Safe and Fast Flow Synthesis of Functionalized Oxazoles with Molecular Oxygen in a Microstructured Reactor

Article abstract of DOI:10.1021/acs.oprd.6b00118

The synthesis of hydroperoxymethyl oxazoles by oxidation of alkylideneoxazoles with molecular oxygen was implemented in a microstructured reactor for increased safety and larger-scale applications. Elaborate studies on the influence of pressure and temper

Full text of DOI:10.1021/acs.oprd.6b00118

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Full Paper
Safe and fast flow synthesis of functionalized oxazoles
with molecular oxygen in a microstructured reactor
Sarah Bay, Tobias Baumeister, A. Stephen K. Hashmi, and Thorsten Röder
Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.6b00118 • Publication Date (Web): 13 Jun 2016
Downloaded from http://pubs.acs.org on June 13, 2016
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Safe and fast flow synthesis of functionalized
oxazoles with molecular oxygen in a microstructured
reactor
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Sarah Bay‡,§, Tobias Baumeister†,§, A. Stephen K. Hashmi‡,#, Thorsten Röder*,†
‡ OrganischꢀChemisches Institut, RuprechtꢀKarlsꢀUniversität Heidelberg, Im Neuenheimer Feld
270, 69120 Heidelberg, Germany
† Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, Paulꢀ
WittsackꢀStr. 10, 68163 Mannheim, Germany
# Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah,
Saudi Arabia
§ These authors contributed equally.
Corresponding Author
* EꢀMail: t.roeder@hsꢀmannheim.de, Telephone: +49 621 292 6800
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ABSTRACT: The synthesis of hydroperoxymethyl oxazoles by oxidation of alkylideneoxazoles
with molecular oxygen was implemented in a microstructured reactor for increased safety and
largerꢀscale applications. Elaborate studies on the influence of pressure and temperature were
performed, and the apparent activation energy for the oxidation reaction was determined.
Elevated temperatures up to 100 °C and pressures up to 18 bar(a) led to a conversion rate of
approximately 90 % within 4 h of the reaction time, thus displaying the high potential and
beneficial effect of using a microreactor setup with liquid recycle loop for this oxidation. The in
situ reduction of the generated hydroperoxide functionality shows the capability of this setup for
followꢀup transformations.
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Keywords: continuous flow, oxidation, molecular oxygen, functionalized oxazoles, scaleꢀup
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INTRODUCTION
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Oxazoles are versatile motifs in a variety of natural and nonꢀnatural biologically and
pharmaceutically active compounds.1 Different synthesis routes lead to the desired structure, and
the employment of propargylic amides as a starting material is favorable. Either harsh basic
conditions2 or metal catalysis3 can be applied. In homogeneous gold catalysis,4 depending on the
oxidation state of the gold catalyst, either oxazoles or oxazolines can be formed from propargylic
amides.5 As versatile building blocks, oxazolines are primarily obtained when soft metal acids
such as Ag(I), Cu(I) and Au(I) are utilized.6 Functionalization of the oxazole moiety can be
achieved by the choice of starting materials. Alternatively, or additionally, followꢀup reactions
can be performed leading to, e.g., halogenꢀsubstitution.4b,5d,7 The additional employment of
molecular oxygen generates a carbonyl moiety in the 5ꢀposition of the oxazole core.8 By
applying mild conditions with gold(I) catalysis, generating alkylideneoxazolines, and in situ
converting it with molecular oxygen, the oxazole core is built up and immediately functionalized
to efficiently form hydroperoxymethyl oxazoles in an atomꢀeconomic9 and green process.10 The
hydroperoxymethyl group offers potential for multifunctional conversions by reduction,11
rearrangements12 or followꢀup reactions.13 Contrary to other methods that use, e.g., hypervalent
iodine reagents14 or pyridine/quinoline Nꢀoxides15 as oxidizing agents in the formation of
oxazoles, the direct oxidation with molecular oxygen and introduction of a versatile functionality
in one step is very convenient and conforms to the pursuit of atom economy. Molecular oxygen
