C70 as a Photocatalyst for Oxidation of Secondary Benzylamines to Imines

Article abstract of DOI:10.1021/acs.orglett.5b03194

Photosensitive C₇₀ was used for the catalytic oxidation of benzylamines to the corresponding imines. The advantages of using C₇₀ compared to C₆₀ or other commonly used photosensitizers such as tetraphenylporphyrin (TPP) ar

Full text of DOI:10.1021/acs.orglett.5b03194

Letter
pubs.acs.org/OrgLett
C70 as a Photocatalyst for Oxidation of Secondary Benzylamines to
Imines
Rakesh Kumar, Eva H. Gleißner, Elisha Gabrielle V. Tiu, and Yoko Yamakoshi*
Laboratorium fur Organische Chemie, ETH-Zurich, Vladimir-Prelog-Weg 3, CH8093 Zurich, Switzerland
̈
̈
̈
S
* Supporting Information
ABSTRACT: Photosensitive C70 was used for the catalytic oxidation of
benzylamines to the corresponding imines. The advantages of using C70
compared to C60 or other commonly used photosensitizers such as
tetraphenylporphyrin (TPP) are (1) faster reaction rates, especially
under lower energy of light sources, (2) clean reactions with simple
workup without chromatography, and (3) lower catalyst loadings. The
reactions were suitable for various benzylamine derivatives. Subsequent
nucleophilic additions to the imines were successfully carried out on
substituted products. Quenching experiments in the presence of DABCO and benzoquinone implicate the involvement of the
singlet oxygen (1O2) and the superoxide radical anion (O2•−) as important reactive species in the oxidation.
great attention.37 Che and co-workers used tetraphenylporphyr-
he remarkable photosensitivity of fullerenes such as C60 and
TC
in (TPP) as a catalyst for the photooxidation of amines to imines,
which were directly subjected to a subsequent Ugi reaction.34
The same group also reported an organogold(III) complex for
the oxidation of benzylamines to imines, including the oxidative
has been widely known for decades and has been
70
applied in photovoltaic materials and photodynamic therapy
(PDT) agents. In the case of the former, the electron-donating or
-accepting properties of fullerenes, which can be induced by
photoirradiation, is utilized. In the case of the latter, photo-
cyanation of tertiary amines.37 Konig and co-workers used
̈
porphycene in photooxidation reactions of primary and
secondary amines to provide the corresponding imines and
aldehydes.35 Recent work by Seeberger and co-workers
described the photooxidation of amines and subsequent
nucleophilic addition with TPP using continuous-flow photo-
reactor techniques.36,38
induced generation of reactive oxygen species (ROSs) such as
1,2
1O2 and O2 3 produced, respectively, via energy transfer (type
•−
II reaction) and electron transfer (type I reaction) is a key
phenomenon. Importantly, the quantum yields of both type I and
II reactions are quantitiative,4 and therefore, many PDT studies
using fullerenes were reported, influenced by an initial report on
5
In this study, we used C60 and C70 as photocatalysts for the
oxidation of benzylamines to imines. Although the price of
fullerenes is now comparable to other photosensitizers such as
TPP, the application of fullerenes for such a reaction has not been
previously explored. While the initial trials with C60 were not as
efficient when compared to the commonly used photosensitizer
TPP, the use of C70 provided a very effective reaction even with
lower catalyst loadings. In addition, under lower light energy
(blue LED), nucleophilic addition to the imines can be
successfully carried out in the same reaction flask to provide a
substitution at the benzylic position. Due to the low solubility of
C70, the workup of the reactions is very simple and requires only
the removal of C70 by precipitation to provide imines as a single
product. The reaction was successfully applied to various
benzylamines as substrates.
photo DNA-cleavage with C60 using water-soluble fullerene
materials.6 Alternatively, the use of fullerenes as organic reagents
such as a catalyst for oxidation has been studied for decades.
These studies include the oxidation of olefins,7 phenols,8 and
sulfides.9
Imines are important intermediates in the synthesis of
bioactive compounds,10 and there is a high demand for useful
synthetic methods for the production of imines.11−13 Reported
methods for the conversion of amines to imines include the use
of (1) stoichiometric oxidants such as N-tert-butylphenylsulfini-
midoyl chloride14 and o-iodoxybenzoic acid (IBX)15,16 and (2)
metal catalysts in the presence of oxidants10,17−23 or molecular
oxygen.17,24−26 Quinone- and catechol-based aerobic oxidations
of amines were also found to be efficient.27−29 These methods
provide sufficient yields but often require harsh reaction
conditions, stoichiometric oxidizing reagents, or other additives.
