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24th October 2012 @ 06:25
Conversion of carboxylic acid PMY 59-3 to the primary amide using EDC and ammonium hydroxide as for PMY 60-3.

PMY60-3.png

Reaction Start Time: 17.05 24/10/12
PMY 59-3 (102 mg, 0.34 mmol, 1 equiv.) was stirred in DCM (7 mL, 0.05M). Partial solution. EDC.HCl (85 mg, 0.44 mmol, 1.3 equiv.) and HOBt (approx 4 mg) was added. EDC.HCl dissolves quickly. After 10 mins, clear solution with some needles. After 20 minutes, 28% NH4OH (1 mL) was added and the reaction left to stir. After overnight stirring, saturated NH4Cl(aq) was added. The layers were separated and the aqueous layer extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated to a pale yellow solid (113 mg). 1H NMR shows multiple products, peaks close to SM and PMY 60-3; inconclusive. Purified by chromatography on silica (5% MeOH, 1% NH4OH/DCM) gave slightly yellow solid (84 mg). 1H NMR mainly consistent with PMY 60-3 and impurities. Further chromatography on silica (2-5% MeOH/DCM) gave an early running fraction and 2 other fractions, -A and -B, white solids.

TLC visualised with UV and vanillin
TLC crude MeOH/DCM
TLC column 2

10% MeOH/DCM

TLC crude MeOH/NH4OH/DCM

10% MeOH/1% NH4OH/DCM

NMR:
1H NMR crude
1H NMR column 1


See Also:
Hydrolysis of PMY 58-3 methyl ester (PMY 59-3)
Conversion of oxazole carboxylic acid to primary amide (PMY 60-3)
EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Conversion of PMY 59-2-B oxazole carboxylic acid to primary amide (PMY 60-2)
Synthesis of N-p-trifluoromethyl-phenyl analogue of TCMDC-123812 (PMY 25-1)

Risk and Hazard Assessment:
As for: Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
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24th October 2012 @ 03:52
Product obtained in 64% yield.

===

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

PMY59-1.png

Reaction Start Time: 12.30 24/10/12
PMY 58-3 (240 mg, 0.76 mmol, 1 equiv.) was dissolved in hot methanol (15 mL). 5M NaOH(aq) (4 mL) was added and the reaction stirred at room temperature. After 2 hours, reaction not complete. 3 pellets of NaOH added and the mixture heated to reflux briefly then cooled. After 30 minutes, reaction complete. The mixture was acidified using 6M HCl and cooled in a salt/ice bath. Pale yellow needle crystals form. Filtered and washed with water then dried (146 mg, 64%).

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


NMR:
1H NMR


See also:
Cyclodehydration of carboxamide PMY 67-1 (PMY 58-3)
Hydrolysis of PMY 58-2 methyl ester (PMY 59-2)

Risk and Hazard Assessment:
As for Hydrolysis of Ethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (PMY 8-2)
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19th October 2012 @ 01:50
Reaction successful, 51% yield over 2 steps. Product progressed to acid in PMY 59-3

===

Cyclodehydration of PMY 67-1 using XtalFluor-E in 1,2-DCE and subsequent oxidation to the oxazole.

PMY58-1.png

Reaction Start Time: 11.40 19/10/12
PMY 57-1 (509 mg, 1.52 mmol, 1 equiv.) was stirred in 1,2-DCE (20 mL). XtalFluor-E (697 mg, 3.04 mmol, 2 equiv.) was added and the reaction heated to 90 °C. After 80 minutes, TLC shows reaction essentially complete. The reaction was cooled to room temperature and saturated K2CO3(aq) and water (1:1, 20 mL) were added. After stirring vigorously for 5 minutes, the layers were separated and the aqueous layer extracted with DCM (3 × 10 mL). The combined organic layers were washed with water, brine then dried (MgSO4) and concetrated under reduced pressure to a brown oil (563 mg, 117% of theory). Purified by chromatography on silica (20-50% EtOAc/hexane) to give pale brown viscous oil (360 mg, 74% of theory). Consistent with intermediate obtained in PMY 58-1 + residual solvents.

