Total Synthesis Strychnine - Step 9

So it's been such a busy week that I haven't had time to post anything in a while!  But now, it's the Sunday of the Oscars, and I'll try to squeeze in a post on a very common type of reaction, acetylation.

Overview:

Acetylations are so widespread throughout the organic world due to the efficiency and speed of the reactions.  In this case what we are doing is creating an amide from an anhydride.  Before we get into the reaction itself, we should ask ourselves, why?!  Why are we turning this nitrogen into an amide?  The next step is an ozonolysis how should that affect anything?  Well, the ozonolysis in the next step involves reacting the electrophilic ozone molecule (O3) with the nucleophilic veratry group (the di-methoxy benzene).  This works (although the yield is poor) because this group is much more nucleophilic than a normal benzene.  However, we notice that without acetylating the amine, actually it is possible that the benzene group could be cleaved too because the amine is also very strongly electron donating, making the benzene ring a better nucleophile.  It is for this reason that we are turning the amine into an amide, which is a non-electron donating group.

The reaction for this is quite simple and the generic reaction can be found below.

As seen in the mechanism above, there is really an equilibrium of pyridine and acetic acid, however, the equilibrium favors the protonation of the pyridine and the deprotonation of the acetic acid.  A question that may arise is, why do we have the pyridine?  After all, without the pyridine the acetic acid could be released as the acid and all would be well right?  Not so.  Remember that acetic acid wants to be deprotonated because it is an acid, and all amines (including the amine we are trying to acetylate!) like to take away these protons.  So our pyridine is our sacrificial amine essentially that sucks up the protons so that our reactant can still react with the acetic anhydride.  Why then does pyridine not react with acetic anhydride to form an acetylated pyridine?  It's not that nucleophilic, is the answer.  Compared to our secondary amine (which is attached to an aromatic ring which in addition to the sterics is likely why this reaction is heated.  Typically these reactions go at room temp. quite nicely in an hour or two) the pyridine is not nucleophilic and is a tertiary amine.  These are much less likely to react, although its' always probably that a small percentage will.  Other than pyridine, triethylamine (TEA) could also be used for purposes like this.

Again, like I said before, reactions like this usually go at RT and are finished in hours to minutes for simple substrates.  In this case, reflux is used likely to speed up reaction, and perhaps to push reaction forward, as the secondary amine is somewhat hindered, and since the nitrogen electrons are conjugated with the aromatic ring (just like in aniline) it is likely not as nucleophilic.  In addition to amines (the most common substrate) alcohols and thiols can also be acetylated as they are good nucleophiles.

Workup:

I feel like I keep repeating myself with Woodward here.  It's another precipitation into water that produces our product.  Upon cooling for 2 hours and adding a little bit of methanol (another non-solvent) Woodward was able to isolate the crystal as well as remove the pesky pyridine from the reaction.  Additionally the acetic acid can be difficult to remove if you just use a vacuum pump, but in this case, this also goes into the aqueous phase upon filtering and so product plus some minor impurities are obtained.  The product description for this was not given (in terms of its appearance) likely because reactions like this are so commonplace (even though I myself have never done one).  Recrystallization from chloroform/methanol yielded a more pure product.  Also to note are the high yields for these reactions (98.5%).  This is due to the pyridine shifting the equilibrium to the products side by absorbing the proton.  I am not sure what the yield would be without, but I am sure it would be around 50%, as this is when half of the amine has reacted, leaving the other remaining half protonated.

Tune in for the ozonolysis in the next step of the synthesis which actually was a big setback in the synthesis due to the poor yield.  But nevertheless, a poor yield does not necessarily mean a failure of an experiment, although it is certainly a hinderance.  Even in my own research I have one step which is 50% yield for removal of a protecting group.  This means that for every 150mg of material I have, I can only get 60mg out of it.  It's a little depressing because it is a lot more wasteful, but in this case, sheer large mass of material gets the job done.