PIDA cyclisation

[alintheopen]

Poor yielding and very hard to visualise the product or SM for that matter. Have tried using KMnO4, Vanillin, Ninhydrin, and Goofy. Will update with more dips once I've made/stolen/borrowed some. Any ideas? Product and SM very insoluble in DCM, CHCl3, MeCN, EtOAc, even MeOH so this could be another problem. PIDA cyclisations typically in DCM, fluorinated alcohol solvents, sometimes DCM. Ideas to improve reaction: Use of MeCN as solvent - currently being tried Use of HFIP or TFE as solvent Swap to more reactive PIFA Heat reaction? CRO synthesis claims 38% at rt.

@JoieG @PatrickThomson @mattodd

[JoieG]

Hi Alice, I wouldn't worry about the stain since the SM and Products should both be UV active. Upon completion are you working up the reaction or concentrating it to then purify (I was unsure from your notebook)? I would make sure to work up the reaction - dilute with DCM and wash with saturated bicarbonate and brine. This should make it easier to handle the crude product and cause less problems in the purification. If it isn't soluable in DCM or EtOAc you can try 2Me-THF as a solvent in the extraction. It solubalizes almost anything and seperates from AQ layers.

[PatrickThomson]

My students put on an opportunistic overnight stir on 100mg of the nitrile SM with PIDA, but about 10x diluted (to 5ml from 0.6) and they've said the NMR/tlc has completely changed - I'm meeting with them now so will get data looked at and uploaded.

[alintheopen]

Edited as I posted as @newgitontheblock by accident needed to clarify UV vis products. Awesome, I think the dilution will do it. Every other PIDA reaction that I've done worked much better at greater dilution. Joie, I initially did no work up as the CRO prep had none but I worked up the reaction from today. Had some issues updating the lab book but will do tomorrow when the server is working again. I know prod and SM should be uv active but my tlc said otherwise....despite the fact I had product (albeit very little) by NMR....weird! Looking forward to seeing Devon and Eduvie's tlc - hope they have their target. Sorry, just to clarify I couldn't see the pyrazine very well in the UV, could see hydrazine, could just about see imine, but couldn't see cyclised product...perhaps just because my first attempt didn't work so well. Will check the more dilute reaction in the am. See ELN for TLCs ;)

[alintheopen]

Here is a PDF of the product NMR for reference @PatrickThomson http://malaria.ourexperiment.org/data/7703.html

[PatrickThomson]

Extremely helpful - we've got that showing up in our crude NMR alongside what I think is iodobenzene and possibly some SM as well.

[alintheopen]

Great, yes. You should see iodobenzene, which will fly off the column and I wouldn't be surprised if there was some SM (the CRO reported 38% yield). I was rather hoping to improve this yield a bit if possible.

[mattodd]

(newgitontheblock = alintheopen in case that's not obvious) Joie - the TLC behaviour is most odd. So are we all using crude NMR spectra here - i.e. that works? i.e. could be followed that way?

[JoieG]

First suggestion, would be to change the HNMR solvent. It does not look like the material is that soluble in CDCl3. You may be able to pick out the peaks better and understand the by-products, if you take a small aliquot and take the HNMR in DMSO. You should be able to monitor dissapreance of the imine proton this way as well, but it looks like you are getting some product! Second question, are you analyzing the TLC in both long and short wave? Is there a difference in the spot intensity with one or the other - do you see anything? Do you have an LCMS available to use - this could help you understand product formation?

[PatrickThomson]

We're going to have difficulty playing with the NMR in Edinburgh a lot due to a major facility upgrade that's happening from now until some time in November.

[sdebbert]

If PIDA is giving you trouble, I found a ACIE paper that has better luck with Chloramine-T as the oxidant in a similar reaction: DOI: 10.1002/anie.201001999 They also use 2-MeTHF, as mentioned earlier, to good effect in their workup. Almost all the NMR data in the supporting info is in DMSO-d6. I also found a paper where they use PIFA in a solvent-free reaction: DOI: 10.1007/s10593-012-0899-0 . Needless to say, I'm a little more skeptical of that one (if only because I've had bad luck with a mortar and pestle outside the context of making pesto), but if it were legit that would be fantastic.

