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10th December 2016 @ 19:06

12/7/16

STEP 4

Addition of Cl to pyrazine ring with required carbonyl protection

Part A product

C1(C2(OCCO2)CC3=CC=CC=C3)=CN=CC=N1>>[O]

InChI=1S/C14H14N2O2.O/c1-2-4-12(5-3-1)10-14(17-8-9-18-14)13-11-15-6-7-16-13;/h1-7,11H,8-10H2;

YIFIFTZQXBJMLM-UHFFFAOYSA-N

Part B product

ClC1=NC(C2(OCCO2)CC3=CC=CC=C3)=CN=C1

InChI=1S/C14H13ClN2O2/c15-13-10-16-9-12(17-13)14(18-6-7-19-14)8-11-4-2-1-3-5-11/h1-5,9-10H,6-8H2

KPKPSDGULUMWQV-UHFFFAOYSA-N

Part C product

O=C(CC1=CC=CC=C1)C2=CN=C(Cl)C=N2

InChI=1S/C12H9ClN2O/c13-12-8-14-10(7-15-12)11(16)6-9-4-2-1-3-5-9/h1-5,7-8H,6H2

WEZOQKFQIMSBCX-UHFFFAOYSA-N

From literature:

[[Part A - page 7688

Methyl 2-pyrazinecarboxylate (41) (Pyrazine Specialists, 10.04 g, 72.2 mmol) was suspended in 1,2-dichloroethane (100 mL). To the reaction mixture was added mCPBA (32.35 g, 77%, 144 mmol). The reaction was stirred at 60 C for 16 h. The reaction was then allowed to cool to ambient temperature and diluted with CH2Cl2 (300 mL). The precipitate was filtered off and washed with additional CH2Cl2 (3 x 35 mL). The filtrates were combined, dried over K2CO3, filtered, and concentrated. The residue was suspended in hexane (50 mL). The title compound was isolated by filtration and washed with additional hexane (2 x 50 mL) to afford a slightly yellow solid (7.22 g, 64%).

 

Reagent

Molar mass (g/mol)

Mass (g)

mol

Density (g/ml)

Volume (ml)

equiv.

2-(2-benzyl-1,3-dioxolan-2-yl)pyrazine

(Product step 3)

242.28

30 mg

.124  mmol

 
 

1.0

1,2-dichloroethane

98.96

 

mmol

1.256

??

 

mCPBA

172.57

42.8 mg

(42.6)

.248 mmol

 
 

2.0

 

Part B

Pg 7688

Methyl 4-oxy- 2-pyrazinecarboxylate (42) (7.18 g, 45.9 mmol) was dissolved in SOCl2 (50 mL, 687 mmol). The reaction was heated to reflux for 8 h and then allowed to cool to ambient temperature. The SOCl2 was removed under reduced pressure, and the residue was quenched with water (50 mL) at 0 C. The mixture was neutralized by the addition of 1 M K2CO3 (aq) and extracted with CH2Cl2 (5 100 mL). The organic extracts were combined and washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (5% EtOAc in CH2Cl2, Rf = 0.35) to afford the title compound as a thick oil that slowly solidified.

 

Part C

Pg 26-27

Deprotection using H3O+ and heat

The protection group is not included in the desired product, making the use of them less atom economical. However, in order to move to the next step the carbonyl needs to be protected because the SOCl2 could react with the carbonyl instead of the nitrogen ring.]]

 

Actual procedure:

LADvT 3-1 (30 mg) was suspended in 1,2-dichloroethane (~5 mL). To the reaction mixture was added mCPBA (42.8 mg, 77%, 144 mmol). The reaction was stirred at 80 C overnight. The reaction was then allowed to cool to ambient temperature.

12/9/16

Diluted with CH2Cl2 (15 mL). No precipitate present and this crude product was concentrated under reduced pressure to afford a very slightly yellow solid (45.1 mg).

