
yield of 2 is based on substrate 1. ND = not determined.
c Reaction time 1.0 h.
d H2O2 (3.0 mmol) was used.
Thus, we next examined cross condensation accompa-
nied by cyclization. After the copper(II) sulfate catalyzed
oxidation of benzylamine (1a) with hydrogen peroxide in
water was conducted at room temperature for 1.5 hours, o-
phenylenediamine (1p) was added to the resulting mixture,
and the reaction was continued with heating at 100 °C for
20 hours. The reaction successfully afforded 2-phenyl-
benzimidazole (3b) in a moderate yield (Equation 4).
This result prompted us to examine the one-pot oxida-
tive condensation of benzylamine (1a) with o-substituted
aniline derivatives. Thus, we selected o-sulfanylaniline (1q)
as a condensation partner, and one-pot oxidation and cy-
clization reactions were examined using 1.0 mol% of cop-
per(II) sulfate in water with heating at 100 °C (Equation 5).
Heating of 1.5 equivalents of benzylamine (1a) with o-sul-
fanylaniline (1q) for 20 hours resulted in the desired oxida-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

37
K. Marui et al.
Feature
Synthesis
abilities. To the best of our knowledge, the oxidation of
amines catalyzed by metallochlorins has rarely been re-
ported.19,20 Thus, we investigated the oxidation of benzyl-
amine (1a) in the presence of oxovanadium(IV)–chlorin de-
rivative 4 and zinc(II)–chlorin 5 [Zn(TFPC)] as photocata-
lysts in ethanol or benzotrifluoride (BTF). Benzotrifluoride
has attracted significant attention as an eco-friendly sol-
vent in organic synthesis, as it can be used as a replacement
for typical organic solvents such as toluene, benzene, and
dichloromethane because of its low toxicity and suitable
polarity. The reaction mixture was photoirradiated using a
xenon lamp through a Pyrex glass vessel (hν >300 nm), and
oxygen gas was introduced into the flask upon connection
to an oxygen balloon. After one hour, the reaction mixture
was extracted with diethyl ether, and the products were
characterized by 1H NMR spectroscopy (Equation 6).
CuSO4 (0.2 mol%)
H2O2 (2 mmol)
NH2
C6H13NH2
+
H2O (5 mL), r.t., 1.5 h
1a (2 mmol)
1l (2 mmol)
C6H13
N
N
C5H11
N
+
+
3a
26%
3a'
2a
6%
30%
Equation 3 Oxidative cross condensation of benzylamine (1a) with
hexylamine (1l)
1. CuSO4 (0.2 mol%), H2O2 (2 mmol),
N
H2O (5 mL), r.t., 1.5 h
NH2
2.
NH2
N
H
1p (2 mmol)
1a (2 mmol)
3b 41%
cat. 4 or 5 (0.2 mol%)
NH2
O2 (0.1 MPa)
NH2
N
100 °C, 20 h
Xe lamp (hν >300 nm)
solvent (1.0 mL), r.t.
Equation 4 Oxidative condensation and cyclization of benzylamine
(1a) with o-phenylenediamine (1p)
1a (0.5 mmol)
2a
Me
ArF
cat. 4 or 5
N
M = V(=O) 4
EtOH, 2 h
48%
54%
BTF, 1 h
N
N
N
N
CuSO4 (1.0 mol%)
EtOH, 1 h
BTF, 1 h
BTF, 1 h
M = Zn 5
55%
97%
4%a
ArF
ArF
NH2
M
N
H2O2 (2 mmol)
NH2
[Zn(TFPC)]
2a
+
+
H2O (2 mL),100 °C
S
SH
2 mmol
1q
2 mmol
2 mmol
2 mmol
2 mmol
1a
ArF = C6F5
20 h
1 h
20 h
56%
18%
ArF
3c
2 mmol
3 mmol
3 mmol
6%
71%
53%
37%
25%
13%
Equation 6 Oxidation reaction in the presence of photocatalyst 4 or 5.
20 h O2 (0.1 MPa)
a In the dark.
Equation 5 Oxidative condensation and cyclization of benzylamine
(1a) with o-sulfanylaniline (1q)
In ethanol or benzotrifluoride, photocatalysts 4 and 5
successfully catalyzed the oxidation of amine 1a to imine
2a in good yields. Compared to the catalytic activity of va-
nadium complex 4, zinc complex 5 exhibited higher catalyt-
ic activity, and the corresponding imine (2a) was obtained
in 97% yield. Therefore, zinc complex 5 was used as the oxi-
dation catalyst in subsequent experiments. The reaction did
not proceed in the dark, indicating that photoirradiation
was indispensable for this oxidation reaction.
