Acyl Amidines by Pd-Catalyzed Aminocarbonylation: One-Pot Cyclizations and ¹¹C Labeling

Abstract

A protocol for the carbonylative synthesis of acyl amidines from aryl halides, amidines, and carbon monoxide catalyzed by Pd(0) is reported herein. Notably, carbon monoxide is generated ex situ from a solid CO source, and several productive palladium ligands were identified with complementary benefits and substrate scope. Furthermore, sequential one-pot, two-step protocols for the synthesis of 1,2,4-triazoles and 1,2,4-oxadiazoles via acyl amidine intermediates are reported. In addition, this approach was extended to isotopic labeling using [ 11 C]carbon monoxide to allow, for the first time, synthesis of 11 C-labeled acyl amidines as well as a 11 C-labeled 1,2,4-oxadiazole.

Palladium-Mediated Synthesis of [Carbonyl-11C]acyl Amidines from Aryl Iodides and Aryl Bromides and Their One-Pot Cyclization to 11C-Labeled Oxadiazoles

“…The addition of xantphos as an additional ligand dramatically improved the trapping of [ 11 C]­CO in nonvolatile reaction products as well as the formation of 3a (entry 2). Xantphos has previously proved successful in other types of carbonylation reactions with aryl bromides as starting materials. ,, Next, the palladium catalyst was changed (entries 3–5). Here, dipalladium­(π-cinnamyl)­dichloride (Pd 2 (π-cinnamyl)­Cl 2 ) in combination with xantphos gave the best results for both trapping and product selectivity, thus giving an excellent nonisolated radiochemical yield of 92%.…”

“…To optimize the synthesis of [carbonyl- 11 C]acyl amidines from aryl iodides, 4-iodotoluene (1a) and benzamidine (2a) were chosen as model starting materials for the synthesis of N-(imino(phenyl)methyl)-4-methylbenzamide (3a). 1,4-Dioxane and palladium tetrakis(triphenyl-phosphine) were used in the synthesis of [carbonyl- 11 C]acyl amidines in Rydfjord et al, 33 but here the solvent was changed to tetrahydrofuran for the optimization experiments. The catalyst and the reaction temperature were evaluated as shown in Table 1.…”

“…Palladium and other transition metals have been widely used as catalysts together with carbon monoxide or carbon monoxide surrogates in the synthesis of various heterocycles. − Apart from the richness in the types of readily available metal catalysts, there is also a large variation in the types of starting materials that can be utilized for carbonylative heterocycle synthesis. − In a paper published in this issue, the palladium-catalyzed synthesis of acyl amidines from aryl halides and amidines and their subsequent cyclization to form 1,2,4-triazoles and 1,2,4-oxadiazoles was explored . In that paper, the synthetic protocol was adapted to synthesize carbon-11-labeled acyl amidines and 1,2,4-oxadiazoles on a small scale.…”

“…Hydroxylamine hydrochloride dissolved in 50% acetic acid (aq) was used to facilitate the cyclization reaction. The cyclization temperature was set to 150 °C, the same as that in Rydfjord et al 33 In Table 3, entry 1, the temperature was raised to 150 °C 4.5 min into the synthesis of 3a and the cyclization time was set to 5 min. 3a was not isolated before the addition of hydroxylamine hydrochloride.…”

“…The procedures used for the 3. synthesis of the reference compounds can be found in the paper by Rydfjord et al 33 General Procedure for the Synthesis of [Carbonyl-11 C]acyl Amidines. Aryl halide (9 μmol), benzamidine (2.0 equiv), triethylamine (4.0 equiv), and Pd(PPh 3 ) 4 (0.1 equiv) were transferred to a 950 μL oven-dried conical vial and dissolved in tetrahydrofuran (400 μL).…”