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1st October 2015 @ 00:34

Aim of this experiment is to perform nucleophilic aromatic substitution on the upper left hand corner of the triazolopyrazine core produced in BSX 2-1, simiar to the procedure of BSX 3-1 but with 1.00 mmol of core.The Cl atom this time was substituted by a pyridin-2-ylmethanol group.

 


Procedure

The triazolopyrazine core (267 mg, 1 mmol), pyridin-2-ylmethanol (109 mg, 1 equiv.), KOH powder (196 mg, 3.5 equiv.) and 18-crown-6 (19 mg, 0.07 equiv.) were introduced to a small vial and stirred at room temperature for 20 mins before TLC attached was taken. However, an amount of the reaction mixture was spilled, approximately half, leading to an inaccurate yield for this experiment. TLC was taken with 100% EtOAc solvent mixture. Reaction product was very dark in colour, almost black and quite viscous. 

The reaction mixture was diluted with water before being washed four times with EtOAc, preserving the organic upper layer each time as the aqueous layer was washed. Sufficient brine and MgSO4 were added before the mixture was filtered. The filtrate was transferred to a round bottom flask before being put in the rotary evaporator under low pressure.

Column purification was performed and columns 5-9 and 10-14 yielded evidence of the product and as a result was further tested using NMR. The spectra for NMR are attached below.

NMR spectra reveal possible presence of water in the sample due to a high peak around 1.56.

Overall the spectra showed the successful production of the molecule however there are more peaks than can be expected. I am unsure why.

 

The yield for this experiment was 17.6%. I believe the low yield was attributed to selecting very few solutions from the column separation. Only 5 tubes were used and the rest discarded were likely to still contain amounts of product.

 

HIRAC

Attached below.

 

Strings

SMILES

OCC1=CC=CC=N1

and

ClC1=CN=CC2=NN=C(C3=CC(F)=CC(F)=C3)N21

to

FC1=CC(C2=NN=C3N2C(OCC4=CC=CC=N4)=CN=C3)=CC(F)=C1

 

InChi

InChI=1S/C6H7NO/c8-5-6-3-1-2-4-7-6/h1-4,8H,5H2

and

InChI=1S/C11H5ClF2N4/c12-9-4-15-5-10-16-17-11(18(9)10)6-1-7(13)3-8(14)2-6/h1-5H

to

InChI=1S/C17H11F2N5O/c18-12-5-11(6-13(19)7-12)17-23-22-15-8-20-9-16(24(15)17)25-10-14-3-1-2-4-21-14/h1-9H,10H2

Attached Files
21st September 2015 @ 07:31


Lithium aluminium hydride (399 mg, 10.52 mmol, 1.5 equiv.) was dissolved in anhydrous THF (10 mL) and then stirred at 0 ˚C. AEW  252-1 (1.32 g, 7.01 mmol, 1 equiv.) was dissolved in anhydrous THF (5 mL) and added dropwise to the solution at 0˚C and then stirred whilst reaching rt for x h.

Data:

AEW 254-1.pdf
AEW 254-1.zip

Hazard and Risk Assessment:

HIRAC AEW 254-1.doc
HIRAC AEW 254-1.pdf

Strings:

InChI=1S/C9H16O4/c1-7(9(10)11-2)13-8-5-3-4-6-12-8/h7-8H,3-6H2,1-2H3

to

InChI=1S/C8H16O3/c1-7(6-9)11-8-4-2-3-5-10-8/h7-9H,2-6H2,1H3

O=C(OC)C(C)OC1OCCCC1

to

OCC(C)OC1OCCCC1

Attached Files
17th September 2015 @ 02:25

See also: Synthesis of methyl 2-hydroxy-2-methylpropanoate (AEW 189-1)

 

Procedure:

