Open odohertymatthew opened 7 years ago
Great @odohertymatthew - these would be valuable compounds! Welcome aboard, guys.
When you say "blogging about progress" do you mean a lab notebook here? If not, then could you let us know where are you planning to post experimental data?
Great news
@mattodd @drc007 Thanks! We will put our experimental data on the lab notebook link you provided.
Perfect! You'll notice OSM has a fair number of contributors. Feel free to have one lab notebook each if you like, or a combined one (Dr Cranwell may have a preference). When you create it, can you please start the name of the ELN with "Reading" - like the Haverford guys have done. This can just help a little with keeping track of which lab book belongs to whom. @alintheopen wrote a nice explainer for how to use the ELN - some links are here.
Hello everyone! I think 1-benzoyl 4-formylpiperazine would be a good fragment to try - Should be easy to produce from N-formylpiperazine and BzCl
Addendum: Might be worth switching to a air-stable metal complex like Pd-XPhos?
Thanks for the warm welcome guys.
@mattodd I think we'll be submitting individual lab notebooks but of course we will label accordingly, an interesting read from @alintheopen, we'll be sure to take some pointers from here
@MFernflower looks interesting, we can certainly look into it, we'll keep you updated.
Somehow I missed this thread! Welcome Reading! So happy to be working with you all :)
On Tue, Oct 11, 2016 at 8:37 PM, TomFreeman3 notifications@github.com wrote:
Thanks for the warm welcome guys.
@mattodd https://github.com/mattodd I think we'll be submitting individual lab notebooks but of course we will label accordingly, an interesting read from @alintheopen https://github.com/alintheopen, we'll be sure to take some pointers from here
@MFernflower https://github.com/MFernflower looks interesting, we can certainly look into it, we'll keep you updated.
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Just as a teaser; some good progress is being made towards the targets! Posts to follow!
Such great notebooks! I think we should maybe have a some prizes for the best kept student notebook each year - what do you reckon @mattodd? Thanks for the teaser to @PBCranwell :)
Thank you, @alintheopen @mattodd for your kind words. I have successfully synthesised my compound (4-morpholinobenzadlehyde) I found the SnAr route more effective. The next step is to add it to the triazolopyrazine core which @TomFreeman3 has just synthesised. I believe @tzortzi and Will have also synthesised their compounds also and will be doing the same in the upcoming weeks.
Our group, the Paragroupers, managed to synthesise 3 out of 4 of the benzaldehydes that we originally proposed. It was not possible to synthesise the bis-(2-methoxyethyl)amine derivative. The Buchwald-Hartwig amination was attempted for all substrates, but after two attempts with minimal success, the nucleophilic aromatic substitution reaction was favoured and produced a much higher yield (except for bis-(2-methoxyethyl)amine), and a purer product. In addition, an nucleophilic aromatic substitution reaction using sonication was attempted for bis-(2-methoxyethyl)amine and pyrrolidine, but did not produce any product. As the project moved forward, Tom created the pyrazine core, which in turn was attached successfully to the benzaldehyde-amine complexes. Following that the intermediates were cyclised. Upon cyclisation we realised that several different isomers had been formed; imine bond geometric isomers and possible rotamers around the N-N bond. When we realised this, we went back to the condensation reaction step to figure out how to isolate the isomers formed using different solvents for both the reaction and the column eluents, to try to verify this argument.
• Alexander Tzortzi (@Tzortzi) - Formation of AT-01-012 (17%) and AT-01-012 (29%)
• William Attwood (@WillAttwood) – Formation of WA-01-002 (13%) and WA-01-003 (27%)
• Matthew O’Doherty (@odohertymatthew) – unsuccessful MOD-1-005
• Tom Freeman (@TomFreeman3)- unsuccessful TRF1-01
The reaction formed a low amount of impure product which could not be used in the next experiments.
• Alexander Tzortzi – 1g scale AT-01-012 (orange solid, 85%)
• Matthew O’Doherty- MOD-1-011 (51%) followed by scale up MOD-1-016 (81%)
• William Attwood – 1g scale WA-01-004 (62%) yellow/orange solid, that turned pink upon being left for a week, most likely from the Iodine.
• Tom Freeman - unsuccessful TRF1-02
Due to the success for Matthew O’Doherty, the reaction was scaled up to 1g and initially performed at this scale for Alexander Tzortzi and William Attwood.
• Alexander Tzortzi – Unsuccessful AT-01-012
• Tom Freeman – Unsuccessful TRF1-03 The reaction was only run by Alex and Tom, of which it was unsuccessful, no product was made.