[alintheopen]

Thanks @sdebbert! That's great...I also agree with you about the P&M. I think the PIDA is working OK now, it was a dilution issue but if the yield doesn't improve I'll try the prep you cite. Now onto the cyanides...just waiting for a new bottle of TMSCN. Cheers everyone.

[alintheopen]

got the product pure, dilution is a winner! http://malaria.ourexperiment.org/data/files/7732/AEW%2097-3%20proton.pdf

[mattodd]

File has nothing in it? (zero bytes)...

[alintheopen]

apologies...I am having a few problems with 'empty' uploads....this should work... My NMR: http://malaria.ourexperiment.org/data/7739.html, CRO NMR: http://malaria.ourexperiment.org/data/7703.html

[mattodd]

That's dynamite, Alice.

On 29 October 2013 21:17, alintheopen notifications@github.com wrote:

apologies...I am having a few problems with 'empty' uploads....this should work... My NMR: http://malaria.ourexperiment.org/data/7739.html, CRO NMR: http://malaria.ourexperiment.org/data/7703.html

— Reply to this email directly or view it on GitHubhttps://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/97#issuecomment-27291022 .

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[alintheopen]

1g scale synthesis led to a whopping 12% yield of the product....although of course both previous reactions weren't purified (as per the CRO experimental) so its probably a tad higher. Still not amazing, so I'll try to optimise this and perhaps Eduvie and Devon can try this too @PatrickThomson whilst waiting for SM. It is important to note that the Rf is more like 0.6 rather than 0.1 as reported in the CRO experimental.

[JoieG]

@alintheopen If there is left over AcOH from the reaction than this can potentially change the Rf of the product. What are your ideas for reaction improvement?

[PatrickThomson]

@alintheopen Yes, Devon found that a 100% EtOAc column ran off product and major impurities in the same first few fractions - we're slowing it down to get a small reference sample.

The way to go forward with this that I'd suggest is to find a bunch of alternative conditions, and anything where I have material available in-house (thanks to Edinburgh's chemical inventory manager) we'll try, or anything with cheap reagents that we'll get delivered quickly. Devon has a gram of the hydrazide available for 100mg-scale test reactions, and we can get more.

[PatrickThomson]

@JoieG @alintheopen we found that the Rf was more like 0.6 - after a basic workup. We ran the fractions off the top of the column.

Question is, is that low yield from side-products, incomplete reaction, or E/Z discrimination? If it's the latter, can we equilibrate the isomers in-situ?

[PatrickThomson]

Just a quick update - we did a quick reaction with Dess-Martin Periodinane and got nothing back. Going to try both conditions from @sdebbert earlier post - Chloramine-T, PDF and mechanochemical with PIDA pdf

[mattodd]

Sounds good, Patrick.

[PatrickThomson]

Oh man, the Chloramine-T reaction has certainly done something appropriate... It looks like the elevated temperatures might even cause hydrazone "epimerisation" - I'm literally shadowing a TLC plate now.

[PatrickThomson]

We'll get a mass yield tomorrow but it looks like chloramine-T has done the job - eyeballing the NMR, there's maybe >50% product, a few other misc. aromatic peaks possibly the same C-cyclisation product Alice found.

[PatrickThomson]

Ok, the crude reaction mixture evaporates to this: 1:0.7 of product to mysterious other thing that has a peak at 8.6 and some other peaks, possibly C-cyclisation as opposed to N-cyclisation, or possibly unreacted hydrazone isomer.

[PatrickThomson]

The two large peaks at 7.6 are an unknown contaminant present in other NMRs - I suspect the undergraduates have gotten into our chloroform. The doublet at 7.3 appears to integrate 2:3 with the chloramine-T methyl peak at 2.46. So in here, then, we have product, and one of the hydrazone isomers and absolutely nothing else. We'll try increasing the reaction time, and possibly some acid or base to labilise the hydrazone.

