Continuous flow synthesis of a key 1,4-benzoxazinone intermediate via a nitration/hydrogenation/cyclization sequence

Article abstract of DOI:10.1021/acs.oprd.6b00409

The preparation of a functionalized 4H-benzo-[1,4]-oxazin-3-one was completed via a three-step nitration/ hydrogenation/cyclization sequence. The unstable nature of the nitro and amino intermediates, in addition to the hazards associated with the nitration of organic compounds in general, makes this procedure exceedingly difficult to perform on industrial scale. To overcome these limitations, we have developed a fully integrated continuous protocol in which the aromatic starting material (2,2-difluoro-2-(3-fluorophenoxy)-N,N-dimethylacetamide) is subjected to an initial continuous flow dinitration using 20% oleum in combination with 100% HNO3 (2.5 equiv) using a microstructured device heated to 60 °C. This was followed directly by continuous flow hydrogenation of the dinitrointermediate over a Pd/C fixed bed catalyst at 45 °C. The resulting airsensitive diamino derivative was then directly cyclized to the desired 6-amino-2,2,7-trifluoro-4H-benzo-[1,4]-oxazin-3-one target compound via an acid-catalyzed cyclization step at 80 °C using a tubular reactor. Uninterrupted continuous flow processing was achieved by integrating liquid-liquid membrane separation technology and the inline removal of excess of hydrogen gas using gas permeable tubing into the process. The overall product yield for the continuous flow process was 83%, a significant increase compared to yield reported for the batch process (67%).

Full text of DOI:10.1021/acs.oprd.6b00409

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Full Paper
Continuous Flow Synthesis of a Key 1,4-Benzoxazinone
Intermediate via a Nitration/Hydrogenation/Cyclization Sequence
David Cantillo, Bernd Wolf, Roland Goetz, and C. Oliver Kappe
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00409 • Publication Date (Web): 26 Dec 2016
Downloaded from http://pubs.acs.org on December 27, 2016
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Continuous Flow Synthesis of a Key 1,4ꢀ
Benzoxazinone Intermediate via a
Nitration/Hydrogenation/Cyclization Sequence
David Cantillo,†‡ Bernd Wolf,§ Roland Goetz,§ and C. Oliver Kappe*,†‡
Institute of Chemistry, University of Graz, Heinrichstrasse 28, A-8010 Graz, Austria,
Research Center Pharmaceutical Engineering (RCPE), Inffeldgasse 13, 8010 Graz, Austria,
and BASF SE, Global Research and Development Crop Protection - Process Development,
67056 Ludwigshafen, Germany
____________________
* Corresponding author. Eꢀmail: oliver.kappe@uniꢀgraz.at
† University of Graz
‡ Research Center Pharmaceutical Engineering GmbH
§ BASF SE
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ABSTRACT: The preparation of a functionalized 4Hꢀbenzoꢀ[1,4]ꢀoxazinꢀ3ꢀone was
completed via a threeꢀstep nitration/hydrogenation/cyclization sequence. The unstable nature
of the nitro and amino intermediates, in addition to the hazards associated with the nitration of
organic compounds in general, makes this procedure exceedingly difficult to perform on
industrial scale. To overcome these limitations, we have developed a fully integrated
continuous protocol in which the aromatic starting material (2,2ꢀdifluoroꢀ2ꢀ(3ꢀ
fluorophenoxy)ꢀN,Nꢀdimethylacetamide) is subjected to an initial continuous flow dinitration
using 20% oleum in combination with 100% HNO3 (2.5 equiv) using a microstructured
device heated to 60 °C. This was followed directly by continuous flow hydrogenation of the
dinitrointermediate over a Pd/C fixed bed catalyst at 45 °C. The resulting airꢀsensitive
diamino derivative was then directly cyclized to the desired 6ꢀaminoꢀ2,2,7ꢀtrifluoroꢀ4Hꢀ
benzoꢀ[1,4]ꢀoxazinꢀ3ꢀone target compound via an acidꢀcatalyzed cyclization step at 80 °C
using a tubular reactor. Uninterrupted continuous flow processing was achieved by integrating
liquidꢀliquid membrane separation technology and the inline removal of excess of hydrogen
gas using gas permeable tubing into the process. The overall product yield for the continuous
flow process was 83%, a significant increase compared to yield reported for the batch process
(67%).
