Rapid Optimization of Photoredox Reactions for Continuous-Flow Systems Using Microscale Batch Technology

Article abstract of DOI:10.1021/acscentsci.1c00303

Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the pharmaceutical sector, recent efforts have focused on perf

Full text of DOI:10.1021/acscentsci.1c00303

http://pubs.acs.org/journal/acscii
Research Article
Rapid Optimization of Photoredox Reactions for Continuous-Flow
Systems Using Microscale Batch Technology
María González-Esguevillas, David F. Fernández, Juan A. Rincón, Mario Barberis, Oscar de Frutos,
Carlos Mateos, Susana García-Cerrada, Javier Agejas, and David W. C. MacMillan*
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ABSTRACT: Photoredox catalysis has emerged as a powerful and
versatile platform for the synthesis of complex molecules. While
photocatalysis is already broadly used in small-scale batch chemistry
across the pharmaceutical sector, recent efforts have focused on
performing these transformations in process chemistry due to the
inherent challenges of batch photocatalysis on scale. However,
translating optimized batch conditions to flow setups is challenging,
and a general approach that is rapid, convenient, and inexpensive
remains largely elusive. Herein, we report the development of a new
approach that uses a microscale high-throughput experimentation
(HTE) platform to identify optimal reaction conditions that can be
directly translated to flow systems. A key design point is to simulate
the flow-vessel pathway within a microscale reaction plate, which
enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This
approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately
to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to
photocatalysis will allow rapid identification of numerous flow protocols for scale.
photon flux throughout the reaction medium and improved
reaction efficiency. This observation has inspired recent efforts
to develop (i) laser-based reaction platforms that employ high-
intensity photon sources, which in combination with
continuous stirred tank reactors (CSTRs) provide powerful
improvements with respect to photon penetration in a batch-
flow setting, and (ii) continuous-flow photoreactors, which
naturally permit better light penetration due to the narrow
tubing diameter; such systems have been shown to permit
gram- and kilogram-scale transformations.18,19 In general, flow
reactor platforms offer many advantages over batch chem-
istry20−26 with respect to photon efficiency, reproducibility,
scale-up, safety, waste generation, and productivity regarding
both yield and reaction time (Figure 1a). Along these lines, a
number of research groups have adopted flow photochemistry
strategies for the synthesis of molecules of pharmaceutical
interest (Figure 1b).27−29 Despite these advantages, the
optimization of a flow chemistry process typically can be an
INTRODUCTION
■
The past decade has witnessed exponential growth in the
development of photoredox catalytic methods for organic
synthesis. Photocatalysis, in which photon-harvesting mole-
cules convert light energy to chemical energy, offers many
useful advantages. In addition to being ecofriendly and
sustainable,1,2 photocatalytic methods are uniquely capable of
promoting challenging bond formations34 and novel chemical
transformations5−7 due to their ability to access high-energy
intermediates in a controlled and selective manner. Photoredox
catalysis is now used in the synthesis of agrochemicals, fine
chemical intermediates, active pharmaceutical compounds
(APIs), and finished dosage forms (FDFs).8 While photo-
catalytic methods have found increasing industrial application,
one remaining hurdle to widespread adoption of this platform
is the inherent complexity in adapting photochemical reactions
to large-scale settings, such as those required for process
chemistry.9−13 A critical outcome of the Beer−Lambert Law,
with respect to the scale-up of photochemical transformations,
is that photon-flux penetration decreases exponentially with
depth in a given reaction medium, ultimately leading to
attenuation in the transfer of photons.14 Thus, visible-light-
mediated reactions take place only in the proximal area (within
2 mm) of the vessel wall.15−17 As such, a decrease in the
diameter of the reaction vessel should lead to an increase in
Received: March 7, 2021
Published: June 8, 2021
© 2021 The Authors. Published by
American Chemical Society
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strategies, it has been possible to build foundational results
from which reaction optimization can be examined thereafter
in continuous-flow systems. However, a limitation of existing
optimization platforms is the difficulty in translating HTE
outcomes to continuous-flow platforms, a feature that often
relates to the change in vessel, light intensity, and light path-
length considerations.49,51−55 A complementary approach was
beautifully described by the Stephenson group56 at the outset
of the preparation of this manuscript, demonstrating a flow-
based HTE platform by developing a droplet microfluidic
system for the development of photochemical reactions. This
study is focused on the generation of compound libraries,
ultimately increasing the chemical space with great time and
material efficiency. Notwithstanding, to the best of our
knowledge, a general HTE strategy for the translation of
optimized photoredox reactions seamlessly to similar outcomes
on a flow platform remains undeveloped and would be of a
great interest to both discovery programs and process
chemistry alike.