was used in combination with high temperatures and very polar solvents to oxidize oxazolines to
oxazoles16 or in a copperꢀcatalyzed [2+2+1] cycloaddition17 without generating an additional
functional group. Nevertheless, molecular oxygen as an oxidizing agent is often neglected
because of its propensity to form explosive mixtures or peroxides with many common solvents
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and reagents, e.g., by autoxidation processes especially under harsh conditions.18 This can be
prevented by executing the reaction in microstructured reactors, where high temperatures and
pressures can be applied in a safe and simple fashion.19 The main advantage of microreactor
technology is transport intensification due to microfluidic phenomena for mixing, heat transfer
and high temperature leading to short residence times, faster mixing of miscible phases,
improved heat transport and improved safety.20 The twoꢀphase flow oxidation of aldehydes with
molecular oxygen in microstructured reactors displays these advantages in enabling this highly
exothermic reaction in a safe and beneficial manner.21 The desirability and capability of
combining oxazole synthesis with microreactor technology was shown by Ley et al. in cyclizing
Nꢀ(βꢀhydroxyalkyl)carboxamides in a microreactor.22
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In this work, we present a study of the reaction parameters, temperature and pressure, and reactor
modifications that can lead to a safe and scalable fast synthesis of hydroperoxymethyl oxazoles
using a microstructured reactor. Due to the reaction time of 4 to 5 h a reactor setꢀup with a
recycleꢀloop of the liquid stream was chosen to combine the safety of a microreactor with the
flexibility of a batch process. For the calculation of the activation energy from the experimental
data, a kinetic model was established to describe the temperature dependent reaction rate.
Furthermore, the generated hydroperoxymethyl reaction product could be reduced using
continuous flow of its solution through granular NaBH4 in a capillary.
SYNTHESIS OF STARTING MATERIAL AND BATCH EXPERIMENTS
Propargyl amide 1 was synthesized according to a procedure in the literature.10 Briefly, the
published conditions for the synthesis of oxazolines consisting of 2 mol% of preformed
PPh3AuNTf2, which could be optimized to 0.5 mol% IPrAuCl/AgNTf2 with in situ activation of
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the gold catalyst using dichloromethane (DCM) as solvent at room temperature. In addition to
the low catalyst loading, it was possible to upscale the reaction to 20 mmol with a very good
yield of 92 % within 24 h. This is remarkable because most goldꢀcatalyzed reactions are
performed at much smaller scales and with higher catalyst loadings23 (scheme 1, table 1).
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“Scheme 1. Synthesis of starting material.”
“Table 1. Upꢀscaling of oxazoline synthesis.”
Reaction
scale
Catalyst
loading
2 mol%
Entry
Catalyst
Time
Conversiona Yieldb
1
PPh3AuCl/AgNTf2 2 mmol
3 h
100 %
100 %
100 %
98 %
86 %
97 %
88 %
92 %
2
3
4
2 mol%
2 mol%
0.5 mol%
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
IPrAuCl/AgNTf2
2 mmol
3 h
10 mmol 20 h
20 mmol 24 h
a Determined by 1H NMR assays of the reaction mixture. b Isolated yield.
The transfer to a microreactor setꢀup of the oxidation reaction of oxazoline 2 to oxazoleꢀ
hydroperoxide 3 with molecular oxygen allows and requires adaptation of reaction conditions.
High temperature and pressure can be applied safely in the microreactor in contrast to
experiments using standard laboratory equipment. The published conditions (THF, 50 °C, 48 h)
could be modified to allow the use of 2ꢀmethoxyethyl acetate, which is a solvent with higher
boiling point, that does not typically form explosive peroxides, thereby enabling reaction
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temperatures of up to 100 °C leading to shorter reaction times ꢀ a necessity to use the
microreactor setup. Furthermore, an addition of 10 mol% of the radical starting reagent
azobisisobutyronitrile (AIBN) could significantly accelerate the reaction to obtain conversions of
more than 95 % within 48 h (scheme 2). An additional increase of the starting material
concentration to 0.2 M seemed to be suitable to perform the reaction under flow conditions.
