Palladium‐mediated oxidative carbonylation reactions for the synthesis of ¹¹C‐radiolabelled ureas

Abstract

Palladium(II)-mediated oxidative carbonylation reactions have been used to synthesize (11) C-radiolabelled ureas via the coupling of amines with [(11) C]carbon monoxide, in a one-pot process. Following trapping of (11) CO in a solution of copper(I) tris(3,5-dimethylpyrazolyl)borate, homocoupling reactions of primary aliphatic amines proceed in the presence of Pd(PPh3 )2 Cl2 to give the corresponding N,N-disubstituted [(11) C]ureas. Secondary amines do not produce the corresponding N,N,N,N-tetrasubsituted [(11) C]ureas under these conditions. This difference in reactivity allows for the formation of unsymmetrical N,N',N'-trisubstituted [(11) C]ureas using a mixture of a primary amine and a reactive secondary amine. The potential use of this method in positron emission tomography (PET) was demonstrated by the synthesis of the M1 muscarinic acetylcholine receptor radiotracer, [(11) C-carbonyl]GSK1034702.

Low‐Pressure Radical 11C‐Aminocarbonylation of Alkyl Iodides through Thermal Initiation

“…Amides, , , are the most common class of compounds explored in palladium‐mediated 11 C‐carbonylation (Scheme ). Other structures that have been obtained directly from [ 11 C]CO by using palladium include aldehydes,, carboxylic acids,, , esters,, , , hydrazides, imides, ketones,, thioesters, and ureas . There are also a few examples of compounds obtained from multi‐step synthesis starting with 11 C‐carbonylation; these include 11 C‐labelled hydroxamic acid from esters, and alkyl iodides, from aldehydes/carboxylic acids through olefin carbonylation.…”

“…Other structures that have been obtained directly from [ 11 C]CO by using palladium include aldehydes, [26,39] carboxylic acids, [10,26,40] esters, [4,26,41,42] hydrazides, [40] imides, [43] ketones, [26,44] thioesters, [45] and ureas. [24] There are also a few examples of compounds obtained from multi-step synthesis starting with 11 C-carbonylation; these include 11 C-labelled hydroxamic acid [46] from esters, and alkyl iodides [11,39] from aldehydes/ carboxylic acids through olefin carbonylation. However, palladium-mediated carbonylation is restricted to organic halides lacking beta-hydrogen atoms; methyl, aryl, benzyl, and alkenyl iodides are good examples of such species.…”

Recent developments in carbonylation chemistry using [13C]CO, [11C]CO, and [14C]CO

“…Complex 123 (Cu(Tp*)) was later used in a series of Pd‐mediated 11 C‐carbonylations to synthesize simple 11 C‐labeled amides, carboxylic acids, and ureas . Furthermore, it was possible to prepare [ 11 C ]MK‐0233 ( 124 ), a PET tracer for the neuropeptide Y Y5 receptor using this methodology (Scheme ) …”

Efficient Synthesis of 11C‐Acrylesters, 11C‐Acrylamides and Their Application in Michael Addition Reactions for PET Tracer Development

“…However, only low conversions were observed by using this strategy (Table 1, entries 1-3, 6). [10] The optimal radiochemical conversion in the synthesis of acrylester [ 11 C]3 and acrylamide [ 11 C]4 was established with use of [(cinnamyl)PdCl] 2 as a catalyst [23] (Table 1, entries [4][5]9). [10] The optimal radiochemical conversion in the synthesis of acrylester [ 11 C]3 and acrylamide [ 11 C]4 was established with use of [(cinnamyl)PdCl] 2 as a catalyst [23] (Table 1, entries [4][5]9).…”

“…To perform PET imaging the availability of the desired PET tracers, compounds labeled with a positron-emitting nuclide and administered in trace amounts to the study subject, is crucial. [3][4][5] Other carbon-11 labeling reactions are known, but hardly applied for PET tracer development. Therefore, the development of synthesis methods for the introduction of positron-emitting radionuclides into molecules to yield PET agents is important and thus an active area of research.…”