Upscaling Photoredox Cross-Coupling Reactions in Batch Using Immersion-Well Reactors

Article abstract of DOI:10.1021/acs.oprd.0c00070

Herein we describe a straightforward approach for the scale-up of photoredox cross-coupling reactions from milligram to multigram scale using immersion-well batch reactors with minimal reoptimization of the reaction conditions. This approach can be applied to both homogeneous and, more significantly, heterogeneous reaction mixtures. Furthermore, we have used an immersion-well side-loop reactor to perform a reaction on a 400 mmol scale (86 g of aryl bromide).

Full text of DOI:10.1021/acs.oprd.0c00070

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Communication
Upscaling Photoredox Cross-Coupling Reactions in Batch Using
Immersion-Well Reactors
Isabelle Grimm, Simone T. Hauer, Tim Schulte, Gina Wycich, Karl D. Collins, Kai Lovis,
and Lisa Candish*
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ABSTRACT: Herein we describe a straightforward approach for the scale-up of photoredox cross-coupling reactions from milligram
to multigram scale using immersion-well batch reactors with minimal reoptimization of the reaction conditions. This approach can
be applied to both homogeneous and, more significantly, heterogeneous reaction mixtures. Furthermore, we have used an immersion-
well side-loop reactor to perform a reaction on a 400 mmol scale (86 g of aryl bromide).
KEYWORDS: photoredox, scale-up, cross-coupling, immersion well, side-loop reactor
continuous flow, with good yields and short residence times
reported.9 However, the typical need for homogeneous reaction
media and the equipment and knowledge required often
render flow solutions unsuitable for upscaling when fast
turnaround is required.10 Moreover, given the large numbers of
compounds synthesized in a discovery project, developing
individual solutions for the scale-up of a single compound is
often not viable for early discovery research projects.11
Given the broad applicability and great potential impact of
these reactions within the early drug discovery process, we
considered that a method enabling the direct scale-up of
heterogeneous reactions from the milligram scale to the gram
scale was required. To this end, we sought a solution that
would enable us to directly reproduce a “Med-Chem” lab
synthesis (approximately 100 mg scale) on a 1−100 g scale
without the need for significant reoptimization, even if the
reaction is heterogeneous in nature.
Our initial multigram-scale reactions, performed using
jacketed round-bottom flasks and multiple high-powered blue
LED lamps, were unsuccessful. With this setup, it was visibly
apparent that most of the light was reflected off the reaction
vessel and lost to the surrounding area. Since the challenge of
scaling up light-mediated reactions in batch increases
exponentially with the reaction volume because of poor light
penetration,12 it was not a surprise that extended reaction
times and increased generation of byproducts were observed
(Figure 1b).13 Not to be discouraged, we hypothesized that if
we could minimize the photon loss, the reaction efficiency
would be restored. Consequently, we turned to a solution
INTRODUCTION
■
Photoredox catalysis (PRC) is a powerful tool that enables
novel disconnections, distinct reactivity pathways, and facile
access to otherwise difficult to synthesize molecules.1 With the
rapid development of the field, the utility of this technology
within the life science industry has become increasingly
apparent in recent years. The often-mild reaction conditions
make PRC ideal for the preparation of the polar and densely
functionalized molecules typically encountered in this
industry.2 Moreover, access to novel scaffolds and the ability
to rapidly explore structure−activity relationships (SARs) not
readily accessible with other chemical technologies further
enhance its potential value. Unfortunately, our experience has
demonstrated that despite the apparent uptake of this powerful
tool in industrial research laboratories, the challenge of
effectively upscaling these reactions even moderately is
providing a major hurdle to fully realizing the potential of
this important technology, an opinion seemingly shared across
the industry.3
Key transformations, such as the photoredox-mediated sp2-
sp3 cross-coupling reactions developed by the groups of
MacMillan, Doyle, Molander, and others,4,5 are incredibly
powerful tools for incorporating a diverse range of alkyl groups
into polyfunctionalized compounds (Figure 1a). Consequently,
they have great potential to become “go-to” reactions for SAR
exploration in both drug and agrochemical discovery programs,
in a similar vein to the now-pervasive Suzuki−Miyaura
palladium-catalyzed cross-coupling reaction. However, the
inability to readily scale up these reactions and access the
material required (1−100 g) for compound profiling beyond
the first in vitro and pharmacokinetic studies is limiting their
widespread application.
Received: February 24, 2020
Flow chemistry is generally considered an ideal solution for
upscaling photochemical reactions,6,7 and numerous examples
of contemporary photoredox methods have been demonstrated
by the pharmaceutical industry.8 Photoredox-mediated sp2-sp3
cross-coupling reactions have also been performed in
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A

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Figure 2. (a) IW reactor. Legend: (1) reaction vessel; (2) immersion
tube; (3) LED light rod; (4) hosing for cooling water to cool the LED
lamps. (b) Decarboxylative sp2/sp3 reaction mixture containing
Cs2CO3.
reactions, and an isolated yield of 88% was obtained on a 30
mmol scale. This reaction mixture was heterogeneous as
cesium carbonate (14 g in the 30 mmol scale reaction) is only
sparingly soluble in N,N-dimethylformamide (DMF) (Figure
2b).
