Rhodium-Catalyzed Addition of Organozinc Iodides to Carbon-11 Isocyanates

Abstract

A synthetic pathway for PET-labeled amides is described using rhodium-catalyzed coupling of organozinc iodide reagents and in situ prepared carbon-11 isocyanates. A scope prepared using carbon-12 isocyanates yielded products from 13-87% using readily prepared sp 3 and sp 2 organozinc iodides. By manipulation of fixation, dehydration, and coupling conditions, the incorporation of [ 11 C]CO2 into 11 C-amide products proceeded in moderate to strong yields, as determined by radioHPLC. Among the compounds prepared are the biologically-relevant tert-butyl protected [ 11 C]N-acetyl glutamic acid ([ 11 C]6d), the agrochemical [ 11 C]propanil ([ 11 C]6f), and a pharmaceutically-relevant [ 11 C]acetanilide ([ 11 C]4m). The synthetic utility of the labeling methodology was demonstrated through the isolation of [ 11 C]N-(4-fluorophenyl)-4-methoxybenzamide ([ 11 C]6g) with a molar activity of 267 GBq•mol -1 and a radioactivity yield of 12%, 21 minutes after beginning of synthesis.

Interrupted Aza-Wittig Reactions Using Iminophosphoranes to Synthesize 11C-Carbonyls

“…4,11,12 Importantly, the former strategy displays poor tolerance towards anilines and the highly acidic conditions pose challenges for maintaining efficient trapping of [ 11 C]CO2 in solution. The latter technique has displayed improved utility for synthesizing asymmetrical ureas 12 and also amides using either Grignard reagents 13 or organozinc coupling reactions, 14 though high mass loading of azo reagents and phosphines may complicate radiotracer purification. Each strategy requires careful control of temperature and reagent concentrations during sequential reaction steps in order to prevent formation of complex mixtures of symmetrical byproducts and heterocycles.…”

Phosgene‐Free Carbonyl Insertion: Hot Advances in 11C‐Chemistry

“…[1] Radionuclides are generated using a cyclotron and then incorporated into a radiopharmaceutical. 11 C provides a unique opportunity in labelling of pharmaceuticals as all organic molecules contain a carbon atom. [2] This limits the need for extra biological testing as the molecule remains effectively unchanged in contrast to fluorine-18 which can have unpredictable effects when added to a relevant molecule and the biological activity must be tested prior to use.…”

“…[4] Overall, there has been limited diversity in widespread use of 11 C in tracers due to the complicated nature of incorporating cyclotron produced 11 C into biologically relevant molecules. [5] Modern cyclotrons produce 11 C from nitrogen-14 which reacts with trace amounts of oxygen or hydrogen in situ to produce the gas synthons; [ 11 C] CO 2 or [ 11 C]CH 4 . [6] These products are typically converted into [ 11 C]CH 3 I or [ 11 C]CH 3 OTf and used for methylation reactions.…”

“…Where 11 C-isocyanates are synthesized using cyclotron produced [ 11 C]CO 2 and Mitsunobu conditions in analogy to the use of phosgene for this purpose. [11] Testing Pd(OAc) 2 , [Rh(Cl)(cod)] 2 , and [Rh(OH)(cod)] 2 they found that the hydroxy complex was optimal for the formation of amides. Both aryl and alkyl zinc reagents were tolerated, however, alkyl zincs provided much lower yields.…”

“…1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 Steric and electronic trends between aryl and alkyl zinc reagents were the same; electron-poor isocyanates produced higher RCY, ortho-substituted isocyanates produced moderate yields, and electron-donating groups produced poor yields. With optimal conditions for their rhodium-catalyzed coupling of isocyanates and organozinc iodides, 11 C was used to explore the substrate scope on biologically relevant compounds including tert-butyl-[ 11 C]N-acetyl glutamate, [ 11 C]propanil, and [ 11 C] acetanilide. The authors report wide range of RCY for substrates limited mainly to arylamines with only one akylamine synthesized in 55 � 14 % RCY.…”