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26th October 2016 @ 17:01

 

Date of Reaction: 4 Oct. 2016

Step 1. R: Oxone, S: CH2Cl2, S: H2O

General Protocol:

 2-Methylpyrazine 1N,4Ndioxide:

2-Methylpyrazine (2.5 g, 26.625 mmol) in 150 mL CH2Cl2was stirred with (35.5 g, 57.75 mmol) of Oxone in 175 mL of H2O at room temperature. After 24 hours the organic layer was separated from the aqueous layer and then concentrated. The aqueous layer was put back in the flask and stirred for another 24 hours with another 150 mL of CH2Cl2. The organic layer from this second reaction period was also separated and concentrated. This reaction yielded off-white flakey crystals.

A TLC was taken with the product of this reaction to determine if the reaction had gone to completion and H NMR and C NMR were taken to analyze the product: H NMR (200 MHz, CDCl3) 𝞭 2.47 (s, 3H), 𝞭 7.95 (m, 1H), 𝞭 8.07 (m, 2H); C NMR (200 MHz, CDCl3) 𝞭 78(s, 1C) 

Source: McKay, S., Oxidation Methods for Aromatic Diazines: Substituted Pyrazine-N-Oxides, Pyrazine-N,N'-Dioxides and 2,2':

 

Table of Reagents:

 
 

2-Methylpyrazine

Oxone

DCM

H2O

2-Methylpyrazine 1N,4Ndioxide (product)

g

2.5

35.5

 
 

3.35

mL

 
 

150

175

 

Density

 
 
 
 
 

Molecular Weight

 
 
 
 
 

mmols

26.625

57.75

 
 

26.625

 

 

   

Alternative Step 1. “A”.

    Lanes: SM (2-methylpyrazine), CS, Product (2-methylpyrazine, 1,4- dioxide)

 Rf: S 0.44; P 0.085
 
 
 

Summary of reaction: H NMR (200 MHz, CDCl3) 𝞭 2.47 (s, 3H), 𝞭 7.95 (m, 1H), 𝞭 8.07 (m, 2H);

Theoretical yield: 3.35 g

Actual yield: 780 mg, 6.18 mmol

Percent yield: 23.3%


Attached Files
26th October 2016 @ 01:08

Alternate Route: Step 2

Date of Reaction: 18 Oct 2016

 

 

General Protocol: To the 2-methylpyrazine 1N,4N-dioxide from the B reaction (770 mg, 6.87 mmol) was added 2 mL of POCl3 and then stirred 70ºC for an hour. The product was then alkalized with 20% NaOH in an ice bath. The organic layer was then extracted with diethyl ether and then filtered by letting it pass through a small pad of silica gel. TLC taken to see if the reaction had gone to completion. H NMR (200 MHz, CDCl3) 𝞭 1.5(s), 𝞭 2.5(s), 𝞭 7.2 (s), 𝞭 8.5 (d); C NMR (200 MHz, CDCl3) 𝞭 78(s, 1C),𝞭 66(s, 1C).

 

Source: Fang, M.; Cadwallader, K. R., Convenient Synthesis of Stable Deuterium-Labeled Alkylpyrazines for Use in Stable Isotope Dilution Assays.

 

Table of Reagents:

Reagent

SM

POCl3

Molecular Weight (g)

112.09

153.33

grams

0.770

3.16

mol

0.00687

0.0206

Mol ratio

1

3

Density

--

1.645

mL

--

1.92- so add 2 mL to RB

 
 

Silica Gel

90:10 EtoAC/Hex

UV Light


Alternative Method Step 2.  

Lanes: SM (2-methylpyrazine, 1,4- dioxide), CS, Product (2,6-dichloro-2-methylpyrazine, 1,4- dioxide)

 Rf: S 0.094; P 0.39


Summary of Reaction: NMR and GC/MS data did not appear to support the double chlorination.

Theoretical Yield: 1.03 g

Actual Yield: 0.13 g

Percent Yield: 12.62%


NMR, GC/MS ATTACHED BELOW
Attached Files
26th October 2016 @ 00:42
Date of Reaction: 15 October 2016.

 

General Protocol:

2-Methylpyrazine (2.5 g, 26.56 mmol) was combined with acetic acid and  hydrogen peroxide (30% in H2O) in a 1:5:2 mol ratio respectively. The mixture was then heated to 95ºC in an oil bath and left overnight. The acetic acid was removed as the product was then concentrated by dilutions with H2O repeated rotary evaporation, and then left on the high vacuum to remove the rest of the water and acetic acid. The residue was then washed with hot chloroform (60ºC), vacuum filtered and then washed again with cold methanol to form small white crystals: H NMR (200 MHz, CDCl3) 𝞭 2.47 (s, 3H), 𝞭 7.94 (m, 1H), 𝞭 8.07 (m, 2H); C NMR (200 MHz, CDCl3) 𝞭 78(s, 1C),𝞭 68(s, 1C).