Encouraged by this initial success, we further explored the
scale-up of both the decarboxylative cross-coupling and
MacMillan’s sp2-sp3 reductive coupling (Figure 3A,B).16 In
practice, for each reaction a small base/solvent screen (three to
five reactions) on a 0.1 mmol scale was first performed to find
conditions, as per our standard workflow, and the best
conditions were then directly scaled up to 25, 30, or 60
mmol scale. For each reaction, the LCMS trace for the crude
reaction mixture of the large-scale reaction was comparable to
or even better (cleaner/higher conversion) than that of the
corresponding 0.1 mmol scale reaction (see sections 4 and 5 in
the Supporting Information (SI)). Furthermore, benzyl
chloride and N-Boc-DL-proline were coupled on a 30 mmol
scale using the IW reactor, enabling the rapid synthesis of a
valuable building block (Figure 3C).17 Additionally, the cross-
coupling of alkyltrifluoroborates with aryl halides, which has
been extensively developed by Molander and co-workers,5a was
also readily scaled up to provide >5 g of the desired product
(Figure 3D).
Having established that dual Ni/Ir photoredox cross-
coupling reactions could be readily scaled up to from the
milligram scale to the gram scale in IW reactors, we set a new
challenge: finding a scale-up solution to perform reactions on
∼100 g scale (approximately 400−500 mmol, 5 L reaction
volume).
Once again, the central challenge was maintaining a short
optical path length to enable efficient light penetration when
upscaling the reaction, and therefore, we could not simply
increase the size of the reaction vessel. Instead, we investigated
whether the reactions could be further scaled up using an IW
reactor with a side loop as a circulating batch system (Figure
4). To this end, the IW reactor vessels (internal volume = 250
mL or 1 L, optical path length = 5 or 10 mm, respectively) and
a side-loop tank (a storage tank for the reaction mixture that is
in excess of the reactor vessel) were coupled with a pump to
circulate the reaction mixture. The reaction mixture is
circulated using a magnetic drive pump from the bottom of
the loop tank through the pump and into the bottom of the IW
Figure 1. (a) Photoredox cross-couplings provide a rapid way to
explore SAR via late-stage diversification. (b) Cross-coupling product
and the byproducts often observed. (c) Potential workflow for
upscaling: initial milligram-scale reactions in vials, 10−100 g scale
reactions in batch involving minimal optimization of reaction
conditions (this work), and large-scale reactions using continuous
flow processes.
historically utilized for classical UV photochemistry: immer-
sion-well (IW) reactors (Figure 1c).14,15
RESULTS AND DISCUSSION
■
IW reactors consist of a reaction vessel fitted with an
immersion tube that encases the light source.14 The reaction
vessel sits on a magnetic stirrer plate and a magnetic stir bar or
disk in the vessel is used for stirring. Thus, reactions can be
readily carried out with both homogeneous and heterogeneous
reaction mixtures. The IW reactor used (Figure 2a), purchased
from Peschl Utraviolet GmbH, has vessels with an internal
volume between 150 and 850 mL when the immersion tube is
inserted and an optical path of between 6.5 and 27 mm. The
volume of the reactor and the optical path length are
determined by the combination of the reaction vessel and
immersion tube size. The LED light rod used has an emission
maximum of 460 nm and a radiant flux of 27 W and is cooled
by water to prevent overheating.
To survey the utility of IW reactors for upscaling photoredox
cross-couplings reactions, we first examined the decarbox-
ylative coupling of amino acids with aryl halides.5b Methyl 4-
bromobenzoate was coupled with N-Boc-DL-proline under
literature conditions on 10, 15, 20, and 30 mmol scales.
Surprisingly, consistent yields were observed across all
B
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Figure 3. (A) Decarboxylative coupling. (B) sp2/sp3 reductive coupling. (C) Decarboxylative coupling with benzyl chloride. (D) Cross-coupling of
a
alkyltrifluoroborate salt. Yields were determined by LCMS calibrated with a standard. Abbreviations: ppy, 2-phenylpyridine; dtbbpy, 4,4′-di-tert-
butyl-2,2′-dipyridyl; TMG, 1,1,3,3-tetramethylguanidine; DME, 1,2-dimethoxyethane; DMA, N,N-dimethylacetamide; TFT, α,α,α-trifluorotoluene;
BOC, tert-butoxycarbonyl.
reactor. The solution is then pumped through the reactor,
where it is irradiated, and then back into the top of the loop
tank; there is no irradiation in the loop tank. PTFE tubing
(internal diameter of 4 mm or 12 mm) connects the loop tank,
pump, and reactor. Overall, this is a highly modular solution
that can be readily adapted to a wide range of scales simply by
changing the volume of the loop tank as desired.
The reductive coupling of methyl 4-bromobenzoate with 3-
bromopropanenitrile was selected to test this setup. Prior to
further upscaling, a small base screen was performed to identify
the optimal base for the reaction, and 2,6-lutidine was found to
be superior to Na2CO3 (see SI section 8.1 for details). While
the reaction mixture was initially homogeneous, formation of a
precipitate (presumably the HBr salt of the base) upon
irradiation caused the reaction mixture to become heteroge-
neous within 15 min. The coupling was initially tested in the
side-loop reactor on a 40 mmol scale (reaction volume = 500
mL, internal volume of IW reactor vessel = 250 mL, flow rate =
9 L/min) using an LED light rod with a radiant flux of 47 W
(λmax = 420 nm). Through close monitoring of the reaction
using calibrated LCMS, it was determined that the reaction
Figure 4. IW side-loop reactor setup running a reductive coupling on
a 40 mmol scale.