• Tom Freeman – TRF17-01 (orange solid, 80%)
2-chloro-6-hydrazinylpyrazine (TRF17-01) was successfully synthesised. The product was pure and was sequentially used by the other group members for the duration of the project.
Synthesis of the amine-benzaldehyde complex for Tom ceased after 3 unsuccessful attempts. It was instead decided that a non-amine-substituted benzaldehyde would be added to TRF17-01 and furthermore the triazlopyrazine synthesis.
The reaction involved adding TRF17-01 to the individual amine-benzaldehyde complexes (just benzaldehyde for Tom) via a condensation reaction.
• Alexander Tzortzi – AT-01-023 (91% crude, red solid)
• Matthew O’Doherty- MOD-1-022 (92% crude, yellow solid)
• Tom Freeman – TRF21-01 (64% crude, orange solid)
• William Attwood – WA-01-007 (55% crude, red solid)
This reaction proved successful for all group members. However, TLC and NMR analysis confirmed the presence of two isomers, assumingly geometric about the imine bond. Nonetheless cyclisation continued using these products in the hope that the isomers would conform to the correct orientation during the reaction.
• Tom Freeman – TRF25-01 final product (sand yellow solid, 15%)
• Alexander Tzortzi – Unsuccessful AT-01-025 (50% crude)
• Matthew O’Doherty- Unsuccessful MOD-1-026 (74% crude)
• William Attwood – Unsuccessful WA-01-011 (34% crude)
The reaction was unsuccessful for Alex (90% crude), Will (86% crude) and Matt. The proton NMR of the crude showed unreacted SM in various isometric states and the cyclised product was unable to be identified from the spectra, separation of the product (if any) through flash column chromatography was also unsuccessful. It was concluded that for cyclisation to happen effectively the SM must be only a single isomer, and so the condensation reaction was reassessed. The plan was to isolate one isomer from the various products from the condensation step.
Two condensation reactions were performed, one in ethanol again and the other in acetonitrile to see if the solvent systems would favour the formation of one isomer over the other. HNMR analysis determined that the solvent system had no significant effect on isomer formation. Furthermore, the two reactions products were mixed together and the crude purified in a flash column in an attempt to separate the isomers by chromatography.
• Tom Freeman – TRF21-05 product (orange solid, 33%)
• Alexander Tzortzi – Unsuccessful AT-01-023 (90% crude)
• Matthew O’Doherty- Unsuccessful MOD-1-034 (91% crude)
• William Attwood – Unsuccessful WA-01-011 (34% crude)
The final product was not cyclised again due to time constraints; however, the cyclisation was proven to be successful in exp 6 by Tom.
Its been a pleasure working in collaboration with the OSM team, we hope our findings are of use.
Team Paragroupers signing out!
An excellent report. Sorry for the delay in responding.
Quick fire questions @odohertymatthew
1) Are you saying that the cyclization step performed poorly under the usual conditions? 2) What's your reason for thinking you have isomers of the hydrazone? 3) Are the isomers present in your samples, but not other samples that you've seen of the hydrazones made by other people? i.e. is there something unusual about these particular molecules? 4) Why do you think that the presence of isomers matters to the cyclisation? 5) Do you have physical samples remaining in the kind of quantity that someone else could use, if you mailed them? 6) Will you be producing written final reports on your project that we could link to somewhere?
(It's on me to ensure that this Issue is linked to on the wiki somewhere. Obviously what you've done is a quite generally applicable method for the variation of the northeast of the molecule that others could follow up)
@odohertymatthew @mattodd Just though I should jump in here just to put in my tuppence worth!
@PBCranwell Would using DMP instead of PIDA make any difference to this reaction?
@MFernflower Not sure. You would still be in hypervalent iodine-land and would presumably be a similar reaction pathway so I am not convinced, but it is worth a try. I realised I didn't finish point 3...the 2 reaction pathways could be cyclisation from N (as we want), or from the pyrazine ring itself generating a tertiary carbocation next to nitrogen, that could then rearomatise generating some kind of pyrazolopyrazine-type scaffold.
Thanks @PBCranwell . @tscmacdonald 's Honours thesis is online and contains a fair bit of characterisation of the hydrazones. I seem to remember Tom being interested in exactly this issue of hydrazone isomers, but I may be misremembering.
In looking again just now, I see that @JoannaUbels 's Honours thesis is not online, which is an oversight! This contains more on NMR characterisation of hydrazones. I'll rectify this ASAP. It'll be a nice section to include in the first Series 4 paper we ought to be writing.
Re your students' final reports: Understood. What about after the assessment period is over?
Potentially. That will be in June/July, once the externals have been in and verified everything. I just don't want to compromise all their hard work! I will ask some questions this end.
