Visible-light photoredox catalysis in flow

Article abstract of DOI:10.1002/anie.201200961

Photoredox catalysis: A variety of organic transformations mediated by visible-light-active photoredox catalysts have been conducted in a photochemical flow reactor. The reactor design is very simple and can be easily implemented in any laboratory (see pi

Full text of DOI:10.1002/anie.201200961

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Angewandte
Communications
DOI: 10.1002/anie.201200961
Photochemistry
Visible-Light Photoredox Catalysis in Flow**
Joseph W. Tucker, Yuan Zhang, Timothy F. Jamison, and Corey R. J. Stephenson*
Photoredox catalysts have recently been used as powerful
tools for synthetic chemists to exploit the energy gained by
the absorption of low-energy light within the visible spectrum
to initiate a variety of organic transformations.[1] The devel-
opment of methods based on the single-electron transfer
properties of photoredox catalysts, particularly in the last
several years, has represented a shift in models with respect to
the way synthetic chemists consider both photochemistry and
redox manipulations of organic molecules.[2–4]In addition, the
advent of new technologies has enabled chemists to conduct
Figure 1. Photoredox catalysis in flow. Enabling increased efficiency by
reactions with greater efficiency than ever before. Among
these new technologies is the development and wide imple-
mentation of flow reactors.[5,6] Conducting transformations in
flow has many advantages compared to the more traditional
batch reactions, in particular: a more predictable reaction
scale-up, decreased safety hazards, and improved reproduci-
bility. In addition, for photochemical transformations, the
high surface-area-to-volume ratios typical of flow reactors
allow for more efficient irradiation of a reaction mixture.[7]
Due to this feature, we reasoned that a mesofluidic photo-
chemical flow reactor would be amenable to our groupꢀs
ongoing study of visible-light-induced organic transforma-
tions mediated by photoredox catalysts (Figure 1).[8]
reactor technology (SET=single-electron transfer).
problem we sought to design a reactor having a considerably
smaller path length through which the light must travel. In
addition, a reactor having a greater surface-area-to-volume
ratio would result in an increased photon flux density,
potentially accelerating the reaction.[12] Commercially avail-
able PFA (perfluoro alkoxy alkane) tubing having an internal
diameter of 0.762 mm was identified as a viable choice
because of its chemical resistance and optical transparency.
Furthermore, a photoreactor of this size will allow for optimal
absorbance at typical catalyst concentrations (around
1.0 mm). For instance, the molar extinction coefficient of
Ru(bpy)3Cl2 (bpy = 2,2’-bipyridine) has been measured to be
13000mÀ1 cmÀ1,[13] as such the thickest portion of the tubing
allows for the absorption of 90% of the incident radiation.
Likewise, when carried out in batch reactors, 99% of the
incident radiation is absorbed by the reaction medium
residing within 1.5 mm of the reactor surface while the
remaining internal volume receives little productive radia-
tion.[14]
In designing our reactor, we sought to make it as simple as
possible without using specialized equipment in the hopes
that a similar design could be readily implemented in other
laboratories. Our optimized reactor involved wrapping
105 cm (corresponding to a 479 mL reactor volume) of PFA
tubing in figure-eights around a pair of glass test tubes. We
then used a peristaltic pump to pump the reaction mixture
through the tubing with irradiation from a commercially
available assembly of seven blue light emitting diodes
(LEDs).[15] Finally a silver-mirrored Erlenmeyer flask was
positioned above the reactor to reflect any incident light back
onto the tubing.[16]
Our group has studied the use of both the oxidative and
reductive quenching cycles of photoredox catalysts to initiate
synthetically useful manipulations of organic molecules such
as intra- and intermolecular radical reactions,[8] formal C H
À
oxidation reactions,[9] and the halogenation of alcohols.[10]
During these studies, it was commonly observed that large-
scale reactions were often slower than those conducted on
smaller scale.[11] As a consequence of the Beer–Lambert law,
the penetration of visible light through a reaction medium
decreases exponentially with increasing path length. We
hypothesized that this may be one reason for the observed
loss of reaction efficiency. To potentially circumvent this
[*] J. W. Tucker, Prof. Dr. C. R. J. Stephenson
Department of Chemistry, Boston University
Boston, MA 02215 (USA)
E-mail: crjsteph@bu.edu
Homepage: http://people.bu.edu/crjsteph/
Dr. Y. Zhang, Prof. Dr. T. F. Jamison
Department of Chemistry, Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
[**] Financial support for this research from the NSF (grant number
CHE-1056568), the NIH-NIGMS (grant number R01-GM096129),
the Alfred P. Sloan Foundation, Amgen, and Boehringer Ingelheim
is gratefully acknowledged. J.W.T. thanks The American Chemical
Society, Division of Organic Chemistry and Amgen for a graduate
fellowship. NMR (CHE-0619339) and MS (CHE-0443618) facilities
at BU are supported by the NSF.
Our initial experiments focused on the oxidative gener-
ation of iminium ions from N-aryl tetrahydroisoquinolines,
using reaction conditions similar to those we recently
reported.[9c] Employing BrCCl3 as the terminal oxidant, we