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“Scheme 2. Conditions for the synthesis of oxazoleꢀhydroperoxide 3.”
MATERIALS AND METHODS OF MICROREACTOR EXPERIMENTS
The synthesis of oxazoleꢀhydroperoxide 3 was carried out under flow conditions starting with
oxazoline 2 by an oxidation with molecular oxygen in a temperature range from 70 to 100 °C at
two different pressures (1 and 18 bar(a)). Oxazoline 2 was synthesized according to the
procedure described in the experimental section. All other substrates were purchased from
commercial suppliers and used without further purification. Prior to the reaction, the liquid
reactant oxazoline 2 (0.2 M solution in 2ꢀmethoxyethyl acetate) was homogeneously mixed with
the radical starting reagent AIBN (10 mol%), an internal analytical standard nꢀdodecane (0.2 M)
and the solvent 2ꢀmethoxyethyl acetate. The conversion (scheme 2) was performed in a
microstructured reactor, consisting of a PTFEꢀTꢀMixer (inner diameter: 0.5 mm) and a 1/8”
PTFE residence time capillary (inner diameter: 1/16“, length: 5500 mm). The liquid feed was
preheated in a 1/8” PTFE capillary (inner diameter: 1/16“, length: 1000 mm). Both capillaries
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were rolled up to a helical coil for easier attachments in a bath thermostat. The oxygen gas was
not preheated because the heat capacity of a gas is negligible compared to a liquid. The
temperature control of the preheating, mixing process and chemical reaction was achieved in the
bath thermostat. The continuous feed stream of the liquid reactant was provided by a continuous
syringe pump (SyrDos 2, Hitec Zang GmbH, Germany) equipped with two 1 ml glass syringes.
The oxygen stream into the reactor (purity: 99.5%, Linde AG, Germany) was controlled with a
thermal mass flow controller (ELꢀFLOW Select, Bronkhorst HighꢀTech, Netherlands).
Depending on the reaction conditions, controllers with different operating ranges (i.e., 0.02 to 10
mln and 80 to 4000 mln) were used. The pressure inside the microreactor was measured with a
piezoresistive pressure transmitter (0 to 100 bar, Sꢀ11, WIKA, Germany) in the liquid stream. To
carry out the reaction at higher pressures, a back pressure regulator (17 bar, Pꢀ764, IDEX, United
States of America) was applied. With the use of a laboratory automation system (LabBox and
LabVision Software, Hitec Zang GmbH, Germany), automated procedures, such as flow rate
settings of the gas and liquid stream and pressure control could be included.
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“Figure 1. Microreactor setup for the continuous synthesis of oxazoleꢀhydroperoxide 3 from
oxazoline 2. Dotted lines symbolize the starting setꢀup. Once a stable operating state has been
reached, the liquid stream is conducted in a recycle loop (solid lines).”
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Due to the relatively long reaction time (4 to 5 h) for a chemical conversion in a microstructured
reactor, a process setꢀup with a recycleꢀloop of the liquid stream was chosen (figure 1). At the
beginning of the reaction, the reactor was filled with liquid reactant and oxygen until a stable
flow condition was reached. This typically requires two residence times (4 to 40 minutes
depending on the phase ratio of gas to liquid). Once a stable operating state was attained, the
liquid phase was collected in a headspaceꢀvial at the outlet of the microreactor, while the oxygen
was separated. After a total volume of 5 ml had been collected, the pump inlet was switched into
the headspaceꢀvial to receive a liquid recycle stream. Behind the outlet of the microreactor, the
liquid stream was cooled by air. The liquid reservoir was stirred with a magnetic stirring bar,
thus maintaining room temperature. Due to the high temperature difference between the
microreactor and the liquid reservoir, the extent of reaction in the reservoir was negligible.
