Continuous Flow Synthesis of Carbonylated Heterocycles via Pd

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Continuous Flow Synthesis of Carbonylated Heterocycles via Pd-Catalyzed Oxidative Carbonylation Using CO and O2 at Elevated Temperature and Pressure Yuesu Chen, Christopher A. Hone, Bernhard Gutmann, and C. Oliver Kappe Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.7b00217 • Publication Date (Web): 28 Jun 2017 Downloaded from http://pubs.acs.org on June 28, 2017

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Organic Process Research & Development

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Continuous Flow Synthesis of Carbonylated Heterocycles via Pd-Catalyzed Oxidative Carbonylation Using CO and O2 at Elevated Temperature and Pressure

Yuesu Chen,† Christopher A. Hone, †,‡ Bernhard Gutmann†,‡ and C. Oliver Kappe*,†,‡ †

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria

‡

Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria

* C. Oliver Kappe. E-mail: [email protected].

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TABLE OF CONTENTS GRAPHICS


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ABSTRACT: A continuous-flow Pd-catalyzed oxidative carbonylation protocol utilizing CO and O2 gas for the synthesis of carbonylated heterocycles is described. Optimization of temperature, pressure, CO/O2 ratio, catalyst loading and reaction time resulted in process intensified conditions for this transformation. The optimized continuous flow conditions (120 °C, 20 bar pressure, 24 min residence time) were used to prepare a number of benzoxazolone, 2-benzoxazolidinone and other biologically and synthetically important five- and sixmembered carbonylated heterocycles in good overall yield and purity (14 examples). The continuous-flow process enables the safe and scalable oxidative carbonylation using CO/O2 under elevated pressure and temperatures.

Keywords: carbon monoxide; continuous-flow; microreactor; oxygen; palladium



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INTRODUCTION Carbon monoxide is a cheap and synthetically useful C1 building block in organic chemistry, and CO is readily available in large quantities from the bulk chemical industry.1,2 Since the development of a high-pressure technique in the early 20th century, a large number of carbon monoxide reactions were discovered and rapidly found their application in the chemical industry, among them carbonylation reactions.2,3 The carbonyl group is a key component in aldehydes, ketones, carboxylic acids and their derivatives, and also appears in biologically active compounds, natural products and a broad spectrum of fine chemicals.4 Carbonylation has become a straightforward approach for the introduction of such linkage into organic molecules. For synthetic chemists, Pd-catalyzed carbonylation reactions in particular provide an alternative strategy for the atom economic preparation of several classes of organic molecules that are otherwise not easily accessible.5 Pd-catalyzed carbonylations have become a powerful methodology in organic synthesis given its diverse chemistry, mildness and atom efficiency compared to classical oxidations, such as Friedel-Crafts acylation, and other carbonyl forming reactions.5b Pd-catalyzed carbonylations are particularly important for the formation of 5- and 6-membered rings containing carbonyl groups.5 Carbonylated heterocycles are of key biological and synthetic significance. Benzoxazolone derivatives for example have shown promising bioactivity, including for anticancer,6a anti-mycobacterial6a and anti-convulsant applications.6b-c In addition, the pure enantiomers of substituted 2-oxazolidinones are valuable Evans’ chiral auxiliaries.7 The classical approach for the synthesis of benzoxazolone and 2-oxazolidinone is through the condensation of 2-aminophenol and 2-aminoalcohols with carbonic acid derivatives, such as phosgene,8 carbonates9 or urea (Figure 1).10 Alternatively, carbonylated heterocycles are also accessible via Pd-catalyzed oxidative carbonylation reactions using CO and O2 as reagent.11 The PdI2/KI system developed by Gabriele and co-workers is highly efficient for the conversion of 2-aminophenol11a and 2-aminoalcohols.11e-f Compared to most of the traditional condensation reactions, oxidative carbonylation methods do not rely on corrosive reagents such as phosgene and are cheaper and more atom-economic than condensation with urea and carbonates, because the only byproduct is water.


