WO2013041106A1

WO2013041106A1 - System providing controlled delivery of gaseous 11co for carbonylation reactions in the preparation of radiopharmaceuticals for pet imaging

Info

Publication number: WO2013041106A1
Application number: PCT/DK2012/050349
Authority: WO
Inventors: Troels Skrydstrup; Anders Thyboe Lindhardt; Thomas GØGSIG; Rolf Hejle Taaning; Hélène AUDRAIN; Dirk Andreas BENDER; Stig Düring FRIIS
Original assignee: Aarhus Universitet; Region Midtjylland
Priority date: 2011-09-20
Filing date: 2012-09-19
Publication date: 2013-03-28

Abstract

A carbonylation system comprising an enclosure sealed from the surrounding atmosphere. The enclosure comprises at least one solid support arranged for ¹¹CO being sorped thereto, and at least one carbon monoxide consuming chamber comprising carbonylation reagents. The at least one carbon monoxide consuming chamber is arranged for performing carbonylation reactions in a gas-diffusion process between ¹¹CO from the solid support and said carbonylation reagents to form a reaction product.

Description

System providing controlled delivery of gaseous ¹¹CO for carbonylation reactions in the preparation of radiopharmaceuticals for PET imaging

Technical field of the invention

The present invention relates to carbonylation reactions. In particular the present invention relates to a system providing delivery of gaseous ⁿCO for carbonylation reactions in the preparation of radiopharmaceuticals for PET imaging.

Background of the invention

Carbon monoxide (CO) has throughout the recent decades, in combination with transition metal catalysis, become a versatile reagent in organic synthesis. Not only does the introduction of CO into a complex molecule add an extra carbon to the growing molecule, it simultaneously introduces a carbonyl functionality which is one of the most common functionalities in bioactive compounds and which is an easily transformable moiety in organic chemistry. These intrinsic qualities of CO in combination with recent developments in transition metal catalysis, makes CO an obvious reagent for the synthetic chemist.

Positron emission tomography (PET) is an imaging technique routinely used for screening, diagnosing and staging chronic conditions such as cancer and neurodegenerative diseases. In addition to clinical applications, PET is also widely used to gain a fundamental understanding of the underlying biology of these diseases and to discover new treatments. All PET scans require the injection into the body of a radiopharmaceutical labeled with a positron emitting radioisotope. The synthesis, preparation and purification of radiopharmaceuticals for PET imaging are not easy processes. The short half-lives of the common cyclotron- generated PET radioisotopes (ⁿC: ti_/2 = 20.4 min,

¹⁸F: ti 2 = HO min, ¹³N : ti_/2 = 9.96 min, ¹⁵0: ti_/2 = 2.04 min), coupled with extremely low radio-isotopic amounts (only pmol - nmol amounts of ⁿC is delivered from the cyclotron) represent the main challenges in the synthesis of positron emitting labelled compounds. Hence, in combination with the short half- life, the synthesis must be rapid. Microfluidics has recently emerged as an important technology for the rapid synthesis of short-lived radiopharmaceuticals for PET. The advantages

of using microfluidic reactors for organic chemistry are well documented and include the benefits associated with miniaturisation : smaller reaction volumes (nL-mL) and lower reagent quantities (nmol-mmol), controlled and predicable mixing, efficient heat transfer and enhanced processing capabilities. Microfluidic reactors for PET radiosynthesis have generated considerable interest primarily because miniaturised reaction systems have the potential to address the challenges of increasing the speed of labelling reactions, reducing their scale and improving the overall efficiency of radiolabelling reaction processes. However, the device setup is complex and expensive.

The majority of the work published on catalyzed carbonylations, require CO at elevated pressures and reactions performed at pressures of 30-50 bars is not uncommon. It is recognized within the field that high pressure is required to overcome the low solubility of CO in almost any organic or inorganic solvent. WO2002102711 discloses a method for the production and use of a carbon- isotope monoxide enriched gas-mixture from an initial carbon-isotope dioxide gas mixture. The method comprises the steps of providing carbon-isotope dioxide in a suitable carrier gas, converting carbon-isotope dioxide to carbon-isotope monoxide by introducing said gas mixture in a reactor device, trapping carbon- isotope monoxide in a carbon monoxide trapping device, wherein carbon-isotope monoxide is trapped but not said carrier gas, and releasing said trapped carbon- isotope monoxide from said trapping device in a well-defined micro-plug, whereby a volume of carbon-isotope monoxide enriched gas-mixture is achieved, which is confined in a reactor and pressurized with a reagent. The high-pressure technique utilizes a high-pressure resistant reaction chamber that is first loaded with the carbon-isotope monoxide enriched gas-mixture at a pressure of 3-5 atm. Then an HPLC-pump (High Performance Liquid Chromatography), or any liquid-pump capable of pumping organic solvents, delivers the reactants in a solvent to the reaction chamber at pressures around 400 atm. However, the device setup is complex and expensive.

Hence, an improved system for carbonylation reactions would be advantageous, and in particular a more simple, efficient and controllable system would be advantageous. This is in particular valid as it is currently consensus in the PET radiochemistry community that introduction of ⁿCO will be a predominant technique to produce new radiotracers in the coming years. Summary of the invention

The use of the prior art methods of ⁿC-carbon labelling are limited, and

carbonylation reactions with carbon monoxide have not been exploited to a high extent because the existing methods are not general and require sophisticated equipment.

An object of the present invention relates to the application of ⁿCO as labelling reagent for the preparation of ⁿC-labelled radiopharmaceuticals. For this purpose, a new highly efficient protocol was developed so as to release carbon monoxide from a solid support with ⁿCO sorped thereto into a CO consuming chamber (comprising the carbonylation reagents of interest) in a closed gas-diffusion system at a relatively low pressure (1-10 atm) compared to the current methods of pressures above 30 atm (often about 400 atm). This system relieves the workload for the scientists at e.g. the PET centres, and requires less sophisticated equipment than current technology.

In particular, it is an object of the present invention to provide a carbonylation system that solves the above mentioned problems of the prior art.