With this in mind, we sought to design an HTE platform
that mimics the conditions of a flow reactor.48−55 A requisite
goal would be that the optimization data collected via this
HTE platform should be directly transferrable to a flow system,
permitting the rapid translation of small-scale batch-vessel
photoredox reactions to large-scale flow systems. Thus, the
HTE setup should allow us to perform miniaturized reactions
while simulating continuous photonic flow chemistry proto-
cols.
A compelling benefit of such a system is the ability to
simultaneously explore numerous reaction variables, including
the catalyst, photon intensity, base, solvent, and so on, in
parallel while employing short residence times. We describe
herein the development of this HTE platform and its validation
in the context of four representative photoredox trans-
formations.
Figure 1. (a) Photoredox reactions can take place in batch, which
normally requires a small scale, or in flow, for more efficient light
penetration. However, general optimization methods in flow systems
remain elusive. (b) Continuous-flow systems have been used for the
synthesis of many active pharmaceutical ingredients (ref 28). (c) We
disclose a general approach to the optimization of any photoredox
reaction from batch to flow using a microscale parallel experimenta-
tion to simulate the flow conditions.
FLOSIM PLATFORM DESIGN
■
Design Plan of an HTE Platform to Simulate
Continuous-Flow Systems. Successfully modeling photo-
chemical flow reactions in a high-throughput setting requires
designing a system that adequately captures the distribution of
photonic energy present throughout the entire protocol
employed within the flow apparatus.57,58
onerous task for several reasons: (i) it is traditionally not
possible to perform parallel optimization experiments in the
context of a flow system; (ii) the optimal reaction conditions
are highly dependent on the size of the individual reactor; and
(iii) each flow chemistry experiment requires significant
amounts of material compared to the analogous reaction
conducted in batch.30,31 A number of strategies have been
pursued to streamline optimization of flow-based photoredox
methods, including reducing the reaction vessel size,32−37
leveraging mathematical equations38 and algorithms,36,39,40 and
adapting new technologies (segmented41,42 or microflow43−46
and industry 4.047).
Over the past decade, high-throughput experimentation
(HTE) methodologies have been successfully employed in the
optimization of numerous catalytic transformations.48−51 Such
technology has been adopted within both academic and
industrial settings to allow the evaluation of reaction
parameters while minimizing economic and waste constraints.
Recently, the optimization of photoredox protocols has also
been conducted using HTE technology.34,35 Using such
In a photoredox-catalyzed transformation, wherein the
approximations of the Beer−Lambert law operate, the photon
absorption is described as a function of the incident radiation
and the absorption coefficient.59 Given the angular and spatial
dependence of the spectral specific intensity and the complex
geometric considerations required to accurately describe
irradiation in flow, we recognized that determining the specific
spectral intensity to enable design of a corresponding high-
throughput setup would prove to be challenging at best.