C
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Figure 5. Photoredox sp2-sp3 reductive couplings performed in an IW side-loop reactor setup on a 400 mmol scale with a radiant flux of 47 W (λmax
= 420 nm). (left) Time course of the reaction. (right) Photograps of (A) the reactor setup and (B) the IW reaction under irradiation. aDetermined
by LCMS calibrated with a standard.
reached completion after 8 h of irradiation (87% yield, 4.4
mmol/h) (see SI section 8.2 for details).
and then the flask was sealed (note: this setup is not gastight
the CO2 generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S2).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (8.0 g, 88%
yield). The data were in accordance with those previously
reported.5b
With this promising result in hand, we further scaled up this
reaction 10-fold to 400 mmol scale (86 g of methyl 4-
bromobenzoate, reaction volume = 5 L). The reaction was
performed in a 1 L IW reactor combined with a 5 L looping
tank (Figure 5, photo A) and gave the desired product in 76%
yield. Minimal incident light is lost when this IW setup is used
(see Figure 5, photo B), thus resulting in efficient irradiation of
the reaction mixture and high yields (yield = 12.2 mmol/h).
Detailed investigation of the reactor design and profiling of the
reaction parameters, including light penetration, stirring
efficiency, and photon flux, are still required. To that end,
analysis of more powerful light sources is currently ongoing to
determine whether the reaction time can be further decreased.
Synthesis of Ethyl 6-(1-tert-Butoxycarbonylpyrroli-
din-2-yl)imidazo[1,2-a]pyridine-2-carboxylate on a 30
mmol Scale. To the reaction flask fitted with a stirring
magnet were added ethyl 6-bromoimidazo[1,2-a]pyridine-2-
carboxylate (30 mmol, 8.07 g), 1-tert-butoxycarbonylpyrroli-
dine-2-carboxylic acid (45 mmol, 9.69 g), Ir[dF(CF3)-
ppy]2(dtbbpy)PF6 (0.3 mmol, 337 mg), NiCl2·DME (3
mmol, 659 mg), and dtbbpy (4.5 mmol, 1.21 g). The
immersion tube was fitted into the reactor, and DMF (400
mL) was added to the flask, followed by TMG (45 mmol, 5.63
mL). The mixture was degassed by bubbling argon through the
solution for 20 min, and then the flask was sealed (note: this
setup is not gastightthe CO2 generated is released through the
seals, preventing pressure buildup!). The reaction mixture was
placed in the PhotonCabinet, and the lamp was placed inside
the immersion tube. The reaction mixture was irradiated for 21
h, then the crude reaction mixture was analyzed by LCMS
(Figure S3 SI). Following the reaction, water (200 mL) was
added, and the mixture was extracted with EtOAc (3 × 200
mL). The combined organic phases were washed with water
and brine, dried with Na2SO4, and filtered. The reaction
mixture was concentrated and purified by silica gel column
chromatography on a gradient column to provide the pure
product (3.9 g, 36% yield) as a mixture of rotamers (1:1 A:B).
1H NMR (600 MHz, DMSO-d6) δ ppm 8.68−8.63 (m, 1H),
7.63−7.54 (m, 1H), 7.47−7.38 (m, 1H), 6.82−6.70 (m, 1H),
5.40−5.29 (m, 1H), 4.41−4.34 (m, 2H), 3.66−3.63 (m, 1H),
CONCLUSION
■
We have demonstrated that immersion-well reactors are an
effective solution for upscaling photoredox cross-coupling
reactions in batch. Because of the reduced loss of incident
photons achieved through the use this reaction setup, we have
found that reaction conditions developed on a milligram scale
can be applied on a multigram scale. More specifically, four
different photoredox-catalyzed carbon−carbon cross-couplings
have been investigated on 10−400 mmol scale. By sharing our
solution to this challenge, we hope that chemists working in
both the life science industry and academia will recognize that
these highly valuable cross-coupling reactions can be readily
applied on preparative scale in batch.
EXPERIMENTAL METHODS
■
Synthesis of tert-Butyl 2-(4-Methoxycarbonylphenyl)-
pyrrolidine-1-carboxylate on a 30 mmol Scale. To the
reaction flask fitted with a stirring magnet were added methyl
4-bromobenzoate (30 mmol, 6.45 g), 1-tert-butoxycarbonyl-
pyrrolidine-2-carboxylic acid (45 mmol, 9.69 g), Cs2CO3 (45
mmol, 14.7 g), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.3 mmol, 337
mg), NiCl2·DME (3 mmol, 659 mg), and dtbbpy (3.6 mmol,
966 mg). The immersion tube was fitted into the reactor, and
DMF (400 mL) was added to the flask. The mixture was
degassed by bubbling argon through the solution for 20 min,
D
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3.49−3.46 (m, 1H), 2.48−2.31 (m, 1H), 1.98−1.89 (m, 1H),
1.88−1.72 (m, 2H), 1.42 (s, 9H, A), 1.38−1.31 (m, 3H), 1.04
(m, 9H, B). 13C NMR (126 MHz, DMSO-d6) δ ppm 163.3,
154.0, 153.5, 145.8, 142.1, 141.0, 136.6, 136.5, 127.1, 116.4,
116.3, 115.6, 115.4, 109.5, 109.1, 79.7, 79.1, 60.79, 57.3, 57.0,
47.2, 46.9, 31.3, 30.0, 28.6, 28.1, 23.8, 23.3, 14.8 (five signals
overlapping). HRMS (ES-TOF) m/z calcd for C19H25N3O4H
[M + H]+ 360.1918, found 360.1909.
