Synthesis of Series 4 complexes - University of Reading 2017

[Viliyana]

We are Chemistry BSc students at University of Reading currently undertaking our third-year organic research project. Over the next few weeks, we will be aiming to synthesize four molecules based on series 4 (triazolopyrazine core) with two variations on the triazole ring and 2 variations of the pyrazine ring to create more diversity for screening. The proposed four molecules are shown below.

We will start by taking the para-bromo benzaldehyde and reacting this with 2-choloro-6-pyrazinehydrazine generating the hydrazone. We intend to cyclise the hydrazone using BAIB and dichloromethane and then install the top left fragment using a SNAr reaction using either 2-(4-fluorophenyl)ethan-1-ol or 2-(3,4-difluorophenyl)ethan-1-ol. Our intention is to use a Pd-catalyst and Buchwald-Hartwig cross-coupling to install the amine derivatives, morpholine and pyrrolidine and potentially piperdine if we have enough time. As a group, we will investigate which alcohol is most effective and which derivative is most successful in the coupling. In an attempt to optimise the SNAr, we will look into using NaH instead of KOH/18-c-6 to see which reagent is more effective. This will be following on from the research conducted in #541. We will regularly be blogging our progress.

My name is Nicola and I will be undertaking the synthesis of the compound 5-(3-flurophenethoxy)-3-(4-(pyrrolidine-1-yl)phenyl)-[1,2,4]triazole[4,3-a]pyrazine. I intend to use a SNAr reaction using 2-(4-fluorophenyl)ethan-1-ol to install the top left fragment and then use Buchwald-Hartwig coupling to install the pyrrolidine ring to this product. During the first few weeks, I will be producing more of the 2-chloro-6-pyrazineyl hydrazine for the team, then making the requisite hydrazone, which will be followed by a cyclisation. Lab book

My name is Viliyana and I will be synthesizing a molecule based on a triazolopyrazine core with 3,4-difluorophenethyl alcohol substitution on the pyrazine ring and 1-phenylpyrrolidine chain attached to the triazole heterocycle. During the first week, I will be preparing the 3,4-difluorophenethyl alcohol from 2-(3,4-difluorophenyl)acetic acid via reduction using lithium aluminium tetrahydride. I will then synthesise more of the hydrazone intermediate and complete the cyclisation using BAIB. I will attach the 3,4-difluorophenethyl alcohol via SNAr to the pyrazine side. Next, I will initiate Buchwald-Hartwig coupling with a palladium catalyst to couple the pyrrolidine to the triazole core. This will give the final 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidine-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine molecule below. Lab Book

Synthesis of 3,4-difluorophenethyl alcohol

Synthesis of 5-(3,4-difluorophenethoxy)-3-(4-(pyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-a]pyrazine

My name is Sam and I will be aiming to produce the sample of 4-(4-(5-(4-fluorophenethoxy)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)phenyl)morpholine following the same initial steps in the synthetic route as the rest of the group but differing in the side chains attached via SNAr for the addition of the alcohol and the Buchwald-Hartwig coupling for the addition of morpholine after cyclisation. Lab book

My name is Flora and in this research, I will be optimising the nucleophilic aromatic substitution reaction, which involves the reaction of the cyclised hydrazone product and 2-(3,4-difluorophenyl)ethan-1-ol under basic conditions. The triazolopyrazine core from the previous step will be reacted with the benzyl alcohol and sodium hydride to fully deprotonate the alcohol (under Barbier conditions) and initiate the SNAr reaction. The purpose of this step is to insert a long chain fragment around the benzene ring of the molecule to make the compound more drug-like. The product I synthesise will then be used in the final step of the reaction which is a Buchwald-Hartwig cross-coupling reaction between my product and morpholine in the presence of Pd(0). At the end of this research I will have synthesised 4-(4-(5-(3,4-difluorophenethoxy)-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)morpholine.

[mcoster]

Awesome thorough write-up, team. Looking forward to seeing how things progress!

Just a suggestions - the first reaction scheme shows a 4-chlorophenylethanol reagent, then a 3-fluorophenyl substituted product, but the text mentions a 4-fluorophenyl substituted product.

Good luck!

[Viliyana]

@mcoster Thank you for pointing this out and for the positive comment! I fixed the scheme. We are all very excited to be involved and hope that you will enjoy our future work!

[MFernflower]

It's worth noting that JohnPhos works better than BINAP for these type of couplings - see http://malaria.ourexperiment.org/triazolopyrazine_se/byuser/plus.google.com-109263878592735967907

[mattodd]

Looks great, @Viliyana ! Welcome. Exciting stuff @PBCranwell.

Main, first thing: Can you please install links to lab notebooks above, for each team member, and please refer to those directly whenever you're writing about a particular reaction - just so that we can see the reaction and all the data?

Second thing: I've added you to the "core contributing team" meaning you should now be able to add yourself as the person responsible for this Issue, and you should be able to add any relevant tags, such as the "being synthesised now" tag and anything else you'd like.

Third thing: I've added your targets to the DCNYS section of the wiki, just so we don't lose track. Given that we're talking about a collection of compounds I can't add InChI/SMILES/InChiKeys, but please do add those to any post where you're talking about a specific molecule. We can all help you with that if I'm being confusing with those terms...

I'm excited to see your progress. Note that @maratsydney has been working on a Suzuki route that seems to be working now and may provide you with another synthetic option later on. #537

[Viliyana]

@MFernflower Thank you for the useful comment! I am looking forward to testing some couplings tomorrow. In the link you sent, I couldn't find yields - I was hoping to compare results from BINAP vs JohnPhos just to know what to expect. Also in most literature, the scale of Pd catalyst and the ligand is in mol%, whereas in the reaction you recommended the amounts are 10 times larger. Is there any reason for that? Thank you in advance!

[MFernflower]

The work I posted was from a researcher who quit the project quite some time ago - It's odd that didn't post his yields but he did have issues with BINAP as @mattodd can confirm - I would start by using the normal amounts of palladium and JohnPhos and then work on different conditions! If I had to guess why BINAP does not work - it would be because it's many times more bulky than JohnPhos

[Viliyana]

@MFernflower Thank you! I will try both tomorrow as well as different bases - so very excited. I just realised that this poor guy was working on the scale of micromoles and probably was difficult to weigh such small amounts of the catalyst. I will use the standard amounts.Thank you again!