Scalability of Visible-Light-Induced Nickel Negishi Reactions: A Combination of Flow Photochemistry, Use of Solid Reagents, and In-Line NMR Monitoring

Article abstract of DOI:10.1021/acs.joc.8b02358

The scale up of light-induced nickel-catalyzed Negishi reactions is reported herein, with output rates reaching multigram quantities per hour. This level of throughput is suitable to support preclinical medicinal chemistry programs in late lead optimization, where tens of grams to hundreds of grams of final product is needed. Adjusting reaction times and concentrations was critical in achieving this robust output. This example demonstrates how visible photochemistry and use of solid metal reagent can be used and how the progress of the reaction can be followed by in-line NMR monitoring.

Full text of DOI:10.1021/acs.joc.8b02358

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Article
Scalability of Visible Light Induced Nickel Negishi Reactions: A Combination
of Flow Photochemistry, use of Solid Reagents and in-line NMR Monitoring
Irini Abdiaj, Clemens R. Horn, and Jesus Alcazar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02358 • Publication Date (Web): 18 Oct 2018
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Scalability of Visible Light Induced Nickel Negishi Reactions: A Com-
bination of Flow Photochemistry, use of Solid Reagents and in-line
NMR Monitoring.
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Irini Abdiaj†, Clemens R. Horn‡, Jesus Alcazar†*
† Lead Discovery, Janssen Research and Development, Janssen-Cilag, S.A., Jarama 75A, 45007 Toledo, Spain, E-mail: jalca-
zar@its.jnj.com
‡Corning S.A.S, Corning European Technology Center, 7 bis avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex,
France
ABSTRACT: The scale up of light induced nickel catalyzed Negishi reactions is reported herein, with output rates reaching
multigram quantities per hour. This level of throughput is suitable to support preclinical medicinal chemistry programs in
late lead optimization, where tens of grams to hundreds of grams of final product is needed. Adjusting reaction times and
concentrations was critical in achieving this robust output. This example demonstrates how visible photochemistry and use
of solid metal reagent can be used, and how the progress of the reaction can be followed by in-line NMR monitoring.
To start with, we selected compound 3 (Table 1), an example
that was already scaled up with our Vapourtec reactor8 using
a 10 mL coil of fluorinated ethylene propylene (FEP). This re-
actor provided a throughput of 800 mg/h, very convenient for
Drug Discovery purposes.6 However, due to size limitations of
the reactor, the higher productivities necessary for the prepa-
ration of clinical candidates for preclinical biological studies
cannot be reached.9 Therefore, an appropriate pilot scale de-
signed reactor was selected to increase productivity. In collab-
oration with CORNING SAS, Corning G1 photoreactor was
chosen to perform the experiments.10
INTRODUCTION
Using light to accelerate a chemical reaction is one of the most
promising opportunities to access new chemical transfor-
mations in a more effective and sustainable way.1 However, for
larger scale reactions, the logarithmic decrease in light trans-
mission versus pathlength of the liquid medium, defined by
the Lambert-Beer Law, limits photochemical transfor-
mations.2 Therefore, in large batch reaction vessels, the reac-
tion mixture is inefficiently irradiated and low reaction rates
may be obtained. These limitations can be avoided by chang-
ing from traditional batch processes to continuous flow ap-
proaches. The large surface to volume ratio ensures efficient
irradiation of the entire reaction mixture. This results in sig-
nificantly intensified protocols and allows scaling up of these
novel chemistries.3
The photoinduced Negishi cross-coupling is a two-step reac-
tion that requires the formation of the organozinc reagent in
flow followed by coupling with the aryl halide. The first step
of the reaction, formation of organozinc reagent, is key for the
overall outcome of the reaction and involves the use of solid
zinc. We sought a method to capture organozinc formation in
real time, in order to optimally minimize reaction times.
However, developing photochemistry, especially at pilot/in-
dustrial scale where significant productivity is required, con-
tinues to be a challenge.4 In general, photochemical processes
are not used in industry because thermal driven batch proto-
cols are considered to be superior in terms of affordability and
convenience.5 In addition, solid reagents cannot be utilized
due to their likelihood to cause reactor clogging.5c
NMR spectroscopy is a great technique for monitoring organic
reactions due to its high degree of functional group specific-
ity.11 Despite being one of the most powerful analytical tech-
niques, the use of the NMR integrated into processes12 has
been scarcely reported and mainly used in by-pass configura-
tions, flow cells in high field NMR machines or micro coils for
microfluidic applications.13 Nowadays, apart from our previous
work6, NMR spectra for organozinc reagents are scarcely pre-
sented in literature. This is due to their instability in open air.
