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28th November 2011 @ 01:22
Synthesis of (2Z,5Z)‐5‐((1‐(4‐fluorophenyl)‐2,5‐dimethyl‐1H‐pyrrol‐3‐yl)methylene)‐2‐(phenylimino)thiazolidin‐4‐one from 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxaldehyde and 2-phenyliminothiazolidin-4-one

reactionscheme.png

Experiment start time: 13:50 EST 28/11/11
2-phenyliminothiazolidin-4-one (PMY 13-1) (178.2 mg, 0.927 mmol, 1.0 equiv.) was dissolved in ethanol (10 mL) and combined with piperidine (0.138 mL, 1.40 mmol, 1.5 equiv.). 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxaldehyde (LMW 4-1) (200.8 mg, 0.924 mmol, 1.0 equiv.) was dissolved in ethanol (5 mL) and added to the mixture, and the resulting clear brown solution was heated to 60 °C. After around 45 minutes the mixture was yellow and opaque. TLC at 4 hr 30 minutes showed almost complete disappearance of the aldehyde, and the mixture was removed from the heat and left overnight at room temperature. The following day the yellow precipitate was filtered off and dried under vacuum to give a yellow powder (269.2 mg, 74% yield). Mass spectrometry was consistent with the expected product. The product was recrystallized from ethanol to give a very fine, pale yellow powder (154 mg, 43% yield).

Data summary table:
Yield % Melting point °C 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 3-1 74 decomposes ~ 273Needs checking (H and C pdf, all NMR .zip) Needs checkingNAYes (pdf, .dx) ESI 374 M+H (pdf)


Comparison with literature:
Product is a known compound (CAS: 347315-65-5 or 1321816-74-3 depending on stereochemistry yet to be determined).

High resolution mass spectrometry:
HRMS (ESI (+)) Calcd. for [C22H19N3OSH+]: 374.1322, found: 374.1311.

Reference:
Method taken from this paper:
DOI: 10.1016

Product taken forward to:
Acetylation of unsubstituted arylpyrrole near neighbour analogue (ZYH 16-1)

TLC (10% EtOAc/petrol) visualised with UV and Vanillin:
TLC at 3 hr
TLC at 3 hr 45 min
TLC at 4 hr 30 min
TLC of product after filtration and drying
TLC of filtrate


Reaction mixture
reaction mix at 3 hrs


Hazard and risk assessment:
Hazard and risk assessment
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24th November 2011 @ 00:10
Vilsmeier Haack Synthesis of 2,5-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbaldehyde from 2,5-Dimethyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrrole
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Experiment Start Time: 15:30 EST 24/11/11
DMF (2 mL, 26 mmol, 10 equiv.) was stirred under a nitrogen atmosphere in an ice bath. Phosphoryl chloride (0.24 mL, 2.5 mmol, 1.2 equiv.) was added and the reaction stirred for 25 minutes. The mixture had a white haze. A solution of LMW 3-1 (500.9 mg, 2.1 mmol, 1 equiv.) in DMF (5 mL) was added dropwise over 2 minutes. After 5 minutes, the flask was removed from ice and the mixture stirred a further 55 minutes. TLC at 45 minutes showed the reaction to be complete. The reaction mixture was then poured on to ice (40 mL) and the pH adjusted with sodium hydroxide (20% aqueous solution). The addition went further than intended and a final pH of around 10 resulted. The mixture was then stirred overnight and in the morning pH was 5. pH was then adjusted to 11 using sodium hydroxide (20% aqueous solution) and the mixture bathed in a brine ice bath for 20 minutes. The product was filtered off and washed with a small amount of water then dehydrated under vacuum to give a fine, pale brown powder (509 mg, 91%). Recrystallization was attempted from acetonitrile then ethanol but neither was successful, and the solvent was removed under reduced pressure. NMR showed the product to be quite clean.

Data summary table:
Yield % Melting point 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 2-1 91 86-87Consistent (pdf, all NMR .zip) Consistent (pdf, multiplets)Yes (pdf)Yes (pdf, .dx) ESI 268 M+H (.pdf, .raw)


Comparison with literature:
The product is a known compound (CAS: 256529-25-6) but no experimental data are available. The H NMR and C NMR spectra are similar to predicted.

High resolution mass spectrometry:
HRMS (ESI (+)) Calcd. for [C14H12F3NONa+]: 290.0763, found: 290.0762.