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Figure 1. Different strategies for the synthesis of carbonylated heterocycles. Oxidative carbonylation provides a carbonylative coupling of two donor (nucleophilic) groups,12d which in many ways is complimentary to classical donor-acceptor carbonylation chemistry.12 The mechanism of oxidative carbonylation is generally considered to be a palladium redox cycle.12 The conversion of the substrate molecule to the product involves the removal of two electrons, via the reduction of Pd(II) to Pd(0).12 Correspondingly, the regeneration of the Pd(II) catalyst necessitates the use of an external oxidant to complete the catalytic cycle (Figure 2a).12 Liquid phase oxidants, such as metal salts,13 peroxides14 and benzoquinone15 have been utilized for the reoxidation of Pd(0), but this is inherently atom inefficient due to the generation of a stoichiometric quantity of waste. Molecular oxygen is a highly abundant, cheap and a suitable green alternative to existing oxidizing agents. In the catalytic cycle, O2 is reduced to environmentally benign water, which does not complicate product isolation. O2 cannot reoxidize Pd(0) directly in the liquid phase, thus a cocatalyst (iodide11a-h or copper salt11i) is introduced to serve as electron carrier (Figure 2b). However, utilization of O2 in the presence of an organic solvent as a fuel and an ignition source often results in a potentially flammable mixture. In practice, the reaction is most commonly performed in glass flasks fitted with gas balloons17a at atmospheric pressure or in highpressure autoclaves. A strategy to improve the operational safety is to dilute the mixture either with an inert gas (e.g. N2)16 or with a large excess of either CO11b-e,17 or O211f to deviate the composition from the range of the explosive limit18 (15.5 – 93.9 vol % CO in O2).19 However, the use of pure gases without dilution typically provides higher reaction rates and process efficiency.22b For the case of oxidative carbonylation, a technique which enables the safe handling of highly flammable mixtures of CO, solvent vapor and pure O2 is clearly required.



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Figure 2. Pd-catalyzed oxidative carbonylation reaction: (a) general sketch and (b) the role of the cocatalyst when O2 is used as oxidant. Over the past decade, continuous-flow technology has received significant attention from organic and process chemists,20-22 especially those working with hazardous reagents21 and gaseous feedstocks.22 The characteristic features of flow reactors (i.e., fast heat and mass transfer, precise control over reaction time, easiness of scale-up etc.) facilitate operation under extreme conditions (especially high T, p, high concentrations of reactive and explosive intermediates) with the presence of minimum amount of hazard.21 In microreactors, the mass transfer effects are reduced for a gas-liquid reaction, because a segmented flow pattern inside the reactor channel provides a high interfacial area between the gas and liquid phases. The high interfacial area significantly accelerates the dissolution of the gases into the liquid phase.22 The safety of the operation is guaranteed,23 even for a worst case scenario, since a properly designed metallic microreactor is able to sustain an explosion event for a mixture of flammable gases and O2.22b,23 By virtue of these advantages, a large variety of gas-liquid reactions using hazardous reagents have been performed in continuous-flow reactors.21,22 Based on previous research and our experience in safely handling molecular oxygen24 and ACS Paragon Plus Environment

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CO25-26 in flow reactors, we herein present a continuous-flow oxidative carbonylation protocol utilizing molecular oxygen and CO for the synthesis of carbonylated heterocycles. To the best of our knowledge, this is the first example of liquid-phase oxidative carbonylation chemistry performed under continuous-flow conditions.27,28