Recently, the use of photosensitizers has emerged as a
promising method for the conversion of amines to imines.
Photocatalysts such as organic dyes30,31 and transition-metal
complexes30,32,33 have been explored for various organic
transformations. Specifically, recent reports on the oxidation of
amines using 1O2 generated from photosensitizers such as
porphyrin derivatives34−36 and gold catalysts have received a
As an initial trial for the oxidation of benzylamines to imines,
1,2,3,4-tetrahydroisoquinoline 1 was used as a substrate in the
presence of C60 (99.95%, MTR Ltd.) as a photocatalyst under
white light irradiation by a tungsten lamp. The reaction rates
were compared in the several different solvents as listed in Table
Received: November 5, 2015
© XXXX American Chemical Society
A
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Table 1. Photoinduced Oxidation of Amine 1 in the Presence
of Photosensitizer (C60, TPP or C70) and under White Light
a
Irradiation
Figure 1. 1H NMR spectra of the starting material 1 (a) and the crude
extract of the reaction mixture (b) after white light irradiation with 0.1
mol % of C60 for 21 h in CHCl3 at room temperature.
a
Amine 1 (50 mg, 0.38 mmol) was subjected in the reaction with 5
b
mL of solvent. Satd: oxygen was saturated by bubbling (about 11.5
mM of O2 in CHCl3). Air: reaction mixture was exposed to the air by
c
using an open flask (about 2.1 mM of O2 in CHCl3). A 200 W
tungsten lamp (white light) at a distance of 20 cm (20000−20500 lx).
d
The time required for completion (with no detectable 1 by NMR)
and the time for 50% conversion from 1 to 2 (t1/2). N.D.: not
e
determined. Obtained from the integration of 1H NMR spectra of the
reaction mixture. N.R.: no reaction with starting material recovery.
f
g
Without light and under a thermal condition (40 °C). C60-mono-
Bingel derivative (structure is provided in Figure S14, SI).
Figure 2. Reaction process of oxidation under (a) white tungsten lamp
(200 W, 20000−20500 lx), (b) blue diode (emission maximum: 470
nm, 14000−14500 lx), (c) green diode (emission maximum: 520 nm,
73000−74000 lx). (d) Structures of the photosensitizers. The reactions
were carried out using 0.1 mol % of photosensitizer and 50 mg (0.38
mmol) of amine 1 in CHCl3. The value of % product was estimated by
1H NMR spectra integration.
1 (runs 1−4), and these studies revealed that CHCl3 was the
most efficient solvent. This solvent effect may be partially related
to the lifetime of the 1O2 in each solvent (250 10, 91 10, 30
10, and 54 μs for CHCl3, CH2Cl2, THF, and CH3CN,
respectively39,40). The very slow reaction in CH3CN (run 4)
was presumably due to the low solubility of C60 in this polar
solvent. A similar situation was observed in the reaction of the
more soluble C60−Bingel adduct (SI, Figure S14), in which a
slightly faster reaction rate was shown compared to the less
soluble pristine C60 (runs 5, 11). None or only trace product
generation was observed in the absence of C60 or light (runs 8,
10). The saturated oxygen concentration was advantageous than
the ambient condition with open flask (run 9).
Importantly, the oxidation of 1 with C60 proceeded in a clean
manner to show a single product 2 in the crude extract (Figure 1)
after a simple workup of precipitation of C60 fraction by MeOH
and subsequent Celite filtration. However, the reaction efficiency
was not sufficient when compared with TPP, a commonly used
photosensitizer (runs 5, 12).As an alternative, we used C70
(99.5%, MTR Ltd.) as a catalyst, which has stronger absorbance
of visible light (Figure S25) and a longer triplet state (3C70*)
lifetime than C60 or TPP. As expected, the reaction with C70 was
much faster than the one with C60 and almost the same as the one
with TPP (runs 5, 12, 13 and Figure 2a). Importantly, we could
lower the catalyst loading of C70 to 0.01 mol % and still complete
the oxidation in a practical reaction time (28 h, run 15).
