Pinacol rearrangement of adrenaline - first try

This week, Alicia, James and Brett started in the lab. Their first task was to generate the catechol aldehyde using an amino-pinacol type rearrangement of adrenaline. As mentioned previously, we want to avoid using perchloric acid so we tried using sulfuric acid in a mixture of water and methanol.

The adrenaline free base proved to be practically insoluble in water, methanol or methylene chloride but dissolved readily in 1M aqueous sulfuric acid. Thus, 25 mg of adrenaline free base was dissovled in 5 mL of 1M aqueous sulfuric acid to give a clear solution. 20 mL of methanol were added and the solution was refluxed for 2 hours in open air and remained clear.

Samples taken a 0, 30, 60 and 120 minutes were run on TLC both directly and after treatment with sodium bicarbonate powder. As show in the TLC plates below, there was no change after 2 hours of reflux. The spots did not migrate in 4:1 hexanes/methylene chloride or pure methylene chloride. Streaks were obtained in pure methanol, with the samples treated with bicarbonate migrating less.

I suggest that we increase the sulfuric acid concentration tenfold and try again.


From left to right TLC's run in methanol from the reaction at 0, 30, 60 and 120 minutes. On each slide, the left spot is the untreated solution and the spot on the right is after treatment with excess sodium bicarbonate powder.

Chris Hulme on the Ugi synthesis

I just heard back from Christopher Hulme about his opinion on doing a Ugi synthesis in the presence of phenols and other alcohols. Here are his comments:

The reaction is sensitive to the reagents used. Generally aliphatic aldehydes, non-anilinic amines, most isonitriles (TOSMIC does give lower yields - electron deficient) and acids are ok. I believe you will see some product with phenols and primary alcohols, although I suspect yields would be higher if protected.

This is pretty much in line with our thoughts so far. Cautious optimism that we might not need to protect alochols.

ChemRefer answers Ugi phenol question

I contacted ChemRefer about their unsatisfactory answer concerning the problem of phenols in a Ugi synthesis and they promptly came back to me with a beauty:

Phenol Ugi-Smiles Systems: Strategies for the Multicomponent N-Arylation of Primary Amines with Isocyanides, Aldehydes, and Phenols
Laurent El Kaïm, Dr. *, Laurence Grimaud, Dr. *, Julie Oble
Volume 44, Issue 48 , Pages 7961 - 7964 Published Online: 15 Nov 2005

It turns out that phenols can react like acids in a Ugi reactions but their reactivity is dependent upon electron-withdrawing groups on the aromatic ring. In the case of our target aldehyde, our phenolic system is a catechol so I would not expect the reaction with the phenol to be fast compared to the carboxylic acid. However, one difference in our case is that the phenol would be attacking intramolecularly, though I have not yet made the model to see if the meta position of the phenol group can even reach to cyclize.

I would still ask everyone in our group to continue reading up on the Ugi reaction and post if you find anything relevant. But my overall impression after reading this article is that there is enough of a chance for the unprotected aldehyde to work that we should give it a shot.

By the way this article also points out that aldehydes are much more reactive than ketones so we may also be able to get away with unprotected ketones in our starting materials.

Help from ChemRefer

ChemRefer is a free service that finds articles for chemical questions, using advertising to make money.

I asked them for an article where a phenol was used in a Ugi synthesis.

They found a JACS article where phenol and Ugi were keywords but unfortunately in the Ugi reaction there was no free phenols and no explanation that phenols need to be protected in that step.

The answer to this question is important because it will change the starting materials we will buy.

Next step in automation

As we get more compounds into the UsefulChem-Molecules blog, automation will become more important. What we would like to know are things like how many compounds have non-zero entries in Chmoogle or QueryChem and list only those compounds, which compounds do not have CAS numbers, which compounds are missing commercial sources, etc.

Ruslan has been working on this type of processing but unfortunately it is in Perl, which is inconvenient for our current team members, who have little programming experience. What would be nice is the translation of this type of code to VBA for Excel. This is a strategy that we used extensively in a prior project and I think it would work as well here because it just involves opening Excel, clicking on a button and retrieving the resulting list in a worksheet.

Hopefully we'll come across somebody with VBA experience willing to help.

Also, to anyone who is processing the molecules blog, don't hesitate to describe the kind of automation that would make your job easier.

meeting report

The UsefulChem group had 2 meetings this week. Here are some points that came out:

1) Everyone needs to subscribe to the UsefulChem blog, the UsefulChem-Molecules blog and the UsefulChem Wiki. Subscribing to the blogs is easy - just click on the Bloglines icon at the top of the blog. To subscribe to the wiki click on "Recent Changes" then "Notify Me" then click on the top RSS orange button. It will take you to an XML page - just copy the URL and paste it in Bloglines (under "ADD")

2) We spend most of our time on the Ugi synthesis. I think everyone in the group is now able to find the 3 components required to make the target diketopiperazine potential anti-malarials.

3) James started to create a database so we could keep track of which molecules have been processed and what we need to make them. If you are subscribed to the wiki RSS feed you will be able to see this database grow. Anyone is welcome to add to it.

4) We have people at very different levels of experience in the group. Do what you feel capable of doing. The simplest contribution is probably finding CAS numbers, commercial sources and other similar info that you see other molecules in the blog have. You don't need to understand any of the projects to do this.