Continuous-flow catalytic asymmetric hydrogenations: Reaction optimization using FTIR inline analysis

Article abstract of DOI:10.3762/bjoc.8.32

The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow microreactors has been developed. Reaction monitoring was achieved by using an inline ReactIR flow cell, which allows fast and conveni

Full text of DOI:10.3762/bjoc.8.32

Continuous-flow catalytic asymmetric
hydrogenations: Reaction optimization
using FTIR inline analysis
Magnus Rueping*, Teerawut Bootwicha and Erli Sugiono
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 300–307.
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg
1, D-52074 Aachen, Germany
doi:10.3762/bjoc.8.32
Received: 03 January 2012
Accepted: 13 February 2012
Published: 23 February 2012
Email:
Magnus Rueping* - magnus.rueping@rwth-aachen.de
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
Keywords:
asymmetric reduction; binolphosphoric acid; Brønsted acid; Hantzsch
dihydropyridine; IR spectroscopy; real-time analysis
© 2012 Rueping et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The asymmetric organocatalytic hydrogenation of benzoxazines, quinolines, quinoxalines and 3H-indoles in continuous-flow
microreactors has been developed. Reaction monitoring was achieved by using an inline ReactIR flow cell, which allows fast and
convenient optimization of reaction parameters. The reductions proceeded well, and the desired products were isolated in high
yields and with excellent enantioselectivities.
Introduction
In recent years, a growing interest in microreactor technology Continuous flow microreactors have been applied to a number
has been seen in the scientific community and the development of standard transformations in organic synthesis [56-80];
of microfabricated reaction systems is actively pursued. Micro- however, examples regarding asymmetric reactions as well as
reactor technology offers numerous advantages, including organocatalytic reactions are scarce [81-96]. Herein, we present
precise control of reaction variables, enhanced mixing quality, the first example of a continuous-flow organocatalytic asym-
improved operational safety, reduced reagent consumption and metric transfer hydrogenation performed in a microreactor. In
ready scale-up of chemical processes. Due to the high surface- this work a ReactIR flow cell was coupled with the micro-
area-to-volume ratios of microstructured reactors, a high reactor and applied as an inline monitoring device for opti-
thermal rate and high portability of substrates can be achieved, mizing the reactions.
which leads to improved product formation [1-42]. Further-
more, by incorporating inline analytical devices the progress of Results and Discussion
reactions can be monitored and analyzed in real time, allowing The continuous-flow microreactor system for the experiment
fast reaction screening and optimization [43-55].
was set up according to Scheme 1. The flow device was set up
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Beilstein J. Org. Chem. 2012, 8, 300–307.
either with a single reactor, or with multiple reactors when a
prolonged residence time was needed. The reagents were intro-
duced separately, by using a syringe pump, through two inlets
connected to Y-shaped connectors. The internal reaction
temperature was monitored with an internal thermal sensor. The
ReactIR 45m microflow cell equipped with a DiComp ATR
(diamond-composite attenuated total reflection) probe was at-
tached to the microreactor at the end of the reaction stream and
was used as an inline analytical tool to determine the optimum
reaction conditions. The IR spectra were recorded at predefined
intervals and the raw data were analysed with iC-IR analysis
software.
Scheme 2: Asymmetric hydrogenation of benzoxazines.
control the reaction and to determine the use of educts and for-
mation of product, reference spectra of the starting materials,
The first reaction examined the asymmetric organocatalytic solvents and reagents were recorded. Figure 1b and Figure 1c
transfer hydrogenation [97-101] of benzoxazine 3a in the pres- show real time IR spectra of the reaction mixtures after the
ence of Hantzsch dihydropyridine 2a as hydrogen source and a subtraction of solvent in the spectral region of 1440 and
catalytic amount of chiral Brønsted acid 1a (Scheme 2) [102].
1530 cm−1. For direct inline analysis the signals at
=
1479 cm−1 and = 1495 cm−1 were ideal as they could easily
Initial experiments were carried out at 0.1 mL min−1 flow rate be assigned to benzoxazine 3a and dihydrobenzoxazine 4a.
in a commercial glass microreactor, which was attached to the Thus, in continuous flow the substrate consumption and product
ReactIR flow cell for in situ reaction monitoring. In order to formation could readily be determined.
