Continuous Flow Synthesis of Benzoxazoles Derivatives by … · 2019. 9. 2. · Electronic Supporting Information Continuous Flow Synthesis of Benzoxazoles Derivatives by Manganese‐Based

Electronic Supporting Information

Continuous Flow Synthesis of Benzoxazoles Derivatives by Manganese‐Based Heterogeneous Catalyst.

Francesco Ferlin,a Mitchell Van der Hulst,a Stefano Santoro,a Daniela Lanari,b and Luigi Vaccaroa*

a Laboratory of Green S.O.C. – Dipartimento di Chimica, biologia e Biotecnologie, Università degli Studi di

Perugia, Via Elce di Sotto 8, 06123 – Perugia, Italy. E‐mail: [email protected];

http://www.dcbb.unipg.it/greensoc.

b Dipartimento di Scienze Farmaceutiche, Università di Perugia, Via del Liceo, 1, 06123 Perugia, Italy

CONTENTS

Page ESI 1 Contents

Page ESI 2 General information

Page ESI 2–6 General small and larger scale batch and flow procedures, details of

the flow reactor, E‐factor calculations

Page ESI 7 Leaching of Manganese species during flow procedure

Page ESI 7 Graphic data for off‐line analysis in continuous flow synthesis of 6a

Page ESI 7‐8 E‐factor calculation for literature protocols

Page ESI 8 Table of manganese leaching in different reaction medium

Page ESI 8 Catalyst regeneration screening

Page ESI 9–14 Characterization data

Page ESI 14 References

Page ESI 15‐33 Tables of the characterization data

Page ESI 34–75 Copies of the 1H‐ and 13C‐NMR and 19F‐NMR spectra

ESI - 1

Electronic Supplementary Material (ESI) for Green Chemistry.This journal is © The Royal Society of Chemistry 2019

General Information

Unless otherwise stated, all solvents and reagents were used as obtained from commercial sources without

further purification. GC analyses were performed using a Hewlett‐Packard HP 5890A equipped with a capillary column DB‐35MS (30 m, 0.53 mm) and a FID detector. GC‐EIMS analyses were carried out using a

Hewlett‐Packard HP 6890N Network GC system/5975 MassSelective Detector equipped with an electron impact ionizer at 70 eV. NMR spectra were recorded on a Bruker DRX‐ADVANCE 400 MHz (1H at 400 MHz

and 13C at 100.6 MHz). The deuterated solvent used was CDCl3. Elemental analyses were conducted on a

Fisons EA1108CHN. Melting points were measured on a Büchi 510. Metal leaching in solution measurements were carried out using an Agilent 4210 MP‐AES instrument. Flow procedures were performed using tailored pressure tubes as a reagents reservoir and Supelco HPLC Column Blank as catalyst

columns. Characterization data and copies of the 1H‐NMR, 13C‐NMR and 19F‐NMR are reported below.

Procedures for catalyst synthesis:

General procedures for K‐OMS synthesis:

MnSO4 hydrate (4.4 g, 26.0 mmol) and concentrated HNO3 (1.5 mL) were dissolved in deionized water (15.0

mL). Then a solution made by dissolving KMnO4 (2.9 g, 18.4 mmol) in deionized water (40.0 mL) was added

drop‐wise to make a brown slurry. The slurry was then refluxed at 100–110 °C in a 250 mL round‐bottom

flask for 24 h. The product was washed with copious amounts of deionized water to remove unreacted precursors, filtered, and then dried at 120 °C overnight, yielding 4.2 g of K‐OMS. A small aliquot of the resulting material was dissolved in a 10 mL volumetric flask into 5 mL of HCl/HNO3 solution (3:1, aqua regia)

and stirred at 50 °C for 30 minutes or until complete dissolution take place. The solution was adjusted to 10

mL with deionized water and then measured with MP‐AES instrument. Manganese loading was 62% w/w.

General procedures for H‐OMS synthesis:

K‐OMS (2 g) from the previous synthesis were stirred in a 1M solution of HNO3 (20 mL) at 70 °C for 24 h. The

product was washed with copious amounts of deionized water to remove unreacted precursors, filtered,

and then dried at 120 °C overnight, yielding 1.8 g of H‐OMS. A small aliquot of the resulting material was

dissolved in a 10 mL volumetric flask into 5 mL of HCl/HNO3 solution (3:1, aqua regia) and stirred at 50 °C

for 30 minutes or until complete dissolution take place. The solution was adjusted to 10 mL with

deionized water and then measured with MP‐AES instrument. Manganese loading was 62% w/w.

XRD of the materials:

0 10 20 30 40 50 60 70 80800

1000

1200

1400

1600

1800

2000

2200

cou

nts

pe

r se

cond

2

K-OMS-2

0 10 20 30 40 50 60 70 801600

1800

2000

2200

2400

2600

2800

3000

coun

ts p

er s

econ

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2

H-OMS-2

ESI - 2

General procedures for batch optimization of reaction conditions:

General procedures for benzyl alcohol oxidation in batch with stoichiometric quantity of catalyst:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, benzyl alcohol (1) (1 mmol, 103 μL), the

desired solvent (0.25 M, 4 mL), and catalyst (100 mol%) were consecutively added, and the resulting

mixture was left under stirring at reflux temperature for 30 minutes. The reaction mixture was then

removed from the heating plate and cooled to room temperature. An aliquot of the reaction mixture was

filtered through a short pad of celite and analyzed by GLC to determine the conversion, using samples of

pure compounds as reference.

General procedures for benzyl alcohol oxidation in batch with catalytic quantity of catalyst:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, benzyl alcohol (1) (1 mmol, 103 μL), the

desired solvent (0.25 M, 4 mL), and catalyst (20 mol%) were consecutively added, and the resulting mixture

was left under stirring at reflux temperature for 24 h. The reaction mixture was then removed from the

heating plate and cooled to room temperature. An aliquot of the reaction mixture was filtered through a

short pad of celite and analyzed by GLC to determine the conversion, using samples of pure compounds as

reference.

General procedures for imine (5) formation:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, benzaldehyde (2) (0.4 mmol, 41 μL), o‐

aminophenol (4) (0.2 mmol, 21.8 mg) and CPME (0.1 M, 2 mL), were consecutively added, and the resulting

mixture was left under stirring at the temperature indicated (Table 3 of main text) for 10 minutes. The

reaction mixture was then removed from the heating plate and cooled to room temperature. An aliquot of

the reaction mixture was taken and analyzed by GLC to determine the conversion, using samples of pure

compounds as reference.

General procedures for the synthesis of 6 via oxidative cyclization of 5 with stoichiometric quantity of

catalyst:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, imine (5) (1 mmol, 197.2 mg), the

desired solvent (0.25 M, 4 mL), and catalyst (100 mol%) were consecutively added, and the resulting

mixture was left under stirring at reflux temperature for 30 minutes. The reaction mixture was then

removed from the heating plate and cooled to room temperature. An aliquot of the reaction mixture was

filtered through a short pad of celite and analyzed by GLC to determine the conversion, using samples of

pure compounds as reference.

General procedures for the synthesis of 6 via oxidative cyclization of 5 with catalytic quantity of catalyst:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, imine (5) (1 mmol, 197.2 mg), the

desired solvent (0.25 M, 4 mL), and catalyst (20 mol%) were consecutively added, and the resulting mixture

was left under stirring at reflux temperature for 24 h. The reaction mixture was then removed from the



reference.

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General multistep procedure and E‐factor calculation for the synthesis of 6 in batch conditions:

In a 4 mL screw‐capped vial equipped with a magnetic stirring bar, benzyl alcohol (1) (0.4 mmol, 41 μL),

CPME (0.1 M, 2 mL), and H‐OMS (100 mol%, 0.4 mmol of Mn, 35.4 mg) were consecutively added, and the

resulting mixture was left under stirring at 106 °C for 30 minutes. The reaction mixture was then removed

from the heating plate and cooled to room temperature. The heterogeneous mixture was filtered over sintered glass funnel into a 4 mL screw‐capped vial containing o‐aminophenol (0.2 mmol, 21.8 mg). The resulting yellowish solution was vigorously stirred at 106 °C for 10 minutes and K‐OMS (100 mol%, 0.2 mmol, 17.7 mg) was then added. The resulting mixture was left under stirring at 106 °C for 30 minutes. A

small aliquot of the reaction mixture was subjected to MP‐AES analysis to determine the manganese leaching. The heterogeneous mixture was finally filtered over sintered glass funnel and washed with CPME

(2x2mL). The solvent was distilled under reduced pressure and recovered as pure (98 % of the total amount, confirmed by 1H‐NMR), 2 mL of EtOH was added and then evaporated to remove unreacted benzaldehyde furnishing the pure product as white crystals (0.18 mmol, 36.7 mg) in 94 % yield.

