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21st November 2011 @ 04:47
21/11/11

Repeat of MNR11-12 preparation with monitoring of reaction progress by LCMS.

Scheme%201-1.png

Hazard and Risk Assessment
HIRAC 1-1


Procedure
MNR8-1 (100 mg, 0.22 mmol), MW45-3 (1,1’-Binaphthalene-2,2’-disulfonic acid, 20 mg, 0.04 mmol) and toluene (4 mL) was heated at reflux (115C).

Reaction at 90C at 5:00 pm. The catalyst did not dissolve immediately and remained mostly at the bottom of the flask.

22/11/11

Mini Workup (LCMS) - 24 hours after reaction start: ~10 mg of sample was quenched in saturated sodium carbonate and extracted with ethyl acetate before dilution in methanol. The sample was added to the LCMS queue, results pending.
The reaction mixture changed in appearance as the catalyst further dissolved over 24 hours.
24 hours



23/11/11

There was no change in appearance of the reaction mixture.

The LCMS of the KAB1-1 at 24 hours showed no sign of the starting materials, nor the expected peaks at corresponding retention times. See MNR11-12.

LCMS at 24 hours
KAB1-1 24 hours, MS of LC peak at 10.975 min
KAB1-1 24 hours, MS of LC peak at 10.975 min
KAB1-1 24 hours, MS of LC peak at 10.992 min


Mini Workup (LCMS) - 45 hours after reaction start: ~10 mg of sample was quenched in saturated sodium carbonate, before extraction with ethyl acetate (3 x 5 mL). The solution was dried over magnesium sulfate then diluted in methanol. LCMS was recorded.

Again, LCMS showed no useful information. The spectrum was similar to KAB1-1 at 24 hours.

LCMS at 45 hours
KAB1-1 LCMS at 45 hours
KAB1-1 45 hours, MS of LC peak at 10.992 min
KAB1-1 45 hours, MS of LC peak at 12.392 min


A time "zero" was prepared by scaling down of the procedure performed on 21/11/11 (above). The work up performed on the 45 hour sample was done on the "zero" sample <10 minutes after its preparation. LCMS for the sample was recorded.
Very weak signal was observed for the starting material (MNR8-1).

LCMS at time "zero"
KAB1-1 LCMS at 0 hours
KAB1-1 0 hours, MS of LC peak at 10.7 min
KAB1-1 0 hours, MS of LC peak at 12.9 min


The LCMS of MNR11-12 was re-run, following dilution in MeOH.

It was completely different to the previously recorded spectrum. However, with the exception of the KAB1-1 "zero" sample, the results were similar, i.e. no clear, identifiable peaks and little to no signals corresponding to either the starting materials or the expected product.

Re-run LCMS of MNR11-12
MNR11-12 LCMS re-run
MNR11-12 re-run, MS of LC peak at 11.650 min
MNR11-12 re-run, MS of LC peak at 10.992 min
MNR11-12 re-run, MS of LC peak at 10.783 min


Could possibly be interference from the dilution in methanol. Murray previously ran MNR11-12 in MeCN. The three KAB1-1 samples: "zero," 24 hours and 45 hours were re-prepared in MeCN for LCMS analysis overnight.

LCMS Re-run of samples
KAB1-1 0 hours LCMS re-run
KAB1-1 24 hours LCMS re-run
KAB1-1 45 hours LCMS re-run



28/11/11

The reaction mixture was taken off heat then quenched with saturated sodium bicarbonate (20 mL), 7 days (161 hours) after the reaction start. The aqueous layer was extracted with ethylacetate (3 x 15 mL) and the combined organic fractions were dried over magnesium sulfate. The solvent was removed under reduced pressure to give crude KAB1-1 as a dark red oil.

161 hours

KAB1-1 reaction mixture at 161 hours, immediately before quenching of reaction

29/11/11

Crude KAB1-1 was purified by column chromatography (silica gel 12 cm, diameter 2.5 cm in EtOAc:hexane, 1:1). Elution of product was monitored by TLC.
TLC frac 1-11


Data
KAB1-1 NMR



****Experimental procedure finished. No further characterisation performed as of 08/12/11. The results were inconclusive (poor LCMS data), but based on following experiments, it is likely that product of the reaction was the enediamide intermediate.

Reaction conditions adapted in the parallel Pictet-Spengler cyclisation of PZQ and analogues.
Linked Posts
Attached Files
Scheme 1-1
HIRAC 1-1
24 hours
161 hours
TLC frac 1-11
KAB1-1 NMR
KAB1-1 LCMS at 0 hours
KAB1-1 0 hours, MS of LC peak at 10.7 min
KAB1-1 0 hours, MS of LC peak at 12.9 min
KAB1-1 LCMS at 24 hours
KAB1-1 24 hours, MS of LC peak at 10.975 min
KAB1-1 24 hours, MS of LC peak at 10.992 min
KAB1-1 LCMS at 45 hours
KAB1-1 45 hours, MS of LC peak at 10.992 min
KAB1-1 45 hours, MS of LC peak at 12.392 min
KAB1-1 LCMS at 64 hours
KAB1-1 64 hours, MS of LC peak at 10.783 min
KAB1-1 64 hours, MS of LC peak at 12.408 min
KAB1-1 0 hours LCMS re-run
KAB1-1 24 hours LCMS re-run
KAB1-1 45 hours LCMS re-run
MNR11-12 LCMS re-run
MNR11-12 re-run, MS of LC peak at 11.650 min
MNR11-12 re-run, MS of LC peak at 10.992 min
MNR11-12 re-run, MS of LC peak at 10.783 min