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29th February 2012 @ 03:37
Synthesis of (Z)-2-((4-fluorophenyl)imino)thiazolidin-4-one (PMY 40-1) from rhodanine, ethyl bromoacetate and 4-fluoroaniline. Reference contains an error between text and experimental, therefore also present in SciFinder. Literature experimental procedure omits alkylation of sulphur, prior to subsitution by the aniline.

PMY40-2.png

Reaction Start Time: 14:10 29/02/12
Rhodanine (500 mg, 3.75 mmol, 1 equiv.) was stirred in IPA (5 mL). Does not dissolve on brief heating. Triethylamine (0.58 mL, 4.13 mmol, 1.1 equiv.) was added and the mixture heated to 60 °C. After 5 minutes, the reaction was an orange solution. Reaction was cooled slightly and ethyl bromoacetate (0.46 mL, 4.12 mmol, 1.1 equiv.) added, reaction turns red and a precipitate forms (<5 mins). Reaction was heated to 80 °C. After 1 hours 20 mins, rhodanine consumed. 4-fluoroaniline (0.39 mL, 4.12 mmol, 1.1 equiv) was added portionwise to the hot reaction. After 2 hours, reaction was allowed to cool. After a further 16 hours, the reaction was a thick brown slurry. TLC shows reaction complete. IPA (10 mL) added and stirred for 5 minutes to thin the slurry, then filtered to obtain a brown/grey powder. Recrystallised from hot IPA/water to obtain dark tan needles (0.85 g, 107% of theory). Poorly soluble in CDCl3 but 1H NMR appears to show CH2 and 4 × aryl-H. Requires DMSO NMR.

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 1 hour 20
TLC stage 2, 1 hour
TLC stage 2, 18 hours

Stage 2:left spot is rhodanine for comparison, top spot is intermediate seen in first plate (limiting reagent for stage 2).

NMR:
1H NMR CDCl3


Reference:
doi:10.1016/j.bmc.2010.05.073

Risk and Hazard Assessment:
As for Synthesis of (Z)-2-((4-fluorophenyl)imino)thiazolidin-4-one (PMY 40-1), additional risk of lachromator and toxic ethyl bromoacetate.
Attached Files
28th February 2012 @ 05:35
TLC did not show significant amounts of new product. Repeated in PMY 40-2.
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Synthesis of (Z)-2-((4-fluorophenyl)imino)thiazolidin-4-one (PMY 40-1) from rhodanine and 4-fluoroaniline.

PMY40-1.png

Reaction Start Time: 17.00 28/02/12
Rhodanine (500 mg, 3.75 mmol, 1 equiv.) was stirred in IPA (5 mL). Does not dissolve on brief heating. Triethylamine (0.58 mL, 4.13 mmol, 1.1 equiv.) was added and the mixture heated to 60 °C. After 5 minutes, the reaction was a solution. 4-fluoroaniline (0.39 mL, 4.13 mmol, 1.1 equiv.) was added. After 16 hours at 60 °C the reaction was cooled. No obvious precipitate. TLC shows starting material and streaking. The reaction is very dark due to starting aniline (essentially black). Water was added and a precipitate forms. Filtered to a tan solid (small quantity).

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 16 hours


Reference:
doi:10.1016/j.bmc.2010.05.073

Risk and Hazard Assessment:
Risk Assessment
Linked Posts
Attached Files
28th February 2012 @ 04:14
Starting material recovered (90%) cleaner than original.

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Reduction of the un-substituted near-neighbour PMY 14-4 to avoid the deacetylation seen in PMY 36-2.