E‐factor: [5.16 g (CPME) + 0.035 g (H‐OMS) + 0.043 g (benzyl alcohol) + 0.022 g (o‐aminophenol) + 0.017 g (K‐OMS) + 1.58 g (EtOH)] – [0.035 g (H‐OMS) + 0.017 g (K‐OMS) + 5.05 (CPME recovered) + 0.037 g (product, 94 % yield)]/ 0.037 g (product, 94 % yield)] = 46.4

General procedure for multistep continuous flow protocol for the synthesis of 6

Description of Flow system:

O2

H-OMST-piece

Reservoir

REACTOR 1

= Back pressure regulator

LINE 1

3

C1 C2 C3

C41

off-linesampling

C5

LINE 1:

C1: Stainless steel tube 6mm (supplied by Nordival srl), 20 cm

C2: PTFE tube (1/16’’), Internal Diameter (ID): 1 mm. Length: 30 cm

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C3: PTFE tube (1/16’’), ID: 1 mm. Length: 2 cm


C5: PTFE tube (1/16’’), ID: 1 mm. Length: 3 cm connected to a needle valve (supplied by Nordival srl) used

for off‐line analysis

PTFE tube (1/16’’) has been supplied by ABreg srl.

Reactor 1: Supelco HPLC Column Blank 20 cm

Back Pressure Regulator 1: 75 psi BPR (supplied by Upchurch)

T‐Piece: stainless steel T‐piece 6mm with 6mm – 1/16’’ reducer (supplied by Nordival srl)

Reservoir: tailor made PTFE reservoir end capped tailor made PTFE plug (Fig. S1) with 6mm Tube adapter

(supplied by Nordival srl).

Figure. S1. Tailor made PTFE plug

LINE 2:

C1: Stainless steel tube 6mm (supplied by Nordival srl), 20 cm

Reservoir: tailor made PTFE reservoir end capped tailor made PTFE plug (Fig. S1) with 6mm Tube adapter (

supplied by Nordival srl).

C2: PTFE tube (1/16’’), Internal Diameter (ID): 1 mm. Length: 20 cm

T‐Piece: stainless steel T‐piece 6mm with 6mm – 1/16’’ reducer (supplied by Nordival srl)




C4: PTFE tube (1/16’’), ID: 1 mm. Length: 60 cm (loop)

Reactor 2: Supelco HPLC Column Blank 20 cm




ESI - 5

C7: PTFE tube (1/16’’), ID: 1 mm. Length: 3 cm connected to a needle valve (supplied by Nordival srl) used

for off‐line analysis

PTFE tube (1/16’’) has been supplied by ABreg srl.

Product collector: graduated cylinder.

General information: reactor 1, reactor 2 and loop have been thermostated into a stainless steel box. All

the connection between 1/16’’ tubes, BPRs and reactors have been realized with PTFE HPLC peek (supplied

by ABreg srl).

Small scale continuous flow procedures and E‐factor calculation (4 mmol):

Reservoir 1 was charged with 4 mL of CPME and benzyl alcohol (4 mmol, 0.432 g, 414 μL), then the oxygen

line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of

H‐OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit

of column 1, the nitrogen line was set to 5 bar and the o‐aminophenol solution (3.7 mmol, 0.404 g in 4 mL

of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T‐piece. The resulting

mixture continuously flowed through the loop, in which imine formation took place, before reaching

column 2 (filled with 68 mg of K‐OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the

end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash

the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered

via distillation under reduced pressure (98% of the total amount, confirmed by 1H‐NMR) and the residue

was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6 (3.6

mmol, 0.708 g) in 98% yield.

E‐factor = [24 g (CPME) + 0.432 g (benzyl alcohol) + 0.404 g (o‐aminophenol) + 3.9 g (EtOH)] – [23.5 (CPME

recovered) + 0.708 g (product, 98 % yield)]/ 0.708 g (product, 98 % yield)] = 6.4

Multi‐gram scale continuous flow procedures and E‐factor calculation (280 mmol):

Reservoir 1 was charged with 1M CPME (300 mL) solution of benzyl alcohol (308 mmol, 33.3 g, 32 mL), then

the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled

with 78 mg of H‐OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow

reached the exit of column 1, the nitrogen line was set to 5 bar and the o‐aminophenol solution (280 mmol,

30.5 g in 300 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T‐

piece. The resulting mixture continuously flowed through the loop, in which imine formation took place,

before reaching column 2 (filled with 68 mg of K‐OMS) at a flow rate of 0.2 mL/min with a residence time of

40 min. At the end of the process the system has been completely flushed, both line with 55 mL of CPME in

order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME

was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H‐NMR)

and the residue was washed with 90 mL of EtOH in order to remove unreacted benzaldehyde, furnishing

pure product 6 (274.4 mmol, 53.5 g) in 98% yield with a productivity of 2.3 g/h after steady state was

reached.

E‐factor = [ 610 g (CPME) + 33.3 g (benzyl alcohol) + 30.5 g (o‐aminophenol) + 71 g (EtOH)] – [598 (CPME

recovered) + 53.5 g (product, 98 % yield)]/ 53.5 g (product, 98 % yield)] = 1.7

ESI - 6

Leaching of Manganese species during flow procedure over 40 mmol

Graphic data for off‐line analysis in continuous flow synthesis of 6a

E‐factor calculation for literature protocols for the synthesis of 2‐arylbenzoxazoles

Reference Procedure E‐factor Pan et al. Tetrahedron Lett. 2002, 43, 951–954

To a solution of 2‐aminophenol (0.109 g, 1.0 mmol) in MeOH (5 mL) was added benzaldehyde (0.106 g, 1.0 mmol). The resulting mixture was heated at 45°C for 12 h. After concentration under reduced pressure, theresidue was dissolved in CH2Cl2 (10 mL) and DDQ (0.250g, 1.1 mmol) was then added. After stirring at roomtemperature for 30 min, the resulting mixture wasdiluted with additional CH2Cl2 (10 mL) and washedsequentially with saturated Na2CO3 (10 mL×2) and brine(10 mL). The organic layer was dried over anhydrousNa2SO4. After evaporation, the crude was purified byflash column chromatography. Yield 93 %

{0.109 g [aminophenol] + 3.9 g [MeOH] + 0.106 g [benzaldehyde] + 26.6 g [DCM] + 0.250 g [DDQ] + 22.0 g [sodium carbonate] + 11.5 g [brine] – 0.181 g [product]} /0.181 g [product] = 355

P. H. Tran et al. RSC Adv., 2018, 8, 11834–11842

2‐Aminophenol (109 mg, 1.0 mmol) was treated with benzaldehyde (106 mg, 1.0 mmol) in the presence of triphenyl(butyl‐3‐sulphonyl)phosphonium toluenesulfonate (20.5 mg, 7 mol%) in a 10 mL glass tube at 100 C under solvent‐free magnetic stirring. Upon completion of the reaction as indicated by TLC after 30 min, the mixture was diluted and extracted with diethyl ether (10 x 5 mL). Then the ethereal solution was washed with water (2 x 20 mL) and dried over Na2SO4. The final

{0.109 g [aminophenol] + 0.106 g

[benzaldehyde] + 0.02 g [catalyst] + 35.6 g

[Diethyl Ether] + 40.0 g [water] – 0.177 g

[product] – 0.02 g [catalyst]} / 0.177 g

[product] = 427

00,050,1

0,150,2

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40Mn Lea

ching (ppm)

mmol

96,5

97

97,5

98

98,5

99

99,5

100

0,5 1

1,5 2

2,5 3

3,5 4

4,5 5

5,5 6

6,5 7

7,5 8

8,5 9

9,5 10

10,5 11

11,5 12

12,5 13

13,5 14

14,5 15

15,5 16

16,5 17

17,5 18

18,5 19

19,5 20

20,5 21

21,5 22

22,5 23

23,5

Conversion (%)

time (h)

Analytical Data for continuous flow synthesis of 6a

C (%) of 1a C (%) of 4 into 5a conversion of 5a to 6a

ESI - 7

product was obtained after solvent removal by a rotary evaporator followed by the purifcation on a silica gel column chromatography using acetone/petroleum ether (1/19) as an eluent solvent. Yield 91 %

Panahi et al. ACS Catal. 2014, 4, 1686−1692

To a mixture of primary alcohol (1 mmol) and 2‐aminophenol (1 mmol) in toluene (2 mL), DABCO (0.5 mmol), PFMN (50 mg), and Ru2Cl4(CO)6 (10 mg) were added, and the resulting mixture was heated to the refluxing temperature of toluene for 24 h under N2 gas. After completion of the reaction, the mixture was cooled to room temperature, and the PFMN ligand was magnetically separated from the reaction mixture. The reaction mixture was quenched with water and extracted with diethyl ether (10 mL, 3 times), and the organic phase was dried over Na2SO4. The benzoxazole product was purified by column chromatography and obtained in 77 % yield.

{0.112 g [benzyl alcohol] + 0.109 g

[aminophenol] + 2.6 g [Toluene] + 0.06 g

[DABCO] + 0.05 g [PFMN] + 0.01 g

[catalyst] + 21.4 g [diethyl ether] – 0.05 g

[PFMN] – 0.152 g [product]} / 0.152 g

[product] = 158

Table of Manganese leaching in different reaction medium

Table S1. Leaching of Mn in different reaction medium for the oxidation of 1a.a

Entry Medium T (°C) C (%)b H‐OMS

Leaching of Mn (ppm)c

1 Toluene 110 >99 7.32

2 CH3CN 82 47 2.63

3 Toluene/EtOH (1:1) 110 29 5.70

4 Toluene/EtOH (3:7) 110 9 ‐

5 EtOH 78 3 ‐

6 EtOAc 77 38 4.76

7 BuOH 82 30 3.28

8 tBuOH 82 41 3.56

9 Solvent‐free ‐ 2 ‐

10 2‐MeTHF 80 55 0.83

11 TAME 86 > 99 1.04

12 CPME 106 > 99 0.06

a Reaction condition: 1a (1 mmol), medium 4 mL [0.25M], reaction time 30 min, K‐ or H‐OMS: 1 eq.

b Conversion to 2a, measured by GLC analyses

using samples of pure compounds as reference. c Leaching measurement has been determined with MP‐AES.