Based on the promising results of using C70 under white light
above, along with the fact that C70 has absorbance in longer
wavelength region, which has less risk of decomposition of the
compounds involved in the reaction, we used commercially
available, inexpensive diode lamps for irradiation. We compared
the reaction rates in the presence of C60, C70, and TPP. As a
result, under both blue (max: 470 nm, Figure 2b) and green
(max: 520 nm, Figure 2c) LED lights, the reaction with C70
proceeded faster than those with either TPP or C60, indicating the
advantage in the use of C70 as a photocatalyst. In addition, under
green light, the reaction of C60 was faster than that of TPP,
despite the fact that the absorbance of TPP at around 520 nm is
B
DOI: 10.1021/acs.orglett.5b03194
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much higher than the one of C60 (Figure S25). This is
presumably because the quantum yields in 1O2 generation
Table 3. Photoinduced Oxidation of Benzylamine Derivatives
Catalyzed by C70
1
from photoexcited fullerenes are quite high (0.96 0.04 for C60
and 0.81 0.15 for C702 in benzene at 532 nm) compared to the
one from TPP (0.62 0.20 in benzene at 532 nm).41
Based on the above results for the efficient oxidation with C70,
we simultaneously carried out amine oxidation and nucleophilic
addition (Table 2). An initial attempt of this one-step protocol
substrate 5
R1
a
run
R2
reaction time [h]
yield [%]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
H
Bn
7
9
97
95
92
93
97
90
95
95
91
Table 2. Combination of Amine Oxidation and Nucleophilic
Addition
p-Me
p-OMe
p-F
p-MeBn
p-OMeBn
p-FBn
a
6.5
8
p-Cl
p-ClBn
6
o-Cl
o-ClBn
15
8
5g
5h
5i
m-Cl
p-CF3
m-CF3
m-ClBn
p-CF3Bn
m-CF3Bn
10
20
a
Isolated yields.
two-step conditions
catalyst, and indicate (1) that C70 itself does not have any
influence in the selectivity of amine oxidation and (2) that
oxidation is suitable for various kinds of benzylamine derivatives.
In addition, when an aliphatic amine (e.g., piperidine) was used
as a substrate, no imine formation was observed as a limitation of
this amine oxidation reaction. Benzylamine oxidation works
better presumably due to the stable benzylic radical formation as
an important intermediate to provide imine.
step I (light)
step II (dark)
time TMS-CN time NMR yield yield of
b
c
run S (mol %) hν
[h]
[equiv]
[h]
of 3 [%]
4 [%]
1
2
3
C60 (1.0)
W
W
B
15
7
2.0
1.5
1.5
1.5
4
73
>99
>99
65
71
75
C
C
70 (0.1)
70 (0.1)
2
4
one-step conditions (light)
In order to elucidate aspects of the reaction mechanism, the
photooxidations were carried out in the presence of ROS
quenchers. In a detailed examination previously reported by the
groups of Seeberger38 and Baciocchi,42 two possible mechanisms
were proposed for the 1O2-mediated oxidation of amines. Both
start from initial coordination of 1O2 to amine nitrogen to cause
an exciplex formation followed by the generation of benzylic
radical through either (1) single-electron transfer to provide
amine radical cation and O2•− and subsequent deprotonation at
the benzyl position or (2) direct hydrogen abstraction. Since we
used a photosensitizer with a higher oxidation potential as
compared to TPP, it was important to clarify what kind of ROS is
c
TMS-CN
time
[h]
NMR yield of yield of 4
b
run S (mol %) hν
[equiv]
3
[%]
[%]
d
4
5
6
C
60 (0.1)
C70 (0.1)
70 (0.1)
W
W
B
1.5
1.5
1.5
45
10
3
<5
N.D.
74
>99
>99
C
76
a
b
Reactions were carried out using amine 1 (133 mg, 1.0 mmol). The
NMR yield was obtained by NMR integration. Obtained yields of 4
by one-time precipitation in HCl/Et2O. Imine 2 was observed after
slight generation of 3 in the reaction process by NMR (Figure S27).
c
d
using 0.1 mol % of C60 and white light resulted only in the
generation of imine 2, presumably due to the decomposition of 3
by white light irradiation (run 4). This was overcome by a one-
pot/two-step protocol (run 1) involving an initial step of
photooxidation with 1 mol % of C60 under white light and the
subsequent second step of nucleophile addition in dark to
provide 4 in 65% yield. By switching the photocatalyst to C70, the
yield by a one-pot/two-step protocol was improved to 71%
(white light, run 2) and 75% (blue light, run 3) with shorter
reaction times and lower catalyst loading. Furthermore, using C70
(0.1 mol %), the one-pot/one-step protocol was successfully
achieved to provide 4 in good yield with shorter reaction
intervals, especially under blue light irradiation (runs 5, 6).
The C70-catalyzed photooxidation was applied to various
benzylamines 5a−i with substituents on the aromatic ring in the
presence of C70 (0.1 mol %) under white light. As a result, all
reactions provided the corresponding imines in good yields
(>90%) within 20 h. There was no significant effect of
substituents with electron-donating groups (Me and OMe,
Table 3, runs 2, 3) or electron-withdrawing groups (F, Cl, and
CF3, runs 4, 5, and 8) in the para-position on the reaction rate.
