Tag Archives: Malaria

Re-Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine (isomer isolation)

MOD-1-030 MOD-1-034

Re-Synthesis of 4-(4-((2-(6-chloropyrazin-2-yl)hydrazineylidene)methyl)phenyl)morpholine (isomer isolation)

Reaction Scheme for resynthesis

Reaction 1-MOD-1-034

Reagent

Equivalent

Molecular weight

mmol

Quant.

2-chloro-6-hydraziynlpyrazine

1.00

144.56

0.35

50 mg

4-morpholinobenzaldehyde

1.00

191.23

0.35

62 mg

Ethanol

 

46.07

-

4 mL

 

 

 

 

 





Procedure

2-chloro-6-hydrazinylpyrazine (50 mg) was stirred into ethanol (4 mL). 4-morpholinobenzaldehyde (62  mg) was then added and stirred at ambient temperature for 8 hours.

 

MOD-1-034 reaction T=8.png

The reaction mixture changed colour from yellow to orange after 8 hours.

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 7:3) the solvent was removed under reduced pressure to give the product MOD-1-034 as a orange solid (0.0995 g, 0.31 mmol, 90.17%).

TLC 1.png

1H NMR of the product MOD-1-034 was taken in different solvents to compare which was the best solvent and the see isomer seperation. MeOD was determined as the best solvent. The NMR showed that many isomers of the product were afforded.

 

Reaction 2-MOD-1-030

Reagent

Equivalent

Molecular weight

mmol

Quant.

2-chloro-6-hydraziynlpyrazine

1.00

144.56

0.35

50 mg

4-morpholinobenzaldehyde

1.00

191.23

0.35

62 mg

MeCN

 

60.05

-

0.045 mL

AcOH

 

41.01

-

1 mL

 

Procedure

2-chloro-6-hydrazinylpyrazine (50 mg) was stirred into MeCN (1 mL). 4-morpholinobenzaldehyde (62  mg) and AcOH (0.045 mL) was then added and stirred at ambient temperature for 8 hours.

The reaction mixture changed colour from yellow to red after 8 hours.

MOD-1-030 reaction T=8.png

Upon completion (as detemrined by TLC analysis (Pet. Ether/ EtOAc 7:3) the solvent was removed under reduced pressure to give the product MOD-1-030 as a red solid (0.1048g, 0.33 mmol, 92.23%).

TLC 1.png

1H NMR of the product MOD-1-034 was taken in different solvents to compare which was the best solvent and the see isomer seperation. MeOD was determined as the best solvent. The NMR showed that many isomers of the product were afforded.

Isomer Seperation

Due to both MOD-1-030 and MOD-1-034 containing isomers the products were combied. The best solvent system was determined as (Toluene/Acetone 19:1).

Solvent system analysis 1.png

Solvent system analysis 2.png

The crude mixture was purified via flash chromatography on silica gel (Toluene/Acetone 19:1). Forming fractions MOD-1-034-3-4, MOD-1-034-5-42, MOD-1-034-43-54. The fractions all contained isomers and therfore were not successfully seperated. 

References

1.T. York, Open Source Malaria, Malaria.ourexperiment.org, 2016.

2.C. Xia, Open Source Malaria, Malaria.ourexperiment.org, 2016.

3.B. Xie, Open Source Malaria, Malaria.ourexperiment.org, 2016.

 

Synthesis of (E)-2-chloro-6-(2-(4(pyrrolindin-1-yl)benzylidene)hydrazine)pyrazine from 4-(pyrrolindin-1-yl)benzaldehyde and 2-chloro-6-hydrazinylpyrazine in a condensation reaction

AT-1-023

Synthesis of (E)-2-chloro-6-(2-(4(pyrrolindin-1-yl)benzylidene)hydrazine)pyrazine (AT-1-023) from 4-(pyrrolindin-1-yl)benzaldehyde and 2-chloro-6-hydrazinylpyrazine in a condensation reaction

 reaction scheme

 

 

Reagent

Eq

Mw

mmol

w/vol

4-(pyrrolindin-1-yl)benzaldehyde

1

175.23

0.9823

172mg

2-chloro-6-hydrazinylpyrazine

1

144.56

0.9823

142mg

Ethanol

~

46.07

~

8ml

 

Experimental Procedure

 

2-chloro-6-hydrazinylpyrazine (0.142g, 0.9823mmol) and ethanol (8ml) were placed into a round bottom flask. 4-(pyrrolindin-1-yl)benzaldehyde (0.172g, 0.9823mmol) was also added to the round bottom flask. The reaction was stoppered and put on to mix for 2.5 hours.

