A mixture of anh. acetonitrile 12mL and isopropyl alcohol 1.4mL (18mmol) in a 25mL flask was cooled to 0C and N,N,N’,N’-tetramethylguanidine 1.9 mL (15mmol) was added under Ar, followed by azidotrimethyl silane 2.0 mL (15mmol), dropwise over 5 min – an exothermic reaction. The resulting solution of TMG-azide was warmed up to RT and then transferred by syringe to 2-chloro-4-iodo-5-trifluoromethylpyridine 3.075g (10 mmol) solid. The mixture was stirred under Ar on a 40C bath for 6 hours, then cooled to ambient temperature and portioned between half-saturated NaHCO3 solution 70mL and ether 80mL. The aqueous phase was re-extracted with ether 80mL. The organic extracts were washed with additional half-saturated bicarbonate 70mL, combined, dried with magnesium sulfate and filtered. The obtained solution of crude azidopyridine was placed on ambient water bath, water 1mL was added followed by 1M trimethylphosphine solution in toluene 11mL (11 mmol; exothermic reaction). The mixture was stirred at RT for 30 min, then washed twice with water (2x250mL) to remove Me3PO, the aqueous phases were re-extracted with ether (250mL). The combined extracts were dried (MgSO4) and evaporated. The residue (2.0g) was re-crystallized from cyclohexane 120mL to provide 1.517g of a 95%-pure product as white feathers (77% overal).
1H(d6-DMSO, 400MHz): 8.170(s, 1H), 6.932(br s, 2H), 6.758(s, 1H); 19F(d6-DMSO, 376.5Mhz): -61.93 (s, 3F);
Note: The neat crude monoazido intermediate can be isolated as a colorless oil (and separated from a crystalline side-product, posibly derived from bis-azido pyridine) but 4-pyridylazides are rather unstable and reducing them in diluted state without further purification is a safer alternative. TMS-N3 is skin and gloves-permeable and causes unpleasant acute azide poisoning (= nasty headaches). PMe3 has a pungent, obnoxious odor.
This procedure uses organic-soluble azide salt. TMG.HN3 can be isolated and stored; it is an extremely-hygroscopic crystalline solid (Org Prep Daily September 25, 2006). The preparation of the starting iodo pyridine was also discussed here, in Strange bits from Schlosser, on June 7, 2008.