2-Hydroxyisobutyric acid (5 g, 48 mmol, 1.0 equiv.) and pTsOH (827mg, 4.8 mmol, 0.1 equiv.) were dissolved in MeOH (100 mL) and the reaction mixture was heated to reflux for 3 h. The crude mixture was concentrated in vacuo and then dissolved in EtOAc (30 mL) and washed with a saturated solution of sodium bicarbonate solution (10 mL x 2), brine (10 mL) and then dried (MgSO4) to give a colourless liquid 600 mg ?! - possibly left on high vac for too long, volatile? Emptied trap and took nmr:

 

 

Data:

 Hazard and Risk Assessment:

 See: Synthesis of methyl 2-hydroxy-2-methylpropanoate (AEW 189-1)

InChI:

InChI=1S/C4H8O3/c1-4(2,7)3(5)6/h7H,1-2H3,(H,5,6)

to

InChI=1S/C5H10O3/c1-5(2,7)4(6)8-3/h7H,1-3H3

17th September 2015 @ 01:24

 

 

AEW 248-1 (1 g, 5.61 mmol, 1.0 equiv.) was dissolved in MeOH (11.2 mL) and cooled to 0 ˚C. NaBH4 (106 mg, 2.81 mmol, 0.5 equiv.) was added in portions and the reaction mixture was stirred at 0 ˚C for 30 mins and then allowed to stir whilst reaching rt for 2 h.

TLC showed no SM 

Reaction mixture cooled to 0 ˚C and then a saturated solution of ammonium chloride (10 mL) added dropwise with stirring (no vigourous reaction). Volatiles were removed in vacuo to give a yellow ppt. Reaction mixture partioned between EtOAc (20 mL) and a saturated solution of ammonium chloride (20 mL) and then layers separated. Aqueous washed with EtOAc (2 x 15 mL) and then combined organic washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated to give a yellow liquid that was dried on the high vac o/n 590 mg crude.

 

Data:

TLC 50% EtoAc in Hexane

AEW 253-1 50% EtOAc in Hexane.jpeg
AEW 253-1 50% EtOAc in Hex KMnO4 stain.JPG

200 MHz NMR data

AEW 253-1.pdf
AEW 253-1.zip

Hazard and Risk Assessment:

HIRAC AEW 253-1.pdf
HIRAC AEW 253-1.doc

Strings:

InChI=1S/C10H10O3/c1-2-13-10(12)9(11)8-6-4-3-5-7-8/h3-7H,2H2,1H3

to

InChI=1S/C10H12O3/c1-2-13-10(12)9(11)8-6-4-3-5-7-8/h3-7,9,11H,2H2,1H3

 

O=C(C(OCC)=O)C1=CC=CC=C1

to

OC(C(OCC)=O)C1=CC=CC=C1

Attached Files
17th September 2015 @ 01:07

Started prior to SM NMR check due to long wait for instrument

Crude AEW 175-3 (1.0 g, 9.61 mmol, 1 equiv.) and DHP (1.37 mL, 16.3 mmol, 1.7 equiv.) were dissolved in anhydrous CH2Cl2 (10 mL) under Argon at 0 ˚C. PPTS (72 mg, 0.29 mmol, 0.03 eq.) was added and the reaction mixture was stirred at 0 ˚C for and then allowed to reach room temperature whilst stirring for 3 h. Reaction was quenched by the addition of ice cold water (10 mL) and then extracted with CH2Cl(3 x 20 mL), dried (MgSO4), filtered and evaporated to yield a pale yellow oil crude 1.32 g. Used directly in next reaction.


Data:

AEW 252-1 crude.zip

AEW 252-1.pdf

Hazard and Risk Assessment:

HIRAC AEW 252-1.pdf
HIRAC AEW 252-1.doc

Strings:

InChI=1S/C4H8O3/c1-3(5)4(6)7-2/h3,5H,1-2H3

to

InChI=1S/C9H16O4/c1-7(9(10)11-2)13-8-5-3-4-6-12-8/h7-8H,3-6H2,1-2H3

O=C(OC)C(C)O

to

O=C(OC)C(C)OC1OCCCC1

Attached Files