Thus, one aspect of the invention relates to a carbonylation system comprising - an enclosure sealed from the surrounding atmosphere, the enclosure comprising

- at least one solid support arranged for ⁿCO being sorped thereto, and

- at least one carbon monoxide consuming chamber comprising

carbonylation reagents, wherein said at least one carbon monoxide consuming chamber is arranged for performing carbonylation reactions in a gas-diffusion process between ⁿCO from the solid support and said carbonylation reagents to form a reaction product,

wherein the solid support is arranged within the enclosure so as to allow an external application of heat to warm up the solid support in order to free ⁿCO therefrom and drive the ⁿCO into contact with the carbonylation reagents by means of diffusion.

Such system is advantageous, since it is capable of providing a carbonylation process within an enclosure which can be implemented by simple means since the pressure during the reaction can be low. E.g. the system can be implemented as a disposable low cost kit with an enclosure element purely or at least predominantly formed by a polymer or a glass. The solid support traps carbon monoxide in a cold state, and releases the carbon monoxide in a warm state. This means that a kit with a solid support is loaded with ⁿCO at the end user.

The gas-diffusion process allows a simple system without the need for a liquid pump (e.g. a HPLC pump) within the enclosure, and without the need for complex mechanisms for driving the ⁿCO into contact with the carbonylation reagents. Still, the system is capable of providing a reaction product with a high degree of radiochemical purity.

Even though the system itself is simple, it can be delivered to an end user as a kit and requires only a minimum of external equipment for functioning and producing the reaction product.

Brief description of the figures

Figs, la and lb show examples of a carbonylation system where one chamber is situated within the other,

Fig. 2 shows examples of a carbonylation system where one chamber is aligned with the other, and

3 shows an example of a carbonylation system with six chambers.

The present invention will now be described in more detail in the following. Detailed description of the invention

Tracers labelled with short-lived positron emitting radionuclides (e.g. ⁿC, ti_/2 = 20.4 min) are frequently used in various non-invasive in vivo studies in combination with positron emission tomography (PET). Because of the

radioactivity, the short half-lives and the sub-micromolar amounts of the labelled substances, extraordinary synthetic procedures are required for the production of these tracers. An important part of the elaboration of these procedures is the development and handling of new ⁿC labelled tracers. This is important not only for labelling new types of compounds, but also for increasing the possibility of labelling a given compound in different positions.

Carbonylation reactions using carbon-isotope labelled carbon monoxide has a primary value for PET-tracer synthesis since biologically active substances often contain carbonyl groups or functionalities that can be derived from a carbonyl group. The syntheses are tolerant to most functional groups, which mean that complex building blocks can be assembled in the carbonylation step to yield the target compound/tracer. This is particularly valuable in PET-tracer synthesis where the unlabelled substrates should be combined with the labelled precursor as late as possible in the reaction sequence, in order to decrease synthesis-time and thus optimize the uncorrected radiochemical yield.

Positron emission tomography (PET) is a powerful non-invasive technique for investigating physiological parameters in the living human and animal body after injection of a radiopharmaceutical bearing short-lived radioisotopes, e.g. ¹⁸F, ti_/2 = 109.7 min; ⁿC, ti_/2 = 20.4 min. PET provides important information on metabolic processes in patients and hence is complementary to MRI scanning. This molecular imaging technique has shown high utility for the diagnosis of tumors and coronary heart disease, and also holds great promise for the early stage detection of neurological disorders such as Alzheimer's and Parkinson's disease.

Although PET has proven to be superior in many respects as a technique for the diagnosis of certain diseases, the types of molecules that can be labelled with the radioisotopes are still rather limited. Approximately 85% of all PET examinations are performed with a single ¹⁸F-labeled sugar analogue. The strength of PET is therefore only exploited to a limited extent. This is because the current methods for isotope labelling require molecules with specific substituents that can be subjected to simple chemical transformations. Hence, PET cannot use many organic-based molecules, which could potentially represent more selective probes for disease diagnosis, because the chemistry for its isotope labelling is lacking or the setup is too complicated for general use.

With this invention, there is provided a simple setup as a device, preferably a medical device, which can give straightforward access to ⁿC-radiolabeled tracers via carbonylation chemistry using carbon monoxide. ⁿC-carbon has an important advantage over ¹⁸F-fluorine as its use furnishes radiolabeled biologically active molecules without alterations in their chemical structure, whereas ¹⁸F-fluorine is typically introduced as an external substituent. Unfortunately, the methods of ⁿC- carbon labelling are limited and carbonylation reactions with carbon monoxide have not been exploited to a high extent because the existing methods are not general and require sophisticated equipment.

Nevertheless, many bioactive molecules contain carbonyl groups (C=0), carbon bound to oxygen via a double bond, and their installation can arise from a carbonylation reaction with carbon monoxide. Hence, a simple setup for carrying out these reactions would be of high interest.

The carbonylation system

An object of the present invention relates to the application of ⁿCO as labelling reagent for the preparation of ⁿC-labelled radiopharmaceuticals. For this purpose, a new highly efficient protocol was developed so as to release carbon monoxide from a solid support with ⁿCO sorped thereto into a CO consuming chamber (comprising the carbonylation reagents of interest) in a closed gas-diffusion system at a relatively low pressure (1-10 atm, preferably 1-5 atm) compared to the current methods of pressures above 30 atm (often about 400 atm). This system relieves the workload for the scientists at e.g. the PET centres, and requires less sophisticated equipment than current technology.

Since ⁿC-labelled CO may in many cases become the most costly ingredient of the total reaction, one obvious problem emerge when a small amount of CO is to be applied in carbonylation chemistry; How to quantify and deliver an exact amount of CO with high efficiency? The present invention solves this problem.

The carbon monoxide system (in specific embodiments in the form of a kit) presented herein is ideally suited for the synthesis of ⁿC-labelled compounds. This is most prominently expressed by the ability to easily handle and incorporate small quantities of CO, especially in substoichiometric amounts.

