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31st July 2012 @ 00:21
Product obtained (1H NMR evidence only) in 52% yield. Used without further purification.

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Hydrolysis of PMY 58-2 methyl ester to the acid using aqueous sodium hydroxide.

PMY59-1.png

Reaction start time: 13.40 30/07/12
PMY 58-2 (126 mg, 0.4 mmol, 1 equiv.) was stirred in MeOH (5 mL). Partial solution, yellow solution, some white crystals. Sodium hydroxide (160 mg, 4.0 mmol, 10 equiv.) was dissolved in water (2 mL) and added to the solution of PMY 58-2. After 1.5 hours, the reaction was mostly complete by TLC. 2M HCl(aq) was added until pH 1. The mixture was then extracted with DCM (3 × 5 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated to a yellow solid (62 mg). 1H NMR consistent with product. Some further crystals precipitate from aqueous, further extraction required. Material used without further purification.

TLC (50% acetone/hexane) visualised with UV and vanillin:
TLC 1.5 hours
TLC 1 hour


NMR:
1H NMR


See also:
Scaled-up cyclodehydration of carboxamide PMY 57-2 (PMY 58-2)
Hydrolysis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 44-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)

Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)

[Reaction reporting delayed to 31/07/12 due to server error]
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25th July 2012 @ 23:57
Reaction successful (approx 30% yield) but the the product is not quite as pure original. Probably best to keep to carry out the reaction at room temperature or under.

===

Cyclodehydration of PMY 57-2 using XtalFluor-E in 1,2-DCE and subsequent oxidation to the oxazole.

PMY58-1.png

Reaction Start Time: 15.00 25/07/12
PMY 57-2 (1.00 g, 3.0 mmol, 1 equiv.) was stirred in 1,2-DCE (40 mL). XtalFluor-E (1.40 g, 6.0 mmol, 2 equiv.) was added and the reaction heated to 90 °C under nitrogen. After 18 hours, reaction is complete by TLC. The reaction was cooled to room temperature and a solution Na2CO3 (1:1 saturated soln/water, approx 30 mL) was added. The reaction was stirred for 10 minutes, then separated. The aqueous layer was extracted with DCM (3 × 20 mL). The combined organic extracts were washed with brine then dried (MgSO4) and concentrated to a brown foam (1.04 g, 110% of theory). 1H NMR consistent with PMY 58-1 intermediate.

13.40 26/07/12 The intermediate was dissolved in DCM (50 mL). DBU (1.3 mL, 8.7 mmol, 2.9 equiv.) and bromotrichloromethane (0.88 mL, 8.9 mmol, 3.0 equiv.) were added. The reaction was heated to reflux. TLCs show reaction progress. At 3.5 hrs, a new product spot was observed. Reaction cooled to 25 °C for overnight reaction. After overnight reaction, TLC shows consumptions of SM and some impurities. The reaction was concentrated under reduced pressure and purified by chromatography on silica (5-20% acetone/hexane). Long drawn out product spot, late and early running impurities not observed. PMY 58-2 (322 mg, 34%), slightly yellow solid consistent with PMY 58-1 by TLC. Column flush using 5% MeOH/DCM brought out impurities, brown solid (192 mg).

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC stage 1
TLC stage 2, 0.5 hours
TLC stage 2, 1.5 hrs
TLC stage 2, 3.5 hours
TLC overnight


NMR:
1H NMR intermediate
1H NMR PMY 58-2


50% acetone/hexane
Column TLC, 20% acetone/hexane

20% acetone/hexane
58-2 vs 58-1, acetone/hexane


See also:
Scaled-up coupling of pyrrole acid chloride and serine methyl ester (PMY 57-2)
Cyclodehydration of carboxamide PMY 57-1 (PMY 58-1)
Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)
Synthesis of aryl pyrrole oxazole ester from aldehyde and Serine methyl ester (PMY 46-1)
Synthesis of aryl pyrrole oxazole ester (PMY 45-1)

Risk and Hazard Assessment:
RA
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23rd July 2012 @ 01:30
Product obtained in 28% yield overall.

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Coupling of pyrrole acid chloride and serine methyl ester for cyclisation to the oxazole. As for PMY 57-1 but 10-fold scale-up. Serine/base to be scaled according to triturated acid chloride mass.

PMY57-1.png

Reaction Start Time: 10.25 23/07/12
JRC 2-1 (2.50 g, 10.7 mmol, 1 equiv.) was stirred in PhMe (20 mL). Thionyl chloride (1.6 mL, 21.4 mmol, 2 equiv.) was added and the mixture stirred at room temperature. After 4 hours, the reaction was concentrated under a reduced pressure. Then triturated with hexane (30 + 10 mL) and filtered by syringe. The hexane extract was concentrated to a yellow solid (1.26 g, 47%). [Extraction possibly not thorough enough, harder on large scale, less efficient stirring etc.]

In a separate vessel, DL-serine methyl ester hydrochloride (857 mg, 5.51 mmol, 1.1 equiv.) was stirred in THF (10 mL). DIPEA (0.62 mL, 3.54 mmol, 3.3 equiv.) was added and the reaction stirred for 5 minutes. 15.55 A THF solution of the acid chloride (1.26 g, 5.01 mmol, 1 equiv. in 25 mL) was added to the suspension/solution of serine methyl ester and stirred at room temperature. After approx 42 hours, reaction shows new product but also non-polar product not observed in PMY 57-1. Saturated NaHCO3(aq) and water (1:1) were added to the residue and extracted with DCM (3 × 25 mL). The combined extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to an orange foam (1.75 g). Purified by chromatography on silica (1-4% MeOH/DCM) to give early impurities and PMY 57-2 (1.01 g, 60% from acid chloride, 28% overall), consistent with PMY 57-1 by TLC. No starting material isolated. 1H NMR consistent with PMY 57-1.