RESULTS AND DISCUSSION Design and Construction of the Microreactor. We were inspired by the work of Gabriele and co-workers using a PdI2/KI catalyst system for the oxidative carbonylation of amines, βamino alcohols, and 2-aminophenols in batch (1 mol% PdI2, 10 mol% KI, 32 bar CO + 8 bar air).11a We commenced our investigation with the synthesis of 2a via the oxidative carbonylation of 2-aminophenol (1a) using a palladium/iodide catalyst system, but both PdI2 and KI proved poorly soluble in organic solvents. We wanted to obtain homogeneous feed solutions to make the chemistry more amenable for continuous processing. Pd(OAc)2 and tetrabutylammonium iodide (n-Bu4N+I-,TBAI) were used as catalyst and cocatalyst respectively, because of their good solubility in organic solvents. Acetonitrile was selected as solvent and provided good solubility for all reactants and products. Moreover, we observed that 1a and Pd(OAc)2 form a precipitate within a few minutes of mixing,29 therefore the Pd catalyst and substrate were introduced as two separate feed streams. Based on the above considerations, a continuous-flow setup was constructed as outlined in Figure 3. A stainless steel coil (R) (internal volume V = 20 mL, inner diameter 1.0 mm) fitted with a temperature control unit was utilized as the reactor. The entrance of the reactor coil was connected to a four-way mixer (M) to introduce the feed streams (catalyst, substrate, CO and O2). A back-pressure regulator (BPR) was installed downstream of the reactor to control the system pressure. The outlet of R and the inlet of BPR were connected with a piece of transparent PFA tubing (L0) for the observation of flow pattern and color changes. The solution of Pd(II) catalyst in MeCN (stream 1), the solution of 1a and TBAI in MeCN (stream 2), CO (stream 3) and O2 (stream 4) were directed into M; the resulting gasliquid mixture then entered the reaction coil (R), where the oxidative carbonylation took place. After the reaction, the reaction mixture containing the product exited the reactor through the outlet of the BPR, and was finally collected in a test tube. The two liquid feeds were injected through injection loops (L1 and L2). The flow rates of the gas streams were monitored using calibrated Bronkhorst mass flow controllers (MFCs) (for more details of the setup, see the Supporting Information) ACS Paragon Plus Environment


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Figure 3. Construction of the microreactor for the oxidative carbonylation Optimization of the Reaction Conditions. Initially, the influence of temperature, pressure and gas flow rate were investigated to identify the optimal reaction conditions for the continuous-flow oxidative carbonylation of 2-aminophenol (1a) (Figure 4). For this preliminary optimization, CO and O2 were fed in excess at equal flow rates, whilst the concentration of 1a in the feed stream was 0.10 M. Under 15 bar pressure, the conversion reached a plateau at 90 °C (curve a). When higher pressure (20 bar) was exerted for those experiments above 90 °C (curve b), the molar fraction (area % by GC) of benzoxazolone (2a) reached 97% at 120 °C within 17 min residence time. Doubling the gas flow rates resulted in a decrease in conversion, probably from the reduced reaction time (curve c).


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Figure 4. Influence of the reaction temperature, pressure and the gas flow rate. (a) 15 bar, FCO = FO2 = 4.40 mLN/min, residence time tR = 15 min; (b) 20 bar, FCO = FO2 = 4.40 mLN/min, tR = 17 min; (c) 15 bar, FCO = FO2 = 8.80 mLN/min, tR = 8 – 10 min. (Concentration of 1a in feed stream 0.10 M, corresponding to 0.05 M within the reactor; liquid flow rates 0.50 mL/min for each stream; analyzed by GC-FID. Subscript “N” denotes volume under STP (273.15 K, 1 bar) condition.) During the optimization studies, we discovered that the internal surface of the reactor coil became coated with some of the Pd catalyst over time. A control run without the addition of Pd within the feed demonstrated that the residual Pd on the coil still retained some activity and was catalyzing the reaction, albeit at lower levels (Table 1, entry 1). This phenomenon was also observed by us in the Pd catalyzed continuous-flow Mizoroki–Heck coupling30 and by some other researchers.31 In organic solvent under high temperature, the Pd(II) catalyst will be rapidly converted into Pd(0) colloids/nanoparticles, from which Pd black is formed.32 The Pd deposited on the reactor coil can be re-oxidized by I2 (from TBAI) to re-form the active Pd(II) catalyst.33,11g To guarantee the reproducibility of our results, the residual Pd