NMR was run on this crude product. It does not appear that the expected product was synthesized.
 
10th December 2016 @ 17:47

12/7/16

Attempt 2 at synthesizing 2-(2-benzyl-1,3-dioxolan-2-yl)pyrazine

C1(C2(OCCO2)CC3=CC=CC=C3)=CN=CC=N1

InChI=1S/C14H14N2O2/c1-2-4-12(5-3-1)10-14(17-8-9-18-14)13-11-15-6-7-16-13/h1-7,11H,8-10H2

XXKCDWUSXLRLIU-UHFFFAOYSA-N

 

Reagent

Molar mass (g/mol)

Mass (g)

mol

Density (g/ml)

Volume (ml)

equiv.

2-phenyl-1-(pyrazin-2-yl)ethan-1-one

(Product step 2)

198.23

0.2791 g

1.4 mmol

 
 

1.0

Ethylene glycol

62.07

0.433 g

6.97 mmol

1.114

.3888

4.98

TsOH-H2O

190.22

0.0418 g

.22 mmol

 
 

.1577

Toluene

92.14

 
 
 

~5

 

LADvT 2-2, LADvT 2-3 and recovered step 2 product from LADvT 3-1 were combined (0.2791 g) and added to a solution of ethylene glycol (0.4 ml), and TsOH-H2O (30 mg, 2.6 mol %) in toluene (35 mL) was heated under a nitrogen atmosphere with use of a Dean-Stark water trap for 4 h.

Reflux turned off at 9:00 pm. The cooled reaction mixture was diluted with ~30 mL of hexanes and extracted successively with saturated NaHCO3 (1.89 mL, actually ~30-40 ml?), water (3 X 20 mL), and brine (20 mL). The organic layer was dried, and the volatiles were removed in vacuo to afford crude product as an oil.

TLC

20:80 EtOAc/Hexanes

left = crude product step 4

middle left = crude product step 3 attempt 1 (top spot is starting material/product step 2)

middle right = crude product step 3 attempt 2 (no starting material spot)

right = product step 2

 

Did not purify this product prior to getting NMR, thus spectrum shows significant impurities.

10th December 2016 @ 17:14

11/30/16

STEP 3

Synthesizing 2-(2-benzyl-1,3-dioxolan-2-yl)pyrazine

C1(C2(OCCO2)CC3=CC=CC=C3)=CN=CC=N1

InChI=1S/C14H14N2O2/c1-2-4-12(5-3-1)10-14(17-8-9-18-14)13-11-15-6-7-16-13/h1-7,11H,8-10H2

XXKCDWUSXLRLIU-UHFFFAOYSA-N

 
Lit procedure (page 4139 of journal):

A solution of "starting material" (1.60 g, 6.02 mmol), ethylene glycol (1.88 g, 30 mmol), and TsOH-H2O (30 mg, 2.6 mol %) in toluene (35 mL) was heated under a nitrogen atmosphere with use of a Dean-Stark water trap for 3 h. The cooled reaction mixture was diluted with 150 mL of hexanes and extracted successively with saturated NaHCO3 (30 mL), water (3 X 50 mL), and brine (50 mL). The organic layer was dried, and the volatiles were removed in vacuo to afford crude "product" as an oil.

 

Reagent

Molar mass (g/mol)

Mass (g)

mol

Density (g/ml)

Volume (ml)

equiv.

2-phenyl-1-(pyrazin-2-yl)ethan-1-one

(Product step 2)

198.23

0.1006 g

.5075 mmol

 
 

1.0

Ethylene glycol

62.07

.1570

2.53 mmol

1.114

.1410

4.98

TsOH-H2O

190.22

.00251

.0041 mmol

 
 

.1577

Toluene

92.14

 
 
 

2.2001

 
 

Very little reflux reached 110 C at approx 4pm

First increased temp to 120 and added Al foil to insulate glassware set up. Added 5 ml dry toluene to sidearm.