Next, the photoinduced amine oxidation was carried
out under various conditions (Table 7). When acetonitrile,
toluene, and tetrahydrofuran were used as the solvent,
product 2a was obtained in excellent yields (entries 2–4),
similar to that when the reaction was carried out in ben-
zotrifluoride (entry 1). When the reaction time was short-
ened, the product yield decreased somewhat (entry 5). The
reaction did not proceed in the absence of the photocatalyst
or oxygen (entries 6 and 7). The photoirradiation of amine
1a using a tungsten lamp through Pyrex (hν >300 nm) af-
forded imine 2a in 90% yield (entry 8). When a xenon lamp
was used through a glass filter (hν >400 nm), imine 2a was
obtained in an excellent yield (entry 9).
tion and cyclization to directly afford 2-phenylbenzothi-
azole (3c) in 71% yield. Notably, the same reaction occurred
when oxygen was used as the oxidant instead of hydrogen
peroxide.18
Thus, the copper(II) sulfate catalyzed oxidation can be
easily performed, and the oxidation of amines to the corre-
sponding imines can be carried out at room temperature in
1.5 hours under mild conditions by using hydrogen perox-
ide in water. In addition, the method can be applied to the
synthesis of N-containing heterocycles.
Since a method with a good catalyst and very mild cata-
lytic oxidation conditions could be developed, we next in-
vestigated energetically useful oxidation systems. For envi-
ronmentally benign oxidation reactions using photoenergy
such as sunlight as the driving force, metal complexes with
strong absorption in the visible region and high electron-
transfer abilities are required. Chlorins are suitable photo-
catalysts owing to their strong photoabsorption properties;
moreover, they can form complexes with various metals, af-
fording metallochlorins with desirable electron-transfer
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38
K. Marui et al.
Feature
Synthesis
Table 7 Oxidation of Amine 1a by Using Photocatalyst 5
Table 8 Photoinduced Oxidation of Amines 1 to Imines 2
5 (0.2 mol%)
5 (0.2 mol%)
NH2
O
2 (0.1 MPa)
N
O
2 (0.1 MPa)
Ar
NH2
Ar
N
Ar
Xe lamp (hν >300 nm)
solvent (1.0 mL), r.t.
Xe lamp (hν >300 nm)
BTF (1.0 mL), r.t.
1a (0.5 mmol)
2a
1 (0.5 mmol)
Substrate 1
2
Entry
Solvent
Time (h)
Yielda (%)
Entry
1
Time (h) Product 2 Yielda (%)
1
BTF
1
97
93
95
81
81
1
NH2
NH2
1b
1c
1d
1i
1.0
1.0
1.0
2b
2c
2d
2i
92
95
96
2
MeCN
toluene
THF
1
Cl
3
1
4
1
2
3
Me
5
BTF
0.5
1
6b
7c
8d
9e
BTF
NH2
BTF
1
3
MeO
BTF
3
90
97
4
5
1.0
1.5
58
99
NH2
OMe
BTF
1
a Yield determined by 1H NMR.
b No catalyst was used.
MeO
c N2 (0.1 MPa) was used.
d Tungsten lamp was used.
NH2
NH2
6
1h
1.0
2h
95
e Xe lamp through a glass filter (hν >400 nm) was used.
7
8
1.0
1.5
77
98
1j
2j
The photoinduced oxidation of various benzylamines 1
was also carried out using a xenon lamp through Pyrex (Ta-
ble 8). The oxidation of benzylamines 1 with diverse sub-
stituents such as p-chloro, p-methyl, p-methoxy, m-meth-
oxy, and p-tert-butyl afforded the corresponding N-benzyl-
benzylideneamines 2 in excellent yields (entries 1, 2, 3, 6,
and 9). The oxidation of benzylamines containing o-meth-
oxy and p-trifluoromethyl groups as electron-donating and
-withdrawing substituents, respectively (entries 4 and 7),
was completed in 1.5 hours, affording the corresponding
imines 2i and 2j in excellent yields (entries 5 and 8). The
oxidation of dibenzylamine (1e), a secondary amine, afford-
ed the corresponding imine 2a in 90% yield (entry 10). The
results clearly indicate that the oxidizing ability of the pho-
tocatalyst toward secondary amines is greater than that of
copper(II) sulfate.
