Biologically Active ¹¹C-Labeled Amides Using Palladium-Mediated Reactions with Aryl Halides and [¹¹C]Carbon Monoxide

Abstract

Using [11C]carbon monoxide in palladium-mediated synthesis, six amides were labeled with 11C. Phenyl and benzyl halides with halides as additional substituents were carbonylated and reacted with primary and secondary amines. Four of the selected amides were receptor ligands, one was a precursor to a receptor ligand, and one was a model compound. The 11C-labeled amides were obtained with good to almost quantitative radiochemical yields with specific activities up to 1000 GBq/μmol. The radiochemical purity of the final products exceeded 98%. In one case, the corresponding 13C-substituted compound was produced to verify the position of the label. In a typical experiment starting with 5.0 GBq of [11C]carbon monoxide, 2.2 GBq of LC-purified N-(2-aminoethyl)-4-chloro[carbonyl-11C]benzamide was obtained within 15 min from the start of the carbonylation reaction (74% decay-corrected radiochemical yield). The presented approach gives significant new possibilities for 11C-labeling and is seen to be valuable also for synthesis of 13C- and 14C-substituted compounds.

The Use of Lithium Amides in the Palladium‐Mediated Synthesis of [Carbonyl‐11C]Amides

“…[7,9] It was shown that yields with unreactive amines, such as anilines, may be increased by converting them into the corresponding lithium amides before carbonylation with [ 11 C]-carbon monoxide.…”

“…[4][5][6] A compelling, but not yet explored, synthetic route to such analogues is palladium-mediated carbonylation of aryl halides or triflates using [ 11 C]carbon monoxide. [7] We intended to use this approach to create a library of structurally related [carbonyl- 11 C]amides using amine 1 (Figure 1) and various aryl iodides. [8] However, the previously described procedure [7] provided only 0-15 % decaycorrected radiochemical yields of the amides.…”

“…[7] We intended to use this approach to create a library of structurally related [carbonyl- 11 C]amides using amine 1 (Figure 1) and various aryl iodides. [8] However, the previously described procedure [7] provided only 0-15 % decaycorrected radiochemical yields of the amides. The bottleneck was, conceivably, the low reactivity of parent amine 1.…”

Synthesis of [11C-carbonyl]hydroxyureas by a rhodium-mediated carbonylation reaction using [11C]carbon monoxide

“…14 15 A solution containing azidotrimethylsilane, [Rh(cod)Cl)] 2 , dppe and O-(trimethylsilyl)hydroxylamine in THF was transferred and pressurized to 35 MPa into the micro-autoclave. The reaction proceeded at 1208C for 5 min.…”

Synthesis of diethyl [carbonyl-11C]malonate from [11C]carbon monoxide by rhodium-promoted carbonylation and its application as a reaction intermediate

“…5 This experimental setup had been successfully used to explore the reactivity of [ 11 12 and also in radical-mediated reactions. 13 All these methods permit the synthesis of 11 C-labelled compounds in high specific radioactivity in a range between 100 and 1500 GBq/mmol.…”