Then temperature raised to 140 C over 30 min and additional 10 ml dry toluene added -- approx 7pm.

Reflux turned off at 11pm.

 

12/1/16 

The cooled reaction mixture was diluted with ~10 mL of hexanes and extracted successively with saturated NaHCO3 (1.89 mL, actually ~10-20 ml), water (3 X 3.14 mL), and brine (3.14 mL). The organic layer was dried, and the volatiles were removed in vacuo to afford crude product as an oil.

12/2/16 

Flash chromatography done

30:70 EtOAc/Hexanes

0.2 g loaded into biotage

Fraction 8-9 look like SM (50.9 mg)

Fraction 13-14 look like product (27.2 mg)

12/5/16

NMR for step 3 fractions 8-9 and 13-14

The NMR above shows product Step 3 successfully made

Impurities

2ppm ethyl acetate

1.5ppm water

7.26 CDCl3 (H) containment

(CDCl3) δ: 8.65 (m, 1 H), 8.65 (m, 1H), 8.62 (m, 1H,), 7.26 - 7.17 (m, 5H), 3.86 (d,4H), 3.34 (d,2H)

ChemDraw Predictions

δ: 8.58 (m, 1 H), 8.58 (m, 1H), 8.67 (m, 1H,), 7.21 - 7.23 (m, 5H), 3.87-3.62 (d,4H), 2.76 (d,2H)


NMR for fractions 8-9 

Show starting material recovered which is product from Step 2, so this was used to repeat step 3.

8-9 step  3 (productt 2).PNG
 
10th December 2016 @ 15:26

11/30/16

Step 2 attempt 3

Procedure scaled  .3925 g SM

Full procedure for 2-Phenyl-1-pyrazinylethanone (phenylacetylpyrazine).

2-Phenyl 2-carbethoxy-1-pyrazinylethanone (0.3925 g) in 190 proof ethanol (24 mL) and H2O (16 mL) containing concentrated HCl (.59 mL) was heated under reflux at 100°C overnight. Completion of the reaction was checked by TLC after a "mini-workup". Saturated aqueous sodium bicarbonate was added to the reaction mixture which was then extracted with dichloromethane (3 × 40 mL), washed with brine, dried (MgSO4), and evaporated to give a brown oil which solidified on cooling. The product was purified by flash chromatography on silica using 80:20 hexane/ethyl acetate to give white crystals.

Reflux start at approx 2pm

Reflux overnight and reaction mixture is orange color. Turned a very strange color/mixture (different from last time with some dark solid - similar to what product looked like after microwaving the first time of this decarboxylation with different procedure)

TLC with 20:80 EtOAc/Hexanes

12/2/16
Extractions done on step 2 attempt 3

Saturated aqueous sodium bicarbonate was added to the reaction mixture which was then extracted with dichloromethane (3 × 100 mL), washed with brine, dried (MgSO4), and evaporated to give a brown oil which solidified on cooling (~700 mg). The product was purified by flash chromatography on silica using 90:10 hexane/ethyl acetate to give white crystals (~500 mg).


NMR is consistent that we succesfully made Step 2 Product in attempt 3 though contains same impurities

8-9 step  3 (productt 2).PNG




10th December 2016 @ 14:54

11/21/16

Step 2 decarboxylation with HCl method

Full procedure:

2-Phenyl-1-pyrazinylethanone (phenylacetylpyrazine).

