Continuous flow organocatalytic C-H functionalization and cross-dehydrogenative coupling reactions: Visible light organophotocatalysis for multicomponent reactions and C-C, C-P bond formations

Article abstract of DOI:10.1021/cs400350j

A continuous flow procedure for the efficient metal-free, visible light photoredox-catalyzed α-functionalization of tertiary amines has been developed. Rose Bengal has been identified as an effective organic photocatalyst for continuous flow C-C and C-P b

Full text of DOI:10.1021/cs400350j

Research Article
pubs.acs.org/acscatalysis
Continuous Flow Organocatalytic C−H Functionalization and Cross-
Dehydrogenative Coupling Reactions: Visible Light
Organophotocatalysis for Multicomponent Reactions and C−C, C−P
Bond Formations
Magnus Rueping,* Carlos Vila, and Teerawut Bootwicha
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A continuous flow procedure for the efficient metal-free, visible light photoredox-catalyzed α-functionalization of
tertiary amines has been developed. Rose Bengal has been identified as an effective organic photocatalyst for continuous flow C−
C and C−P bond formations as well as multicomponent reactions.
KEYWORDS: Photocatalysis, Sustainable Catalysis, Organocatalysis, Photoreactor, Rose Bengal
organocatalytic photoredox-catalyzed multicomponent reaction
n the past few years, visible light photoredox catalysis has
Iattracted considerable attention in synthetic organic using continuous flow technology.
Continuous flow methodologies have attracted considerable
chemistry because visible light is a safe, abundant, inexpensive,
renewable, and eco-friendly energy scource.1−8 In this context,
ruthenium and iridium complexes have been used as photo-
redox catalysts in several chemical transformations.9−47 These
inorganic complexes are readily available, and their reactivity
can be easily tuned by varying the ligands. In addition, organic
dyes, which are inexpensive and easy to modify and handle,
have been successfully applied in several photoredox
reactions.48−59 However, only a few C−C bond-forming
reactions have been reported. Therefore, we decided to
investigate a new oxidative organophotoredox-catalyzed multi-
component reaction of amines, isocyanides, and water to obtain
valuable amino acid amides (Scheme 1).
interest60 because they can have advantages over the traditional
batch reactions. These include facile automation, energy
efficiency, reproducibility, precise control of reaction parame-
ters, and predictable reaction scale-up. In the case of
photoredox catalysis, the productivity in batch reactors may
be impeded by limited light penetration through the reaction
media. Thus, continuous flow processes in microreactors
present an alternative to batch conditions because the small
reaction channels and the larger surface-to-volume ratio allow
efficient, uniform, and homogeneous irradiation of the reaction
mixture.61−64 These advantages result in shorter reaction times
and may, as such, prevent undesired side reactions. Very
recently, initial reports of visible light photoredox catalysis in
continuous flow have been reported.65−69
Unfortunately, most of the organic dyes did not result in the
desired product or provided satisfactory yields only after long
reaction times. Therefore, we decided to examine this new
We here report the use of an organophotocatalyst in various
continuous flow C−C and C−P bond-forming reactions,
including unprecedented visible light organophotoredox
catalyzed multicomponent reactions.
To implement a successful continuous flow procedure, we
designed our photoreactor using commercially available
Scheme 1. First Organocatalytic Photoredox
Multicomponent Reaction
Received: May 13, 2013
© XXXX American Chemical Society
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fluorinated ethylene polymer (FEP) tubes with an internal
diameter of 0.8 mm. FEP tubes are chemical-resistant,
mechanically flexible, easy to handle, and optically transparent
in the visible region of the light spectrum (Figure 1).
Bengal was used, and the corresponding product was isolated in
92% yield (entry 8).
With the optimal conditions in hand, we explored the
substrate scope of the oxidative coupling reaction of N-aryl
tetrahydroisoquinolines with nitroalkanes (Table 2, entries 1−
Table 2. Substrate Scope for the Flow Photoredox Reaction
Catalyzed by Rose Bengal
Figure 1. Schematic diagram of the organocatalytic photoredox
continuous flow reactor.
a
entry
1
R1
Ar
Nu
product
yield %
b
1
1a
1a
1a
1b
1c
1d
1a
1b
1c
1d
1e
1a
1a
1b
1c
1e
1a
1b
1c
1d
1e
H
Ph
Ph
Ph
2a
2b
2c
2a
2a
2a
4
3a
3b
3c
3d
3e
3f
92
76
78
85
86
91
87
77
64
67
75
71
73
53
51
55
59
56
60
49
56
The tube (4.6 m, corresponding to a 9.3 mL reactor volume)
was wrapped around a glass tube. Inside the glass tube, we
placed the strip of green LEDs, and the flow rate was controlled
by a HPLC pump. To maintain the temperature, air was
allowed to pass between the glass tube and the green LEDs.
