Continuous photochemical benzylic bromination using: In situ generated Br2: Process intensification towards optimal PMI and throughput

Article abstract of DOI:10.1039/c9gc03662h

The detailed development of photochemical benzylic brominations using a NaBrO₃/HBr bromine generator in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photochemical reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of organic solvent, allowed a reduction in PMI from 13.25 to just 4.33. The photochemical transformation achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s. The organic solvent-free preparation of two pharmaceutically relevant building blocks was demonstrated with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromination (15 g scale in 20 min, PMI = 3.64).

Full text of DOI:10.1039/c9gc03662h

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Continuous photochemical benzylic bromination
using in situ generated Br2: process intensification
towards optimal PMI and throughput†
Cite this: DOI: 10.1039/c9gc03662h
c
Alexander Steiner,a,b Jason D. Williams, a,b Oscar de Frutos,c Juan A. Rincón,
a,b
Carlos Mateos c and C. Oliver Kappe
*
The detailed development of photochemical benzylic brominations using a NaBrO3/HBr bromine genera-
tor in continuous flow mode is reported. Optimization of the bromine generator enables highly efficient
mass utilization by HBr recycling, coupled with fast interphase transfer within a microstructured photo-
chemical reactor (405 nm LEDs). Intensification of the reaction system, including complete removal of
organic solvent, allowed a reduction in PMI from 13.25 to just 4.33. The photochemical transformation
achieved exceptionally high throughput, providing complete conversion in residence times as low as 15 s.
The organic solvent-free preparation of two pharmaceutically relevant building blocks was demonstrated
with outstanding mass efficiency, by monobromination (1.17 kg scale in 230 min, PMI = 3.08) or dibromi-
nation (15 g scale in 20 min, PMI = 3.64).
Received 24th October 2019,
Accepted 10th December 2019
DOI: 10.1039/c9gc03662h
rsc.li/greenchem
photochemical benzylic bromination reactions have been
reported in flow.4
Introduction
Benzyl bromides serve as important and frequently used build-
The most frequently used bromine source in these reactions
ing blocks towards target molecules in the pharmaceutical, is N-bromosuccinimide (NBS), owing to its safe and convenient
agrochemical and materials industries (Fig. 1a). Their syn- handling as a crystalline solid.4b–e These procedures are then,
thesis is generally performed by radical bromination of a
toluene derivative, proceeding via thermally or photochemi-
cally generated bromine radicals.1 Carrying out these chem-
istries in a cost-effective, sustainable and safe manner is a
topic of significant interest for both small and large scale
applications.
The application of photochemistry can achieve the desired
reactivity without the need for additional reagents (such as
radical initiators) or high temperatures, as has been commonly
employed.2 The scalability and productivity of photochemical
methods such as these can be significantly enhanced by flow
processing, which has the major advantage of providing
uniform irradiation of a shorter path length, when compared
to large scale batch processes.3 Indeed, many examples of
aCenter for Continuous Flow Synthesis and Processing (CC FLOW), Research Center
Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria.
E-mail: oliver.kappe@uni-graz.at; http://goflow.at
bInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010
Graz, Austria
cCentro de Investigación Lilly S. A. Avda. de la Industria 30, 28108 Alcobendas-
Fig. 1 (a) A selection of Active Pharmaceutical Ingredients (APIs) con-
taining building blocks accessible using photochemical benzylic bromina-
tion reactions; (b) the concept described here, for the photochemical
benzylic bromination of toluene derivatives, using a Br2 generator in flow.