The invention provides a carbonylation system comprising

- an enclosure sealed from the surrounding atmosphere, the enclosure comprising

- at least one solid support arranged for ⁿCO being sorped thereto, and

- at least one carbon monoxide consuming chamber comprising

In an preferred embodiment the enclosure may comprise only the at least one solid support and the at least one carbon monoxide consuming chamber, i.e. the invention provides a carbonylation system comprising

- an enclosure sealed from the surrounding atmosphere, the enclosure containing

- at least one solid support arranged for ⁿCO being sorped thereto, and

- at least one carbon monoxide consuming chamber comprising

wherein the solid support is arranged within the enclosure so as to allow an external application of heat to warm up the solid support in order to free ⁿCO therefrom and drive the ⁿCO into contact with the carbonylation reagents by means of diffusion. In embodiments of the system, the system does not comprise a liquid pump, such as an HPLC pump, within the enclosure. The exclusion of a liquid pump is possible due to the diffusion process, and this allows the system to be simple and suitable to implement as a kit with a minimal requirement for external equipment to use the kit.

In some embodiments, the enclosure is arranged for providing an inlet and an outlet to allow a flow of a gas to pass the solid support in order to allow ⁿCO contained in the gas to be sorped to the solid support. Hereby, the end user can supply ⁿCO to the solid support prior to the reaction process. Such inlet and outlets can be implemented by means of needles or small tubes cast into the enclosure material. Alternatively or additionally, a part of the enclosure material may be made so as to allow penetration of a needle during the process of sorption of ⁿCO to the solid support, and then the needles can be removed when this process is finished. The enclosure is preferably arranged for providing a reaction product outlet to allow removal of the reaction product from the carbon monoxide consuming chamber. Also, this outlet can be made by means of a needle or a small tube cast into the enclosure material or by means of a needle to be inserted through a penetrable part of the enclosure. In specific embodiments, a boundary of a part of the enclosure is formed by a barrier, such as a diaphragm or membrane, arranged for penetration of a needle so as to provide said inlet or outlets. The pressure within the enclosure is preferably within the range of 1-10 atm, e.g. 1-5 atm, during carbonylation. With such low pressure, the enclosure material and sealing for implementing inlets/outlets are relaxed, thus allowing a low cost element to form the enclosure. The carbonylation reagents may be encapsulated with one or more solvents having a melting point as measured with a differential scanning calorimeter (DSC) within the range of -75-100 degrees Celsius.

The at least one carbon monoxide consuming chamber may further comprises one or more catalysts. The at least one carbon monoxide consuming chamber may comprise a reaction mixture of carbonylation reagents suitable for the reaction selected from the group consisting of hydroformylation, reductive carbonylation, Fischer-Tropsch synthesis, aminomethylation, homologation of carboxylic acid, CO hydrogenation, homologation of alcohols, silylformylation, hydrocarboxylation, hydroesterification, CO copolymerization with olefins, CO terpolymerization with olefins, Reppe carbonylation, oxidative carbonylations of olefins, Pauson-Khand reaction, carbonylative cycloadditions, cyclo-carbonylations, alkoxycarbonylation, aminocarbonylation, carbonylative lactonization, carbonylative lactamization, hydroxycarbonylation, thiocarbamoylation, thiocarbonylation, amidocarbonylation, oxidative bisoxycarbonylation, oxidative carbonylation of alcohols, oxidative alkoxycarbonylation, oxidative aminocarbonylation, oxidative carbonylation of amines, carbonylative annulations, CO complexation by a metal, acyl-metal complexes generation, acid fluoride synthesis, carbonylation of alcohols, carbonylation of esters, carbonylation of aziridines, carbonylation of aldehydes, carbonylation of epoxides, carbonylation of amines, carbonylative Heck - Mizoroki reaction, carbonylative Suzuki - Miyaura coupling reaction, carbonylative Stille coupling reaction, carbonylative Sonogashira coupling reaction, carbonylative cross-couplings, carbonylative cross coupling reaction with organometallic reagents, CO reduction, CO oxidation, water-gas shift reaction, ring opening carbonylation, ring opening carbonylative polymerization, ring expansion carbonylation, radical carbonylations, carbonylation of organometallic reagents, carbonylation of organolithium reagents, carbonylation of organomagnesium reagents, carbonylation of organoboranes, carbonylation of organomercurials, and carbonylation of organopalladium compounds.

The solid support preferably has a specific surface area of at least 1 m²/g, measured by BET surface area technique, such as within the range of 1-2500 m²/g, e.g. within the range of 10-1500 m²/g, such as within the range of 10-500 m²/g, e.g. within the range of 10-100 m²/g.

Especially, the solid support is selected from the group consisting of molecular sieve, silica, active charcoal, palladium on charcoal 5%, palladium on charcoal 10%, Pd(OH)₂ on charcoal, celites, zeolites, GC packaging materials, such as carbospheres, and metal-organic frameworks (MOFs). The solid support may comprise molecular sieves with a pore size within the range of 1-15 Angstroms.

It is to be understood, that the enclosure can be formed by many different materials, and it can be formed with different shapes and configurations of the carbon monoxide consuming chamber and position of the solid support in relation thereto. Since the system can be made of low cost elements, some embodiments can be made for disposal after use. In some embodiments, the enclosure is constituted by an element forming the carbon monoxide consuming chamber and a carbon monoxide releasing chamber containing the at least one solid support, wherein said chambers are operationally connected by a passage allowing diffusion of ⁿCO from the carbon monoxide releasing chamber to the carbon monoxide consuming chamber. Preferably, a single enclosure element is used, thus making connection of separate chambers with tubes superfluous, thereby providing a system which is easy and fast to use. In one specific embodiment, the two chambers are aligned next to each other, e.g. separate by one common wall with an opening forming the passage between the chambers.

In some embodiments, the enclosure is constituted by an element forming the carbon monoxide consuming chamber, and wherein the solid support is arranged within the carbon monoxide consuming chamber. Especially, the solid support may be positioned within its own chamber, e.g. a chamber formed by a separate element. This chamber may then be positioned within the carbon monoxide consuming chamber.

It is appreciated, that the carbonylation system is especially advantageous for use in carbon-isotope labelling, such as for use in connection with PET scanning.

The at least one solid support with ⁿCO sorped thereto is from where the ⁿCO is released, and the at least one carbon monoxide consuming chamber is wherein the carbon monoxide is consumed. The release of ⁿCO from the solid support may preferably be achieved by thermal release. The solid support will in such a situation be of a material which in a cold state (e.g. -196°C as in liquid nitrogen or -186 °C as in liquid argon) selectively trap (e.g. by sorption) carbon monoxide and in a warm state (e.g. +50°C) releases the trapped carbon monoxide.