09.40 23/10/12 Intermediate was dissolved in DCM (10 mL) and DBU (0.51 mL, 3.4 mmol, 3 equiv.) and bromotrichloromethane (0.34 mmol, 3.4 mmol, 3 equiv.) were added. The mixture was heated to reflux. After 80 minutes, TLC shows formation of product and SM. Reaction not complete after 7 hours. Left overnight. Reaction not complete by TLC. Concentrated to viscous brown oil which was purified by chromatography on silica (10-18% acetone/hexane) to give a white crystalline solid (244 mg, 68%). Some SM and mixed fractions also obtained.

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC 80 mins
TLC stage 2


NMR:
1H NMR intermediate
1H NMR step 2


See also:
Coupling of pyrrole acid and serine methyl ester (PMY 67-1)
Scaled-up cyclodehydration of carboxamide PMY 57-2 (PMY 58-2)
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:
See: Cyclodehydration of carboxamide PMY 57-1 (PMY 58-1)
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17th October 2012 @ 03:34
Product obtained in 62% yield.

===

Coupling of pyrrole acid OSM-S-4 and serine methyl ester using EDC/HOBt.

PMY67-1.png

Reaction Start Time: 14.20 17/10/12
Acid OSM-S-4/JRC 2-1 (2.00 g, 8.6 mmol, 1 equiv.) was stirred at room temperature in DCM (60 mL) under nitrogen. Dark solution. HOBt (0.12 g, 0.9 mmol, 0.1 equiv.) and EDC.HCl (1.97 g, 10.3 mmol, 1.2 equiv.) was added followed by DIPEA (3.6 mL, 20.8 mmol, 2.4 equiv.). After 10 minutes, DL-serine (1.47 g, 9.4 mmol, 1.1 equiv.) was added. Mostly in solution, a few clumps. After 40 minutes, the reaction is a solution. TLC at 1 hour shows SM, non-polar impurity [as seen in previous couplings... but not observed in Alice's hydrazine couplings. Maybe because she doesn't use a base?] and new products. After overnight at room temperature NH4Cl was added and the mixture then 1M HCl added until pH 1. The layers were separated and the organic layer washed with water (3 × 20 mL), Na2CO3 (20 mL), water (3 × 20 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a brown foam (2.67 g). Purification by chromatography on silica (2-5% MeOH/DCM) gave tan foam (1.79g, 62% of theory).

TLC (5% MeOH/DCM) visualised with UV and vanillin:
TLC 1 hour


NMR:
1H NMR


See also:
EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Conversion of oxazole carboxylic acid to primary amide (PMY 60-3)
Scaled-up coupling of pyrrole acid chloride and serine methyl ester (PMY 57-2)

Risk and Hazard Assessment:
As for: Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
Linked Posts
Attached Files
16th October 2012 @ 04:21
1H NMR and LC/MS hint toward product. Not quite clean enough.

===

Conversion of recovered carboxylic acid PMY 60-2 to the primary amide using EDC and ammonium hydroxide.

PMY60-3.png

Reaction Start Time: 14.10 16/10/12
PMY 60-2 (15 mg, 0.05 mmol, 1 equiv.) was stirred in DCM (5 mL) under nitrogen at room temperature. Reaction was a hazy solution. EDC.HCl(12 mg, 0.06 mmol, 1.2 equiv.) and HOBt (approx 1 mg) was added and the reaction stirred. After 20 minutes, 28% ammonium hydroxide solution (1 mL) was added. After 3 hours, LC/MS shows conversion to amide.

LC/MS:
Crude LC/MS


NMR:
1H NMR crude


See Also:
EDC Coupling of Pyrrole Carboxylic acid with Hydrazine Hydrate (AEW 14-2)
Conversion of PMY 59-2-B oxazole carboxylic acid to primary amide (PMY 60-2)
Synthesis of N-p-trifluoromethyl-phenyl analogue of TCMDC-123812 (PMY 25-1)

Risk and Hazard Assessment:
As for: Synthesis of N-Phenyl analogue of TCMDC-123812 (PMY 23-1)
Linked Posts
Attached Files