Madrid, Spain
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9gc03662h
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however, limited to comparatively low concentrations, benchtop 19F NMR (Magritek Spinsolve Ultra 43 MHz).18 After
restricted by the solubility of NBS, particularly when an excess a screen of reaction solvents in batch, with 400 nm irradiation,
of this reagent is required. The resulting reaction conditions it was found that aprotic solvents in general were favored.18
can inevitably lead to significantly heightened solvent wastage, Chlorobenzene was selected as the most suitable solvent at
which is often a leading contributor to high process mass this point, due to its good solubilizing properties and favor-
intensity (PMI)5 for an isolated reaction step.6 A multitude of able health and environmental characteristics when compared
other reagents have been employed for these reactions, such to other chlorinated solvents.19
8
as CBrCl3,7 CBr4 and tribromoisocyanuric acid,9 but these
Flow experiments were performed using a commercial glass
generally suffer from similar issues of poor solubility and/or plate-based flow photochemical reactor (Corning Lab Photo
low reactivity. Reactor) with an irradiated volume of 2.8 mL, an internal
The use of molecular bromine relieves these restrictions, mixing structure and a jacket for heat exchange fluid.20 The
allowing a faster rate of reaction and more concentrated oper- initial Br2 generator conditions were adapted from a previous
ating conditions.4f Molecular bromine is, however, an exceed- flow methodology.16a Here, NaBr was added to solubilize the
ingly undesirable reagent to transport and handle.10 In generated Br2 in the aqueous phase, as a 1 M solution, prior to
keeping with the principles of green chemistry, a multitude of mixing with the organic substrate stream. Inside the reactor
protocols report the formation of Br2 in situ – generally by plate, Br2 is extracted into the organic phase, whilst irradiation
mixing an oxidant with a source of bromide ions, under acidic by 405 nm LEDs (56.8 W output power) initiates the radical
conditions. This generator concept has been demonstrated to bromination reaction (Fig. 2).
provide excellent mass efficiency, in many cases even compar-
Using this setup, the influence of residence time, concen-
tration, temperature and Br2 equivalents on the product ratio
able to direct use of Br2.11
The most common oxidant for this role is H2O2,12 which is was established (Table 1). High flow rates (short residence
stored and used as an aqueous solution. However, there are
safety concerns associated with the decomposition of such per-
oxides in storage. Alternatively, NaBrO3 is a crystalline solid,
with a very high decomposition temperature of 310 °C,13 allow-
ing safer transport and storage. Reports using this oxidant
have hypothesized BrOH as an intermediate, which further
reacts with bromide ion to form Br2.14
The oxidation of bromide is a highly exothermic process,
particularly when concentrated conditions are used (achieving
a lower PMI). Consequently, the use of flow processing is desir-
able for its vastly improved heat and mass transfer, which is
especially important when considering larger volume pro-
cesses.15 Surprisingly, considering its excellent suitability, only
scarce reports exist in which a Br2 generator is utilized in
Fig. 2 Initial experimental setup using 1st generation Br2 generator.
flow.16
According to our interests in flow photochemistry, reaction
intensification and chemical generator concepts, we sought to
Table 1 Optimization of reaction conditions for the benzylic bromina-
tion of 1 in flow, using the 1st generation Br2 generator
develop a highly optimized bromine generator system, for use
in continuous flow photochemical benzylic bromination reac-
tions (Fig. 1b). By conducting a thorough investigation with a
focus on minimizing PMI, whilst maximizing throughput, we
aimed to develop a safe protocol suitable for implementation
at production scale.
Conc. tRes
Entry [M] [sec] [°C]
Temp. Br2
[equiv]
1
a [%]
2
a [%]
3
a [%]
Results and discussion
Initial optimization
1
2
3
4
5
6
7
8
9b
1
2
4
4
4
4
4
4
4
15
20
1
19
57
93
69
20
47
23
0
73
42
7
31
74
52
70
25
0
8
15 20
1
1
1
1
1
1
2
1
1
0
0
6
1
7
15
30
60
60
30
60
60
20
20
20
5
50
50
50
Reaction optimization was initiated using 4-fluorotoluene (1)
as a model substrate, which is a structural component of mul-
tiple Active Pharmaceutical Ingredients (APIs) such as the HIV
treatment, raltegravir (Fig. 1a).17 It has previously been demon-
strated to undergo photochemical benzylic bromination in
flow, with a short residence time.4f Furthermore, the reaction
performance could be quantified rapidly and effectively using
75
0
100
a Product ratios were determined by benchtop 19F NMR. b Reaction was
run without irradiation.
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time) were expected to be required, to allow good mass transfer
between the aqueous and organic phases.21 The result at 1 M
concentration, 20 °C, 15 s (entry 1) showed a very similar
product distribution to the optimal seen in batch experi-
ments.18 Conversion of 81% starting material 1 was observed,
yielding 73% of the desired monobrominated product 2 and
8% of the dibrominated side product 3.