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black inside the reactor was removed after each experiment by washing the reactor with 20% HNO3 (aq) at 70 °C. The subsequent optimization of the catalyst type and catalyst loading was carried out under double the substrate feed concentration (0.20 M) and halved liquid flow rate. Under these conditions, good conversions were obtained when using 5.0 mol% Pd(OAc)2 and Pd(TFA)2 (Table 1, entries 2 and 3). Reducing the catalyst loading also resulted in a decrease in conversion (Table 1, entries 4 and 5). The increase of residence time for 1.0 mol% catalyst loading failed to improve the conversion any further, instead a large amount of oxidation product (7a) was formed11e presumably via a sequential oxidation/1,4-addition mechanism (Table 1, entry 6).34 In the control experiment without catalyst, only oxidation of the substrate took place (Table 1, entry 7). Furthermore, 20 mol% cocatalyst was found to be necessary to obtain high substrate conversion in a residence time appropriate to flow processing (Table 1 entry 8).

Table 1. Optimization of Catalyst Type and Loading.

entry

a

catalyst

tR b

flow rate (mLN/min)

cocatalyst

molar fraction c (%)

(TBAI)

F1

F2

FCO

FO2

(min)

1a

2a

7a d

1

reactor not cleaned

20 mol%

0.25

0.25

4.40

4.40

24

36

46

18

2

Pd(OAc)2 5.0 mol%

20 mol%

0.25

0.25

4.40

4.40

24

4

94

2

3

Pd(TFA)2 5.0 mol%

20 mol%

0.25

0.25

4.40

4.40

24

5

91

4

4

Pd(OAc)2 2.5 mol%

20 mol%

0.25

0.25

4.40

4.40

24

9

87

4

5

Pd(OAc)2 1.0 mol%

20 mol%

0.25

0.25

4.40

4.40

24

24

68

8

6

Pd(OAc)2 1.0 mol%

20 mol%

0.12

0.12

2.20

2.20

48

23

48

29

7

no catalyst

20 mol%

0.25

0.25

4.40

4.40

24

74

0

26

8

Pd(OAc)2 5.0 mol%

10 mol%

0.25

0.25

4.40

4.40

24

12

83

5

Conditions: 0.20 M concentration of 1a in feed, corresponding to 0.10 M within the reactor, cocatalyst TBAI

20 mol%, 120 °C, 20 bar. Reactor was washed with HNO3 before each experiment (unless otherwise mentioned). b

Residence time measured by a stop watch. c Determined by GC-FID. d Byproduct stemmed from the oxidation

of 1a.


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The influence of the CO/O2 ratio on the reaction was also investigated (Figure 5). The experiments under 15 bar and 20 bar indicated that CO/O2 = 1.0 is the optimal gas phase composition. A high CO concentration is favored by the carbonylation. However the presence of too much CO can also cause faster deactivation of the Pd(II) catalyst by reduction to Pd(0). A higher O2 concentration is necessary to maintain the presence of iodine, which reoxidizes Pd(0) to Pd(II) in the liquid phase;33 whereas pure O2 can slowly oxidize the substrate at high temperature and long residence time11e (Table 1, entries 5 and 6). The contradictory effects of CO and O2 finally led to the optimum ratio CO/O2 (1:1), under which the best conversion of 1a is achieved. Since potentially explosive gas mixtures can be safely handled in flow, it is permitted that the gas composition could be further optimized to conditions that are within the explosive regime without the use of dilution gases, whereas heating a pressurized explosive mixture of CO and O2 in an autoclave is strictly forbidden.

Figure 5. Influence of CO/O2 ratio on product formation. (a) 90 °C, 15 bar, tR = 15 min; concentration of 1a in feed stream 0.10 M, corresponding to 0.05 M within the reactor. (b) 120 °C, 20 bar, tR = 17 min, concentration of 1a in feed stream 0.20 M. (liquid flow rates F1 = F2 = 0.50 mL/min; total gas flow rate FCO + FO2 = 8.80 mLN/min; analyzed by GC-FID.) ACS Paragon Plus Environment


