It is easy have a hit lead structure and and see two positions we can beat the compound up and tease out the activity data. I see the discussion in a room now:  the chemist in the corner has his Aldrich catalog out looking up the 100 starting materials to use to meet productivity metrics. Ho hum, and here I am saying use microwaves to help you out right. If you ask me I will always say, microwave reactors are an innovative tool in your arsenal and generally no substitute for the creative synthetic mind — hopefully you get both.

An interesting paper I came across (Molecules 2013), involved just that…the scenario, hit lead compound, good assay for activity and a place to get some SAR fleshed out. The situation: I blink twice with scepticism when I see a sulfone in a lead compound, but not enough to do some of the initial work, especially in the area of antiproliferative properties (structure shown). So a good disconnection would be with a leaving group on the methyl group at the 4-position of the thiazole. However, displacement of the group would be using a sulfinate as the nucleophile — and not too many people doing that (very few commercial sulfinates).

Screen Shot 2013-11-02 at 8.46.50 AM

Starting point for SAR

Their initial literature scheme lead to using the 4-chloromethyl thiazole SN1 reaction with phenyl sulfinate in anhydrous methanol under a 60W lamp for 24 hours (ouch). Good thing this group decided to look for an alternative route (below).

Screen Shot 2013-11-02 at 8.55.50 AM

Sulfinate SN2 microwave 30 min (H2O)

A comparison of the two routes made this an easy decision (time and yield). An initial grouping of commercial sulfinates provided some of the starting analogs. And here is were you can get stuck — the rest of the sulfinates needed to be prepared and… could they be used by the method already developed (sometimes it doesn’t work out right?). If you are like me on an initial read, I nearly stopped reading because of my experience with sulfinates — there isn’t a lot of good information out there — and now the method is in water (generally good because it is green, but sometimes the chemistry isn’t set-up for it). Good thing I read the remaining portion because they found a nice method for making the sulfinates to be used directly by mixing in the starting 4-chloromethylthiazole to generate the desired compounds in high yield under the same conditions. In preparation of the sulfinate — simply by taking starting sulfonyl chlorides, NaHCO3 and Na2SO3 in H2O at 100C for 20 min under microwave heating then adding the thiazole and heating for an additional 30 min to give the product. What a nice and create method for obtaining this one-pot preparation by changing conditions then applying some know-how to keep the advantage of the microwave reaction.

Screen Shot 2013-11-02 at 9.05.13 AM

MW sulfinate formation, then addition of second reactant

The challenge in taking something home from this kind of work is finding a way to apply the concept to our own work. I see real value in thinking about the way the microwave was applied in the sequence rather than the fact that they used a microwave at all. Happy hunting everyone!

Advertisements