Light-mediated heterogeneous cross dehydrogenative coupling reactions: Metal oxides as efficient, recyclable, photoredox catalysts in C-C bond-forming reactions

Article abstract of DOI:10.1002/chem.201103242

Let there be light: A heterogeneous photocatalytic system based on easily recyclable TiO₂ or ZnO allows cross dehydrogenative coupling reactions of tertiary amines. The newly developed protocols have successfully been applied to various C-C and

Full text of DOI:10.1002/chem.201103242

DOI: 10.1002/chem.201103242
Light-Mediated Heterogeneous Cross Dehydrogenative Coupling Reactions:
À
Metal Oxides as Efficient, Recyclable, Photoredox Catalysts in C C Bond-
Forming Reactions
Magnus Rueping,*[a] Jochen Zoller,[a] David C. Fabry,[a] Konstantin Poscharny,[a]
Renꢀ M. Koenigs,[a] Thomas E. Weirich,[b] and Joachim Mayer[b]
In the past years, the cross dehydrogenative coupling re-
action has attracted considerable interest among synthetic
organic chemists, as it offers an attractive and elegant path-
way for the efficient and atom-economic construction of
known,[9,10] the use as a catalyst for organic synthesis has
mainly been neglected.
Initial studies to develop an easily recyclable photoredox
catalysis procedure concentrated on the light mediated
(standard household 11 W fluorescent bulb) oxidative aza-
Henry reaction of N-aryl-tetrahydroisoquinoline (THIQ)
derivatives and nitromethane in the presence of a metal
oxide.
To our delight, we observed the formation of the desired
reaction product in good to excellent yields using commer-
cially available TiO2 nanoparticles (Evonik-Degussa Aero-
xide P25) (Table 1, entries 1 and 2). Only traces of product
were obtained when the reaction was performed in the ab-
sence of the light source (entry 3). The reaction can also be
performed using catalytic amounts of TiO2. However, the re-
action is more efficient if one equivalent of photocatalyst is
applied.
À
À
À
new C C and C heteroatom bonds through C H activation
without the need for prior functionalization of both coupling
partners.[1] In particular, this approach takes advantage of
the ease of oxidation of tertiary amines that form highly re-
active iminium ion intermediates for further functionaliza-
[2–4]
À
tion including the construction of carbon carbon
or
[5]
À
carbon heteroatom bonds.
Recently, the application of visible light attracted signifi-
cant interest as an efficient and sustainable tool to conduct
cross dehydrogenative coupling reactions. Different groups
have reported on the aerobic photochemical oxidation of
tertiary amines using metal- and metal-free photoredox cat-
alysts.[7,8]
In this context we wondered whether aerobic photocata-
lytic cross dehydrogenative coupling reactions[8] can be
turned more environmentally benign by using an inexpen-
sive heterogeneous catalyst that can easily be reisolated
after the reaction and which does not suffer from deactiva-
tion through bleaching. Thus we decided to investigate com-
mercially available, cheap titanium dioxide as a new type of
heterogeneous catalyst for cross dehydrogenative coupling
reactions. Additionally, successful application would not
only represent the first example of TiO2 in photocatalytic
Table 1. Survey of different metal oxide catalysts.
Entry[a]
Metal oxide
Equivalent
Solvent
Yield [%][b]
1
2
TiO2 (P25)
TiO2 (P25)
TiO2 (P25)
TiO2 (rutil)
TiO2 (anatas)
ZnO
0.1
1
1
1
1
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
88
93
traces
77
94
3[c]
4
À
À
carbon carbon or carbon heteroatom bond forming reac-
tions but more importantly it would provide the basis for
further application and extension of visible light mediated
reactions.
5
6
1
69
[a] Reaction conditions: 0.1 mmol 1a, 1 equiv of metal oxide, 1 mL
EtOH, 10 equiv nitromethane, irradiation with 11 W halogen lamp from
3 cm distance for 40 h, reactions in the dark are wrapped with aluminium
foil. [b] Yield after chromatographic purification. [c] Performed in the
dark.
Although the application of titanium dioxide in photoca-
talytic oxidations of hydrocarbons or alcohols is well
[a] Prof. Dr. M. Rueping, Dipl.-Chem. J. Zoller, D. C. Fabry,
Dipl.-Chem. K. Poscharny, Dipl.-Chem. R. M. Koenigs
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
In addition, different solvents were examined, yet only
polar solvents, as DMF, MeCN or alcohols provided the de-
sired reaction product.[11] Of all solvents investigated EtOH
gave the best results in terms of yield and environmental
compatibility.
As the modifications of TiO2 in Aeroxide P25 may have a
significant influence on the catalytic efficiency, we decided
to additionally investigate commercially available pure
E-mail: magnus.rueping@rwth-aachen.de
[b] Priv.-Doz. Dr. T. E. Weirich, Prof. Dr. J. Mayer
Central Facility for Electron Microcopy, RWTH Aachen University
Ahornstrasse 55, 52074 Aachen (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201103242.
3478
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2012, 18, 3478 – 3481