Importantly, however, we recognized that the key components
of spectral intensity could be appropriately accounted for by
selection of a light source that results in the same radiant flux
for both systems.60 Furthermore, the incident radiation could
now be approximated by ensuring the same path length of
irradiation under both flow and high-throughput batch
conditions. With this in mid, we sought to accomplish a
path-length matching feature by the operationally simple step
of varying the volume in a standard 96-well plate to generate a
solution height matching the internal diameter (ID) of the
transparent fluorinated ethylene propylene (FEP) tubing
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chosen of the flow system (Figure 2a, see Supporting
Information for details).
different materials at different positions along the plate (see
Supporting Information).61 In Figure 2c, we outline the
general workflow for the translation of a photoredox reaction
from batch to flow using a multiscreening platform. Route
scouting to identify optimal reaction conditions begins with
validation of the reaction, in batch, across different wave-
lengths. Next, reaction optimization is performed on micro-
scale using the flow simulation (FLOSIM) HTE setup. Briefly,
the 96-well glass plate is loaded inside a nitrogen-filled
glovebox, sealed with transparent film, and placed in the
benchtop HTE device, where it is exposed to light irradiation
for a short period of time equivalent to the desired residence
time in the flow system. Following completion of screening,
the crude reaction mixtures are analyzed by ultraperformance
liquid chromatography (UPLC). This two-step process, HTE
screening of different conditions, and analysis of results via
UPLC, can be performed iteratively until the desired results are
obtained.
Last, the optimal conditions, as determined from the HTE
microscale platform, were directly reproduced in the
commercial flow system using the preferred wavelength, light
intensity, substrate/reagent concentrations, residence time,
solvent, base, and so on. As described below, the optimized
conditions identified at the 60 μL scale in the glass plate
system were found to be directly transferrable to a UV-150
Vapourtec E-Series system equipped with a 2 mL or 10 mL
reactor coil. We have demonstrated the utility and generality of
this FLOSIM HTE optimization protocol in the context of
four representative photocatalytic reactions widely employed
in medicinal chemistry.
RESULTS AND DISCUSSION
■
Optimization of Decarboxylative Arylation for Flow.
In 2014, we reported a novel decarboxylative arylation,62
wherein amino acids are transformed into benzylic amines
under synergistic photoredox and nickel catalysis (Figure 3a).
In optimizing this transformation for a flow system, we selected
N-Boc-Proline (Boc-Pro-OH) and 1-bromo-4-(trifluorometh-
yl)-benzene as model substrates. We first validated the reaction
using a bench setup: under published conditions with a 26 W
CFL light bulb and Cs2CO3 base, the desired product was
isolated in 88% yield after 36 h. We began optimization studies
by evaluating the efficiency of the decarboxylative arylation
across a variety of wavelengths (PR160 Kessil LEDs); these
investigations revealed 427 nm to be the optimal wavelength
for the transformation. An important consideration in
developing flow reactions is the need to avoid heterogeneous
conditions,63−65 which often clog the tubular flow reactors.
With this criterion in mind, we set out to optimize the
transformation using the HTE FLOSIM−UPLC setup, with an
eye toward identifying suitable organic bases and solvents to
ensure a homogeneous solution (see Supporting Information).
Approximately 300 “flow-type” reaction conditions were tested
in short order to examine the effect of residence time, solvent,
concentration, organic base, photocatalyst, catalyst loading, as
well as the nature of the transition metal complex (see
Supporting Information). As shown in Figure 3b, these studies
led to the identification of homogeneous conditions that
afforded the desired transformation in only 45 min with 79%
yield. We next sought to transfer these conditions to a flow
platform: a UV-150 Vapourtec E-Series system equipped with
a 2 mL reactor coil and 420 nm LED. We were pleased to find
that the HTE-optimized reaction conditions were directly
Figure 2. Simulation process and sequential optimization method. (a)
By using the inner diameter of the reactor-coil tubing as the height on
the plate, we can calculate the required reaction volume. (b) To
simulate the flow reactor, a reflected FLOSIM device was built and
validated across various parameters, such as the position, lights, and
cooling system. The FLOSIM device was optimized to obtain both
high reactivity in conjunction with homogeneity across the plate. (c)
Workflow: Selection of the optimal wavelength for the reaction is
followed by optimization in the 96-well glass plate FLOSIM device.
After the reaction, the sample is diluted and analyzed by UPLC. The
selected conditions are then validated through transfer into the
commercial flow system.