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KEYWORDS: Catalytic Hydrogenation, Continuous Processing, Flow Chemistry,
Membrane Separation, Microreactors, Nitration
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INTRODUCTION
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Benzoxazinones are an important class of naturally occurring compounds involved in the
defense mechanisms of plants against pests.1 Owing to their wellꢀknown antifungal,
antimicrobial, phytotoxic, and antifeedant properties, benzoxazinone derivatives are being the
subject of intense research efforts as natural templates for the preparation of novel
herbicides.1,2 Certain benzoxazinones also possess interesting pharmacological properties,
with applications as analgesics and muscle relaxants, antiinflammatories, antidepressants, or
anticontraceptives.3 Therefore, extensive research on structureꢀactivity relationship,
phytotoxicity enhancement, as well as development of efficient synthetic routes towards these
types of compounds have been carried out over the past few decades.2
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While the biosynthetic route for the generation of benzoxazinones in plants follows the
indole pathway,4 chemists have developed many alternative synthetic procedures starting
from readily available precursors,2 thus enabling access to tailored benzoxazinones with
enhanced biological properties. In this context, 6ꢀaminoꢀ2,2,7ꢀtrifluoroꢀ4Hꢀbenzoꢀ[1,4]ꢀ
oxazinꢀ3ꢀone (1) (ABO) (Figure 1) is an important intermediate in the preparation of
herbicidal benzoxazinones for phytosanitary compositions.5
Figure 1. Preparation of herbicidal benzoxazinones from ABO.
Using 2,2ꢀdifluoroꢀ2ꢀ(3ꢀfluorophenoxy)ꢀN,Nꢀdimethylacetamide (FPAA, 2) as starting
material the desired ABO compound can be prepared in a threeꢀstep sequence (Scheme 1).6 In
the first step FPAA (2) is dinitrated using a suitable nitrating mixture. Then, the nitro groups
are selectively reduced and the resulting diaminoꢀFPAA (4) is then cyclized under acidic
conditions (Scheme 1). This apparently straightforward procedure presents, however,
significant complications especially when carried out on large scale. The first intermediate in
the sequence, dinitroꢀFPAA (3), is a potentially explosive material as indicated by the Könen
tube test.7 Thus, isolation, handling and/or storage of the dinitro intermediate 3 is undesired,
especially in large quantities. Moreover, diaminoꢀFPAA (4) is an unstable, air and light
sensitive compound, particularly problematic when stored in solution. Due to these
limitations, a oneꢀpot sequential process which directly transforms FPAA (2) into ABO (1)
would be highly desirable.
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Scheme 1. Synthetic Sequence for the Preparation of the ABO Benzoxazinone.6
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Apart from the above mentioned issues related to the stability of the dinitroꢀ and diaminoꢀ
FPAA intermediates 3 and 4, nitration and hydrogenation reactions on their own constitute
inherently hazardous transformations when performed on a large scale. Nitration reactions are
generally highly exothermic and constitute one the most hazardous industrial processes.8
Safety risks are even more significant when the produced nitro compound has explosive
properties as in the case of dinitroꢀFPAA (3). Against that background, continuous flow
processing has been shown as a safe alternative for the generation and use of hazardous
reaction intermediates.9 The enhanced heat transfer experienced in microfluidic devices can
control the exotherm generated during nitration reactions. Therefore these hazardous
processes can be carried out in a safe, controlled, and scalable manner using flow devices.9
Application of these principles to nitration reactions have received particular attention, with
examples being reported as early 1956.10,11 A typical experimental setup for continuous
nitration of aromatic compounds consist of two feeds, containing the substrate and the
nitrating agent, respectively. The two feeds are mixed in a micromixing device under
thermostated conditions, followed by a residence time unit.11 Catalytic hydrogenations using
batch conditions are also inherently hazardous as pressurized hydrogen gas can cause
explosions. Thus, pressure resistant autoclave reactors and special safety precautions are
typically required.12 Continuous flow hydrogenation is a common technique in modern
organic synthesis,13 and specifically designed reactors for catalytic hydrogenations on
laboratory scale are commercially available. In addition to the safe, on demand generation of
hydrogen gas characteristic of this type of devices, preꢀpacked catalyst cartridges are
employed, thus avoiding the handling of often pyrophoric metal catalysts.13
To overcome the above mentioned issues for the large scale preparation of this type of
benzoxazinones, we envisaged a fully continuous flow protocol for the synthesis of ABO 1 in
which FPAA (2), used as starting material, is subjected to a sequential continuous flow
nitration/hydrogenation/cyclization. The explosive dinitroꢀFPAA (3) generated is extracted
from the nitrating mixture using a suitable organic solvent and separated with a continuous
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liquidꢀliquid membrane separator. The organic phase is then subjected to continuous
hydrogenation, immediately consuming the dinitroꢀFPAA (3) without the need for isolation or
purification, thus avoiding the handling of this dangerous material. The resulting solution of
the labile diaminoꢀFPAA (4) is directly acidified and heated under flow conditions, providing
the desired ABO product (1) via a cyclization process. Herein, we describe in detail a fully
continuous uninterrupted threeꢀstep process for the generation of ABO (1) on a laboratory
scale.
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RESULTS AND DISCUSSION
Initial Considerations. Our study initiated with a batch investigation and continuous flow
optimization of the dinitration reaction. In principle, nitration of FPAA (2) to dinitroꢀFPAA
(3) is the most challenging reaction step in the sequential process and we expected to face
several issues regarding temperature control and mixing efficiency. The hydrogenation of
dinitroꢀFPAA (3) to diaminoꢀFPAA (4) is the only step in the sequential process in which the
scale cannot be easily modified using the lab scale HꢀCube Pro hydrogenator.13 This is due to
the fact that the packed bed reactors (CatCarts) have fixed dimensions (70 × 4 mm, 0.8 mL
internal volume). Thus, the flow rate and throughput (mmol hꢀ1) of the overall process will
depend on the maximum flow rate that can be used in the HꢀCube Pro hydrogenation since the
reactor dimensions cannot be increased. All other reactor parts (nitration, separation,
cyclization) will therefore have to be adapted to the optimal flow rate of this reaction step.