I will look into the hydrazone thing more. Interestingly, Tom (who didn't have a p-nitrogen) managed to make the target material whereas the others, who did, were unsuccessful.
Anisa (in the BAES UoR group) managed to make her target too albeit in low yield (https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/458) - I will direct you to their report when they upload it...should be soon - and she had a nitrogen in the 2-position on the appended aromatic ring. The others were less conclusive.
One thought before I head out caroling for the evening (currently in the UK): When we were doing this, we thought we had issues with hydrazone isomers. It later turned out that what we'd actually done was formed a condensation product from acetone and the arylhydrazine, presumably from traces of washing acetone on our glassware:
I forget exactly what the circumstances were leading to this, but with hindsight we spent a remarkably long time trying to work out what we had. I don't think we ever actually had any hydrazone isomers, and I wouldn't expect to; the barrier to rotation isn't really that big.
Not sure how applicable that is to your problems, but it's possible you're doing the same we did and this can all be averted by being more careful with acetone washes.
(UK WOO!) An interesting thought, I don't suppose you have a link to your research? It'd be good to compare. We believed our isomers could have been geometric about the imine bond, not necessarily comformers
@TomFreeman3 Do you see anything on the NMR that is indicative of that isopropyl product? I really do not think isomers of the central hydrazone would effect the ring closing because the barrier of rotation is so so low
@MFernflower As mentioned there appeared to be unreacted hydrazone in the crude of the cyclised product. Of course it could simply be left over hydrazone that did not react.
We suggested isomers because the NMR's of the pure hydrazone looked to be as expected, however TLC analysis showed the presence of two different Molecules.
It could also just be that the pure hydrazone was not as clean as first thought, I will take a closer look at the NMR data and also look into @tscmacdonald suggestion
That sounds consistent with what we had: two products we thought were hydrazone isomers, but which actually turned out to be 1) desired product, and 2) the isopropylhydrazone (presumably formed first, with the remaining hydrazine then condensing with the aryl aldehyde).
Triazolopyrazines series- Synthesis of N15, and similar para substituted RHS compounds
We are Chemistry BSc students at the University of Reading with a passion for organic chemistry, and are currently undertaking our third year project. Over the next few weeks we intend to synthesize four different para substituted benzaldehydes to be added to the RHS of the Triazolopyrazine core. Below are the proposed RHS compounds for synthesis and the synthetic route as discussed by Dr Cranwell at a recent meeting. Our intention is to use Buchwald-Hartwig coupling, although other routes will be attempted if this is unsuccessful. These molecules are seen as being desirable targets as per #390. We intend to prepare these compounds and use a condensation reaction to unite them to the main Triazolopyrazine core (Figure 1). We will be regularly blogging our progress.
Proposed RHS compounds
Synthesis of 4-morpholinobenzaldehyde (N 15) My name is Matt and I will be undertaking the synthesis of the interesting compound 4-morpholinobenzaldehyde (N15) by using Buchwald-Hartwig coupling. My nitrogen-containing compound is morpholine, which I will be reacting with bromobenzaldehyde in toluene in the presence of a suitable palladium catalyst. If this approach fails, a proposed alternative is to use an SNAr reaction with 4-fluorobenzaldehyde, morpholine and an appropriate base.
Synthesis of 4-(piperidinyl)benzaldehyde My name is Will and my target aldehyde is 4-piperinylbenzaldehyde. I also intend to use a Buchwald-Hartwig cross-coupling reaction to prepare my target aldehyde, using similar conditions to Matt, above.
Synthesis of 4-(bis(methoxyethyl)amino) benzaldehyde My name is Tom @TomFreeman3 and my contribution will first be the synthesis of the para-substituted aromatic aldehyde 4-(bis(methoxyethyl)amino)benzaldehyde, starting from p-bromobenzaldehyde and a secondary amine; bismethyoxyethylamine. I intend to make use of the palladium-catalysed Buchwald-Hartwig coupling, however in the event this fails, other reactions are possible to achieve results, namely replacing the bromobenzaldehyde with its fluoro counterpart and using an SNAr reaction. If time allows, both reactions will be run and results will be compared for the two.
Synthesis of 4-(pyrrolidin-1-yl)benzaldehyde I am @tzortzi Alexander, a third year chemistry student from the University of Reading. My nitrogen-containing compound is pyrrolidine. I also intend to follow the Buchwald-Hartwig reaction route to create the product, 4-(pyrrolidin-1-yl)benzaldehyde. I will compare the palladium-catalysed approach with an SNAr approach and appraise which route affords better yields and product purity.
This Issue has been created for community feedback on the routes, which will be attempted in the lab by us. We will be blogging our progress on this issue.