Scheme 1: Experimental setup for the asymmetric transfer hydrogenation.
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Beilstein J. Org. Chem. 2012, 8, 300–307.
Figure 1: In situ ReactIR monitoring: (a) Trend curve of product formation at different temperatures. (b) Reaction spectra showing the consumption of
the substrate and the formation of product at different temperatures. (c) Three-dimensional time-resolved spectral data.
In order to find the optimal temperature for the asymmetric By performing the reaction with a residence time of 20 min, the
continuous-flow reduction, a temperature profile was recorded. product was isolated in 50% yield. With residence times of
The reaction temperature was initially 5 °C and was increased 40 min and 60 min, the product was isolated in 87% and 98%
to 60 °C over a period of 8 h, while the conversion was moni- yields, respectively (Table 1).
tored by inline IR-spectroscopy. Figure 1a shows the real-time
plot of the peak intensity versus reaction time for the 1495 cm−1
Table 1: Optimization of the Brønsted acid catalyzed reduction of
absorption band at different temperatures. The trend-curve
analysis by peak-height integration of this absorption band
shows increased product formation with increasing temperature.
By monitoring the signal change in this spectral region over the
time of the reaction, the product formation ( = 1495 cm−1) and
substrate consumption ( = 1479 cm−1) can be determined in
real time. Analysis of the spectra provided us with an optimal
temperature of 60 °C for this reaction. In general the IR-flow-
cell technology is a good tool for in situ monitoring and
provides a fast read out of reaction progress as the intensity of
substrate and product peaks can be directly related to the
conversion. Thus, as exemplified above, applying the inline
analysis to different reaction parameters provides a fast and
convenient method for reaction optimization.
benzoxazines.a
Entry
1a
Residence time
[min]
Flow rate
[mL min−1]
Yield
[%]b
[mol %]
1
2
3
2
2
2
20
40
60
0.1
0.1
0.1
50%
87%
98%
aReaction conditions: 3a, 2a (1.2 equiv), 1a in CHCl3 (0.05 M) at
60 °C. bIsolated yields after column chromatography.
By using the optimized reaction temperature and flow rate of
0.1 mL min−1, further experiments were conducted to examine
the influence of the residence time on the conversion (Table 1).
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Beilstein J. Org. Chem. 2012, 8, 300–307.
Having found the optimum reaction conditions, we next investi- described above. The effects of catalyst loading and residence
gated the scope of the Brønsted acid catalyzed reduction of time on the conversion and the enantioselectivity are summa-
3-aryl-substituted benzoxazines 3 (Table 2). In general, 3-aryl rized in Table 3. Performing the reaction at 60 °C with 5 mol %
benzoxazines 3 bearing either electron-withdrawing or electron- of Brønsted acid 1a and residence time of 20 min afforded the
donating groups can be reduced in a continuous fashion and the desired product in 88% yield and 94% enantioselectivity
products 4 were isolated in good yields and with excellent (Table 3, entry 1). When the catalyst loading was reduced from
enantioselectivities.
5 mol % to 2 mol %, a residence time of 40 min was found to
be optimal to achieve comparable results (Table 3, entry 1
Encouraged by the results, we next studied the transfer hydro- versus entry 2). A slight improvement of the conversion was
genation of quinolines 5 [103-106]. The optimum reaction observed by increasing the residence time to 60 min (Table 3,
temperature was determined according to the experiment entry 3 versus entry 2). The catalyst loading can be decreased to
0.5 mol % without loss of reactivity and selectivity; the desired
tetrahydroquinoline was isolated in 96% yield with 94% enan-
Table 2: Scope of the Brønsted acid catalyzed reduction of benzox-
tiomeric excess (Table 3, entry 5). A further decrease of cata-
lyst loading to 0.1 mol % resulted in a significant drop in chem-
ical yield, affording the product in lower yield while enantio-
selectivity was maintained (Table 3, entry 6).
azines.a
Although continuous-flow reactions provide many advantages,
in certain cases it can be beneficial to conduct reactions under
classical batch conditions. Therefore, we decided to carry out a
direct comparison. Transferring the reaction conditions from
continuous-flow to the batch showed a noticeable drop in
conversion and the product was isolated only in 67% yield
(Table 3, entry 5 vs entry 7). This observation is general, and
typically lower reactivities were obtained. This can be explained
by the better heat transfer in the microreactors as compared to
the glass flask typically used in our batch reactions.
