Three-necked 2L flask with a mechanic stirrer, addition funnel and reflux condenser (equipped with an outlet tube adapter attached to a wide tubing vented into the hood intake – noxious gases).
Also needed: a 24/40 fritted outlet adapter (or filtration finger), a positive-pressure filtration funnel with the upper joint 24/40 or wider (a short chromatographic column with a sintered glass bottom also works).
Before the experiment, a mixture of solid KF 40.1g (Aldrich “spray-dried” grade, 690mmol) and potassium hexafluorophosphate 116.0g (630 mmol) was pre-dried by spinning at 160C/0.3 Torr/3hours using a large Kugelrohr “coffee can” apparatus. (Dry stirring on oil bath on highvac overnight also works)
Oxalyl chloride 70mL (800 mmol) was added in one portion to a solution of tetramethylurea 69.7g (72.6 mL, 600mmol) in toluene 1L with vigorous stirring and with cooling on ambient oil bath. (Two-layer mixture formed, non-exothermic addition). After complete addition, the heating was turned on and the bath temperature was gradually increased to 60C over 20 min. With gas evolution, the bottom layer gradualy solidified. The mixture was stirred at 60C for 2 hours and then cooled to ambient temperature. The addition funnel was replaced with a fritted adapter, the supernatants were decanted under mild positive pressure of nitrogen and the intermediate in the reaction flask was rinsed with toluene (2x300mL).
To this chloroformamidinium chloride in the reaction flask (heavy hygroscopic solid, containing some toluene) under blanket of nitrogen, the pre-dried KF+KPF6 mixture was quickly added in one portion. Dry acetonitrile 1L was added and the reaction mixture was stirred at 55C for 1 hour. The cooled mixture was quickly filtered through a large coarse filtration funnel (the solids were washed with acetonitrile (3×150 mL). The combined filtrates were evaporated from ambient bath and the obtained oily residue was dissolved in dichloroethane 0.7L with heating. The resulting cloudy solution was filtered while hot using a medium-porosity filtration funnel and the filtrates were concentrated to approx 450 mL volume. THF 600mL was added with stirring, the flask was then gently shaken (2 min) to promote crystallization. The mixture was allowed to crystallize at ambient bath for 1 hour. The precipitated product was collected by filtration under positive pressure of nitrogen and washed with additional THF (2x250mL). A stream of nitrogen was passed through the product for 20 min, the drying was completed on highvac (2h). The product was stored at +5C in parafilm-sealed teflon-lined wide-mouth flask.
Y=143.0g (90% th) of a white crystalline product, m.p. 112-113C 1H(DMSO-d6, 300MHz): 3.150 (apparent d)
Note: The solvents used in large-scale prep were not specifically anhydrous, a good grade (HPLC) from freshly-opened 4L bottle works well. Drying the salts is important, so is the filtration under positive pressure (fortunately the intermediate and the TFFH product are coarse heavy solids that filter well.) Dried TFFH is not hygroscopic but it does decompose slowly at RT with HF formation.
Note: Oxalyl chloride has to be added to a cold solution of tetramethyl urea in one portion. Oxalyl chloride plus tetramethyl urea form a non-volatile liquid adduct that controlably decomposes upon gentle heating with gas evolution to produce the chloroformamidinium chloride. The reaction rate (= the gas evolution rate) is controled best by adjusting the bath temperature. (Adding oxalyl chloride at 60C is a bad alternative – unreacted oxalyl chloride is readily carried into the condenser due to the gas evolution so addition rate would need to be very slow).
TFFH is a useful reagent for making acyl fluorides from acids in situ (dichloromethane, 2 eq. of Hunig’s base, RT, 20min), the only side-product is teramethylurea and amine salts. TFFH reacts with amines to form teramethylguanidines so the activation needs to be done in separate step, before the coupling.
TFFH is available from Aldrich. It is ridiculously expensive and it will be, until the Carpino’s patents expire.