observed rapid formation of the iminium ion, 2, from the
corresponding tetrahydroisoquinoline, 1. Optimization stud-
ies showed that subjecting a solution of 1, BrCCl3, and
Ru(bpy)3Cl2 (0.5 mol%) in dimethylformamide (DMF) to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200961.
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Chemie
irradiation in our newly designed flow photoreactor, required
only a very short residence time (tR) for complete consump-
tion of 1. In particular, pumping this mixture through the
photoreactor at a rate corresponding to a tR of 0.5 min and
collecting the mixture in a flask containing 5.0 equivalents of
a diverse set of nucleophiles allowed for the efficient and
rapid generation of a variety of a-functionalized amines, in
yields comparable to those observed in the batch reactions
(Scheme 1). As expected with the flow reactor, the scale-up of
the reaction was trivial and allowed for the oxidative aza-
Scheme 2. Intramolecular radical reactions in flow.
pyrrole functionalization, when preformed on large scale in
batch (> 2.0 g, 6.2 mmol), failed to afford complete conver-
sion of the starting material even after prolonged reaction
time (> 2 days). However, the use of the flow reactor could
allow for the transformation of large quantities of substrate
without the need to perform multiple smaller scale reactions
to achieve the desired conversion.
Likewise, the Ir(ppy)2(dtbbpy)PF6 (ppy = 2-phenylpyri-
dine and dtbbpy = 4,4’-di-tert-butyl-2,2’-bipyridine) catalyzed
radical cyclization/rearrangement afforded the product in
good yield, but required a slightly longer residence time, tR =
3.0 min. Again, performing these reactions in flow afforded
a much higher rate of material throughput when compared to
the transformation conducted in batch. Notably, for the
cyclization/rearrangement cascade catalyzed by Ir(ppy)2-
(dtbbpy)PF6, the batch reaction only afforded a substrate
conversion rate of 0.048 mmolhÀ1 (tR = 4.0 min corresponds
to a material throughput of 0.96 mmolhÀ1 with our photo-
reactor).
Intermolecular radical reactions are also feasible in this
flow setup (Scheme 3). Intermolecular malonation of indoles,
using the triarylamine reductive quencher, 4-MeO-C6H4-
NPh2, proceeded smoothly with a tR = 1.0 min.[8d] Further-
more, the bromopyrroloindoline coupling with 1-methyl-
indole-2-carboxaldehyde, similar to the key transformation
used in the recent synthesis of gliocladin C from our group,
proceeded efficiently with a residence time of 4.0 min.[8f] This
result is particularly promising since the scale-up of this
reaction required prolonged reaction times, up to several days
for a 10 g scale reaction.[17]
Scheme 1. Oxidation of tetrahydroisoquinolines in flow.
Henry reaction of 1 with MeNO2 to be conducted on a 1.0 g
scale with none of the issues observed for scaling up batch
reactions. Furthermore, when conducted in batch, a reaction
time of 3 h was required for complete oxidation of 1 on
a 0.24 mmol scale. This corresponds to a material throughput
of 0.081 mmolhÀ1. However, using the flow apparatus (with
a reactor volume of 479 mL) enables a much higher rate of
substrate conversion, 5.75 mmolhÀ1. In addition, this rate can
be increased by using a photoreactor having a greater internal
volume which would require only the use of a longer section
of tubing.
Having validated our hypothesis of increased reaction
efficiency of photoredox-mediated transformations per-
formed in
a photochemical flow setup, we examined
a number of other reactions developed by our group. Firstly,
a number of intramolecular radical cyclization reactions were
evaluated, including: intramolecular heterocycle functionali-
zation,[8b] hexenyl radical cyclization,[8c] and a tandem radical
cyclization/Cope rearrangement sequence (Scheme 2).[8g] We
were delighted to find that both radical cyclizations onto
heteroaromatics and terminal olefins catalyzed by Ru-
(bpy)3Cl2 proceeded efficiently with short residence times,
1.0 min, affording the products in yields comparable to those
observed in batch reactions. Notably, the intermolecular
Finally, we applied this new reaction technology to our
reported protocol for the intermolecular atom transfer radical
addition (ATRA) using the oxidative quenching pathway of
the photocatalyst, Ir(dF(CF3)ppy)2(dtbbpy)PF6 (Scheme 4;
dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-trifluoromethylpyr-
idine).[8e] While requiring slightly longer residence times than
those observed for the transformations using the reductive
quenching cycle of Ru- and Ir-based catalysts, this trans-
formation proceeded efficiently and cleanly to give the
corresponding ATRA products in good yields. Again,
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conversion (in terms of mmol of material per hour) are
possible simply by employing a photoreactor with a greater
internal volume. Further studies into applying this technology
to a greater range of photoredox methods is underway.
Received: February 3, 2012
Published online: March 16, 2012
Keywords: photochemistry · photoredox catalysis · radicals
.
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[15] The LED assembly [5.88 W, lmax = 447 nm] is commercially
available from Luxeon Star LEDs. See the Supporting Informa-
tion for more details.
[16] For more information on the reactor design please see the
Supporting Information.
[17] L. Furst, C. R. J. Stephenson, unpublished results.
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