Thus, when the hydrogenation in the HꢀCube Pro was optimized, the obtained maximum
throughput was used to develop the other reactor parts building two separate continuous
setups: 1) dinitration/liquidꢀliquid extraction/phase separation; 2) hydrogenation/gas
removal/cyclization. Once both processed were individually optimized the complete setup
was constructed using the optimized reaction parameters.
Crude reaction mixtures have been analyzed by quantitative HPLC (215 nm), GCꢀMS,
and in the case of the final ABO product ICPMS analysis has been carried out to determine
any potential leaching of the Pd catalyst during the hydrogenation (for details on the analytics
and experimental procedures see the Experimental Section and Supporting Information).
Nitration of FPAA (2). Batch Experiments and Continuous Flow Optimization. The
patent procedure for the synthesis of dinitroꢀFPAA (3) utilizes 100% HNO3 (4.7 equiv)
combined with concentrated H2SO4 (98%) and occurs at 40 °C during a period of 3 h.6 Our
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initial goal was to optimize the dinitration reaction conditions to reduce as much as possible
the reaction time and enhance the selectivity of the process. As small amounts of water in the
reaction mixture can easily cleave the ArOꢀCF2 bond 98% H2SO4 was substituted by oleum
(20% free SO3) to scavenge the water which is formed during the nitration.
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A set of preliminary batch experiments was carried out in order to obtain information
on the required reaction time, temperature, and amount of nitrating agent required. For this
purpose silicon carbide (SiC) parallel heating platforms14 were used to ensure rapid heat
transfer to the reaction mixture (see Experimental Section for details). As the initial exotherm
produced during the reagents mixing is expected to affect the observed reaction time, addition
of the substrate to the nitrating mixture was carried out slowly (over 1 min) at 0 °C.
Subsequently, the vial containing the reaction mixture was transferred to a SiC platform
preheated at the desired temperature. The data obtained (Figure 2) reveal that at 50 ºC the
reaction is not complete after 30 min, both when 2.2 equiv or 2.5 equiv of 100% HNO3 were
used. The temperature was then increased to 60 ºC and the amount of nitrating agent kept at
2.5 equiv. Under these conditions good results were obtained, with a 95% conversion to the
desired dinitroꢀFPAA (3) (HPLC analysis) in the crude reaction mixture. These conditions
(2.5 equiv HNO3, 60 ºC, 30 min) were selected for the initial flow experiments. It is worth
noting that an alternative protocol using NH4NO3 as a nitrating agent was also evaluated. In
this case the reaction was much faster, and after ca. 15 min nearly full conversion is obtained
(see Figure S4 in the Supporting Information). However, due to safety reasons relating to the
potential use of NH4NO3 on large scale reactions using this reagent were not further
evaluated.
Figure 2. Preliminary batch experiments for the dinitration of FPAA (2).
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The initial flow setup consisted of two feeds containing a sulfonitric mixture (5 M HNO3 in
oleum) prepared in a volumetric flask (Feed A) and the neat substrate FPAA (2) (Feed B) (for
details see Figure S5 in the Supporting Information). Oleum is highly corrosive for many
materials, and therefore the components of the setup had to be carefully selected. The two
feeds were injected using glass syringe pumps (Syrris), and were mixed in a standard Teflon
Tꢀmixer (i.d. 0.5 mm). Perfluoroalkoxy alkanes (PFA) tubing and Teflon connections were
used in all the reactor parts. Other connection materials such as PEEK showed rapid
degradation in contact with the nitrating mixture.
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For the preliminary flow experiments a total flow rate of 100 ꢁL minꢀ1 was selected.
The correct stoichiometry is hence achieved using 73.6 ꢁL minꢀ1 for Feed A and 26.3 ꢁL minꢀ
1
for Feed B. HPLC analysis of aliquots of the crude reaction mixture collected from the
reaction output revealed a nonꢀconstant conversion/purity profile over time most probably due
to inefficient mixing of the reaction components in the standard Tꢀmixer (Figure 3). The
nitrating mixture in oleum as well as the neat FPAA (2) substrate are very viscous liquids.15
When the continuous mixing in the flow reactor is not at adequate concentration gradients,
inhomogeneous mixtures will be produced along the tubing, resulting in a nonꢀconstant
composition of the crude reaction mixture obtained over time. Notably, an improved
conversion profile was obtained when the Tꢀmixer was sonicated during processing (Figure
3). Gratifyingly, excellent and constant conversion and purity for the dinitroꢀFPAA 3 were
achieved when a glass static mixer (Uniqsis, 1 mm i.d. channels with active mixing
geometries, 1.5 mL internal volume) was installed. In this case the mixer (1.5 mL internal
volume) was used both for mixing and as residence time unit. Thus, it was directly immersed
in the water bath at 60 °C. For this experiment the flow rate was reduced to 67 ꢁL minꢀ1 in
total. At this flow rate the residence time is ca. 18 min. Under these conditions a constant
stream with high purity for the desired dinitroꢀPFAA (3) was obtained during the complete
processing time (see Figure 4).