Catalyst regeneration screening

General procedures for catalyst regeneration and reuse:

In a 5 mL schlenk pressure tube equipped with a magnetic stirring bar, benzyl alcohol 1a (1 mmol, 103 μL),

CPME (0.25 M, 4 mL), and H‐OMS were consecutively added, and the resulting mixture was left under

stirring at reflux temperature for the desired time. The reaction mixture was then removed from the



reference. The reaction mixture was filtered over a Büchner funnel to recover the catalyst and washed with

CPME (2x5 mL). The recovered catalyst has been placed in a schlenk pressure tube and heated at 100 °C

under the desired gas pressure during 1h.

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Table S2. Regeneration screening of the catalyst for the oxidation of 1a with catalytic quantities of H‐OMS.a

Entry C (%)b in Run 1 additive used for regeneration Pressure (bar) C (%)c over consecutive runs

Run 2 Run 3 Run 4 Run 5

1 > 99 O2 1 > 99 96 90 88

2 > 99 N2 1 26 ‐ ‐ ‐

3 > 99 Air 1 72 46 ‐ ‐

4 > 99 Argon 1 22 ‐ ‐ ‐

5 > 99 O2 2 > 99 > 99 > 99 > 99

6 > 99 Air 2 92 85 83 77

7 > 99 ‐ ‐ 32 ‐ ‐ ‐

8 > 99 O2 3 > 99 > 99 > 99 > 99

9 > 99 H2O2 (1 eq) ‐ 58 43 ‐ ‐

10 > 99 H2O2 (10 eq) ‐ 72 57 37 ‐a Reaction condition: 1a (1 mmol), medium 4 mL [0.25M], reaction time 24 h, H‐OMS: 20 mol %.

b Conversion of 1a, measured by GLC analyses using

samples of pure compounds as reference, data refers to run 1 executed following optimized condition. c Conversion of 1a over consecutive runs

measured by GLC analyses using samples of pure

Table S3. Regeneration screening of the catalyst for the oxidation of 1a with stoichiometric quantities of H‐OMS.a

Entry C (%)b in Run 1 additive used for regeneration Pressure (bar) C (%)c over consecutive runs

Run 2 Run 3 Run 4 Run 5

1 > 99 O2 1 > 99 96 90 88

2 > 99 N2 1 55 20 ‐ ‐

3 > 99 Air 1 89 44 ‐ ‐

4 > 99 Argon 1 44 21 ‐ ‐

5 > 99 O2 2 > 99 > 99 > 99 > 99

6 > 99 Air 2 95 87 85 81

7 > 99 ‐ ‐ 55 18 ‐ ‐

8 > 99 O2 3 > 99 > 99 > 99 > 99

9 > 99 H2O2 (1 eq) ‐ 73 60 22 ‐

10 > 99 H2O2 (10 eq) ‐ 74 66 37 ‐a Reaction condition: 1a (1 mmol), medium 4 mL [0.25M], reaction time 30 min, H‐OMS: 100 mol %.

b Conversion of 1a, measured by GLC analyses

using samples of pure compounds as reference, data refers to run 1 executed following optimized condition. c Conversion of 1a over consecutive

runs measured by GLC analyses using samples of pure compounds as reference.

ESI - 9

Characterization data for compound 6 a‐s

2‐phenylbenzo[d]oxazole (6a)1 has been synthesized following multi‐gram scale flow

procedure using benzyl alcohol (40 mmol) and o‐aminophenol (37 mmol) in 98% Yield. White crystals. M.p.

102‐105. 1H‐NMR (400 MHz, CDCl3) δ 8.29 – 8.26 (m, 2H), 7.81 – 7.79 (m, 1H), 7.62 – 7.50 (m, 4H), 7.37 – 7.35 (m,

2H). 13C‐NMR (101 MHz, CDCl3) δ 163.1, 150.8, 142.1, 131.5, 128.9, 127.6, 127.2, 125.1, 124.6, 120.0, 110.6. GC‐EIMS

(m/z, %): 195 (100), 181 (68), 180 (54), 161 (62), 145 (22), 121 (16). Elemental Analysis calculated for C13H9NO: C,

79.98; H, 4.65; N, 7.17; experimental: C, 79.91; H, 4.68; N, 7.02

2‐phenylbenzo[d]thiazole (6b)2 has been synthesized following small scale flow procedure

using the appropriate benzyl alcohol (4 mmol) and o‐aminothiophenol (3.7 mmol) in 98% Yield. White crystals. M.p.

116‐118. 1H‐NMR (400 MHz, CDCl3) δ 8.15 – 8.08 (m, 3H), 7.94 – 7.89 (m, 1H), 7.54 – 7.48 (m, 4H), 7.42 – 7.39 (m,

1H). 13C‐NMR (101 MHz, CDCl3) δ 168.09, 154.18, 135.10, 133.65, 131.00, 129.05, 127.59, 126.35, 125.22, 123.27,

121.65. GC‐EIMS (m/z, %): 211 (100), 184 (25), 108 (75), 82 (34), 68 (54). Elemental Analysis calculated for C13H9NS: C,

73.90; H, 4.29; N, 6.63; S, 15.17; experimental: C, 74.01; H, 3.98; N, 6.53; S, 15.12

2‐(4‐fluorophenyl)benzo[d]oxazole (6c)3 has been synthesized following small scale

flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 95% Yield. Pale

yellow crystals. M.p. 94‐96. 1H‐NMR (400 MHz, CDCl3) δ 8.32 – 8.21 (m, 2H), 7.81 – 7.71 (m, 1H), 7.63 – 7.54 (m, 1H),

7.36 (dd, J = 6.0, 3.2 Hz, 2H), 7.22 (t, J = 8.6 Hz, 2H). 13C‐NMR (101 MHz, CDCl3) δ 164.9 (d, JCF= 251.2 Hz), 162.2, 150.8,

142.0, 129.9 (d, JCF= 8.9 Hz), 125.2, 124.7, 123.5 (d, JCF= 3.0 Hz), 120.0, 116.2 (d, JCF= 22.1 Hz), 110.6. 19F‐NMR (376

MHz, CDCl3) δ ‐ 107.4. GC‐EIMS (m/z, %): 213 (100), 194 (63), 193 (17), 180 (57), 161 (30), 121 (18). Elemental Analysis

calculated for C13H8FNO: C, 73.23; H, 3.78; N, 6.57; experimental: C, 73.18; H, 3.59; N, 6.40

2‐(4‐(trifluoromethyl)phenyl)benzo[d]oxazole (6d)3 has been synthesized following

small scale flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 96% Yield.

White crystals. M.p. 145‐146. 1H‐NMR (400 MHz, CDCl3) δ 8.37 (d, J = 8.1 Hz, 2H), 7.80 (t, J = 8.3 Hz, 3H), 7.65 – 7.57

(m, 1H), 7.40 (td, J = 6.1, 5.0, 3.5 Hz, 2H). 13C‐NMR (101 MHz, CDCl3) δ 161.5, 150.9, 141.9, 133.0 (q, JCF= 32.8 Hz),

130.4, 127.9, 125.9 (q, JCF= 3.7 Hz), 125.8, 125.0, 122.4 (q, JCF= 270.8 Hz), 120.4, 110.8. 19F‐NMR (376 MHz, CDCl3) δ –

63.0. GC‐EIMS (m/z, %): 263 (100), 244 (62), 243 (15), 181 (60), 121 (24). Elemental Analysis calculated for C14H8F3NO:

C, 63.88; H, 3.06; N, 5.32; experimental: C, 63.64; H, 2.98; N, 5.12

ESI - 10

2‐(4‐methoxyphenyl)benzo[d]oxazole (6e)1 has been synthesized following small scale

flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 98% Yield. Pale yellow crystals. M.p. 99‐101.1H‐NMR (400 MHz, CDCl3) δ 8.21 (d, J = 8.9 Hz, 2H), 8.08 (d, J = 8.8 Hz, 1H), 7.83 – 7.67 (m,

1H), 7.59 – 7.52 (m, 1H), 7.37 – 7.28 (m, 2H), 7.03 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H). 13C‐NMR (101

MHz, CDCl3) δ 163.2, 162.4, 150.6, 142.1, 132.3, 129.5, 124.7, 124.5, 121.8, 119.6, 119.5, 114.4, 113.7, 110.4, 55.5. GC‐

EIMS (m/z, %): 225 (100), 195 (80), 181 (64), 160 (25), 121 (15), 107 (55). Elemental Analysis calculated for C14H11NO2:


2‐(4‐(methylthio)phenyl)benzo[d]oxazole (6f)1 has been synthesized following small

scale flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 94% Yield. Pale

yellow crystals. M.p. 105‐107. 1H‐NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 2H), 7.82 – 7.68 (m, 1H), 7.62 – 7.51 (m,

1H), 7.41 – 7.30 (m, 4H), 2.55 (s, 3H). 13C‐NMR (101 MHz, CDCl3) δ 162.9, 150.6, 143.8, 142.0, 127.9, 125.8, 125.0,

124.6, 123.2, 119.8, 110.5, 15.0. GC‐EIMS (m/z, %): 241 (100), 196 (74), 195 (82), 181 (77), 121 (28), 106 (53).