PMY39-1.png

Reaction Start Time: 14.50 28/02/12
PMY 14-4 (100 mg, 0.25 mmol, 1 equiv.) was stirred in acetonitrile (10 mL, slurry). Material did not dissolve on heating to reflux. MeOH (approx. 5 mL) was added. Dissolved on heating to reflux, precipiated on cooling to room temperature (not completely). Sodium borohydride (approx 50 mg, 1.3 mmol, 5 equiv.) was added, slight exotherm and bubbling observed. After 10 minutes bubbling had ceased, reaction heated briefly to reflux. On cooling, the reaction remained as a solution. TLC 1.5 hours, shows no reaction. Further sodium borohydride (approx 50 mg) was added and the reaction heated to 60 °C. After 20 hours, TLC shows no reaction, yellow colour remains. Water (10 mL) and EtOAc (20 mL) added. The layers separated. The organic layer was washed with water (2 × 10 mL), brine and dried (MgSO4) then concentrated under reduced pressure to a yellow powder (90 mg). 1H NMR shows very clean SM, cleaner than original PMY 14-4. Material to be used for biological testing.

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


NMR:
1H NMR


See also:
Reduction of 4-fluoro near-neighbour Michael-acceptor (PMY 36-2)
Synthesis of 4-Fluoro substituted near neighbour (PMY 14-4)

Risk and Hazard Assessment:
See: Reduction of 4-fluoro near-neighbour Micheal-acceptor (PMY 36-1) and Reduction of pyrrole-3-carbaldehyde using sodium borohydride (PMY 18-1)
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Attached Files
27th February 2012 @ 04:44
Reaction did not reduce the alkene of the product. The isolated material was mostly deacetylated product.

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Reduction of 4-fluoro near-neighbour Michael-acceptor (PMY 36-2) using sodium borohydride.

PMY36-2.png

Reaction Start Time: 15.30 EST 27/02/12
PMY 36-1 (40 mg, 0.09 mmol, 1 equiv.) was dissolved in acetonitrile (11 mL, just soluble). The solution was cooled in ice/water and sodium borohydride (30 mg, 0.79 mmol, 8.6 equiv.) was added as a solution in water (approx 3 mL) was added. The reaction was allowed to warm to room temperature. The bright yellow solution turns noticeably less coloured (30 minutes). Reaction allowed to stir overnight. After 18 hours, TLC shows reaction complete. Water (15 mL) added, no precipitation. Forms hazy solution when cooled in ice. Mixture was extracted with EtOAc (3 × 15 mL) and the extracts washed with brine and dried (MgSO4) then concentrated under reduced pressure to a yellow powder (35 mg). 1H NMR matches de-acetylated product (e.g PMY 14-1).

TLC (10% MeOH/DCM) visualised with UV and vanillin:
TLC 18 hours, vanillin
TLC 18 hours, visible


NMR:
1H NMR


Risk and Hazard Assessment:
See: Reduction of 4-fluoro near-neighbour Micheal-acceptor (PMY 36-1) and Reduction of pyrrole-3-carbaldehyde using sodium borohydride (PMY 18-1)
Linked Posts
Attached Files
22nd February 2012 @ 03:07
NMR showed disappearance of pyrrole-H, did not reduce alkene to a significant degree.

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Reduction of 4-fluoro near-neighbour Micheal-acceptor PMY 35-1 by hydrogenation.

PMY36-1.png

Reaction Start Time: 15.10 EST 22/02/12
10% Palladium on charcoal (approx. 20 mg) was stirred in EtOH (2 mL) at 0 °C under an inert atmosphere. PMY 35-1 (100 mg, 0.23 mmol, 1 equiv.) was suspended in EtOH (16 mL, partial solution) and added to the catalyst suspension. The reaction was placed under a hydrogen atmosphere (balloon) and the reaction allowed to warm to room temperature. TLC shows new product and SM at 1 hour. No change after 18 hours by TLC. Hydrogen was purged from the reaction (nitrogen). The reaction was filtered through celite and the filtrate concentrated under reduced pressure.

TLC visualised with UV and vanillin:
TLC 1 hour, 50% EtOAc/hexane
TLC 1 hour, 10% MeOH/DCM


NMR:
1H NMR


Reference:
Patent: WO2009137133 (A2)

Risk and Hazard Assessment:
Risk Assessment
Linked Posts
Attached Files