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A mechanism based on earlier reports11,12 and our experiments is proposed for the oxidative carbonylation of 1a (Figure 6). Substrate 1a is a bidentate ligand which is present in large excess with respect to palladium, therefore the formation of chelates 3a and 6a are thermodynamically favored. However, in the absence of a strong base, the insoluble complex 6a forms rather slowly.29 Thus, this allows electron-deficient (14e) precursor 3a, which may also exist as a dimer, to coordinate with CO for the subsequent migratory insertion and the reductive elimination, giving 2a and Pd(0). The Pd(0) species is present in the form of Pd nanoparticles, Pd black suspension (and ultimately deposited on the reactor wall) in the reaction system. These Pd(0) species are then reoxidized by I2 (generated by the oxidation of iodide) forming Pd(II) for the next catalytic cycle.33,11h

Figure 6. A proposed mechanism for the oxidative carbonylation of 1a. Using the optimized reaction conditions (Table 1, entry 1), an array of five and six-membered carbonylated heterocycles (2) were prepared from their corresponding precursors (1) (Figure 7). Most of the compounds were isolated in good yield after purification by flash chromatography. The only exceptions were the precursors which are readily oxidized (1d and


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1l) or less reactive to achieve complete conversion (1k and 1n). Alkyl substituted 2aminophenols (1b and 1c) and alkyl substituted catechol (1m) gave higher yields than their unsubstituted counterparts (1a and 1l respectively), since the alkyl substituents resist oxidative dimerization34 by steric hindrance without making the aromatic ring too electronrich. Amino group and phenolic hydroxyl group interact stronger with Pd(II) than alcoholic hydroxyl groups. For the conformational flexible 1j and 1k, a stronger linkage with Pd atom is necessary to stabilize the intermediates containing six-(3 and 4) and seven-(5) membered palladacycles; as a result, 1j (with phenolic OH) was converted completely to afford 2j, whereas 1k (with alcoholic OH) reacted rather slowly. Glycol 1n bears only two alcoholic OH-groups, failed to achieve complete conversion within the given residence time.

Figure 7. Synthesis of carbonylated heterocycles via oxidative carbonylation. (Reported values refer to isolated yields, for more details see Experimental Section). ACS Paragon Plus Environment


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Among the molecules in the scope, there are some structures of medicinal and synthetic significance. 5-t-Butyl-benzoxazolone (2c) exhibits cytotoxicity against cancer cells.6a Chiral oxazolidinones 2e and 2f served as chiral auxiliaries for stereoselective synthesis35 and the preparation of highly isotactic, optically active polymers.36 The enantiomers of 4benzyloxazolidin-2-one (2g and 2h) are a pair of Evans chiral auxiliaries used in asymmetric synthesis;37 their precursors (1g and 1h) are prepared from the reduction of phenylalanine.38 All chiral oxazolidinones (2e-h) are obtained with excellent enantiopurity (e.e. > 99.5%), no racemization occurred during the course of the conversion. (For the analysis of their purity, see Experimental section). As we have mentioned in the Introduction part before, compounds in the scope (2) have been synthesized from their precursors (1) by the condensation with carbonic acid derivatives8-10 and the oxidative carbonylation in batch.11 Compared to traditional condensation procedures, the use of corrosive reagent (phosgene) and the formation of hazardous waste (HCl and NH3) are avoided in the oxidative carbonylation. In the continuousflow oxidative carbonylation described above, the safe use of the optimal CO/O2 ratio in the explosive regime is permitted and therefore allows the reaction time to be shortened from 24 hours11a to merely 24 min. For the reaction in a segmented gas-liquid flow pattern, only a small excess of CO (4 equiv.) and O2 (8 equiv.) is needed, whereas the reaction in an autoclave requires much more (ca. 127 equiv. CO, 13 equiv. O2).11a Although the catalyst loading is relatively high, the continuous-flow operation has made this reaction more scalable than the batch alternatives. Similar to the classical carbonylation reactions22a and the oxidation using molecular oxygen22 in microreactors, the oxidative carbonylation in flow took advantage of the intensified mass transfer and the pressure resistance of microchannels. Even though, the simplicity of some devices for the homogeneous catalyzed reactions using O224f and CO25c is maintained.

