All Notebooks | Help | Support | About
15th December 2011 @ 19:45
Synthesis of near neighbour from PMY 13-1 and ZYH 4-2

7-1reactionscheme.png

Experiment start time: 9:30 EST 15/12/11
2-phenyliminothiazolidin-4-one (PMY 13-1) (58.2 mg, 0.303 mmol, 1.0 equiv.) was dissolved in ethanol (10 mL) and combined with piperidine (0.135 mL,1.35 mmol, 1.5 equiv.). 2,5-dimethyl-1-(3,5-bis(trifluoromethyl)phenyl-1H-pyrrole-3-carboxaldehyde (ZYH 4-2) (302.6 mg, 0.90 mmol, 1.0 equiv.) was dissolved in ethanol (5 mL) and added to the mixture, and the clear brown-orange solution was heated to 60 °C. A precipitate was observed after 90 minutes and the reaction appeared complete by TLC. The mixture was cooled slowly and filtered off to give a brownish-yellow powder (203.1 mg, 44% yield).

Data summary table:
Yield % Melting point °C 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 7-2 44 decomposes ~ 255Not assigned (1H, 13C and 2D pdf) Not assignedNeededYes (pdf, .dx) APCI 510 M+H


Comparison with literature:
The product was not found in the literature.

High resolution mass spectrometry:
HRMS (APCI (+)) Calcd. for [C24H17F6N3OSH+]: 510.1069, found 510.1080.

Conclusions:
Reaction was run more concentrated and using a larger quantity than 7-1 with much better results. The product appears more soluble in ethanol than the other near neighbour analogues and yield was relatively low but the quantity obtained was sufficient.

TLC (10% methanol in dichloromethane) visualized using UV and vanillin:
TLC at 90 min

Spots from left to right: aldehyde; aldehyde plus reaction mix; reaction mixture; PMY 13-1 plus reaction mix; PMY 13-1.

NMR spectra:
1H NMR
raw data


IR spectrum:
IR spectrum


Hazard and risk assessment:
Refer to:
Synthesis of phenyliminothiazolidinone-substituted arylpyrrole (ZYH 3-1)
Linked Posts
Attached Files
7th December 2011 @ 23:49
Synthesis of near neighbour from PMY 13-1 and ZYH 6-1

10-1reactionscheme.png

Sodium hydride (60% suspension in mineral oil, ~10 mg, 2.5 mmol, 2 equiv.) was combined with DMF (1 mL) under a nitrogen atmosphere on a brine ice bath and stirred, and a solution of ZYH 6-1 (50.8 mg, 0.115 mmol, 1 equiv.) in DMF (2 mL) was added dropwise over 2 minutes. The mixture was allowed to stir at room temperature for 10 minutes and then cooled on ice. Bromoacetonitrile (~20 μL, 3 mmol, 2 equiv.) was then added, resulting in an immediate colour change to dark brown. The mixture was stirred at room temperature and TLC after half an hour showed disappearance of the starting material and formation of two products. The reaction was quenched by dropwise addition of water and the mixture extracted using ether (5 x 20 mL) then washed with water (3 x 20 mL) and brine (1 x 20 mL) and dried over magnesium sulfate. The solution was then concentrated under reduced pressure to give a brown oil (~ 300 mg), and TLC again showed two product spots, well separated in 50% ethyl acetate/hexane eluent. The oil was adsorbed on to silica and separated by column chromatography to give two fractions, a yellow oil with a strong odour and pale brown oil which were frozen for storage over two weeks. NMR indicated these were two distinct products, well separated and both quite clean apart from traces of solvents.

Reference:
See Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore DOI: 10.1021/jm100762r

TLC (50% ethyl acetate in hexane) visualised with UV and vanillin:
TLC after extraction
TLC showing disappearance of start materials


Data:
For full data see Synthesis of acetonitrile substituted p-trifluoromethyl near neighbour analogue (ZYH 10-2)
Proton NMR fraction A
Proton NMR fraction B


Hazard and risk assessment:
Hazard and risk assessment
Linked Posts
Attached Files
7th December 2011 @ 00:31
Paal Knorr synthesis of 2-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine from 2-aminopyridine and 2,5-hexanedione.

9-1reactionscheme.png

Experiment start time: 12:00 EST 07/12/11
2-aminopyridine (10.1 g, 108 mmol, 1 equiv.) was combined with 2,5-hexanedione (12.7 mL, 108 mmol, 1 equiv.) and heated to 80 °C. After five days the reaction was incomplete by TLC and the mixture was cooled and extracted with ethyl acetate and washed with citric acid (30 mL), water (30 mL) and brine (30 mL) then dried over magnesium sulfate and concentrated under reduced pressure to give a dark brown oil which was frozen for storage over two weeks. The oil was then purified by column chromatography to give a pale yellow oil (3 g, 17% yield). NMR was consistent with the expected product and suggested the sample was clean.

Conclusions:
The aminopyridine based arylpyrrole was obtained in low yield but sufficient quantity.

Data summary table:
Yield % Melting point 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 9-1 17 liquid at room temperatureYes (pdf, all NMR .zip) Yes (.pdf)NAYes (pdf, .dx) APCI 173 M+H (.pdf, .raw)


Comparison with literature:
The product is a known compound (CAS: 32570-88-0). H NMR (*check extra splitting), C NMR and IR spectra are consistent with the literature1.