It was found that the reaction is significantly slower under
more concentrated conditions (entries 1–3). This is proposed to
be because a higher substrate concentration results in a higher
proportion of aqueous phase (larger aqueous slugs), which
hinders mass transfer between the phases. In order to continue
working at higher concentration, the residence time was extended
to 30 s (entry 4), then to 60 s (entry 5), by which point the same
optimal product ratio was observed again (entry 1 vs. entry 5).
A lower temperature of 5 °C resulted in a slower reaction,
which still yielded a small amount of dibrominated product 3,
implying that no significant improvement in selectivity is poss-
ible (entry 6). Increasing the temperature to 50 °C permitted
the residence time to be reduced back to 30 s (entry 7). Upon
increasing the quantity of Br2 to 2 equivalents (by altering the
flow rate ratio of generator to substrate), the dibrominated
product 3 could be favored, implying that under forcing con-
ditions this could be obtained as the sole product (entry 8).
The tribrominated product was not observed at any point, nor
was any extent of (electrophilic) ring bromination. Finally, a
control experiment was performed without light, to confirm
that the reaction could not be promoted by the elevated temp-
erature alone (entry 9).14a
Fig. 3 Summary of three “generations” of Br2 generator, including their
flow setup, PMI of Br2, aqueous volume efficiency and productivity in
the conversion of 1 to monobrominated product 2. The displayed flow
rates show the required values for a residence time of 30 s.
The mono- versus dibromination selectivity of this trans-
formation appears to be intrinsic to the substrate, as deter-
mined by the low energy barrier to reaction for both the first previously) and delivering a more uniform quantity of Br2.
and second functionalization steps.4c Nevertheless, the most This uniform delivery, in turn, provided
a significantly
favorable conditions up until this point (Table 1, entry 7) pro- enhanced rate of reaction (generator v2, Fig. 3c).18 Following a
vided an excellent productivity of 35 g h−1 (space–time yield = brief intensification study, the generator v2 system provided
12.5 kg L−1 −1). On the other hand, a substantial quantity of product 2 in a much improved productivity of 74 g h−1 (space–
h
waste is generated, with a PMI of 13.55 – the major contri- time yield = 26.7 kg L−1 h−1). Perhaps more importantly, the
bution (10.73) arising from the Br2 generator.
PMI of the overall bromination process was reduced to 6.93,
due to the far higher aqueous feed concentrations.
Br2 generator optimization
Upon revisiting the overall reaction stoichiometry, it was
With the aim of minimizing PMI, the bromine generator was noted that each successful bromination releases HBr as a by-
identified as a major source of wastage. Accordingly, efforts product. This can be recycled, reducing the required flow rate
were initiated to streamline the generator (Fig. 3a). The initial of the HBr feed and further decreasing mass waste (Fig. 3d).6
system had been developed to provide
a homogeneous Moreover, it was hypothesized that effective mass transfer
aqueous solution of bromine for extraction at a later stage within the currently utilized flow reactor would enable the
(Fig. 3b). By using a reactor with an internal mixing struc- required interphase mixing of produced HBr back into the
ture,21 this was expected to be unnecessary. Consequently, aqueous phase.21 A short study was carried out, gradually redu-
NaBr could be entirely removed from the system, since its cing the equivalents of HBr (denoted as X in Fig. 3a), from 2 to
main purpose was to improve the aqueous solubility of Br2.
1, which revealed that this alteration is indeed possible
Although the efficiency was significantly improved in this (Fig. 4). The reaction performance was maintained when
manner, the reaction rate appeared to drop, likely due to ineffi- moving from 2 equiv. to 1.5 equiv., yet showed a very minor
cient transfer of bromine into the organic phase. To further decrease in yield of desired product 2 at 1 equiv. and a further
improve interphase mixing, the organic phase was premixed decrease to 66% using 0.9 equiv. Performance at 1 equiv.
with the HBr stream in a T-piece, prior to entering the reactor could be restored by using more concentrated HBr (48%,
plate. As a result, Br2 was generated within the mixing struc- 8.8 M). This effect is likely due to the lower aqueous volume,
ture, preventing any accumulation (which had been observed allowing more efficient biphasic mixing.