IMG_2808.png

IMG_2811.png

During this time the colour of the reaction changed from orange to bright red.

TLC’s ( 1:1 pet ether/ EtOAc) had to go through a mini work up before TLC’s could be taken as the mixture was too concentrated and distorted the spots.

IMG_2826.png

The TLC showed the loss of the starting material from the product and the formation of what we assumed to be product. Once this was confirmed, the solvent was removed in vacuo and an NMR was taken. It showed some solvent impurities so the solution was washed in d-chloroform and the solvent was removed in vacuo  again. The Final product was given as an red solid (0.2706g, 0.899mmol, 91%). 1H NMR showed that the product had been formed had some ethanol impurities, even after washing in d-chloroform. Apart from that the product seemed to be clean.

 

crude nmr at-23.png

final nmr at-23.png

at-23 cosy.png

Reference

  1. Open source malaria: our experiment, http://malaria.ourexperiment.org/triazolopyrazine_se/9268/Synthesis_of_E2chloro62naphthalen2ylmethylenehydrazinylpyrazine_TY_21.html, date accessed: 04/11/16

 

Synthesis of 4-(Pyrrolidin-1-yl)benzaldehyde from 4-Fluorobenzaldehyde and Pyrrolidine via SNAr using sonication

AT-1-012

Synthesis of 4-(Pyrrolidin-1-yl)benzaldehyde from 4-Fluorobenzaldehyde and Pyrrolidine via SNAr using sonication

 reaction scheme

 

 

Reagent

Eq

Mw

mmol

w/vol

4-Fluorobenzaldehyde

1

124.11

2.2

0.21ml

Pyrrolidine

3

71.12

2.2

0.18ml

DMSO

-

78.13

-

2ml

K2CO3

1.5

138.21

2.2

0.304g

 

Experimental Procedure

 

Pyrrolidine (0.18ml, 2.2mmol) was added to DMSO (2ml), in a round bottom flask and then anhydrous K2CO3 (0.304g, 2.2mmol) and 4-Fluorobenzaldehyde (0.21ml, 2.2mmol) were added sequentially. The round bottom flask was placed into a sonication machine and turned on and left to react for 15 minutes.

After 15 minutes, a TLC was taken from the mixture (5:3 Pet. Ether: Diethyl ether), this showed the reaction hadn’t moved far due to the large amounts of starting material present in the product. The reaction was put on for a further 45 minutes and a TLC was taken after this time, but it showed almost no change.

IMG_2615.png

The reaction to synthesise 4-(Pyrrolidin-1-yl)benzaldehyde using sonication didn’t produce results, so the previous experiment using SNAr reaction without sonication was decided to be used as the route of synthesis for 4-(Pyrrolidin-1-yl)benzaldehyde as it produced a good yield to move forward. No successfull yield was produced so no NMR data was taken as it was deemed unnecessary.

Reference:

  1. Magdolen, Peter, Tetrahedron, 2001 ,  vol. 57,  # 22  p. 4781 – 4785
  2. Organic-chemistry, sonochemistry, http://www.organic-chemistry.org/topics/sonochemistry.shtm, accessed 16th Oct 2016

 

 

 

 

 

Resynthesis of (E/Z)-2-(2-benzylidenehydrazineyl)-6-chloropyrazine and isolation of the isomers formed

Date experiment was active 21-29/11/16

TRF25-01 was successfully synthesised via cyclisation of product TRF21-01 (exp 6). However, the yield was low (15%). TRF21-01 exists as two geometric isomers; it was suspected that one isomer did not cyclise- accounting for the lack of yield. This was confirmed during exp 6 when TLC27-03 showed the presence of two spots when using TRF21-01 as the SM in the TLC, this also suggested that the two isomers had different rf values and could be isolated through chromatography. For this experiment TRF21-01 was resynthesized using two different solvent systems for the reaction (reaction A- ethanol, reaction B- acetonitrile/acetic acid) to see if the solvent favoured one isomer formation. Following this isolation of one of the isomers through chromatography ensued. 