[2nd step went badly for some reason, usually scaled according to initial acid. Therefore a larger equivalence of base and serine may be helpful.]

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC 42 hours


NMR:
1H NMR


See also:
Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)
Synthesis of aryl pyrrole oxazole ester from aldehyde and Serine methyl ester (PMY 46-1)
Synthesis of aryl pyrrole oxazole ester (PMY 45-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Synthesis of pyrrole acid chloride (PMY 32-3)
Coupling of crude PMY 53-2 and pyrrole acid chloride (PMY 55-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)
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18th July 2012 @ 07:58
Product obtained in 30% overall yield.

===

Cyclodehydration of PMY 57-1 using XtalFluor-E in 1,2-DCE and subsequent oxidation to the oxazole.

PMY58-1.png

Reaction Start Time: 17.10 18/07/12
PMY 57-1 (103 mg, 0.3 mmol, 1 equiv.) was stirred in 1,2-DCE (4 mL) and heated to 90 °C under nitrogen. XtalFluor-E (141 mg, 0.6 mmol, 2 equiv.) was added. After 16 hours, reaction mostly complete by TLC. The reaction was cooled to room temperature (13 °C) and 1:1 saturated Na2CO3/water added (10 mL) and the reaction stirred for 10 minutes. The layers were separated and the aqueous extracted with DCM (3 × 10 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a brown gum (93 mg). 1H NMR is consistent with expected intermediate product.

1440 19/07/12 The material was dissolved in DCM (5 mL) and bromotrichloromethane (91 μL, 0.92 mmol, 3 equiv.) and DBU (138 μL, 0.92 mmol, 3 equiv.) were added. TLC at 2 hours at 15 °C (room temperature) shows formation of a new product and SM. After 18 hours,, SM still remains. Reaction concentrated to approx 1 mL and purified by chromatography (5-15% acetone/hexane) to obtain a white solid (30 mg, 30% over 2 steps). 1H and 13C NMR are consistent with expected product.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC stage 1
TLC stage 2, 2 hours


NMR:
1H NMR step 1
1H, 13C, 19F NMR PMY 58-1


Mass Spec:
Intermediate oxazoline:
HRMS (ESI+) found 317.13035 [M+H], C17H18N2O3F requires 317.12960.

Product oxazole:
HRMS (ESI+) found 337.09628 [M+Na], C17H15N2O3FNa requires 337.09589.

See also:
Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)
Synthesis of aryl pyrrole oxazole ester from aldehyde and Serine methyl ester (PMY 46-1)
Synthesis of aryl pyrrole oxazole ester (PMY 45-1)

Reference:
doi:10.1016/j.tetlet.2012.05.130

Risk and Hazard Assessment:
RA
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Attached Files
17th July 2012 @ 04:28
Product synthesised in 46% yield over two steps.

===

Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1) for cyclisation to the oxazole.

PMY57-1.png

Reaction Start Time: 12.00 17/07/12
JRC 2-1 (250 mg, 1.07 mmol, 1 equiv.) was stirred in PhMe (2 mL). Thionyl chloride (0.16 mL, 2.14 mmol, 2 equiv.) was added and the mixture stirred at room temperature. After 4 hours, the reaction was concentrated and triturated with hexane (5 mL) and concentrated once more, then dissolved in THF (3 mL).

In a separate vessel, DL-serine methyl ester hydrochloride (183 mg, 1.18 mmol, 1.1 equiv.) was stirred in THF (10 mL). Insoluble. DIPEA (0.62 mL, 3.54 mmol, 3.3 equiv.) was added. 1700 Acid chloride solution added to the suspension/solution of serine methyl ester. TLC at 16 hours shows reaction complete (relative to acid). Reaction concentrated under reduced pressure. saturated NaHCO3(aq) and water (1:1) were added to the residue and extracted with DCM (3 × 15 mL). The extracts were then washed with brine and dried (MgSO4) and concentrated to a tan foam (241 mg). Purification by chromatography on silica (1-4% MeOH/DCM) gave a mixed fraction, trace SM acid and prod by TLC, PMY 57-1-A (79 mg) and single spot product white foam PMY 57-1-B (87 mg). 1H NMR consistent with expected product. Both fractions clean (total 166 mg, 46%).

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC 16 hours


NMR:
1H NMR
1H NMR PMY 57-1-A
1H, 13C, 19F NMR PMY 57-1-B


Mass Spec:
HRMS (ESI+) found 357.12285 [M+Na], C17H19N2O4FNa requires 357.12211.

See also:
Synthesis of aryl pyrrole oxazole ester from aldehyde and Serine methyl ester (PMY 46-1)
Synthesis of aryl pyrrole oxazole ester (PMY 45-1)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (JRC 2-1)
Synthesis of pyrrole acid chloride (PMY 32-3)
Coupling of crude PMY 53-2 and pyrrole acid chloride (PMY 55-1)
Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123812 via acid chloride (PMY 10-6)
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Attached Files