CONCLUSION A continuous-flow protocol for the synthesis of carbonylated heterocycles via a liquid phase palladium catalyzed oxidative carbonylation is developed. The continuous-flow operation in a stainless steel capillary enables safe manipulation of pressurized CO/O2 mixture within the explosive regime. The flow reaction uses pure gases as feedstock to ACS Paragon Plus Environment

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generate gas-liquid segmented flow patterns allows the reaction to be completed within 24 min residence time with much smaller excess (4 equiv. CO, 8 equiv. O2) of gases than batch. Fourteen examples have been prepared proving the applicability of this protocol to the synthesis of five- and six-membered carbonylated heterocycles.

EXPERIMENTAL SECTION General Methods. NMR spectra were recorded on a 300 MHz instrument (75 MHz for 13C). Chemical shifts (δ) are expressed in ppm downfield from TMS as internal standard. The letters s, d, t, q and m stand for singlet, doublet, triplet, quadruplet and multiplet. GC-FID analysis was performed using a HP5 column (30 m × 0.250 mm × 0.025 µm). After 1 min at 50 °C the temperature was increased in 2 °C min-1 stepped up to 80 °C, then in 25 °C min-1 stepped up to 300 °C and kept at 300 °C for 4 minutes. The detector gas for the flame ionization is H2 and compressed air (5.0 quality). GC−MS spectra were recorded using a HP5MS column (30 m × 0.250 mm × 0.25 µm) with helium as carrier gas (1 mL/min constant flow) coupled with a mass spectrometer (EI, 70 eV). After 1 min at 50°C, the temperature was increased in 25 °C/min steps up to 300 °C and kept at 300 °C for 1 min. Chiral HPLC was performed using a chiral column (250 mm × 4.6 mm, particle size 5 µm) using heptane/iPrOH = 90:10 as mobile phase; flow rate 1.0 mL/min; column temperature 30 °C; injection volume 5 µL. All solvents and chemicals were obtained from standard commercial vendors and were used without any further purification. Products were characterized by 1H and

13

C

NMR and identified by comparison of the spectra with those reported in the literature. All compounds synthesized herein are known in the literature. Proof of purity was obtained by 1H NMR spectroscopy. CAUTION: Risk of explosion and CO poisoning! CO is an odorless, toxic and flammable gas; its mixture under certain conditions with air or oxygen is potentially explosive. All the experiments must be performed in a well-ventilated fume cupboard with a fitted CO detector. A thorough safety assessment should be made before conducting any experiments. Oxidative Carbonylation Reaction. The solution of 0.01 M palladium salt in MeCN (5.50 mL) (stream 1) and the solution of 0.20 M substrate (1) and 0.04 M n-Bu4N+I- in MeCN (5.00 mL) (stream 2) were loaded into their corresponding injection loops. The flow rates of the gas streams (streams 3 and 4) were measured and controlled by two mass flow controllers (MFCs) (gas flow rates FCO = FO2 = 4.40 mLN/min). The reaction temperature and the flow ACS Paragon Plus Environment


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rates of the liquid streams (liquid flow rates F1 = F2 = 0.25 mL/min) were measured and monitored by the control platform of the pumping system. After the temperature (120 °C) and the pressure (20 bar) became stable and a biphasic flow appeared in the observation loop (L0), the injection of the liquid reagents and timing were started. When colored reaction mixture appeared in L0 (residence time tR = 24 min), timing was ceased and product collection was started by directing the discharge into a glass test tube. When no colored solution was coming out from the outlet, collecting was stopped. The collected solution was analyzed by GC-FID and GC-MS thereafter.

Workup and Product Isolation. The collected reaction mixture was concentrated in vacuo, dissolved in ethyl acetate and then washed with 1 M HCl (aq) (3 × 10 mL) and distilled water (1 × 10 mL) (2l, 2m, 2n were washed with 3 × 10 mL distilled water; no HCl wash was needed). The combined organic phase was dried over anhydrous Na2SO4, filtered and the solvent removed under reduced pressure. Subsequently the reaction mixture was purified by silica gel flash chromatography using hexane and ethyl acetate (gradient: 5 – 90% EtOAc over 15 CV, and then maintained at 90% EtOAc for another 10 CV) as eluent to afford the product (2).