Elemental Analysis calculated for C14H11NOS: C, 69.68; H, 4.59; N, 5.80; S, 13.29; experimental: C, 69.33; H, 4.12; N,

5.64; S, 13.25

2‐(4‐(sec‐butyl)phenyl)benzo[d]oxazole (6g) has been synthesized following small

scale flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 99% Yield. White crystals. M.p. 98‐101.1H‐NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.0 Hz, 2H), 7.81 – 7.73 (m, 1H), 7.61 – 7.54 (m,

1H), 7.38 – 7.28 (m, 4H), 2.56 (d, J = 7.2 Hz, 2H), 1.94 (dt, J = 13.5, 6.8 Hz, 1H), 0.94 (d, J = 6.6 Hz, 6H). 13C‐NMR (101

MHz, CDCl3) δ 163.4, 150.7, 145.9, 142.1, 129.7, 127.5, 124.9, 124.6, 124.5, 119.9, 110.5, 45.5, 30.2, 29.7, 22.4. GC‐

EIMS (m/z, %): 251 (100), 223 (43), 222 (32), 196 (77), 195 (63), 145 (20), 121 (33). Elemental Analysis calculated for

C17H17NO: C, 81.24; H, 6.82; N, 5.57; experimental: C, 81.09; H, 6.64; N, 5.32

2‐(3‐methoxyphenyl)benzo[d]oxazole (6h) has been synthesized following small scale

flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 98% Yield. White

crystals. M.p. 70‐72. 1H‐NMR (400 MHz, CDCl3) δ 7.86 (d, J = 7.7 Hz, 1H), 7.79 (dd, J = 6.2, 2.9 Hz, 2H), 7.58 (dt, J = 7.4,

3.7 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.36 (dd, J = 6.0, 3.3 Hz, 2H), 7.09 (dd, J = 8.2, 2.6 Hz, 1H), 3.92 (s, 3H). 13C‐NMR

(101 MHz, CDCl3) δ 163.0, 160.0, 150.8, 142.0, 130.0, 128.3, 125.2, 124.6, 120.1, 120.0, 118.4, 111.9, 110.6, 55.5. GC‐

EIMS (m/z, %): 225 (100), 195 (82), 181 (60), 180 (17), 160 (28), 121 (18). Elemental Analysis calculated for C14H11NO2:


ESI - 11

2‐(3‐chlorophenyl)benzo[d]oxazole (6k) has been synthesized following small scale flow

procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 98% Yield. White crystals.

M.p. 125‐127. 1H‐NMR (400 MHz, CDCl3) δ 8.26 (d, J = 1.9 Hz, 1H), 8.14 (dd, J = 7.5, 1.1 Hz, 1H), 7.81 – 7.75 (m, 1H),

7.62 – 7.56 (m, 1H), 7.53 – 7.42 (m, 2H), 7.42 – 7.33 (m, 2H). 13C‐NMR (101 MHz, CDCl3) δ 161.7, 150.8, 141.9, 135.1,

131.5, 130.3, 128.9, 127.6, 125.7, 125.6, 124.8, 120.2, 110.7. GC‐EIMS (m/z, %): 231 (33), 229 (100), 197 (52), 196 (44),

181 (29), 160 (37). Elemental Analysis calculated for C13H8ClNO: C, 67.99; H, 3.51; N, 6.10; experimental: C, 67.83; H,

3.34; N, 6.01

2‐(3‐bromophenyl)benzo[d]oxazole (6i) has been synthesized following small scale flow

procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 96% Yield. Pale brown crystals. M.p. 128‐129. 1H‐NMR (400 MHz, CDCl3) δ 8.41 (t, J = 1.8 Hz, 1H), 8.18 (d, J = 7.8 Hz, 1H), 7.81 – 7.75 (m, 1H),

7.65 (dt, J = 8.1, 1.4 Hz, 1H), 7.61 – 7.55 (m, 1H), 7.42 – 7.33 (m, 3H). 13C‐NMR (101 MHz, CDCl3) δ 161.5, 150.8, 141.9,

134.4, 130.5, 130.5, 129.1, 126.1, 125.6, 124.8, 123.0, 120.2, 110.7. GC‐EIMS (m/z, %): 275 (100), 273 (100), 247 (32),

245 (31), 194 (51), 166 (23), 139 (17). Elemental Analysis calculated for C13H8BrNO: C, 56.96; H, 2.94; N, 5.11;

experimental: C, 56.93; H, 2.90; N, 5.03

2‐(3‐nitrophenyl)benzo[d]oxazole (6j)4 has been synthesized following small scale flow

procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 92% Yield. Yellow crystals. M.p. 209‐211. 1H‐NMR (400 MHz, CDCl3) δ 9.11 (t, J = 2.0 Hz, 1H), 8.59 (d, J = 7.8 Hz, 1H), 8.43 – 8.36 (m, 1H), 7.87 –

7.78 (m, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.69 – 7.60 (m, 1H), 7.49 – 7.35 (m, 2H). 13C‐NMR (101 MHz, CDCl3) δ 160.6, 150.9,

148.7, 141.8, 133.0, 130.2, 129.0, 126.1, 125.8, 125.2, 122.5, 120.5, 110.9. GC‐EIMS (m/z, %): 240 (100), 224 (17), 196

(22), 195 (47), 121 (22). Elemental Analysis calculated for C13H8N2O3: C, 65.00; H, 3.36; N, 11.66; experimental: C,

65.10; H, 3.12; N, 11.43

2‐(3,5‐dibromophenyl)benzo[d]oxazole (6l) has been synthesized following small scale flow

procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 98% Yield. Pale brown crystals. M.p. 132‐133. 1H‐NMR (400 MHz, CDCl3) δ 8.34 (d, J = 1.8 Hz, 2H), 7.88 – 7.72 (m, 2H), 7.65 – 7.54 (m, 1H),

7.45 – 7.36 (m, 2H). 13C‐NMR (101 MHz, CDCl3) δ 160.1, 150.8, 141.7, 136.7, 130.4, 129.1, 126.0, 125.1, 123.5, 120.4,

110.8. GC‐EIMS (m/z, %): 355 (49), 353 (100), 351 (50), 274 (22), 272 (22), 193 (17), 165 (18). Elemental Analysis

calculated for C13H7Br2NO: C, 44.23; H, 2.00; N, 3.97; experimental: C, 44.18; H, 2.01; N, 3.78

ESI - 12

2‐mesitylbenzo[d]oxazole (6m) has been synthesized following small scale flow

procedure using the appropriate benzylalcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 98% Yield. White crystals.

M.p. 112‐115. 1H‐NMR (400 MHz, CDCl3) δ 7.87 – 7.80 (m, 2H), 7.64 – 7.55 (m, 1H), 7.40 – 7.37 (m, 1H), 6.98 (s, 2H),

2.36 – 2.30 (m, 9H). 13C‐NMR (101 MHz, CDCl3) δ 163.3, 150.6, 141.6, 140.3, 138.5, 130.5, 128.7, 125.0, 124.9, 124.2,

120.2, 110.6, 21.3, 20.4. GC‐EIMS (m/z, %): 237 (100), 222 (48), 208 (43), 194 (20), 130 (26), 118 (52). Elemental

Analysis calculated for C16H15NO: C, 80.98; H, 6.37; N, 5.90; experimental: C, 80.82; H, 6.17; N, 5.88

2‐(2,3,4,5,6‐pentamethylphenyl)benzo[d]oxazole (6n) has been synthesized following


White crystals. M.p. 130‐131. 1H‐NMR (400 MHz, Chloroform‐d) δ 7.93 – 7.79 (m, 1H), 7.63 – 7.55 (m, 1H), 7.45 – 7.33

(m, 2H), 2.31 (s, 3H), 2.25 (s, 6H), 2.09 (s, 6H). 13C‐NMR (101 MHz, CDCl3) δ 164.8, 150.7, 141.5, 137.6, 133.4, 132.9,

126.3, 124.9, 124.2, 120.2, 110.7, 18.1, 17.0, 16.3. GC‐EIMS (m/z, %): 265 (100), 250 (52), 235 (25), 157 (46), 132 (22),

114 (16). Elemental Analysis calculated for C18H19NO: C, 81.47; H, 7.22; N, 5.28; experimental: C, 81.27; H, 7.14; N, 5.18

2‐(benzo[d][1,3]dioxol‐5‐yl)benzo[d]oxazole (6o) has been synthesized following


Pale yellow crystals. M.p 137‐138. 1H‐NMR (400 MHz, CDCl3) δ 7.84 (dd, J = 8.2, 1.7 Hz, 1H), 7.78 – 7.69 (m, 2H),

7.59 – 7.52 (m, 1H), 7.39 – 7.29 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 6.08 (s, 2H). 13C‐NMR (101 MHz, CDCl3) δ 162.88,

150.68, 150.58, 148.24, 142.19, 124.79, 124.51, 122.81, 121.17, 119.73, 110.43, 108.75, 107.70, 101.77. GC‐EIMS

(m/z, %): 239 (100), 238 (82), 209 (25), 181 (32), 153 (44), 119 (51), 63 (55). Elemental Analysis calculated for

C14H9NO3: C, 70.29; H, 3.79; N, 5.86; experimental: C, 70.01; H, 3.70; N, 5.78

6‐methyl‐2‐phenylbenzo[d]oxazole (6p) has been synthesized following small scale flow

procedure using benzyl alcohol (4 mmol) and 3‐methyl‐2‐aminophenol (3.7 mmol) in 98% Yield. White crystals. M.p.