Additionally, the specific gas/liquid interface in the liquid reservoir was lower compared to the
microreactor. Analytic samples for GC analysis were collected from the headspaceꢀvial. The
operating parameters of the flow experiments are displayed in table 2.
A scaleꢀup of the reaction was performed by using a residence time capillary with a larger inner
diameter of 2.4 mm. The ratio of the inner diameter to capillary length was kept constant. This
enabled a scaleꢀup factor of 3.46 for the microreactor and the liquid reservoir volume (34.6 and
17.3 ml) and for liquid and oxygen flow rates (0.86 and 0.97 ml/min). In this case, the residence
time in the microreactor was kept constant compared with the previous experiment. The higher
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flow rates of gas and liquid could be obtained with the same syringe pumps and mass flow
controllers.
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“Table 2. Operating parameters for the flow oxidation of oxazoleꢀhydroperoxide 3 from
oxazoline 2 with molecular oxygen.”
Parameter
Range
10
Scaleꢀup
34.6
microreactor volume
inner diameter
length
(ml)
(mm)
(m)
1.58
5.5
2.40
7.65
liquid reservoir
liquid flow rate
(ml)
5
17.3
(ml/min)
0.25
0.86
starting concentration of 2
starting feed rate of 2
oxygen feed rate
oxygen flow rate
temperature
(mol/l)
0.2
0.2
(mmol/min)
(mmol/min)
(ml/min)
(°C)
0.05
0.173
0.033
0.97
80
0.161ꢀ3.065
0.28ꢀ5
70ꢀ100
1/18
pressure
(bar(a))
1
A continuous reduction of the generated oxazoleꢀhydroperoxide 3 was performed by leading the
microreactor outlet stream through a 6 mm PTFE capillary (inner diameter: 4 mm, length: 35
mm) filled with granular sodium borohydride. The wash out of sodium borohydride was
prevented by a PTFE filter (10 µm) at the end of the capillary. The reduced product was
collected in a headspaceꢀvial as in the previous experiments and analyzed by GC.
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Quantitative analyses of the reactions were carried out using GC (7820A with flame ionization
detector (FID), Agilent Technologies, Inc., United States of America) equipped with an HP5
column (length: 30 m, diameter: 0.320 mm, film thickness: 0.25 µm). All samples were analyzed
immediately after collection, since the samples were not stable for a long time period. The best
results were achieved with a split injection (split ratio: 100:1) and an injection volume of 5 µl.
An initial oven temperature of 60 °C was kept constant for 3 minutes and then increased to 250
°C with a temperature ramp of 15 °C/min and held for 2.5 minutes. To quantify the molar
concentrations of oxazoline 2 and oxazoleꢀhydroperoxide 3, the response factors with the
analytical standard nꢀdodecane were obtained (see S5 and S6 in the Supporting Information).
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RESULTS
At the beginning of the flow experiments, the influence of the radical starting reagent AIBN was
investigated. The addition of 10 mol% AIBN led to good results in the batch experiments
without use of a microreactor (i.e., conversions > 95 % within 48 h). The batch experiment with
liquid recycle loop was conducted with the same amount of AIBN at 80 °C and 1 bar(a) in the
described microreactor setꢀup with a liquid flow rate of 0.25 ml/min and an oxygen flow rate of 5
ml/min. To determine the AIBN influence, an experiment with the same reaction conditions but
without the radical starting reagent was conducted. The results show a significant increase of the
reaction rate by the addition of 10 mol% AIBN. The conversion of oxazoline 2 was increased
from 13 to 31 % within a total reaction time of 3 h. As an additional effect, the selectivity for the
desired product 3 relative to oxazoline 2 was increased from 50 % to 65 %. The results of the
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AIBN influence on the reaction process are displayed in the Supporting Information (S7). For all
following experiments, AIBN was used to accelerate the oxidation of oxazoline 2.