However, with the use of NMR-inline monitoring, we ex-
pected that we could directly monitor the conversion of the
starting material in organozinc reagent before flowing into the
photoreactor. Effectually, we observed that the singlet of the
benzylic CH2 of trifluoromethoxy benzyl bromide 1 has a dis-
tinct upfield shift (or a distinct right shift) when we form the
organozinc reagent (Figure 1).
Recently, we published a new visible light induced photosen-
sitizer free nickel catalyzed Negishi reaction for C(sp3)-C(sp2)
cross coupling. This new protocol presents a broader scope
than traditional Negishi reaction and dual catalytic processes
in terms of halogenated derivatives that can be used.6 In view
of the medicinal chemists’ need nowadays for new methodol-
ogies to enrich drug candidates with (sp3) motifs,7 we consider
it a valuable reaction and therefore we aimed to test its scala-
bility in pilot scale photoreactor.
RESULTS AND DISCUSSION
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The protons corresponding this signal are shielded due to the
reduced to 90% (Table 1, entry 3). Maintaining both the tem-
perature at 60 °C and the pressurized system while reducing
the residence time to 15 minutes provided the best combina-
tion of yield and throughput (Table 1, entry 5).
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higher electron density at the carbon bonded the metal. The
same effect is observed even in 19F NMR, but the difference
between 2 and 4 in ppm is lower (-57,04 and -57.27 ppm) (see
Figure S1 supporting information). Thus, we selected 1H NMR
analysis to monitor the reaction. We calculated the concen-
tration of the outcoming organozinc solution by integrating
the aromatic hydrogens with respect to solvent tetrahydrofu-
ran (THF) hydrogens. Our flow NMR cell was made from PTFE
tube connected with Teflon connectors at both ends. In this
way we could support the 4 bars of pressure inside the NMR.
Table 1. Optimization of the conditions Experiment 1
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Entry
tR (min)
T (°C)
60
Conversion (%)
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100
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Figure 1. NMR monitoring for the formation of 2.
20a
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aNo pressure in the system. Reaction conditions: Methyl 4-
bromobenzoate (1 eq., 15 mmol); 4-(trifluoromethoxy)benzyl
bromide (2 eq., 30 mmol); Nickel catalyst (0.02 eq., 0.3 mmol);
dtbbpy (0.03 eq., 0.45 mmol). tR (Residence time)
With the optimized conditions, the reaction was run for 6.5 h.
Conversion was analyzed by GCMS sampling every 30 minutes
(Figure 2). In-line NMR analysis showed a stable concentra-
tion of organozinc solution over time with slight variation be-
tween 4 to 5% during the run (see Figure S3 supporting infor-
mation). There were no traces of benzyl bromide in the NMR
spectra.
In the initial setup, the zinc column was fed from gear pump 1
controlled from MFC1 (Mass-flow controller). At the exit of
the zinc column, a Magritek benchtop NMR was connected
for in-line monitoring of the organozinc formation. The NMR
output line was fed directly into the photo reactor. A second
gear pump controlled from MFC2 fed Methyl 4-bromobenzo-
ate 3 and catalyst into the photoreactor. Moreover, by moni-
toring the energy the pump uses under a stable flow rate, we
could observe abrupt pressure drops, which can be caused by
fouling that could lead to clogging. To assure a stable flow rate
the entire system was used under a pressure of 3.5-4 bars using
a back-pressure regulator (BPR) at the exit of the photoreactor
(Scheme 1).
According to the results obtained in Table 1, entry 2, where the
reaction was run in the absence of back pressure regulator, the
presence of bubbles had a detrimental effect on the reaction.
We decided to introduce some nitrogen bubbles in the reac-
tion by moving the inlet frit of compound 3 (limiting reagent)
out of the solution. The conversion of the corresponding frac-
tion was reduced to 93%. Beyond that fraction, the overall
conversion remained 98% for the rest of the process and the
final isolated yield was 93%. 36.6 g of product were obtained
after purification, increasing seven times the productivity,
from 0.8 g/h to 5.6 g/h (Table 2).