COMMUNICATION
Table 3. Substrate scope of the oxidative Mannich reaction.
rutile and anatas phases in the photocatalytic oxidative aza-
Henry reaction under otherwise identical conditions. While
similar results were obtained using the pure anatas phase,
the rutil phase proved to be considerably less reactive
(Table 1, entries 4 and 5). Moreover, we examined ZnO in
the photocatalytic oxidative aza-Henry reaction. However, a
significant decrease in reactivity was observed (Table 1,
entry 6). Nonetheless, this information is of great impor-
tance as it shows that oxidative cross dehydrogenative cou-
pling reactions can also be performed with a different metal
oxide catalyst.
With the optimal conditions in hand we decided to inves-
tigate the substrate scope of the light-mediated TiO2 cata-
lyzed oxidative aza-Henry reaction. In general, different N-
aryl substituted THIQ derivatives could be successfully ap-
plied providing the desired reaction products in good to ex-
cellent yields (Table 2, entries 1–9). In comparison to the
corresponding iridium-catalyzed photochemical transforma-
tion, this new protocol allows an economic and cheap oxida-
tive cross dehydrogenative coupling, as the reaction can be
performed under ambient conditions without the need for
expensive catalysts.
Entry[a]
Substrate
R
Ar
Yield [%][b]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1j
H
H
H
H
H
H
H
MeO
phenyl
75
73
98
58
69
85
54
86
4-Me-phenyl
4-Et-phenyl
4-MeO-phenyl
4-F-phenyl
4-Br-phenyl
3-MeO-phenyl
phenyl
1i
[a] Reaction conditions: 0.1 mmol 1a–f, 1i–j, 1 equiv of TiO2 (P25), 1 mL
EtOH, 10 equiv acetone, irradiation with 11 W fluorescent lamp from
3 cm distance for 40 h. [b] Yield after chromatographic purification.
tions in order to obtain valuable a-amino-nitriles. Again the
efficiency of ZnO and TiO2 (Aeroxide P25) was investigated
and TiO2 proved to be the superior catalyst. The desired
amino-nitriles were obtained in excellent yield (Table 4).[11]
Table 2. Substrate scope of the oxidative aza-Henry reaction.
Table 4. Substrate scope of the oxidative cyanation reaction.
Entry[a]
Substrate
R
Ar
Yield [%][b]
Entry[a]
Substrate
Ar
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
H
H
H
H
H
H
H
H
phenyl
93
84
60
1
2
3
4
5
6
1a
1c
1d
1e
1 f
1j
phenyl
95
90
99
95
94
79
4-Me-phenyl
4-Et-phenyl
4-MeO-phenyl
4-F-phenyl
4-Br-phenyl
2-Me-phenyl
2-naphthyl
phenyl
4-Et-phenyl
4-MeO-phenyl
4-F-phenyl
4-Br-phenyl
3-MeO-phenyl
68/89[c]
61
86
96
75
96
[a] Reaction conditions: 0.1 mmol 1a, 1c–f, 1j, 1 equiv of TiO2 (P25),
1 mL EtOH, 1.2 equiv KCN, 5 equiv AcOH, irradiation with 11 W fluo-
rescent lamp from 3 cm distance for 40 h. [b] Yield after chromatographic
purification.
MeO
[a] Reaction conditions: 0.1 mmol 1a–i, 1 equiv of TiO2 (P25), 1 mL
EtOH, 10 equiv nitromethane, irradiation with 11 W fluorescent lamp
from 3 cm distance for 40 h. [b] Yield after chromatographic purification.
[c] Reaction performed in neat MeNO2.
Recently, we were able to develop new visible light medi-
À
ated photoredox catalyzed C P bond forming reactions with
the use of rather expensive Ru- and Ir-bipyridyl and phenyl-
pyridyl complexes.
To further evaluate the catalytic performance of TiO2 and
to underline the efficiency of this heterogeneous photocata-
lyst, we evaluated other oxidative cross dehydrogenative
coupling reactions. Subsequently, we investigated the oxida-
tive Mannich and cyanation reactions, as they offer a practi-
cal approach to valuable b-amino-ketones and a-amino-ni-
triles, respectively.
Just like the above described aza-Henry reaction, the oxi-
dative Mannich reaction also proceeded smoothly in the
presence of TiO2 together with catalytic amounts of proli-
ne[8b] to provide the desired amino-ketones in high yield
(Table 3). Surprisingly, when ZnO was applied, decomposi-
tion of the starting materials was observed.[11]
Therefore, we investigated the applicability of TiO2 (Aer-
oxide P25) and ZnO in the oxidative phosphonylation of
amines. In this case the use of ZnO provided the desired
amino-phosphonates in better yields.[11] Different N-aryl
THIQ derivatives were also subjected to this protocol, al-
lowing an operationally simple access to valuable amino-