143‐145. 1H NMR (400 MHz, CDCl3) δ 8.26 – 8.23 (m, 2H), 7.54 – 7.52 (m, 3H), 7.47 (d, J = 8.8 Hz, 1H), 7.29 (d, J = 2.4

Hz, 1H), 6.97 (dd, J = 8.9, 2.6 Hz, 1H), 3.89 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 163.81, 157.41, 145.42, 142.91, 131.42,

128.90, 127.50, 127.25, 113.74, 110.73, 102.87, 55.93. GC‐EIMS (m/z, %): 209 (100), 208 (75), 195 (35), 194 (25), 130

ESI - 13

(55), 118 (32). Elemental Analysis calculated for C14H11NO: C, 80.36; H, 5.30; N, 6.69; experimental: C, 80.34; H, 5.28;

N, 6.68

5‐methoxy‐2‐phenylbenzo[d]oxazole (6q) has been synthesized following small scale

flow procedure using benzyl alcohol (4 mmol) and 4‐methoxy‐2‐aminophenol (3.7 mmol) in 98% Yield. White crystals. M.p. 155‐157. 1H NMR (400 MHz, CDCl3) δ 8.29 – 8.23 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 7.58 – 7.52 (m, 3H), 7.42 (s, 1H), 7.20 (dd, J = 8.2, 1.5 Hz, 1H), 2.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 162.58, 155.68, 151.07, 139.92, 135.59, 131.30, 128.89, 127.47, 125.83, 119.35, 110.78, 21.83. GC‐EIMS (m/z,%): 225 (100), 195 (75), 194 (35), 181 (45), 180 (37), 160 (25), 158 (55), 121 (40). Elemental Analysis calculated for C14H11NO2: C, 74.65; H, 4.92; N, 6.22; experimental: C, 74.61; H, 4.88; N, 6.20

7‐chloro‐2‐phenylbenzo[d]oxazole (6r) has been synthesized following small scale flow

procedure using benzyl alcohol (4 mmol) and 6‐chloro‐2‐aminophenol (3.7 mmol) in 95% Yield. Pale yellow crystals. M.p. 118‐121. 1H NMR (400 MHz, CDCl3) δ 8.32 (dd, J = 7.7, 2.0 Hz, 2H), 7.69 (dd, J = 7.7, 1.2 Hz, 1H), 7.59 – 7.55 (m,

3H), 7.39 – 7.28 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 163.45, 158.64, 147.40, 143.36, 131.99, 129.00, 127.88, 126.56,

125.43, 125.33, 118.48. GC‐EIMS (m/z, %): 231 (35), 229 (100), 197 (22), 196 (64), 194 (44), 181 (32), 160 (57), 158

(25). Elemental Analysis calculated for C13H8ClNO: C, 67.99; H, 3.51; N, 6.10; experimental: C, 67.93; H, 3.46; N, 6.11

2‐(3,5‐dichlorophenyl)benzo[d]oxazole‐6‐carboxylic acid (Tafamidis) has been

synthesized following small scale flow procedure using 3,5‐dichlorobenzyl alcohol (4 mmol) and 4‐amino‐3‐

hydroxybenzoic acid (3.7 mmol) in 92% Yield. Pale yellow crystals. M.p. 187‐188. 1H NMR (400 MHz, Acetone‐d6) δ

8.92 (s, 1H), 8.15 (d, J = 2.0 Hz, 2H), 7.63 – 7.58 (m, 2H), 7.48 (d, J = 8.7 Hz, 1H). 13C NMR (101 MHz, Acetone‐d6) δ

166.27, 157.95, 152.25, 139.57, 135.17, 130.80, 130.72, 127.54, 126.05, 121.41, 120.07, 112.44. GC‐EIMS (m/z, %):

310 (63), 308 (100), 306 (50), 292 (22), 294 (27), 272 (47), 264 (44), 236 (38), 181 (25). Elemental Analysis calculated

for C14H7Cl2NO3: C, 54.58; H, 2.29; N, 4.55; experimental: C, 54.57; H, 2.25; N, 4.58

E‐factor = [24 g (CPME) + 0.708 g (3,5‐dichlorobenzyl alcohol) + 0.566 g (o‐aminophenol) + 3.9 g (EtOH)] –

[23.5 (CPME recovered) + 1.05 g (product, 92 % yield)]/ 1.05 g (product, 92 % yield)] = 4.4

References:

[1] N. Khatun, S. Guin, S. K. Routa, B. K. Patel RSC Adv., 2014, 4, 10770‐10778

[2] K. Chakrabarti, M. Majia, S. Kundu Green Chem., 2019, 21, 1999‐2004

[3] L. Tang, Z. Yang, T. Sun, D. Zhang, X. Ma, W. Rao, Y. Zhou Adv. Synth. Catal. 2018, 360, 3055–3062

[4] P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy J. Org. Chem., 2009, 74, 8719–8725

ESI - 14

Chem. Name 2-phenylbenzo[d]oxazole (6a)

Lit. Ref.

METHOD: Reservoir 1 was charged with 1M CPME solution of benzyl alcohol (43.2 mmol, 4.7 g, 4.5 mL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (40 mmol, 4.3 g in 43 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 25 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 15 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6a (39.2 mmol, 7.7 g) in 98% yield with a productivity of 2.3 g/h after steady state was reached.

Mol Formula C13H9NO m.p. 102-105 °C Elemental Analysis: Calc.: C, 79.98; H, 4.65; N, 7.17; found: C, 79.91; H, 4.68; N, 7.02

1H NMR 400 MHz CDCl3

value No. H Mult. j value/Hz

7.37 – 7.35 2 m

7.62 – 7.50 4 m

7.81 – 7.79 1 m

8.29 – 8.26 2 m

13C NMR (100.6 MHz, CDCl3) δ : 163.1, 150.8, 142.1, 131.5, 128.9, 127.6, 127.2, 125.1, 124.6, 120.0, 110.6.

GC-EIMS (m/z, %): 195 (100), 181 (68), 180 (54), 161 (62), 145 (22), 121 (16).

ESI - 15

Chem. Name 2-phenylbenzo[d]thiazole (6b)

Lit. Ref. K. Chakrabarti, M. Majia, S. Kundu Green Chem., 2019, 21, 1999-2004

METHOD: Reservoir 1 was charged with 4 mL of CPME and benzyl alcohol (4 mmol, 0.432 g, 414 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminothiophenol solution (3.7 mmol, 0.463 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6b (3.6 mmol, 0.766 g) in 98% yield

Mol Formula C13H9NS m.p. 116-118 °C Elemental Analysis: Calc.: C, 73.90; H, 4.29; N, 6.63; S, 15.17; found: C, 74.01; H, 3.98; N, 6.53; S, 15.12



7.42 – 7.39 1 m

7.54 – 7.48 4 m

7.94 – 7.89 1 m

8.15 – 8.08 3 m

13C NMR (100.6 MHz, CDCl3) δ : 168.09, 154.18, 135.10, 133.65, 131.00, 129.05, 127.59, 126.35, 125.22, 123.27, 121.65

GC-EIMS (m/z, %): 211 (100), 184 (25), 108 (75), 82 (34), 68 (54)

ESI - 16

Chem. Name 2-(4-fluorophenyl)benzo[d]oxazole (6c)

Lit. Ref. L. Tang, Z. Yang, T. Sun, D. Zhang, X. Ma, W. Rao, Y. Zhou Adv. Synth. Catal. 2018, 360, 3055–3062

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL W

F

FF

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-fluoro benzyl alcohol (4 mmol, 436 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6c (3.5 mmol, 0.749 g) in 95% yield

Mol Formula C13H8FNO m.p. 94-96 °C

Elemental Analysis: Calc.: C, 73.23; H, 3.78; N, 6.57; found: C, 73.18; H, 3.59; N, 6.40



8.32 – 8.21 2 m

7.81 – 7.71 1 m

7.63 – 7.54 1 m

7.36 2 dd 6.0, 3.2

7.22 2 t 8.6

13C NMR (100.6 MHz, CDCl3) δ : 164.9 (d, JCF= 251.2 Hz), 162.2, 150.8, 142.0, 129.9 (d, JCF= 8.9 Hz), 125.2, 124.7, 123.5 (d, JCF= 3.0 Hz), 120.0, 116.2 (d, JCF= 22.1 Hz), 110.6

GC-EIMS (m/z, %): 213 (100), 194 (63), 193 (17), 180 (57), 161 (30), 121 (18)

ESI - 17

Chem. Name 2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole (6d)

Lit. Ref. L. Tang, Z. Yang, T. Sun, D. Zhang, X. Ma, W. Rao, Y. Zhou Adv. Synth. Catal. 2018, 360, 3055–3062

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-trifluoromethyl benzyl alcohol (4 mmol, 548 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6d (3.6 mmol, 0.935 g) in 96% yield