F3C
NH2
9
1k
1e
1.0
1.0
2k
2a
97
90
tBu
Ph
N
Ph
10
H
a Yields were determined by 1H NMR.
5 (0.2 mol%), additive
2 (0.1 MPa)
O
nC5H11
NH2
nC5H11
N
nC5H11
Xe lamp (hν >300 nm)
BTF (1.0 mL), r.t., 1.0 h
1l (0.5 mmol)
2l
complex mixturea
76%a
additive = none
MS4A (100 mg)
The photoinduced oxidation of amine 1f afforded a mix-
ture of three oxidation products, namely 2f, 6, and 7 (Table
9, entries 1–3). Monitoring the reaction by H NMR spec-
Equation 7 Oxidation of amine 1l. a Determined by 1H NMR.
1
troscopy revealed that the desired product 2f was gradually
converted into 7, probably by reaction with water. There-
fore, 4 Å molecular sieves (MS4A) were added to the reac-
tion mixture; this afforded imine 2f in very good yield
without formation of 7 (entry 4). This reaction also took
place when a tungsten lamp was used as the light source
(entry 5).
Next, the oxidation of hexylamine (1l), an aliphatic
amine, was investigated (Equation 7). However, a complex
mixture was obtained. When 4 Å molecular sieves were
used, the reaction afforded the desired imine 2l in good
yield.
Finally, this method was applied to the oxidation of ben-
zylamines 1 in open air (Table 10). The oxidation of benzyl-
amines 1a, 1i, and 1j afforded the corresponding imines 2a,
2i, and 2j in excellent yields.
Although further detailed mechanistic experiments are
required to elucidate the true mechanism, a possible path-
way for the presented photoinduced oxidation of amines is
shown in Scheme 2. The reaction of the photoactivated
zinc–chlorin catalyst 5 [Zn(TFPC)] with molecular oxygen
generates singlet oxygen (8); subsequent electron transfer
from the amine results in the formation of a radical cation 9
and superoxide (10). Abstraction of a proton from the radi-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

39
K. Marui et al.
Feature
Synthesis
Table 9 Photoinduced Oxidation of Amine 1f
hν
3O2
1O2
+
Zn(TFPC)
Zn(TFPC)*
Zn(TFPC)
5
5 (0.2 mol%)
8
O2 (0.1 MPa)
NH
1f (0.5 mmol)
Xe lamp (hν >300 nm)
BTF (1.0 mL), r.t.
+
NH2
1O2
Ph
Ph
NH2
+
+
O2
1a
8
9
10
+
+
NH
NH
NH
H
H
O
Ph
NH
Ph
NH
HO2
+
H2O2
+
2f
6
7
11
Entry
Time (h)
Yielda (%)
Ph
NH
2f
6
7
1
0.5
1.0
1.5
0.5
2.5
47
11
0
3
13
Ph
NH2
Ph
NH2
+
Ph
NH
Ph
N
Ph
– NH3
2
12
40
36
0
2a
3b
4c,d
5c,e
13
2
Scheme 2 Possible reaction pathway of the photoinduced oxidation of
amines
87
83
2
0
a Yields were determined by 1H NMR.
b Complex mixture.
In summary, a series of eco-friendly oxidation reactions
of amines to form the corresponding imines was developed.
Firstly, we found that the vanadium complex [VO(Hhpic)2]
is a highly effective catalyst for the selective oxidation of
benzylamines to the corresponding imines by molecular
oxygen in acetonitrile. In addition, in ionic liquids the vana-
dium complex [VO(Hhpic)2] could be employed as a reus-
able catalyst for the oxidation of benzylamines to imines.
Secondly, copper(II) sulfate catalyzed oxidation of amines
to the corresponding imines was developed. The method is
simple to perform, and the oxidation of the amines to the
corresponding imines proceeds under very mild conditions,
with hydrogen peroxide used in water at room tempera-
ture. Finally, we found that the photoinduced oxidation of
amines to imines using a zinc(II)–chlorin complex as the
photocatalyst proceeds under mild conditions, with oxygen
or air used as oxidant, in benzotrifluoride at room tempera-
ture. Photoenergy was successfully employed as the driving
force, and primary and secondary amines were oxidized to
the corresponding imines in excellent yields. These novel
oxidation methods are expected to facilitate the develop-
ment of the green oxidation of other functional groups.
c MS4A (100 mg) was used.
d Xe lamp through a glass filter (hν >400 nm) was used.
e Tungsten lamp was used.
