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Taking Over of the Synthesis of the "Hetero-oxadiazole" #463

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mxberger opened this Issue Nov 14, 2016 · 3 comments

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mxberger commented Nov 14, 2016

Darshan Magar, Bereket Gebregziabher and I will be taking over the synthesis of the of the Hetero-oxadiazole from the first quarter by @audreyjallen1 and Benjamin Burke. They changed their initial synthesis plan ( #406) to a new procedure based on Foks et al (#448) . When they left off, they were dealing with problems in analyzing their products from the initial reaction with NMR ( #449) and it is from here where we will begin by repeating that synthesis and analysis.

The reaction scheme is shown below in png format.

image
image

Based on previous comments, we should add to/replace the above scheme with one that is machine readable such as in a SMILE format, correct? If so, this will be added soon.

Our experiment will be detailed in this lab notebook, which will also be updated soon to reflect the work we have done thus far and then kept up to date for those who wish to follow along.

This is just an introduction and so we would like any feedback on the synthesis method or formatting of these posts and the ELN. Is it possible for us to tag our posts with the relevant information (e.g. "Series 4") or is this something that is done by others? We'll make any edits and then close this in about a week.

Thank you for all of your help!

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MFernflower Nov 15, 2016

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@mattodd Do you think they should buy the methyl 6-chloropyrazine-2-carboxylate for 90 USD a gram or is the (CH₃)₃SiCHN₂ route they are using safe if taken with right precautions?

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MFernflower commented Nov 15, 2016

@mattodd Do you think they should buy the methyl 6-chloropyrazine-2-carboxylate for 90 USD a gram or is the (CH₃)₃SiCHN₂ route they are using safe if taken with right precautions?

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mattodd Nov 16, 2016

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Hi @mxberger - great to hear, and thanks for providing an update for everyone. The links you included above are very useful; they're also listed in the DCNYS section of the wiki. Please do check out some general intro remarks I made recently here, particularly about how to maintain the lab notebook so it's complete and can be understood by an outsider. Yes, it's essential that things are machine-readable, particularly in the lab notebooks, so we can most easily find things. Usually this means including the structure of the intended product, and the actually-isolated product If different) as SMILES, Inchi and InChiKey. One wonderful day we will all be using a lab notebook that takes care of this automatically. But until that day...

Re the synthetic approach, you're in charge here, but I liked both of @JohnATucker's suggestions here. Both the heterocycle synthesis and its possible linkage to the chlorinated core should have some precedent. I know this means potentially re-thinking what you're doing, but the oxadiazole fragment can be made from the nitrile you were proposing anyway.

@MFernflower I think the problem with the S/M you suggest, IIRC (@alintheopen, @edwintse ?), is that the hydrazine reacts with the ester as well as the C-Cl, which is why the amides were constructed as they were. Another reason to like John's suggestion, @rbroadrup-HC ?

And @MFernflower safety is always a concern for every reaction, but the researcher doing the reaction must decide this for themselves in collaboration with their PI and in line with all the local guidelines. Always nice to find alternatives that are safer, though, sure.

Given that we're in the second phase of trying to make this molecule (thanks to the efforts of @audreyjallen1 and Benjamin Burke) I'll close a few earlier issues to keep us focussed, but everything should be cross-linked back to here and the wiki.

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mattodd commented Nov 16, 2016

Hi @mxberger - great to hear, and thanks for providing an update for everyone. The links you included above are very useful; they're also listed in the DCNYS section of the wiki. Please do check out some general intro remarks I made recently here, particularly about how to maintain the lab notebook so it's complete and can be understood by an outsider. Yes, it's essential that things are machine-readable, particularly in the lab notebooks, so we can most easily find things. Usually this means including the structure of the intended product, and the actually-isolated product If different) as SMILES, Inchi and InChiKey. One wonderful day we will all be using a lab notebook that takes care of this automatically. But until that day...

Re the synthetic approach, you're in charge here, but I liked both of @JohnATucker's suggestions here. Both the heterocycle synthesis and its possible linkage to the chlorinated core should have some precedent. I know this means potentially re-thinking what you're doing, but the oxadiazole fragment can be made from the nitrile you were proposing anyway.

@MFernflower I think the problem with the S/M you suggest, IIRC (@alintheopen, @edwintse ?), is that the hydrazine reacts with the ester as well as the C-Cl, which is why the amides were constructed as they were. Another reason to like John's suggestion, @rbroadrup-HC ?

And @MFernflower safety is always a concern for every reaction, but the researcher doing the reaction must decide this for themselves in collaboration with their PI and in line with all the local guidelines. Always nice to find alternatives that are safer, though, sure.

Given that we're in the second phase of trying to make this molecule (thanks to the efforts of @audreyjallen1 and Benjamin Burke) I'll close a few earlier issues to keep us focussed, but everything should be cross-linked back to here and the wiki.

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@mattodd Thanks for reminding me that the hydrazine process destroys esters. TMSDiazomethane is one of the few compounds that scares me alongside α-amanitin. So there was a bit of a jaw drop when I saw that the process was going to use TMS diazomethane. However I fully understand why it is being used

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MFernflower commented Nov 16, 2016

@mattodd Thanks for reminding me that the hydrazine process destroys esters. TMSDiazomethane is one of the few compounds that scares me alongside α-amanitin. So there was a bit of a jaw drop when I saw that the process was going to use TMS diazomethane. However I fully understand why it is being used

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