In one embodiment of the present invention, the release of the trapped carbon monoxide is effectuated by heating the system, or simply heating the solid support, to a warm state in the range of 10-200 degrees Celsius, e.g. 15 degrees Celsius, such as in the range of 20-190 degrees Celsius, e.g. 25 degrees Celsius, such as in the range of 30-180 degrees Celsius, e.g. 35 degrees Celsius, such as in the range of 40-170 degrees Celsius, e.g. 45 degrees Celsius, such as in the range of 50-160 degrees Celsius, e.g. 55 degrees Celsius, such as in the range of 60-150 degrees Celsius, e.g. 65 degrees Celsius, such as in the range of 70-140 degrees Celsius, e.g. 75 degrees Celsius, such as in the range of 80-130 degrees Celsius, e.g. 85 degrees Celsius, such as within the range of 100-120 degrees Celsius. In a preferred embodiment, the release of the trapped carbon monoxide is effectuated by heating the system to the reaction temperature of the

carbonylation reaction.

In one embodiment of the present invention, the CO is released from the solid support prior to initiation of the carbonylation reaction. The ⁿCO is presumably released before the solvent of the carbonylation reaction melts, if this solvent chosen in the melting point range -75 to 100 degrees Celsius.

The at least one solid support with ⁿCO sorped thereto and the carbon monoxide consuming chamber are connected in a manner as to allow only the

desorped/trapped carbon monoxide to pass from the solid support to the at least one carbon monoxide consuming chamber without contamination or obstruction of the carbonylation reaction. The figures 1-3 show non-limiting examples of such systems.

Figs, la and lb show two embodiments, with the same basic configuration of the enclosure, namely where the solid support SLS with ⁿCO sorped thereto is situated inside a carbon monoxide releasing chamber 1 which is situated within the carbon monoxide consuming chamber 2 where the carbonylation reagents CR are placed. However, it is to be understood that the chambers 1, 2 could alternatively be arranged the other way around, i.e. wherein the carbon monoxide consuming chamber 2 is situated within the carbon monoxide releasing chamber 1. The chambers 1, 2 may be formed by a polymer or glass material, and the shown generally cylindrical shape with a rounded bottom is suitable for use of a stirring pin to stir the carbonylation reagents CR. However, the chambers 1, 2 may have other shapes, e.g. they may have a general rectangular shape, if preferred. The inner chamber 1 can be kept in place within the outer chamber 2 by means of a number of glass or polymer distance pieces. Alternatively, the two chambers 1, 2 may be cast together, in case they are made of polymer.

In Figs, la and lb, the enclosure is formed by the carbon monoxide consuming chamber 2, where the carbonylation reaction takes place, when the solid support SLS is supplied with external heat and the ⁿCO sorped thereto is released and brought in contact with the carbonylation reagents CR by diffusion which drives the ⁿCO out of the opening of the inner chamber 1 and into the outer chamber 2. This diffusion is illustrated by the dashed arrow. The external heat to warm up the solid support SLS to provide the ⁿCO diffusion may be applied by placing the system in hot liquid, preferably such that a lower part of the outer chamber 2 is in contact with the hot liquid, thereby heating also the inner chamber 1 and thus the solid support SLS via the carbonylation reagents CR.

In one embodiment, as in Figs, la and lb, the carbon monoxide releasing chamber 1 is situated within the carbon monoxide consuming chamber 2. In another embodiment, the carbon monoxide consuming chamber 2 is situated within the carbon monoxide releasing chamber 1.

The multi-chamber system is a closed system sealed from the surrounding atmosphere, at least it is so during the reaction process. In one embodiment, and as shown in Figs, la and lb, this sealing may be done by a cap or plug 3 covering the opening in the outer chamber 2, i.e. the carbon monoxide consuming chamber 2 Fig. la illustrates needles G_I, G_0, RP_0 penetrating a membrane in the cap or plug 3. The gas inlet needle G_I and the gas outlet needle G_0 are used to circulate a gas (the carrier gas transporting the ⁿC-CO) inside the carbon monoxide releasing chamber 1, when ⁿCO is to be sorped to the solid support SLS. These needles G_I, G_0 can then be removed after the sorption process. Another needle RP_0 is shown to penetrate the cap or plug 3, namely a needle RP_0 serving to remove from the carbon monoxide consuming chamber 2 the reaction product resulting from the carbonylation process. Yet one needle (not shown) may be required to allow aligning of the pressure inside the enclosure for sucking out the reaction product. As with the needles G_I, G_0 for the ⁿCO sorption process, the reaction product outlet needle RP_0 can be removed, and thus none of the needles G_I, G_0, RP_0 need to be present during the carbonylation process.

Fig. lb illustrates a variant of the embodiment of Fig. la, where to avoid contamination of the individual reactions in the individual chambers, a filter or membrane 4 is placed between the chambers 1 and 2, as illustrated the filter or membrane 4 is mounted to cover the opening of the exemplified in figure lb. The filter or membrane 4 may be discriminative towards all substances (e.g. solvents, reagents, other gasses, by-products and catalysts) but carbon monoxide, i.e. only permeable to carbon monoxide, or merely to individual substances, such as solvents, reagents, other gasses, by-products and/or catalysts. The term "filter or membrane" is to be understood as a device that is designed to physically block certain objects or substances while letting others through. In the embodiment of Fig. lb, of course the filter or membrane should allow ⁿCO to pass by a diffusion process so as to enable the ⁿCO to react with the carbonylation reagents CR. In another embodiment of the present invention, a transfer tube may be in a center portion of the membrane or filter 4 for transferring the major portion of the non-permeate product gas from the non-permeate portion of the membrane to the non-permeate product gas outlet conduit. In yet another embodiment of the present invention, the filter is filter paper as generally known in the art.