Table 10 Oxidation of Amines 1 under Aira
4 (0.2 mol%)
air (0.1 MPa)
Ar
N
Ar
Ar
NH2
Xe lamp (hν >400 nm)
BTF (1.0 mL), r.t.
1 (0.5 mmol)
2
Entry
Substrate 1
Time (h)
Product 2
Yieldb (%)
1
2
3
1a
1i
1.5
2.0
2.0
2a
2i
97
91
90
1j
2j
a Through a glass filter (hν >400 nm).
b Yields were determined by 1H NMR.
cal cation 9 by superoxide, followed by hydrogen absorp-
tion, leads to N-unsubstituted imine 11 and hydrogen per-
oxide. Nucleophilic substitution of imine 11 with another
molecule of the amine affords an N-substituted amine.
Then, 2a is formed with concomitant formation of ammo-
nia.
1H NMR (300 or 400 MHz) and 13C NMR (75 or 100 MHz) spectra were
recorded on JEOL JNM−ALICE, JEOL JNM-ECX FT NMR, or JEOL JNM-
ECS FT NMR spectrometers of samples in CDCl3 at room temperature.
The chemical shifts are reported in parts per million downfield from
tetramethylsilane (δ = 0.0 ppm) as internal standard for 1H NMR or
CDCl3 (δ = 77.0 ppm) for 13C NMR. Melting points were determined
using a Yanaco MP-J3 instrument. [VO(Hhpic)2] was prepared follow-
ing a published procedure.12 1-Hexyl-3-methylimidazolium hexafluo-
rophosphate {[hmim]PF6} was synthesized and characterized accord-
ing to a published procedure.21 MeCN was distilled over CaH2 prior to
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, 31–42

40
K. Marui et al.
Feature
Synthesis
use. Unless otherwise noted, other reactants and reagents were pur-
chased from commercial sources and were used as received without
further purification.
was concentrated under reduced pressure. The yield of the product
was confirmed by 1H NMR by using 1,3,5-trioxane as the internal
standard.
Imines 2 by Vanadium-Catalyzed Oxidation of Benzylamines 1 in
Sealed Equipment (Tables 1 and 2); General Procedure 1
N-Benzylbenzylideneamine (2a) (Table 6, entry 2)
Purification by column chromatography (silica gel, hexane–EtOAc–
Et3N, 80:19:1).
The reactions were carried out in a stainless steel autoclave (50 mL).
The vanadium catalyst (0.03 mmol), amine 1 (1.5 mmol), and MeCN
(6 mL) were added sequentially to the autoclave, and O2 was intro-
duced (0.1 MPa). The autoclave was placed over an oil bath (120 °C),
and the reaction mixture was stirred magnetically for the desired re-
action time. The reaction mixture was filtered through Celite and
washed with Et2O. After evaporation of the solvent, the crude product
was purified by column chromatography (silica gel, hexane–EtOAc);
this afforded the corresponding analytically pure imines 2.
Yield: 140.6 mg (72%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 8.36 (s, 1 H), 7.78−7.76 (m, 2 H),
7.40−7.22 (m, 8 H), 4.80 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 161.88, 139.22, 136.08, 130.67,
128.51, 128.41, 128.20, 127.89, 126.89, 64.95.
HRMS: m/z [M]+ calcd for C14H13N:195.1048; found: 195.1044.
N-(4-Chlorobenzyl)-4-chlorobenzylideneamine (2b) (Table 6, en-
try 4).
Imines 2 by [VO(Hhpic)2]-Catalyzed Oxidation of Benzylamines 1
in Ionic Liquids (Table 3); General Procedure 2
Purification by column chromatography (silica gel, hexane–EtOAc–
Et3N, 80:19:1).
A mixture of [VO(Hhpic)2] (10.3 mg, 0.03 mmol), benzylamine 1
(160.7 mg, 1.5 mmol), and ionic liquid (2 mL) was added to a 30 mL
two-necked glass vessel, stirred, and heated at 120 °C for 6 h under
atmospheric O2. The reaction mixture was extracted with Et2O. The
extract was concentrated under vacuum. The product was character-
ized by 1H NMR; 1,2-diphenylethane was used as the internal stan-
dard.
