26 Feb
Published by Matin

As I alluded to at the end of my previous entry, I've been working on a way to make sulfonamides of the arryl pyrrole series for the OSDD Malaria project.

Figure 1. Examples of sulfonamides that are currently being made for testing as anti-malarials.

It seems sulfonamides form readily by introducing an amine to a sulfonyl chloride. So my main pathway has been to add a sulfonate group to 1-(4-fluorophenyl)-2,5-dimethyl-1H-pyrrole, chlorinate it then add the amine half after. Various ways that have been attempted to form the sulfonamide are listed below:
1) Chlorosulfonic acid

There has been some issues with the sulfonation of the pyrrole ring using this method, as it has been shown that sulfonation occurs at position 3- and 4- on the pyrrole ring forming a bis-substituted pyrrole sulfonate. Best illustrated by the work done by Paul Ylioja and Patrick Thompson.

2) Sulfur trioxide-pyridine followed by thionyl chloride:

While the sulfonate formation using Sulfur trioxide-pyridine has been a success. The chlorination method as described here and here has been unsuccessful to date. NMR experiments carried out here seem to show strange behaviour again by the chlorinating agent. The spectra posted show the loss of the hydrogen on the pyrrole ring of the sulfonate leading me to believe that thionyl chloride may be substituting itself into the 4- position. At the moment this is just a prediction but it has caused me to pause using this method.

3) Sulfur trioxide-pyridine followed by phosphorous pentachloride:

The chlorination method described here has been promising, after adding the amine I've been able to isolate a fraction that has a HNMR that I believe looks to be the sulfonamide. I was only able to isolate 5 mg (1% yield) which makes me worry that something has gone wrong. I'm am redoing the experiment while changing various conditions to see if I can get something close to a reasonable yield.
As always any and all comments are welcome!


Patrick's picture

Hi Matin,
As per my tweet/lab book here, it looks like I've got these to chlorinate cleanly with oxalyl chloride - so I should ask, do we want both compounds you've shown here? E.g. the ones based on glycine (NH) and sarcosine (NMe). I can make both here relatively easily, as I have a bit more of the sulfonic acid lying around.

Hi there, just watched Tom's Google Tech Talk and thought I'd have look around.
I worked on a project that used sulfonamides and we found the tetrazole was a good bioisostere.  It may reduce the solubility as you'd have 3 aromatics in conjugation but it's a option if you want some variety or to explore how the sulfonamide contributes to binding.