A combined continuous microflow photochemistry and asymmetric organocatalysis approach for the enantioselective synthesis of tetrahydroquinolines

Article abstract of DOI:10.3762/bjoc.9.284

A continuous-flow asymmetric organocatalytic photocyclization-transfer hydrogenation cascade reaction has been developed. The new protocol allows the synthesis of tetrahydroquinolines from readily available 2-aminochalcones using a combination of photochemistry and asymmetric Bronsted acid catalysis. The photocylization and subsequent reduction was performed with catalytic amount of chiral BINOL derived phosphoric acid diester and Hantzsch dihydropyridine as hydrogen source providing the desired products in good yields and with excellent enantioselectivities.

Full text of DOI:10.3762/bjoc.9.284

A combined continuous microflow photochemistry
and asymmetric organocatalysis approach
for the enantioselective synthesis of
tetrahydroquinolines
Erli Sugiono* and Magnus Rueping*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2457–2462.
Institute of Organic Chemistry, RWTH Aachen University,
Landoltweg 1, D-52074 Aachen, Germany
doi:10.3762/bjoc.9.284
Received: 25 July 2013
Email:
Accepted: 18 October 2013
Published: 13 November 2013
Erli Sugiono* - erli.sugiono@rwth-aachen.de; Magnus Rueping* -
magnus.rueping@rwth-aachen.de
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
* Corresponding author
Keywords:
asymmetric transfer hydrogenation; binolphosphate; continuous-flow
reactors; flow chemistry; microreactors; organocatalysis;
photochemistry
© 2013 Sugiono and Rueping; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A continuous-flow asymmetric organocatalytic photocyclization–transfer hydrogenation cascade reaction has been developed. The
new protocol allows the synthesis of tetrahydroquinolines from readily available 2-aminochalcones using a combination of photo-
chemistry and asymmetric Brønsted acid catalysis. The photocylization and subsequent reduction was performed with catalytic
amount of chiral BINOL derived phosphoric acid diester and Hantzsch dihydropyridine as hydrogen source providing the desired
products in good yields and with excellent enantioselectivities.
Introduction
Tetrahydroquinolines [1-4] represent a well-known structural tuted quinolines represents the most widely used and efficient
motif found in a large number of biologically active natural method to prepare this class of N-heterocyclic compound
products. Optically active tetrahydroquinolines are important [5-17].
building blocks for the pharmaceutical and agrochemical indus-
tries. Due to their importance, new and efficient procedures for In the past years, continuous-flow chemistry has received
their synthesis have been developed. Among the synthetic considerable attention and microstructured continuous-flow
protocols developed for the preparation of optically active devices have emerged as useful devices for different chemical
tetrahydroquinolines, the asymmetric hydrogenation of substi- reactions [18-22]. Microreactor technology offers numerous
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Beilstein J. Org. Chem. 2013, 9, 2457–2462.
practical advantages such as better reaction yield due to Here we report the development of continuous-flow photo-
enhanced mixing quality, better control of reaction variables, chemical reaction in combination with asymmetric Brønsted
reduced safety hazards, reduced reagent consumption, enhanced acid catalysis for the synthesis of optically active tetrahydro-
heat and mass transfer due to the high surface-to-volume ratio quinolines. Readily available substituted 2-aminochalcones
and rapid experimentation and optimization.
were envisioned to undergo photocyclization to the corres-
ponding quinolines which in the presence of a chiral BINOL-
Recently, microreactor devices have been adopted for photo- derived phosphoric acid diester and Hantzsch dihydropyridine
chemical applications and microflow photochemistry has as hydride donor [32-37] could provide the desired enantioen-
emerged as efficient synthesis tool [23-31]. The narrow inner riched tetrahydroquinolines (Scheme 1) [38].
dimensions of microfabricated reactors is advantageous for
photochemical synthesis since it allows better light penetration Results and Discussion
and uniform irradiation through the entire reactor and the The continuous-flow microreactor system for the experiment
complete reaction medium, in comparison with reactions was set up according to Scheme 2. The flow device was set up
performed in conventional batch systems.
with multiple commercially available glass reactors connected
Scheme 1: Photocyclization–reduction of 2-aminochalcone.
Scheme 2: Experimental setup of continuous-flow photocyclization–reduction cascade.
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Beilstein J. Org. Chem. 2013, 9, 2457–2462.