Mol Formula C14H8F3NO m.p. 145-146 °C




8.37 2 d 8.1

7.80 3 t 8.3

7.65 – 7.57 1 m

7.40 2 td 6.1, 5.0, 3.5

13C NMR (100.6 MHz, CDCl3) δ : 161.5, 150.9, 141.9, 133.0 (q, JCF= 32.8 Hz), 130.4, 127.9, 125.9 (q, JCF= 3.7 Hz), 125.8, 125.0, 122.4 (q, JCF= 270.8 Hz), 120.4, 110.8

GC-EIMS (m/z, %): 263 (100), 244 (62), 243 (15), 181 (60), 121 (24)

ESI - 18

Chem. Name 2-(4-methoxyphenyl)benzo[d]oxazole (6e)

Lit. Ref. N. Khatun, S. Guin, S. K. Routa, B. K. Patel RSC Adv., 2014, 4, 10770-10778

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL W

MeO

OMeMeO

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-methoxy benzyl alcohol (4 mmol, 497 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6e (3.6 mmol, 0.817 g) in 98% yield

Mol Formula C14H11NO2 m.p. 99-101 °C




8.21 2 d 8.9

8.08 1 d 8.8

7.83 – 7.67 1 m

7.59 – 7.52 1 m

7.37 – 7.28 2 m 8.1

7.03 2 d 8.9

6.95 1 d 8.9

3.89 3 s

13C NMR (100.6 MHz, CDCl3) δ : 163.2, 162.4, 150.6, 142.1, 132.3, 129.5, 124.7, 124.5, 121.8, 119.6, 119.5, 114.4, 113.7, 110.4, 55.5

GC-EIMS (m/z, %): 225 (100), 195 (80), 181 (64), 160 (25), 121 (15), 107 (55)

ESI - 19

Chem. Name 2-(4-(methylthio)phenyl)benzo[d]oxazole (6f)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-methylthio benzyl alcohol (4 mmol, 617 mg), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6f (3.4 mmol, 0.820 g) in 94% yield

Mol Formula C14H11NOS m.p. 105-107 °C Elemental Analysis: Calc.: C, 69.68; H, 4.59; N, 5.80; S, 13.29; found: 69.33; H, 4.12; N, 5.64; S, 13.25



8.17 2 d 8.6

7.82 – 7.68 1 m 8.1

7.62 – 7.51 1 m 8.9

7.41 – 7.30 4 m 8.9

2.55 3 s

13C NMR (100.6 MHz, CDCl3) δ : 162.9, 150.6, 143.8, 142.0, 127.9, 125.8, 125.0, 124.6, 123.2, 119.8, 110.5, 15.0

GC-EIMS (m/z, %): 241 (100), 196 (74), 195 (82), 181 (77), 121 (28), 106 (53)

ESI - 20

Chem. Name 2-(4-(sec-butyl)phenyl)benzo[d]oxazole (6g)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-secbutyl benzyl alcohol (4 mmol, 672 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6g (3.6 mmol, 0.919 g) in 99% yield

Mol Formula C17H17NO m.p. 98-101 °C




8.17 2 d 8.0

7.81 – 7.73 1 m

7.61 – 7.54 1 m

7.38 – 7.28 4 m

2.56 2 d 7.2

1.94 1 dt 13.5, 6.8

0.94 6 d 6.6

13C NMR (100.6 MHz, CDCl3) δ : 163.4, 150.7, 145.9, 142.1, 129.7, 127.5, 124.9, 124.6, 124.5, 119.9, 110.5, 45.5, 30.2, 29.7, 22.4

GC-EIMS (m/z, %): 251 (100), 223 (43), 222 (32), 196 (77), 195 (63), 145 (20), 121 (33).

ESI - 21

Chem. Name 2-(3-methoxyphenyl)benzo[d]oxazole (6h)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3-methoxy benzyl alcohol (4 mmol, 497 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6h (3.6 mmol, 0.816 g) in 98% yield





7.86 1 d 7.7

7.79 2 dd 6.2, 2.9

7.58 1 dt 7.4, 3.7

7.43 1 t 8.0

7.36 2 dd 6.0, 3.3

7.09 1 dd 8.2, 2.6

3.92 3 s

13C NMR (100.6 MHz, CDCl3) δ : 163.0, 160.0, 150.8, 142.0, 130.0, 128.3, 125.2, 124.6, 120.1, 120.0, 118.4, 111.9, 110.6, 55.5

GC-EIMS (m/z, %): 225 (100), 195 (82), 181 (60), 180 (17), 160 (28), 121 (18)

ESI - 22

Chem. Name 2-(3-chlorophenyl)benzo[d]oxazole (6k)

Lit. Ref.

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL WClCl

Cl

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3-chloro benzyl alcohol (4 mmol, 471 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6k (3.6 mmol, 0.827 g) in 98% yield

Mol Formula C13H8ClNO m.p. 125-127 °C




8.26 1 d 1.9

8.14 1 dd 7.5, 1.1

7.81 – 7.75 1 m

7.62 – 7.56 1 m

7.53 – 7.42 2 m

7.42 – 7.33 2 m

13C NMR (100.6 MHz, CDCl3) δ : 161.7, 150.8, 141.9, 135.1, 131.5, 130.3, 128.9, 127.6, 125.7, 125.6, 124.8, 120.2, 110.7

GC-EIMS (m/z, %): 231 (33), 229 (100), 197 (52), 196 (44), 181 (29), 160 (37)

ESI - 23

Chem. Name 2-(3-bromophenyl)benzo[d]oxazole (6i)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3-bromo benzyl alcohol (4 mmol, 354 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6i (3.5 mmol, 0.973 g) in 96% yield

Mol Formula C13H8BrNO m.p. 128-129 °C




8.41 1 t 1.8

8.18 1 d 7.8

7.81 – 7.75 1 m

7.65 1 dt 8.1, 1.4

7.61 – 7.55 1 m

7.42 – 7.33 3 m

13C NMR (100.6 MHz, CDCl3) δ : 161.5, 150.8, 141.9, 134.4, 130.5, 130.5, 129.1, 126.1, 125.6, 124.8, 123.0, 120.2, 110.7

GC-EIMS (m/z, %): 275 (100), 273 (100), 247 (32), 245 (31), 194 (51), 166 (23), 139 (17)

ESI - 24

Chem. Name 2-(3-nitrophenyl)benzo[d]oxazole (6j)

Lit. Ref. P. Saha, T. Ramana, N. Purkait, M. A. Ali, R. Paul, T. Punniyamurthy J. Org. Chem., 2009, 74, 8719–8725

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3-nitro benzyl alcohol (4 mmol, 475 μL), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6j (3.4 mmol, 0.818 g) in 92% yield

Mol Formula C13H8N2O3 m.p. 209-211 °C




9.11 1 t 2.0

8.59 1 d 7.8

8.43 – 8.36 1 m 7.8

7.87 – 7.78 1 m

7.74 1 t 8.0

7.69 – 7.60 1 m

7.49 – 7.35 2 m

13C NMR (100.6 MHz, CDCl3) δ : 160.6, 150.9, 148.7, 141.8, 133.0, 130.2, 129.0, 126.1, 125.8, 125.2, 122.5, 120.5, 110.9.

GC-EIMS (m/z, %): 240 (100), 224 (17), 196 (22), 195 (47), 121 (22).

ESI - 25

Chem. Name 2-(3,5-dibromophenyl)benzo[d]oxazole (6l)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3,5-dinitro benzyl alcohol (4 mmol, 1.06 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6l (3.6 mmol, 1.3 g) in 98% yield

Mol Formula C13H7Br2NO m.p. 132-133 °C




8.34 2 d 1.8

7.87 – 7.78 1 m

7.88 – 7.72 1 m 8.0

7.65 – 7.54 1 m

7.45 – 7.36 2 m

13C NMR (100.6 MHz, CDCl3) δ : 160.1, 150.8, 141.7, 136.7, 130.4, 129.1, 126.0, 125.1, 123.5, 120.4, 110.8

GC-EIMS (m/z, %): 355 (49), 353 (100), 351 (50), 274 (22), 272 (22), 193 (17), 165 (18)

ESI - 26

Chem. Name 2-mesitylbenzo[d]oxazole (6m)

Lit. Ref.

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL W

Me

MeMe

Me

Me

Me

Me

Me Me

METHOD: Reservoir 1 was charged with 4 mL of CPME and 2,4,6-trimethyl benzyl alcohol (4 mmol, 0.600 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6m (3.6 mmol, 0.854 g) in 98% yield





7.87 – 7.80 2 m

7.64 – 7.55 1 m

7.40 – 7.37 1 m

6.98 2 s

2.36 – 2.30 9 m

13C NMR (100.6 MHz, CDCl3) δ : 163.3, 150.6, 141.6, 140.3, 138.5, 130.5, 128.7, 125.0, 124.9, 124.2, 120.2, 110.6, 21.3, 20.4

GC-EIMS (m/z, %): 237 (100), 222 (48), 208 (43), 194 (20), 130 (26), 118 (52)

ESI - 27

Chem. Name 2-(2,3,4,5,6-pentamethylphenyl)benzo[d]oxazole (6n)

Lit. Ref.

