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Final blog University of Reading 2017 #556

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Viliyana opened this Issue Jan 5, 2018 · 14 comments

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Viliyana commented Jan 5, 2018

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Our group managed to synthesise one out of the four molecules that we set out to achieve, although satisfactory purification was not possible.

At the start of the project, Nicola generated the requisite hydrazine and Viliyana and Flora synthesised the (3,4-difluorophenyl ethan-1-ol) alcohol. The hydrazine formation, BAIB-mediated cyclisation and SNAr reactions were all successfully completed in reasonable yield. The Buchwald-Hartwig was attempted multiple times for each substrate using a variety of different combinations of ligands, bases and sources of palladium:

1. Pd2(dba)2 (0.5mol%), BINAP(4.5mol%), NaOtBu(1.4 eq.), amine (1.2 eq.).
2. Pd(OAc)2(3mol%), BINAP(4.5mol%), Cs2CO3 (1.4 eq.), amine (1.2 eq.).
3. Pd2(dba)2(0.5mol%), JohnPhos(0.5mol%), NaOtBu (1.4 eq.), amine (1.2 eq.).

Few reactions changed into a dark brown to black colour which suggested that some of the palladium catalyst had coagulated. Most of the reactions turned from clear to a golden brown solution within few hours, however, TLC analysis showed that a product was not formed. All reactions were initially set at 80ºC. After a week no product was formed and the temperature was increased to 100ºC. After another week only one reaction lead to a product formation – Nicola’s NH1-005-3. An observation that in NH1-005-3 was accidentally added more amine made us reconsider our protocol and increase the equivalents of amine added from 1.2 to 2.4 as shown below:

4. Pd2(dba)2(0.5mol%), JohnPhos(0.5mol%), NaOtBu (1.4 eq.), amine (2.4 eq.).
5. Pd2(dba)2(0.5mol%), SpanPhos(0.5mol%), NaOtBu (1.4 eq.), amine (2.4 eq.)
6. Pd2(dba)2(0.5mol%), DPPF(0.5mol%), NaOtBu (1.4 eq.), amine (2.4 eq.)

The change in the conditions did not lead to a subsequent product formation. To verify our results and to see if our substrate had any effect on the amine installation, we attempted a Buchwald-Hartwig coupling between bromobenzene and morpholine using Pd2(dba)2(0.5mol%), JohnPhos(0.5%mol), NaOtBu (1.4 eq.), amine (2.4 eq.) but this was also unsuccessful.

Buchwald-Hartwig reaction:

  • Nicola Hollock – Successful NH1-005-3 followed by scale-up which was unsuccessful NH1-008 and NH1-005-1/2
  • Viliyana – VTM005, VTM006, VTM007 and VTM011 and VTM012 unsuccessful
  • Sam – SBM006-9 unsuccessful
  • Flora – FC-005-01 unsuccessful
    Due to the success of the small-scale experiment for NH1-005-3, the reaction could not be carried through to the next stage.

Nucleophilic Aromatic Substitution

Two different alcohols were attached. (3,4-difluorophenyl ethan-1-ol and 4-fluorophenyl ethan-1-ol) using NaH.

  • Nicola Hollock – formation NH1-004 (68%) followed by scale-up NH1-007 (24%)
  • Viliyana – VTM004 (45% yield) and VTM010 (48 % yield)
  • Sam – SBM005 (66.82% yield)
  • Flora – FC-004 (0.1318g, 16.79%)

Formation of alcohol

  • Viliyana – VTM001 (33% yield)
  • Flora- FC-003 (0.729g, 79.85%)

Cyclisation of triazolopyrazine core

  • Nicola Hollock – formation NH1-003 (25%)
  • Viliyana – VTM003 (27% yield) and VTM009 (30% yield)
  • Sam – SBM004 (54.53% yield)
  • Flora – FC-002 (0.5854g, 39.13%)

Cyclisation step consistently resulted in low yields suggesting lower yields are to be expected for this reaction.