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Figure 3. Conversion profiles obtained for the continuous flow dinitration of FPAA (2) using
different mixing methods.
Figure 4. Representative HPLC chromatogram (215 nm) of the crude nitration reaction
mixture obtained from the reactor output using the glass static mixer.
To demonstrate that the dinitration process can be readily scaled using our optimized
conditions we decided to intensify the process by increasing the throughput to 1 mmol minꢀ1.
Thus, the injection of neat FPAA 2 was increased to 179 ꢁL minꢀ1 and the nitration mixture to
500 ꢁL minꢀ1. To compensate this flow rate increase and keep the residence time constant an
additional residence time unit (PFA tubing, 0.8 mm internal diameter, 13.5 mL internal
volume) was installed at the output of the glass static mixer (Figure 5). Moreover, two
additional feeds with water (quench) and toluene were incorporated to obtain a solution of
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dinitroꢀFPAA (3) in the organic solvent suitable to be used for the next step of the synthesis.
The flow rate for the toluene and water in the intensified process were set to 3.3 mL minꢀ1 and
5 mL minꢀ1, respectively, and mixed in an ice bath (0 °C) to avoid a possible partial nitration
of toluene with the excess of nitric acid. At these flow rates a 0.3 M solution of dinitroꢀFPAA
(3) in toluene can be obtained. The setup was run and after 1h of stabilization several fractions
of the biphasic mixture were collected at intervals of 5 min. Quantitative HPLC analysis of
the organic phase revealed an average yield for the desired dinitroꢀFPAA (3) of 93%.
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Figure 5. Continuous flow setup for the continuous dinitration process using an increased
throughput of 1 mmol minꢀ1.
Continuous Flow Hydrogenation of Dinitro-FPAA (3). Hydrogenation reactions employing
heterogeneous catalysts in fixed bed reactors exhibit several benefits using continuousꢀflow
processing apart from the obvious safety advantages.12 In continuous flow hydrogenations, the
hydrogen/substrate mixture is pumped through packed catalyst columns by highꢀpressure
pumps (Figure 6). Due to the large interfacial areas and the short diffusion paths in the packed
columns, very efficient gas–liquid–solid interactions, and thus hydrogenation, takes place.12
Hydrogenation of dinitroꢀFPAA (3) under continuous flow conditions was performed
in a commercial high pressure hydrogenator (HꢀCube Pro, Thales Nanotechnology Inc.)
enabling heterogeneous hydrogenations at temperatures up to 150ꢀ°C and 100 bar of hydrogen
pressure.12 The reaction mixture is introduced into the reactor by a HPLC pump (max. 3 mL
minꢀ1). The system was equipped with a preꢀpacked, commercially available cartridge (70 mm
length × 4mm i.d., 0.8 mL volume) of the heterogeneous 10% Pd/C catalyst. In all cases, the
instrument was set to “full H2” mode which corresponds to a gas flow rate of 60 mL minꢀ1.
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Figure 6. Schematic diagram of the continuous flow hydrogenation of dinitroꢀFPAA (3)
(top), and HꢀCube Pro continuous flow hydrogenator and preꢀpacked CatCart column reactors
used in this work.
The nitration/extraction process preceding the hydrogenation step produces a solution of
dinitroꢀFPAA (3) in toluene, which then enters the HꢀCube Pro hydrogenator. However, the
resulting diaminoꢀFPAA (4) product is not soluble in toluene and clogging of the reactor may
occur during the hydrogenation if no coꢀsolvent is added. Solubility tests indicated that
diaminoꢀFPAA (4) is well soluble in a toluene/methanol 2:1 mixture even at a concentration
of 0.2 M. Thus, addition of methanol after the liquid/liquid extraction step is necessary.
A set of continuous flow reductions was carried out to establish the optimal reaction
conditions, in particular H2 pressure and flow rate. A 0.2 M solution of dinitroꢀPFAA (3) in
toluene/methanol 2:1 was used as starting reaction mixture in all cases, and the temperature
was set to 45 °C in accordance with the literature batch protocol.6 The results (Table 1)
indicated that a successful reduction can be carried out up to a flow rate of 1 mL minꢀ1.
Although dinitroꢀFPAA (3) was consumed in all cases, it was not fully converted to diaminoꢀ
FPAA (4) when a flow rate of 2 mL minꢀ1 was employed, even at a pressure of 20 bar. In
these cases variable amounts of the nitro/aminoꢀFPAA intermediate were observed. HPLC
and GCꢀMS analyses of the crude reaction mixtures obtained at 1 mL minꢀ1 revealed that the
desired diaminoꢀFPAA (4) was obtained in very high purity (see Figure S6 in the Supporting
Information), with small amount of the final ABO (1) material being the main side product.
