EE107 SP 02B Directional Derivatives Directional Derivatives
Continuous Flow Synthesis of Benzoxazoles Derivatives by … · 2019. 9. 2. · Electronic...
Transcript of Continuous Flow Synthesis of Benzoxazoles Derivatives by … · 2019. 9. 2. · Electronic...
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
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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
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.
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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
C4: 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)
C3: PTFE tube (1/16’’), ID: 1 mm. Length: 2 cm
Back Pressure Regulator 2: 75 psi BPR (supplied by Upchurch)
C4: PTFE tube (1/16’’), ID: 1 mm. Length: 2 cm
C4: PTFE tube (1/16’’), ID: 1 mm. Length: 60 cm (loop)
Reactor 2: Supelco HPLC Column Blank 20 cm
C5: PTFE tube (1/16’’), ID: 1 mm. Length: 5 cm
Back Pressure Regulator 2: 40 psi BPR (supplied by Upchurch)
C6: PTFE tube (1/16’’), ID: 1 mm. Length: 5 cm
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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
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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
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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
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. 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.
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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:
C, 74.65; H, 4.92; N, 6.22; experimental: C, 74.50; H, 4.84; N, 6.16
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:
C, 74.65; H, 4.92; N, 6.22; experimental: C, 74.54; H, 4.82; N, 6.20
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
small scale flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 99% Yield.
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
small scale flow procedure using the appropriate benzyl alcohol (4 mmol) and o‐aminophenol (3.7 mmol) in 99% Yield.
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
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 63.88; H, 3.06; N, 5.32; found: C, 63.64; H, 2.98; N, 5.12
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 74.65; H, 4.92; N, 6.22; found: C, 74.50; H, 4.84; N, 6.16
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 81.24; H, 6.82; N, 5.57; found: C, 81.09; H, 6.64; N, 5.32
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C14H11NO2 m.p. 70-72 °C
Elemental Analysis: Calc.: C, 74.65; H, 4.92; N, 6.22; found: C, 74.54; H, 4.82; N, 6.20
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 67.99; H, 3.51; N, 6.10; found: C, 67.83; H, 3.34; N, 6.01
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 56.96; H, 2.94; N, 5.11; found: C, 56.93; H, 2.90; N, 5.03
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 65.00; H, 3.36; N, 11.66; found: C, 65.10; H, 3.12; N, 11.43
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 44.23; H, 2.00; N, 3.97; found: C, 44.18; H, 2.01; N, 3.78
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C16H15NO m.p. 112-115 °C
Elemental Analysis: Calc.: C, 80.98; H, 6.37; N, 5.90; found: C, 80.82; H, 6.17; N, 5.88
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C18H19NO m.p. 130-131 °C
Elemental Analysis: Calc.: C, 81.47; H, 7.22; N, 5.28; found: C, 81.27; H, 7.14; N, 5.18
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C14H9NO3 m.p. 137-138 °C
Elemental Analysis: Calc.: C, 70.29; H, 3.79; N, 5.86; found: C, 70.01; H, 3.70; N, 5.78
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C14H11NO m.p. 143-145 °C
Elemental Analysis: Calc.: C, 80.36; H, 5.30; N, 6.69; found: C, 80.34; H, 5.28; N, 6.68
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Mol Formula C14H11NO2 m.p. 155-157 °C
Elemental Analysis: Calc.: C, 74.65; H, 4.92; N, 6.22; found: C, 74.61; H, 4.88; N, 6.20
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 67.99; H, 3.51; N, 6.10; found: C, 67.93; H, 3.46; N, 6.11
1H NMR 400 MHz CDCl3
value No. H Mult. j value/Hz
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
Elemental Analysis: Calc.: C, 54.58; H, 2.29; N, 4.55; found: C, 54.57; H, 2.25; N, 4.58
1H NMR 400 MHz Acetone-d6
value No. H Mult. j value/Hz
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
2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole (6d)
ESI - 42
-140-130-120-110-100-90-80-70-60-50-40-30-20-100ppm
-62.981
2-(4-(trifluoromethyl)phenyl)benzo[d]oxazole (6d)
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