[mattodd]

Sounds excellent Patrick - let us know what happens. It's good to receive these updates on GH while also seeing the data on the ELN.

On 22 November 2013 09:52, PatrickThomson notifications@github.com wrote:

The two large peaks at 7.6 are an unknown contaminant present in other NMRs - I suspect the undergraduates have gotten into our chloroform. The doublet at 7.3 appears to integrate 2:3 with the chloramine-T methyl peak at 2.46. So in here, then, we have product, and one of the hydrazone isomers and absolutely nothing else. We'll try increasing the reaction time, and possibly some acid or base to labilise the hydrazone.

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THE UNIVERSITY OF SYDNEY Rm 519, F11 | The University of Sydney | NSW | 2006 T +61 2 9351 2180 | F +61 2 9351 3329 | M +61 415 274104 E matthew.todd@sydney.edu.au | W http://sydney.edu.au/science/chemistry/research/todd.html

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[PatrickThomson]

We're finding that Chloramine-T is still leaving us with a mixture of one of the hydrazone isomers (presumably Z) and product, but much cleaner than with PIDA. Solubility is higher, etc. Running it overnight didn't make any improvement, running it with acetic acid didn't make a difference, and we're running it with TFA now to see if we can coerce the hydrazone to "epimerise" and give us a form of Dynamic Kinetic Resolution. However, an old paper seems to imply that heavy metal oxidants such as lead tetra-acetate will cause the desired effect - every other literature hit about this oxidation uses the E-isomer and gets >85% yields, whereas ours are slightly favouring Z it seems.

[PatrickThomson]

acid addition seems to hinder the oxidation, looks like we might have to try the distinctly un-friendly lead conditions.

[mattodd]

Patrick - exact timing to be confirmed, but we'll be having an online meeting later this week, likely Friday morning. a) are you available to come along, and b) would you mind preparing a single ppt slide or chemdraw image summarising what you've been up to on this chemistry, to bring people up to speed? We're going to trial me using a powerpoint presentation/screenshare which I will need to assemble beforehand. Growing agenda: http://malaria.ourexperiment.org/uri/48f Let know if want to add any items.

On 1 December 2013 00:12, PatrickThomson notifications@github.com wrote:

acid addition seems to hinder the oxidation, looks like we might have to try the distinctly un-friendly lead conditions.

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[PatrickThomson]

Unfortunately I'm visiting family then. I'll prepare a slide and upload it tomorrow, but it looks unlikely that I'll have enough technology with me on holiday to commit to attending.

The labbook seems to be down? Or at least, inaccessible from the UK. In any case, I can't see the agenda.

[PatrickThomson]

Single slide about my oxidative cyclisation stuff - the Amide work is basically at the "we've synthesised a bunch of starting materials" so nothing interesting yet.

[mattodd]

Excellent, thanks. Finishing agenda and presentation today, so more soon.

On 18 December 2013 01:22, PatrickThomson notifications@github.com wrote:

Single slide about my oxidative cyclisation stuffhttps://drive.google.com/file/d/0B6rAjqmPhHy5NlZId0lrZWpEU1E/edit?usp=sharing- the Amide work is basically at the "we've synthesised a bunch of starting materials" so nothing interesting yet.

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[sabinllm]

@PatrickThomson Could you send me the best protocol you have for the cyclisation step?

[PatrickThomson]

2-methyl THF (15 ml/mmol), chloramine-T (1.12eq), 60°C (lit, or 75 ours due to oil bath drifting), 1.5 hours. Lab book here but I've just noticed the millimole quantities for Chloramine is wrong consistently - I'm chasing it up now.

