2 for 1 deal at Columbia University!


Allen, J. M.; Lambert, T.H. Tropylium Ion Mediated α-Cyanation of Amines Journal of the American Chemical Society January 4, 2011 ASAP

WOW. All I can say is this is probably one of the best articles I’ve read in some time. It puts the last paper I reviewed to shame. Really to shame. I mean this article is on a COMPLETELY different topic, but still. The impact factor of this article as compared to Lee’s is immeasurable.  However, I can’t say I didn’t see this paper coming. I had known (from my time at Columbia) that Dr. Lambert was interested in the tropyllium ion (I like to call it tropyl cause it’s easier.) . And I had thought that it would make a good oxidant. I knew he was looking into this idea. But man, I wouldn’t have tried to oxidize amines. That’s a nifty trick. Anyway…on with the review.
The article begins by describing some of the history of imines and how the only real (effective) way to make them is condensation reactions. And let me tell you. They either work really well or blow super hard. Anyway, Lambert had the idea of oxidizing amines the same way you would alcohols to get at those pesky imines. While it seems easy, it’s not. There are a lot factors in the way like side reactions, enamine formation, and the fact that most current methods rely on toxic heavy metals or DDQ (also not fun, and somewhat limited in scope). So Lambert thought why not use the tropyl cation as an oxidant. Again, this idea isn’t completely knew. There have been sporadic reports of it being used as an oxidant (in similar fashions to the trityl cation). However, I like what Lambert did next. Not only did he give a short review of the tropyllium tetrafluoroborate (which was only isolated in the mid 1950s) but he also explained where he was coming from. Apparently there had been an article published in the Canadian Journal of chemistry which basically did one substrate and was being used to form the corresponding aldehydes. Boy did that group drop the ball on that reaction. They even knew that they had imines!

Anyway, he basically took that idea that the Canadian article mentioned and ran with it. He specifically went with sterically encumbered teriary amines. Understandably so, cause otherwise he’d have a mess with enamine formation (I wonder what that could lead to…). He found he was able to get quantitative, that’s right quantitative, conversion to the imine in 3 hours at room temperature in acetonitrile using triisobutyl amine. Now that in and of itself isn’t all too special but is kinda nice due to the fact that you have a volatile 1,2,5 cycloheptatriene byproduct and a water soluble tetrafluoroborate salt(b.p. 116 degrees Celsius). It makes the workup simple, kinda like the Bobbitt reagent (UCONN PRIDE!). What he did next made it awesome. He (really Julia Allen, cause she’s the grad student, Lambert just gets the grants) used an insoluble salt, KCN, in the reaction hoping to effect C-C bond formation via cyanation. And boy did that work. Interestingly as the imine formed, the KCN dissolved. While he couldn’t explain this, I do have a theory (which I won’t explain until I try it myself, sorry :P) but I’ll give you a hint: I don’t think this is a through space hydride transfer…



After establishing the ideal conditions for the reaction, he then set out to explore the scope (as I would expect any good methodologist to do). The scope was pretty reasonable and the yields were pretty good for the most part (typically in the mid 70s). Plus he was even able to demonstrate the use of his method in the context of a biologically significant molecule, (-)-sparteine. It was even regioselective for monocyanation and could be performed on a large scale! I like large scales! Some of the substrates required a kick, namely heating up to 120 degrees Celsius but some simply just went at room temperature.
I did entitle this as “2 for 1” deal didn’t I? Well, the second reaction was an aza-cope reaction using the tropyl cation (the second reaction in the first figure). He was able to get this reaction to go by first forming the imine as part of their standard methodology and then heating it to 120 degrees Celsius to get the rearrangement to occur. It was done in pretty good yield, 73%, starting from a pretty easy to prepare material (cyclohexylmethyl amine with benzophenone to get the imine, then allyl magnesium bromide to get the allyl group on there). Overall I rate this article A++++ (that right 4 pluses). I plan on looking into some tropyl chem of my own!
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