Figs. 2a and 2b illustrate alternative configurations of the enclosure, where the carbon monoxide releasing chamber 1 and the carbon monoxide consuming chamber 2 are respectively formed by respective circular tubes placed next to each other and connected by one or more connecting units 5 forming a passage. E.g. the unit 5 is made of the same material as the chambers 1, 2. The connecting unit 5 allows ⁿCO to pass from the at least one carbon monoxide releasing chamber 1 to the at least one carbon monoxide consuming chamber 2 by diffusion, as illustrated by the dashed arrow so as to allow a reaction between the ⁿCO and the carbonylation reagents CR. The connecting unit 5 may comprise a filter or membrane 6, as exemplified in Fig. 2b. In another embodiment of the present invention, the connecting unit 5 is a filter or membrane. Each of the chambers 1, 2 have respective caps or membranes 3 which are preferably penetrable by needles to allow ⁿCO and removal of reaction product, such as illustrated and explained in connection with Fig. la.

Fig. 3 illustrates yet another embodiment of the present invention, where the carbonylation system comprises multiple carbon monoxide releasing chambers 1 and/or multiple carbon monoxide consuming chambers 2. The amount of chambers may be unlimited, such as in the range of 1-1000 carbon monoxide releasing chambers 1 and 1-1000 carbon monoxide consuming chambers 2, e.g. 500 carbon monoxide releasing chambers 1 and 400 carbon monoxide consuming chambers 2, such as in the range of 2-50 carbon monoxide releasing chambers 1 and 1-300 carbon monoxide consuming chambers 2, e.g. 25 carbon monoxide releasing chambers 1 and 150 carbon monoxide consuming chambers2 , such as in the range of 5-15 carbon monoxide releasing chambers 1 and 2-100 carbon monoxide consuming chambers 2, e.g. 10 carbon monoxide releasing chambers 1 and 2 carbon monoxide consuming chambers 2. In the specific example illustrated in Fig. 3, three sets of carbon monoxide releasing chambers 1 and multiple carbon monoxide consuming chambers 2 are shown each with solid support SLS and carbonylation reagents CR and configured with the two chambers 1, 2 within each other such as also shown in Fig. la. The three sets of such chambers 1, 2 are placed next to each other, and two neighbouring carbon monoxide consuming chambers 2 are connected by connecting units 5, thus allowing ⁿCO released from the solid support SLS in one carbon monoxide releasing chamber 1 to pass through the connecting unit 5 to the neighbour carbon monoxide consuming chamber 2 as well as to the carbon monoxide consuming chambers 2 immediately surrounding the carbon monoxide releasing chamber 1. Each set of chambers 1, 2 is supplied with a closing cap or membrane 3 covering the top of each of the carbon monoxide consuming chambers 2 in a manner illustrated and described also for Fig. la. In some embodiments, the carbonylation system comprises multiple carbon monoxide releasing chambers and/or multiple carbon monoxide consuming chambers, wherein the carbon monoxide releasing chamber 1 is situated within the carbon monoxide consuming chamber 2. In other embodiments, the carbonylation system comprises multiple carbon monoxide releasing chambers and/or multiple carbon monoxide consuming chambers, wherein the carbon monoxide consuming chamber 2 is situated within the carbon monoxide releasing chamber 1. In yet other embodiments, solid support with ⁿCO sorped thereto is situated inside the carbon monoxide consuming chamber 2, i.e. a separate carbon monoxide releasing chamber may be eliminated. E.g. the solid support may be placed within the carbon monoxide consuming chamber but separated from the carbonylation reagents by being placed on a shelf or the like positioned within the carbon monoxide consuming chamber. In one embodiment of the present invention, the solid support is placed on top of the solid solvent having a melting point within the range of -75-100 degrees Celsius.

The carbonylation reaction

The method according to the present invention is applicable to a variety of reaction types known to the person skilled in the art as well as to substrates not considered by conventional methodologies to be very amenable to carbonylation reactions. Non-limiting examples of reaction types and references to non-limiting examples of carrying out the reaction type are presented in the following list: Hydroformylation (1 : Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; 2: Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85; 3: Wender, I. Fuel Process. Techno!. 1996, 48, 189-297), reductive carbonylation (1 : Barnard, C. F. J. Organometallics 2008, 27, 5402-5422; 2: Brennfuhrer, A. ; Neumann, H. ; Beller, M. Angew. Chem. Int. Edit. 2009, 48, 4114-4133), Fischer- Tropsch synthesis (1 : Wender, I. Fuel Process. Techno!. 1996, 48, 189-297; 2: Khodakov, A. Y. ; Chu, W. ; Fongarland, P. Chem. Rev. 2007, 107, 1692-1744), aminomethylation (1 : Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; 2: Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), homologation of carboxylic acid (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), CO hydrogenation (Beller, M. ; Cornils, B. ; Frohning, C. D.; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), homologation of alcohols (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), silylformylation (Beller, M. ; Cornils, B. ; Frohning, C. D. ;

Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85),

hydrocarboxylation (Wender, I. Fuel Process. Technol. 1996, 48, 189-297), hydroesterification (Wender, I. Fuel Process. Technol. 1996, 48, 189-297), CO copolymerization with olefins (1 : Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; 2: Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17- 85), CO terpolymerization with olefins, Reppe carbonylation (Kiss, G.

Chem. Rev. 2001, 101, 3435-3456), oxidative carbonylations of olefins, Pauson-Khand reaction (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), carbonylative cycloadditions, cyclo-carbonylations, alkoxycarbonylation (Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim),

aminocarbonylation (1 : Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim; 2: Barnard, C. F. J.

Organometallics 2008, 27, 5402-5422), carbonylative lactonization, carbonylative lactamization, hydroxycarbonylation (1 : Kollar, L. ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA,

Weinheim; 2: Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), thiocarbamoylation (Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA,

Weinheim), thiocarbonylation, amidocarbonylation (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), oxidative bisoxycarbonylation (Beller, M. ; Cornils, B. ; Frohning, C. D. ;

Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), oxidative carbonylation of alcohols, oxidative alkoxycarbonylation, oxidative aminocarbonylation, oxidative carbonylation of amines (Kollar, L. ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA,

Weinheim), carbonylative annulations (Kollar, L. ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim), CO complexation by a metal (Kuhlmann, E. J. ; Alexander, J. J. Coord. Chem. Rev. 1980, 33, 195-225), acyl-metal complexes generation (Kuhlmann, E. J. ;

Alexander, J. J. Coord. Chem. Rev. 1980, 33, 195-225), acid fluoride synthesis (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A- 5 Chem. 1995, 104, 17-85), carbonylation of alcohols, carbonylation of

esters, carbonylation of aziridines (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), carbonylation of aldehydes (Beller, M. ; Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), carbonylation of epoxides (Beller, M. ;

10 Cornils, B. ; Frohning, C. D. ; Kohlpaintner, C. W. J. Mol. Catal. A-Chem. 1995, 104, 17-85), carbonylation of amines, carbonylative Heck - Mizoroki reaction, carbonylative Suzuki - Miyaura coupling reaction (Brennfuhrer, A. ; Neumann, H. ; Beller, M. Angew. Chem. Int. Edit. 2009, 48, 4114-4133), carbonylative Stille coupling reaction (Brennfuhrer, A.; Neumann, H. ; Beller,

15 M. Angew. Chem. Int. Edit. 2009, 48, 4114-4133), carbonylative Sonogashira coupling reaction (Brennfuhrer, A.; Neumann, H. ; Beller, M. Angew. Chem. Int. Edit. 2009, 48, 4114-4133), carbonylative cross-couplings (1 : Kollar, L;

Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2: Brennfuhrer, A. ; Neumann, H. ; Beller, M. Angew. Chem. Int. Edit.

20 2009, 48, 4114-4133), carbonylative cross coupling reaction with

organometallic reagents (Brennfuhrer, A. ; Neumann, H. ; Beller, M. Angew. Chem. Int. Edit. 2009, 48, 4114-4133), CO reduction, CO oxidation

(Smitrovich, J. H. ; Davies, I. W. Org. Lett. 2004, 6, 533-535), water-gas shift reaction (1 : Kiss, G. Chem. Rev. 2001, 101, 3435-3456; 2: Wender, I. Fuel

25 Process. Techno!. 1996, 48, 189-297), ring opening carbonylation , ring

opening carbonylative polymerization (Church, T. L ; Getzler, Y. ; Byrne, C. M. ; Coates, G. W. Chem. Commun. 2007, 657-674), ring expansion

carbonylation (Church, T. L ; Getzler, Y. ; Byrne, C. M. ; Coates, G. W. Chem. Commun. 2007, 657-674), radical carbonylations (Ryu, I. ; Sonoda, N. Angew.

30 Chem. Int. Edit. 1996, 35, 1050-1066), carbonylation of organometallic

reagents , carbonylation of organolithium reagents (Narayana, C ;

Periasamy, M. Synthesis 1985, 253-268), carbonylation of organomagnesium reagents (Narayana, C ; Periasamy, M. Synthesis 1985, 253-268),

carbonylation of organoboranes (Narayana, C ; Periasamy, M. Synthesis 1985,

35 253-268), carbonylation of organomercurials (Narayana, C ; Periasamy, M. Synthesis 1985, 253-268), carbonylation of organopalladium compounds

(Narayana, C ; Periasamy, M. Synthesis 1985, 253-268), carbonylative Hiyama coupling (Hatanaka, Y. ; Fukushima, S. ; Hiyama, T. Tetrahedron 1992, 48, 2113- 2126).

Since the first reports by Heck and co-workers in the 1970s on palladium catalyzed carbonylation reactions, the scope of CO chemistry has expanded considerably. CO is a high affinity ligand for palladium, in both oxidation zero and two, by its dual ability to act as a sigma-doner and pi-acceptor. The classical examples of palladium catalysed carbonylative couplings using halides or pseudohalides with a suited nucleophile includes alkoxycarbonylation,

aminocarbonylation, carbonylative Heck, carbonylative Suzuki-Miyaura,

carbonylative Sonogashira etc. Whereas, the alkoxycarbonylation using alcohols as the nuclephile is the most developed and robust method for the preparation of esters, the aminocarbonylation to create an amide bond is of the highest interest to the pharmaceutical industry. Furthermore, transition metal catalyzed carbonylation reactions holds the advantages of introducing the carbonyl functionality in one step by electrophilic means. Typical reaction types, wherein the present method is anticipated to be applicable, are furthermore illustrated by the non-limiting series of reaction types I-V:

Type I reactions involve an activated substrate (R-X) and a nucleophile (Nu), both reacting with a carbon monoxide unit mediated by a metallic or organometallic catalyst each forming one single bond to the carbon of the CO to obtain a new carbonyl compound.

[M] O

R-X + CO + Nu - II

R Nu

Suitable nucleophiles are for example amines, alcohols, thiols, hydride ions, alkenes, alkynes, boric acids, boronic acids, carboxylate ions, malonate-type ions, enolate-type ions, azide ions, cyanide ions, halide ions, phosphines R₃P wherein R is aryl, heteroaryl or alkyl, metal organic compounds like organomagnesium compounds, organozinc compounds, organotin compounds, organolithium compounds, and/or organo silanes. The term "activated" is intended to mean that the carbon atom of the substrate with which the carbon atom of carbon monoxide bonds to during the reaction, shares, at the onset of the reaction, a bond with a group or atom which has a lower bond dissociation energy than a carbon-hydrogen bond.

In these types of reactions, the X acts as an electrophile, the Pd-catalyst is a nucleophile (once activated). However, once e.g. the Ar-Pd-X is formed, the Ar is nucleophilic and the Pd is electrophilic. Carbon monoxide acts as an electrophile. In addition to the examples listed above which serve to activate the substrate, the activating group may be an epoxide or an aziridine. In such cases, the product is typically the corresponding lactone or [beta]-lactam, respectively.

These 3-component reactions (i. CO; ii. ArX or alk-X; iii. nucleophilic specie) may be intramolecular. That is to say that the nucleophilic species and the activated substrate are each moieties of a single molecule.

In intermolecular reactions, i.e. where the organic reactant and the activated substrate are not moieties of a single molecule, the reaction mixture also contains an additional reactant. Suitable additional reactants are selected from the group consisting of amines, alcohols, thiols, hydride ions, alkenes, alkynes, boric acids, boronic acids, carboxylate ions, malonate-type ions, enolate-type ions, azide ions, cyanide ions, halide ions, phosphines R₃P wherein R is aryl, heteroaryl or alkyl, metal organic compounds.

Furthermore, in addition to the examples listed above which serve to activate the substrate, X may be hydroxyl, such that the substrate is a primary, secondary, or tertiary alcohol (Chaudhari et al, Organic Letters, 2000, 2 (2), 203). In such embodiments, a halide promoter and/or an acid promoter may additionally be required. A halide promoter may be Li-halide (Chaudhari et al, 2000) wherein the corresponding halo derivative is a reaction intermediate. Within this embodiment, water may be used as the nucleophile, in which case the corresponding carboxylic acid is the product. An alcohol, thiol, or amine may suitably be used as

nucleophile so as to provide an ester, thioester, or amide, respectively.

Alternatively, in the suitable embodiment wherein X is hydroxyl, the hydroxyl may be converted in situ to its corresponding mesylate, triflate, phosphonate, tosylate, or boronic acid using methods known to the person skilled in the art. The catalyst is typically a catalyst involving palladium.

Non-limiting examples of type 1 are:

Aminocarbonylation

As example of type I reactions can be found aminocarbonylations (type la). In such reactions as described in Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, amide functionality is created from an activated substrate, carbon monoxide and a primary or secondary amine as the nucleophilic species as previously described for type I reactions. An intramolecular version of this reaction is possible when the activated substrate and the nucleophilic species are linked. Gaseous carbon monoxide is applied, preferentially with pressures between 0.1 and 10 atm. Primary or secondary amine is related to the number of substituents on the nitrogen, respectively one or two, which can be but not limited to aryls (Ar), such as phenyl, benzyl, or heteroaryl; alkyls such as Cl-12-alkyl; alkenyls, such as C2-12-alkenyl; or an alkynyl group such as C2-12-alkynyl, each of which may be optionally substituted. The metal catalyst is preferentially a palladium-based catalyst and more precisely composed of a palladium source and a ligand with typical loadings between 0.1 and 5 mol%. Palladium and ligands can be introduced from the same precursor like PdCl₂(PPh₃)₂ or from two different source. The palladium source can be a palladium(II) species, like Pd(OAc), Pd(CI)₂, or a palladium(O) species, like

Pd(dba)₂, Pd₂(dba)₃. Ligands are preferably phosphine ligands, either

monodentate ligands such as triphenylphosphine, tri-tert-butylphosphine, cataCXium® A, bidentate ligands such as Xantphos, BINAP, dppf, or salts thereof. Aminocarbonylations are typically run with a base present in order to abstract the excess proton arriving with the nucleophile and to ensure proper regeneration Pd(0). Bases are typically inorganic bases, such as Na₂C0₃, alkoxide species with a counter-ion, such as sodium phenoxide, potassium tert- butoxide, or organic bases, such as the tertiary amines, e.g., triethylamine, diisopropylethylamine, or heterocyclic amine bases such as pyridine or DBU (l,8-diazabicyclo[5.4.0]undec- 7-ene). Reactions can take place in various solvents, preferentially toluene or dioxane.

Alkoxycarbonylation As example of type I reactions can be found alkoxycarbonylations (type lb). In such reactions as described in Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, ester functionalities are constructed from an activated substrate, carbon monoxide and an alcohol as the nucleophilic species as previously described for Type I reaction. An intramolecular version of this reaction is possible when the activated substrate and the

nucleophilic species are linked. Gaseous carbon monoxide is applied, preferentially with pressures between 0.1 and 10 atm. The metal catalyst is preferentially a palladium-based catalyst and more precisely composed of a palladium source and a ligand with typical loadings between 0.1 and 5 mol%. Palladium and ligands can be introduced from the same precursor like PdCl₂(PPh₃)₂ or from two different source. The palladium source can be a palladium(II) species, such as Pd(OAc) and Pd(CI)₂, or a palladium(O) species, such as Pd(dba)₂ and Pd₂(dba)₃. Ligands are preferably phosphine ligands, either monodentate ligands, such as

triphenylphosphine, tri-tert-butylphosphine, cataCXium® A, bidentate ligands, such as Xantphos, BINAP, dppf, or salts thereof. Bases are typically inorganic bases such as Na₂C0₃, alkoxide species with a counter-ion, such as sodium phenoxide, potassium tert- butoxide or organic bases such as the tertiary amines, e.g., triethylamine, diisopropylethylamine, or heterocyclic amine bases such as pyridine or DBU (l,8-diazabicyclo[5.4.0]undec-7-ene). Reactions can take place in various solvents, preferentially toluene or dioxane. Alkoxycarbonylation can benefit from the addition of a nucleophilic amine based catalyst, preferentially DMAP. Alkoxycarbonylations have been utilized as an alternative approach towards aminocarbonylation by initial alkoxycarbonylation with a phenol derivative and subsequent nucleophilic substitution with an amine nucleophile.

Carbonylative Heck reaction

As example of type I reactions can be found Carbonylative Heck - Mizoroki reaction (type Ic). In such reactions as described in Beller et a/, J. Am. Chem. Soc. 2010,132, 14596-14602, a ketone functionality is constructed from an activated substrate, carbon monoxide and an alkene as the nucleophilic species as previously described for type I reactions. An intramolecular version of this reaction is possible when the activated substrate and the nucleophilic species are linked. Gaseous carbon monoxide is applied, typically with pressures between 5 and 10 atm. The metal catalyst is preferentially a palladium-based catalyst and more precisely composed of a palladium source and a ligand with typical loadings between 1 and 6 mol%. The palladium source can be a palladium(II) species, such as Pd(OAc) and [(cinnamyl)PdCI]₂, or a palladium(O) species, such as Pd(dba)₂ and Pd₂(dba)₃. Ligands are preferably phosphine based ligands. Bases are typically inorganic bases, such as Na₂C0₃, alkoxide species with a counter-ion, such as sodium phenoxide, potassium tert- butoxide or organic bases, such as the tertiary amines, e.g., triethylamine and diisopropylethylamine, or heterocyclic amine bases, such as pyridine or DBU (l,8-diazabicyclo[5.4.0]undec-7-ene).

Reactions can take place in various solvents, preferentially dioxane.