The ortho- and meta-substitution had a slight effect to diminish
the reaction rate (runs 6, 7, 9), presumably due to steric
hindrance. These results are very similar to recent reports by
Seeberger and co-workers,38 where TPP is used as a photo-
involved as reactive species in the current oxidation reaction. We
used DABCO and benzoquinone as quenchers of 1O2 and O2
,
•−
respectively. In addition, anthracene was added as a competitive
1
substrate for oxidation by O2 (cycloaddition). As shown in
Table 4, significant suppression of the oxidation reaction was
observed in the presence of DABCO (run 1) with a linear
correlation in Stern−Volmer plotting (Figure S96), which
a
Table 4. Effects of ROS Quenchers on Oxidation
b
quencher
(equiv to amine)
reaction time
[h]
NMR yield
[%]
run
solvent
1
2
3
4
DABCO (1.0)
CHCl3
CHCl3
CHCl3
CHCl3
4
4
4
4
7
85
anthracene (1.0)
benzoquinone (0.1)
c
25
>99
a
All reactions were carried out with amine 1 (15 mg, 0.11 mmol).
b
c
Observed by 1H NMR of crude mixture. Reaction was carried out in
the presence of smaller amounts of quencher to avoid complex side
reactions observed in the presence of larger amounts of benzoquinone.
C
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Organic Letters
Letter
indicates that 1O2 is an important reactive species involved in the
oxidation. In addition, a moderate decrease of yield was observed
in the presence of anthracene (run 2). On the other hand, a
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slower reaction was also observed in the presence of
•−
benzoquinone (run 3) indicating the involvement of O2
,
which is probably generated by the electron transfer from an
amine to 1O2. The detailed investigation of the mechanism is still
in progress.
Finally, the reaction was carried out on a larger scale to test the
recovery of catalyst C70. As described above, separation of C70
from reaction mixture is easily done by precipitation from
MeOH. In a reaction of 1 (2.0 g) using 12.6 mg (0.1 mol %) of
C70 (9 h under blue light), 10.1 mg of the C70 fraction was
recovered, which was subjected to a recycled reaction with 1 (2.0
g) to provide 97% yield in 10 h reaction time under blue light.
The recovered C70 fraction contained substantial amounts of C70
mono- and diepoxides as detected by HPLC and MALDI-TOF-
MS (Figures S101, S102).43 By thermal treatment (reflux in o-
dichlorobenzene for 17 h), most of the C70 epoxides were easily
converted back to underivatized C70 as indicated by both HPLC
and MALDI-TOF-MS (Figures S103, S104).
In conclusion, we successfully developed a clean and efficient
oxidation of benzylamines with a simple workup process. Due to
the efficiency of C70 as a photosensitizer, we achieved lower
catalyst loading and provided a high yield of the products. This
photoexcited C70-mediated oxidation reaction is also applicable
to many benzylamine derivatives and is suitable for simultaneous
nucleophilic additions. Easy recovery of C70 fraction, which can
be converted by simple thermal treatment to C70, enabled the
recycling of the C70 catalyst.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03194.
Syntheses of amines; detail of photoinduced oxidation
reaction; oxidation−nucleophile addition with full spectral
data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(35) Berlicka, A.; Konig, B. Photochem. Photobiol. Sci. 2010, 9, 1359.
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(36) Ushakov, D. B.; Gilmore, K.; Kopetzki, D.; McQuade, D. T.;
Seeberger, P. H. Angew. Chem., Int. Ed. 2014, 53, 557.
(37) To, W. P.; Tong, G. S.; Lu, W.; Ma, C.; Liu, J.; Chow, A. L.; Che,
C. M. Angew. Chem., Int. Ed. 2012, 51, 2654.
*E-mail: yamakoshi@org.chem.ethz.ch.
Notes
The authors declare no competing financial interest.
(38) Ushakov, D. B.; Plutschack, M. B.; Gilmore, K.; Seeberger, P. H.
Chem. - Eur. J. 2015, 21, 6528.
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(43) A trace amount of an amine adduct of C70 produced by
nucleophilic addition was observed in the reaction mixture, but it was
minor compared to the C70 epoxides.
ACKNOWLEDGMENTS
■
This research was supported in part by the Swiss National
Foundation (200021-140451, 200021-156097, Y.Y.), ETH
Research Grant (ETH-25 11-1, Y.Y.), and PRESTO program
from JST (Y.Y.). We thank Mr. Aroua in LOC of ETH for
providing a mono-Bingel adduct of C60. We thank Mr. Hsieh and
Mr. Nasuda in LOC of ETH for their technical support for diode
setup. MS and NMR services of LOC at ETH are acknowledged.
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