 

Procedure (Reaction A)
 

Compound CAS Moles (mmol) Quantity Equiv.

2-chloro-6-hydrazineylpyrazine (TRF17-01)

  0.36 52.3 mg 1.0
Benzaldehyde 100-52-7 0.39 0.04 mL 1.0
Ethanol  64-17-5 68.5 4 mL 190.4

 

Both reactions were carried out on a micro scale using small glass vials. TRF17-01 (52.3 mg, 0.36 mmol), benzaldehyde (0.04 mL, 0.39 mmol) and ethanol (4 mL) were mixed together. After 2.5 hrs TLC analysis (TLC32-01, Pet. Ether/EtOAc 7:3) confirmed the reaction had gone to completion with no SM present. The solvent was removed in vacuo leaving a sand-yellow crude (85.8 mg). 1HNMR data was obtained (NMR32-01-CRUDE; CDCl3), the NMR resembled that of NMR23-01 (NMR taken for TRF21-01 in exp 5) showing the same product was made again. 

 

Procedure (Reaction B)
 

Compound CAS Moles (mmol) Quantity Equiv.

2-chloro-6-hydrazineylpyrazine (TRF17-01)

  0.37 53.1 mg 1.0
Benzaldehyde 100-52-7 0.39 0.04 mL 1.0
Acetonitrile 75-05-8 19.1 1.0 mL 190.4
Acetic acid (glacial) 64-19-7 0.87 0.05 mL 2.3

 

TRF17-01 (53.1 mg, 0.37 mmol), benzaldehyde (0.04 mL, 0.39 mmol), acetonitrile (1.0 mL) and glacial acetic acid (0.05 mL) were mixed together. After 2 hrs TLC analysis (TLC36-03, following a mini-work up of the reaction in ethyl acetate and water- Pet. Ether/EtOAc 7:3) confirmed the reaction had gone to completion. The solvent was removed in vacuo leaving a sand-yellow crude (84.7 mg). 1HNMR data was obtained (NMR37-01-CRUDE; CDCl3). 

The NMR data from reactions A and B confirmed the same product was made, it was concluded that the different solvent system did not significantly favour one isomer, so an attempt to separate the isomers ensued. 


P28-01, picture showing the identical products from reaction A (left) and B (right) in solvent. 

 

Isomer separation

TRF21-02 and 03 were mixed together, TRF21-04. The solvent was removed in vacuo, new weight obtained was 144.9 mg (note: the combined mass of both reactions products should have equalled 170.05 mg, so there appeared to be a loss of 25.6 mg at some point in the combination). The crude mixture was purified via flash chromatography on silica gel (MP: Pet. Ether/ethyl acetate 9:1). TLC analysis (TLC38-3, Pet. Ether/ethyl acetate 9:1) confirmed 2 products were obtained from the 48 vials. Vials 4-6 produced a bright yellow solid (58.7 mg) and vials 7-39 produced an orange solid (55.7 mg). 



P39-01, picture showing the extracts from the flash purification of TRF21-04, vials 4-6 on the right and vials 7-39 on the left. 

1H NMR data were obtained for vials 4-6 and 7-39 (NMR39-02 and NMR39-01; CDCl3) respectively.  

 

 

Data and discussion

Vials 7-39 contained one species that fluoresced only when exposed to a long UV wavelength (366 nm). TLC38-02, shows the presence of only one product throughout. TLC's 38-03a and 38-03b show the product from vials 7-39 only showing up under a longer UV wavelength (left) and not under a shorter wavelength (right). 