Scheme 1. Schematic overview of the initial flow set-up
Table 2. Comparison of productivity Experiment 1
Vapourtec
Corning G1
Yield
Time
93%
93%
20 min
10 mL
0.8 g/h
15 min
40 mL
5.6 g/h
Reactor size
Throughput
The mass flow controllers were used not only to control the
gear pumps but also to directly monitor the flow rates, thereby
giving indirect information about what is happening in both
reactors, Zn column reactor and the photoreactor. After the
run we observed that while in the catalyst feed (MFC2) the re-
port showed a stable and linear graph in time, the benzyl bro-
mide feed presented various instabilities (Figure 3 and Figure
S4 supporting information). The monitoring graph showed a
linear line parallel to the (X) axis. A fouling is at least at the
This set up was designed for our preliminary experiments,
with the aim of adjusting the components for reaction optimi-
zation. Our previously reported conditions6 provided full con-
version to compound 4 (Table 1, entry 1). When the instru-
ment was run at atmospheric pressure, several bubbles were
observed in the line, probably due to the partial evaporation
of THF (boiling point 68 °C). This likely contributed to the
lower conversion of 79% (Table 1, entry 2). Decreasing the
temperature to 40 °C was not beneficial, as conversion was
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beginning also linear. It is in the course of time that fluctua-
solution. In this way density can be used as an additional pa-
rameter of control when NMR monitoring does not provide
suitable information about this first step of the reaction.
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tions became more frequent, however only in the benzyl bro-
mide feed (MFC1). This suggested us that these instabilities
could be originated by zinc consumption over time. Neverthe-
less, productivity was not affected. The mass flow controller
gave a very sensitive measurement of the flow rates in time;
one every 1/10 of a second. Thus, even though we had small
spikes every tenth of a second the effect produced in conver-
sion is insignificant. This observation showed us that the sys-
tem needed further optimization.
To test this new set up, the coupling between benzyl zinc bro-
mide 5 and 2-amino-5-iodopyrimidine 7 was used as a model.
The free amino group in this example makes it an especially
useful product, suitable for further derivatization.7a
As in the previous example, the original conditions provided
full conversion (Table 3, entry 1). Reducing the residence time
to 15 minutes also provided full conversion (entry 2). Shorten-
ing the reaction times further was insufficient for full conver-
sion of starting material (entry 3). Increasing the concentra-
tion of 5 to 1 M had the same result as using 0.5 M, but due to
solubility issues of 7 pure DMF was used to dissolve the cata-
lyst feed reagents (entry 6). Three equivalents of benzyl bro-
mide were necessary to obtain full conversion (entry 5). In the
absence of light, only 34% of isolated product was obtained
(entry 7).
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Figure 2. Monitoring of the conversion of starting material in
product
The final scale up reaction was performed using the condi-
tions of entry 6 in Table 2 as it could be run at higher concen-
tration increasing significantly the productivity of the reactor
to 3.4 g/h, more than 10 times larger than our initial report
using a reactor only 4 times larger (Table 4).6
Figure 3. Pump monitoring showing fluctuations over time.
Scheme 2. Schematic overview of the optimized flow set-up
Table 3. Optimization of the conditions Experiment 2
To avoid the potential back flow into the zinc column caused
by zinc consumption, a modified set up able to keep the zinc
column under higher pressure than the photoreactor was put
in place with several additions to the system. A needle valve
was placed just after the NMR in order to maintain the first
part of the reaction under 4 bars of pressure. This was moni-
tored with a pressure sensor. To observe the exact flow rate
entering the photoreactor after the zinc column, a mass flow
meter (MFM) was added. In order to monitor the lower pres-
sure in the photoreactor, a new pressure sensor was added at
its entrance which was controlled from the BPR (Back Pres-
sure Regulator) at the exit of the photoreactor (Scheme 2).
