Continuous flow photocyclization of stilbenes-scalable synthesis of functionalized phenanthrenes and helicenes

Article abstract of DOI:10.3762/bjoc.9.221

A continuous flow oxidative photocyclization of stilbene derivatives has been developed which allows the scalable synthesis of backbone functionalized phenanthrenes and helicenes of various sizes in good yields.

Full text of DOI:10.3762/bjoc.9.221

Continuous flow photocyclization of stilbenes –
scalable synthesis of functionalized phenanthrenes
and helicenes
Quentin Lefebvre, Marc Jentsch and Magnus Rueping*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1883–1890.
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg
1, D-52074 Aachen, Germany
doi:10.3762/bjoc.9.221
Received: 12 July 2013
Email:
Accepted: 14 August 2013
Published: 17 September 2013
Magnus Rueping* - magnus.rueping@rwth-aachen.de
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Guest Editor: A. Kirschning
Keywords:
continuous-flow reactor; flow chemistry; helicenes; light-driven
cyclization reaction; photocyclization; stilbenes
© 2013 Lefebvre et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
A continuous flow oxidative photocyclization of stilbene derivatives has been developed which allows the scalable synthesis of
backbone functionalized phenanthrenes and helicenes of various sizes in good yields.
Introduction
Phenanthrenes are versatile intermediates toward polycyclic concentration (~10−3 mol·L−1) and usually long reaction times
aromatic hydrocarbons which are relevant for materials (>20 h). Therefore, most of the applications of this method are
sciences, as well as toward helicenes, an intriguing class of limited to small scale (<0.5 mmol), making it unsuitable for
molecules which show remarkable chiroptical properties due to gram-scale synthesis of helicene-like molecules [9-12]. Much
their helical pitch. The rapidly expanding field of application of effort has devoted to the development of alternative pathways
helicene-like molecules in materials sciences and optics toward helicenes, but most approaches require lengthy
demands the development of scalable and flexible syntheses syntheses of the precursors [13-15]. It should be noted that an
[1-5].
elegant semi-one-pot procedure for the synthesis of phenan-
threnes from styrenes and benzene was recently reported [16].
Following the pioneering examples of Scholz [6] and Martin [7] However, also in this case, the scale of the reaction is limited by
in 1967, the photocyclization of stilbene derivatives under the size of the photoreactor.
UV-light irradiation is now a classical method for the synthesis
of phenanthrenes and helicene-like molecules [8]. However, the Reactions in flow are typically faster and cleaner compared to
scalability of these reactions is limited by the required low the corresponding reactions in batch. A flow setup is particu-
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larly well-suited for photo-catalysed reactions as the efficiency
of the transformation is no longer related to the scale [17-21].
Therefore, the development of an efficient protocol for the
photocyclization of stilbene derivatives in flow would be of
great interest. A recent contribution described the flow-syn-
thesis of [5]helicene under visible light in the presence of a
sensitizer [22], but, to the best of our knowledge, no reports on
broadly applicable light-induced oxidative photocyclizations in
flow are known. Herein, we report the first photocyclization of
polysubstituted olefins using a continuous flow process and
discuss advantages and limitations of this new protocol. Gener-
ally, the oxidative photodehydrogenation of E-stilbene results in
the formation of phenanthrene (Scheme 1). In this reaction the
E-olefin (or a E/Z mixture of the olefin) is photoisomerised to
Scheme 1: Photocyclization of stilbene to phenanthrene.
the reactive Z-olefin, which undergoes photocyclization. The The flow-reactor setup used for the optimization (Table 1) is
corresponding dihydrophenanthene is subsequently oxidized shown in Figure 1. UV-transparent ethylene propylene
with iodine to give the desired phenanthrene and HI, which can copolymer capillary (FEP, outer/inner diameter 1/0.5 mm, total
be quenched by propylene oxide or THF.
volume 5 mL) was tightly wrapped around the water-cooling
unit (Duran glass) of a high-pressure mercury lamp (TQ 150,
UV-Consulting Peschl). Further optimization and scope was
Results and Discussion
In order to accomplish a first general photocyclization we performed with a similar setup using a bigger capillary (FEP,
started with the photocyclization of stilbene. Optimization of outer/inner diameter 4/2 mm, total volume 24 mL). For the sake
the reaction conditions in a small flow setup (5 mL FEP tubing, of safety and to enhance the efficiency of irradiation by reflec-
150 W UV-lamp) is presented in Table 1. Although both THF tion, the setup was placed into a laboratory Dewar flask and the
and propylene oxide showed good ability to quench HI, we exposed parts of the setup were covered with aluminium foil
choose THF as additive due to its lower cost, volatility and toxi- (the temperature inside the Dewar was determined to be around