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Table 1. Results obtained for the continuous hydrogenation of dinitroꢀFPAA 3 in the HꢀCube
Pro using Pd/C as catalyst.
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Pressure
(bar)
Flow Rate
(mL minꢀ1)
Substrate
Conversion (%)a
Diamino/monoamino
Selectivity (%)b
Entry
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a HPLC peak integration area (215 nm). b GCꢀMS peak integration area.
As mentioned above, the scale of the hydrogenation reaction using the HꢀCube Pro instrument
is limited by the size of the commercially available CatCart catalyst cartridges (70 mm length
× 4mm i.d., 0.8 mL volume). Under these conditions an optimal productivity of 0.2 mmol
minꢀ1 can be obtained. This value was used as reference for adjusting the flow rates of the
other parts of the sequential process adapted for a throughput of 0.2 mmol minꢀ1.
Sequential Continuous Dinitration/Liquid-liquid Extraction Process. With the aim of
obtaining a continuous stream of dinitroꢀFPAA (3) in toluene ready to be introduced in the
hydrogenation reactor (after inline addition of methanol) a nitration setup incorporating a
membrane based liquidꢀliquid separator was built.16 Details on the optimization of the
nitration process are described above. The flow rates for the neat FPAA (2) substrate,
nitration mixture, and toluene were set according to the values calculated for a productivity of
0.2 mmol minꢀ1 (Figure 7). To obtain a residence time of ca. 20 min in the thermostated bath a
residence time unit (1.5 mL volume, 0.8 mm inner diameter PFA tubing) was added to the
glass static mixer output. The residence time unit then entered a second water bath at 0ꢀ10 °C,
where water and toluene are added simultaneously to the reaction mixture using an Xꢀmixer.
By adding both solvents simultaneously at low temperature precipitation of the dinitroꢀFPAA
(3) in the water phase and a possible nitration of toluene are avoided. For the extraction
process a 4 mL volume tubing was installed. The inner diameter for the extraction tubing was
increased to 1.6 mm to augment the contact surface between the toluene and water phases and
enhance the extraction. A picture of the setup with details on the liquidꢀliquid segments is
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contained in the Supporting Information (Figure S7). A commercial membrane based
liquid/liquid separator (Zaiput) was utilized to separate the organic and aqueous phases in
continuous flow.16
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Figure 7. Schematic diagram of the setup used for the combined flow dinitration/liquidꢀliquid
extraction process. For a photograph of the continuous flow setup see Figure S7 in the
Supporting Information.
The continuous flow reactor was started setting all parameters as stated in Figure 7. The
system was run for 60 min to assure stability and steadyꢀstate concentration conditions. Then,
10 mL of the toluene phase were collected from the corresponding membrane separator
output. In a separate cylinder 10 mL of the aqueous phase were additionally collected from
the water output of the membrane separator. HPLC analyses of the organic and aqueous phase
revealed excellent efficiency in the extraction process, with a toluene/water dinitroꢀFPAA (3)
distribution coefficient of 38:1 (determined by 215 nm peak area integration) (HPLC
chromatograms of the organic and aqueous phases are shown in Figure S8 in the Supporting
Information). The organic phase was then evaporated under reduced pressure until all
volatiles were removed. Cyclohexane was added and the pale yellow precipitate filtered off,17
1
yielding 92% of pure, dinitroꢀFPAA (3) (a H NMR spectrum of the solid product obtained
without further purification is shown in Figure S9 in the Supporting Information). This
remarkable yield and purity is in stark contrast with the reported batch protocol, in which 82%
yield of dinitroꢀFPAA (3) with 78% purity could be obtained.6
Sequential Continuous Hydrogenation/Cyclization Process. The hydrogenation reaction
mixture exiting the HꢀCube Pro reactor consists of a solution of diaminoꢀFPAA (4) in
toluene/methanol 2:1 together with a large amount of H2 gas. Although the presence of H2 gas
should not affect the cyclization reaction, it does have an influence in the process because the
residence time cannot be easily controlled. We therefore performed an inline removal of the
excess of H2 after the reduction using gas permeable Teflon AF2400 tubing.18,19 As diaminoꢀ
FPAA (4) is relatively unstable in the presence or air and light, we decided to optimize both
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degassing and cyclization simultaneously, directly using the crude reaction mixture obtained
from the hydrogenator. Thus, a Teflon AF2400 tubing (1.5 mL volume) in the form of a
“tubeꢀinꢀtube” reactor (Uniqsis)18 was installed at the output of the HꢀCube Pro (Figure 8).