Benzo[d]oxazol-2(3H)-one (2a): 98.0 mg (73%); pale yellow crystals; mp 140.5 – 141.5 °C (lit.6a 134 – 136 °C); 1H NMR (300 MHz, CDCl3) δ 9.90 (s, 1H), 7.26 – 7.09 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 156.3, 143.9, 129.4, 124.2, 122.8, 110.3, 110.2.

4-Methylbenzo[d]oxazol-2(3H)-one (2b): 119.0 mg (80%); light brown crystals; mp 171.3 – 172.5 °C (lit.39a 156 – 158 °C); 1H NMR (300 MHz, CDCl3) δ 10.44 (s, 1H), 7.13 – 6.95 (m, 3H), 2.42 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 143.6, 128.6, 125.4, 122.5, 120.6, 107.6, 16.1 (lit.39b).

5-(tert-Butyl)benzo[d]oxazol-2(3H)-one (2c): 169.3 mg (88%); grey crystals; mp 135.5 – 136.0 °C C (lit.39c 146 – 147 °C); 1H NMR (300 MHz, CDCl3) δ 10.11 (s, 1H), 7.23 – 7.09 (m, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 157.0, 148.0, 141.8, 129.3, 119.6, 109.3, 107.7, 34.9, 31.6 (lit.39d).

5-Methoxybenzo[d]oxazol-2(3H)-one (2d): 79.0 mg (48%); orange crystals; mp 162.3 – 163.0 °C (lit.39e 168 – 170 °C); 1H NMR (300 MHz, CDCl3) δ 9.63 (s, 1H), 7.12 (d, J = 8.8 Hz, 1H), 6.77 – 6.58 (m, 2H), 3.82 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 156.6, 138.0, 130.0, 110.5, 107.9, 96.8, 56.0 (lit.39f).


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(S)-4-Phenyloxazolidin-2-one (2e): 106.5 mg (65%); pale yellow crystals; mp 128.6 – 129.8 °C (lit.39g 128 – 130 °C); 1H NMR (300 MHz, CDCl3) δ 7.47 – 7.29 (m, 5H), 6.70 (s, 1H), 5.02 – 4.91 (m, 1H), 4.72 (t, J = 8.7 Hz, 1H), 4.16 (dd, J = 8.5, 6.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 160.2, 139.6, 129.1, 128.7, 126.0, 72.6, 56.4 (lit. 39h); e.e. = 99.63%.

(R)-4-Phenyloxazolidin-2-one (2f): 94.4 mg (58%); white crystals; mp 130.1 °C 11a

(lit.

128 – 130 °C); 1H NMR (300 MHz, CDCl3) δ 7.46 – 7.25 (m, 5H), 6.73 (s, 1H), 5.02 –

4.90 (m, 1H), 4.71 (t, J = 8.7 Hz, 1H), 4.15 (dd, J = 8.5, 6.9 Hz, 1H);

13

C NMR (75 MHz,

CDCl3) δ 160.2, 139.6, 129.1, 128.7, 126.0, 72.5, 56.4 (lit.11a); e.e. = 100.00%.

(S)-4-Benzyloxazolidin-2-one (2g): 123.0 mg (69%); white crystals; mp 86.7 – 87.4 °C (lit. 39i 89 – 90 °C); 1H NMR (300 MHz, CDCl3) δ 7.41 – 7.24 (m, 3H), 7.24 – 7.14 (m, 2H), 6.04 (s, 1H), 4.51 – 4.37 (m, 1H), 4.21 – 4.03 (m, 2H), 2.97 – 2.79 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 159.6, 135.9, 129.0, 129.0, 127.2, 69.6, 53.8, 41.4 (lit.

39j

); e.e. =

100.00%.