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (6.0 g, 57%
yield) as a mixture of rotamers (9:1 A:B). 1H NMR (600 MHz,
DMSO-d6) δ ppm 8.00−7.93 (m, 2H, A+B), 7.64 (d, J = 7.5
Hz, 1H, A+B), 7.51 (d, J = 7.5 Hz, 1H, A+B), 7.29−7.24 (m,
4H, A+B), 7.19−7.21 (m, 1H, A+B), 4.93−4.90 (m, 1H, A),
4.83−4.77 (m, 1H, B), 3.91 (s, 3H, A+B), 3.13 (dd, J = 13.7,
4.9 Hz, 1H, A+B), 2.95 (dd, J = 13.7, 10.4 Hz, 1H, A+B), 1.30
(s, 9H, A), 1.12 (s, 9H, B). 13C NMR (151 MHz, DMSO-d6) δ
ppm 165.3, 162.7, 155.2, 146.7, 138.5, 138.1, 129.2, 128.1,
126.2, 124.5, 123.3, 78.0, 57.3, 52.4, 40.5, 28.2. HRMS (ES-
TOF) m/z calcd for C20H24N2O4H [M + H]+ 357.1809, found
357.1811.
Synthesis of tert-Butyl 2-{3-Trifluoromethoxy-4-
[methyl(phenyl)sulfamoyl]phenyl}piperidine-1-carbox-
ylate on a 30 mmol Scale. To the reaction flask fitted with a
stirring magnet were added 4-bromo-2-hydroxy-N-methyl-N-
phenylbenzenesulfonamide (30 mmol, 12.3 g), 1-tert-butox-
ycarbonylpiperidine-2-carboxylic acid (45 mmol, 10.3 g),
Cs2CO3 (45 mmol, 14.7 g), Ir[dF(CF3)ppy]2(dtbbpy)PF6
(0.3 mmol, 337 mg), NiCl2·DME (3 mmol, 659 mg), and
dtbbpy (4.5 mmol, 1.21 g). The immersion tube was fitted into
the reactor, and DMF (400 mL) was added to the flask. The
mixture was degassed by bubbling argon through the solution
for 20 min, and then the flask was sealed (note: this setup is not
gastightthe CO2 generated is released through the seals,
preventing pressure buildup!). The reaction mixture was placed
in the PhotonCabinet, and the lamp was placed inside the
immersion tube. The reaction mixture was irradiated for 21 h,
and then the crude reaction mixture was analyzed by LCMS
(Figure S6). Following the reaction, water (200 mL) was
added, and the mixture was extracted with EtOAc (3 × 200
mL). The combined organic phases were washed with water
and brine, dried with Na2SO4, and filtered. The reaction
mixture was concentrated and purified by silica gel column
chromatography on a gradient column to provide the pure
product (8.8 g, 57% yield). 1H NMR (500 MHz, DMSO-d6) δ
ppm 7.75 (d, J = 8.2 Hz, 1H), 7.40−7.37 (m, 1H), 7.34−7.30
(m, 2H), 7.28−7.25 (m, 1H), 7.21 (s, 1H), 7.19−7.17 (m,
2H), 5.31−5.28 (m, 1H), 3.95−3.91 (m, 1H), 3.28 (s, 3H),
2.70 (t, J = 3.3 Hz, 1H), 2.23−2.19 (m, 1H), 1.87−1.79 (m,
1H), 1.60−1.53 (m, 2H), 1.47−1.39 (m, 1H), 1.36 (s, 9H),
1.19−1.14 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm
154.5, 149.9, 145.4, 140.5, 132.0, 129.0, 128.0, 127.2, 126.1,
125.2, 118.6, 120.2 (q, J = 261.00 Hz), 79.3, 53.0, 38.2, 28.0,
27.8, 24.3, 18.7 (one signal overlapping). HRMS (ESI-TOF)
m/z calcd for C24H29F3N2O5SH [M + H]+ 515.1822, found
515.1822.