Taking advantage of the fact that Mini CORI-FLOWTM
MFC/MFM (Mass Flow Meter) can also measure the density
in-line, the density of the solution was measured before and
after the zinc column. As expected, the density of the or-
ganozinc solution was higher than the starting material
E. tR (min) T (°C)
Eq. 5
Light
[7](M)
Con. (%)
3
3
On
On
On
On
On
On
Off
0.375
0.375
0.375
0.375
0.375
0.750
0.750
1
2
3
4
5
6
7
20
15
12
15
15
15
15
60
60
60
60
60
60
60
100
100
>95
3
2
>95
2.5
3
>95
100(94)a
34a
3
aIsolated yield, DMF used as solvent. Reaction conditions: 2-
amino-5-iodopyrimidine (1 eq., 15 mmol); benzyl bromide (3
eq., 45 mmol); Nickel catalyst (0.02 eq., 0.3 mmol); dtbbpy
(0.03 eq., 0.45 mmol).
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EXPERIMENTAL SECTION
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Table 4. Productivity of the reaction
1
2
General information
The reactions were conducted in a standard Corning © Ad-
vanced-FlowTM G1 Photo reactor equipped with 5 glass fluidic
modules connected in series (8.2 ml volume each). Each mod-
ule was illuminated from both sides by a multiple wave-
length LED (Light Emitting Diode) panel (>100mW/cm2). The
chosen wavelength was 405 nm and the intensity was adjusted
to 100%. The temperature of the fluidic modules was regulated
by a LAUDA® Proline RP45 thermostat using ethylene gly-
col as thermofluidic (transparent at 405 nm), the LED panels
were cooled by a second LAUDA® Proline RP45 thermostat.
The liquids were pumped with micro gear pumps (HNP
Mikrosysteme MZR®- 7255), which were controlled directly by
Mini CORIFLOWTM M14 mass flow controllers using the soft-
ware flowplot for monitoring (Bronkhorst High-Tech B.V).
The pressure was regulated with a back-pressure regulator
from Zaiput flow technologies. In-line NMR analysis was car-
ried out with a 43 MHz SpinsolveTM NMR spectometer from
Magritek, the flow cell was a PTFE tube (OD 5 mm, ID 4mm).
For the preparation of the organozinc reagent SolventPlusTM
Omnifit column (bore: 35 mm, length: 150 mm, AF (1× adjust-
able & 1× fixed endpiece); Omnifit, cat. no. 006SCC-35-15-AF.
The needed parts are the glass tube, two 30 μm × 35 mm pol-
ytetrafluoroethylene (PTFE) frits, one fixed end piece as a bed
support and one adjustable end piece (plunger) to adjust the
3
4
5
6
7
8
9
Vapourtec
Corning G1
Yield
93%
20 min
10 mL
0.375 M
0.3 g/h
94%
15 min
40 mL
0.750 M
3.4 g/h
Time
Reactor size
Conc. RM
Throughput
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In order to avoid chromatographic purification on this Discov-
ery Process scale reaction, it was decided to perform a recrys-
tallization in water after an aqueous work up.14-16 To remove
zinc salts, extraction with aqueous ammonia solution (pH=9)
was required. Then the organic phase was separated and con-
centrated to perform the recrystallization in water affording
the desired product as a white crystalline solid (see Figure S6
supporting information).
In this second experiment, NMR monitoring provided clear
information about the formation of the benzyl zinc bromide
under more concentrated conditions. The singlet correspond-
ing to the benzylic protons was shifted downfield when benzyl
zinc bromide 6 was formed. The integration of aromatic pro-
tons provided information about the concentration of the out-
coming organozinc reagent, in this case varying between
8.5%-9.8% (see Figure S7 supporting information). The con-
centration remained stable in time without important varia-
tions. The density sensors showed similar results as the NMR
monitoring. There was a clear difference between the density
of the benzyl bromide solution (0.959 g/mL) and the benzyl
zinc bromide solution (1.022 g/mL) and this difference re-
mained stable over the run. Under the new reaction condi-
tions, the report showed stable flow rates in both feeds. More-
over, the system seems to get more stable over time. Even
though some nitrogen bubbles were intentionally introduced
into both feeds at different points in time, minor alterations
were observed (see Figure S8 supporting information).
bed
height.
(https://www.dibaind.com/wpcontent/uploads/2015/01/2015
01_1_OFLW_CAT.pdf).
GC measurements were performed using a 6890 Series Gas
Chromatograph (Agilent Technologies) system comprising a
7683 Series injector and auto sampler, J&W HP-5MS column
(20 m x 0.18 mm, 0.18 μm) from Agilent Technologies coupled
to a 5973N FID Flame Ionization Detector. Thin layer chroma-
tography (TLC) was carried out on silica gel 60 F254 plates
(Merck) using reagent grade solvents. Unless otherwise spec-
ified, reagents were obtained from commercial sources and
used without further purification.