Next, in order to simulate the flow-system environment in
the context of a photochemical reaction, it would be crucial to
recreate the reactor-coil element. Accordingly, we assembled a
multienvironment 96-well plate glass device that enables a high
level of light exposure (Figure 2b). This platform was equipped
with two Kessil LEDs (PR160) and two ThorLabs concave
lenses (see Supporting Information for details), while temper-
ature control was maintained through air convection methods.
The use of a glass 96-well plate allows complete penetration
and reflection of the light inside the device in all directions,
and the uniformity of photon dispersion is accomplished across
the platform using a ThorLabs concave lens and several high-
density reflection mirrors.
In order to evaluate the system’s ability to facilitate
photoredox reactions with satisfactory consistency within the
plate, we conducted a series of simple test reactions using
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Figure 3. C−C and C−N coupling via decarboxylative protocols. (a) The reaction between N-Boc-proline with 1-bromo-4-(trifluoromethyl)-
benzene was evaluated with a variety of light sources using standard conditions; superior results were obtained with the 427 nm LEDs (see
Supporting Information). (b) A range of results have been obtained for several conditions, with high, moderate, or low yield being replicated
between the FLOSIM device and the commercial flow setup (see Supporting Information). (c) The reaction was successfully scaled using a
Vapourtec E-Series with a 10 mL reactor coil (1.3 mm ID). (d) Reaction between activated carboxylic acid iodonium salts and 3-chloro-indazole as
the N-nucleophile via dual-photoredox copper catalysis. Superior results were obtained with a 390 nm Kessil LED light source. (e) A range of
results have been obtained for several conditions, with high, moderate, or low yield being replicated between the FLOSIM device and the
commercial flow setup (see Supporting Information). (f) The reaction was successfully scaled at a 40 mmol level affording 7.6 g of the desired
product (69% yield) using a Vapourtec E-Series with a 10 mL reactor coil (1.3 mm ID). PC corresponds to 4CzIPN.
translatable to the Vapourtec, delivering the desired product
with comparable levels of efficiency (74% yield) using the same
conditions including 45 min of residence time (Figure 3b). In
order to be confident that the HTE platform offers an accurate
simulation of the Vapourtec flow system, we sought to
determine the consistency of data between both systems using
a variety of reaction conditions. As shown in Figure 3b, we
selected two sets of conditions that gave mediocre and poor
results respectively with the HTE setup (i.e., 50 and 7% yield).
Indeed, when these suboptimal conditions were transferred to
the Vapourtec reactor, we again found a remarkable level of
consistency between the HTE FLOSIM batch reactors and the
flow efficiencies (56 and 6% yield, respectively). These results
suggest that the optimization data obtained in the context of
the HTE platform are, indeed, indicative of performance in
flow. Moreover, time studies conducted for both the HTE
setup and the flow setup under optimal conditions reveal a
strong correlation between the two systems with respect to
conversion as a function of reaction time (see Supporting
Information).
Next, we aimed to demonstrate the feasibility of this flow-
optimized method in processes of different scale. As shown in
Figure 3c, when the reaction was conducted at the 60 mmol
level using the optimized conditions with a larger coil size
reactor (10 mL), the desired product was isolated in 70% yield.
Moreover, 13.2 g of product was isolated after an 11.7 h total
flow reactor time using the Vapourtec system. In comparison
to the laboratory vial reactor procedure, which provides 111
mg of desired product in 36 h, we were able to demonstrate a
366-fold increase in efficiency by way of this rapid, flow
optimization protocol.
Optimization of C−N Arylation Coupling for Flow. In
2018, our group reported a new transformation that allows the
decarboxylative alkylation of N-nucleophiles via the merger of
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Figure 4. Optimization platform for cross-electrophile coupling. (a) The reaction takes place between 4-bromotetrahydropyrane and methyl-4-
bromobenzoate via silane-mediated metallaphotoredox catalysis using 427 nm Kessil LEDs as the optimal light source (see Supporting
Information). (b) HTE optimization allows the desired product in the flow system (77% yield) to be obtained in 45 min of residence time instead 6
h of reaction time using a standard setup. Several conditions were evaluated for both setups (see Supporting Information for exact experimental
conditions). (c) Lutidinium bromide was detected during the course of the reaction obstructing the flow reactor coil by accumulation. The use of
thicker tubing allows the reaction to be scaled up to 8 mmol. (d) The effectivity of this reaction has been proved using a 60 mmol scale affording
10.3 g of the desired product (78% yield).