Synthesis of tert-Butyl 2-[6-(3,5-Dimethylpyrazol-1-
yl)pyrimidin-4-yl]pyrrolidine-1-carboxylate on a 30
mmol Scale. To the reaction flask fitted with a stirring
magnet were added 4-chloro-6-(3,5-dimethylpyrazol-1-yl)-
pyrimidine (30 mmol, 6.26 g), 1-tert-butoxycarbonylpyrroli-
dine-2-carboxylic acid (45 mmol, 9.69 g), LiOH (45 mmol,
1.08 g), Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.3 mmol, 337 mg),
NiCl2·DME (3 mmol, 659 mg), and dtbbpy (4.5 mmol, 1.21
g). The immersion tube was fitted into the reactor, and DMF
(400 mL) was added to the flask. The mixture was degassed by
bubbling argon through the solution for 20 min, and then the
flask was sealed (note: this setup is not gastightthe CO2
generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, then the crude
reaction mixture was analyzed by LCMS (Figure S4).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (6.4 g, 63%)
1
as a mixture of rotamers (3:2 A:B). H NMR (600 MHz,
DMSO-d6) δ ppm 8.98−8.93 (m, 1H, A+B), 7.72 (s, 1H, A),
7.68 (s, 1H, B), 6.22 (s, 1H, A+B), 4.86−4.75 (m, 1H A+B),
3.58−3.44 (m, 2H, A+B), 2.67 (s, 3H, A+B), 2.44−2.28 (m,
1H, A+B), 2.21 (s, 3H, A+B), 1.96−1.81 (m, 3H, A+B), 1.44−
1.36 (m, 9H, B), 1.14 (m, 9H, A). 13C NMR (126 MHz,
DMSO-d6) δ ppm 173.4 (A), 172.6 (B), 158.8 (A), 158.6 (B),
157.5(0) (B), 157.4(5) (A), 153.6 (B), 153.1 (A), 151.1 (A),
151.0 (B), 142.4 (B), 142.3 (A), 111.0 (B), 110.9 (A), 106.3
(A), 106.2 (B), 78.9 (B), 78.5 (A), 61.5 (A), 61.2 (B), 47.1
(B), 46.9 (A), 33.2 (A), 32.1 (B), 28.0 (B), 27.7 (A), 26.27,
23.4 (B), 22.9 (A), 15.0 (B), 13.4 (A) (one signal
overlapping). HRMS (ES-TOF) m/z calcd for C18H25N5O2H
[M + H]+ 343.2081, found 343.2082.
Synthesis of Methyl 6-[1-(tert-Butoxycarbonylami-
no)-2-phenylethyl]pyridine-2-carboxylate on a 30
mmol Scale. To the reaction flask fitted with a stirring
magnet were added methyl 6-chloropyridine-2-carboxylate (30
mmol, 5.15 g), 2-(tert-butoxycarbonylamino)-3-phenylpropa-
noic acid (45 mmol, 11.9 g), Cs2CO3 (45 mmol, 14.7 g),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.3 mmol, 337 mg), NiCl2·
DME (3 mmol, 659 mg), and dtbbpy (4.5 mmol, 1.21 g). The
immersion tube was fitted into the reactor, and DMF (400
mL) was added to the flask. The mixture was degassed by
bubbling argon through the solution for 20 min, and then the
flask was sealed (note: this setup is not gastightthe CO2
generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S5).
Following the reaction, water (200 mL) was added, and the
Synthesis of Methyl 4-(2-Cyanoethyl)benzoate on a
60 mmol Scale. To the reaction flask fitted with a stirring
magnet were added methyl 4-bromobenzoate (60.0 mmol,
12.9 g), Na2CO3 (120 mmol, 12.7 g), and Ir[dF(CF3)-
ppy]2(dtbbpy)PF6 (0.6 mmol, 673 mg), followed by DME
(600 mL). A stock solution of NiCl2·DME (0.3 mmol, 65.9
mg) and dtbbpy (0.3 mmol, 80.5 mg) in DME (20 mL) was
prepared and added to the reaction mixture. 3-Bromopropa-
nenitrile (120 mmol, 9.92 mL) was added to the reaction
mixture, and the mixture was degassed by bubbling argon
through the solution for 20 min. After the reaction mixture was
degassed, TTMSS (60 mmol, 18.5 mL) was added, and the
E
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flask was sealed (note: this setup is not gastightthe CO2
generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S7).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (8.7 g, 77%
yield). The data were in accordance with those previously
reported.18
placed in the PhotonCabinet, and the lamp was placed inside
the immersion tube. The reaction mixture was irradiated for 21
h, and then the crude reaction mixture was analyzed by LCMS
(Figure S9). Following the reaction, water (200 mL) was
added, and the mixture was extracted with EtOAc (3 × 200
mL). The combined organic phases were washed with water
and brine, dried with Na2SO4, and filtered. The reaction
mixture was concentrated and purified by silica gel column
chromatography on a gradient column to provide the pure
product (8.8 g, 65% yield). 1H NMR (500 MHz, DMSO-d6) δ
ppm 7.69−7.66 (m, 1H), 7.44−7.41 (m, 2H), 7.36−7.31 (m,
2H), 7.28−7.24 (m, 1H), 7.20−7.16 (m, 2H), 4.12−4.02 (m,
2H), 3.26 (s, 3H), 2.88 (tt, J = 12.2, 3.4 Hz, 1H), 2.84−2.71
(m, 2H), 1.79−1.75 (m, 2H), 1.49 (qd, J = 12.2, 4.4 Hz, 2H),
1.41 (s, 9H). 13C NMR (126 MHz, DMSO-d6) δ ppm 154.3,
153.8, 145.1, 140.5, 131.7, 129.0, 127.8, 127.1, 126.0, 125.6,
119.7, 119.6 (q, J = 259.21 Hz), 78.6, 54.9, 41.2, 38.1, 32.0,
28.1. HRMS (ESI-TOF) m/z calcd for C24H29F3N2O5SNa [M
+ Na]+ 537.1641, found 537.1637.