Activation of the Zn column:
A solution 1.0 M trimethylchlorosilane (TMSCl) and 0.24 M 1-
bromo-2-chloroethane was prepared under nitrogen (N2) at-
mosphere in a dried flask by dissolving 6.25 mL of TMSCl and
1.25 mL of 1-bromo-2-chloroethane in 50 mL of dried tetrahy-
drofuran (THF). 25 mL of this solution were passed through
the 35 mm internal diameter Omnifit column containing Zn
(150 g) using the MFC1 at room temperature and 4 mL /min
flow rate.
CONCLUSION
In conclusion, visible light induced nickel catalyzed Negishi
reaction can be scaled up in quantities that would support the
preparation of potential drugs for preclinical experiments.
This protocol provides an example of how the use solid rea-
gents and photochemistry can be scaled up using flow chem-
istry. NMR monitoring provided an excellent readout for the
organozinc formation. In-line density monitoring has been
identified as an alternative when NMR is not suitable. Herein
we proved this two-step reaction works in gram scale with
productivities that ranges from 3.4 to 5.6 g/h (ideally from 82
to 270 g/day). The nickel loading was kept at 2 mol%. The op-
timized system and the controlled parameters give autonomy
to the chemist and reproduce situations that can be found in
a production plant. Future work for a completely automated
system can bring the process to direct industrial production
and will be matter of future publications.
Methyl 4-[[4-(trifluoromethoxy)phenyl]methyl]benzoate (4). A
solution of 4-(trifluoromethoxy) benzyl bromide 1 (254 mmol;
2 eq.+50 mmol) in 608 mL of THF was pumped through a col-
umn containing activated zinc at room temperature at 1.35 mL
/min using the MFC1. The outcoming solution of the or-
ganozinc compound was analyzed by in line NMR monitoring
and once the organozinc reagent started to flow, inserted into
the photoreactor. The outcoming solution was combined with
a solution of methyl 4-bromobenzoate 3 (1 eq. 127 mmol),
NiCl2 glyme (0.02 eq., 2.54 mmol), dtbbpy (0.03 eq., 3.81
mmol) in 407 mL of THF and 101 mL of DMF in Corning G1
Photoreactor at 1.35 mL /min each line (tR= 15 min; coil vol-
ume= 40 mL) at 60 °C irradiating with 405nm blue LEDs. The
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system was maintained under 3.5-4 bars of pressure with a
The project leading to this application has received funding
from the European Union’s Horizon 2020 research and inno-
vation program under the Marie Sklodowska-Curie (grant
agreement No 641861). Authors also thanks Dr. Christa
Chrovian, Dr. José Manuel Alonso and Mr. Alberto Fontana
for her help during the preparation of this manuscript.
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back-pressure regulator. The out coming of the reactor was
collected in fractions of 80 mL each. The collected fractions
were concentrated by evaporating the THF and then diluted
with ethyl acetate and added to a separatory funnel containing
1 L of ammonium chloride saturated aqueous solution. The or-
ganic layer was separated, dried with MgSO4, filtered and then
the solvents evaporated. Purification by flash chromatography
using Heptane: Ethyl acetate from 100:0 to 75:25 afforded 36.6
REFERENCES
(1)
(a) Beeler, A. B.; Introduction: Photochemistry in or-
1
g of 4 as a transparent liquid, 93% isolated yield. H NMR
ganic synthesis Chem. Rev. 2016, 116, 9629–9630; (b) Turro, N.;
Schuster, G.; Photochemical reactions as a tool in organic synthe-
ses. Science 1975, 187, 302-312.
9
(CDCl3, 500 MHz): δ = 7.97 (d, J = 8.4 Hz, 2H), 7.22-7.27 (m,
2H), 7.09-7.21 (m, 4H), 4.03 (s, 2H), 3.90 ppm (s, 3H). 13C NMR
(CDCl3, 126 MHz): δ = 166.9, 147.8, 145.7, 138.9, 130.2, 130.0,
128.9, 128.4, 121.5, 121.0, 52.1, 41.2 ppm. 19F NMR (CDCl3, 471
MHz): δ = -57.93 ppm (br s, 1F). HRMS (ESI-TOF) m/z: Calcd
[M+H]+ for C16H14F3O3 311.0895; Found 311.0897.