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The second parameter investigated was the oxygen pressure. To study the pressure dependence
on the reaction progress, experiments were carried out at 1 bar(a) and 18 bar(a), while the phase
ratio of gas to liquid was kept constant in the microreactor. Therefore, the oxygen flow rate was
increased from 5 ml/min to 90 ml/min at normal pressure for the experiments at 18 bar(a). The
liquid flow rate was held at 0.25 ml/min. The results of the GC analysis showed no acceleration
of the reaction progress due to the higher oxygen pressure (see Supporting Information S8). This
presumes that a higher O2 solubility in the liquid phase or a higher mass transfer over the
gas/liquid interface under pressure had no influence on the oxidation progress under the
investigated conditions.
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The reaction temperature varied from 70 to 80 to 100 °C at normal pressure and application of a
gas to liquid ratio of 20 led to a significant increase in the conversion. A temperature increase of
just 10 °C doubled the conversion to 39 % after 4 h reaction time. Raising the temperature to 100
°C led to a conversion of 64 % after 4 h, suggesting an approximately linear correlation of the
conversion with the temperature (figure 2). Simultaneously, the yield could be enhanced with an
increase in the reaction temperature. The corresponding yields of the experiments are shown in
Figure S9ꢀ1 in the Supporting Information. A decrease in selectivity going along with the
formation of small amounts of a side product, 5ꢀmethylꢀ2ꢀphenyloxazole (see Figure S9ꢀ2 in the
Supporting Information) were observed at elevated temperatures.
Furthermore, an elevation of the temperature of more than 100 °C was not possible due to the
boiling point and vapor pressure of the solvent. Reaction temperatures higher than 100 °C at
1 bar(a) led to parts of the solvent being gaseous within the microreactor making it impossible to
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establish a stable working state. Because high conversions were reached by 100 °C, further
experiments to apply higher temperatures were not explored.
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“Figure 2. Kinetic model and experimental data for the conversion of oxazoline 2 at different
reaction temperatures 70, 80, 100 °C, 1 bar(a), O2 flow rate of 5 ml/min, liquid flow rate of
0.25 ml/min and a gas to liquid ratio of 20.“
To gain further insights into the reaction kinetics, we determined the apparent activation energy
of the oxidation process. An effective kinetic model was established to describe the
experimentally obtained data. The scope of this model is to provide reliable data for a further
scaleꢀup without bias toward the molecular reaction mechanism. A simple approach, shown in
scheme 3, was used as a basis for a data fitting per square with MATLAB software (MathWorks,
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Inc., United States of America). The kinetic model includes two reaction paths with rate constant
k2 for the reaction including AIBN and k1 for the reaction path without the radical starting
reagent. We simplified this model with an apparent rate constant kap (1/s) for both reaction paths.
Rate constants for the decomposition of AIBN can be found in the literature for a variety of
different solvents.24 The used model implies a constant concentration of the radical concentration
cRad. This approach was chosen because both reaction paths contribute to the conversion of
oxazoline 2 in the same range (see Figure S7ꢀ1 in the Supporting Information). Mass transfer
limitations were not considered, and isothermal conditions were assumed in the reaction
modeling. Due to the experimental results for the influence of the oxygen pressure on the
reaction progress a constant oxygen concentration was assumed and neglected. Due to the
observed slugꢀflow behavior, we adopted plugꢀflow conditions for the reaction modeling. The
liquid recycleꢀloop was also considered in the reaction modeling.
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“Scheme 3. Assumed reaction scheme for kinetic modeling.”