Synthesis of tert-Butyl 4-Cyano-4-(4-isobutylphenyl)-
piperidine-1-carboxylate on a 25 mmol Scale. To the
reaction flask fitted with a stirring magnet were added tert-
butyl 4-(4-bromophenyl)-4-cyanopiperidine-1-carboxylate
(25.0 mmol, 9.13 g), Na2CO3 (50 mmol, 5.30 g), and
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.25 mmol, 280 mg), followed
by α,α,α-trifluorotoluene (240 mL) and DMA (40 mL). A
stock solution of NiCl2·DME (0.125 mmol, 27.5 mg) and
dtbbpy (0.125 mmol, 33.6 mg) in DMA (20 mL) was prepared
and added to the reaction mixture. 1-Bromo-2-methylpropane
(75 mmol, 8.02 mL) was added to the reaction mixture, and
the mixture was degassed by bubbling argon through the
solution for 20 min. After the reaction mixture was degassed,
TTMSS (25 mmol, 7.71 mL) was added, and the flask was
sealed (note: this setup is not gastightthe CO2 generated is
released through the seals, preventing pressure buildup!). The
reaction mixture was placed in the PhotonCabinet, and the
lamp was placed inside the immersion tube. The reaction
mixture was irradiated for 21 h, and then the crude reaction
mixture was analyzed by LCMS (Figure S8). Following the
reaction, water (200 mL) was added, and the mixture was
extracted with EtOAc (3 × 200 mL). The combined organic
phases were washed with water and brine, dried with Na2SO4,
and filtered. The reaction mixture was concentrated and
purified by silica gel column chromatography on a gradient
Synthesis of [5-(4-Cyclohexylphenyl)-2-furyl]-
(morpholino)methanone on a 25 mmol Scale. To the
reaction flask fitted with a stirring magnet were added [5-(4-
bromophenyl)-2-furyl](morpholino)methanone (25.0 mmol,
8.41 g), bromocyclohexane (75.0 mmol, 9.02 g), Na2CO3 (50
mmol, 5.30 g), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.25 mmol,
280 mg), followed by DME (600 mL). A stock solution of
NiCl2·DME (0.125 mmol, 27.5 mg) and dtbbpy (0.125 mmol,
33.6 mg) in DME (20 mL) was prepared and added to the
reaction mixture. The mixture was degassed by bubbling argon
through the solution for 20 min. After the reaction mixture was
degassed, TTMSS (25 mmol, 7.71 mL) was added, and the
flask was sealed (note: this setup is not gastightthe CO2
generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S10).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (4.2 g, 52%
1
column to provide the pure product (6.2 g, 72% yield). H
NMR (500 MHz, DMSO-d6) δ ppm 7.44 (d, J = 8.2 Hz, 2H),
7.23 (d, J = 8.2 Hz, 2H), 4.20−4.03 (m, 2H), 3.01 (br s, 2H),
2.47−2.45 (m, 2H), 2.11 (br d, J = 12.3 Hz, 2H), 1.96−1.77
(m, 3H), 1.42 (s, 9H), 0.86 (d, J = 6.6 Hz, 6H). 13C NMR
(126 MHz, DMSO-d6) δ ppm 153.6, 141.1, 137.0, 129.5,
125.3, 121.6, 79.1, 43.9, 41.7, 35.0, 29.5, 28.0, 22.1 (one signal
overlapping). HRMS (ESI-TOF) m/z calcd for
C21H30N2O2Na [M + Na]+ 365.2199, found 365.2186.
Synthesis of tert-Butyl 4-{3-Trifluoromethoxy-4-
[methyl(phenyl)sulfamoyl]phenyl}piperidine-1-carbox-
ylate on a 25 mmol Scale. To the reaction flask fitted with a
stirring magnet were added 4-bromo-2-hydroxy-N-methyl-N-
phenylbenzenesulfonamide (25.0 mmol, 10.3 g), tert-butyl 4-
bromopiperidine-1-carboxylate (75.0 mmol, 19.8 g), and
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.25 mmol, 280 mg), followed
by DME (600 mL). A stock solution of NiCl2·DME (0.125
mmol, 27.5 mg) and dtbbpy (0.125 mmol, 33.6 mg) in DME
(20 mL) was prepared and added to the reaction mixture. The
mixture was degassed by bubbling argon through the solution
for 20 min. After the reaction mixture was degassed, TTMSS
(25 mmol, 7.71 mL) was added, and the flask was sealed (note:
this setup is not gastightthe CO2 generated is released through
the seals, preventing pressure buildup!). The reaction mixture was
1
yield). H NMR (500 MHz, DMSO-d6) δ ppm 7.68 (m, J =
8.2 Hz, 2H), 7.31 (m, J = 8.2 Hz, 2H), 7.13 (d, J = 3.5 Hz,
1H), 7.04 (d, J = 3.5 Hz, 1H), 3.87−3.69 (m, 4H), 3.69−3.63
(m, 4H), 2.56−2.52 (m, 1H), 1.79 (br d, J = 11.3 Hz, 4H),
1.70 (br d, J = 12.3 Hz, 1H), 1.46−1.31 (m, 4H), 1.23 (br d, J
= 12.3 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ ppm
158.1, 154.5, 148.1, 145.8, 127.3, 127.0, 124.1, 118.2, 106.4,
66.2, 43.5, 33.7, 26.2, 25.5 (one signal overlapping). HRMS
(ESI-TOF) m/z calcd for C21H25NO3H [M + H]+ 340.1909,
found 340.1907.
