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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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Organic Process Research & Development

Safe and fast flow synthesis of functionalized oxazoles with molecular oxygen in a microstructured reactor Sarah Bay‡,§, Tobias Baumeister†,§, A. Stephen K. Hashmi‡,#, Thorsten Röder*,† ‡ Organisch-Chemisches Institut, Ruprecht-Karls-Universität Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany † Institute of Chemical Process Engineering, Mannheim University of Applied Sciences, PaulWittsack-Str. 10, 68163 Mannheim, Germany # Chemistry Department, Faculty of Science, King Abdulaziz University (KAU), 21589 Jeddah, Saudi Arabia § These authors contributed equally.

Corresponding Author * E-Mail: [email protected], 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 larger-scale 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 follow-up transformations.

Keywords: continuous flow, oxidation, molecular oxygen, functionalized oxazoles, scale-up


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INTRODUCTION Oxazoles are versatile motifs in a variety of natural and non-natural 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, follow-up reactions can be performed leading to, e.g., halogen-substitution.4b,5d,7 The additional employment of molecular oxygen generates a carbonyl moiety in the 5-position 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 atom-economic9 and green process.10 The hydroperoxymethyl group offers potential for multifunctional conversions by reduction,11 rearrangements12 or follow-up reactions.13 Contrary to other methods that use, e.g., hypervalent iodine reagents14 or pyridine/quinoline N-oxides15 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 copper-catalyzed [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 two-phase 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 N-(β-hydroxyalkyl)carboxamides in a microreactor.22 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 set-up with a recycle-loop 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 gold-catalyzed reactions are performed at much smaller scales and with higher catalyst loadings23 (scheme 1, table 1).

“Scheme 1. Synthesis of starting material.” “Table 1. Up-scaling of oxazoline synthesis.” Reaction scale

1

Catalyst loading 2 mol%

2

2 mol%

IPrAuCl/AgNTf2

2 mmol

3h

100 %

97 %

3

2 mol%

IPrAuCl/AgNTf2

10 mmol

20 h

100 %

88 %

4

0.5 mol%

IPrAuCl/AgNTf2

20 mmol

24 h

98 %

92 %

Entry

a

Time

Conversiona Yieldb

PPh3AuCl/AgNTf2 2 mmol

3h

100 %

86 %

Catalyst

Determined by 1H NMR assays of the reaction mixture. b Isolated yield.

The transfer to a microreactor set-up of the oxidation reaction of oxazoline 2 to oxazolehydroperoxide 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 2-methoxyethyl 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.

“Scheme 2. Conditions for the synthesis of oxazole-hydroperoxide 3.”

MATERIALS AND METHODS OF MICROREACTOR EXPERIMENTS The synthesis of oxazole-hydroperoxide 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 2-methoxyethyl acetate) was homogeneously mixed with the radical starting reagent AIBN (10 mol%), an internal analytical standard n-dodecane (0.2 M) and the solvent 2-methoxyethyl acetate. The conversion (scheme 2) was performed in a microstructured reactor, consisting of a PTFE-T-Mixer (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 (EL-FLOW Select, Bronkhorst High-Tech, 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, S-11, WIKA, Germany) in the liquid stream. To carry out the reaction at higher pressures, a back pressure regulator (17 bar, P-764, 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 oxazole-hydroperoxide 3 from oxazoline 2. Dotted lines symbolize the starting set-up. Once a stable operating state has been reached, the liquid stream is conducted in a recycle loop (solid lines).”

Due to the relatively long reaction time (4 to 5 h) for a chemical conversion in a microstructured reactor, a process set-up with a recycle-loop 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 headspace-vial 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 headspace-vial 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 headspace-vial. The operating parameters of the flow experiments are displayed in table 2. A scale-up 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 scale-up 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.

“Table 2. Operating parameters for the flow oxidation of oxazole-hydroperoxide 3 from oxazoline 2 with molecular oxygen.” Parameter

Range

Scale-up

microreactor volume

(ml)

10

34.6

inner diameter

(mm)

1.58

2.40

length

(m)

5.5

7.65

liquid reservoir

(ml)

5

17.3

liquid flow rate

(ml/min)

0.25

0.86

starting concentration of 2

(mol/l)

0.2

0.2

starting feed rate of 2

(mmol/min)

0.05

0.173

oxygen feed rate

(mmol/min)

0.161-3.065

0.033

oxygen flow rate

(ml/min)

0.28-5

0.97

temperature

(°C)

70-100

80

pressure

(bar(a))

1/18

1

A continuous reduction of the generated oxazole-hydroperoxide 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 headspace-vial 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 oxazole-hydroperoxide 3, the response factors with the analytical standard n-dodecane were obtained (see S5 and S6 in the Supporting Information).

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 set-up 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. 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. 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 S9-1 in the Supporting Information. A decrease in selectivity going along with the formation of small amounts of a side product, 5-methyl-2-phenyloxazole (see Figure S9-2 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.

“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 scale-up 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 S7-1 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 slug-flow behavior, we adopted plug-flow conditions for the reaction modeling. The liquid recycle-loop was also considered in the reaction modeling.

“Scheme 3. Assumed reaction scheme for kinetic modeling.” The following rate expressions were used for the calculation:

= − −

(1)

= − + = −

(2)

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. 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 S10-1 in the Supporting Information). Additionally, the average selectivity values for the desired product, oxazolehydroperoxide 3, relative to oxazoline 2 were 85 % at 70 °C and 63 % at 80 °C (see Figure S10-2 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 scale-up 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 scale-up 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 scaled-up reactor, leading to the conclusion that the scale-up was successful and that a pilot


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plant or production scale process could be possible. The same flow regime (slug-flow) could be maintained, which was a critical concern for the scale-up. 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.

“Figure 4. Kinetic model and experimentally determined conversion of oxazoline 2 for two different reactor volumes 10 ml and 34.6 ml (scale-up) 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 fixed-bed column filled with granular sodium borohydride equipped with a PTFE-filter at the end. The GC spectra indicated that the oxazole peroxide 3 peak vanished and a new peak appeared (see Supporting Information S5) indicating that 3 was converted. Analysis by GC/MS and 1H NMR (see Supporting Information S2/3) verified the formation of oxazole methyl alcohol 4. By coupling the central oxidation reaction with a follow-up reaction, as in the presented reduction, the potential of this microreactor set-up 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 recycle-loop 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 scale-up 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.

EXPERIMENTAL SECTION Synthesis of 5-methylene-2-phenyl-4,5-dihydrooxazole 2: in a dried, round-bottomed Schlenkflask, 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). GC-MS (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. Batch-synthesis of 5-(hydroperoxymethyl)-2-phenyloxazole 3: in a round-bottomed 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 oxazole-


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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). GC-MS (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.

Supporting Information. General Information (S1),

1

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 oxazolehydroperoxide 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 oxazole-hydroperoxide 3 and selectivity at 80 °C (S8), Corresponding yields of oxazole-hydroperoxide 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 oxazole-hydroperoxide 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 oxazolehydroperoxide 3 and selectivity to the scale-up 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 flow-pattern 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 Corresponding Author * E-Mail: [email protected], Telephone: +49 621 292 6800 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 Baden-Württemberg, Germany (MWK, Funding Code 2014.001-Röder).

Notes The authors declare no competing financial interests.


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