NMR assignment:
1H NMR (CDCl3, 300 MHz): δ = 2.00 (s, 3H), 2.30 (s, 3H), 6.42 (s, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 9.90 (s, 1H) ppm. 13C NMR (CDCl3, 300 MHz): δ = 11.3 (1C), 12.8 (1C), 106.6 (1C), 122.5 (2C), 123.7 (q, J = 272.4, 1C), 126.9 (q, J = 3.6 Hz, 1C), 128.7 (2C), 130.8 (1C), 131.3 (q, J = 32.9 Hz, 1C), 138.4 (1C), 140.3 (1C), 185.4 (1C) ppm

Method taken from:
Vilsmeier Haack Synthesis of 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carbaldehyde (LMW 4-1)

Product taken forward to:
Synthesis of p-trifluoromethyl arylpyrrole based near-neighbour analogue (ZYH 6-1)
Scale up of preparation of 4-trifluoromethyl arylpyrrole based near neighbour (ZYH 6-2)

TLC (10% EtOAc/petrol) visualised with UV and Vanillin:
TLC at 45 min for first step

Left: starting material with DMF; centre: starting material and reaction mixture; right: reaction mixture.
TLC after reaction completion

Left: starting material with DMF; centre: starting material and product; right: product.

Hazard and risk assessment
risk assessment
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22nd November 2011 @ 23:04
Paal-Knorr synthesis of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole from 2,5-hexanedione and 3,5-bis(trifluoromethyl)aniline.

Reaction Scheme

Reaction start time: 14:35 EST 23/11/2011
2,5-hexanedione (2.9 mL, 25 mmol, 1 equiv.) was added to 3,5-bis(trifluoromethyl)aniline (3.9 mL,25 mmol, 1 equiv.) and heated to 80 °C on an oil bath. TLC at 1 hr showed no reaction, and heat was increased to 120 °C. TLC at 3hr showed minor formation of product, and the reaction was left overnight at 120 °C. In the morning appearance was dark brown and TLC showed reaction not complete. TLC at 22 hr and 26 hr showed the reaction to be still incomplete, and it was left to continue overnight. TLC at 42 hr showed the reaction still incomplete, and development of a new impurity, and the reaction was removed from the heat. The dark brown mixture was extracted with ethyl acetate (20 mL) and washed with citric acid (10%, 20 ml, then 5%, 20 mL) and water (20 mL) followed by brine (20 mL), then dried over magnesium sulfate and filtered. The solution was then concentrated under reduced pressure. The resulting dark brown liquid (6.97 g, 91% of expected mass) was cooled on a brine ice bath but did not crystallize and NMR showed the presence of impurities. The liquid was purified by chromatography on silica (2% ethyl acetate in hexane) to give pure, impure and remainder fractions. The pure fraction was a pale yellow oil (2.67 g, 35%) which did not crystallize and the impure fraction formed a dark brown gum (2.62 g, 34%; remainder was 20%, mass balance 89%).

Data summary table:
Yield Melting point 1H NMR 13C NMR19F NMR IR Mass spec
1-1 (pure) 34% Liquid at room tempconsistent, suggests rotamers (pdf, all NMR .zip) consistent, fluorine quartets found (pdf, multiplets)(pdf)Yes (pdf, .dx) APCI 308 M+H (.pdf, .raw)


Comparison with literature:
The product is a known compound (CAS: 175205-51-3) but no experimental data were found.

High resolution mass spectrometry:
HRMS (APCI (+)) Calcd. for [C14H11F6NH+]: 306.0712, found: 306.0705.

NMR assignment:
1H NMR (CDCl3, 300 MHz): δ = 2.07 (d, (rotamers) 6H), 5.96 (d, (rotamers) J = 1.7 Hz, 2H), 7.72 (d (rotamers), J = 0.3Hz, 2H). 13C NMR (CDCl3, 300 MHz): δ = 13.1 (2C), 107.6 (2C), 121.5 (dq, J = 3.5, 3.8 Hz, 1C), 123.1 (q, J = 272.6, 2C), 128.6 (q, J = 3.6 Hz, 2C), 128.8 (2C), 133.0 (q, J = 33.9 Hz, 2C), 140.9 (2C).

Conclusions:
The impure fraction was used unsuccessfully in a Vilsmeier-Haack reaction (ZYH 4-1), resulting in a mixture of products. Vilsmeier-Haack reaction of the pure fraction was successful (ZYH 4-2, ZYH 4-3). Some small additional peaks in the NMR spectra suggest the product is not completely pure, and the oil became darker over time. Remaining pure fraction was stored in the freezer.

Method taken from:
Scale-up (100 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-6)

Product taken forward to:
Synthesis of 3,5-bis(trifluoromethyl) arylpyrrole based near neighbour analogue (ZYH 7-2)

TLC (10% EtOAc/petrol) visualised with UV and Vanillin:
TLC at 3 hr
TLC at 26 hr
TLC after washes

Spots from left to right: aniline; aniline and reaction mixture; reaction mixture; hexanedione and reaction mixture; hexanedione.
TLCs from chromatography test tubes (10% EtOAc/petrol) visualised with UV and Vanillin:
Chomatography TLC1
Chromatography TLC2


Risk and hazard assessment:
Risk assessment
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