The advantage of using a tubeꢀinꢀtube reactor is that the H2 released from the inner to the
outer tube can be readily removed by the ventilation system of the fume hood. HCl (37%) was
introduced into the system after the tubeꢀinꢀtube reactor with a standard Tꢀmixer (20 ꢁL minꢀ1,
1.2 equiv). The acidified solution entered a new residence time unit (0.8 mm inner diameter
tubing) immersed in an oil bath (Figures 8 and S9). A back pressure regulator (BPR) was
installed at the end of the reactor. The purpose of the BPR is to avoid boiling of the solvent
during the cyclization if high temperatures are required, and to enhance removal of H2
through the AF2400 material. Several BPR were tested, and complete removal of the H2
excess within the 1.5 mL AF2400 tube was achieved when the pressure was increased to 18
bar.
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Figure 8. Schematic diagram of the setup used for the continuous hydrogenation/cyclization
process. BPR: back pressure regulator. For a photograph of the experimental flow setup see
Figure S10 in the Supporting Information.
It is worth pointing out that since an 18 bar BPR was installed at the end of the system, the
hydrogenation reaction will also take place at this level of pressure. Under these conditions
full conversion of the dinitroꢀFPAA (3) to the diaminoꢀFPAA (4) can be assured (cf. Table 1).
A residence time of 10 min at 120 °C was initially tested for the cyclization step. At this
temperature full conversion of the diaminoꢀFPAA (4) intermediate was expected and possible
side products for the reaction could be evaluated. As anticipated, HPLC and GCMS analyses
of the crude reaction mixture collected from the output revealed complete conversion of the
starting dinitroꢀFPAA (3) as well as the diaminoꢀFPAA (4) intermediate. The desired ABO
product was formed with very good selectivity, although a small amount (1% according to
GCMS) of hydrolysis product was also observed possibly due to the high temperature used in
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this process. Reaction temperature and residence time were gradually decreased (Table 2) to
ultimately reveal 80 °C and 5 min residence time as optimal conditions for the cyclization.
Under these conditions excellent product selectivity with high purity profiles in both HPLC
and GCMS analyses were achieved. Further temperature decrease (entry 5, Table 2) reduced
the conversion of the diaminoꢀFPAA (4) intermediate.
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Table 2. Results obtained for the sequential hydrogenation/cyclization continuous flow
process.
Temperature
(°C)
Cyclization Residence
Time (min)
Conversion to
ABO (%)a
Entry
Selectivity (%)a
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a Evaluated by GCMS and HPLC peak integration area (215 nm).
Fully Integrated Sequential Dinitration/Liquid-liquid Extraction/Hydrogenation/
Cyclization Process. For the experiments described herein we assembled the two main
reactor
parts
described
above
(i.e.,
dinitration/liquidꢀliquid
extraction
+
hydrogenation/degassing/cyclization). For this purpose, the output of the liquidꢀliquid
membrane separator was connected to a Tꢀmixer where the stream was mixed with methanol,
and then fed to the input pump of the HꢀCube Pro (Figure 9) (for a picture of the complete
flow setup for the sequential process see Figure S11 in the Supporting Information).
Figure 9. Continuous flow setup utilized for the integrated synthesis of ABO (1).
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All 6 feeds in the continuous flow setup were started, setting all reaction parameters as stated
in Figure 9. The system was let run for 60 min to assure stability and steadyꢀstate
concentration conditions of the dinitration part of the setup. After ensuring that the initial
dinitration/liquidꢀliquid extraction part of the setup was performing as expected, the inlet of
the HꢀCube Pro was switched from solvent to the reaction mixture (after the
hydrogenation/degassing/cyclization part of the setup had been previously stabilized). After
approximately 15 min the crude dark brown reaction mixture was collected in fractions of 15
min each, diluted with methanol to a known volume, and analyzed by quantitative HPLC.
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After minor modifications in the setup (the residence time for the cyclization was
increased from 5 to 10 min) the fully integrated continuous flow process to obtain ABO was
carried out for more than 75 min providing excellent results. After ca. 100 min we could
observe that dinitroꢀFPAA (3) was no longer fully hydrogenated to diaminoꢀFPAA (4), with
1ꢀ2% of the mononitro/monoaminoꢀFPAA intermediate being detected. ICPꢀMS analysis of
the crude reaction mixture revealed a Pd content of 14.6 ppm. This value corresponds to a
total amount of Pd being leached from the cartridge of 1.3 ꢁg over a 100 min operation
period. This amount can be considered insignificant compared to the total Pd contained in the
CatCart catalyst cartridge utilized (27.5 mg). We ascribe the small decrease in conversion
observed to poisoning of the heterogeneous catalyst with some of the reaction components.
To achieve longer process operation recovery of the catalyst by cleaning with additional
solvents has been described.20 Quantitative HPLC analysis of the crude reaction mixture
obtained during the initial 60 min revealed a product yield for the overall process of 83%.
