TCMDC_ArylPyrrole

 

Product obtained in 89% yield.

===
Scale up of PMY 1-5 from 20 mmol to 100 mmol scale.



Experiment start time: 1751 EST 31/08/11
4-fluoroaniline (10.4 mL, 110 mmol, 1.1 equiv.) and 2,5-hexanedione (11.7 mL, 100 mmol, 1 equiv.) were heated to 110 °C (oil bath temp.). After 15 hours, reaction was cooled to room temp. Stirring stopped. After 20 minutes, no precipitation. a couple of crystals of PMY 1-5a were added resulting in instant precipitation. EtOH (15 mL) was added and the solid dissolved by heating to 45 °C with stirring. After dissolution (about 5 mins.) the mixture was allowed to cool slowly, reaction precipitated and set solid. Dissolved again and a premixed solution of EtOH (30 mL) and 10% citric acid (15 mL) were added and the reaction allowed to cool. The resulting crystals were filtered and washed with water approx (200 mL) to obtain the product as tan crystals (14.98 g, 79%) after drying under vacuum. A second crop of brown crystals (1.89 g, 10%) was obtained from the mother liquor. Total of 89% yield from 2 crops.

Risk and Hazard Assessment:
As for Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-2), except reaction carried out neat and on a larger scale. 5 fold increase from PMY 1-5. Ice bath on stand by if required on initial mixing.

See also:
Scale-up (20 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-5)
Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-4)
Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-3)
Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-2)
Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-1)

===

Pinnick oxidation of PMY 2-3 to the corresponding carboxylic acid.



Experiment start time: 1015 EST 01/09/11
Aldehyde PMY 2-3 (100 mg, 0.46 mmol, 1 equiv.), NaH₂PO₄ (0.44 g, 3.7 mmol, 8 equiv.) and 2,3-dimethyl-2-butene (0.55 mL, 4.6 mmol, 10 equiv.) were dissolved in THF/Water/t-BuOH (4:4:1, 10 mL). Emulsion forms on stirring, all solids dissolved. NaClO₂ ( 0.17 g, 1.8 mmol, 4 equiv.) was dissolved in THF/Water/t-BuOH (4:4:1, 2 mL) and added to the reaction. After 30 minutes at room temp, no reaction observed by TLC. At 2 hours 50 min, potential new overlapping spot (orange vs pink) or no reaction. After a further hour, EtOAc (40 mL) added and 2M HCl (10 mL). Separated and washed with further 1M HCl (3 × 15 mL), brine and dried (MgSO₄) then concentrated to a yellow oily solid (158 mg).

TLC (50% EtOAc/petrol, drops AcOH) visualised with UV and vanillin:

Left plate, 30 mins. Right plate, 2 hr 50 mins.

Mass Spectrometry (ESI +/-):
No mass ions consistant with SM or products were observed. 12.00 EST 08/09/2011

References:
http://dx.doi.org/10.1021/jm2001053
http://dx.doi.org/10.1016/j.bmcl.2010.10.079

See also:

• 
  

Oxone oxidation of Pyrrole-3-carbaldehyde PMY 2-3, to corresponding acid (PMY 3-4)
Sodium chlorite oxidation of Pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-3)
Oxidation of pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-2)
Oxidation of pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-1)


Risk and Hazard Assessment:
As for Sodium chlorite oxidation of Pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-3).

===

Oxidation of aldehyde to acid using Oxone (Potassium peroxymonosulfate).



Reactions start time: 1600 EST 30/08/11
PMY 2-3 (100 mg, 0.46 mmol, 1 equiv.) was dissolved in DMF (5 mL, 0.09 M). Oxone (105 mg, 0.69 mmol, 1.5 equiv.) was added. TLC at 60 mins and 16.5 hours show SM and a new (less polar?) product. Reaction a brown solution with a small amount of pale precipitate. Further Oxone (105 mg, 0.69 mmol, 1.5 equiv.) was added. After 2 hours, no change by TLC. 2M HCl (4 mL) added. Extracted with EtOAc (2 × 15 mL). Organics washed with 1M HCl (3 × 10 mL) and brine. Dried (MgSO₄) and concentrated to brown oil (121 mg).

TLC (50% EtOAc/petrol, drops AcOH) visualised with UV and vanillin:

Left plate: 60 minutes. Right plate: 16.5 hours.

Mass Spectrometry (ESI +/-):
No mass ions consistant with SM or products were observed. 11.44 EST 08/09/2011

References:
Travis, B. R.; Sivakumar, M.; Hollist, G. O.; & Borhan, B; Organic letters, 2003 5, 7, 1031-1034. doi:10.1021/ol0340078

Risk and Hazard Assessment:
As for Sodium chlorite oxidation of Pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-3) and Oxidation of pyrrole-3-carbaldehyde PMY 2-2, to corresponding acid (PMY 3-1) except using oxone and DMF.

Product obtained in 23% yield. Scale up resulted in decrease of yield.

===

Scale up of PMY 2-2 to 10.5 mmol scale.



Experiment start time: 1433 EST 29/08/11
DMF (5.0 mL) was stirred under a nitrogen atmosphere in an ice-bath. Phosphoryl chloride (1.18 mL, 12.7 mmol, 1.2 equiv.) was added and the reaction stirred for 35 minutes. Reaction now bright yellow. A solution of pyrrole PMY 1-5a (2.00 g, 10.5 mmol, 1 equiv.) in DMF (5 mL) was added dropwise over 3 minutes. After 45 minutes, rxn complete by TLC. Poured over ice 40 ml. pH adjusted to 11 (approx. 20% NaOH), filtered. Solid recrystallised from MeCN (5 mL) and water to obtain brown crystalline product (640 mg, 23%). No further precipitate from mother liquor on addition of excess water.

Poor yield due to Vilsmeier reagent intermediate formation or recryst? Carried out on a larger scale and more concentrated for addition of POCl₃, so may require slower addition.

¹H NMR Spectra


Hazard and Risk Assessment:
As for Scale up (3 mmol): Formylation of 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole (PMY 2-2).

===

Oxidation of PMY 2-2 using NaClO₂ in aqueous acetone in presence of sulfamic acid.



Reaction start time: 1450 EST 26/08/11:
PMY 2-2 (100 mg, 0.46 mmol, 1 equiv.) was dissolved in acetone (1 mL) at room temperature. sulfamic acid (89 mg, 0.92 mmol, 2 equiv.) in water (4 mL) was added. Precipitate formed. Water (40 mL) and acetone (4 mL) were added. After 20 minutes still not completely dissolved. Still no dissolution on further dilution (60 mL water). Reaction left over weekend at room temp. Colour darker orange (0800 EST 29/08/11). TLC shows trace SM and new products. Extracted with EtOAc (3 × 10 mL). Extracts washed with brine, dried (MgSO₄), and concentrated to brown solid (86 mg). Recrystallised from EtOH/water to obtain a pale brown crystalline solid (49 mg).

Mass Spectrometry (ESI +/-):
No mass ions consistant with SM or products were observed. 11.54 EST 08/09/2011

NMR Spectra:
Crude (red) and recrystallised (blue)


Colour change

Reaction at 30 minutes (left) and reaction at 55 hours (right).

References:

1. OrgPrepDaily
   
2. Colombo, L; Gennari, C.; Santandrea, M.; Narisano, E.; Scolastico, C; J. Chem. Soc., Perkin Trans., 1980, 136-140. doi: 10.1039/P19800000136
   

Risk and Hazard Assessment: