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Last-stage carboxylations developed within ISOTOPICS
Del Vecchio et al54 also pursued the replacement of [14C]phosgene (and/or [14C]urea) to label cyclic ureas. They established a click-chemistry-like protocol to incorporate 14CO2 in cyclic ureas as shown in Scheme 9. Herein they reported using 14CO2 directly in a sequential Staudinger/aza-Witting reaction with a high functional group tolerance. Ureas are a commonly used functional group found in various pharmaceutical compounds. The short reaction time of only 5 minutes allowed this method to be implemented with 11CO2.
Destro et al55 were inspired by the HIE methods which allows a radionuclide to be introduced on previously synthesized drug in a single step (Scheme 10). This methodology was developed to allow dynamic carbon isotope exchange, using the same principle; utilizing the desired drug molecule as the starting material without the need of any structural modification. Herein, carboxylate cesium salts were used for this exchange, using cheap copper catalyst in the presence of 3 equiv 14CO2. The reaction is currently limited to aromatic substrates; moreover, it suffers from isotopic dilution. A major byproduct formed in the reaction is unlabeled CO2, which can react like 14CO2, providing a maximum of 75% isotopic enrichment.
Carbonylation in Carbon Isotope Chemistry
Carbonylation reactions with carbon monoxide (CO) were first identified in 19th century.56 Since the first reports of palladium catalyzed carbonylation, the substrate scope has expanded considerably.57 CO can be introduced into complex molecules by adding a single carbon unit as a carbonyl group, which is prevalent in many bioactive compounds. The initial Heck carbonylation disclosed a three-component reaction, involving an electrophile, nucleophile and carbon monoxide, and was catalyzed by palladium.58–61 Aryl, alkenyl and benzyl halides have been well documented as the electrophile constituent. In contrast, alkyl halides often encounter difficulties, due to slow oxidative addition step of the metal center. β-Hydride elimination can be an important step in many transition-metal catalyzed reaction, but it can be a major side reaction too, which is encountered when alkyl halides62,63 are used as the coupling partner, this is depicted in Scheme 11.64 The nucleophilic component of the carbonylation reaction can be an amine, alcohol, thiol or phosphine.
Palladium-Catalyzed Carbonylation – Catalytic Cycle
The general palladium catalyzed carbonylation for aryl halide can be depicted in a catalytic cycle as shown in (Scheme 12). The catalytic cycle is initiated with the oxidative addition of a 14-electron Pd(0) species across to an aryl-halide (Ar-X) bond. CO coordinates to the Pd(II) complex, followed by a 1,1-insertion of CO onto the Ar-Pd(II) bond, to give an acyl-Pd(II) complex. The nucleophile attacks this acyl-Pd(II) complex; is immediately followed by a reductive elimination to give the carbonylated product. The base in the reaction scavenged the protons produced in the reaction which leads to the regeneration of the Pd(0) complex. If an organo-metallic reagent is used, a transmetalation occurs after the CO insertion, and the catalytic cycle is closed with a reductive elimination that gives the carbonylated product along with regeneration of the Pd(0) catalyst.
General methods for Carbonylation using [14C]Carbon Monoxide
Transition metal-catalyzed carbonylation reactions are already a powerful tool for incorporating labeled CO into advanced molecules, due to the high functional group tolerance of the method. However, the method is mostly limited to aryl, vinyl and benzyl (pseudo)-halides for late-stage labeling; there are a few examples of the carbonylation of alkyl halides with unlabeled CO or 11CO.65 Carbonylation reactions are of particular interest due to the availability of isotopically modified carbon monoxide (11CO, 13CO and 14CO).
CO is inexpensive and readily available; on the contrary, 14CO is very expensive and has a short shelf life, due to radiolytic decomposition66. Therefore, most procedures rely on in situ or ex situ generation of the labeled gas. In the late 1940s, three routes for the preparation of 14CO were described (Scheme 13). Method A required heating of Ca14CO3 with zinc dust at 700 °C to give quantitative conversion to 14CO.67 A related method B 14CO2 reduced over a zinc dust at 400 °C.68 Both methods required very high temperature for reduction and specialized apparatus. While the zinc dust method is a frequently used method for producing 14CO, the method is of great value for reduction of 11CO2 to 11CO.69 The third method C is more laboratory-friendly as it involves dehydration of [14C]formic acid prepared in situ from 14CO2.
Synthetic approaches towards carbonylation of unactivated alkyls
Palladium catalyzed carbonylation reactions have found many applications in isotope chemistry. However, as discussed before, the method is mostly restricted to substrates such as aryl, vinyl, and benzyl (pseudo)-halides. Alkyl halides are mainly restricted by the competing β-hydride elimination of the metal-alkyl species formed by the oxidative additions. In the 1980s it was discovered that transition metal catalysis, combined with photoirradiation can improve carbonylation of alkyl iodides.86,87 Since then, notable progress has been made in the functionalization of unactivated C(sp3)-substrates with unlabeled carbon monoxide.
C(sp3)-halide substrates in combination photoirradiation promotes the generation of alkyl-metal species via a radical mechanism; this species undergoes CO insertion to form an acyl-metal species. Despite the compatibility of this radical dehalogenation with a range of alkyl halides, the carbonylation step often requires elevated CO pressures and highly specialized equipment.
Radical Carbonylation – Thermal Initiator
Chow et al89 developed a metal free aminocarbonylation using 2,2′-azobis(2-methylpropionitrile) (AIBN) as the radical initiator to generate isotopically labeled alkyl amides (Scheme 22). The radical is induced by AIBN and propagated by (TMS)3SiH to form alkyl radicals. The alkyl radicals react with 11CO with a subsequent nucleophilic attack by an amine to produce C-11 labeled alkyl amides. Due to the toxic and explosive nature of AIBN the use of this method is limited, despite its success with carbonylation with sub-stoichiometric amount of labeled CO.
Development of Visible-light Enabled Palladium Catalysis
After the evaluation the utility of several other carbonylation methods towards labeling, we aimed to evaluate visible-light conditions with Pd-catalysis.94,95 Unlabeled CO was used as the limiting reagent with cyclohexyl iodide 1 and morpholine 2 as the model substrates. The CO was generated from COgen, which provides a readily transferable, solid form of CO and has been used with labeled CO (13/14CO).83 In order to limit costs and generation of waste, the optimization of the procedure and part of the scope were performed using unlabeled COgen. We paid particular attention to the set-up of the reaction in order to ensure direct implementation of the protocol onto C-14 radiolabeling. The dual chamber system (COware, (Figure 14A)) was used as previously described.96 As COgen is moisture sensitive and undergoes hydrolysis, fresh batches of COgen were made before each experiment.
To facilitate the visible-light chemistry in a parallel fashion, a photoreactor was constructed (Figure 14B-C). Blue LEDs surround a central compartment, which contains a heating block to enable the liberation of CO from COgen at 70 ᵒC. The carbonylation chamber was kept at room temperature; a fan was used to circulate the air in the reactor to regulate the heat emitted from the LEDs. The setup could facilitate six parallel reactions; however, this setup could potentially be used for larger libraries, too.
Table of contents :
1. INTRODUCTION 19
Drug Development
Need of Isotopic Labeling in Drug Development
Stable Isotopes in Drug Development
SIL Compounds as Clinical Agents 23 Radionuclides in Drug Development
Radioligands for Lead Discovery
Administration, Distribution, Metabolism and Excretion
Clinical Trials
Considerations in Radiochemistry 31 Carbon-14
C-14 Building Blocks
[14C]Cyanide
[14C]Acetylene
[14C]Cyanamide
[14C]Carbon Dioxide
Last-stage carboxylations developed within ISOTOPICS 41 Carbonylation in Carbon Isotope Chemistry
Palladium-Catalyzed Carbonylation – Catalytic Cycle 43 General methods for Carbonylation using [14C]Carbon Monoxide
[14C]Calcium Carbonate Pyrolysis
[14C]Formate based [14C]carbonylation chemistry
14COgen 50 Objectives
2. METHOD DEVELOPMENT: VISIBLE-LIGHT ENABLED AMINOCARBONYLATION OF UNACTIVATED ALKYL IODIDES WITH STOICHIOMETRIC CARBON MONOXIDE FOR APPLICATION ON LATE-STAGE CARBON ISOTOPE LABELING
Synthetic approaches towards carbonylation of unactivated alkyls
Radical Carbonylation – Thermal Initiator
Nickel-Catalyzed Carbonylation
Visible-light enabled carbonylation
Aim
Development of Visible-light Enabled Palladium Catalysis
Optimization of the reaction
Investigation of the Reaction scope
Conclusion and future perspectives
3. METHOD DEVELOPMENT: REDUCTION OF 14CO2 TO 14CO, COMPARISON OF TWO METHODS
Aim
Preliminary Results
Electroreduction of 13CO2
Reduction of 13CO2 by disilanes catalyzed by F-
Summary and Future Perspectives
4. METHOD DEVELOPMENT: RADIOSYNTHESIS OF [18F]CRIZOTINIB, A POTENTIAL RADIOTRACER FOR PET IMAGING OF THE P-GLYCOPROTEIN TRANSPORT FUNCTION AT THE BLOOD-BRAIN BARRIER
P-glycoprotein
Positron Emission Tomography
Labeling with short-lived radionuclides
PET tracers for P-gp
Aim
Fluorine-18
Synthetic approaches
Synthesis of Precursors
Hypervalent Iodine(III) precursor
Deoxyfluorination precursor 50
Radiofluorination
Conclusion and Future Perspectives
5. SUMMARY OF FINDINGS AND FUTURE PERSPECTIVES
6. RESUME DE LA THESE
7. EXPERIMENTAL: VISIBLE-LIGHT ENABLED AMINOCARBONYLATION OF UNACTIVATED ALKYL IODIDES WITH STOICHIOMETRIC CARBON MONOXIDE FOR APPLICATION ON LATE-STAGE CARBON ISOTOPE LABELING
General Information
General Reactions
Reaction Setup
Reaction mixture
Purification
Analysis
LED report of the blue LEDs
General Procedures
General Procedure for Chamber B, CO Producing Chamber
General Procedure for Aminocarbonylation Chamber A, CO Consuming Chamber
Characterization data
8. EXPERIMENTAL: REDUCTION OF 14CO2 TO 14CO, COMPARISON OF TWO METHODS General Information
Procedures and characterization
Electrochemical reduction
Reduction of 13CO2 by disilanes catalyzed by F-
9. EXPERIMENTAL: RADIOSYNTHESIS OF 18F-CRIZOTINIB, A POTENTIAL RADIOTRACER FOR PET IMAGING OF THE P-GLYCOPROTEIN TRANSPORT FUNCTION AT THE BLOOD-BRAIN BARRIER
General Reactions
Reaction Setup
Reaction mixture
Purification
Analysis
Radio synthesis
Quality control
Procedures and characterization data
Precursor synthesis: hypervalent iodine(III) precursor 38
Precursor synthesis: Deoxyfluorination precursor 50
Failed strategies for protection and deprotection
10. REFERENCES