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ance for highly concentrated conditions. In fact, the substrate
could even be pumped neat (9.1 M) and still achieve an excel-
lent level of conversion at 50 °C, with a residence time of 15 s.
This resulted in a significant increase in productivity, to 228 g
h−1 (space–time yield = 82.3 kg L−1 h−1), with a low PMI of
4.33. Following functionalization with morpholine,18 the
desired product was isolated in 73% yield.
In order to reach close to full conversion whilst maintaining a
short residence time, it was found that additional Br2 (1.4 equiv.)
and a higher reaction temperature (55 °C) was required.18 The
resulting conditions afforded 146 g h−1 of the desired product,
with 3% starting material remaining. Following diethylphosphite
reduction, these conditions should provide the desired product 2
in higher purity – an approach likely favored by lower volume
applications, such as pharmaceutical production.
Fig. 4 Chart showing the performance of benzylic bromination upon
altering equivalents of HBr used in the bromine generator.
Conversely, lower temperature (30 °C) and Br2 loading (0.6
equiv.)18 provided a reasonable yield of 2 (50%) with only 3%
of side product 3 (Fig. 6). This equates to a throughput of
234 g h−1. The productivity does increase when working at
partial conversion, due to the lower relative aqueous flow rates
(substrate flow rate = 4.53 mL min−1 at 0.6 equiv. Br2 vs.
2.11 mL min−1 at 1.4 equiv. Br2). Overall, however, there is not
a significant productivity advantage to working at partial con-
version (unlike in many other cases), since the reaction kine-
tics are fast enough to allow high flow rates under the standard
reaction conditions.
The fully optimized generator system (generator v3, Fig. 3e)
now produces 3.8 mmol (607 mg) of Br2 per mL of aqueous
phase. Furthermore, the productivity of monobrominated
product 2 was dramatically increased to 130 g h−1 (space–time
yield = 46.9 kg L−1 −1), due to the reduction in aqueous volume.
h
This system actually incorporates a higher proportion of bromine
atoms into the final product than elemental bromine itself (75%
vs. 50%, respectively), decreasing the mass of waste, and provid-
ing further advantage to using a Br2 generator.
Further intensification using improved Br2 generator
It should be emphasized that under these highly intensified
conditions, the formation of Br2 and the photochemical reac-
tion are both highly exothermic processes. Accordingly, the
use of a jacketed flow reactor with sufficient heat transfer is
vital. Attempts to reproduce this chemistry in a tubing-based
photoreactor resulted in a substantial exotherm within the
first minutes of processing. Furthermore, carrying out this
chemistry in batch would require a significantly extended
reagent addition period to prevent thermal runaway.
With the optimized generator system in hand, the bromination
reaction was revisited to enact further process intensification.
More specifically, it was envisaged that this process could be
operated with one of two sets of conditions, towards either
complete consumption of starting material 1, or complete
selectivity for product 2. Complete starting material consump-
tion would invariably yield a significant quantity of dibromi-
nated side product 3, however this can then be readily reduced
to the desired product using diethylphosphite.22 Alternatively,
operating at incomplete conversion would minimize the quan-
tity of dibrominated product 3 and allow simplified recycling
of starting material 1 (Fig. 5).
Monobromination of 2,6-dichlorotoluene
We sought to demonstrate this methodology in the synthesis
of 2,6-dichlorobenzyl bromide (5) – a commonly-occurring
To our initial surprise, the bromination of 1 using the
improved Br2 generator demonstrated a much improved toler-
Fig. 5 Scheme showing the complementary approaches to obtaining
optimal productivity of desired product 2, by starting material recycling,
or diethyl phosphite reduction.
Fig. 6 Graph comparing conditions optimized towards full conversion
or full selectivity, versus the general conditions.
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building block in medicinal chemistry, notably in the APIs
vilanterol and isoconazole (Fig. 1a).23 In particular, vilanterol
is an important molecule, used in three inhaled combination
therapies marketed by GlaxoSmithKline.24
In reactions of this specific substrate, dibromination was
not observed, likely due to the steric hindrance imparted by two
chlorine atoms flanking the reactive benzylic position. Despite
this, the monobromination was still observed to occur at a fast
rate, under organic solvent-free conditions, achieving full con-
version within 15 s residence time (Fig. 7a).18 In the absence of
fluorine atoms, the final reaction composition could also be
reliably determined by benchtop 1H NMR spectroscopy.