The following rate expressions were used for the calculation:
ꢀꢁ
ꢂ
= − ꢄꢅ ꢆꢇ − ꢄꢇ ꢆꢇꢆꢈꢉꢀ
(1)
(2)
ꢀꢃ
ꢀꢁ
ꢂ
ꢊ
ꢋ
= − ꢆꢇ ꢄꢅ + ꢄꢇ ꢆꢈꢉꢀ = − ꢆꢇꢄꢉꢌ
ꢀꢃ
with the concentration of oxazoline 2 c2 and the concentration of the radical cRad.
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As a result of the data fitting, an apparent activation energy of 90 kJ/mol was calculated by using
the reaction rate kap values obtained from the experiments at three different temperatures from
figure 2. Therefore, ln(kap) was plotted against 1/T in an Arrhenius plot. The apparent activation
energy can be calculated from the slope of the Arrhenius plot (see Supporting Information S13).
The high activation energy indicated no mass transport limitations for the oxidation of oxazoline
2.
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For the following experiments, a gas to liquid ratio of 1.1 (liquid flow rate: 0.25 ml/min, oxygen
flow rate: 0.28 ml/min) was used in contrast to the previous experiments where a gas to liquid
ratio of 20 was used. Under this condition, at 18 bar(a), the residence time of the liquid phase in
the microreactor was nearly ten times longer (18.95 min) compared with the experiments at 1
bar(a) (1.90 min). By applying these conditions at 70 °C and 80 °C, the conversion can be
increased to 45 % and 89 %, respectively, after 4 h reaction time (figure 3). In this case, a yield
of 40 % at 70 °C and 56 % at 80 °C could also be obtained (see Figure S10ꢀ1 in the Supporting
Information). Additionally, the average selectivity values for the desired product, oxazoleꢀ
hydroperoxide 3, relative to oxazoline 2 were 85 % at 70 °C and 63 % at 80 °C (see Figure S10ꢀ2
in the Supporting Information). The higher conversion and yield was mainly due to the longer
residence time in the microreactor and not to the higher partial pressure of oxygen.
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“Figure 3. Kinetic model and experimental data for the conversion of oxazoline 2 at different
reaction temperatures 70 °C and 80 °C, 18 bar(a) pressure, O2 flow rate of 0.28 ml/min, liquid
flow rate of 0.25 ml/min and a gas to liquid ratio of 1.1.“
A scaleꢀup of the reaction was conducted using a residency time capillary with a larger inner
diameter of 2.4 mm. To maintain a basis for comparison, the ratio of the inner diameter to
capillary length was not changed. This leads to a scaleꢀup factor of 3.46 for reactor volume (34.6
ml), liquid reservoir volume (17.3 ml), and liquid and oxygen flow rates (0.86 and 0.97 ml/min).
In this case, the residence time in the microreactor was kept constant as in the previous
experiment. The experiment was carried out at 80 °C, normal pressure and a gas to liquid ratio of
1.1. The conversion (figure 4) and yield (see Supporting Information S11) were reproduced in
the scaledꢀup reactor, leading to the conclusion that the scaleꢀup was successful and that a pilot
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plant or production scale process could be possible. The same flow regime (slugꢀflow) could be
maintained, which was a critical concern for the scaleꢀup. Due to the relatively high dilution of
the reaction system, heat removal was not an issue. The adiabatic temperature rise for the
reaction was estimated with only 17.5 K. The calculation is included in the Supporting
Information S14.
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“Figure 4. Kinetic model and experimentally determined conversion of oxazoline 2 for two
different reactor volumes 10 ml and 34.6 ml (scaleꢀup) at 80 °C, O2 flow rates of 0.28 and 0.97
ml/min, liquid flow rates of 0.25 and 0.86 ml/min and a gas to liquid ratio of 1.1.“
Finally, we investigated whether it was possible to combine the oxidation reaction in the
microstructured reactor with further transformations of the hydroperoxide functionality, e.g., by
reducing with sodium borohydride (scheme 4).10
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“Scheme 4. Reduction of hydroperoxymethyl oxazole 3 to alcohol 4.”
