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29th June 2012 @ 07:46
Product obtained and used crude.

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Hydrogenolysis of PMY 51-1-B to provide N-methyl side-chain.

PMY53-1.png

Reaction Start Time: 16.40 29/06/12
10% Pd/C (40 mg) was stirred in ethanol (10 mL) at 0 °C. PMY 51-1-B (0.41 g, 2.30 mmol) was dissolved in EtOH (10 mL, warmed then cooled) and added to the catalyst suspension. Reaction left at room temperature over the weekend. Hydrogen balloon had deflated. TLC shows SM and new polar spot. 1H NMR confirms SM and new product consistent with expected signals (approx 2.3:3 ratio). Subjected to the same reaction conditions again (14:10 02/07/12). 05/07/12 Purged with nitrogen, celite filtered (water/ethanol) and concentrated under reduced pressure. The mixture was extracted with DCM (3 × 20 mL). The organic extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a white solid (114 mg, 56% of theory). 1H NMR consistent with SM, does not show product from previous NMR. Suspect product is in aqueous phase. Aqueous phase concentrated under reduced pressure. Methanol (approx 30 mL) was added to the residue, sonicated then heated and cooled. The mixture was filtered and the cake washed with further methanol (50 mL). The filtrate was concentrated under reduced pressure to a slightly pink solid. Triturated with CDCl3 (PMY 53-1-B. 1H NMR consistent with expected product and product observed on first NMR (not clean).

NMR:
1H NMR incomplete
PMY 53-1-B, aqueous layer
1H NMR further reaction


See also:
Reductive alkylation of glycinamide (PMY 51-1)

Risk and Hazard Assessment:
See: Reduction of 4-fluoro near-neighbour Micheal-acceptor (PMY 36-1)
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28th June 2012 @ 07:51
Desired product not obtained. Reaction to be repeated at various temperatures and monitored closely. Mass spec (APCI+) confirms presence of bis-bromide. Potential that SM used PMY 52-1 (recovered "SM") was already desired product.

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Bromination of 4-fluorophenylpyrrole PMY 1-6 using NBS in THF. Hopefully going for selective bromination on the 3 position. At -10 °C to room temperature

PMY52-1.png

Reaction Start Time: 16.45 28 June 2012
Recovered pyrrole PMY 52-1(1.00 g, 5.3 mmol, 1 equiv.) was dissolved in THF (20 mL) and cooled to ca. -10 °C (ice/brine). NBS was added portionwise over 5 minutes and the reaction allowed to warm to room temperature. After 17 hours at room temperature. TLC shows 2 new products and SM (by Rf, colour may be deceiving (?), see PMY 52-1). 04/07/12 sodium sulfite (approx 1 g) was added and the reaction stirred for 5 minutes. Water (approx 30 mL) added. The layers were separated and the aqueous extracted with diethyl ether (2 × 20 mL). TLC of the extract shows new polar product and potential product with identical Rf by stain. The organic layers were then washed with brine, dried (MgSO4) and concentrated under reduced pressure to a brown solid (1.76 g, 124% of theory). Stored in the dark overnight, product now red/brown solid. Loaded onto column using EtOAc/DCM (didn't dissolve well, had to use too much, 5-10% EtOAc/hexane), gave partial separation of products. PMY 52-2-A (1.40 g, 99% of theory). 1H NMR shows disappearance of pyrrole-H, still only one methyl peak: consistent with di-bromo product [this yield of dibromo is not possible with 1 equiv. of NBS. Need to figure out what's going on here]. PMY 52-2-B (0.06 g) clean looking unknown. PMY 52-2-A bis brominated (76% yield based on pyrrole). [Yield should be at max 50%. Recovered SM from 52-1 used for this reaction. On second inspection, crude NMR pyrrole-H integrated to 1H, not 2H. Potentially SM for this reaction was already brominated.] APCI+ consistent with bis and mono-brominated material.

TLC (10% EtOAc/hexane) visualised with UV and vanillin:
TLC overnight

Worked-up:
TLC vanillin stained heated
TLC vanillin stained unheated


NMR:
1H, 13C, 19F NMR. PMY 52-2-A
1H PMY 52-2-B


Mass Spec:
Mass Spec

ESI does not show products (mono- or di-brominated) nor SM. SM usually requires APCI:
Mass Spec


See also:
Bromination of aryl pyrrole PMY 1-6 using NBS (PMY 52-1)

Risk and Hazard Assessment:
See: Bromination of aryl pyrrole PMY 1-6 using NBS (PMY 52-1)
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28th June 2012 @ 00:38
Reaction returned starting material. To be repeated at an elevated temperature.

11/07/12: See PMY 52-2; Integral of crude 1H shows only a single pyrrole-H but no change in any H NMR shifts compared to SM [11/07/12 CORRECTION: SM peaks have shifted e.g. pyrrole-H 5.96 compared to 5.89 in SM.]. There is potential that the reaction was complete, as indicated by TLC stain. To be repeated under the conditions used below.

===

Bromination of 4-fluorophenylpyrrole PMY 1-6 using NBS in THF. Hopefully going for selective bromination on the 3 position.