The desired product 5 is a low melting solid, with a melting
point of 55 °C – below the reactor temperature, which ensured
no solid formation. However, this meant that upon reaching
the collection vessel containing Na2S2O3 quench, the product
immediately solidified, encapsulating the small amount of
excess Br2 before it could be effectively quenched. This could
be remedied by heating the collection vessel to 60 °C, which
allows mixing between the liquid product and aqueous phase.
The product could now be isolated as white crystals in 97%
yield, on a 30.7 g scale, in just 5 minutes processing time
(Fig. 7a). An inline quench using a second mixing chip was
also possible, provided residence time and mixing intensity
were sufficient (Fig. 7b).18
A scale-out run was also performed, but with a slightly
lengthened residence time (18 s) to minimize the effect of
pump pulsation. In this case, 1.17 kg (97% yield) of the desired
product 5 was isolated in less than 4 h (230 min) processing
time, corresponding to a productivity of 300 g h−1 (space–time
yield = 108.3 kg L−1 h−1).18 The PMI of this transformation
(including aqueous mass) was calculated to be 3.08 – an excep-
tional value, particularly for a photochemical transformation.
Fig. 8 (a) Graph showing the effect of residence time upon the mono-
(7) to dibrominated (8) product ratio; (b) experimental setup using 3rd
generation Br2 generator for the synthesis of 2,4-dichlorobenzal
bromide 8.
Dibromination of 2,4-dichlorotoluene
Although less frequently reported, photochemical benzylic
dibromination can provide a facile route to masked aldehyde
compounds. For example, dibromination of 2,4-dichloroto-
luene (6) results in 2,4-dichlorobenzal bromide (8).16c The
equivalent aldehyde is also an intermediate in the synthesis of
isoconazole (Fig. 1a). Again, benchtop NMR was sufficient to
determine the ratio of starting material, mono- and dibromi-
nated products (6, 7 and 8, respectively).
As expected, a longer residence time, in combination with a
slightly increased temperature, was required to achieve com-
pletion of the second bromination reaction (Fig. 8a). The quan-
tity of Br2 was maintained at 2.2 equiv., in order to avoid
wastage. Thus, using neat conditions, the masked aldehyde 8
was obtained in 99% isolated yield, with a residence time of
100 s (Fig. 8b). This meant that the productivity was lower than
in monobromination reactions, yet was still a comparatively
high value of 44 g h−1 (space–time yield = 15.9 kg L−1 h−1).
Conclusions
The development of a highly intensified NaBrO3/HBr-based
Br2 generator has been reported and exemplified. A detailed
study of the benzylic bromination reaction was initially carried
out, determining the effects of temperature, residence time,
Fig. 7 (a) Schematic representation of the experimental setup for the
synthesis of 2,6-dichlorobenzyl bromide 5 using the 3rd generation Br2
generator; (b) schematic representation of the in-line sodium thiosulfate
quench setup, ensuring that no Br2 remains.
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Table 2 Summary of the processes described within this work, com-
paring their productivity and PMI
tubing-based photoreactor, the temperature was observed to
increase extremely rapidly, due to the exothermic nature of the
photochemical reaction.
The benzyl bromide products of these reactions have lachry-
matory properties (not listed on their MSDS data), so care
should be taken to ensure their containment within a venti-
lated space.
Entry Product
Yield (%) Productivity (g h−1
)
PMI
1
2
2 (Br2 generator v1) 69
2 (Br2 generator v2) 69
2 (Br2 generator v3) 68
35
13.55
6.93
4.33
5.51
4.12
3.08
3.64
74
228
146
234
300
44
3a
4a
5a
6a
7a
2 (full conversion)
67
50
97
99
2 (full selectivity)
5
8
Procedure for the monobromination of 2,6-dichlorotoluene (4)
A waste collection flask was charged with a small volume of
saturated sodium thiosulfate solution and was stirred with a
magnetic stirrer. A 3-necked flask was charged with ∼50 mL
sodium thiosulfate solution (2.64 M) and equipped with a
stirrer bar. The reactor was turned on (405 nm LEDs and ther-
mostats) and the reactor thermostat was set to 55 °C. After the
temperature of the reactor stabilized, the pumps were turned
on. Flow rates: substrate 3.39 mL min−1, HBr 3.29 mL min−1
and NaBrO3 4.40 mL min−1. Solutions: 2,6-Dichlorotoluene
(neat, 7.79 M), HBr (8.8 M, 1.1 equiv.) and NaBrO3 (2.2 M, 0.37
equiv.). The system was allowed to equilibrate for ∼5 min, then
the reactor output was collected into the stirred 3-necked flask
for 5 min (heated to 60 °C during product collection). The col-
lection flask was then allowed to cool gradually for 16 h,
before the product was filtered, washed with water (∼200 mL)
and then dried under reduced pressure to afford the desired
product as a white crystalline solid (30.7 g, 97% yield).