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL WMe

Me

Me MeMe

Me

Me

Me

Me

Me

Me

Me

Me

Me

Me

METHOD: Reservoir 1 was charged with 4 mL of CPME and 2,3,4,5,6-pentamethyl benzyl alcohol (4 mmol, 0.713 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6n (3.7 mmol, 0.972 g) in 99% yield





7.93 – 7.79 1 m

7.63 – 7.55 1 m 1.8

7.45 – 7.33 2 m

2.31 3 s 8.0

2.25 6 s

2.09 6 s

13C NMR (100.6 MHz, CDCl3) δ : 164.8, 150.7, 141.5, 137.6, 133.4, 132.9, 126.3, 124.9, 124.2, 120.2, 110.7, 18.1, 17.0, 16.3

GC-EIMS (m/z, %): 265 (100), 250 (52), 235 (25), 157 (46), 132 (22), 114 (16)

ESI - 28

Chem. Name 2-(benzo[d][1,3]dioxol-5-yl)benzo[d]oxazole (6o)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and 4-piperyl benzyl alcohol (4 mmol, 0.609 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.404 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6o (3.7 mmol, 0.876 g) in 99% yield





7.84 1 dd 8.2, 1.7

7.78 – 7.69 2 m 1.8

7.59 – 7.52 1 m

7.39 – 7.29 2 m

6.95 1 d 8.2

6.08 2 s

13C NMR (100.6 MHz, CDCl3) δ : 162.88, 150.68, 150.58, 148.24, 142.19, 124.79, 124.51, 122.81, 121.17, 119.73, 110.43, 108.75, 107.70, 101.77

GC-EIMS (m/z, %): 239 (100), 238 (82), 209 (25), 181 (32), 153 (44), 119 (51), 63 (55)

ESI - 29

Chem. Name 6-methyl-2-phenylbenzo[d]oxazole (6p)

Lit. Ref.

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL W

Me

Me

METHOD: Reservoir 1 was charged with 4 mL of CPME and benzyl alcohol (4 mmol, 0.432 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the 3-methyl-2-aminophenol solution (3.7 mmol, 0.455 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6p (3.6 mmol, 0.757 g) in 98% yield





8.26 – 8.23 2 m

7.54 – 7.52 3 m

7.47 1 d 8.8

7.29 1 d 2.4

6.97 1 dd 8.9, 2.6

3.89 3 s

13C NMR (100.6 MHz, CDCl3) δ : 163.81, 157.41, 145.42, 142.91, 131.42, 128.90, 127.50, 127.25, 113.74, 110.73, 102.87, 55.93

GC-EIMS (m/z, %): 209 (100), 208 (75), 195 (35), 194 (25), 130 (55), 118 (32)

ESI - 30

Chem. Name 5-methoxy-2-phenylbenzo[d]oxazole (6q)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and benzyl alcohol (4 mmol, 0.432 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the 4-methoxy-2-aminophenol solution (3.7 mmol, 0.514 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6q (3.6 mmol, 0.810 g) in 98% yield





8.29 – 8.23 2 m

7.67 1 d 8.1

7.58 – 7.52 3 m

7.42 1 s

7.20 1 dd 8.2, 1.5

2.54 3 s

13C NMR (100.6 MHz, CDCl3) δ : 162.58, 155.68, 151.07, 139.92, 135.59, 131.30, 128.89, 127.47, 125.83, 119.35, 110.78, 21.83

GC-EIMS (m/z, %): 225 (100), 195 (75), 194 (35), 181 (45), 180 (37), 160 (25), 158 (55), 121 (40)

ESI - 31

Chem. Name 7-chloro-2-phenylbenzo[d]oxazole (6r)

Lit. Ref.

METHOD: Reservoir 1 was charged with 4 mL of CPME and benzyl alcohol (4 mmol, 0.432 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the o-aminophenol solution (3.7 mmol, 0.531 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product 6r (3.5 mmol, 0.804 g) in 95% yield

Mol Formula C13H8ClNO m.p. 118-121 °C




8.32 2 dd 7.7, 2.0

7.69 1 dd 7.7, 1.2

7.59 – 7.55 3 m

7.39 – 7.28 2 m

13C NMR (100.6 MHz, CDCl3) δ : 163.45, 158.64, 147.40, 143.36, 131.99, 129.00, 127.88, 126.56, 125.43, 125.33, 118.48

GC-EIMS (m/z, %): 231 (35), 229 (100), 197 (22), 196 (64), 194 (44), 181 (32), 160 (57), 158 (25)

ESI - 32

Chem. Name 2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

Lit. Ref.

OH

CPME

O

CPME O

N

NH2

OH

O2O2

K-MnH-Mn H

FL W FL WCl

Cl

Cl

Cl

HO

O

Cl

Cl

HO

O

METHOD: Reservoir 1 was charged with 4 mL of CPME and 3,5-dichlorobenzyl alcohol (4 mmol, 0.708 g), then the oxygen line has been set to 5 bar of pressure and the solvent started to flow through column 1 (filled with 78 mg of H-OMS) at a flow rate of 0.2 mL/min with a residence time of 13 minutes. When the flow reached the exit of column 1, the nitrogen line was set to 5 bar and the 4-Amino-3-hydroxybenzoic acid solution (3.7 mmol, 0.566 g in 4 mL of CPME 0.9M) previously charged into reservoir 2 started to mix with flow 1 into a T-piece. The resulting mixture continuously flowed through the loop, in which imine formation took place, before reaching column 2 (filled with 68 mg of K-OMS) at a flow rate of 0.2 mL/min with a residence time of 40 min. At the end of the process the system has been completely flushed, both line with 10 mL of CPME in order to wash the catalyst columns. The product has been collected into the product reservoir. Then CPME was recovered via distillation under reduced pressure (98% of the total amount, confirmed by 1H-NMR) and the residue was washed with 5 mL of EtOH in order to remove unreacted benzaldehyde, furnishing pure product Tafamidis (3.4 mmol, 1.05 g) in 92% yield

Mol Formula C14H7Cl2NO3 m.p. 187-188 °C


1H NMR 400 MHz Acetone-d6


8.92 1 s

8.15 2 d 2

7.63 – 7.58 2 m

7.48 1 d 8.7

13C NMR (100.6 MHz, Acetone-d6) δ : 166.27, 157.95, 152.25, 139.57, 135.17, 130.80, 130.72, 127.54, 126.05, 121.41, 120.07, 112.44.

GC-EIMS (m/z, %): 310 (63), 308 (100), 306 (50), 292 (22), 294 (27), 272 (47), 264 (44), 236 (38), 181 (25).

ESI - 33

-101234567891011ppm

2.184.261.00

2.07

7.350

7.360

7.367

7.373

7.524

7.529

7.534

7.541

7.547

7.577

7.585

7.592

7.597

7.601

7.785

7.791

7.799

7.807

8.264

8.273

8.283

8.288

2-phenylbenzo[d]oxazole (6a)

ESI - 34

020406080100120140160180ppm

110.610

120.042

124.591

125.119

127.193

127.639

128.923

131.527

142.140

150.779

163.052

2-phenylbenzo[d]oxazole (6a)

ESI - 35

-101234567891011ppm

1.044.29

1.00

2.99

7.378

7.381

7.396

7.399

7.401

7.416

7.419

7.490

7.493

7.499

7.506

7.510

7.514

7.516

7.522

7.528

7.531

7.900

7.903

7.907

7.920

7.923

7.926

8.093

8.096

8.098

8.104

8.108

8.110

8.115

8.119

8.122

8.125

8.128

2-phenylbenzo[d]thiazole (6b)

ESI - 36

020406080100120140160180ppm

121.654

123.270

125.219

126.348

127.591

129.051

130.998

133.651

135.099

154.179

168.092

2-phenylbenzo[d]thiazole (6b)

ESI - 37

-101234567891011ppm

2.062.161.011.00

2.08

7.198

7.219

7.241

7.351

7.359

7.366

7.374

7.570

7.578

7.584

7.586

7.593

7.759

7.765

7.769

7.774

7.782

8.250

8.255

8.263

8.268

8.272

8.286

2-(4-fluorophenyl)benzo[d]oxazole (6c)

ESI - 38

-100102030405060708090100110120130140150160170180ppm

110.596

116.114

116.335

119.984

123.453

123.483

124.707

125.183

129.829

129.918

141.989

150.772

162.194

163.595

166.107 2-(4-fluorophenyl)benzo[d]oxazole (6c)

ESI - 39

-135-130-125-120-115-110-105-100-95-90-85ppm

-107.511

-107.497

-107.489

-107.483

-107.474

-107.466

-107.460

-107.452

-107.438

2-(4-fluorophenyl)benzo[d]oxazole (6c)

ESI - 40

-101234567891011ppm

2.021.003.04

2.04

7.370

7.384

7.388

7.396

7.405

7.410

7.423

7.599

7.603

7.611

7.615

7.622

7.776

7.796

7.805

7.818

8.362

8.382

2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole (6d)

ESI - 41

020406080100120140160180200ppm

110.812

120.415

122.399

124.961

125.830

125.879

125.918

125.956

125.993

127.869

130.440

132.513

132.840

133.165

133.493

141.895

150.870

161.489


ESI - 42

-140-130-120-110-100-90-80-70-60-50-40-30-20-100ppm

-62.981


ESI - 43

-101234567891011ppm

3.33

1.032.31

2.341.131.22

1.002.32

3.890

6.935

6.957

7.020

7.043

7.301

7.314

7.319

7.329

7.338

7.343

7.356

7.544

7.550

7.552

7.567

7.744

7.748

7.754

7.758

7.761

7.766

8.066

8.088

8.199

8.221

2-(4-methoxyphenyl)benzo[d]oxazole (6e)

