Visible-light mediated heterogeneous C-H functionalization: Oxidative multi-component reactions using a recyclable titanium dioxide (TiO2) catalyst

Article abstract of DOI:10.1039/c3gc40587g

Visible-light mediated heterogeneous C-H functionalization of tertiary amines provides access to a variety of α-amino amides. An oxidative, titanium dioxide catalyzed, Ugi-type, three-component reaction has been developed in which the catalyst can be recy

Full text of DOI:10.1039/c3gc40587g

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Visible-light mediated heterogeneous C–H
functionalization: oxidative multi-component reactions
Cite this: DOI: 10.1039/c3gc40587g
Received 27th March 2013,
Accepted 29th May 2013
using a recyclable titanium dioxide (TiO2) catalyst†
DOI: 10.1039/c3gc40587g
Carlos Vila and Magnus Rueping*
www.rsc.org/greenchem
Visible-light mediated heterogeneous C–H functionalization of
tertiary amines provides access to a variety of α-amino amides. An
oxidative, titanium dioxide catalyzed, Ugi-type, three-component
reaction has been developed in which the catalyst can be recycled
without loss of activity.
Scheme 1 Photoredox multi-component reaction catalyzed by metal oxides.
Table 1 Optimization of reaction conditionsa
Over the last few years titanium dioxide has been used as a
viable photocatalyst and is attracting enormous interest due to
its excellent chemical and photochemical stability, high avail-
ability, low cost and non-toxicity.1 The application of TiO2 in
photocatalytic transformations is highly desirable for the
development of environmentally acceptable processes. More-
over, the use of visible light to drive organic transformations
provides a sustainable pathway for green synthesis and has
received considerable interest in recent years.2 Although TiO2
has been widely used for the catalytic degradation of organic
pollutants3 and its application for the photocatalytic oxidation
of alcohols to carbonyl compounds4 and amines to imines5 is
well known, the number of examples of photocatalyzed C–C
and C–heteroatom bond formations in organic synthesis is
still limited.6 Despite the significant advantages of hetero-
geneous inorganic photocatalysts over homogeneous catalysts,
their use in the α-functionalization of tertiary amines remains
less explored.
Therefore, we decided to investigate the α-functionalization
of N,N-dimethylaniline and its derivatives using simple and
inexpensive TiO2 and visible light in the oxidative Ugi-type
reaction (Scheme 1). The Ugi multi-component reaction7 is a
key reaction and has been intensively studied over the past few
decades due to its efficacy in the synthesis of α-amino amides8
which are highly important building blocks in organic syn-
thesis. However, the application of heterogeneous photocata-
lysis in Ugi multi-component reactions is still unexplored,
despite the inherent advantages of these reactions.9–11
Entry
Cat MxOy (x equiv.)
Solvent
Light source
Yieldb (%)
1
2
3
4
5
6
7
8
TiO2 (1)
TiO2 (1)
TiO2 (1)
TiO2 (1)
TiO2 (1)
TiO2 (1)
TiO2 (1)
TiO2 (1)
ZnO (1)
TiO2 (1)
TiO2 (0.5)
TiO2 (0.25)
TiO2 (1)
TiO2 (1)
TiO2 (1)
—
CH3CN
Toluene
CH2Cl2
MeOH
DMF
Ether
EtOAc
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
11 W lamp
Blue LEDs
Green LEDs
In the dark
11 W lamp
33
15
31
21
34
21
47
57
27
80
71
53
51
47
—
—
THF
THF
9
10
11
12
13
14
15
16
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
a Reaction conditions: N,N-dimethylaniline 1a (0.3 mmol), isocyanide
2a (0.15 mmol), H2O (10 equiv.), metal oxide MxOy, 1 mL solvent, 48 h,
30 °C. b Yield after chromatographic purification.
In order to develop a heterogeneous light mediated multi-
component reaction, we began our investigations with the
reaction of N,N-dimethylaniline (1a), p-toluenesulfonylmethyl
isocyanide (2a) and H2O in the presence of TiO2 (Sigma-
Aldrich P25). To our delight, we obtained the corresponding
α-amino amide 3a in 33% yield (Table 1, entry 1) when the
reaction was carried out in acetonitrile. Although the yield of
product 3a was low, this result encouraged us to optimize the
reaction conditions. Next, we studied the effect of solvent in
this multi-component reaction. Interestingly, the best results
were obtained when THF or dioxane was used as a solvent
(Table 1, entries 8 and 10 respectively). Moreover, we examined
RWTH Aachen University, Institute of Organic Chemistry, Landoltweg 1, D-52074
Aachen, Germany. E-mail: magnus.rueping@rwth-aachen.de; Fax: +49 241 8092665
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3gc40587g
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ZnO as a photocatalyst. However, a significant decrease in the
yield of the product 3a was observed (Table 1, entry 9). We also
examined the use of titanium dioxide in catalytic amounts
(Table 1, entries 11 and 12) but we observed lower reactivity,
indicating that the reaction is more efficient if one equivalent
of metal oxide (amine–isocyanide–TiO2 in a 2 : 1 : 1 ratio) is
applied (Table 1, entry 10). Different light sources were
assessed without any improvement on the yield of the α-amino
amide (Table 1, entries 13 and 14). Furthermore, no product