TLC38-02 VIALS 19-30.png

TLC38-02 Pet. Ether/EtOAc 9:1

TLC38-03 (366 nm).png
TLC38-03 (254 nm).png

TLC38-03a
Pet. Ether/EtOAc 9:1, under UV light (366 nm)                        

TLC38-03b
Pet. Ether/EtOAc 9:1, under UV light (254 nm)                       

Vials 4-6 contained two species (TLC38-01), one of which fluoresced under 366 nm UV light, suggesting some product from vials 7-39 was the second species present. 

TLC38-01 VIALS 3-6.png

TLC38-01 Pet. Ether/EtOAc 9:1, shaded dots appeared only under a 366 nm UV light 

As TLC analysis confirms only one species present in vials 7-39, assumingly this is the desired product TRF21-05, however NOSY data will be obtained shortly to hopefully confirm. 

 

The two suspected isomers of TRF21-01:

 


Strings

Strings will be uploaded once a definitive isomer is confirmed.

 


Synthesis of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one (BPVR 1-1)

O=C(C1=NC(Cl)=CN=C1)C(F)(F)F

 

Reference

Holsinger, L.J., Compounds that Inhibit Protease Cathepsins and HCV Replication. U.S. Patent 2008080785, April 30, 2009.

 
 

Substance

Amount

Mol. wt.

mmols

Equiv.

Starting Material

1 g

172.57

5.79

1

trimethylsilyltrifluoro-methane

1 g

142.2

7.032

1.35

caesium fluoride

0.880

151.9

5.79

1

tertbutylammoniun fluoride

1.514 g

261.46

5.79

1

Product

 

1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethan-1-one

1.216 g (Theoretical)

 
 

(Actual)

209.98

5.90 (Theoretical)

 
 

(Actual)

1 (Theoretical)

 
 

(Actual)

 

Procedure:

(11/16/16)

  1. Dissolved starting material in dimethoxy ethane (15 mL).

  2. Dried CsF (1.435g) under vacuum while heating with a heat gun.

  3. Add trimethylsilyltrifluoro-methane (1 g) and CsF (0.880 g) to the starting material solution.

  4. Stirred at room temperature overnight.
    (11/17/16)

  5. The reaction was then concentrated under reduced pressure at room temperature.
    (11/19/16)

  6. The concentrated product was then dissolved in 7.2 mL of THF, 3 mL acetic acid, and treated with 1.514 g of tetrabutylammonium fluoride.

  7. Reaction was aged for 3 hours, while progress was monitored with TLC, and then stopped by diluting the reaction with ethyl acetate (20 mL).

  8. Washed three times with dilute aqueous sodium bicarbonate solution (0.25M, 100 mL portions).

  9. Washed with brine (100 mL).

  10. Dried over anhydrous magnesium sulfate, then filtered.

  11. Concentrated in vacuo.
    (11/21/16)

  12. Attempted to triturated in dichloromethane and hexanes, but it was not successful. TLC was taken showing that product contained significant impurities.
    IMAG0104.jpg
    50% hexanes in EtOAc solvent system, silica gel plate, UV visualization.
    Bottom is starting material, middle is a co-spot and the top is the product.

    (11/21/16)

  13. Attempted to separate the different spots observed in the TLC on the biotage. Several fractions collected containing mixtures of different products.

  14. All the fractions were spotted with TLC and those containing only one product were separated. Fraction 20 which may contain the starting material was separated and concentrated in vacuo. Fractions 23, 24, and 25, which may contain the product, were concentrated. And fractions 12-16 were also concentrated which contain an unknown byproduct. Fractions 21 and 22, which contained a mixture of two products were concentrated together for further separation.
    Notes: Some other oil seemed to have made its way into the fraction 20 concentrate, so it may need further purification.