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35
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2)
Lambeert- Beer Law. J. Photochem. Photobio. 2013, 267, 6-10.
(3) (a) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger,
Parnis, J. Mark; Oldham, Keith B.; Beyond the
P. H. The Hitchhiker’s Guide to Flow Chemistry Chem. Rev. 2017,
117, 11796–11893; (b) Gilmore, K.; Seeberger, P. H. Continuous Flow
Photochemistry. Chem. Rec. 2014, 14, 410–418.
5-Benzylpyrimidin-2-amine (8). A solution of benzyl bromide 5
(351 mmol; 3 eq.+ 100 mmol) in 451 mL of THF was pumped
through a column containing activated zinc at room temper-
ature at 1.35 mL /min using the MFC1. The outcoming solution
of the organozinc compound was analysed by NMR in line
monitoring and once the organozinc reagent started to flow,
inserted into the photoreactor. The outcoming solution was
combined with a solution (B) of 2-amino-5-iodopyrimidine 7
(1 eq. 117 mmol), NiCl2 glyme (0.02 eq., 2.34 mmol), dtbbpy
(0.03 eq., 3.51 mmol) in 351 mL of DMF in Corning G1 Photo-
reactor at 1.35 mL/min each line (tR= 15 min; coil volume= 40
mL) at 60 °C irradiating with 405 nm blue LEDs. The zinc re-
actor was maintained under 4 bars of pressure controlled from
the needle valve and the photoreactor was maintained at 3.5
bars of pressure from the BPR. The out coming of the reactor
was collected in fractions of 80 mL each. The collected frac-
tions were concentrated by evaporating the THF and then di-
luted with dichloromethane and added to a separatory funnel
containing 1 L of aqueous ammonium solution (pH= 9). The
organic layer was separated, dried with MgSO4, filtered and
then the solvents evaporated. The rests were dissolved in min-
imum quantity of dichloromethane and the product was crys-
tallized in water as 20.4 g of 8 a white crystalline solid, 94%
isolated yield. 1H NMR (CDCl3, 400 MHz): δ = 8.15 (s, 2H), 7.27-
7.36 (m, 2H), 7.22 (s, 1H), 7.17 (s, 2H), 4.96 (br s, 2H), 3.80 ppm
(s, 2H). 13C NMR (CDCl3, 101 MHz): δ = 158.4, 139.8, 128.7, 128.6,
126.5, 123.9, 103.6, 35.7 ppm. HRMS (ESI-TOF) m/z: [M+H]+
Calcld for C11H12N3: 186.1031; Found 186.1029. Melting point:
121.86 °C.
(4)
(a) Politano, F.; Oksdah-Mansilla, G.; Light on the hori-
zon: Current research and future perspectives of flow-photo-
chemistry Org. Proces Res. Dev. 2018, 22, 1045-1062; (b) Cambié,
D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Applica-
tions of Continuous-Flow Photochemistry in Organic Synthesis,
Material Science, and Water Treatment. Chem. Rev. 2016, 117,
10276–10341; (c) Su, Y.; Kuijpers, K.; Hessel, V.; Noël, T. A conven-
ient numbering-up strategy for the scale-up of gas–liquid photo-
redox catalysis in flow. React. Chem. Eng. 2016, 1, 73-81; (d) Zhao,
F.; Cambié, D.; Janse, J.; Wieland, E. W.; Kuijpers, K. P. L.; Hessel,
V.; Debije, M. G., Noël, T. Scale-up of a Luminescent Solar Con-
centrator-Based Photomicroreactor via Numbering-up. ACS Sus-
tainable Chem. Eng. 2018, 6, 422-429; (e) Elliot, L. D.; Berry, M.;
Harji, B.; Klauber, D.; Leonard, J.; Booker-Milburn, K. Org. Process
Res. Dev. 2016, 20, 1806-1811.
(5)
(a) Malet-Sanz, L.; Susanne, F. Continuous Flow Synthe-
sis. a Pharma Perspective. J. Med. Chem. 2012, 55, 4062–4098; (b)
Rasheed, M.; Wirth, T. Intelligent Microflow: Development of
Self-Optimizing Reaction Systems. Angew. Chem. Int. Ed. 2011, 50,
357–358; (c) Wegner, J.; Ceylan, S.; Kirschning, A. Ten Key Issues
in Modern Flow Chemistry. Chem. Commun. 2011, 47, 4583.