To obtain a continuous reduction, the reaction solution was passed through a fixedꢀbed column
filled with granular sodium borohydride equipped with a PTFEꢀfilter at the end. The GC spectra
indicated that the oxazole peroxide 3 peak vanished and a new peak appeared (see Supporting
1
Information S5) indicating that 3 was converted. Analysis by GC/MS and H NMR (see
Supporting Information S2/3) verified the formation of oxazole methyl alcohol 4. By coupling
the central oxidation reaction with a followꢀup reaction, as in the presented reduction, the
potential of this microreactor setꢀup was demonstrated.
CONCLUSION
The implementation of the oxidation reaction of alkylidenoxazoles to hydroperoxymethyl
oxazoles by molecular oxygen in a microstructured reactor has been successfully demonstrated.
The influences of pressure and temperature on the reaction outcome were studied, showing that
by applying temperatures up to 100 °C and a pressure of 18 bar(a), conversions up to 90 %, good
selectivity and acceptable yields could be obtained. By using a recycleꢀloop for the liquid stream,
the flexibility of the process was increased. Furthermore, the microreactor afforded a safer
environment for high temperature and pressure reactions with molecular oxygen and organic
reactants. An effective kinetic model was obtained for a scaleꢀup prediction and the calculation
of the apparent activation energy. The obtained activation energy of 90 kJ/mol leads to the
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assumption that the oxidation process was not limited by mass transfer. Additionally, the
reaction could be scaled up by a factor of 3.46 without losses in conversion or yield giving rise to
the assumption that further upscaling of the process could be done. Furthermore, the effective
coupling of two reaction steps (i.e., the oxidation of oxazoline 2 and the reduction of the
hydroperoxymethyl oxazole 3) in the microreactor paved the way for using versatile variations of
the reaction to form structurally diverse oxazoles.
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EXPERIMENTAL SECTION
Synthesis of 5ꢀmethyleneꢀ2ꢀphenylꢀ4,5ꢀdihydrooxazole 2: in a dried, roundꢀbottomed Schlenkꢀ
flask, 3.18 g (20 mmol) propargyl amide 1 were dissolved in 60 ml of dry DCM. Then, 62 mg
(0.5 mol%) IPrAuCl and 39 mg (0.5 mol%) AgNTf2 were added under an atmosphere of
nitrogen. The reaction mixture was stirred for 24 h at room temperature. The solvent was
evaporated, a small amount of PE/EA was added and the raw product was purified by column
chromatography on silica (PE/EA 15:1) to yield 2.94 g (18.4 mmol, 92 %) oxazoline 2 as a light
yellow oil. Rf (PE/EA 5:1 = 0.66). 1H NMR (300 MHz, CDCl3) δ = 4.34 (q, J = 2.7 Hz, 1H), 4.63
(t, J = 2.9 Hz, 2H), 4.80 (q, J = 3.0 Hz, 1H), 7.55 – 7.35 (m, 3H), 8.01 – 7.90 (m, 2H). GCꢀMS
(EI) m/z = 159.0 (M), 144.0 (M – CH2 – H), 131.1, 117.0, 103.0, 89.0, 77.0 (Ph). The analytic
data are in correspondence with the published data.
Batchꢀsynthesis of 5ꢀ(hydroperoxymethyl)ꢀ2ꢀphenyloxazole 3: in a roundꢀbottomed flask
equipped with reflux condenser and an oxygen filled balloon, 80 mg (0.5 mmol) of oxazoline 2
were dissolved in 5 ml isopropyl acetate and flooded with molecular oxygen while heating up to
70 °C for 48 h. The solvent was evaporated and the raw material was purified by column
chromatography on silica (PE/EA 3:1) to yield 57 mg (0.3 mmol, 60 %) of oxazoleꢀ
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hydroperoxide 3 as a colorless solid. Rf (PE/EA 3:1 = 0.31). 1H NMR (30 MHz, CDCl3) δ = 4.98
(s, 2H), 7.12 (s, 1H), 7.49 – 7.29 (m, 3H), 7.88 – 7.75 (m, 2H), 10.16 (s, 1H). GCꢀMS (EI) m/z =
173.1 (M – OH), 144.1 (M – CH2OOH), 116.1 (M – C6H5 + 2H), 89.1. The analytic data are in
correspondence with the published data.