This will only cyclise the E isomer of the hydrazone, and do it cleanly. the Z is a continuing problem (will be tackled here on friday)

Edit: Original paper provided by @sdebbert in this comment

[PatrickThomson]

Commenting here to get it on paper, but this is important: The main conclusion from Devon's project is that the Z-isomer of the hydrazone will not react under reasonable conditions, whereas the E-isomer will cyclise cleanly with PIDA, and even cleaner with Chloramine-T. In most general cases of hydrazone formation, they are E-selective so this isn't a problem. However, our pyrazines generate a mixture of about 0.8:1 E:Z, resulting in low yields. My suggestion would be to form the crucial pyrazine-N bond with cross-coupling on a terminal hydrazone, as the formation of the terminal hydrazones are pretty E-selective.

[mattodd]

OK, this is interesting and important, and is something that Tom is looking into as well. But is there evidence that a) that is what we're seeing, and b) that the isomers are not interconverting under reaction conditions (either in their own synthesis or in the oxidative cyclisation)? I know it's a possible explanation, but did Devon write up the summary of evidence for this?

On 27 March 2014 04:56, PatrickThomson notifications@github.com wrote:

Commenting here to get it on paper, but this is important: The main conclusion from Devon's project is that the Z-isomer of the hydrazone will not react under reasonable conditions, whereas the E-isomer will cyclise cleanly with PIDA, and even cleaner with Chloramine-T. In most general cases of hydrazone formation, they are E-selective so this isn't a problem. However, our pyrazines generate a mixture of about 0.8:1 E:Z, resulting in low yields. My suggestion would be to form the crucial pyrazine-N bond with cross-coupling on a terminal hydrazone, as the formation of the terminal hydrazones are pretty E-selective.

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[PatrickThomson]

Yes, Devon wrote this up in her project report - getting my hands on an electronic copy of this is actualy proving far from trivial, as they have both gone into full-on "exam mode" and stopped answering twitter. We have NMR evidence that there's product and unreacted Z isomer, and the different oxidative conditions or addition of acids to the reaction mixture is unhelpful - a failure to induce Dynamic Kinetic Resolution. We haven't looked at changing the selectivity of the hydrazone formation itself.

[mattodd]

OK. It would, if it's possible, be useful to have copies of those reports, notwithstanding that they're busy with exams. Jimmy Cronshaw posted a copy of his thesis to Figshare, which is a nice way of making it available and discoverable. An alternative is your Uni Institutional Repository.

On 27 March 2014 18:50, PatrickThomson notifications@github.com wrote:

Yes, Devon wrote this up in her project report - getting my hands on an electronic copy of this is actualy proving far from trivial, as they have both gone into full-on "exam mode" and stopped answering twitter. We have NMR evidence that there's product and unreacted Z isomer, and the different oxidative conditions or addition of acids to the reaction mixture is unhelpful - a failure to induce Dynamic Kinetic Resolution. We haven't looked at changing the selectivity of the hydrazone formation itself.

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[PatrickThomson]

After some (internal to my own head) wrangling, I can share the reports out. Because I'm not the author, I can't post them to our repo or figshare, but I can put copies here. I'm not sure how useful it'll still be 2 months on...

https://drive.google.com/file/d/0B6rAjqmPhHy5NkRLaWx3ZEtpUjg/edit?usp=sharing

https://drive.google.com/file/d/0B6rAjqmPhHy5VDltWWZPMk1tUFk/edit?usp=sharing

[mattodd]

Hi Patrick - this is great. So these are PDFs that we need to make sure are available. Presumably there's no problem with posting them to the ELN as "shared data"? And linking to them out of the wiki? Ideally the contents would be incorporated into the wiki in advance of incorporation into a Series 4 synthesis paper. Question on raw data - what % of the raw data do you think is on the ELN? Is there a way of zipping up everything and putting it somewhere, so you think?

[mattodd]

Hi @PatrickThomson I uploaded the reports to the ELN here: http://malaria.ourexperiment.org/osdd_malaria_shared/11335 When you've time it'd be great to incorporate any conclusions into the "synthesis" section of the Series 4 wiki, linking back to data. There may be nothing, but it'd be useful to fold in anything concrete, in preparation for writing the Series 4 paper. This Issue is already linked from the wiki, so now closing.