was observed when the reaction was performed without light
or in the absence of a catalyst (Table 1, entries 15 and 16).
After the reaction conditions were optimized, we decided to
study the substrate scope of the light-mediated, titanium
dioxide catalyzed, multi-component reaction. In general,
different amines 1 and different isocyanides 2 could be suc-
cessfully applied providing the desired α-amino amides 3 in
moderate to good yields (Table 2).
Table 2 Substrate scope of the visible light mediated multi-component
a
reaction catalyzed by TiO2
A variety of N,N-dimethylanilines, which contained a range
of functionalities, were tested. Many valuable functional
groups such as methyl, chloro, bromo, ketone and unsaturated
aldehyde were tolerated under the reaction conditions, provid-
ing ample opportunity for further derivatization of the
products. In addition to the dimethyl amines, N-ethyl-N-
methylaniline was tested under optimized conditions, the
corresponding α-amino amide 3l being obtained with 47%
yield. Moreover, different isocyanides reacted smoothly with N,
N-dimethylaniline 1a providing the corresponding products
with moderate to good yields. The reaction is compatible with
different isocyanides bearing functional groups such as esters
or phosphonates. To summarize, this new protocol allows the
convenient, technically easy and inexpensive synthesis of
α-amino amides and circumvents the need for an expensive
catalyst.
After studying the scope of the reaction, we decided to
probe the recycling of the TiO2 photocatalyst in order to
demonstrate the advantage of having a cheap, readily available,
heterogeneous and robust photocatalyst. Experimentally we
only needed a simple centrifugal separation and the catalyst
was reused without further treatment (Table 3). Gratifyingly,
the TiO2 photocatalyst could be efficiently recycled in 5 con-
secutive catalytic cycles without loss of selectivity and reactiv-
ity, underlining the efficiency of titanium dioxide as a
photocatalyst for the Ugi multi-component type reaction.
The composition of a heterogeneous catalyst is quite impor-
tant for its catalytic activity and often structural changes occur
during the reactions. In order to obtain information about the
catalyst structure, we examined samples of the TiO2 before and
after use in the photoredox Ugi multi-component reaction by
means of high resolution transmission electron microscopy
(HR-TEM). From these measurements no significant changes
in the structure and shape of the catalyst were apparent
(Fig. 1).12 These measurements underline the robustness of
the catalyst for the photocatalytic oxidative Ugi multi-com-
ponent reaction.
a Reactions were performed with amine 1 (0.3 mmol), isocyanide 2
(0.15 mmol), H2O (10 equiv.) and TiO2 (1 equiv.) in 1 mL of dioxane
for 24–96 h at 30 °C. Yield of isolated products after column
chromatography.
Scheme 2 and considers the amine–surface interaction which
is believed to be responsible for the red shift in the absorp-
tion.5 The first step of the cascade reaction is the light-induced
oxidation of tertiary amine 1 into iminium ion (A) in the pres-
ence of a titanium dioxide catalyst. This is the key step of the
reaction. Then, the nucleophilic attack of isocyanide 2 gener-
ates the nitrilium ion B. This nitrilium ion is trapped by water,
A reaction pathway for this oxidative multi-component reac-
tion, catalyzed by TiO2 under visible light, is proposed in
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for other multi-component reactions is currently ongoing and
will be disclosed in due course.
Table 3 Catalyst recycling in the visible-light mediated multi-component
reactiona
Cycle
1
2
3
4
5
Yield of 3a (%)
74
79
72
83
78
Experimental
General procedure for the heterogeneous photocatalyzed Ugi
type multi-component reaction
a Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), H2O (10 equiv.),
P25 TiO2 (1. equiv.), 3 mL of dioxane, irradiation with a 11 W
fluorescent lamp from 3 cm distance for 4 days, yields after column
chromatography.
In a vial TiO2 (P25) (12 mg, 0.15 mmol), amine 1 (0.3 mmol),
isocyanide 2 (0.15 mmol) and H2O (27 μL, 1.5 mmol) were dis-
solved in 1 mL of dioxane. The reaction mixture was stirred
under irradiation with an 11 W fluorescent lamp (distance
approx. 3 cm). After the reaction was complete the solvent was
removed under reduced pressure and the crude mixture was
directly charged on silica gel and purified by column chromato-
graphy (cyclohexane–EtOAc 8 : 2 to 6 : 4) to afford the corres-
ponding α-amino amide 3.
Notes and references
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Scheme 2 Proposed reaction mechanism for the photoredox multi-com-
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thesis of α-amino amides driven by visible-light catalysis and
using cheap, robust, readily available and recyclable titanium
dioxide. The advantage of using such a heterogeneous catalyst
is the simplicity of its recycling and reuse. Thus, the protocol
presented is both environmentally acceptable and economical.
Further investigation into the applicability of this methodology
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