O=C(CC1=CC=CC=C1)C2=CN=CC=N2

InChI=1S/C12H10N2O/c15-12(11-9-13-6-7-14-11)8-10-4-2-1-3-5-10/h1-7,9H,8H2

TUVQXTMNRPVZGT-UHFFFAOYSA-N

Literature procedure: 2-Phenyl 2-carbethoxy-1-pyrazinylethanone (1.0g) in 60% aqueous ethanol (100 mL) containing concentrated HCl (1.5 mL) was heated under reflux at 100°C overnight. Completion of the reaction was checked by TLC after a "mini-workup". Saturated aqueous sodium bicarbonate was added to the reaction mixture which was then extracted with dichloromethane (3 × 100 mL), washed with brine, dried (Na2SO4), and evaporated to give a brown oil which solidified on cooling (~700 mg). The product was purified by flash chromatography on silica using 90:10 hexane/ethyl acetate to give white crystals (~500 mg). 2-Phenyl-1-pyrazinylethanon (phenylacetylpyrazine), yield ~500mg Anal. Calcd for C12H10N2O: C, 72.72; H, 5.09; N, 14.15. Found: 72.16; H, 5.08; N 14.15. 1H NMR (270 MHz, CDCl3) d: 9.3 (m, 1 H), 8.8 (m, 1H), 8.7 (m, 1H,), 7.2 - 7.5 (m, 5H), 4.5 (s, 2H). 13C NMR (68 MHz, CDCl3) d: 198.5, 147.8, 147.3, 144.2, 143.5, 133.8, 129.9, 129.9, 128.6, 127.0, 44.2. MS m/z: 198 (M+, 54), 169 (31), 107 (36), 91(100), 65 (40), 52 (32), 39 (18).

Reflux overnight and reaction mixture is orange color.

TLC with 20:80 EtOAc/Hexanes

 

11/23/16

10:90 EtOAc/Hexanes

Left = starting material (product from step 1)

Middle = cospot

Right = decarboxylation crude product after reflux

10:90 EtOAc/Hexanes

Far left: aqueous layer

Middle left: S2 crude prior to mini extraction

Middle right: cospot (all 3)

Far right: organic layer

 

(same plate/lanes as above)

This mini extraction TCL shows successful removal of acid (bromocresol green stain)

 
 

Reagent

Molar mass (g/mol)

Mass (g)

mol

Volume

ethyl 3-oxo-2-phenyl-3-(pyrazin-2-yl)propanoate

(Product step 1)

270.29

1.0 g

~3.7 mmol

 

Ethanol

46.07

 
 

100 mL

HCl

36.46

 
 

1.5 mL

 

11/28/16

Extraction

Sat. aq. NaHCO3 was added to reaction mixture (clear orange) which was subsequently extracted with DCM (3 × 100 mL), washed with brine and dried over MgSO4. This was then gravity filtered and evaporated, yielding a dark brown oil.

Flash chromatography was done and two sets of fractions were collected.

Frac 24-29

Empty rb: 144.6

Rb + product: 145.2

Product: 0.6 g

Mostly white with small flecks of yellow solid

 

Frac 15-19

Empty rb: 146.5 g

Rb+product: 147.1 g

product : 0.6 g

White crystal

 

TLC

30:70 EtOAc/hexanes

 

Fractions 24-29 has multiple impurities - not product

24-29 less pure 2 .jpeg

 
 
 
 
 

Product in fractions 15-19 some impurities but looks like correct product

15-19 p 2.jpeg

2ppm ethyl acetate

1.5ppm water

7.2 CDCl3 (H) contaminent which is why it doesn’t integrate for 5  

(CDCl3) δ: 9.23 (m, 1 H), 8.75 (m, 1H), 8.68 (m, 1H,), 7.33 - 7.5 (m, 5H), 4.5 (s, 2H)

Lit: (CDCl3) δ: 9.3 (m, 1 H), 8.8 (m, 1H), 8.7 (m, 1H,), 7.2 - 7.5 (m, 5H), 4.5 (s, 2H)

The benzene should have 5H not 9, but may be just from all 5 hydrogens are really at a bit different ppms

 

GCMS

GS P 2.PNG


Small Peak

smaller peak MS P 2.PNG

 
 
 
 

Large Peak

larger peak MS.PNG

 Peaks are consistent with the expected product.