Synthesis of tert-Butyl 7-Cyclohexyl-4-oxospiro-
[chromane-2,4′-piperidine]-1′-carboxylate on a 25
mmol Scale. To the reaction flask fitted with a stirring
magnet were added tert-butyl 7-cyclohexyl-4-oxospiro-
[chromane-2,4′-piperidine]-1′-carboxylate (25.0 mmol, 9.91
g), bromocyclohexane (75.0 mmol, 9.02 g), Na2CO3 (50
mmol, 5.30 g), and Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.25 mmol,
280 mg), followed by DME (600 mL). A stock solution of
NiCl2·DME (0.125 mmol, 27.5 mg) and dtbbpy (0.125 mmol,
33.6 mg) in DME (20 mL) was prepared and added to the
F
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Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Communication
reaction mixture. The mixture was degassed by bubbling argon
through the solution for 20 min. After the reaction mixture was
degassed, TTMSS (25 mmol, 7.71 mL) was added, and the
flask was sealed (note: this setup is not gastightthe CO2
generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S11).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (5.0 g, 53%
yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.53 (d, J = 2.2
Hz, 1H), 7.45 (dd, J = 8.5, 2.2 Hz, 1H), 6.99 (d, J = 8.5 Hz,
1H), 3.78−3.63 (m, 2H), 3.23−3.01 (m, 2H), 2.80 (s, 2H),
1.85 (br d, J = 13.2 Hz, 2H), 1.80−1.73 (m, 4H), 1.69 (br d, J
= 12.3 Hz, 1H), 1.60 (br t, J = 10.4 Hz, 2H), 1.42−1.30 (m,
13H), 1.27−1.10 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ
ppm 191.5, 156.8, 153.7, 140.2, 135.2, 122.8, 119.9, 118.1,
78.7, 77.6, 46.7, 42.5, 33.8, 28.0, 26.2, 25.4 (two signals
overlapping). HRMS (ESI-TOF) m/z calcd for C24H33NO4Na
[M + Na]+ 422.2299, found 422,2302.
Synthesis of tert-Butyl 2-Benzylpyrrolidine-1-carbox-
ylate on a 30 mmol Scale. To the reaction flask fitted with a
stirring magnet were added 1-tert-butoxycarbonylpyrrolidine-2-
carboxylic acid (45 mmol, 9.69 g), K2CO3 (60 mmol, 8.29 g),
Ir[dF(CF3)ppy]2(dtbbpy)PF6 (0.6 mmol, 673 mg), NiCl2·
DME (3 mmol, 659 mg), and 4,4′-dimethoxy-2,2′-bipyridine
(3.0 mmol, 649 mg). The immersion tube was fitted into the
reactor, and acetonitrile (300 mL) was added to the flask,
followed by chloromethylbenzene (30 mmol, 3.45 mL). The
mixture was degassed by bubbling argon through the solution
for 20 min, and then degassed water (600 mmol, 10.8 mL) was
added and the flask was sealed (note: this setup is not gastight
the CO2 generated is released through the seals, preventing pressure
buildup!). The reaction mixture was placed in the Photo-
nCabinet, and the lamp was placed inside the immersion tube.
The reaction mixture was irradiated for 21 h, and then the
crude reaction mixture was analyzed by LCMS (Figure S12).
Following the reaction, water (200 mL) was added, and the
mixture was extracted with EtOAc (3 × 200 mL). The
combined organic phases were washed with water and brine,
dried with Na2SO4, and filtered. The reaction mixture was
concentrated and purified by silica gel column chromatography
on a gradient column to provide the pure product (4.5 g, 57%
yield). The data were in accordance with those previously
reported.17
mixture was analyzed by LCMS (Figure S13). Following the
reaction, water (200 mL) was added, and the mixture was
extracted with EtOAc (3 × 200 mL). The combined organic
phases were washed with water and brine, dried with Na2SO4,
and filtered. The reaction mixture was concentrated and
purified by silica gel column chromatography on a gradient
column to provide the pure product (5.1 g, 58% yield). The
data were in accordance with those previously reported.5a
Synthesis of Methyl 4-(2-Cyanoethyl)benzoate on a
400 mmol Scale in the Side-Loop Reactor. To the
reaction flask fitted with immersion tube and the connected
side loop with PTFE tubing (internal diameter = 12 mm) were
added methyl 4-bromobenzoate (400 mmol, 86.0 g), 2,6-
lutidine (800 mmol, 85.7 g), and Ir[dF(CF3)ppy]2(dtbbpy)-
PF6 (4.0 mmol, 4.49 g), followed by DME (4.59 L). A solution
of NiCl2·DME (2 mmol, 439 mg) and dtbbpy (2 mmol, 537
mg) in DME (300 mL) was prepared and added to the
reaction mixture. 3-Bromopropanenitrile (800 mmol, 66.2 mL)
was added to the reaction mixture, and the mixture was
degassed by bubbling nitrogen through the solution for 10 min.
After the reaction mixture was degassed, the pump was started
to circulate the reaction mixture. TTMSS (400 mmol, 99.4 g)
was added, and the mixture was degassed for a further 45 min.
The reaction mixture was irradiated for 25 h and monitored
with calibrated LCMS. The reaction mixture was circulated
using an IWAKI magnet pump (MD-55F-X magnet-driven
impeller pump) at a flow rate of 10 mL/min. After 25 h, the
product was observed in 76% yield based on calibrated LCMS
analysis.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.oprd.0c00070.