After the analysis a 3 M aqueous solution of NaOH was added dropwise to the crude reaction
mixture until a pH of 4ꢀ5 was reached. The solvent was then evaporated under reduced
pressure to ca. 20% of the initial volume and 150 mL of water were added. The precipitate
formed was filtered off, washed with cold water, and dried at 50 °C under reduced pressure
(2.28 g, 87% yield, 91% pure by quantitative HPLC). Notably, the product yield obtained for
the overall continuous flow process was significantly superior compared to the reported batch
protocol (ca. 67%).6
CONCLUSIONS
We have developed a continuous flow protocol for the preparation of 6ꢀaminoꢀ2,2,7ꢀtrifluoroꢀ
4Hꢀbenzoꢀ[1,4]ꢀoxazinꢀ3ꢀone (ABO, 1) using a fully continuous, threeꢀstep sequential
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nitration/hydrogenation/cyclization process. The sequence starts from the FPAA (2)
precursor, which is dinitrated using 100% HNO3 in oleum. Control of the reaction exotherm
and very efficient mixing has been achieved using a glass static mixer, thus ensuring constant
conversion profiles and purity for the dinitro intermediate. The nitration mixture was then
quenched with water and extracted with toluene at 0 °C. A membrane based liquidꢀliquid
separator was used after the extraction process to separate the aqueous and organic phases.
The first nitration step took place with excellent yield (92% isolated) and purity for the
desired dinitroꢀFPAA (3). The toluene solution of dinitroꢀFPAA (3), after mixing with
methanol, entered a continuous flow hydrogenator, where dinitroꢀFPAA (3) was reduced to
diaminoꢀFPAA (4) using heterogeneous Pd/C as catalyst at 45 °C. The reduced intermediate
was then acidified inline with HCl 37% and cyclized to ABO (1) at 80 °C for 10 min using an
additional residence time unit. The overall yield for the continuous flow process was 83%
(quantitative HPLC) (87% isolated with 91% purity), improving significantly the yield
obtained in the reported batch protocol for the threeꢀstep sequence.
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EXPERIMENTAL SECTION
General. 1HꢀNMR spectra were recorded on a Bruker 300 MHz instrument. 13CꢀNMR spectra
were recorded on the same instrument at 75 MHz. Chemical shifts (δ) are expressed in ppm
downfield from TMS as internal standard. The letters s, d, t, q and m are used to indicate
singlet, doublet, triplet, quadruplet and multiplet. Analytical HPLCꢀUV (Shimadzu LC20)
analysis was carried out on a C18 reversedꢀphase (RP) analytical column (150 × 4.6 mm,
particle size 5 ꢁm) at 37 °C using a mobile phase A (water/acetonitrile 90:10 (v/v) + 0.1 %
TFA) and B (MeCN + 0.1 % TFA) at a flow rate of 1.5 mL minꢀ1. Details on the gradients
applied are collected in the Supporting Information. GC/MS monitoring was based on
electron impact ionization (70 eV) using a HP/5MS column (30 m×0.250 mm×0.025 ꢁm).
After 1 min at 50ꢂ°C the temperature was increased in 25ꢂ°Cꢂminꢀ1 steps up to 300ꢂ°C and kept
at 300ꢂ°C for 1 min. The carrier gas was helium and the flow rate 1.0 mLꢂminꢀ1 in constantꢀ
flow mode. All chemicals were purchased from commercial sources and were used without
further purification. FPAA (2) was prepared according to ref. 6. Catcart preꢀpacked Pd/C
catalyst cartridges (THS X1175) for the HꢀCube Pro were obtained from ThalesNano. ICPMS
analyses were performed on an Agilent 7500ce instrument. Samples were digested at 250 °C
for 30 min with HNO3 and properly diluted prior analysis.
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CAUTION: Reactions/products described herein have the potential to release large amounts
of energy in an uncontrolled way. Nitrations should not be undertaken without stringent
hazard assessment and proper safety precautions put in place.
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Batch Nitration of FPAA (2). To a vial containing fuming sulfuric acid (oleum, 20% SO3) (1
mL) was added 100% nitric acid (2.2 or 2.5 equiv) (Figure 2) under stirring at 0 °C.
Subsequently, FPAA (2) (2 mmol, 358 µL) was added dropwise, under vigorous stirring, over
a period of 40ꢀ60 s. The vial was capped and heated at 50ꢀ60 °C. Reaction monitoring was
carried out by collecting aliquots (~ 2 µL) from the crude reaction mixture, diluting with 2
mL MeCN/H2O, and analyzing by HPLC after 5, 10, 15, 20 and 30 min reaction time.
Sequential Continuous Flow Nitration/Liquid-Liquid Extraction. Using the setup
depicted in Figure 7, FPAA (2) (Feed A, 35.8 µL/min) and a solution of 100% HNO3 (2.5
equiv) in oleum (20% SO3) (Feed B, 100 µL/min) were pumped through the reactor using two
syringe pumps (Syrris). The two streams were mixed using a static glass mixer (1.5 mL
internal volume, Uniqsis) entered a 1.5 mL residence time unit (PFA tubing, 0.8 mm i.d. and
1.59 mm o.d.). The reaction mixture was mixed with water and toluene using a Xꢀmixer at 0
°C, and entered a second residence time unit (4 mL volume, PFA tubing with 1.6 mm i.d. and
3.2 mm o.d) connected to a membrane liquidꢀliquid separator (Zaiput, 0.5 ꢁm pore size, 42
×15 mm). The organic phase obtained was used directly for the next step of synthesis without
further purification. A 10 mL aliquot of the organic phase was collected and evaporated under
reduced pressure. The residue was precipitated with cyclohexane (20 mL) and filtered off,
providing 0.97 g (92%) of dinitroꢀFPAA (3) as a pale yellow solid; mp. 67ꢀ68 °C.17 1H NMR
(300 MHz, CDCl3) δ 8.81 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 10.9 Hz, 1H), 3.25 (s, 3H), 3.09 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 159.3, 157.1, 155.7, 147.9, 124.6, 119.4, 115.7, 112.2,
111.9, 37.2.
