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

Abstract

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.

Dehydrogenative Functionalization of C(sp3)–H Bonds Adjacent to a Heteroatom Mediated by Oxoammonium Salts

“…[14b] Isochromanes 1c and 1d [22] and tetrahydroisoquinolines 1g-j [23] and 1m [24] were prepared following described procedures in the literature. Compound 1k was prepared by reduction of dimethyl 2-[2-(3,4-dihydroisoquinolin-2(1H)-yl)benzylidene] malonate [25] and 1l by coupling of ethyl 3-(2-fluorophenyl)-3-oxopropanoate with tetrahydroisoquinoline.…”

Transition-Metal-Catalyzed Additions of Carbonyl Functionalities to Alkynes

“…35 We have established an annulation of N-arylcarbamoyl chlorides 13 with internal alkynes 9 to afford 2-quinolones 14 efficiently in the presence of an iridium catalyst (Table 8). 38 Thus, the reaction of N-methyl-N-phenylcarbamoyl chloride with dec-5-yne in the presence of a catalytic amount (2.5 mol%) of [IrCl(cod)] 2 and 30 mol% added cod (cycloocta-1,5-diene) in refluxing o-xylene afforded 3,4-dibutyl-1-methyl-2-quinolone in 92% yield.…”

Triphosgene–Amine Base Promoted Chlorination of Unactivated Aliphatic Alcohols

“…It appeared that the selectivity between formation of alkyl chloride and diethylcarbamate was driven by sterics via an intermediacy of acylammonium ion species 7 , where the ensuing nucleophilic attack by chloride ions could competitively occur at two possible electrophilic carbon centers. 13-15 .…”