|Hello, amine equivalent!|
Source: Cumberland Packing Grp.
From a fresh Org. Lett. ASAP, courtesy of the Amgen Process group, comes the 2-amination of some 3,5-disubstituted pyridine N-oxides. The group wants to add in an ammonia surrogate, but faces low conversions and poor regioselectivities (2- vs. 6-) with "standard" literature conditions (excess tert-butylamine, tosic anhydride). Substantial gains occur with a switch to Hunig's base and TsCl, but they need to find a bulky, electron-poor nitrogen source. Since we're potentially talking kilos here, price and availability become major considerations.
So what did the researchers choose as their "N" source? Saccharin. Yup, the artificial sweetener from the pink packets, used on process scale. Saccharin beat out many other "Gabriel-type" protected amines (phthalimide, Boc phosphoramidate, etc.), and you can't beat the price: about $5 / kilo. Under optimized conditions, the group saw yields from 21-97%, and product ratios of ~28:1. Better still, acidic hydrolysis (HCl, 80 degrees) frees up the 2-aminopyridine compounds, most of which are crystalline solids.
Pretty sweet synthesis.