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29th March 2012 @ 06:55
===

Synthesis of the aryl pyrrole oxazole methyl ester from the standard aldehyde and serine methyl ester.

PMY46-1.png

Reaction Start Time: 17.00 29/03/12
PMY 2-5 (200 mg, 0.92 mmol, 1 equiv.) and DL-serine methyl ester hydrochloride (143 mg, 0.92 mmol, 1 equiv.) were stirred in THF (5 mL) with triethylamine (0.26 mL, 1.84 mmol, 1 equiv.) and MgSO4 (approx 200 mg). After 16 hours, the reaction was filtered. TLC shows mainly SM. Mixture concentrated under reduced pressure to an orange oil. Mass spec is inconclusive.

TLC (30% EtOAc/hexane) visualised with UV and vanillin:
TLC 16 hours


NMR:
1H NMR oil
1H NMR crystal


Mass Spec:
ESI mass spec


See also:
Synthesis of aryl pyrrole oxazole ester (PMY 45-1)
Preparation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbaldehyde (PMY 2-5)

Reference:
doi:10.1021/ol101346w

Risk and Hazard Assessment:
RA
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27th March 2012 @ 01:48
SM recovered.

===

Synthesis of an oxazole linked aryl pyrrole ester from PMY 42-1 and ethyl bromopyruvate. Intermediate in synthesis of ester isostere of TCMDC-123812 PMY 10-6

PMY45-1.png

Reaction Start Time: 15.50 27/03/12
PMY 42-1 (80 mg, 0.34 mmol, 1 equiv.) and dried NaHCO3 (145 mg, 1.72 mmol, 5.0 equiv.) were stirred in dry THF (8 mL) at room temperature. Ethyl bromopyruvate (52 μL, 0.41 mmol, 1.2 equiv.) was added and the reaction heated to 57 °C. After 18 hours, reaction showed mostly SM by TLC. A further portion of ethyl bromopyruvate (26 &muL;, 0.20 mmol, 0.6 equiv.) was added and the reaction refluxed for 3 hours and then cooled. The mixture was filtered through celite then concentrated under high vacuum to a brown oil (84 mg). 1H NMR mainly SM. Mass spec is inconclusive.

Mass Spec:
ESI mass spec


NMR:
1H NMR crude


Reference:
doi:10.1021/jo048106q
doi:10.1021/jo702305g

See also:
Synthesis of pyrrole amide (PMY 42-1)
Discussion on The Synaptic Leap.

Risk and Hazard Assessment:
RA


InChi:

Starting Material: InChI=1S/C13H13FN2O/c1-8-7-12(13(15)17)9(2)16(8)11-5-3-10(14)4-6-11/h3-7H,1-2H3,(H2,15,17)
Product: InChI=1S/C18H17FN2O3/c1-4-23-18(22)16-10-24-17(20-16)15-9-11(2)21(12(15)3)14-7-5-13(19)6-8-14/h5-10H,4H2,1-3H3
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26th March 2012 @ 01:10
Product obtained in 74% yield.

===

Hydrolysis of pyrazole core ester to the acid in basic conditions.

PMY44-1.png

Reaction Start Time: 11.30 26/03/12
PMY 43-1 (3.46 g, 15.0 mmol, 1 equiv.) was dissolved in EtOH (20 mL). 5M sodium hydroxide (20 mL, 100 mmol, 6.7 equiv.) was added and the mixture heated to reflux. After 165 mins, reaction not complete by TLC. After approx 4 hours, reaction not complete by TLC. After 6 hours, reaction was allowed cooled to room temperature. lab cooling water shutdown Reaction not complete after 16 hours at room temperature. Heated to reflux. After a further 3 hours at reflux, the reaction was cooled in ice, then acidified with 6M HCl (pH 1). The resulting amber precipitate was allowed to ripen for 20 minutes at 0 °C and then filtered and dried under reduced pressured. The amber product was recrystalled from Et2O (approx 50 mL) to obtain the product as colourless plates (1.08 g, 36%). Mpt. (Et2O) 167-168 °C (literature 169 °C doi:10.1002/jhet.5570190620 they ref: 167-168 L. Claisen, Ann. Chem., 295, 1897 301.) The aqueous layer and recrystallisation mother liquours were concentrated under reduced pressure. The resulting residue was refluxed in EtOH then filtered hot. The filtrate was cooled and the precipitate filtered to obtain further product (1.18 g, 39%; 74% total).