We began our studies on the continuous flow α-
functionalization of tertiary amines through the cross-
dehydrogenative coupling reaction (CDC),70 with the exami-
nation of Rose Bengal as the organophotocatalyst. We started
with the organophotoredox-catalyzed reaction of N-phenyl
tetrahydroisoquinoline with nitromethane32,36,71 to compare
the flow procedure with the reported batch procedure.50
Applying the same reaction conditions as reported by Tan,50 we
performed the reaction with a 4 mL reaction coil at a flow rate
of 0.1 mL min−1. Unfortunately, only 43% conversion was
observed (Table 1, entry 1). Improved conversion was obtained
b
2
H
b
3
H
b
4
H
pTol
b
5
H
pMeO-Ph
Ph
b
6
MeO
H
c
7
Ph
7a
7b
7c
7d
7e
8a
8b
8c
8d
8e
9a
9b
9c
9d
9e
c
8
H
pTol
4
c
9
H
pMeO-Ph
Ph
4
c
10
MeO
H
4
c
11
pBr-Ph
Ph
4
d
12
H
5a
5b
5a
5a
5a
6
d
13
H
Ph
d
14
H
pTol
d
15
H
pMeO-Ph
pBr-Ph
Ph
d
16
H
e
17
H
e
18
H
pTol
6
a
Table 1. Optimization of Reaction Conditions
e
19
H
pMeO-Ph
Ph
6
e
20
MeO
H
6
e
21
pBr-Ph
6
a
b
Yields after column chromatography. Reactions performed using
0.12 mmol of 1 (0.075 M) in a mixture CH3CN/nitroalkane 2/H2O
(1:0.8:0.2 ratio), 5 h. Reactions performed using 5 equiv of 4, 0.15
c
b
entry
flow rate (mL min−1
)
catalyst
t (h)
conv (%)
mmol of 1 (0.075 M) in a CH3CN/H2O mixture (1.7:0.2 ratio), 5 h.
c
1
0.1
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Eosin Y
0.75
2
43
72
46
65
47
22
d
Reactions performed using 0.15 mmol of 1 (0.075 M) in a CH3CN/
c
2
0.05
0.05
0.1
e
malonate 5/H2O mixture (1:0.8:0.2 ratio), 5 h. Reactions performed
c,d
3
4
5
6
7
8
2
using 5 equiv of 6, 0.15 mmol of 1 (0.075 M) in a CH3CN/H2O
e
e
e
e
e
mixture (1.7:0.2 ratio) at 0.05 mL min−1, 3 h.
1.5
1.5
1.5
3
0.1
0.1
Rhodamine B
Rose Bengal
Rose Bengal
f
6). In general, the reactions proceeded smoothly to provide the
corresponding products 3a−f in good to excellent yields (76−
92%). It is important to note that the reaction proceeded faster
under flow conditions than in the batch conditions reported
previously.
Next, we focused our attention on the reaction between N-
aryl tetrahydroisoquinolines (1) and cyanotrimethylsilane (4)
to obtain α-amino nitriles, which are synthetically useful
intermediates in organic synthesis.72,73 Their functionalization
offers access to various important building blocks, such as α-
amino acids, diamines, α-amino aldehydes, and α-amino
ketones as well as α-amino alcohols. This versatility makes
metal-free synthesis in continuous flow very attractive.
Therefore, the standard conditions were directly applied to
the cyanation of N-aryl tetrahydroisoquinolines, and the results
0.05
0.03
82 (73)
f
5
95 (92)
a
Reactions performed using 0.15 mmol of 1a (0.075 M) in a CH3CN/
CH3NO2/H2O mixture (1:0.8:0.2 ratio). Conversion was determined
by H NMR. Using 4 mL reaction coil. Flow reactor was cooled by
water. Using 9 mL reaction coil. Yield after column chromatography.
b
c
d
1
e
f
by decreasing the flow rate to 0.05 mL min−1 (entry 2). When
the FEP tube was wrapped around a cooling condenser, a drop
in the conversion due to lower irradiation was observed. To
improve the conversion, we decided to increase the volume of
the flow reactor to 9.3 mL and studied the aza-Henry reaction
with different organic dyes employing a 0.1 mL min−1 flow rate
(entries 4−6). The best conversion was obtained when Rose
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are summarized in Table 2 (entries 7−11). The reaction times
were much shorter compared with the batch conditions,51 and
the products 7a−e were obtained in good yields. Next, we
turned our attention to the continuous flow Mannich reaction
with dialkylmalonates (Table 2, entries 12−16).74 The
corresponding β-amino diesters were obtained in moderate to
good yields under the optimized conditions. Finally, the visible
light organocatalytic phosphonylation of tertiary amines 1 was
studied in continuous flow manner. α-Amino phosphonates are
a very interesting structural motif in medicinal and organic
chemistry being used as α-amino acid analogues.75−78 Hence,
their synthesis in a metal-free procedure is highly desirable for
their application in medicinal chemistry. As shown in Table 2
(entries 17−21), this methodology can also be applied to C−P
bond formation to give the corresponding α-amino phospho-
nates 9 in moderate yields.