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1
Supporting Information. General Information (S1), H NMR spectra of oxazoline 2,
hydroperoxide 3 and the product after reduction 4 (S2), GC/MS of reaction mixture before
reduction with NaBH4 (S3), GC/MS of reaction after reduction with NaBH4 (S4), GC spectra of
reactants and reaction mixture (S5), Determination of the response factors to determine
conversion and yield (S6), Influence of AIBN on the conversion of oxazoline 2, yield of oxazoleꢀ
hydroperoxide 3 and selectivity at 80 °C / 1 bar(a) (S7), Pressure influence 1 bar(a) ꢀ 18 bar(a)
on the conversion of oxazoline 2, yield of oxazoleꢀhydroperoxide 3 and selectivity at 80 °C (S8),
Corresponding yields of oxazoleꢀhydroperoxide 3 and selectivity of the experiments at 70 °C,
80 °C and 100 °C, 1 bar(a), liquid flow rate 0.25 ml/min, oxygen flow rate 5 ml/min, phase ratio
gas to liquid 20 (Figure 2) (S9), Corresponding yields of oxazoleꢀhydroperoxide 3 and selectivity
of the experiments at 70 °C and 80 °C, 18 bar(a), liquid flow rate 0.25 ml/min, oxygen flow rate
5 ml/min, phase ratio gas to liquid 1.1 (Figure 3) (S10), Corresponding yields of oxazoleꢀ
hydroperoxide 3 and selectivity to the scaleꢀup experiment at 80 °C, 1 bar(a), liquid flow rate
0.86 ml/min, oxygen flow rate 0.97 ml/min, phase ratio gas to liquid 1.1 (Figure 4) (S11),
Observed flowꢀpattern at 18bar(a), liquid flow rate 0.25 ml/min, oxygen flow rate 5 ml/min
(S12), Calculation of the activation energy EA (S13), Estimation of the adiabatic temperature rise
(S14). This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
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* EꢀMail: t.roeder@hsꢀmannheim.de, Telephone: +49 621 292 6800
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Author Contributions
The manuscript was written through the contributions of all authors. All authors have given approval to the final version of the
manuscript. § S. B. and T. B. contributed equally to the experimental work.
Funding Sources
This work was funded (fellowship for T. B.) by the Ministry of Science, Research and the Arts of the State BadenꢀWürttemberg,
Germany (MWK, Funding Code 2014.001ꢀRöder).
Notes
The authors declare no competing financial interests.
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22 Glöckner, S.; Tran, D. N.; Ingham, R. J.; Fenner, S.; Wilson, Z. E.; Battilocchio, C.; Ley, S. V.
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Org. Biomol. Chem. 2015, 13, 207ꢀ214.
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In most reactions of the literature 5 mol% of catalyst are used, for the lowest catalyst loading
used in homogeneous gold catalysis so far, see: (a) Jaimes, M. C. B.; Böhling, C. R. N.; Serranoꢀ
Becerra, J. M.; Hashmi, A. S. K. Angew. Chem. Int. Ed. 2013, 52, 7963ꢀ7966; (b) Jaimes, M. C.
B.; Rominger, F.; Pereira, M. M.; Carrilho, R. M. B.; Carabineiro, S. A. C.; Hashmi, A. S. K.
Chem. Commun. 2014, 50, 4937ꢀ4940.
24 Moroni, A. F. Die Makromolekulare Chemie 1967, 105, 43ꢀ49.
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