Yield: 222.7 mg (84%); white solid; mp 64–65 °C.
1H NMR (400 MHz, CDCl3): δ = 8.31 (s, 1 H), 7.70–7.68 (m, 2 H), 7.39–
7.36 (m, 2 H), 7.31–7.24 (m, J = 8.6 Hz, 4 H), 4.75 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 160.76, 137.57, 136.81, 134.41,
132.76, 129.40, 129.20, 128.87, 128.57, 64.10.
HRMS: m/z [M]+ calcd for C14H11Cl2N: 263.0269; found: 263.0262.
Recycling of the Catalyst in [hmim]PF6 (Table 4)
The first cycle was performed following general procedure 2, using
[hmim]PF6 as the solvent. After the products were separated from
[hmim]PF6 by extraction with Et2O, the [hmim]PF6 layer containing
the catalyst was dried in vacuo for 6 h. The resulting ionic liquid layer
was used for the next oxidation reaction upon adding benzylamine
(1a; 1.5 mmol).
N-(4-Methylbenzyl)-4-methylbenzylideneamine (2c) (Table 6, en-
try 5)
Purification by column chromatography (silica gel, hexane–EtOAc–
Et3N, 80:19:1).
Yield: 157.8 mg (71%); pale yellow solid; mp 83–84 °C.
1H NMR (400 MHz, CDCl3): δ = 8.32 (s, 1 H), 7.65 (d, J = 8.2 Hz, 2 H),
7.22−7.19 (m, 4 H), 7.13 (d, J = 8.2 Hz, 2 H), 4.75 (s, 2 H), 2.36 (s, 3 H),
2.32 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.62, 140.90, 136.44, 136.31,
133.57, 129.24, 129.10, 128.19, 127.90, 64.75, 21.45, 21.05.
Imines 2 by CuSO4-Catalyzed Oxidation of Amines 1 (Equations 3–
4, Tables 5 and 6); General Procedure 3
Amine 1 (2.0 mmol), CuSO4·5H2O (1.0 mg, 0.004 mmol), and H2O (2.0
mL) were added to a two-necked glass vessel. A 10% aqueous solution
of H2O2 was added dropwise to the mixture under stirring. After the
appropriate reaction time, the product was extracted with Et2O. The
organic layer was dried (MgSO4), filtered, and concentrated. The
product was dissolved in CDCl3, and an appropriate amount of 1,3,5-
trioxane was added as the internal standard to determine the yield of
the product by 1H NMR. The products were purified by passing
through a short pad of silica gel (Wakogel C-200; EtOAc–hexane–
Et3N) or by gel permeation chromatography (GPC); this affording the
corresponding analytically pure imine 2. Silica gel was carefully dried
in vacuo prior to use, because the H2O in silica gel reacted with the
imine product. Products 2m and 2n could not be purified satisfactori-
ly by chromatography owing to hydrolysis.
HRMS: m/z [M]+ calcd for C16H17N:223.1361; found: 223.1359.
N-(4-Methoxybenzyl)-4-methoxybenzylideneamine (2d) (Table 6,
entry 7)
Purification by GPC.
Yield: 192.9 mg (76%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.27 (s, 1 H), 7.70 (d, J = 8.7 Hz, 2 H),
7.23 (d, J = 8.7 Hz, 2 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2
H), 4.71 (s, 2 H), 3.80 (s, 3 H), 3.77 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.55, 160.82, 158.53, 131.56,
129.71, 129.06, 113.85, 113.78, 64.29, 55.22, 55.16.
HRMS: m/z [M]+ calcd for C16H17NO2: 255.1259; found: 255.1261.
Oxidation of Amines 1 Catalyzed by a Photocatalyst (Equations 6
and 7, Tables 7–10); General Procedure 4
3,4-Dihydroisoquinoline (2f) (Table 2, entry 5)
Fluorinated chlorins were prepared and metalated according to re-
ported methods, to provide catalysts 4 and 5.22 Amine 1 (0.5 mmol)
and photocatalyst 4 or 5 (0.001 mmol) were added to BTF (1.0 mL) in
a two-necked Pyrex glass vessel. O2 gas was introduced into the vessel
by connecting an O2 balloon, and the reaction mixture was stirred
and irradiated using a Xe lamp through Pyrex (hν >300 nm) for 1 h.
