Triazolopyrazine Series

Reference: https://www.google.com/patents/US6159990

Procedure:

KOH (3.77 g, 67.3 mmol, 10.0 equiv.) was dissolved in MeOH (35 mL) and stirred at 0 ˚C. AEW 316-1 (1.05 g, 6.73 mmol, 1.00 equiv.) was added dropwise at 0 ˚C and then stirred at this temperature for 15 mins. PIDA (4.33 g, 13.5 mmol, 2.00 equiv.) was added portionwise over 20 min and the reaction mixture was stirred at rt for 20 h.

Clear and colourless solution, to clear yellow solution to cloudy yellow mixture.

Solvent was removed in vacuo to provide

Strings:

FC1=C(F)C=C(C(C)=O)C=C1

to

FC1=C(F)C=C(C(OC)(OC)CO)C=C1

InChI=1S/C8H6F2O/c1-5(11)6-2-3-7(9)8(10)4-6/h2-4H,1H3

to

InChI=1S/C10H12F2O3/c1-14-10(6-13,15-2)7-3-4-8(11)9(12)5-7/h3-5,13H,6H2,1-2H3

NB used crude AEW 232-3 prior to NMR owing to time constraints - will check validity of SM asap.

AEW 232-3 (based on 1.96 mmol) was dissolved in EtOH (8 mL). CuCl₂.2H₂O (17 mg, 0.08 mmol, 5 mol%) was added and the reaction heated at reflux for 40 mins. TLC no SM

The solvent was removed and the crude black oil was columned using the Biotage Isolera - EtOAc then 10-20% MeOH in DCM. Multiple black fractions collected.

Data:

TLC

AEW 317-1 Frac 2 NMR 300 MHz

problem accessing NMR data but looks promising

Strings:

FC(OC(C=C1)=CC=C1C2=NN=C3N2C(OCC(COC4OCCCC4)C5=CC=CC=C5)=CN=C3)F

to

OCC(C1=CC=CC=C1)COC2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2

to

InChI=1S/C21H18F2N4O3/c22-21(23)30-17-8-6-15(7-9-17)20-26-25-18-10-24-11-19(27(18)20)29-13-16(12-28)14-4-2-1-3-5-14/h1-11,16,21,28H,12-13H2

Procedure:

To a solution of oxalyl chloride (5.42 mL, 63.2 mmol, 5 equiv.) and 3 Å MS in CH₂Cl₂ (13 mL) at -78 °C under N₂ was added dropwise a solution of DMSO (8.98 mL, 126 mmol) in CH₂Cl₂ (1 mL). After 15 min a solution of the alcohol (2.00 g, 12. 7 mmol, 1 equiv.) in CH₂Cl₂ (40 mL) was slowly added dropwise. After 30 min, Et₃N (26.4 mL, 190 mmol) was added dropwise. The reaction was stirred 30 min at -78 °C then slowly allowed to warm to rt whilst stirring for 20 h.

TLC inconclusive

Reaction partioned with 1M HCl (aq) and organic layers extracted and then washed with 1M HCl (aq) x 2, a saturated aqueous solution of NaHCO₃ (x 3), water, brine and then dried over MgSO₄ filtered and evaporated to give a yellow oil. Crude NMR shows mixture of products.

TLC of crude shows one major product and faint other spots - one that can be seen more clearly when visualised with KMnO₄.

Purified using the Biotage Isolera (10% EtOAc in Hexane gradient, 50 g handpacked column) to yield two products:

Frac 1 - bright yellow liquid - desired product

Frac 2 - bright yellow oil - starting material

Data:

TLC: AEW 316-1 (10% EtOAc in Hex) after work-up

Crude NMR 300 MHz:

Strings:

FC1=C(F)C=C(C(O)C)C=C1

to

FC1=C(F)C=C(C(C)=O)C=C1

InChI=1S/C8H8F2O/c1-5(11)6-2-3-7(9)8(10)4-6/h2-5,11H,1H3

to

InChI=1S/C8H6F2O/c1-5(11)6-2-3-7(9)8(10)4-6/h2-4H,1H3

Literature Reference:

http://www.ochemonline.com/Swern_oxidation

AEW 205 (500 mg, 1.96 mmol, 1 equiv) was suspended in anhydrous toluene (10 mL) along with potassium hydroxide (384 mg, 6.84 mmol, 3.5 equiv) and 18-crown-6 (36 mg, 0.14 mmol, 0.07 equiv). AEW 287-2 (435 mg, 0.67 mmol, 1 equiv) was dissolved in anhydrous toluene and added to the reaction mixture whilst stirring at rt for ten mins. Reaction heated to 40 ˚C with stirring.

After 1h, still SM

The sample was cooled to room temperature and diluted with 10 mL of water. The mixture was extracted with EtOAc (3 x 20 mL). The combined organic layer was washed with water (1 x 10 mL) until the aqueous layer became neutral followed by brine (6 mL) and dried over Na₂SO₄. The orange/yellow fluoro solution was filtered and dried under reduced pressure and in vacuo to yield an orange oil that was dried at the high vac.

Data:

InChi:

InChI=1S/C11H9ClF2N4O/c1-7(3-2-4-19-11(13)14)10-17-16-9-6-15-5-8(12)18(9)10/h2-3,5-6,11H,1,4H2/b3-2-

and

InChI=1S/C13H18O3/c14-10-12(11-6-2-1-3-7-11)16-13-8-4-5-9-15-13/h1-3,6-7,12-14H,4-5,8-10H2

to

InChI=1S/C25H24F2N4O4/c26-25(27)34-19-11-9-18(10-12-19)24-30-29-21-14-28-15-22(31(21)24)33-16-20(17-6-2-1-3-7-17)35-23-8-4-5-13-32-23/h1-3,6-7,9-12,14-15,20,23,25H,4-5,8,13,16H2

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

and

OCC(OC1OCCCC1)C2=CC=CC=C2

to

FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(OCC(OC4OCCCC4)C5=CC=CC=C5)=CN=C3

Procedure

3,4-difluorobenzaldehyde (2.00 g, 14.1 mmol, 1.00 equiv.) was dissolved in anhydrous ether (28 mL) and then stirred at 0 ˚C. MeMgBr (4.74 mL, 14.2 mmol, 1.01 equiv, 3.0 M in THF) (colourless to pale yellow soln) and the reaction mixture stirred at 0˚C for 5 min and then allowed to warm to rt and stirred for 30 mins.

TLC showed no SM (30% EtOAc in Hexane)

Reaction mixture cooled to 0 ˚C and then a saturated solution of 1 M HCl (20 mL) added dropwise with stirring (no vigourous reaction). Volatiles were removed in vacuo to give a yellow ppt. Reaction mixture partioned between EtOAc (40 mL) and a saturated solution of ammonium chloride (40 mL) and then layers separated. Aqueous washed with EtOAc (2 x 30 mL) and then combined organic washed with water (20 mL), brine (20 mL), dried (MgSO₄), filtered and evaporated to give a pale pink liquid (2.00 g, 12.7 mmol, 90% crude yield) which was used as crude in the subsequent Swern Oxidation. 

Data:

200 MHz NMR in CDCl3

Strings

O=CC1=CC(F)=C(F)C=C1

to

FC1=C(F)C=C(C(O)C)C=C1

InChI=1S/C7H4F2O/c8-6-2-1-5(4-10)3-7(6)9/h1-4H

to

InChI=1S/C8H8F2O/c1-5(11)6-2-3-7(9)8(10)4-6/h2-5,11H,1H3