Scheme 2. Substrate Scope for the Photoredox
Multicomponent Reaction in Flow with Rose Bengal
On the basis of this success, the oxidative Ugi multi-
component reaction79−83 using N,N-dimethylaniline (10a), p-
toluenesulfonyl methyl isocyanide (11a), and H2O was studied;
the optimization is shown in Table 3. We started the
Table 3. Flow Photoredox Multicomponent Reaction with
a
Rose Bengal
b
flow rate
catalyst (5
mol %)
conv %
c
entry
(mL min−1
)
t (h)
(yield %)
1
2
3
4
5
0.5
0.5
1
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Rose Bengal
Eosin Y
12
18
18
18
20
18
20
20
22
42
59
2
77
3
81 (79)
17
d
6
1
7
8
3
54
3
Rhodamine B
33
a
Reactions performed using 0.8 mmol of 10a, 0.4 mmol of 11a (0.05
b
M) in a CH3CN/H2O mixture (7.4:0.6 mL). Conversions were
determined by H NMR. Yields after column chromatography. 0.1
c
d
1
M solution of 11a was used.
different isocyanides under the optimized conditions, which
resulted in the desired products 12h−l in good yields. In
addition, for selected examples, we performed the oxidative Ugi
multicomponent reaction in batch conditions,84,85 confirming
the potential of the continuous flow methodology.
optimization by varying the flow rate, catalyst, and concen-
tration (Table 3). To obtain the best results, a recycling process
was run at a flow rate of 3 mL min−1. After 20 h, the
corresponding α-amino amide 12a was isolated in 79% yield
(entry 5). The concentration of the solution was crucial for
good conversion. When a 0.1 M solution was used instead of
0.05 M, a decrease in the conversion was observed (entry 6).
Different organic dyes, such as Eosin Y and Rhodamine B, were
tested in the multicomponent reaction in flow, but lower
conversions were observed (entries 7 and 8). Under the
optimal conditions, the substrate scope of the continuous flow
photoredox oxidative Ugi multicomponent type reaction
catalyzed by Rose Bengal was investigated. In general, different
amines 10 and different isocyanides 11 could be successfully
applied, providing the desired α-amino amides 12 in moderate
to good yields (Scheme 2). For instance, (E)-4-(4-
(dimethylamino)phenyl)but-3-en-2-one was subjected to the
multicomponent reaction obtaining exclusively the desired α-
amino amide 12g in 78% yield. Furthermore, we were
interested in the substrate scope with different isocyanides
11. Therefore, N,N-dimethylaniline 10a was reacted with
In summary, we have developed an environmentally
acceptable, metal-free, photo-organocatalytic, continuous flow
methodology that has been successfully applied in the α-
functionalization of tertiary amines. Nitroalkanes, TMSCN,
dialkyl malonates, and dialkyl phosphites were reacted with
various N-aryl tetrahydroisoquinolines to provide the corre-
sponding products in moderate to excellent yields. Further-
more, N,N-dimethylanilines were successfully reacted with
different isocyanides in the Ugi-multicomponent reaction in
flow, resulting in highly valuable α-amino amides in good
yields. However, most importantly, considerably shorter
reaction times are necessary if compared with the batch
conditions. This is important for further reaction design. In
addition, Rose Bengal is an inexpensive, readily available,
environmentally benign organic dye that can be used as an
efficient visible light photoredox catalyst in continuous flow
fashion.
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(32) Condie, A. G.; Gonzal
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ASSOCIATED CONTENT
* Supporting Information
General procedures, schematic diagram of the flow reactors
(Figure S1), and full characterization of the products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
Chem. Commun. 2011, 47, 8337.
(35) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.;
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C. Chem. Commun. 2011, 47, 2360.
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AUTHOR INFORMATION
Corresponding Author
*Fax: +49 241 8092665. E-mail: magnus.rueping@rwth-aachen.
■
de.
(38) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47,
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Notes
(39) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47,
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The authors declare no competing financial interest.
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