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24th October 2012 @ 05:07
Cyclodehydration of serine methyl ester coupled pyrazole core MJT5-1 using XtalFluor-E in 1,2-DCE and subsequent oxidation to oxazole using bromotrichloromethane and DBU.

3579.png

Reaction Start time 1040 25/10/2012
MJT6-1 (442 mg, 1.37 mmol, 1 equiv.) was stirred in 1,2-dichloroethane (20 mL) giving a colourless solution. XtalFluor-E (640 mg, 2.8 mmol, 2 equiv.) was added and the mixture heated to reflux at 90°C under a nitrogen atmosphere.

After 40 minutes TLC showed consumption of SM and formation of a new product of higher Rf than SM. The reaction is now a dark brown solution, it was allowed to cool to room temperature before adding a solution of Na2CO3 (1:1 saturated soln/water, approx 30 mL). The reaction was stirred for 10 minutes and then separated.
The aqueous layer was washed with DCM (3 x 20 mL) and the combined organic extracts washed with brine (approx 20 mL) before drying over anhydrous MgSO4 and concentration to give the intermediate ( 0.4655g, 1.53 mmol, 112% of theory yield) as a viscous dark brown oil.
TLC of worked up product again showed only one spot. NMR analysis is consistent with expected product but with solvent peak at 3.731 ppm (1,2-DCE) and at 7.26 ppm (DCM). ca 50 mg of intermediate is retained for characterisation.

1555 25-10-2012
Intermediate (0.4013 g, 1.32 mmol, 1 equiv.) is dissolved in DCM (15 mL) to give a brown solution. Bromotrichloromethane (0.39 mL, 3.96 mmol, 3 equiv.) and DBU (0.59 mL, 3.96 mmol, 3 equiv.) are added and the reaction stirred under a nitrogen atmosphere. After 45 minutes, TLC showed consumption of starting materials and formation of a product with a higher Rf value than SM as well as another product of much lower Rf. The reaction is left in the freezer overnight.

1400 26-10-2012
The reaction mixture is concentrated to a viscous dark brown oil (ca. 1.5 g, 375 % theory yield - excess caused by residual BrCCl3 and DBU). Column chromatography (acetone / hexane, 5%; 10%) is used to isolate MJT6-1 as a white solid (ca. 0.4 g, '101%'), NMR consistent with expected structure but with some contaminant signals. This columned product is left in the freezer over the weekend.

Both product and intermediate are novel compounds

TLC (10% MeOH / DCM) with UV visualisation followed by UV staining

TLC cyclisation step
TLC oxidation step


Hazard assessment form
updated hirac


References

M. Pouliot, L. Angers, J. Hamel & J. Paquin, Synthesis of 2-oxazolines and related N-containing heterocycles using [Et2NSF2]BF4 as a cyclodehydration agent. Tetrahedron letters. 53 (2012), 4121-4123.

Cyclodehydration of carboxamide PMY 67-1 (PMY 58-3)

EDC Couplng of pyrazole carboxylic acid MJT 3-2 with serine methyl ester (MJT 5-1)
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21st October 2012 @ 08:18
Coupling of the recrystallised pyrazole carboxylic acid MJT 3-2 with serine methyl ester using N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and hydroxybenzotriazole.

3589.png

Reaction start time: 1510 22-10-2012

MJT 3-2 (1.257 g, 5.7 mmol, 1 equiv.) was stirred in DCM (40 mL), cloudy solution, kept under nitrogen atmosphere. EDCI (1.20 g, 6.3 mmol, 1.1 equiv.) and HOBt (0.085 g, 0.63 mmol, 0.11 equiv.) were added. DIPEA (2.2 mL, 12.6 mmol, 2.2 equiv.) was added, insoluble at first. Solution stirred for ten minutes and DIPEA dissolved. Serine methyl ester hydrochloride (0.977 g, 6.3 mmol, 1.1 equiv.) to give a colourless solution. Mixture stirred overnight at room temperature.

1030AM 23-10-12.
After 19 hours mixture is a colourless solution with some white solid stuck to sides of vessel. TLC shows some starting material (pyrazole carboxylic acid) remains and formation of a product slightly more polar than this starting material as well as multiple more polar products.
NH4Cl (20 mL) is added to the reaction mixture and then HCl (1M) is added until solution is pH 1. The organic layer was then extracted and washed with water (3 x 20 mL), Na2CO3 (20 mL), water (3 x 20 mL) and finally brine (20 mL) before being dried over MgSO4 and concentrated to a white foam (0.5492 g). TLC analysis shows no SM remains and that three products are present, least polar of highest intensity under UV. NMR analysis consistent with expected product but with minor impurities.

12PM 24-10-12
Crude product is purified by column chromatography (5%; 10% MeOH / DCM) to give MJT 5-1 as a white foam (0.44 g, 1.44 mmol, 25%). NMR analysis consistent with expected product.
ca. 50 mg is retained for characterisation.
This is a novel compound

TLC (10 % MeOH / DCM) visuallised with UV then vanillin stain
before workup
TLC after workup


NMR
nmr data crude
crude material NMR pdf


Hazard and risk assessment
HIRAC MJT5-1.pdf


References

EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Hydrolysis of Ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MJT 3-2)
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8th October 2012 @ 04:48
Hydrolysis of the pyrazole core ester to carboxylic acid under basic conditions.