 

(11/28/16)

  1. Prepared fraction 23-25 and fraction 20 for NMR. Both samples were readily dissolved in chloroform.

  2. The fractions were dissolved in acetonitrile and analyzed via Gas Chromatography.

    Fractions 23 - 25:


    Fraction 20:

 
 
  1. Fractions 23-25 and 20 were dissolved in chloroform and analyzed via NMR

Fraction 23-25  Carbon NMR

VRBPBurns2325CarbonNMRchloroform.JPG

Fraction 23-25 Proton NMR

VRBPBurns2325ProtonNMRchloroform.JPG

 
 
 
 
 

Fraction 20 Carbon NMR

VRBPBurns20CarbonNMRchloroform.JPG

Fraction 20 Proton NMR

VRBPBurns20ProtonNMRchloroform.JPG

 
 

Though it was predicted  Fraction 23-25 would be the location of our main product, NMR results suggest product is actually present in Fraction 20. There are many unidentifiable peaks present in both NMR spectra of Fraction 23-25 compared to those of Fraction 20. Proton NMR of Fraction 20 shows all anticipated peaks, though the strong peak at 4 ppm remains to be identified. Carbon NMR also came out as expected for desired product except for small unidentifiable peaks at approximately 50 ppm and 165 ppm. These impurities suggests that a synthesis of 1-(6-chloropyrazin-2-yl)-2,2,2-trifluoroethane-1-one should be attempted again, at a lower temperature and lower equivalence of trimethylsilyltrifluoro-methane.

Scale up synthesis of 2-(4-chlorophenyl)-3-(2-methylpropoxy)-pent-2-enenitrile (SGS 15-3)

2-(4-chlorophenyl)-3-oxopentanenitrile (SGS 10-4, 20.3g, 0.095 mol) was dissolved in a mixture of toluene (200mL) and 2-methylpropan-1-ol (20mL). 18M H2SO4 (2.5 mL) was added and the mixture was refluxed for 6 hours in a Dean Stark apparatus. A TLC (isopropanol) of the reaction mixture indicated that some starting material was still present.  The main products were two close spots corresponding to the E and Z isomers of the enol ether. The organic phase was worked up with a solution of saturated sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The organic phase was still clouldy and was passed through a short silica column to remove the cloudiness.  Dichloromethane was passed through the short column until TLC analysis indicated that the reaction material had been removed from the short silica column.

Addition of 10mL of triethylamine to the reaction mix converted the unreacted starting material to its very polar triethylammonium enolate salt (SGS 14-1). Chromatography silica (100g) was added to the organic phase, which was made up to 400mL with dichloromethane and stirred for two hours.  TLC of the organic phase indicated that the polar baseline material had disappeared from solution and absorbed on to the silica (see photo below).  The organic phase was decanted, rinsed twice with dichloromethane. The organic phase was rinsed with 1M HCL (2 x 50 mL) and deionised water (50 mL) to remove all traces of triethylamine. The solvent was then removed from the organic phase to yield 2-(4-chlorophenyl)-3-(2-methylpropoxy)-pent-2-enenitrile (15.1g, 0.057 mol, 60%) as a red oil.  This product was used in the large scale reaction to synthesis Daraprim.

butylether processing.jpg

1M HCl (100mL) was added to the silica containing the absorbed enolate and dichloromethane was added to produce a freely flowing, stirrable mixture.  After stirring for an hour, the dichloromethane solution was decanted and the silica extracted with a further 100mL of dichloromethane. The two dichloromethane solutions were combined and then the solvent removed to yield a red oil (5.2 g) that was indicated to be a 50:50 mixture of starting material and  2-(4-chlorophenyl)-3-(2-methylpropoxy)-pent-2-enenitrile. This material was kept for recycling in any further reactions.