■
sı
1
Diagrams of the reactor setups, copies of H and 13C
NMR spectra for products, and HPLC traces of reaction
mixtures (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Lisa Candish − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany; orcid.org/
0000-0003-1235-1265; Email: lisa.candish@bayer.com
Authors
Isabelle Grimm − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany
Simone T. Hauer − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany
Tim Schulte − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany
Gina Wycich − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany
Karl D. Collins − Small Molecule Innovations, Bayer AG
Pharmaceuticals, 42113 Wuppertal, Germany
Kai Lovis − Chemical Development, Bayer AG Pharmaceuticals,
42117 Wuppertal, Germany
Synthesis of Methyl 4-Benzylbenzoate on a 40 mmol
Scale. To the reaction flask fitted with a stirring magnet were
added methyl 4-bromobenzoate (40 mmol, 8.60 g), potassium
benzyltrifluoroborate (50 mmol, 9.90 g), Ir[dF(CF3)-
ppy]2(dtbbpy)PF6 (0.4 mmol, 449 mg), NiCl2·DME (1.2
mmol, 264 mg), and dtbbpy (1.6 mmol, 429 g). The
immersion tube was fitted into the reactor, and DMF (400
mL) was added to the flask, followed by 2,6-lutidine (140
mmol, 16.3 mL). The mixture was degassed by bubbling argon
through the solution for 20 min, and then the flask was sealed.
The reaction mixture was placed in the PhotonCabinet, and
the lamp was placed inside the immersion tube. The reaction
mixture was irradiated for 21 h, and then the crude reaction
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.oprd.0c00070
Notes
The authors declare no competing financial interest.
G
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pubs.acs.org/OPRD
Communication
Eds.; Wiley-VCH: Weinheim, Germany, 2018; pp 389−413 and
references therein.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the helpful discussions with the
Bayer Photochemistry Community, in particular Dr. Steffen
Mueller, Dr. Dominik Hager, Dr. Isabel Kerschgens, Dr.
Kathryn Chepiga, Dr. Alexander Sudau, Dr. Daniel Rackl, and
Dr. Robin Meier. We also thank Christian Finke for
experimental work (Bayer) and Dr. Nicolas Guimond
(7) Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph,
M. J.; Lejeune, G.; Edwards, L. J.; Robinson, R. I.; Clemens, I. R.;
Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.; Berry, M. B.; Booker-
Milburn, K. I. Batch versus Flow Photochemistry: A Revealing
Comparison of Yield and Productivity. Chem. - Eur. J. 2014, 20,
15226.
(8) For selected examples, see: (a) Borman, S. Chemists Go 100%
Organic At 2015 NOS. Chem. Eng. News 2015, 93 (29), 33. (b) Yayla,
H. G.; Peng, F.; Mangion, I. K.; McLaughlin, M.; Campeau, L.-C.;
Davies, I. W.; DiRocco, D. A.; Knowles, R. R. Discovery and
mechanistic study of a photocatalytic indoline dehydrogenation for
the synthesis of elbasvir. Chem. Sci. 2016, 7, 2066. (c) Beatty, J. W.;
Douglas, J. J.; Miller, R.; McAtee, R. C.; Cole, K. P.; Stephenson, C. R.
J. Photochemical Perfluoroalkylation with Pyridine N-Oxides:
Mechanistic Insights and Performance on a Kilogram Scale. Chem.
2016, 1, 456. (d) Harper, K. C.; Moschetta, E. G.; Bordawekar, S. V.;
Wittenberger, S. J. A Laser Driven Flow Chemistry Platform for
Scaling Photochemical Reactions with Visible Light. ACS Cent. Sci.
2019, 5, 109.
(9) For three representative examples of the application of
photoredox cross-coupling reactions in flow, see: (a) Hsieh, H.-W.;
Coley, C. W.; Baumgartner, L. M.; Jensen, K. F.; Robinson, R. I.
Photoredox Iridium−Nickel Dual-Catalyzed Decarboxylative Aryla-
tion Cross-Coupling: From Batch to Continuous Flow via Self-
Optimizing Segmented Flow Reactor. Org. Process Res. Dev. 2018, 22,
542. (b) Lima, F.; Kabeshov, M. A.; Tran, D. N.; Battilocchio, C.;
Sedelmeier, J.; Sedelmeier, G.; Schenkel, B.; Ley, S. V. Visible Light
Activation of Boronic Esters Enables Efficient Photoredox C(sp2)−
C(sp3) Cross-Couplings in Flow. Angew. Chem., Int. Ed. 2016, 55,
14085. (c) Brill, Z. G.; Ritts, C. B.; Mansoor, U. F.; Sciammetta, N.
Continuous Flow Enables Metallaphotoredox Catalysis in a Medicinal
Chemistry Setting: Accelerated Optimization and Library Execution
of a Reductive Coupling between Benzylic Chlorides and Aryl
Bromides. Org. Lett. 2020, 22, 410. In all of these examples,
performing the reactions in flow required significant reoptimization of
the batch conditions.
́
́
́
̈
(Bayer) and Adrian Gomez Suarez (Bergisches Universitat
Wuppertal) for insightful discussions.
ABBREVIATIONS
■
PRC, photoredox catalysis; IW, immersion-well; LED, light-
emitting diode; SAR, structure−activity relationship
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I
https://dx.doi.org/10.1021/acs.oprd.0c00070
Org. Process Res. Dev. XXXX, XXX, XXX−XXX