photoredox and copper catalysis.66 Among a large scope of
valuable alkylation substrates, there has been growing interest
in the incorporation of rigid bicyclic structures, such as [1.1.1]-
propellane (BCP) scaffolds, into medicinal compounds, owing
to their capacity to act as bioisosteres of alkynes or para-
substituted benzene rings. With this consideration in mind, we
sought to optimize a flow method for the rapid production of
molecules containing the BCP scaffold via our C−N coupling
platform. We selected 3-(methoxycarbonyl)bicyclo[1.1.1]-
pentane-1-carboxylic acid and 3-chloro-indazole as the model
coupling partners. Using our previously published conditions,
the C−N coupling adduct was obtained in a vial batch in 80%
yield after 1 h. After a subsequent survey of reaction
efficiencies as a function of LED wavelength, it became
apparent that the coupling proceeds well across a variety of
light sources, and 390 nm was selected for further HTE studies
(see Supporting Information). As shown in Figure 3e,
following a short HTE FLOSIM−UPLC optimization
campaign that involved the assessment of ∼300 reactions
(evaluating different reaction times, solvents, concentrations,
catalysts and catalyst loadings, see Supporting Information),
we identified optimal flow conditions that provided com-
parable efficiency (89% yield) within only an 8 min reaction
time.
commercial flow setups for a variety of conditions that were
examined, lending further support to the predictive power of
the HTE setup (Figure 3e).
Finally, the decarboxylative alkylation was performed on a
40 mmol scale using our optimized FLOSIM conditions on a
Vapourtec reactor (385 nm LEDs, 10 mL reactor coil). The
reaction was conducted in the heated mode at 35 °C to
prevent solvent freezing. Under the conditions shown in Figure
3f, 7.6 g of the desired product was isolated in good yield
(69%) after only 10 h, representing a 6.5-fold increase in
reaction efficiency over the vial batch setup.
Optimization of Cross-Electrophile Coupling for
Flow. In 2016, we developed a cross-electrophile coupling
that has found broad application across a variety of medicinal
chemistry campaigns.67 As such, the development of a simple
protocol by which to translate small-scale cross-electrophile
couplings to commercial flow systems would have significant
benefit for the scale-up of critical building blocks and drug-like
fragments or products. Under our standard vial batch setup,
the model substrates, 4-bromotetrahydropyran and methyl-4-
bromobenzoate, underwent cross-coupling to afford the
desired product in 79% yield over the course of 6 h. Moreover,
irradiation at 427 nm was observed to be optimal for this
transformation (see Supporting Information). Given that HBr
is generated as the main byproduct in this coupling protocol,17
we undertook an evaluation of various soluble organic bases.
While initial FLOSIM studies revealed that 2,6-lutidine
appeared to be an effective acid scavenger and compatible
with high coupling yields, the resulting side product, a
These conditions were then directly transferred to the
continuous-flow system (Vapourtec E-Series, 2 mL reactor
coil), and a similar result was obtained (87% yield, 8 min
residence time). As shown in Figure 3e, a time study showed
comparable levels of conversion between the HTE and
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Figure 5. Application for C−O coupling reaction. (a) The reaction takes place between protected pyranose and 4-bromo-acetophenone merging
nickel and photoredox catalysis. (b) With the workflow shown using 456 nm Kessil LEDs, followed by HTE optimization and the corresponding
UPLC analysis, we could obtain in a flow system the desired product (75% yield) in 35 min of residence time instead 24 h of reaction time using a
standard setup. Optimization using our HTE protocol provides a range of conditions, which we could translate successfully to the flow system. (c)
The efficiency of our protocol was also proved by using a powerful continuous-flow system (PhotoSyn). Using the 25% light intensity, we could
observe a correlated result with our HTE setup. Furthermore, increasing the light intensity, we were able to reduce the reaction time with no
changes on the reactivity. (d) The effectivity of this reaction has been proved for both continuous-flow systems affording the same reactivity (72%
yield), resulting in a higher efficiency for the more powerful flow system (26.6 g/day for Vapourtec and 56.3 g/day using PhotoSyn.