in parallel and placed in a water bath [39]. The light required to Noticeable improvement on the chemical yield was observed
perform the reaction is supplied from a high-pressure mercury when the reaction was conducted at a lower concentration
lamp located outside of the reactor. The lamp consists of a providing the product in 74% isolated yield and 94% enan-
double-jacketed water-cooled pyrex immersion well. The tiomeric excess (Table 1, entry 4 vs entry 3). Further decrease
reagents were degassed and introduced into the microreactor of the concentration to 0.03 M gave the best result affording the
using a programmable syringe pump. The product solution was product in 82% yield (Table 1, entry 6). It is worth mentioning
collected in a flask wrapped with aluminium foil to prevent that decreasing the flow rate had only a minimum effect on the
further irradiation.
yield but resulted in significant loss of enantioselectivity
(Table 1, entry 5 vs 4). This result indicates that the residence
Our initial investigation of reaction conditions involved the time plays a crucial role in this photocyclization–reduction
photocyclization–reduction cascade of 2-aminochalcone 1a in cascade. Due to prolonged irradiation of the reaction mixture,
the presence of Hantzsch dihydropyridine 4 as hydrogen source an undesired background reaction initiated by photoexcited
and catalytic amount of chiral Brønsted acid 3. The effect of dihydropyridine occurred leading to the loss of enantio-
temperature, flow rate and concentration on the reaction yield selectivity [40,41].
and enantioselectivity are summarized in Table 1. As shown in
Table 1, performing the reaction in a pyrex test tube (i.d.: With the optimized reaction conditions in hand, the substrate
12 mm; λ > 300 nm) with 1 mol % of Brønsted acid 3 at 40 °C scope of this new photocyclization–asymmetric transfer hydro-
for 60 min afforded the product in 7% isolated yield and 95% genation sequence was examined. The results are summarized
enantioselectivity (Table 1, entry 2). Conducting the reaction in Table 2. In general, different 2-aminochalcones bearing
using the same light source and under the same reaction condi- substituted aromatic residues on both ketone and enone moieties
tions in a single pass flow reaction showed a noticeable impact underwent the desired photocyclization and subsequent asym-
on the yield as the product 2a could be isolated in 59% yield metric reduction to afford the corresponding tetrahydroquino-
and 93% enantiomeric excess (Table 1, entry 1 vs entry 2). lines in good yields and high enantioselectivities.
Improvement of the reaction yield shows the superior perfor-
mance of the microflow reactor since the light penetration Conclusion
through the microchannels was significantly increased. A slight In conclusion, we have demonstrated the great potential of a
improvement of yield was achieved when the reaction was new continuous-flow microreactor system for the photocycliza-
carried out at 55 °C (Table 1, entry 3).
tion–reduction cascade of 2-aminochalcones. Under the contin-
Table 1: Optimization of the Brønsted acid catalyzed transfer hydrogenation of quinolines.a
Entry
Conc. [mol/L]
Temp. [°C]
Time [min]
Flow rate [mL min−1]
Yield [%]b
ee [%]c
1
0.1
40
40
55
55
55
55
55
55
60
0.1
59
7
93
95
96
94
88
94
96
83
2d
3
0.1
60
batch
0.1
0.1
60
64
74
79
82
29
88
4
0.05
0.05
0.03
0.03
0.03
60
0.1
5
120
60
0.05
0.1
6
7d
8
60
batch
0.05
120
aReaction conditions: 1a, 4 (2.4 equiv), 3 (1 mol %) in CHCl3, irradiation with a TQ 150 high pressure mercury lamp. bIsolated yields after column
chromatography. cDetermined by chiral HPLC analysis. dPerformed under batch condition.
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Beilstein J. Org. Chem. 2013, 9, 2457–2462.
Table 2: Scope of the continuous-flow photocyclization–asymmetric reduction domino sequence.a
Entrya
Substrate 1
Product 2
Yield [%]b ee [%]c
1
82
88
94
96
2a
2b
1a
1b
2
3
73
91
1c
2c
2d
2e
2f
4
5
6
7
71
63
73
75
91
89
90
88
1d
1e
1f
1g
2g
2h
8
64
90
1h
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Beilstein J. Org. Chem. 2013, 9, 2457–2462.
Table 2: Scope of the continuous-flow photocyclization–asymmetric reduction domino sequence.a (continued)
9
57
91
1i
2i
aReaction conditions: 1, 4 (2.4 equiv), 3 (1 mol %) in CHCl3 (0.03 M) at 55 °C, flow rate 0.1 mL/min, residence time = 60 min, irradiation with a TQ 150
high pressure mercury lamp. bIsolated yields after column chromatography. cDetermined by chiral HPLC analysis.
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Modern Chemistry; Wiley-VCH: Weinheim, Germany, 2000.
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doi:10.1002/3527601953
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an attractive alternative to the existing procedures and serves as
a basis for further exploration of this new concept.
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