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23rd July 2012 @ 00:30
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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Attached Files
TLC 42 hours
1H NMR