14 g scale-up of Daraprim synthesis (SGS 16-4)

2-(chlorophenyl)-3-(2-methylpropoxy)-pent-2-enenitrile (14.0 g, 53.2 mmol) was dissolved in DMSO (140 mL). Guanidine hydrochloride (10.0 g, 105 mmol) was stirred in to the solution followed by sodium methoxide powder (5.0 g, 93 mmol). The solution became dark red in colour on addition of the sodium methoxide, which dissolved into the solution within an hour. No precipitation of sodium chloride was observed. The solution was allowed to stand at room temperature for 18 hours. After this time, some material (Daraprim) had crystallized from the reaction mix and stirring was recommenced to encourage crystallization of the Daraprim from solution and advance the reaction. 

reaction mix showing Daraprim crystals.jpg
     
Daraprim filtered direct from reaction mix and rinsed.jpg


After 24 hours of reaction time, 0.2 g of Daraprim was isolated from the reaction mix by filtration, however the high viscosity of the reaction mix made the process too laborious and so the reaction was worked up by pouring it into water (500 mL).  The resultant brown precipitate was separated by filtration and dissolved in DCM (500mL). On washing the DCM extract with water, large amounts of white solid (Daraprim) precipitated at the DCM/water interface. This Daraprim was collected and dried.

Large Daraprim quench.jpg
     
Stirring of large Daraprim quench.jpg

The DCM extract was reduced in volume to 150 mL and the resulting crystals of Daraprim were filtered off and washed sparingly with ethanol and allowed to dry overnight.  The dried Daraprim samples were combined (3.67 g, 16.7 mmol, 31.4%).  TLC analysis (isopropanol) indicated that the remaining DCM extract was largely comprised of unreacted starting material and a small amount of Daraprim.

ketonitrile and butyl enol ether precursor with Daraprim.jpg
   
daraprim.png

Comment: The reaction was worked up without further modification after 24 hours due to time pressure to produce a gram quantity sample of Daraprim even though TLC of the reaction mixture indicated that starting material was still present. The reaction yield should be improved by running the reaction at a higher temperature, say 40 or 50 deg C. Vacuum filtration of the reaction mixture is desirable as most of the Daraprim present in the reaction mixture has already crystallized out and is easily rinsed once isolated, obviating the need for copious and wasteful amounts of solvent to intially dissolve and then isolate the Daraprim.

Synthesis of 5-chloro-3-phenyl-[1,2,4]triazolo[4,3-a]pyrazine via cyclisation of TRF21-01

Date experiment was active: 08/11/16



Compound CAS Moles (mmol) Quantity  Equiv.
(E)-2-(2-benzylidenehydrazineyl)-6-chloropyrazine   0.892 0.207 g 1.0
(Diacetoxyiodo)benzene (PIDA) 3240-34-3 0.892 0.28 g 1.0
Dichloromethane 75-09-2 172.3 11 mL 193.1

 

Procedure

PIDA (0.2770 g, ) was added to TRF21-01 (0.207 g) in DCM (11 mL), the mixture was stirred for 1.5 hrs. TLC analysis (TLC26-01, Pet. Ether/EtOAc 7:3) shows the presence of a product the SM was still heavily present however, note the SM shows two dots, most likely from TRF21-01’s two geometric isomers. The shaded dots appeared under a longer wavelength (366nm). The reaction continued for 2 hrs, further TLC analysis (TLC27-03; Pet. Ether/EtOAc 1:1, note a more polar system was required and resulted in the SM isomers separating, this will be considered as a starting basis for isomer separation in future synthesis ), showed the presence of 2 products (note this reaction produces iodobenzene as a side product). PIDA (0.03 g, 0.1 equiv.) and DCM (4.5 mL) were added to the mixture and the reaction was left stirring for 18 hrs. A deep orange solution formed (P27-01).


Picture27-01, picture showing the reaction 22 hrs after start time.

TLC analysis (TLC27-04, Pet. Ether/EtOAc 1:1). showed the presence of 3 products. The mixture was diluted with NaHCO3 (15 mL) and washed with DCM (20 mL x 3), the inorganic layer was extracted and then dried over MgSO4 and the solvent was removed in vacuo. A crude product was obtained (83.5 mg). A 1H NMR of the crude was collected (NMR28-01-CRUDE; CDCl3). The crude product was purified via flash chromatography on silica gel (using a range of eluents starting from pet. Ether/EtOAc 7:3 and ascending to pet. Ether/EtOAc 3:7), two products were separated (P28-01)


Picture28-01, picture of two products that were separated via flash column, product corresponding to NMR29-01 is on the left, and product corresponding to NMR29-02 is on the right.  

