Interrupted aza-Wittig reactions using iminophosphoranes to synthesize ¹¹C–carbonyls

Abstract

Iminophosphoranes are coupled with CO2 and carbon-, nitrogen-, oxygen-, and sulfur-based nucleophiles to synthesize acyclic (radio)pharmaceuticals in high yield.

Parallel Screening with 14C‐Labeled Carbon Dioxide: De‐risking the Staudinger‐Aza‐Wittig Reaction**

“… [8,9] Based on a Staudinger aza‐Wittig sequence (SAW), in presence of an azide, a phosphine, a nucleophile (amine or alcohol) and stoichiometric amounts of labeled CO 2 , a large variety of cyclic and linear carbonyl labeled derivatives could be isolated. The reaction was compatible with all carbon isotopes 11 C, 13 C and 14 C. In addition, the analogous interrupted aza‐Wittig with [ 11 C]CO 2 was also reported by the group of Rotstein in 2021 [10,11] …”

“…The reaction was compatible with all carbon isotopes 11 C, 13 C and 14 C. In addition, the analogous interrupted aza-Wittig with [ 11 C]CO 2 was also reported by the group of Rotstein in 2021. [10,11] Given the importance of the urea functionality in bioactive compounds, including medicinal chemistry and drug design, [12] we reasoned that the development of a screening technology capable of assessing the robustness of the SAW could be beneficial to predict the reaction outcome of future labeling strategies. In order to be useful for future radiosyntheses, this screening method should generate a set of data allowing estimating the compatibility of the reaction with a large number of chemical functions and scaffolds.…”

Synthesis and Evaluation of [11C]MCC950 for Imaging NLRP3-Mediated Inflammation in Atherosclerosis

“…Our goal was to develop a high-yielding reliable synthesis of [ 11 C]­MCC950 using our previously developed iminophosphorane [ 11 C]­CO 2 -fixation methods, and to evaluate this probe for detecting atheromas in ApoE –/– mice. Our in vivo and ex vivo evaluation includes small animal PET imaging and biodistribution to determine tracer kinetics, metabolite analysis to assess tracer stability, and autoradiography under baseline and homologous blockade conditions to detect probe specificity towards NLRP3-mediated inflammation in atheromas.…”

A direct fixation of CO2 for isotopic labelling of hydantoins using iodine–phosphine charge transfer complexes

“…1 In this light, it is advantageous to utilise the primary cyclotron product [ 11 C]CO 2 obtained from proton bombardment of 14 N in presence of O 2 for labelling rather than secondary labelling agents. 4–11 Remaining challenges of [ 11 C]CO 2 are the low reactivity and solubility in organic solvents as well as the limited options for process design in typical PET centres. 6…”

“…One particularly effective strategy to fixate CO 2 between N-atoms is the use of phosphinimines 11 to activate anilines to undergo a pericyclic reaction with [ 11 C]CO 2 to form aryl isocyanates. 9,11,14 Isocyanates readily react with vicinal N-atoms to form hydantoins without the need for strong bases (Scheme 1), which was deemed advantageous to preserve chirality.…”