(R)-4-Benzyloxazolidin-2-one (2h): 126.0 mg (77%); white crystals; mp 88.1 – 88.5 °C (lit. 39j 86 °C); 1H NMR (300 MHz, CDCl3) δ 7.40 – 7.24 (m, 3H), 7.23 – 7.12 (m, 2H), 6.41 (s, 1H), 4.50 – 4.30 (m, 1H), 4.22 – 4.01 (m, 2H), 3.02 – 2.70 (m, 2H); MHz, CDCl3) δ 159.9, 136.0, 129.1, 128.9, 127.2, 69.5, 53.8, 41.3 (lit.

39j

13

C NMR (75

); e.e. = 99.96%.

5-Phenyloxazolidin-2-one (2i): 120.0 mg (77%); white crystals; mp 88.5 – 89.5 °C (lit.

39i

88 – 90 °C); 1H NMR (300 MHz, CDCl3) δ 7.47 – 7.33 (m, 5H), 6.75 (s, 1H), 5.66 –

5.58 (m, 1H), 3.99 (t, J = 8.8 Hz, 1H), 3.55 (dd, J = 8.8, 7.7 Hz, 1H); CDCl3) δ 160.4, 138.5, 128.9, 125.7, 78.00, 48.4 (lit.

13

C NMR (75 MHz,

39k

).

3,4-Dihydro-2H-benzo[e][1,3]oxazin-2-one (2j): 49.1 mg (33%); white crystals; mp 190.0 – 191.0 °C (lit. 39l 185 °C, lit. 39m 193 °C); 1H NMR (300 MHz, CDCl3) δ 7.35 – 7.23 (m, 1H), 7.20 – 7.10 (m, 2H), 7.06 (d, J = 8.1 Hz, 1H), 6.55 (s, 1H), 4.57 (s, 2H);

13

C

NMR (75 MHz, CDCl3) δ 151.8, 149.7, 128.9, 125.8, 124.5, 116.7, 116.6, 42.4 (lit. 39m).

1,4-Dihydro-2H-benzo[d][1,3]oxazin-2-one (2k): 79.8 mg (54%); pale yellow crystals; mp 116.3 – 118.5 °C (lit. 39n 118 – 119 °C); 1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 7.30 – 7.21 (m, 1H), 7.14 – 7.00 (m, 2H), 6.93 (d, J = 7.9 Hz, 1H), 5.33 (s, 2H); NMR (75 MHz, CDCl3) δ 154.2, 135.6, 129.2, 124.1, 123.3, 117.8, 114.4, 68.8 (lit. 39n).


13

C


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Benzo[d][1,3]dioxol-2-one (2l): 35.5 mg (26%); colorless crystals; mp 116.5 – 117.0 °C (lit. 39o 119 – 120 °C, lit. 39p 118 °C); 1H NMR (300 MHz, CDCl3) δ 7.36 – 7.16 (m, 4H) (lit. 39p); 13C NMR (75 MHz, CDCl3) δ 151.2, 143.3, 124.9, 110.5 (lit. 39q).

5-(tert-Butyl)benzo[d][1,3]dioxol-2-one (2m): 128.5 mg (67%); pale yellow crystals; mp 42.7 – 44.1 °C; 1H NMR (300 MHz, CDCl3) δ 7.34 – 7.22 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 1.35 (s, 9H);

13

C NMR (75 MHz, CDCl3) δ 151.7, 149.0, 143.2, 141.0), 121.5,

109.6, 107.7, 35.2, 31.5.

4-Phenyl-1,3-dioxolan-2-one (2n): 43.5 mg (26%); colorless liquid; 1H NMR (300 MHz, CDCl3) δ 7.51 – 7.34 (m, 1H), 5.70 (t, J = 8.0 Hz, 1H), 4.82 (t, J = 8.4 Hz, 1H), 4.36 (dd, J = 8.6, 7.9 Hz, 1H);

13

C NMR (75 MHz, CDCl3) δ 154.9, 135.8, 129.7, 129.2, 125.9,

78.0, 71.2 (lit.37r). Supporting Information Available. More details of the microreactor setup, copies of 1H and 13

C NMR spectra of all compounds and HPLC chromatograms of all chiral compounds. This

material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEGMENT

We thank Dr. Michael Fuchs (University of Graz) for the measurement of chiral purity of compounds 2e, 2f, 2g and 2h.

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