Is science sometimes in danger of getting tunnel vision? Recently published ebook author, Ian Miller, looks at other possible theories arising from data that we think we understand. Can looking problems in a different light give scientists a different perspective?

A 1960s PhD (3) Synthesize Or Fail!

My supervisor finally reappeared, fresh from prolonged summer holidays, and for some reason I could not understand, my brilliant project was not greeted with unqualified enthusiasm. Just maybe he saw problems that eluded my somewhat innocent/inexperienced state but somehow he accepted and so I was off to the bench. The good news was that trans 2-phenylcyclopropylamine was made commercially; it is a monoamine oxidase inhibitor. (Memo to self: emphasize hygiene and clean working! Recalling that baggage, I did not want my brain messed up.) The simplest route was through the Curtius reaction from acids (acid chloride, nucleophilic substitution with azide, thermally decompose azide, acid hydrolysis of isocyanate). So, the problem now was to make the carboxylic acids. The most obvious route was rather long and only gave para substitution: Friedel Crafts with succinic anhydride, borohydride reduction to give the lactone, thionyl chloride to give the 4-(substituted phenyl)-4-chlorobutyroyl chloride, which was then esterified with ethanolic HCl, then cyclization with sodium t-amylate, purified by oxidizing out the olefinic material with alkaline KMnO4. Long-winded, an interesting filtration problem, but seemingly free of big problems.
 
There were two reasons to look for something else. The first was to get something quicker, while the second was to get some meta substitution. The literature said that ethyl diazoacetate on styrene gave a 5% yield of the desired compound. That did not impress me. I tried the zinc-copper couple/di-iodomethane on ethyl cinnamate, but no significant yield of desired product resulted. This was not unexpected, because that reaction was known to be difficult when the olefin was electron poor. The reaction of the ylide from trimethylsulphoxonium iodide on ethyl cinnamate did not work either, although a little help here from supervisor could have come in handy. The reference was from Corey, in a Tet. Lett. It was only much later, in a J. Org Chem., did I learn that the reaction only really works at minus 80 degrees. Silly me, I never thought of that, but a more experienced chemist might have asked, what were those bubbles – try cooling it until they stop. However, I did get a reasonable yield with alkali, triethylphosphonoacetate and styrene oxide. So, I immediately ordered some meta substituted styrenes. The basic problem with this project, of course, was that the electron withdrawing substituent that could show mesomeric effects would be para nitro, and its sigma value was some distance from the others in the line, which meant that the line had to be well-anchored so that the extrapolated "non-mesomeric" value had as little error range as possible.
 
The best way to avoid this difficulty was to make the meta nitro substitution, so while making a number of compounds by the "slow" route while waiting for styrenes, I made a lot of the simple reaction of succinic anhydride with benzene, and nitrated it. That gave me a lot of meta nitro substituted acid, so then I took that down the route to the cyclopropanecarboxylic acid, but when trying to form the cyclopropane ring, disaster! There was essentially a 100% yield of dirty brown rubbish. Supervisor had no suggestions, and it appeared that I was down to extrapolation, or doing something spectacular with one of the styrenes. Which raised the question, a year later, just where were those styrenes? It was around about now I started to get nervous. It was also somewhere about now that supervisor went off on a 9-month sabbatical. More soon!
Posted by Ian Miller on Nov 2, 2012 11:44 PM Europe/London

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