3124.png

Reaction Start Time: 1410, 08-10-2012
MJT2-2 (2.267 g, 9.1 mmol, 1 equiv.), a yellow oil, was dissolved in ethanol (14 mL) and sodium hydroxide (13 mL, 5M, 64 mmol, 7 equiv.) was added. The mixture was heated to reflux at 100 °C. TLC analysis showed reaction completed after 30 minutes. The reaction was left to cool to room temperature and then cooled in ice before HCl (8M) was added until pH1 was reached. The pale yellow solid precipitate was collected by filtration and recrystallised from Et2O (ca. 80 mL) to give MJT3-2 as white needles (1.26 g, 5.7 mmol, 63 %). The aqueous washing was concentrated to give MJT3-2 crude (ca. 400 mg) though this was not used in further reactions.

TLC (30% EtOAc/hexane) visualised with UV and vanillin:
TLC 50 minutes MJT3-2


Reference
Hydrolysis of Ethyl 1-(4-fluorophenyl)-5-methyl-1H-pyrazole-4-carboxylate (MJT 3-1). Hydrolysis of ethyl 5-methyl-1-phenyl-1H-pyrazole-4-carboxylate (PMY 44-1)

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HIRAC
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4th October 2012 @ 00:18
Repeat of synthesis of fluoro derivative of the pyrazole analogue core from ethyl acetoacetate, dimethylformamide dimethyl acetal and 4-fluorophenylhydrazine.

3329.png

Reaction Start Time: 10:45 04/10/12
Dimethylformamide dimethyl acetal (2.0 mL, 15.9 mmol, 1 equiv.) was added to ethyl acetoacetate (2.0 mL, 15.9 mmol, 1 equiv.) with stirring under a nitrogen atmosphere.The 2 colourless solutions combined to give a yellow solution. The reaction mixture was heated to 100 °C and refluxed. After 90 minutes TLC showed the reaction had gone to completion. 4-fluorophenylhydrazine (2.00 g, 15.9 mmol, 1 equiv.) was prepared from the hydrochloride salt, as a brown oil which was dissolved in ethanol (20 mL) and added dropwise to the reaction mixture which was heated to 90 °C and refluxed for 120 minutes. TLC showed consumption of 4-fluorophenylhydrazine and that some of the intermediate remained unreacted (spot on baseline), this is due to loss of 4-fluorophenylhydrazine during the salt break. The reaction was worked up by removing solvent, dissolving in EtOAc (30 mL) and then washing with water (3 x 15 mL), NaHCO3 (15 mL), brine (10 mL) and then drying over MgSO4 to give crude product (3.1151 g, "12.6 mmol", "79%") as a brown oil. Column purification was completed to give MJT2-2 (2.27 g, 9.2 mmol, 58%). NMR showed that the sample was the ester and that there were minor impurities (chemical shift of 1.64 ppm), these were taken through to the hydrolysis (MJT3-2) and will be removed during the subsequent recrystallisation.

Risk and Hazard Assessment form
HIRAC


TLC (20% EtOAc / hexane) with UV analysis then vanillin staining
TLC first step
TLC second step


NMR
NMR analysis
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12th September 2012 @ 05:29
Conversion of carboxylic acid MJT to the acid chloride and subsequent coupling with serinamide hydrochloride.

3155.png

reaction start time 0900AM 17-09-2012

The carboxylic acid (256 mg, 1.16 mmol, 1 equiv.) was stirred in PhMe (3 mL) under nitrogen. Insoluble, the mixture is a white slurry. Thionyl chloride (0.19 mL, 25.6 mmol, 2.2 equiv.) then DMF (0.1 mL, catalyst) were added, on adding DMF a white gas appeared to exit the syringe. The reaction was left to stir at room temperature for 4 hours. The reaction is now a cream slurry. The solvent is removed to give a white solid, the acid chloride, which is dissolved in the minimum amount (1.5 mL) of THF to give a yellow solution.

In a separate vessel, serinamide hydrochloride (0.164 g, 1.16 mmol, 1 equiv.) is stirred with THF (10 mL), no dissolution despite heating and sonication of the mixture. This mixture is added dropwise to the acid chloride solution using a wide mouthed pipette (nitrogen atmosphere briefly disrupted). Subsequently diisopropylethylamine (0.68 mL, 3.84 mmol, 3.3 equiv.) is added dropwise and the mixture left to stir at room temperature over night, the serinamide is now dissolved (only a few rocks remain) and the reaction is a yellow solution. After 16 hours 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 over MgSO4 before being concentrated.
TLC

see also
Coupling of pyrazole PMY 44-1 with serine methyl ester (MJT 1-1), Coupling of pyrrole acid chloride and serine methyl ester (PMY 57-1)

Risk and Hazard Assessment:
HIRAC
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