(6)
Abdiaj, I.; Fontana, A.; Gomez, M. V.; De la Hoz, A.; Al-
cazar, J. Visible-Light-Induced Nickel-Catalyzed Negishi Cross-
Couplings by Exogenous-Photosensitizer-Free Photocatalysis.
Angew. Chem. Int. Ed. Engl. 2018, 57, 8473-8477.
(7)
(a) Dua, R.; Shrivastava, S.; Sonwane, S. K.; Srivastava, S.
K. Pharmacological Significance of Synthetic Heterocycles Scaf-
fold: A Review. Adv. Biol. Res. (Rennes). 2011, 5, 120–144; (b) Wal-
ters, W. P.; Green, J.; Weiss, J. R.; Murcko, M. A. What Do Medic-
inal Chemists Actually Make? A 50-Year Retrospective. J. Med.
Chem. 2011, 54, 6405–6416; (c) Tsukamoto, T. Tough Times for
Medicinal Chemists: Are We to Blame? ACS Med. Chem. Lett.,
2013, 4, 369–370.
ASSOCIATED CONTENT
Supporting Information. 1H, 19F and 13C NMR spectra, con-
trol graphs and reaction details are available free of charge via
the Internet at http://pubs.acs.org.
(8)
For Further Information about Instrument Used Visit
the Web: www.Vapourtec.Com>.
(9)
Alcázar, J. Sustainable Flow Chemistry in Drug Discov-
ery in Sustainable Flow Chemistry. Vaccaro, L., Ed.; Wiley-VCH
Verlag GmbH & Co.; Weinheim, 2017, pg.: 135-164.
AUTHOR INFORMATION
Corresponding Author
(10)
Elgue, S.; Aillet, T.; Loubiere, K.; Conté, A.; Dechy-Cab-
aret, O.; Prat, L.; Horn, C. R.; Lobet, O.; Vallon, S. Flow Photo-
chemistry: A Meso-Scale Reactor for Industrial Applications.
Chim. Oggi 2015, 33, 58–61.
* Jesus Alcazar
Lead Discovery, Janssen Research and Development, Janssen-
Cilag, S.A., Jarama 75A, 45007 Toledo, Spain, E-mail: jalca-
zar@its.jnj.com.
(11)
(a) Nordon, A.; McGill, C. A.; Littlejohn, D. Process
NMRSpectrometry. Analyst 2001, 126, 260–272; (b) Sans, V.; Por-
wol, L.; Dragone, V.; Cronin, L. A Self Optimizing Synthetic Or-
ganic Reactor System Using Real-Time in-Line NMR Spectros-
copy. Chem. Sci. 2015, 6, 1258–1264; (c) Jones, C. J.; Larive, C. K.
Could Smaller Really Be Better? Current and Future Trends in
ACKNOWLEDGMENT
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Page 6 of 7
High-Resolution Microcoil NMR Spectroscopy. Anal. Bioanal.
Spectrosc. 2012, 60, 52–70; (h) Vargas, M. A.; Cudaj, M.; Hailu, K.;
Sachsenheimer, K.; Guthausen, G. Online Low-Field 1H NMR
Spectroscopy: Monitoring of Emulsion Polymerization of Butyl
Acrylate. Macromolecules 2010, 43, 5561–5568; (i) Maiwald, M.;
Fischer, H. H.; Kim, Y. K.; Albert, K.; Hasse, H. Quantitative High-
Resolution on-Line NMR Spectroscopy in Reaction and Process
Monitoring. J. Magn. Reson. 2004, 166, 135–146.
Chem. 2012, 402, 61–68; (d) Goldbach, M.; Danieli, E.; Duchateau,
L. L. A. Preparation of Grignard reagents from magnesium metal
under continuous flow conditions and on-line monitoring by
NMR spectroscopy. Tetrahedron Lett. 2016, 57, 122-125.
1
2
3
4
5
6
(12)
Giraudeau, P.; Felpin, F.-X. Flow Reactors Integrated
within-Line Monitoring using Benchtop NMR Spectroscopy. Re-
act. Chem. Eng. 2018, 3, 399-413.