TLC (10% ethyl acetate in hexane) visualised using UV and vanillin:
TLC at 5 hr
TLC at 20 hr
TLC at 52 hr
TLC at 5 days


References:
1. Indium(III)-Catalyzed Synthesis of N-Substituted Pyrroles under Solvent-Free Conditions (2008). DOI: 10.1590/S0103-50532008000500011

Hazard and risk assessment:
Refer to:
Preparation of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (ZYH 1-1)
Linked Posts
This post is linked by:
Attached Files
6th December 2011 @ 23:19
Paal Knorr synthesis of ethyl 4-(2,5-dimethyl-1H-pyrrol-1-yl)benzoate from ethyl 4-aminobenzoate (benzocaine) and 2,5-hexanedione

8-1reactionscheme.jpg

Experiment start time: 11:00 EST 07/12/11
Ethyl 4-aminobenzoate (15.1 g, 91 mmol, 1 equiv.) was combined with 2,5-hexanedione (10.7 mL, 91 mmol, 1 equiv.) and heated to 80 °C. After five days the reaction was still incomplete and the mixture was removed from the heat and extracted using ethyl acetate (40 mL) and washed in citric acid (10%, 2 x 40 mL), followed by hydrochloric acid (0.5 M, 2 x 45 mL) then water (30 mL) and brine (30 mL). The solution was dried over magnesium sulfate and concentrated under reduced pressure to give a brown oil, which was frozen for two weeks' storage.The product crystallized in the freezer to form an orange-brown solid, which remained solid at room temperature. Recrystallization from ethanol was unsuccessful and the solid was purified by column chromatography (100% hexane) to give a pale yellow crystalline solid (5.8 g, 26% yield). The mixture appeared to be reactive on the silica based on an exotherm during adsorption onto silica and formation of a green colour when the column was left for 1.5 hrs, however any impurity formed moved more slowly than the desired product. NMR was consistent with the expected product and indicated the sample was clean.

Conclusions
5.8 g of benzocaine-based arylpyrrole suitable for conversion to the aldehyde was obtained, despite a relatively low yield.

Data summary table:
Yield % Melting point 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 8-1 26 59.6-60.5Yes (pdf, all NMR .zip) Yes (.pdf)NAYes (pdf, .dx) APCI 244 M+H (.pdf, .raw)


Comparison with literature:
The product is a known compound (CAS: 5159-70-6) and H NMR, C NMR and IR spectra are all consistent with spectra from Bio-Rad Laboratories1.

TLC (10% ethyl acetate in hexane) visualised using UV and vanillin:
TLC at 6 hr
TLC 54 hrs
TLC 5 days
Column TLC

spots from left to right: benzocaine; benzocaine plus reaction mixture; reaction mixture; reaction mixture plus hexanedione; hexanedione.

Hazard and risk assessment:
Refer to:
Preparation of 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (ZYH 1-1)

Reference:
1. Copyright Bio-Rad Laboratories. All Rights Reserved. Accessible through SciFinder, spectra for compound CAS: 5159-70-6.
Linked Posts
This post is linked by:
Attached Files
6th December 2011 @ 04:25
Vilsmeier Haack Synthesis of 2,5-dimethyl-1-(3,5-bis(trifluoromethyl)phenyl)-1H-pyrrole-3-carbaldehyde from 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (ZYH 1-1, remainder of pure fraction)

reactionscheme4-1.png

Experiment start time: 3:20 EST 06/12/11
DMF (2 mL, 26 mmol, 13 equiv.) was stirred under a nitrogen atmosphere in an ice bath. Phosphoryl chloride (0.200 mL, 2.15 mmol, 1.1 equiv.) was added and the reaction stirred for 25 minutes. 1-(3,5-bis(trifluoromethyl)phenyl)-2,5-dimethyl-1H-pyrrole (599.9 mg, 1.95 mmol, 1.00 equiv., ZYH 1-1, pure fraction) was dissolved in DMF (8 mL) and added slowly, then the mixture was removed from the ice after 5 minutes. TLC after 45 min showed the reaction to be complete, and the mixture was poured over ice and the pH adjusted to 7, then left stirring overnight. In the morning, the pH was adjusted to 11 and the mixture cooled on ice for 30 minutes then filtered off, to give a fine, pale brown powder (627 mg, 96% yield). Melting point: 88-89 °C.

Data summary table:
Yield % Melting point 1H NMR 13C NMR19F NMR IR Mass spec
ZYH 4-x 91 85.4-86.8Yes (pdf, all NMR .zip) Consistent (pdf, multiplets)Yes (pdf)Yes (pdf, .dx) Submitted


Comparison with literature:
The product was not found in the literature.

NMR assignment:
1H NMR (CDCl3, 300 MHz): δ = 2.03 (s, 3H), 2.33 (s, 3H), 6.44 (d, J = 0.69 (rotamers), 1H), 7.74 (s, 2H), 8.04 (s, 1H), 9.90 (s, 1H). 13C NMR (CDCl3, 300 MHz): δ = 11.4 (1C), 12.8 (1C), 107.4 (1C), 122.7 (q, J = 273.1, 2C), 122.9 (1C) 123.0 (dq, J = 3.9, 3.8 Hz, 1C), 128.7 (q, J = 3.4 Hz, 2C), 130.6 (1C), 133.6 (q, J = 34.3 Hz, 2C), 138.0 (1C), 138.8 (1C), 185.4 (1C) ppm.

TLC (25% ethyl acetate in hexane), visualised using UV and vanillin:
TLC at 45 min

Spots from left to right: reaction mixture; reaction mix plus starting materials; starting material.

Hazard and risk assessment:
Refer to:
Preparation of 2,5-dimethyl-1-(4-(trifluoromethyl)phenyl)-1H-pyrrole-3-carbaldehyde (ZYH 2-1)
Linked Posts
This post is linked by:
Attached Files