Entry
1
Product 4
Yield [%]b ee [%]c
98
96
98
97
4a
4b
Table 3: Optimization of the Brønsted acid catalyzed transfer hydro-
genation of quinolines.a
2
3
98
98
4c
4d
4e
Entry
1a
[mol %]
t
Flow rate
[mL min−1]
Yield
[%]b
ee
[%]c
[min]
4
5
81
85
97
99
1
2
5
2
20
40
60
60
60
60
60
0.1
0.1
88
91
97
97
96
72
67
94
92
92
92
94
94
94
3
2
0.1
4
1
0.1
5
0.5
0.1
0.5
0.1
6
0.1
7d
batch
aReaction conditions: 5a, 2a (2.4 equiv), 1a in CHCl3 (0,1 M) at 60 °C,
flow rate 0.1 mL min−1. bIsolated yields after column chromatography.
cDetermined by chiral HPLC analysis. dPerformed under batch condi-
tions.
aReaction conditions: 3, 2a (1.2 equiv), 2 mol % 1a in CHCl3 (0.05 M)
at 60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated
yields after column chromatography. cDetermined by chiral HPLC
analysis.
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Beilstein J. Org. Chem. 2012, 8, 300–307.
The scope and applicability of the method was then tested on more difficult to achieve. Using the optimized conditions for the
various 2-substituted quinolines (Table 4). In general the asym- fast inline reaction, we found that the continuous-flow reduc-
metric continuous-flow transfer hydrogenation of 2-substituted tion could be performed using 10 mol % Brønsted acid 1b, a
quinolines 5 proceeded well and afforded tetrahydroquinolines flow rate of 0.1 mL min−1 and 60 min residence time (Table 5).
6a–e with excellent yields and enantioselectivities (Table 4).
To broaden the scope of the asymmetric hydrogenations in
Having established a protocol for a general and highly enantio- continuous flow further, the reduction of 3H-indoles 9 was
selective transfer hydrogenation of quinolines, we decided to
extend its scope to the reduction of quinoxalines 7 (Table 5)
Table 5: Scope of the Brønsted acid catalyzed transfer hydrogenation
[107]. The asymmetric reduction of quinoxalines is typically
of quinoxalines.a
Table 4: Scope of the Brønsted acid catalyzed transfer hydrogenation
of quinolines.a
Entry
Product 8
Yield
[%]b
ee
[%]c
Entry
Product 6
Yield
[%]b
ee
[%]c
1
77
68
90
84
8a
8b
8c
1
96
91
94
96
2
3
6a
6b
6c
2
3
53
86
94
99
4
5
86
41
94
76
4
5
91
97
99
96
8d
8e
6d
6e
aReaction conditions: 5, 2a (2.4 equiv), 5 mol % 1a in CHCl3 (0.1 M) at
60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated
yields after column chromatography. cDetermined by chiral HPLC
analysis.
aReaction conditions: 7, 2a (2.4 equiv), 10 mol % 1b in CHCl3 (0.1 M)
at 60 °C, flow rate 0.1 mL min−1, residence time = 60 min. bIsolated
yields after column chromatography. cDetermined by chiral HPLC
analysis.
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Beilstein J. Org. Chem. 2012, 8, 300–307.
asymmetric continuous-flow hydrogenations of benzoxazines,
quinolines, quinoxalines and 3H-indoles. Following a real-time
continuous-flow optimization, the corresponding products were
obtained in good yields and with excellent enantioselectivities.
By applying the FTIR inline monitoring, reaction parameters
can be screened rapidly in a single reaction setup, and the
optimal reaction conditions can be obtained much faster as
compared to the classical sequence of conducting the reaction
followed by analysis. Further work will include automated inte-
gration and feedback optimization of reaction parameters.
Table 6: Scope of the Brønsted acid catalyzed transfer hydrogenation
of 3H-indoles.a
Entry
Product 10
Yield
[%]b
ee
[%]c
Acknowledgements
The authors acknowledge the funding by the Excellence Initia-
tive of the German federal and state governments and the Euro-
pean Research Council for a starting grant.
1
95d
90
10a
10b
10c
10d
10e
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