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26th February 2013 @ 18:35

 

 Crude product Resynthesis of MD 6-3 (PT-1-4) (120 mg, 62% purity, 0.2 mmol) was suspended in 1ml of dry dichloromethane and to this was added dry dimethylformamide (1 equivalent, 14 mg, 15 ul, ca. 1 drop) followed by dropwise oxalyl chloride (8 equivalents, 203 mg, 137 uL) [1]. The reaction mixture was stirred at room temperature under an atmosphere of dry nitrogen. Thin layer chromatography (t = 5 minutes, PT-1-9-A1) indicated the formation of a new, non-polar spot (Rf = 0.31, 1:3 EtOAc:Heptane) which did not coincide with starting material, oxalyl chloride, or pyridine. The new spot could be transformed into a more polar compound (Rf = 0.1, 1:3 EtOAc:Heptane) by the action of aqueous ammonia, suggesting a sulfonanic acid/sulfonamide conversion. This material displayed a mass spectrum consistent with a primary sulfonamide (m/z = 269, [M+H]+, 252 [M-NH2]+). Significant polar material remained (Rf = 0, 1:19 MeOH:CHCl3), so the reaction was left to stir overnight at room temperature. TLC indicated no further progress [2], and a portion quenched with 10% NaOH slowly reverted to starting material (Rf = 0.1, 1:19 MeOH:CHCl3).

A portion of the reaction mixture was diluted with dichloromethane, washed with water, dried over MgSO4 and concentrated [3]. NMR (PT-1-9-A2) indicated the presence of a mono-substituted compound with intact pyrrole signals and split methyl peaks. The remaining reaction mixture was worked up in the same way to give a brown oil (100.4 mg, >99% recovery) [4], which was dissolved in dry pyridine (10 ml) and mixed with ClH•H-Sar-OMe (1 mmol, 5 eq, 125.55 mg). The reaction mixture was stirred overnight at room temperature. A sample taken was consistent with conversion to the desired product (m/z = 355, NMR consistent) . The solvent was removed in vacuo, and the residue dissolved in dichloromethane and washed with saturated aqueous sodium carbonate, then dried over magnesium sulfate and evaporated directly onto silica and purified by dry column vacuum chromatography [5] (1:3 ethyl acetate:heptane, TLC PT-1-9-C1) to give a cloudy white oil (PT-1-9-C1, 49.5 mg, 140 umol, 70% over 2 steps).

 

Analysis:

Pt-1-9-C1 1H.pdf
PT-1-9-C1 13C.pdf
PT-1-9-C1 MS nominal.jpg


 

 


Proton NMR (PT-1-9-C1) indicates all signals present and accounted for, with correct integrals (4:1:2:3:3:3:3). Comparison to the doubly-substituted pyrrole Attempted synthesis of sulfonamide PT-1-3 indicates several differences that indicate mono-substitution only.

13C shows Carbon-Fluorine coupling, but by comparison with Scale-up (20 mmol) of Paal-Knorr Synthesis of 1-aryl-2,5-dimethyl Pyrrole Core (PMY 1-5) the following changes can be discerned: Pyrrole methyl peaks no longer symmetrical (12.64, 11.75). Additional peaks due to incorporation of Sarcosine: 169.46 (q, sp2), 52.13 (sp3, CH2/OMe) 51.05 (sp3, OMe/CH2), 36.79 (sp3, NMe). The possibility of 19F-13C decoupled spectroscopy is being investigated to clear this up.

Mass spectroscopy: ESI-MS nominal m/z = 377 [M+Na]+ (isotope peaks consistent)

ESI-Acc (Finnegan MAT-900 ESI-Positive HRMS): Expected 354.10441 (for C16H19O4N2FS) Found 354.10425 (0.16 ppm)

 

Notes:

[1] the oxalyl chloride generated copious bubbles without elevating the temperature, probably indicating a rapid reaction with generation of CO rather than the solvent boiling.

[2] By eye, the TLC indicates only small changes (an extra faint spot) happened overnight, suggesting again the reaction was done in 5 minutes, but can mostly tolerate longer reaction times

[3] Most of the expected mass balance (100 ul of RM) survived the workup, in contrast to previous experiments - this would be unlikely if sulfonic acids were the predominant species.

[4] sample displayed a distinctive musty acid-chloride-like odour; this could be due to traces of (COCl)2.

[5] Dry Column Vacuum Chromatography used custom glassware, and procedures as described in the Curly Arrow blog, and references therein.

Linked Entries
Attached Files
PT-1-9-A1 TLC.jpg
NMR detail - 4-1-3-3 peak ratios.png
PT-1-9-A2 NMR.pdf
PT-1-9-A2 NMR Archive.tar
PT-1-9.png
PT-1-9-C1 TLC.jpg
DCVC setup.jpeg.jpg
Pt-1-9-C1 1H.pdf
PT-1-9-C1 13C.pdf
PT-1-9-C1 1H 13C high field raw data.tar
PT-1-9-C1 MS nominal.jpg
PT-1-9 Risk Assessment.pdf
Comments
Re: Attempted chlorination of PT-1-4 by Patrick Thomson
26th February 2013 @ 18:39
Due care has been taken to ensure the experiment can be promptly and fully characterised the next day.
Re: Amination of PT-1-4 (PT-1-9) by Katrina Badiola
2nd March 2013 @ 03:32
I'm curious. Why use DCVC instead of flash chromatography?
Re: Amination of PT-1-4 (PT-1-9) by Patrick Thomson
8th March 2013 @ 11:24
DCVC is a personal choice rather than a requirement - in this case, I was able to run the column in about 45 minutes from sample prep to final vac-down.