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30th November 2012 @ 22:28
Mnr: MNR61-70
MNR65_scheme.png
MNR65-1_table.PNG

Hazard Assessment
HIRAC MNR65.pdf


Procedure
MNR64-1 (5.20 g, 37.1 mmol) and potassium carbonate (12.8 g, 92.8 mmol) were dissolved in methanol (105 mL) and cooled to 0°C. Bromine (3.8 mL, 74.2 mmol) was added dropwise and the reaction mixture was stirred at 0°C for 30 minutes then was allowed to warm to room temperature and stirring was continued for a 2 hours during which time the reaction went from a dark red/brown colour to a milky white colour. Large amounts of precipitate/potassium carbonate were also present during the reaction. The reaction mixture was concentrated and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM. The organic phases were combined and dried over magnesium sulphate, filtered and concentrated to give the crude as a clear oil (6.738 g, 33.3 mmol, 90%). NMR of the crude showed a complex mixture but the signal for the proton at the 4 position was observed. TLC of the worked up crude only showed one spot running several solvent systems so it was decided to follow the prep and carry on to the hydrogenation set without further purification.

NMR
mnr65-1_crude_1H.pdf
mnr65-1_crude_13C.pdf
mnr65-1_conc.zip
Attached Files
29th November 2012 @ 22:44
Mnr: MNR61-70
An alternative route to unsubstituted aryl-pyrroles avoidung the use carbon monoxide and the regioselective problems shown in MNR63-1
alt_route_unsubstituted_pyrrole.png

See - 10.1021/jo00879a010 reaction 38 to 39

- WO2009044162 (A1) ― 2009-04-09 pages 192 ans 193

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MNR64_scheme.png
MNR64-1_table.PNG

Hazard Assessment

Procedure
3-furoic acid (5.0 g, 44.6 mmol) was suspended in ethanol (30 mL) and concentrated sulfuric acid (0.5 mL) was added drop wise. The reaction mixture was then refluxed for 6 hours at which point TLC showed complete consumption of starting material. The reaction was allowed to cool to room temperature and was quenched with a saturated solution of sodium bicarbonate (50 mL) and was extracted with EtOAc (2 x 50 mL). The orangic layers were combined and washed with brine (30 mL), dried over MgSO4 and concentrated under reduced pressurebto give the crude as a brown liquid.

** It should be noted that the product had a boiling point below 100°C and ideally I should have extracted with DCM. Some product was lost on the buchi as I could see it.

The crude (5.497 g, 39.23 mmol, 88%) was taken onto the next step without an further purification.

TLC
In 100% EtOAC
SANY0025.JPG


NMR
crude NMR showed mostly product with slight traces of some other CO2Et compound.
mnr64-1_crude_1H.pdf
mnr64-1_crude_13C.pdf
mnr64-1_conc.zip
Attached Files
29th November 2012 @ 22:32
Mnr: MNR61-70
A seemingly efficient route to unsubstituted aryl-pyrroles would involve the use of carbon monoxide. The availability of this due to it classification as a chemical weapon and it's cost has forced me to look for alternative routes.

CO_route.png

New synthesis of 3-formylpyrrole Synthesis (1973), 422-3.

The first possibility I thought of was via the Vilsmeier approach. This is far from perfect as the Vilsmeier step may be favoured at the 2 position rather than the preferred 3 position. Also, there's a chance of the acid chloride reacting at the 2 position.

vilsmeier_route.png

10.1016/j.tetlet.2006.11.050

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MNR63-1.png
MNR63-1_table.PNG

Hazard Assessment

Procedure
To a mixture of pyrrole (3.11 mL, 44.9 mmol), iodobenze (5.0 mL, 44.9 mmol), CuI (0.427 g, 2,24 mmol), Bu4NBr (0.723 g, 2.24 mmol) and NaOH (3.6 g, 89.7 mmol) under argon was added toluene (30 mL). The reaction mixture was vigorously refluxed for 17 hours.

On cooling to room temperature,
saturated NH4Cl solution (50 mL) was added and the
organic layer was extracted with EtOAc (3·50 mL). The
combined organic layers were washed with brine (50 mL),
dried over MgSO4, filtered and concentrated under
reduced pressure. The residue was purified by flash column
chromatography to afford the N-arylated product.
Attached Files
26th November 2012 @ 04:30
Mnr: MNR61-70
EDC Coupling of PMY59-3 with Ammonium Hydroxide to give MNR62-1

See - Synthesis of AEW16-1
- Synthesis of MNR52-1
Carbodiimide couplings

MNR62_scheme.png
MNR62-1_table.PNG

Hazard Assessment
HIRAC MNR54.pdf


Procedure

reaction on at 300pm 26/11/12

EDCI (0.027, 0.14 mmol) and HOBt (0.002 g, 0.01 mmol) were added to a solution of PMY59-3 (0.035 g, 0.12 mmol) in DCM (2 mL) and the mixture was stirred for 20 minutes, during which time it became a clear solution. Ammonium hydroxide(28%, 0.1 mL) was added and the reaction and iy turned a cloudy white colour and the mixture was stirred at room temperature.

After stirring overnight the TLC still showed signs of starting material but it was decided to work the reaction up. It was quenched with sodium bicarbonate (10 mL) and extracted with DCM (3 x 10 mL), dried over MgSO4, filtered and concentrated to give a brown oil (0.105 g)
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Attached Files
21st November 2012 @ 22:00
AEW%2023-1.png

N.B. Heating in sealed vials, take heed of HIRAC and cautions outlined in reaction procedure

AEW 5-2 (87 mg, 0.3 mmol, 1 equiv.) and InBr3 (52 mg, 0.15 mmol, 0.5 equiv) were weighed into a mL screw cap vial containing a magnetic stirrer. The vials were flushed with Ar and sealed. Freshly distilled CHCl3 (1.5 mL) and then Et3SiH (0.95 mL, 6 mmol, 20 equiv.) were added under an atmosphere of Ar. The sealed vials were placed in an pre-heated aluminium heating block and left to stir at 60 ˚C. Blast shield was installed at the front of the heater stirrer plate. Reaction mixture turned from colourless suspension to orange solution on heating. After 6 hours, the reaction was stopped and allowed to cool. Water (10 mL) was added and the reaction mixture stirred at room temperature for 30 minutes until the orange colour had disappeared. Extracted into DCM, dried over MgSO4, filtered and evaporated to yield an orange solid (50 mg). 1H NMR shows trace of product and LCMS shows correct mass for product. Will attempt purification by HPLC.

LCMS and Crude NMR:
AEW 23-3 6 hours.zip
AEW 23-3 6HOURS.pdf
AEW23-3 LCMS Trace.pdf


Reaction mixture after 6 hours:
AEW 23-3 reaction mixture.jpg


Reaction mixture after stirring with water for 30 minutes:
AEW 23-2 after 30 mins stirring with water.jpg


Hazard and Risk Assessment:
HIRAC AEW 23-1.pdf

Safe set-up:
Apparatus.jpg


Reference:
DOI: 10.1021/jo070814z

See Also:
Reduction of 2-amino-2-oxoethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (AEW 23-1) and Reduction of 2-amino-2-oxoethyl 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole-3-carboxylate (AEW 23-2)
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