PMY52-1.png

Reaction Start Time: 10.05 28 June 2012
Pyrrole PMY 1-6 (1.00 g, 5.3 mmol, 1 equiv.) was dissolved in THF (20 mL) and cooled to ca. -95 °C (acetone/N2, no dry-ice at the moment). NBS (941 mg, 5.3 mmol, 1 equiv.) was added and the mixture slowly warmed to -10 °C. After 4 hours, reaction was complete by TLC (by vanillin stain, not Rf). Sodium sulfite (approx 1 g) was added and the reaction stirred for 20 minutes. Water added and stirred for a further 40 mins. The mixture was diluted with Et2O (50 mL) and the layers separated. The organic layer was washed with water (3 × 15 mL), brine then dried (MgSO4) and concentrated under reduced pressure to a brown oil. 1H NMR reveals only SM, still clean. [11/07/12 CORRECTION: SM peaks have shifted e.g. pyrrole-H 5.96 compared to 5.89 in SM.]

TLC (10% EtOAc/hexane) visualised with UV and vanillin:
TLC 4 hours


NMR:
1H NMR crude


Reference:
doi:10.1021/jo00324a005

Risk and Hazard Assessment:
RA
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25th June 2012 @ 06:55
Mostly clean desired product progressed to next step. Reaction to be scaled up (smaller amount of benzaldehyde) and purified for final characterisation.

===

Double reductive alkylation of glycinamide. First using benzaldehyde to provide benzyl-protected glycinamide, then using formaldehyde to provide the N-methyl.

PMY51-1.png

Reaction Start Time:15.50 25/06/12
Glycinamide.HCl (500 mg, 4.52 mmol, 1 equiv.) was dissolved in minimum water. Sodium hydroxide (0.18 mg, 4.5 mmol, 1 equiv.) was added. A precipitate forms. The mixture was concentrated under reduced pressure. Methanol (15 mL) and AcOH (1.5 mL) and benzaldehyde (0.60 mL, 5.9 mmol, 1.3 equiv.) were added. Sodium cyanoborohydride (370 mg, 5.90 mmol, 1.3 equiv.) was added portionwise to the hazy solution, allowing bubbling to cease between portions. Stirred at room temperature overnight. Concentrated under reduced pressure then basified using 2M NaOH(aq) and extracted using DCM (3 × 20 mL). Washed with brine, dried (MgSO4) and concentrated under reduced pressure to a thick oil. Dried under vacuum to a white solid (0.59 g). The aqueous layer was saturated with brine and re-extracted with DCM (3 × 20 mL), dried (MgSO4) and concentrated. White solid (0.65 g total). 1H NMR consistent with literature NMR values but also unknown signals at 3.64 (s), 3.10 (s) 2:1 integrals). Integration is also out with respect to aromatic region. Mass Spec consistent with product 187.3 [M+Na] and bis-benzylated product 277.5 [M+Na]

The white solid was dissolved in methanol (10 mL) and AcOH (0.25 mL). Aqueous formaldehyde solution (37 wt. %, 0.7 mL, 9 mmol, 2 equiv.) was added. After stirring for approx 5 minutes, sodium cyanoborohydride (300 mg, 4.75 mmol, 1.05 equiv.) was added portionwise over 10 minutes. Reaction stirred overnight at room temperature. Concentrated under reduced pressure. 2M NaOH (10 mL) was added and stirred for 10 minutes. The mixture was extracted using DCM (3 × 15 mL). The extracts were washed with brine then dried (MgSO4) and concentrated under reduced pressure to a colourless translucent thick oil (0.64 g). 1H NMR shows consumption of previous product but some remains, the impurity peaks are retained and peaks consistent with expected product appear. Consistent with 1H NMR reported in patent EP0714885 (A2). Impurity peaks probably bis-benzylated compound, integral ratio and excess aromatic protons support this. Mass spec consistent with product 201.4 [M+Na] and bis-benzyl product 277.5 [M+Na]. Purified by chromatography on silica (4% MeOH/DCM), partial separation; white crystalline solid PMY 51-1-A (0.19 g), colourless viscous oil that solidified on standing PMY 51-1-B (0.41 g, 39%, more polar than A).

PMY 51-1-A bis-benzylated product by 1H NMR. Mpt 95-97 °C
PMY 51-1-B 2-(benzyl(methyl)amino)acetamide, bis-benzyl and other impurities by 1H NMR. Mostly desired product.

TLC visualised with UV and vanillin:
TLC EtOAc/hexane

70% EtOAc/hexane: Left to right: Step 1 crude product, mixture, step 2 crude product, benzaldehyde, benzyl alcohol.

Column TLC

Unstained.

NMR:
1H PMY 51-1-A, bisbenzyl
1H product, impure after column
1H NMR crude
1H NMR crude, step 1


Mass Spec:
Mass Spec step 2
Mass Spec step 1


TLC DCM/MeOH

5% MeOH/DCM: Left to right: Step 1 crude product, mixture, step 2 crude product.

TLC supports that top spot probably the impurity observed in both NMR spectra.

Reference:
doi: 10.1016/j.tetasy.2008.01.016
NMR details: Synthesis 1983, 04, 529
EP0714885 (A2)

Risk and Hazard Assessment:
See: Synthesis of amine-linked analogue of TCMDC-123812 via reductive amination using sodium cyanoborohydride (PMY 38-4)
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25th June 2012 @ 01:31
Coupling of glycolamide and PMY 44-1 via the acid chloride. Using the method used for PMY 10- and PMY 11- etc.

IGNORE! DUPLICATE POST DUE TO LABTROVE DATABASE ERROR
Real entry at http://malaria.ourexperiment.org/uri/106
Synthesis of pyrazole analogue of TCMDC-123812 (PMY 50-1)

Risk and Hazard Assessment:
See: Synthesis of TCMDC-123794 via acid chloride (PMY 11-2)
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