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Synthesis of 5-chloro-3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine (Repeat with different conditions)

Method:

2-chloro-6-(2-hydrazinyl(4-(dimethylamino)benzylidene))pyrazine) (52 mg, 0.18 mmol, 1.00 equiv.) was dissolved in chloroform (20 mL) forming a yellow solution. PIDA (62 mg, 0.19 mmol, 1.1 equiv.) was then added. The reaction was stirred at 50°C and the yellow solution became progressively red-orange within an hour. The reaction was monitored by TLC (3:7 Ethyl acetate: PET ether) and after 4 hours the TLC showed that no starting material remained. The reaction was quenched with saturated sodium hydrogen carbonate solution. The organic layer was isolated by separation with brine before drying over MgSO4. The dried filtrate was concentrated in vacuo to a dark brown crude oil. The crude product was characterised by IR and 1HNMR before purification by silica column (10 g silica) with an initial 1:1 Ethyl acetate: PET ether solvent system, then 7:3 Ethyl acetate : PET ether after starting material had been eluted; this was monitored by TLC. Many fractions were obtained and dried in vacuo, forming dark brown powders. Fraction A (34 mg, 65 %) and Fraction B (32 mg, 62%), were then characterised by IR, 1H NMR, and 13C NMR, DEPT and MS. 5-chloro-3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine. IR taken immediately after their isolation showed presence of product, while NMR spectra showed the absence of aromatic signals, suggesting degradation overnight within the NMR tubes.


Synthesis of 2-chloro-6-hydrazinopyrazine

2,6-Dichloropyrazine (3 g, 20.1 mmol) was vigorously stirred in ethanol (30 mL) and hydrazine hydrate (1 mL, 1.02 g, 20.1 mmol) was added. The resulting mixture was heated at reflux (78 ˚C) overnight (~16 hours), forming a yellow solution. After completion (monitored by TLC, 30% EtOAc in Hexane, Rf = 0.2), a yellow solid precipitated out of solution, and was filtered and dried, yielding fine, yellow crystals of 2-Chloro- 6-hydrazinopyrazine (0.189g, 6.7%). The filtrate was also recovered in vacuo to give a yellow powder (2.001g, 70.96%). Both of these products were characterised by 1H NMR and IR.

Synthesis of 2-chloro-6-(2-hydrazinyl(4-nitrobenzylidene)pyrazine)

Method:

2-chloro-6-hydrazinopyrazine (100.0mg, 0.69 mmol, 1.00 equiv.) was partially dissolved in EtOH (~12 mL) forming a yellow suspension. 4-nitrobenzaldehyde (117.0 mg, 0.77 mmol, 1.1 equiv.) was then added partial dissolution. The mixture was stirred for 10 minutes before being heated to 30°C to aid solubility. The yellow suspension was stirred and heated for a further 2 hours and 40 minutes and became progressively deeper orange coloured; it was monitored by TLC (9:1 PET ether: Ethyl acetate) until completion. The solid was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(4-nitrobenzylidene)pyrazine) as a yellow powder (105.6 mg, 55%). This was characterised by IR and 1H NMR. 


Synthesis of 2-chloro-6-(2-hydrazinyl(2-hydroxybenzylidene)pyrazine)

Method:

2-chloro-6-hydrazinopyrazine (100.0mg, 0.69 mmol, 1.00 equiv.) was partially dissolved in EtOH (~10 mL) forming a yellow solution. 2-hydroxybenzaldehyde (0.1 mL, 0.958 mmol, 1.2 equiv.) was then added giving a clear yellow solution. The mixture was stirred for 2 hours before being heated to 72°C for 5 minutes and became progressively slightly darker in colour; it was monitored by TLC (9:1 PET ether: Ethyl acetate) until completion. The solid was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(2-hydroxybenzylidene)pyrazine) as yellow crystals (20.6 mg, 12%). This was characterised by IR and 1HNMR. The filtrate was also recovered in vacuo to give an orange powder (142.6 mg, 83%) and characterised by IR and 1H NMR.

Synthesis of 2-chloro-6-(2-hydrazinyl(2,4-dimethoxybenzylidene)pyrazine)

Method:

2-chloro-6-hydrazinopyrazine (A) (100.00 mg, 0.70 mmol, 1.00 equiv.) was dissolved in EtOH (10 mL) forming a bright yellow solution, to which 2,4-dimethoxybenzaldehyde (B) (126 mg, 0.76 mmol, 1.1 equiv.) was added. The reaction was stirred for a further 3.5 hours and was monitored by TLC. During this time, a yellow precipitate formed. The reaction mixture was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(2,4-dimethoxybenzylidene))pyrazine) as a yellow powder (59.1 mg, 29.2%) which was characterised by IR and 1H NMR. Remaining product in the filtrate, a dark orange oil, was also recovered in vacuo (98.1 mg, 48.4%). TLC of the filtrate showed a mixture of many compounds which proved very difficult to separate using a silica column, so the filtrate was discarded.