 

Source: Fang, M.; Cadwallader, K. R., Convenient Synthesis of Stable Deuterium-Labeled Alkylpyrazines for Use in Stable Isotope Dilution Assays.

 

Table of Reagents:

 
 

2-Methylpyrazine

30% H2O2

Acetic Acid

g

2.5

15.05

3.1904

mL

2.43

13.565

3.0414

Density (g/mL)

1.03

1.11

1.049

Molecular Weight (g/mol)

94.11

34.01

60.85

mmols

26.625

442.52

53.1

 

Silica Gel

90:10 EtoAC/Hex

UV Light

Lanes: SM (2-methylpyrazine), CS, Product (2-methylpyrazine, 1,4- dioxide)

Rf: S 0.369; P 0.123
 

Theoretical Yield: 3.3545 g

Actual Yield: 0.78 g

Percent Yield: 23.35%

1H and 13C NMR ATTACHED BELOW.
Attached Files
20th October 2016 @ 18:52

Date of Reaction: 30 September 2016

New Protocol for Step 1: Rxn  C


General Protocol:

Dry THF (30 mL) was added to a 3-neck round-bottom flask prepared with an addition funnel evacuated under reduced pressure. The flask was cooled to -78ºC in a dry ice and acetone bath. n-BuLi (18.5 mL, 77.178 mmol) and 2,2,6,6-tetramethylpiperidine (14.613, 85.87) were added to the flask under argon. The reaction flask was moved to an ice bath at 0ºC and allowed to stir for 60 minutes. The flask was cooled to -94ºC in an N2 (l) and hexanes bath. The starting material, 2,6-dichloropyrazine was dissolved in dry THF (10 mL) and added to the reaction flask dropwise under argon. After 120 minutes, CH3I in 500% excess (8.433 mL, 148.53 mmol) was added via the addition funnel. The reaction was allowed to proceed for 24 hours. EtoAC and H2O were added to the reaction flask. The contents were transferred to a separatory funnel, and the organic layer was isolated, dried with MgSO4, and filtered. The product was separated with a Biotage (Silica gel, 85:15 (Hexanes/EtoAC) as reference). The resulting fractions were concentrated under vacuum.

No data to report because reaction was unsuccessful.

Source: Walker, J.A.; Liu, W.; Wise, D.S.;Drach, J.C.; Townsend, L.B; Synthesis and Antiviral Evaluation of Certain Novel Pyrazinoic Acid C-Nucleosides. Journal of Medicinal Chemistry. 1998, 41, 1236-1241.


Table of Reagents:


 

2,6-dichloropyrazine

TMP

MeI

n-BuLi

MW (g/mol)

147.96

141.25

141.94

163

g

4.01

12.129

21.0825

--

mmol

27.1

85.87

148.53

77.178

mL

--

14.613

8.433

18.5

density

--

0.83 g/mL

2.5 g/mL

0.68 g/mL

 
TLC plate:
 

Silica Gel

80:15 Hex/EtoAC

UV Light


Step 2. Rxn C. TLC of fraction after Biotage at 254 nm peak. Suggests starting material degradation and incomplete reaction.


Summary of Reaction:

Rxn C was deemed unsuccessful due to TLC data and lack of supporting NMR data. Could be due to degraded starting material.


Theoretical Yield: 4.42 g

Actual Yield: -- Determined product was not recovered. 
20th October 2016 @ 15:04

Date: 23, Sept. 2016

Dates of reactions: Rxn A: 23 Sept. 2016, Rxn B: 23 Sept. 2016


General Protocol:

Stage 1.1: R: 2,6-dichloropyrazine, R:CsF, R:H2NNH2, S: DMSO, 25ºC; Overnight.

The products from reactions A and B were each dissolved in DMSO and stirred with anhydrous Hydrazine and CsF in a 1:1:3 mol ratio and left overnight.


Table of Reagents: Rxn A

 

Single methylated product

CsF

Hydrazine

Product (predicted)

mw

163

151.9

32.04516

144.562

Equiv.

1

3

1

1

mol

0.000184

 

0.000184

0.000154

mg

23

   

22

mL

   

0.00589

 

g/mL

   

1.021

 
  • At this point in the process we thought we were working with a methylated product. However, upon analysis we realized that the reaction did not go to completion and we were left with the starting material which has a molecular weight of 148.978 meaning that we used 0.000154 mol of our starting material, and that our product would be 2-chloro-6-hydrazineylpyrazine. This table shows our calculations for the reagents that we thought we were using but predicts the yield for the product using the actual reagents.