phosphonates in moderate to excellent yield (Table 5, en-
tries 1–10).
With the advantage of having found cheap, readily avail-
able, heterogeneous catalysts for light mediated oxidative
cross dehydrogenative coupling reactions, we decided to
probe the recycling of the TiO2 and ZnO photocatalysts by
applying a simple centrifugal separation and their subse-
Furthermore, we investigated the application of heteroge-
neous photoactive metal oxides in oxidative cyanation reac-
Chem. Eur. J. 2012, 18, 3478 – 3481
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M. Rueping et al.
Table 5. Substrate scope of the oxidative phosphonylation reaction.
Entry[a]
Substrate
Ar
Yield [%][b]
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1k
1j
phenyl
93
72
96
90
89
74
74
40
69
61
4-Me-phenyl
4-Et-phenyl
4-MeO-phenyl
4-F-phenyl
4-Br-phenyl
4-Cl-phenyl
3-MeO-phenyl
2-Me-phenyl
2-naphthyl
1g
1h
10
[a] Reaction conditions: 0.1 mmol 1a–h, 1j–k, 1 equiv of ZnO, 1 mL
EtOH, 10 equiv diethyl phosphite, irradiation with 11 W fluorescent lamp
from 3 cm distance for 40 h. [b] Yield after chromatographic purification.
quent reuse. Gratifyingly, both catalysts could be efficiently
recycled in consecutive catalytic cycles without loss in reac-
tivity and selectivity, underlining the catalytic efficiency of
both metal oxide catalysts (Table 6).
Figure 1. TEM and HR-TEM analysis of TiO2 (top) and ZnO
(bottom).[11]
À
highly robust and can be applied to different carbon carbon
Table 6. Evaluation of catalyst recycling.
À
and carbon phosphorous bond forming reactions to provide
Cycle
1
2
3
4
5
products, such as b-nitro amines, b-amino ketones, amino-ni-
triles or amino-phosphonates in high chemical yield. Fur-
thermore, the catalysts can be simply recycled and reused
which demonstrates that this environmentally friendly and
economical protocol is an improvement over previously re-
ported procedures. Additionally, no change in the chemical
composition of the metal oxides was observed which under-
lines the robustness of the catalysts in light mediated cross
dehydrogenative coupling reactions.
TiO2 (P25) in aza-Henry reaction[a]
ZnO in phosphonylation[b]
85
86
83
94
87
86
92
88
87
[a] Reaction conditions: 1.0 mmol 1a, 1 equiv of TiO2 (P25), 5 mL
EtOH, 10 equiv nitromethane, irradiation with 11 W fluorescent lamp
from 3 cm distance for 40 h, yields after chromatographic purification. [b]
Reaction conditions: 0.3 mmol 1a, 1 equiv of ZnO, 3 mL EtOH, 10 equiv
diethyl phosphite, irradiation with 11 W fluorescent lamp from 3 cm dis-
tance for 40 h, yields after chromatographic purification.
The composition of heterogeneous catalysts is of impor-
tance and often structural changes occur during the reac-
tions. In order to obtain information about the catalyst
structure we examined samples of both catalysts, before and
after use in the photocatalytic reactions, by means of high
resolution transmission electron microscopy (HR-TEM) and
annular dark field (ADF) scanning electron microscopy.
From these measurements no significant changes in the
shape and composition of the catalysts were apparent
(Figure 1).[11] Additionally, energy dispersive X-ray spectros-
copy revealed the chemical composition of the metal oxide
catalysts with lateral resolution on the nanometer scale.
Again, no changes of the metal oxide either before or after
use were observed, which underlines the robustness of these
catalysts in cross dehydrogenative coupling reactions. Fur-
thermore, these measurements demonstrated that there are
no mixed metal oxides present.[11]
Acknowledgement
We gratefully acknowledge financial support by the ERC for a starting
grant and C. Herwartz and F. Dorn for performing the TEM measure-
ments.
À
Keywords: C C coupling
·
heterogeneous catalysis
·
photocatalysis · redox reaction
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Chem. Eur. J. 2012, 18, 3478 – 3481

Heterogeneous Cross Dehydrogenative Coupling Reactions
COMMUNICATION
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Received: October 13, 2011
Published online: February 7, 2012
Chem. Eur. J. 2012, 18, 3478 – 3481
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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