Continuous Flow Hydrogenation of Dinitro-FPAA (3). A 0.3 M solution of dinitroꢀFPAA
(3) in toluene (1.33 mL) (see above) was diluted with methanol (0.66 mL). The hydrogen
level of the HꢀCube Pro was set to “full H2” mode, the reactor containing a Pd/C cartridge
was preꢀheated to 45 °C and the flow rate and pressure were set to according to Table 1.
When the system was stable the reaction mixture was pumped through the reactor. The crude
solution obtained from the reactor output was diluted with acetonitrile and analyzed by
HPLC.
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Sequential Continuous Flow Nitration/Hydrogenation/Cyclization of FPAA (2). The
continuous flow reactor depicted in Figure 9 was started, setting all parameters as stated. The
thermostated baths and the column reactor from the H Cube Pro were preheated to the
appropriate temperatures. The H Cube Pro pump was set to 1 mL minꢀ1 and the instrument to
“full H2 mode”. Susequently, neat FPAA (2) (35.8 ꢁL minꢀ1) was pumped through the reactor.
When the system had stabilized, the crude reaction was collected from the reactor output for
60 min. The obtained biphasic mixture was homogenized with methanol (40 mL) and the pH
adjusted with 3 M NaOH to 4ꢀ5. The solvent was evaporated under reduced pressure to
approximately 20% of the initial volume. After addition of water and stirring for 10 min the
precipitate was filtered off, washed with water, and dried at 50 °C (2.28 g, 87%, 91% pure by
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1
quantitative HPLC); mp. 210ꢀ220 °C (dec.); H NMR (300 MHz, DMSO) δ 11.71 (s, 1H),
7.13 (d, J = 11.1 Hz, 1H), 6.51 (d, J = 8.6 Hz, 1H), 5.29 (s, 2H). 13C NMR (75 MHz, DMSO)
δ 154.6, 154.1, 153.6, 148.0, 144.9, 134.7, 134.6, 127.6, 127.5, 121.6, 121.6, 117.2, 113.7,
110.2, 105.5, 105.2, 102.8.
Supporting Information: Additional experimental information and supplementary figures.
This material is available free of charge via the Internet at http://pubs.acs.org.
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(13) For a recent review, see: Irfan, M.; Glasnov, T. N.; Kappe, C. O. ChemSusChem,
2011, 4, 300ꢀ316.
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(14) Damm, M.; Kappe, C. O. Mol. Diversity 2009, 13, 529ꢀ543.
(15) FPAA (2) viscosity at 25 °C: 11.7 mPas. 100% HNO3/oleum viscosity at 20 °C: 45.1
mPas.
(16) (a) Glöckner, S.; Tran, D. N.; Ingham, R. J.; Fenner, S.; Wilson, Z. E.; Battilocchio,
C.; Ley, S. V. Org. Biomol. Chem. 2015, 13, 207ꢀ214. (b) Hamlin, T. A.; Lazarus, G.
M. L.; Kelly, C. B.; Leadbeater, N. E. Org. Process Res. Dev., 2014, 18, 1253ꢀ1258.
(c) Adamo, A.; Heider, P. L.; Weeranoppanant, N.; Jensen, K. F. Ind. Eng. Chem.
Res., 2013, 52, 10802ꢀ10808.
(17) CAUTION: handling and storage of pure dinitroꢀFPAA (3) is potentially hazardous
due to its explosive properties. Hazard assessment and proper safety precautions
should be taken.
(18) Brzozowski, M.; O’Brien, M.; Ley, S. V.; Polyzos, A. Acc. Chem. Res., 2015, 48, 349ꢀ
362
(19) For previous reports on the use of this material for inline gas removal, see: (a) Koos,
P.; Gross, U.; Polyzos, A.; O’Brien, M.; Baxendale, I.; Ley, S. V. Org. Biomol. Chem.
2011, 9, 6903ꢀ6908. (b) O’Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley,
S. V. Chem. Sci. 2011, 2, 1250ꢀ1257. (c) Skowerski, K.; Czarnocki, S. J.;
Knapkiewicz, P. ChemSusChem, 2014, 7, 536ꢀ542. (d) Fink, M. J.; Schön, M.;
Rudroff, F.; Schnurch, M.; Mihovilovic, M. D. ChemCatChem, 2013, 5, 724ꢀ727.
(20) Knudsen, K. R.; Holden, J.; Ley, S. V.; Ladlow, M. Adv. Synth. Catal. 2007, 349, 535ꢀ
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