AKA “Things I love to work with”

I’ve been out of the lab for the last few days, enjoying the summer weather and perhaps contracting a bit of “Vacation Madness” .  So, I thought I’d share one of my favourite reactions.  It’s not elegant and it’s not beautiful, but it works well.  I’ve used the same conditions on about half a dozen different substrates (mostly aminoglycosides) and it hasn’t failed once.

So, in true OrgPrepDaily fashion:

The amine of interest is dissolved in a 10/10/7 solution of water, methanol and triethylamine.  As the solution is stirred Boc2O(s) (1.6eq) is slowly added, with a small amount of methanol used to rinse the weigh boat/paper.  The solution is then heated to 55°C for 16hr (overnight), during which time the production of t-butanol will result in a thick slurry.

Following the reaction the solution is allowed to cool to room temperature and the stir bar is removed (if possible).  The slurry is evaporated to dryness on a combined high vacuum/rotary evaporator setup, using dry ice as a coolant.  The resulting white solid is then left under high vacuum for a minimum of 72hr, during which time residual Boc2O will sublimate into the dry ice trap.  The product may then be used without further purification.

No muss, no fuss.  Anhydrous and anoxic conditions are not required, though if your amine is provided as a salt you’ll have to do an extraction with sodium bicarbonate prior to final Boc2O removal.  Standard Boc protection conditions don’t seem to generally use water as a solvent, but I`ve found it helps increase the solubility of the initial unprotected amines.  YMMV.

Strangely, despite the fact that the entire reaction and “purification” takes place in a single round bottom flask my yields are generally in the 90-97% range.  The current theory is that the missing mass shows that the starting material was fairly wet, likely from a previous lyophilization (CO2 entrapment by the multiple amine groups is a close second).

The original reference:
Quader S, Boyd SE, Jenkins ID, & Houston TA (2007). Multisite modification of neomycin B: combined Mitsunobu and click chemistry approach. The Journal of organic chemistry, 72 (6), 1962-79 PMID: 17298096