TCMDC_ArylPyrrole

See also: Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2) but with EDCI and HOBt.

Procedure:
Boc-Gly-OH (400 mg, 2.28 mmol, 1 equiv.), EDCI (524 mg, 2.74 mmol, 1.2 equiv.) and HOBt (30 mg, 0.22 mmol, 0.1 equiv.) were stirred in CH₂Cl₂ (20 mL) and stirred at room temperature for 15 minutes. 4-Aminoantipyrine (510 mg, 2.54 mmol, 1.1 equiv.) was added and the reaction mixture stirred overnight.

A saturated aqueous solution of NaHCO₃ was added and the the layers were separated and the aqueous layer was extracted with CH₂Cl_2. Combined organic layers were washed with water, brine and then dried (MgSO₄) to give an orange/brown oil. 

No NMR data recorded - inconclusive result.

Data:

TLC in 10% MeOH in CH₂Cl₂

Hazard and Risk Assessment:

See Coupling of Boc-Gly-OH and 4-aminoantipyrine (PMY 29-2)

AEW 81-1 (275 mg, 1.72 mmol, 1 equiv.), EDCI (395 mg, 2.06 mmol, 1.2 equiv.) and HOBt (23 mg, 0.17 mmol, 0.1 equiv.) were stirred in CH₂Cl₂ (15 mL) and stirred at room temperature for 15 minutes. 4-Aminoantipyrine (238, 1.49 mmol, 1.1 equiv.) was added and the reaction mixture stirred for 16 hours.

A saturated aqueous solution of NaHCO₃ was added and the the layers were separated and the aqueous layer was extracted with CH₂Cl_2. Combined organic layers were washed with water, brine and then dried (MgSO₄) to give a red/brown tar that didn't dissolve in NMR solvents.

Reaction abandonded.

Hazard and Risk Assessment

See AEW 64-1

Problems with product decomposing before HRMS result. Query biological results.

See also Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-1) and Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-2)

Procedure:

AEW (100 mg, 0.46 mmol, 1 equiv) was dissolved in anhydrous MeOH (4 mL) and AcOH (0.15 mL) was added. Pyrrolidine (44 mg, 0.05 mL, 0.3 mmol, 1.3 equiv) in anhydrous MeOH (1 mL) was added and the reaction mixture stirred at room temperature for 1h. Sodium cyanoborohydride (32 mg, 0.52 mmol, 1.1 equiv.) was added in two portions over two minutes and the reaction mixture stirred at room temperature for 12 h. Then volatiles removed in vacuo, residue treated with aqueous 1 M NaOH and extracted with DCM (x2). Organics washed with brine, drieed and then filtered and evaporated to yield a crude orange oil (160 mg).

Hazard and Risk Assessment:

See Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride in acidic conditions (AEW 12-1)

Repeat of Reductive amination of pyrrole aldehyde with crude PMY 53-2 (PMY 56-1)

AEW (100 mg, 0.46 mmol, 1 equiv.) and crude AEW 83-1 (75 mg) were dissolved in MeOH (5 mL) and acetic acid (0.13 mL) and stirred at room temperature for 1 h. Sodium cyanoborohydride (32 mg, 0.5 mmol, 1.1 equiv.) was added in 3 portions over 5 mins and stirred at room temperature overnight. Reaction complete by TLC.

MeOH removed in vacuo and then the crude orange oil treated with 1M NaOH (5 mL). The mixture was then extracted with DCM (2 x 10 mL). The organic extracts were washed with brine then dried (MgSO₄) and concentrated to give an orange oil.

Crude indicated desired product - Purified by flash column (1-20% MeOH with 0.5% NH₃) no product recovered.

Data: (TLC, 5% MeOH in CH₂Cl₂₎

Hazard and Risk Assessment:

See Reductive amination of pyrrole aldehyde with crude PMY 53-2 (PMY 56-1)

Resynthesis of PMY 53-2 for characterisation. Pure SM obtained which should aid synthesis.

AEW 74-1 (330 mg, 1.85 mmol, 1 equiv.) and 10% Pd/C (50 mg, 15 wt%) were suspended in ethanol (12 mL) in EtOH was added to the catalyst suspension and the mixture hydrogenated in the high pressure tube overnight at 100 psi initial. Reaction mixture was stirred for 16.5 hours and the pressure had fallen to 70 psi by morning. 

Septum was pierced and the reaction mixture was filtered over Celite, washed with MeOH and evaporated to provide a very pale straw liquid which crystallised at the high vac. 270 mg recovered- indicative of reaction not being complete. Shown by ¹H NMR to be a 1:0.8 mixture of product and SM. To be resubmitted to the same reaction conditions at 5pm as hydrogen cylinder in use by UG lab.

Stirred for 4 further days at 100psi H₂ under the conditions outlined above and then the same work-up was performed.

Clear oil with white crystal flakes formed: NMR indicates complete reduction to the desired product with some impurities underneath the aliphatic signals. Decided to use crude in AEW 83-1.

Data:

Hazard and Risk Assessment: