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18th August 2016 @ 00:49

Reference:Organic Process Research & Development 2006, 10, 762-769

Procedure:

The ratio between the reactants in this flask was as follows:100mg of 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine(428.35µmol,1equiv.) ,12.32mg of Pd(dba)2(21.42µmol,0.05equiv.),33.21mg of piperazine(385.52µmol,0.9equiv),61.75mg of t-BuONa(642.53µmol,1.5equiv.),20.00mg of BINAP(32.13µmol,0.07equiv.) The reactants were dissolved/suspended in 2ml of toluene and stirred under Nat room temperature.The reaction will be monitored by TLC

HIRAC

HM 6-2.docx

 

String

From 

InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H

to

InChI=1S/C9H11ClN6/c10-7-5-12-6-8-13-14-9(16(7)8)15-3-1-11-2-4-15/h5-6,11H,1-4H2

Log

18th Aug

The reaction started at 2:10pm. Solid reactants were added to the flask then purged with argon. Afterwards, toluene was added, and mixture was purged again with argon. 

TLC was performed at 4:00pm under condition of 25%ethyl acetate in petroleum. The SM consuming step was quite fast even if it's under RT. quite a lot of the SM was consumed, and many byproducts formed.  One of the top spots was assumed to be BINAP. Reaction was left overnight.

19th Aug

TLC was performed(50%ethy acetate in petroleum) at 10:00am.The SM spot was gone. No other obvious difference from the one performed yestaday. Reaction was warmed up to 40℃.

TLC was performed under the same condition at 11:30am. Obviously, there was no SM left. and main product looked like the top spot which could be SM coupled with itself when considering that only 0.9equiv of piperazine was added. 

 

23th Aug

The reaction was switched off and the mixture was concentrated and then columned.

4 fraction was collected yet in so small amout that the first two fraction was difficult to scratch off from the flask. Fraction 3 was not soluable in CDCl3 thus almost no signle in the spectrum. This one needs repeating in DMSO.Fraction 4 looks quite promising.

 

NMR data

HM 6-2 frac 4.pdf
HM 6-2 frac 4.zip
Attached Files
HM 6-2.png
HM 6-2.docx
IMG_2766.JPG
IMG_2769.JPG
IMG_2783.JPG
IMG_2785.JPG
HM 6-2 frac 4.pdf
HM 6-2 frac 4.zip
Comments
Re: Synthesis of 5-chloro-3-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (HM 6-2) by Alice Williamson
18th August 2016 @ 01:46
HIRAC seen and approved - note one change, minimum volumes are being used. Take care when measuring flammable solid - CLASS 2 owing to small quantities.
Re: Synthesis of 5-chloro-3-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (HM 6-2) by Haochuan Mao
18th August 2016 @ 05:14
Thank you Mandrake. Fingers' crossed
Re: Synthesis by Mandrake Fernflower
18th August 2016 @ 16:54
If the reaction is successful, I was wondering if you could couple the free N on the piperazine to benzoyl chloride? That is my take on Neil's N16 idea and I was wondering if you think it would be worth trying?

Addendum: BINAP may not be the best ligand for this reaction. Should this reaction fail it would be wise to try SPhos/Xantphos/Johnphos
Re: Synthesis of 5-chloro-3-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (HM 6-2) by Haochuan Mao
22nd August 2016 @ 14:55
I think the reaction between the product and benzoyl chloride should be easy.Because I think acyl chloride and amine are good electrophile and nucleophile respectively. I'm not sure whether the coupling is worth trying as far as bioactivity is concerned. But I agree that piperazine is quite nice to be coupled with the core because the free N gives us more possibility.
Re: Synthesis of 5-chloro-3-(piperazin-1-yl)-[1,2,4]triazolo[4,3-a]pyrazine (HM 6-2) by Mandrake Fernflower
22nd August 2016 @ 18:19
I think it would be interesting to see what different substituents on the free N do to bio-activity, I recommended benzoyl chloride because of it's low cost and the fact that the ketone is a good hydrogen bond acceptor