lutidinium bromide salt, has poor solubility and ultimately
causes the flow system to clog. As such, we were unable to
translate this initial set of HTE-optimized conditions beyond
an 8 mmol scale using the commercial flow reactor (Figure 4c;
also see Supporting Information) due to the need to
incorporate frequent wash cycles to remove salt byproducts.
Given the broad interest in this coupling protocol across the
industrial sector,68−70 we undertook a second optimization
campaign using the HTE FLOSIM device, with the goal of
identifying homogeneous conditions that would provide
improved properties for scale-up. In this regard, we performed
approximately 1000 experiments via HTE FLOSIM to evaluate
a variety of reaction components (bases, solvents, concen-
trations, reaction times, metal complexes, catalyst loadings,
additives, and cosolvents; see Supporting Information).
Through this process, we determined that (i) decreasing the
amount of base from 2 to 1 equiv, (ii) switching to a more
polar solvent [N,N-dimethylacetamide (DMA)], and (iii)
extending the reaction time to 45 min provided optimal
efficiency without issues related to salt precipitates. Moreover,
with these conditions in hand, we were able to achieve high
efficiency in both the HTE setup (77% yield) and the
commercial flow system (77% yield) (Figure 4d). Most
importantly, as shown in Figure 4d, we were able to scale
this reaction to 60 mmol using the Vapourtec E-Series (10 mL
reactor coil and 420 nm LEDs) to obtain 10.3 g of the coupled
product in 78% yield after 23 h.
In comparison to the initial vial batch protocol (87 mg
obtained), this result represents a 30.9-fold improvement in
efficiency.
Optimization of Visible-Light-Mediated C−O Aryla-
tion Coupling for Flow. Our photocatalytic C−O coupling
reaction71 has emerged as a versatile strategy for the synthesis
of alkyl aryl ethers. Under the standard bench setup, using a
relatively complex protected pyranose model substrate and an
aryl bromide, the etherification generated the desired product
in 82% yield after 24 h. Irradiation at 456 nm was found to
provide optimal reaction efficiency (see Supporting Informa-
tion). Optimization studies with the HTE FLOSIM platform
(∼450 experiments to evaluate all the components in the
reaction, see Supporting Information) revealed the inexpensive
organic photocatalyst, 2,4,5,6-tetra(9H-carbazol-9-yl)-
isophthalonitrile (4CzIPN), to be the ideal catalyst, generating
the coupling product in 80% yield after 35 min (Figure 5b).
Translating these optimal HTE conditions to the commercial
flow system yielded similar results (75% yield), and time
studies demonstrated a strong correlation between these two
platforms. Once again, the results generated from the HTE
system were consistent with those obtained from the flow
system across a variety of optimal and nonoptimal conditions
(Figure 5b).