(14)
(a) Schoenmakers, P. Chromatography in Industry.
7
8
9
(13)
(a) Bart, J.; Kolkman, A. J.; Vries, A. J. O. De; Koch, K.;
Annu. Rev. Anal. Chem. 2009, 2, 333–357; (b) Brown, P. R.; Grushk,
E. Advances in Chromatography, (2nd ed.); Miller, J. M., Ed.; 1994,
Wiley-VCH: New York.; (c) Heftmann, E. Chromatography, (3rd
ed).; 1974, New York.; (d) Braithwaite, A.; Smith, F. J. Chromato-
graphic Methods, (4th ed.); 1985, London; (e) Mandík, L. Applica-
tions of Gel Permeation Chromatography in the Paint Industry.
Prog. Org. Coatings 1977, 5, 131–198.
Nieuwland,P. J.; Janssen, H. J. W. G.; Van Bentum, J. P. J. M.;
Ampt, K. A. M.; Rutjes, F. P. J. T.; Wijmenga, S. S.; et al. A Micro-
fluidic High-Resolution NMR Flow Probe. J. Am. Chem. Soc. 2009,
131, 5014–5015; (b) Fratila, R. M.; Gomez, M. V.; Sýkora, S.; Velders,
A. H. Multinuclear Nanoliter One-Dimensional and Two-Dimen-
sional NMR Spectroscopy with a Single Non-Resonant Microcoil.
Nat. Commun. 2014, 5, DOI: 10.1038/ncomms4025. (c) Nordon, A.;
Diez-Lazaro, A.; Wong, C. W. L.; McGill, C. A.; Littlejohn, D.; We-
erasinghe, M.; Mamman, D. A.; Hitchman, M. L.; Wilkie, J. Con-
sideration of Some Sampling Problems in the On-Line Analysis of
Batch Processes by Low-Field NMR Spectrometry. Analyst 2008,
133, 339–347; (d) Buser, J. Y.; McFarland, A. D. Reaction Charac-
terization by Flow NMR: Quantitation and Monitoring of Dis-
solved H 2 via Flow NMR at High Pressure. Chem. Commun. 2014,
50, 4234–4237; (e) Gomez, M. V.; Verputten, H. H. J.; Díaz-Ortíz,
A.; Moreno, A.; de la Hoz, A.; Velders, A. H. On-Line Monitoring
of a Microwave-Assisted Chemical Reaction by Nanolitre NMR-
Spectroscopy. Chem. Commun. 2010, 46, 4514; (f) Gökay, O.; Al-
bert, K. From Single to Multiple Microcoil Flow Probe NMR and
Related Capillary Techniques: A Review. Analytical and Bioanalyt-
ical Chemistry 2012, 402, 647-669; (g) Dalitz, F.; Cudaj, M.; Mai-
wald, M.; Guthausen, G. Process and Reaction Monitoring by
Low-Field NMR Spectroscopy. Prog. Nucl. Magn. Reson.
10
11
12
13
14
15
16
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20
21
22
23
24
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(15)
(a) Walters, I. A. S. A Convenient One-Pot Negishi Cou-
pling of Amino-Heteroaryl Chlorides and Alkyl Bromides. Tetra-
hedron Lett. 2006, 47, 341–344; (b) Otzen, T.; Wempe, E. G.; Kunz,
B.; Bartels, R.; Lehwark-Yvetot, G.; Hänsel, W.; Schaper, K. J.; Sey-
del, J. K. Folate-Synthesizing Enzyme System as Target for Devel-
opment of Inhibitors and Inhibitor Combinations against Can-
dida Albicans - Synthesis and Biological Activity of New 2,4-Dia-
minopyrimidines and 4′-Substituted 4-Aminodiphenyl Sulfones.
J. Med. Chem. 2004, 47, 240–253.
(16)
(a) Joachim Ulrich. The Crystallization Technology
Handbook, 2nd ed.; A. Marsmann, Ed.; American Chemical Soci-
ety: 2001, New York.; (b) Crystallization: Basic Concepts and In-
dustrial Applications, 1st ed.; Beckmann, W., Ed.; 2013, Wiley-
VCH.
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NMR
BPR
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Zn
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Ar
R
Ar
X
mol
2
NiCl
%
2 glyme
dtbbpy
to 5.6
to 94%
Up
Up
g/h
yield
Br
R
7
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