a Reaction carried out using Br2 generator v3.
concentration and Br2 loading. This model substrate was then
used for further optimization of the Br2 generator, which was
found to be mixing sensitive, and could be intensified for
exceptional mass efficiency (Table 2). Key prerequisites for the
success of this transformation are: effective mass transfer for
interphase mixing, but also heat transfer to control the
exothermic nature of both Br2 generation and the photochemi-
cal reaction itself.
Using the optimized Br2 generator, it was found that the
reaction concentration could be increased further, even per-
mitting pumping the starting material neat, which drastically
reduces mass wastage. This could be optimized towards full
conversion or full selectivity by tuning the temperature and
equivalents of Br2 used. Ultimately, the desired product could
be isolated in 73% yield, following derivatization with morpho-
line. The optimized Br2 generator system could also be applied
to other bromination processes in flow.
Finally, the protocol was demonstrated in the synthesis of
two further API building blocks: monobromination of 2,6-
dichlorotoluene (4) was exemplified on a 1.17 kg scale in 97%
yield. Using a linear scale-up strategy for this chemistry, the
exceptional productivity and PMI can be maintained by preser-
ving mass transfer, heat transfer and irradiation character-
istics. This would allow access to a throughput of 4.8 kg h−1 in
a 5-plate Corning G1 Photo Reactor (45 mL), or 32 kg h−1 in a
5-plate G3 Photo Reactor (300 mL).18 Dibromination of 2,4-
dichlorotoluene 6 was less productive, due to its longer resi-
dence time. However, a 14.8 g batch could be isolated in
20 min processing time, which would also achieve high
throughput when performed in a larger scale reactor.
Procedure for the dibromination of 2,4-dichlorotoluene 6
A waste collection flask was charged with a saturated solution
of sodium thiosulfate and was stirred with a magnetic stirrer.
The reactor was turned on (405 nm LEDs and thermostats)
and the reactor thermostat was set to 65 °C. After the tempera-
ture of the reactor had stabilized, the pumps were turned on.
Flow rates: substrate 0.302 mL min−1, HBr 0.581 mL min−1
and NaBrO3 0.779 mL min−1. Solutions: 2,4-Dichlorotoluene
(neat, 7.74 M, 46.7 mmol in 20 min), HBr (48%, 103 mmol, 2.2
equiv.) and NaBrO3 (2.2 M, 34.3 mmol, 0.73 equiv.). The
system was allowed to equilibrate for ∼15 min, then for 20 min
the mixture was collected in a stirred round bottom flask con-
taining sodium thiosulfate solution (2.2 M). The quenched
reaction mixture was extracted with DCM (3 × 20 mL) and the
organic phase was then washed with sodium bicarbonate solu-
tion (1 × 20 mL) and dried over Na2SO4. After removal of the
solvent under reduced pressure, product 8 was obtained as a
pale yellow oil (14.8 g, 99% yield).
Experimental
Safety notes
Conflicts of interest
The Br2 generation and quenching of Br2 by Na2S2O3 are
exothermic processes. HBr and NaBrO3 should be stored separ-
ately. Extreme caution is advised, particularly when quenching
waste or unused solutions – this should be carried out with
care and under dilute conditions where possible.
There are no conflicts to declare.
Acknowledgements
This reaction under the intensified conditions described
should be carried out only in a reactor system with sufficient The CC Flow Project (Austrian Research Promotion Agency
temperature control. When attempting this reaction in a FFG No. 862766) is funded through the Austrian COMET
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