1H NMR were taken of both products (NMR29-01 + NMR29-02; CDCl3), NMR29-01 appeared to show desired product TRF25-01. The final product existed as a sand yellow solid- TRF25-01 (0.0304 g, 0.13 mmol, 15%).

 

Data

NMR data will be uploaded shortly.

TLC26-01.png
TLC27-03.png
TLC27-04.png

TLC26-01
Pet. Ether/EtOAc 7:3, permanganate stained

TLC27-03
Pet. Ether/EtOAc 1:1, permanganate stained
TLC27-04
Pet. Ether/EtOAc 1:1, permanganate stained

 

Strings

ClC1=CN=CC(N/N=C/C2=CC=CC=C2)=N1 to
ClC1=CN=CC2=NN=C(C3=CC=CC=C3)N12

InChI=1S/C11H9ClN4/c12-10-7-13-8-11(15-10)16-14-6-9-4-2-1-3-5-9/h1-8H,(H,15,16)/b14-6+
to InChI=1S/C11H7ClN4/c12-9-6-13-7-10-14-15-11(16(9)10)8-4-2-1-3-5-8/h1-7H  

 

References

Open source malaria: our experiment, http://malaria.ourexperiment.org/triazolopyrazine_se/9259/Synthesis_of_5Chloro124triazolo43apyrazine_TZ_61.html, date accessed: 04/11/16

Synthesis of (E)-2-(2-benzylidenehydrazineyl)-6-chloropyrazine

Date experiment was active: 07/11/16


Compound CAS Moles (mmol) Quantity Equiv.
2-chloro-6-hydrazineylpyrazine 63286-29-3 1.389 0.2095 g 1.0
Benzaldehyde 100-52-7 1.389 0.14 mL 1.0
Ethanol 64-17-5 171.26 10 mL 26.0

  

Procedure

TRF17-01 (0.2095 g, 1.389 mmol) was added to ethanol (10 ml) and stirred. Benzaldehyde (0.142 ml) was added, the mixture was stoppered and stirred for 1.5 hrs. TLC  (TLC22-01; Pet. Ether/EtOAc 5:3) shows that the SM had mostly reacted, multiple products were present however. The reaction continued for another 1.5 hrs. TLC (TLC21-03; Pet. Ether/EtOAc 5:3, reaction mixture was separated in ethanol and water) analysis shows the presence of only one product following the mini-workup, reaction had gone to completion, a light orange product had formed (P22-01).


Picture22-01, picture showing the final product before solvent removal. 

The solvent was removed in vacuo to give a light orange solid TRF21-01 (0.207 g, 64%, 0.89 mmol). 1HNMR (NMR23-01; MeOD) was collected. It was deduced from the NMR that the reaction made two different geometric isomers. Separation of the isomers will be further explored, cylisation will also commence to see how the geometries impact the ring formation. 


Data

NMR data will be uploaded shortly.

TLC21-03.png
                              
TLC22-01.png

TLC21-03
Pet. Ether/EtOAc 5:3, permanganate stained

  TLC22-01
Pet. Ether/EtOAc 5:3, under UV (366nm) 


Strings

ClC1=CN=CC(NN)=N1 to
ClC1=CN=CC(N/N=C/C2=CC=CC=C2)=N1

InChI=1S/C4H5ClN4/c5-3-1-7-2-4(8-3)9-6/h1-2H,6H2,(H,8,9) to 
InChI=1S/C11H9ClN4/c12-10-7-13-8-11(15-10)16-14-6-9-4-2-1-3-5-9/h1-8H,(H,15,16)/b14-6+

 

References 

Open source malaria: our experiment, http://malaria.ourexperiment.org/triazolopyrazine_se/9268/Synthesis_of_E2chloro62naphthalen2ylmethylenehydrazinylpyrazine_TY_21.html, date accessed: 04/11/16