TLC (30% EtOAc/hexane) visualised with UV and vanillin:
TLC 4 hours
TLC 165 mins


NMR:
1H NMR


See also:
Synthesis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 43-1)

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

InChi:
Starting materials: InChI=1S/C13H14N2O2/c1-3-17-13(16)12-9-14-15(10(12)2)11-7-5-4-6-8-11/h4-9H,3H2,1-2H3
Product: InChI=1S/C11H10N2O2/c1-8-10(11(14)15)7-12-13(8)9-5-3-2-4-6-9/h2-7H,1H3,(H,14,15)
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21st March 2012 @ 06:36
Product obtained in 96% yield overall.

===

Synthesis of pyrazole analogue core from ethyl acetoacetate, dimethylformamide dimethyl acetal and phenylhydrazine.

PMY43-1.png

Reaction Start Time: 08.35 22/03/12
Ethyl acetoacetate (2.0 mL, 15.7 mmol, 1 equiv.) and dimethylformamide dimethyl acetal (2.2 mL, 16.6 mmol, 1.06 equiv.) were mixed then heated to 100 °C. The mixture turns yellow to orange. After 20 minutes, the reaction is a red solution, refluxing at <80 °C, indicating possible evolution of MeOH. After 50 minutes (<=90 °C) reaction is a bright red oil, TLC shows consumption of ethyl acetoacetate. Reaction cooled to room temperature and concentrated under reduced pressure. The red oil was dissolved in EtOH (20 mL). Phenylhydrazine (1.5 mL, 15.7 mmol, 1 equiv.) in EtOH (20 mL) was added dropwise to the reaction over 5 minutes. The reaction was then heated to reflux. After 2 hours TLC shows formation of new product and consumption of phenylhydrazine, the reaction was allowed to cool to room temperature. The mixture was concentrated under reduced pressure. The resulting oil was dissolved in DCM (40 mL) and washed with water (20 mL), 10% NaHCO3 (20 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil (3.46 g, 96% over 2 steps).

TLC (20% EtOAc/hexane) visualised with UV and vanillin:
TLC 50 minutes
TLC stage 2, 2 hours


NMR:
1H NMR intermediate
1H NMR crude
1H NMR crude PDF


Risk and Hazard Assessment:
RA


Reference:
doi:10.1002/jhet.5570240634

InChi:
Starting materials: InChI=1S/C6H10O3/c1-3-9-6(8)4-5(2)7/h3-4H2,1-2H3 AND InChI=1S/C5H13NO2/c1-6(2)5(7-3)8-4/h5H,1-4H3
Product: InChI=1S/C13H14N2O2/c1-3-17-13(16)12-9-14-15(10(12)2)11-7-5-4-6-8-11/h4-9H,3H2,1-2H3
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21st March 2012 @ 00:20
Product probably obtained.

===

Synthesis of aryl pyrrole primary amide from pyrrole acid chloride PMY 32-3 and gaseous ammonia.

PMY42-1.png

Reaction Start Time: 15.40 21/03/12
PMY 32-2 (98 mg, 0.39 mmol, 1 equiv.) was stirred in anhydrous THF (5 mL).hexane switched to THF as the acid chloride was made into a stock solution before reaction for PMY 11-6. Anhydrous ammonia was bubbled through the solution for 5 minutes via a balloon. A pale precipitate forms leaving the reaction a milky suspension. After 1 hours, TLC shows reaction complete. The reaction was concentrated under a stream of nitrogen. The residue was stirred with DCM (20 mL) and water (10 mL) then separated. The aqueous was extracted once more with DCM (10 mL) and the combined organic extracts washed with brine then dried (MgSO4) and concentrated under reduced pressure to a pale yellow solid (94 mg, 104%). 1H NMR consistent with expected product but poorly shimmed.

TLC (66% EtOAc/hexane) visualised with UV and vanillin:
TLC 1 hour


NMR:
1H NMR crude
1H NMR PDF


See Also:
Synthesis of pyrrole acid chloride (PMY 32-3)

Risk and Hazard Assessment:
RA


InChi:
Starting Material: InChI=1S/C13H11ClFNO/c1-8-7-12(13(14)17)9(2)16(8)11-5-3-10(15)4-6-11/h3-7H,1-2H3
Product: InChI=1S/C13H13FN2O/c1-8-7-12(13(15)17)9(2)16(8)11-5-3-10(14)4-6-11/h3-7H,1-2H3,(H2,15,17)
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Attached Files