Translation of the HTE FLOSIM Platform to Multiple
Commercial Flow Reactors. Throughout most of this
project, we employed a UV-150 Vapourtec E-Series as a
representative flow reactor for scale-up. In order to
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demonstrate the generality of this approach for practitioners in
this field, we sought to test our protocol in a second,
commercial flow system. In this context, we evaluated the
PhotoSyn flow photoreactor as developed and manufactured
by Uniqsis Ltd. This photoreactor is equipped with a 10 mL
reactor coil (ID = 1.0 mm) and more powerful LEDs (455 nm
LEDs, 700 W total power, approximately 200 W output
power) compared to the Vapourtec system. According to
literature precedent,33 flow reactors that incorporate high-
powered photonic sources may offer numerous benefits,
including faster reaction rates, shorter reaction times, and
amenability to nonhomogeneous conditions. On this basis, we
evaluated the efficiency of the above-mentioned C−O coupling
protocol in the PhotoSyn flow system using various light
intensities as determined via our HTE FLOSIM platform. As
shown in Figure 5c, using 25% light intensity, we were able to
achieve satisfactory yield (76% yield in HTE FLOSIM vs 79%
in PhotoSyn) with a residence time of 35 min. Moreover, by
increasing the light intensity to 75%, we obtained a comparable
79% yield with a much shorter reaction time of 13.75 min
(Figure 5c, also see Supporting Information). Finally, we
attempted a gram-scale synthesis of the product with each
continuous-flow system (Figure 5d). Under optimized
conditions, the Vapourtec system provided 12.2 g of final
product in 11 h (72% yield), while the PhotoSyn system is able
to generate 26.2 g of the same product in the same time frame
(72% yield). Thus, compared to a batch setup, which provides
310 mg of product in 24 h, the flow system can lead to an 86-
fold efficiency acceleration using the Vapourtec system and
185-fold efficiency enhancement using the PhotoSyn photo-
reactor. More importantly, we have demonstrated that our
HTE FLOSIM optimization strategy can be applied across
various commercial flow reactors.
AUTHOR INFORMATION
■
Corresponding Author
David W. C. MacMillan − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
States; orcid.org/0000-0001-6447-0587;
Email: dmacmill@princeton.edu
Authors
María González-Esguevillas − Merck Center for Catalysis at
Princeton University, Princeton, New Jersey 08544, United
States; orcid.org/0000-0003-3779-5516
David F. Fernández − Merck Center for Catalysis at Princeton
University, Princeton, New Jersey 08544, United States;
orcid.org/0000-0003-3482-0894
Juan A. Rincón − Centro de Investigación Eli Lilly, S. A.,
28108 Madrid, Spain
Mario Barberis − Centro de Investigación Eli Lilly, S. A.,
28108 Madrid, Spain
Oscar de Frutos − Centro de Investigación Eli Lilly, S. A.,
28108 Madrid, Spain
Carlos Mateos − Centro de Investigación Eli Lilly, S. A.,
28108 Madrid, Spain
Susana García-Cerrada − Centro de Investigación Eli Lilly, S.
A., 28108 Madrid, Spain
Javier Agejas − Centro de Investigación Eli Lilly, S. A., 28108
Madrid, Spain
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscentsci.1c00303
Author Contributions
M.G.-E. and D.F.F. performed and analyzed the experiments.
M.G.-E, D.F.F., and D.W.C.M. designed the experiments.
J.A.R., M.B., O.F., C.M., S.G.-C., and J.A. provided intellectual
contributions. M.G.-E, D.F.F., and D.W.C.M. prepared this
manuscript.
CONCLUSION
Funding
■
In summary, we have designed an HTE FLOSIM device that
can simulate a continuous-flow setup to enable the
optimization and direct translation of small-scale photoredox
methods to large-scale flow reactors. This system permits the
reproduction of the same reaction pathways in both an HTE
setup and a continuous-flow setup and therefore serves as a
general platform to rapidly optimize any photoredox reaction
at microscale. We have evaluated this optimization platform in
the context of four prominent photocatalytic transformations,
and in each case, we have been able to significantly improve
the efficiency of these methodologies at large scale compared
to standard batch conditions. Moreover, the generality of this
platform with regard to different flow reactors has been
demonstrated. Considering the widespread interest in photo-
redox catalysis across the pharmaceutical industry, we expect
this optimization platform to be widely adopted in both
medicinal and process chemistry settings.
Research reported in this publication was supported by the
NIH National Institute of General Medical Sciences
(R35GM134897-01) and the Princeton Catalysis Initiative
(PCI). This work was supported by Eli Lilly and Company
through the Lilly Research Award Program (LRAP) as well as
kind gifts from Merck, Janssen, BMS, Genentech, Celgene, and
Pfizer. D.F.F. thanks Xunta de Galicia for a postdoctoral
fellowship (ED481B-2019-005).
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Yufan Liang and Dr. Chun Liu for their
assistance with the preparation of this manuscript.
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscentsci.1c00303.
Experimental procedures and spectral data (PDF)
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