After extraction of the reaction mixture with Et2O, the organic layer
Purification by column chromatography (silica gel, hexane–EtOAc–
Et3N, 75:24:1).
Yield: 155.7 mg (78%); pale yellow oil.
1H NMR (CDCl3, 300 MHz): δ = 8.32 (s, 1 H), 7.34 (m, 1 H), 7.28−7.26
(m, 2 H), 7.14 (d, J = 7.2 Hz, 1 H), 3.79−3.73 (m, 2 H), 2.73 (t, J = 7.3 Hz,
2 H).
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41
K. Marui et al.
Feature
Synthesis
13C NMR (CDCl3, 75 MHz): δ = 160.29, 136.27, 131.02, 128.44, 127.38,
127.16, 127.03, 47.30, 24.97.
13C NMR (100 MHz, CDCl3): δ = 161.64, 154.05, 149.74, 136.41,
133.54, 128.04, 127.63, 125.48, 125.34, 64.78, 34.85, 34.42, 31.36,
31.19.
HRMS: m/z [M]+ calcd for C22H29N: 307.2300; found: 307.2293.
N-Benzylideneaniline (2g) (Table 2, entry 6)
Purification by column chromatography (silica gel, hexane–EtOAc–
Et3N, 80:19:1).
N-(Cyclohexylmethyl)cyclohexylmethyleneamine (2n) (Table 6,
entry 18)
Yield: 203.9 mg (75%); pale yellow oil.
Purification by GPC.
1H NMR (CDCl3, 300 MHz): δ = 8.40 (s, 1 H), 7.89−7.86 (m, 1 H),
7.44−7.34 (m, 5 H), 7.22−7.18 (m, 3 H).
Yield: 118.5 mg (57%); pale yellow oil.
13C NMR (CDCl3, 75 MHz): δ = 160.23, 151.97, 136.12, 131.26, 129.04,
128.70, 128.65, 125.83, 120.77, 54.05.
1H NMR (400 MHz, CDCl3): δ = 7.42 (d, J = 4.6 Hz, 1 H), 3.18 (d, J = 6.4
Hz, 2 H), 2.20–2.12 (m, 1 H), 1.78–1.53 (m, 11 H), 1.35–1.08 (m, 8 H),
0.93–0.83 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 168.69, 68.27, 43.31, 38.37, 31.15,
N-(3-Methoxybenzyl)-3-methoxybenzylideneamine (2h) (Table 6,
entry 9)
29.70, 26.47, 25.92, 25.87, 25.31.
HRMS: m/z [M]+ calcd for C14H25N: 207.1987; found: 207.1979.
Purification by column chromatography (silica gel, EtOAc–Et3N, 99:1).
Yield: 231.1 mg (90%); pale yellow oil.
1H NMR (400 MHz, CDCl3): δ = 8.26 (s, 1 H), 7.37 (s, 1 H), 7.26–7.19
(m, 3 H), 6.95–6.88 (m, 3 H), 6.78–6.75 (m, 1 H), 4.73 (s, 2 H), 3.74 (s,
3 H), 3.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 161.68, 159.64, 159.53, 140.63,
137.34, 129.30, 129.22, 121.34, 120.03, 117.18, 113.40, 112.11,
111.51, 64.55, 54.97, 54.81.
Acknowledgment
This research was supported by a Grant-in-Aid for Exploratory Re-
search (26620149), Scientific Research (C, No. 23550057), A-STEP, and
Nanotechnology Platform Program of the Nara Institute of Science
and Technology (NAIST) from the Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan. The authors also
thank Professor S. Yano (NAIST) for synthetic support of catalysts and
Professor M. Ueshima for his advice about oxidation reactions.
N-(2-Methoxybenzyl)-2-methoxybenzylideneamine (2i) (Table 6,
entry 11)
Purification by GPC.
Yield: 168.9 mg (66%); pale yellow oil.
References
1H NMR (400 MHz, CDCl3): δ = 8.84 (s, 1 H), 8.03 (dd, J = 7.8, 1.8 Hz, 1
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13C NMR (100 MHz, CDCl3): δ = 158.66, 158.22, 156.95, 131.69,
129.01, 128.02, 127.82, 127.37, 124.75, 120.64, 120.40, 110.88,
110.07, 59.55, 55.40, 55.22.
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1H NMR (400 MHz, CDCl3): δ = 8.46 (s, 1 H), 7.90 (d, J = 8.2 Hz, 2 H),
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