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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.

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12th February 2013 @ 05:12
Mnr: MNR91-100

Attempted Solvent Free, 1-Pot Synthesis of Ether MNR98-2 

Starting material AEW2-2

 Hazard Assessment

HIRAC MNR98.pdf

Procedure

Methyl bromoacetate (1 mL, 10.2 mmol) was added to a flask with tpye 3A molecular sieve powder and AEW2-2 (0.10 g, 0.46 mmol) was added.  Sodium borohydride (19 mg, 0.51 mmol) was added and the reaction was allowed to stir at room temperature overnight.  TLC in the morning showed no reaction, so it was left.  After 24 hours TLC still showed no reaction and was not taken any further. 

Strings

Starting material

InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Product

InChI=1S/C16H18FNO3/c1-11-8-13(9-21-10-16(19)20-3)12(2)18(11)15-6-4-14(17)5-7-15/h4-8H,9-10H2,1-3H3

 

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12th February 2013 @ 05:06
Mnr: MNR91-100

Starting material AEW2-2

Attempted 1-pot synthesis of MNR98-1 in an aportic solvent.

 

 

 Hazard Assessment

HIRAC MNR98.pdf

Procedure

To a solution of AEW2-2 (0.10 g, 0.46 mmol) in THF (8 mL) at room temperature was added sodium borohydride (19 mg, 0.51 mmol) follwed by methyl bromoacetate (0.07 mL, 0.76 mmol) and the reaction was left to stir overnight (16 hours).  TLC in the morning showed mainly starting material and a new lower running spot, this looked promising but the spot on the slowly stained blue on sitting, characteristically similar to alcohol MNR97-1.  Actone (5 mL) was added the the mixture was left to stir for 5 mniutes then concentrated under vacuum.  Water (5 mL) was then added and extracted with DCM (10 mL x 3).  The organics were combined, dried, filtered and concentated to give a brown solid.  Crude NMR showed only starting material and degraded alcohol.  Reaction not taken any further forward. 

Strings

Starting material

 InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Product

InChI=1S/C16H18FNO3/c1-11-8-13(9-21-10-16(19)20-3)12(2)18(11)15-6-4-14(17)5-7-15/h4-8H,9-10H2,1-3H3

 

NMR

*Feb 2015 - Crude NMR was not uploaded at the time and can't be found on the servers. It may have been mislabelled or it may have been run under another user name seeing as it was just a quick crude run.  

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12th February 2013 @ 00:17
Mnr: MNR91-100

Starting material from AEW2-2

Procedure modified from AEW3-2

Hazard Assessment

HIRAC MNR97.pdf

Procedure

AEW 2-2 (0.200 g, 0.92 mmol) was dissolved in MeOH (15 mL) at room temperature and sodium borohydride (44 mg, 1,15 mmol) was added.  The reaction was stirred for 4 hours at which point TLC only faint traces of starting material so the reaction was worked up due to the time.  Acetone (5 mL) was added and the raction was stirred for a further 10 minutes then it was concentrated under vacuum.  Water (5 mL) was added and extracted with DCM (5 mL x 3), the organics were combined, dried, filtered and concentrated to give a bark brown oil. 

NMR

Starting material

aew2-2_1H.pdf
aew2-2_rerun.zip

 

The NMR of the crude was far from clean but it showed signs of product.

Crude

mnr97-1_crude_1H.pdf
mnr97-1_crude.zip

 

Same sample after 17 hours at room temperature.

mnr97-1_crude_17hours_1H.pdf
mnr97-1_17hours.zip

Overlay of the above spectra.

The product has completely decomposed overnight at room temperature 

mnr97-1_crude_overlay.pdf

Conclusion


The alcohol should be taken on straight away due to it's instabilities 

Strings

Starting material

InChI=1S/C13H12FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-8H,1-2H3

Product

InChI=1S/C13H14FNO/c1-9-7-11(8-16)10(2)15(9)13-5-3-12(14)4-6-13/h3-7,16H,8H2,1-2H3

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6th February 2013 @ 09:49

 

 

 

Several portions of crude product Resynthesis of MD 6-3 (PT-1-4) (31 mg, 62% purity, 54 umol) were suspended in 750 ul of solvents and stored in NMR tubes in the following ways:

A: CDCl3 with 5 equivalents SOCl2 (19 ul)

B: 10:90 CDCl3:SOCl2

C: CDCl3 with 5 equivalents oxalyl chloride (23 ul) and 0.1 equivalents DMF (~1 ul)

D: CDCl3 with 2 equivalents chlorosulfonic acid

 

The tubes were sonicated and inverted to produce a homogenous suspension ( where insoluble ) and analysed by NMR at the following time points: 3 weeks. Results inconclusive, experimenter was unduly distracted. Recommendation: further experiments.

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