Synthesis of the hydrazone

  • Nicola Hollock – Orange solid - NH1-002 (77%)
  • Viliyana – VTM002 (66% yield) and VTM008 (98 % yield)
  • Sam – SBM003 (95.68% yield)
  • Flora – FC-001 (3.2011g, 92.62%)

Formation of 2-chloro-6-pyrazine hydrazine

  • Nicola Hollock – Orange Solid NH1-001 (10.88g,100%)

@Viliyana Viliyana added the Series 4 label Jan 5, 2018

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MFernflower commented Jan 6, 2018

"Our group managed to synthesise one out of the four molecules that we set out to achieve, although satisfactory purification was not possible." @Viliyana Will the impure compound be send to be purified and then later tested?

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drc007 commented Jan 7, 2018

Would be great if this work could be continued. Perhaps try http://pubs.acs.org/doi/abs/10.1021/acs.orglett.7b03854

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maratsydney commented Jan 17, 2018

Hi there! Nice work, just want to point out some copy/paste mistakes in calculation in entry VT010. Was interested to look at changes that lead to such impressive yield compare to VT004 but found that must be something wrong in calculations: you making product with greater Mr than starting material and getting smaller mass while your yield so close to 100%.

Speaking of Buchwald-Hartwig, I would suggest to increase catalyst loading to at least 10 mol% of Pd and 20% of ligand. The reason for such high catalyst loading is our heterocycle substrate that can compete with ligands and in general this reaction with heterocycle substrates less studied and proved to be more challenging as mentioned, for instance, in this review 10.1039/c0sc00331j by Buchwald group.

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Viliyana commented Jan 17, 2018

@maratsydney Thank you for pointing this out, my moles for the starting material are wrong. Apologies, I'll correct that.

I absolutely love everyone's suggestions, it will be great to see Buckwald reaction working! We wrote the 'Final blog ' to inform everyone about our progress as our projected ended before Christmas and we are writing our dissertations now. However, I hope that our work can serve as a stepping stone for the future groups and hopefully they can benefit from our success and mistakes to advance the research towards completion of the targets' synthesis.

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maratsydney commented Jan 19, 2018

@PBCranwell I was looking at boronic acid/esters available and found that these compounds can be made through suzuki coupling using 4-Pyrrolidinophenylboronic and 4-Piperidinophenylboronic acid esters. So am seeking your advice, would you mind if I finish these compounds this way?

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MFernflower commented Jan 19, 2018

@maratsydney I assume that would be okay as per @Viliyana 's comment "However, I hope that our work can serve as a stepping stone for the future groups and hopefully they can benefit from our success and mistakes to advance the research towards completion of the targets' synthesis."

Totally unrelated but about a year ago I had this idea to use nitro as a replacement for the OCHF2 portion of the S4 drugs - do you have some p-nitrophenylboronic acid in stock to try and test this? I know nitro isn't the nicest thing in a drug but I feel it's worth a shot as a replacement for the difficult to make OCHF2 fragment!

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PBCranwell commented Jan 19, 2018

@maratsydney please feel free to continue our work. This has been put out there so anyone else can have a go, and seeing as we won't be back on this until October at the earliest I am more than happy for you to complete it :-)

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maratsydney commented Feb 21, 2018

@PBCranwell @Viliyana I am pleased to say that these three compounds were made and will be shipped with the next batch for biological activity evaluation.
2018 02 21 scheme for github reading uni

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Viliyana commented Feb 21, 2018

@maratsydney , that's great news! Can you link the procedure?

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PBCranwell commented Feb 22, 2018

@maratsydney nice work! The students are currently writing their final report, so any information about whether they used their procedures, and what worked for the final B-H coupling, would be a valuable addition to their work. Good luck with the biological testing!

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maratsydney commented Feb 22, 2018

@Viliyana @PBCranwell As I mentioned above, different approach was used to make these compounds. Suzuki coupling was utilized instead of Buchwald-Hartwig, example of reaction scheme below. Links to ELN: MK043-1, MK034-1, MK042-1.
mk042-1

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Viliyana commented Nov 6, 2018

@maratsydney , did you get the results from the potency testing of MK043-1?

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maratsydney commented Nov 7, 2018

@Viliyana , yes we received data while ago. Unfortunately all compounds ( MK043-1, MK034-1, MK042-1) came back as completely inactive.

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Viliyana commented Nov 8, 2018

@maratsydney , thank you for letting me know. Good luck with your future work!

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