Synthesis of 5-chloro-3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

2-chloro-6-(2-hydrazinyl(4-(dimethylamino)benzylidene))pyrazine) (51 mg, 0.18 mmol, 1.00 equiv.) was dissolved in DCM (20 mL) forming a yellow solution. PIDA (62 mg, 0.19 mmol, 1.1 equiv.) was then added. The yellow solution became progressively orange within two hours. The reaction was stirred for 2.5 hours at room temperature before heating to 30 °C for a further two hours. The reaction was monitored by TLC (3:7 Ethyl acetate : PET ether) however starting material remained so it was left stirring at room temperature overnight. After 22.5 hours the solution was a darker orange and TLC showed that only a small amount of starting material remained. The reaction was quenched with saturated sodium hydrogen carbonate solution. The organic layer was isolated by separation with brine before drying over MgSO4. The dried filtrate was concentrated in vacuo to a dark brown crude oil. The crude product was characterised by IR and 1HNMR before purification by silica column (5 g silica) with a 1:1 Ethyl acetate : PET ether solvent system. A dark brown powder (13.2 g, 26 %) was obtained and the pure product, 5-chloro-3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine, was then characterised by IR, 1HNMR, and 13CNMR, DEPT and MS.

 *Combined fractions 10-23 as pure product, fractions 3-9 were combined and retained in case of later analysis.

Synthesis of 2-chloro-6-(2-hydrazinyl(4-chlorobenzylidene))pyrazine)

Method

2-chloro-6-hydrazinopyrazine (A) (101.0 mg, 0.70 mmol, 1.00 equiv.) was partially dissolved in EtOH (10 mL) forming a yellow solution. 4-chlorobenzaldehyde (B) (105.0 mg, 0.75 mmol, 1.1 equiv.) was then added causing full dissolution. The yellow solution was stirred for five minutes at room temperature before a pale yellow solid precipitated out of the reaction mixture. The reaction was stirred for a further 2.5 hours and was monitored by TLC (3:7 Ethyl acetate : PET ether)* until completion. The solid was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(4-chlorobenzylidene))pyrazine) as a pale yellow powder (103.9 mg, 56.5 %). This was characterised by IR and 1HNMR. The filtrate was also recovered in vacuo and characterised by IR and 1HNMR but excess 4-chlorobenzaldehyde starting material was also present so an accurate yield could not be determined.

*4-chlorobenzaldehyde is unstable to TLC (see 2DTLC).


Synthesis of 2-chloro-6-(2-hydrazinyl(4-(dimethylamino)benzylidene))pyrazine)

Method

2-chloro-6-hydrazinopyrazine (A) (100.7mg, 0.70 mmol, 1.00 equiv.) was partially dissolved in EtOH (10 mL) forming a yellow solution. 4-(dimethylamino)benzaldehyde (B) (115.3 mg, 0.77 mmol, 1.1 equiv.) was then added causing full dissolution. The orange-yellow solution was stirred for five minutes at room temperature before an orange solid precipitated out of the reaction mixture. The reaction was stirred for a further 2.5 hours and became progressively more red-orange; it was monitored by TLC (3:7 Ethyl acetate : PET ether) until completion. The crude solid was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(4-(dimethylamino)benzylidene))pyrazine) as an orange powder (129.2 mg / 67.3 %). This was characterised by IR and 1HNMR. The filtrate was also recovered in vacuo to give a deep red powder and characterised by IR and 1HNMR.


Synthesis of 2-chloro-6-(2-hydrazinyl(benzylidene)pyrazine)

Method:

2-chloro-6-hydrazinopyrazine (A) (100.7 mg, 0.70 mmol, 1.00 equiv.) was partially dissolved in EtOH (10 mL) after it was diluted by a factor of 10, forming a white solution. Benzaldehyde (B) (81.0 mg, 0.77 mmol, 1.1 equiv.) was then added causing full dissolution. The solution was stirred for five minutes at room temperature before a solid precipitated out of the reaction mixture. The reaction was stirred for a further 2.5 hours with no significant change in colour observed; it was monitored by TLC (1:9 Ethyl acetate : PET ether for half the reaction and  3:7 Ethyl acetate : PET ether for the other half) until completion. The solid was filtered under vacuum to give 2-chloro-6-(2-hydrazinyl(benzylidene)pyrazine) as a white powder (71.3 mg,44.5%). This was characterised by IR and 1HNMR. 

 

 

Synthesis of benzaldehyde (6-chloro-pyrazin-2-yl)-hydrazone

Method:

2-chloro-6-hydrazinopyrazine (A) (100.7 mg, 0.70 mmol, 1.00 equiv.) was partially dissolved in EtOH (10 mL) after it was diluted by a factor of 10, forming a white solution. Benzaldehyde (B) (81.0 mg, 0.77 mmol, 1.1 equiv.) was then added causing full dissolution. The solution was stirred for five minutes at room temperature before a solid precipitated out of the reaction mixture. The reaction was stirred for a further 2.5 hours with no significant change in colour observed; it was monitored by TLC (1:9 Ethyl acetate : PET ether for half the reaction and  3:7 Ethyl acetate : PET ether for the other half) until completion. The solid was filtered under vacuum to give benzaldehyde (6-chloro-pyrazin-2-yl)-hydrazone as a white powder (71.3 mg,44.5%). This was characterised by IR and 1HNMR.