ESI - 44

020406080100120140160180ppm

55.475

110.414

113.730

114.403

119.557

119.591

121.836

124.503

124.679

129.470

132.323

142.050

150.633

162.415

163.212

2-(4-methoxyphenyl)benzo[d]oxazole (6e)

ESI - 45

-101234567891011ppm

3.10

4.010.981.00

1.97

2.552

7.337

7.344

7.349

7.360

7.365

7.559

7.566

7.568

7.571

7.577

7.582

7.750

7.756

7.761

7.763

7.766

7.773

8.155

8.177

2-(4-(methylthio)phenyl)benzo[d]oxazole (6f)

ESI - 46

020406080100120140160180ppm

15.010

110.530

119.777

123.237

124.644

125.025

125.749

127.898

141.947

143.840

150.639

162.910

2-(4-(methylthio)phenyl)benzo[d]oxazole (6f)

ESI - 47

-101234567891011ppm

6.21

1.12

2.02

3.950.941.00

1.99

0.932

0.948

1.901

1.918

1.935

1.952

1.969

2.553

2.571

7.298

7.318

7.333

7.343

7.346

7.356

7.565

7.575

7.588

7.757

7.762

7.769

7.772

7.780

8.161

8.181

2-(4-(sec-butyl)phenyl)benzo[d]oxazole (6g)

ESI - 48

020406080100120140160ppm

22.374

29.718

30.194

45.450

110.515

119.849

124.503

124.616

124.889

127.507

129.711

142.141

145.905

150.706

163.358

2-(4-(sec-butyl)phenyl)benzo[d]oxazole (6g)

ESI - 49

-101234567891011ppm

3.27

1.00

2.06

1.09

1.05

2.00

1.04

3.92

0

7.07

57.

081

7.09

57.

101

7.33

8 7.

349

7.35

77.

364

7.37

27.

382

7.41

17.

431

7.45

17.

566

7.57

77.

585

7.59

27.

600

7.61

07.

774

7.78

27.

786

7.79

07.

797

7.84

77.

866

2-(3-methoxyphenyl)benzo[d]oxazole (6h)

ESI - 50

020406080100120140160ppm

55.542

110.629

111.903

118.407

120.011

120.143

124.640

125.205

128.303

130.027

141.989

150.746

159.961

162.976

2-(3-methoxyphenyl)benzo[d]oxazole (6h)

ESI - 51

-101234567891011ppm

2.162.080.991.00

1.050.89

7.354

7.366

7.372

7.376

7.379

7.384

7.389

7.402

7.441

7.461

7.480

7.493

7.497

7.501

7.518

7.581

7.587

7.595

7.604

7.763

7.773

7.781

7.785

7.791

7.796

7.805

8.132

8.135

8.151

8.153

8.255

8.260

8.264

2-(3-chlorophenyl)benzo[d]oxazole (6k)

ESI - 52

020406080100120140160ppm

110.724

120.242

124.837

125.564

125.656

127.635

128.867

130.247

131.508

135.092

141.907

150.790

161.653

2-(3-chlorophenyl)benzo[d]oxazole (6k)

ESI - 53

-101234567891011ppm

3.171.020.971.00

1.02

0.89

7.361

7.367

7.371

7.374

7.378

7.384

7.391

7.411

7.574

7.580

7.585

7.589

7.597

7.639

7.642

7.646

7.659

7.663

7.666

7.768

7.776

7.780

7.791

8.171

8.190

8.410

8.414

8.419

2-(3-bromophenyl)benzo[d]oxazole (6i)

ESI - 54

020406080100120140160ppm

110.724

120.234

123.028

124.844

125.576

126.090

129.056

130.468

130.517

134.420

141.872

150.781

161.488

2-(3-bromophenyl)benzo[d]oxazole (6i)

ESI - 55

-101234567891011ppm

2.161.031.091.00

0.95

1.00

0.83

7.395

7.409

7.415

7.424

7.433

7.439

7.453

7.633

7.636

7.650

7.656

7.719

7.739

7.759

7.813

7.819

7.826

7.832

7.836

8.377

8.380

8.383

8.385

8.400

8.403

8.584

8.604

9.100

9.105

9.110

2-(3-nitrophenyl)benzo[d]oxazole (6j)

ESI - 56

020406080100120140160180200ppm

110.917

120.531

122.519

125.148

125.812

126.098

128.984

130.153

133.044

141.811

148.731

150.901

160.597

2-(3-nitrophenyl)benzo[d]oxazole (6j)

ESI - 57

-101234567891011ppm

2.431.202.17

2.00

7.389

7.398

7.407

7.412

7.586

7.591

7.597

7.601

7.604

7.610

7.774

7.780

7.783

7.786

7.792

7.797

7.812

7.817

7.821

8.343

8.347

2-(3,5-dibromophenyl)benzo[d]oxazole (6l)

ESI - 58

020406080100120140160ppm

110.830

120.442

123.537

125.072

125.992

129.133

130.358

136.714

141.734

150.830

160.104

2-(3,5-dibromophenyl)benzo[d]oxazole (6l)

ESI - 59

-101234567891011ppm

9.10

1.87

1.910.951.00

2.295

2.356

6.980

7.373

7.381

7.387

7.395

7.579

7.587

7.592

7.596

7.602

7.818

7.825

7.829

7.834

7.842

2-mesitylbenzo[d]oxazole (6m)

ESI - 60

020406080100120140160180200ppm

20.355

21.298

110.619

120.155

124.237

124.905

124.983

128.652

130.544

138.491

140.298

141.586

150.635

163.313

2-mesitylbenzo[d]oxazole (6m)

ESI - 61

-101234567891011ppm

5.936.002.96

1.930.951.00

2.087

2.253

2.307

7.374

7.380

7.383

7.387

7.390

7.397

7.571

7.579

7.583

7.588

7.594

7.818

7.824

7.829

7.833

7.841

2-(2,3,4,5,6-pentamethylphenyl)benzo[d]oxazole (6n)

ESI - 62

020406080100120140160180200ppm

16.337

16.995

18.072

110.700

120.198

124.239

124.884

126.290

132.856

133.398

137.583

141.456

150.679

164.762

2-(2,3,4,5,6-pentamethylphenyl)benzo[d]oxazole (6n)

ESI - 63

-1012345678910ppm

2.11

1.02

2.041.001.801.00

6.079

6.942

6.962

7.314

7.327

7.330

7.332

7.340

7.347

7.350

7.353

7.366

7.547

7.553

7.557

7.565

7.570

7.708

7.712

7.731

7.736

7.743

7.747

7.754

7.826

7.830

7.846

7.851

2-(benzo[d][1,3]dioxol-5-yl)benzo[d]oxazole (6o)

ESI - 64

020406080100120140160180ppm

101.773

107.696

108.752

110.426

119.725

121.174

122.813

124.514

124.788

142.194

148.239

150.582

150.683

162.879

2-(benzo[d][1,3]dioxol-5-yl)benzo[d]oxazole (6o)

ESI - 65

-101234567891011ppm

3.21

1.01

1.041.023.03

2.00

3.885

6.952

6.959

6.975

6.981

7.282

7.288

7.460

7.482

7.524

7.528

7.536

7.542

8.237

8.247

8.256

8.261

6-methyl-2-phenylbenzo[d]oxazole (6p)

ESI - 66

2030405060708090100110120130140150160170180ppm

55.930

102.875

110.726

113.735

127.496

128.902

131.421

142.911

145.418

157.414

163.808

6-methyl-2-phenylbenzo[d]oxazole (6p)

ESI - 67

-101234567891011ppm

3.12

1.151.093.07

1.06

2.00

2.537

7.184

7.188

7.205

7.209

7.415

7.538

7.547

7.554

7.658

7.678

8.253

8.262

8.265

8.271

8.277

5-methoxy-2-phenylbenzo[d]oxazole (6q)

ESI - 68

020406080100120140160180ppm

21.829

110.782

119.351

125.825

127.473

128.887

131.298

135.593

151.067

155.682

162.582

5-methoxy-2-phenylbenzo[d]oxazole (6q)

ESI - 69

01234567891011ppm

2.153.140.96

2.00

7.285

7.296

7.316

7.336

7.362

7.365

7.382

7.385

7.551

7.565

7.569

7.578

7.583

7.589

7.596

7.682

7.685

7.701

7.704

8.305

8.311

8.325

8.329

7-chloro-2-phenylbenzo[d]oxazole (6r)

ESI - 70

0102030405060708090100110120130140150160170ppm

118.483

125.333

125.429

126.559

127.882

128.997

131.986

143.362

147.396

158.637

163.454

7-chloro-2-phenylbenzo[d]oxazole (6r)

ESI - 71

01234567891011ppm

1.04

2.02

2.01

1.00

7.471

7.481

7.484

7.493

7.593

7.598

7.603

7.608

7.615

8.144

8.149

8.917

2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

ESI - 72

020406080100120140160180200ppm

112.442

120.067

121.413

126.048

127.538

130.722

130.795

135.172

139.571

152.248

157.947

166.266

2-(3,5-dichlorophenyl)benzo[d]oxazole-6-carboxylic acid (Tafamidis)

ESI - 73

Continuous Flow Synthesis of Benzoxazoles Derivatives by … · 2019. 9. 2. · Electronic Supporting Information Continuous Flow Synthesis of Benzoxazoles Derivatives by Manganese‐Based

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