Debenzylation of Tertiary Amines Using Phosgene or Triphosgene:  An Efficient and Rapid Procedure for the Preparation of Carbamoyl Chlorides and Unsymmetrical Ureas. Application in Carbon-11 Chemistry

Efficient and rapid preparations of carbamoyl chlorides and unsymmetrical ureas from tertiary amines and phosgene or its safe equivalent triphosgene [bis(trichloromethyl)carbonate, BTC] are described. First, the reaction of stoichiometric amounts of phosgene with secondary amines was revisited, and it was shown that the formation of carbamoyl chlorides in high yields required careful adjustments of experimental conditions and the use of pyridine as an HCl scavenger. A phosgene-mediated dealkylation of triethylamine was observed when this base was used instead of pyridine. Taking advantage of this observation, a strategy of synthesis of carbamoyl chlorides from tertiary amines and phosgene has been developed. N-Alkyl-N-benzyl(substituted)tetrahydroisoquinolines, -piperazines, -piperidines, or -anilines were treated with stoichiometric amounts of phosgene (or BTC) in CH(2)Cl(2). Tertiary amines bearing electron-enriched benzyl group(s) afforded carbamoyl chlorides in excellent yields and without any contamination by symmetrical ureas. Subsequent additions of primary or secondary amines to these carbamoyl chlorides produced unsymmetrical ureas in single-pot and high-yielding operations. This methodology was applied in (11)C-chemistry. From [(11)C]phosgene, a common precursor used in the preparation of radiotracers for positron emission tomography, a rapid and efficient synthesis of (11)C-carbamoyl chlorides and (11)C-unsymmetrical ureas derived from tetrahydroisoquinoline and piperazine is described. The first example of (11)C-amide formation from the reaction of a (11)C-carbamoyl chloride and an organometallic (cyanocuprate or a Grignard reagent in the presence of a nickel catalyst) is also presented.