city [23,24]. Under the optimized conditions, E-stilbene (1a) 40 °C). The reaction mixture was injected into the system using
could be converted to phenanthrene (2a) in 95% NMR yield a syringe pump and collected at the outlet of the tubing into a
with a retention time of 83 min (Table 1, entry 5).
round bottom flask.
Table 1: Proof of principle and screening of reaction conditions.
Additive
(20 equiv)
Concentration
Flow rate
(mL/min)
Entrya
Yieldb (%)
(mol/L)
1
2
3
4
5
6
7
8
propylene oxide
THF
0.01
0.01
0.06
0.04
0.02
0.06
0.06
0.06
0.08
0.06
33
37
44
99
95
–c
THF
0.01
propylene oxide
THF
0.001
0.002
0.002
0.002
0.003
cyclohexene
THF
68
50
THF
a1.1 equiv of iodine were used. The solvent was dry toluene. bDetermined by 1H NMR using mesitylene as internal standard. cMainly Z-stilbene was
observed.
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Table 2: Optimisation of the scale-up setup.
Additive
(20 equiv)
Flow rate
(mL/min)
Yieldb
(%)
Entrya
1
propylene
oxide
0.2
66
2
3
THF
THF
THF
0.25
0.2
40
85
94
4c
0.2
a1.1 equiv of iodine were used. Dry toluene was used as solvent.
bDetermined by 1H NMR using mesitylene as internal standard.
cDegassed toluene was used.
phenanthrene (2a) was obtained in 94% yield when a flow rate
of 0.2 mL/min (retention time of 120 min) was applied
(Table 2, entry 4).
With the optimised conditions in hand, we explored the scope
of the reaction. Although photocyclization of disubstituted
olefins in batch was well documented in the literature, only few
cases of photocyclization of tri- and tetrasubstituted olefins
were reported [16,25]. Therefore, we decided to demonstrate
our methodology on both di- and trisubstituted olefins
Figure 1: Flow-reactor setup used in the optimization study.
Additionally, we developed a 5-fold bigger setup to enhance the (Table 3). We disclose here the first photocyclization of trisub-
throughput (Table 2). Slightly longer retention times were stituted olefins in flow, giving access to backbone-function-
required, and degassed toluene provided better yields. Finally, alised phenanthrene derivatives.
Table 3: Scope of the photocyclization of stilbene derivatives in continuous flow to give substituted phenanthrenes.
Entrya
Substrate
Product (2)
Yieldb (%)
1
64
2a
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Table 3: Scope of the photocyclization of stilbene derivatives in continuous flow to give substituted phenanthrenes. (continued)
2
3
4
5
64
61
2b
2c
77
2d
31/34
2e and 2e’
6
77
2f
7
8
89
64
2g
2h
aReaction conditions: 1.1 equiv iodine, 20 equiv THF, UV-light, 2 h retention time. bYield after chromatography.
We choose stilbenes with bromide and methyl substituents, as but nitro- and amino groups containing stilbenes showed low
the latter can be used in subsequent oxidation, deprotonation, conversion or decomposition. Meta-substituted substrates gave
and radical addition reactions, whereas the former opens access inseparable regioisomers, and ortho-substitution led to low
to various functional groups via lithium-halogen exchange or conversion. In the case of substrate 1e, a separable 1:1 mixture
cross-coupling chemistry. Methoxy groups were also tolerated, of regioisomers 2e and 2e’ was obtained (Table 3, entry 5).
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However, generally a series of stilbenes reacted smoothly to the toluene a single regioisomer 2k was isolated (Table 4, entry 3),
desired phenantrenes in good yields.
whereas the reaction in acetonitrile resulted in a separable 1:1
mixture of regioisomers 2k and 2k’ (Table 4, entry 4).
Recently, an unexpected synthesis of [4]helicenes was disclosed
[26]. However, no 2-substituted [4]helicenes were synthesised Finally, we decided to apply our photo-flow methodology in the
using this method. Therefore, we investigated the photocycliza- synthesis of functionalised [5]helicenes and [6]helicenes. We
tion of the corresponding stilbene derivatives in our flow setup, identified 3-acetyl-9,10-dimethoxyphenanthrene [27] as a
for both di- and trisubstituted olefins (Table 4).
powerful intermediate for the two-step synthesis of functionalis-
able helically chiral products. As shown in Scheme 2, Wittig or
Again, various functional groups were tolerated in the flow Horner–Wadsworth–Emmons reactions gave the corresponding
photocyclization. Interestingly, if substrate 1k was irradiated in olefins 1o–r in good yields, which were subjected to photocy-
Table 4: Scope: synthesis of [4]helicenes by photocyclization in flow.
Yieldb
(%)
Entrya
Substrate
Product (2)
1
85
2i
2j
2
75
3
74
2k
4c
40/41
2k and 2k’
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Table 4: Scope: synthesis of [4]helicenes by photocyclization in flow. (continued)
5
75
2l
6
7
73
2m
99
2n
aReaction conditions: 1.1 equiv iodine, 20 equiv THF, UV-light, 2 h retention time. bYield after chromatography. cReaction was performed in dry,
degassed acetonitrile.
Scheme 2: Photo-flow synthesis of [5]- and [6]helicenes. aFor experimental details see Supporting Information File 1. bReaction conditions: 1.1 equiv
iodine, 20 equiv THF, UV-light, 2 h retention time.
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