Type II reactions are intended to anticipate 3-component reactions involving direct carbonylation (i.e. unactivated systems) of a substituted aryl or optionally substituted heteroaryl and resulting in acylation of said substrate. The aryl may be substituted with a directing group (Dir) so as to direct the regiochemistry of the carbonylation. The directing group may be, for example, an oxazoline, oxazine, thioazine or pyridine group (Murai et al, J. Org. Chem., 2000, 65, 1475). The directing group may also be an imine so as to form an optionally substituted benzaldehyde imine. The product formed therefrom may serve as an intermediate in intramolecular aldol-type reactions. In some selected examples where the aryl group contains heteroatoms no directing group is needed.

The aryl ring may be a heteroaryl. In a suitable embodiment, the carbonylation may involve the direct carbonylation (of a C-H bond; un-activated system) of heteroaryl, without the use of a directing group. Quite obviously, the heteroaryl may also be substituted with a directing group.

An alkenyl other than ethylene may also be used, as may trimethylvinylsilane, as the nucleophile. The alkenyl may be an optionally substituted C2-8-alkenyl.

The catalyst used in Type II reactions is typically Pd, V, Pt, Ru, and Rh and suitable precatalysts are Pd(OAc)₂, (PPh)₃RhCI (Wilkinson's catalyst), Ru₃(CO)i₂, [RhCI(coe)₂]₂, RuH₂(CO)(PPh₃)₃ and Cp*Rh(C₂H₃SiMe₃)₂.

Type Ilia reactions involve hydroformylations such as asymmetric

hydroformylations. The metal-catalyst is typically selected from the group consisting of Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Ir, Co, and Ru, preferably selected from Pd, Pt, Rh, Ir, Co, Ru, and Ni, most preferably in this reaction Type, the metal-catalyst selected is Rh, Ir, and Co. The alkenyl may be of any length and may be optionally substituted.

The hydrogen source may be hydrogen gas or may be a bimolecular equivalent of H₂. One suitable embodiment of this involves the use of a reagent comprising a weakly acidic proton source, such as ethanol, and a hydride source, such as trialkyl silane (HS1R3), which is added to the reaction mixture.

Type Illb reactions involve aminomethylation of an alkenyl. The reaction proceeds via the following process: hydroformylation (Ilia), condensation and

hydrogenation.

The alkenyl may be of any length and may be optionally substituted.

The metal-catalyst in this reaction type is typically selected from the group consisting of Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Ir, Co, and Ru, preferably selected from Pd, Pt, Rh, Ir, Co, Ru and Ni, most preferably selected from Rh, Ir, and Co. Water may serve as the reductant in conjunction with CO. Alternatively, hydrogen may be provided. The hydrogen source may be hydrogen gas or may be a bimolecular equivalent of H₂. One suitable embodiment of this involves the use of a reagent comprising a weakly acidic proton source, such as ethanol, and a hydride source, such as trialkyl silane (HS1R3), which is added to the reaction mixture.

Oxidative carbonylation (type IV)

Type IV reactions as described in Kollar, L ; Modern Carbonylation Methods, 2008, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim involve two

nucleophiles which react with a carbon monoxide unit mediated by a metallic or organometallic species which undergoes a reduction and in this aids the formation of a single bond between each nucleophile and the carbon of the CO to afford a new carbonyl compound. In order to achieve a catalytic reaction with the active metallic species, a stoichiometric amount of oxidant is typically added which regenerates the active catalyst by re-oxidization of the metal center.

Nu + CO + Nu' + [M]^(x) (x+2)

[M]

Nu' Nu' Suitable nucleophiles are for example alcohols, amines, alkenes, alkynes, aryl, aryl- or alkenylboronic acid derivatives, aryl- or alkenyl organometallic

derivatives... The metal may be Ni, Mo, Ru, Rh, Co, Au, Pd, preferentially Pd and oxidants regenerating the active catalyst by re-oxidization of the metal are typically but not exclusively benzoquinone, CuCI, I₂ or 0₂.

Oxydative carbonylation of amines

Oxydative carbonylation of amines (Type IVa) as reviewed by White et a/, Eur. J. Org. Chem. 2007, 4453-4465, is a reaction employing amines, carbon monoxide, a metal and an oxidant to afford symmetrical or unsymmetrical ureas. This reaction can be achieved using various metals like Mn, Fe, Co, Cu, Ni, Ru, Rh, Pd, W, Pt, Ir, or Au, preferably Pd. The palladium source can be a palladium(II) species, such as Pd(OAc), PdCI₂(PPh₃)₂, Pdl₂, or a palladium(O) species, such as Pd(dba)₂ and Pd₂(dba)₃. A ligand can be added if required. The co-oxidant can be but is not limited to CuCI, I₂ or 0₂.

Oxydative carbonylation of alcohols

Oxydative carbonylation of alcohols (Type IVb) as described in Rivetti et al, J. Organomet. Chem., 1979, 174, 221-226, is a reaction employing an alcohol, carbon monoxide, a metal and an oxidant (typically but not limited to 0₂) to afford organic carbonates. This reaction can be achieved using various metals like Mn, Fe, Co, Cu, Ni, Ru, Rh, Pd, W, Pt, Ir, or Au, preferably Pd or Cu. For example, the palladium source can be Pd(OAc)₂(PPh₃)₂ or PdCI₂(PPh₃)₂, copper sources can be CuCI.

Oxydative carbonylation of boronic acid derivatives

Oxydative alkoxycarbonylation of boronic derivatives (Type IVc) as described by Yamamoto, Adv. Synth. Catal. 2010, 478-492, is a reaction employing an aryl- or alkenylboronic acid derivative, carbon monoxide, an alcohol as the nucleophile and an oxidant to afford aryl- or alkenylesters. This reaction can be achieved using preferentially a palladium catalyst. The palladium source can be a palladium(II) species, such as Pd(OAc), or a palladium(O) species, such as Pd(dba)₂ and Pd₂(dba)₃. The ligand is typically a phosphine ligand, preferably PPh₃. The oxidant is typically benzoquinone. The reaction conditions (e.g. selection of catalyst) shown for each of the reaction types are merely to exemplify an embodiment within the reaction type. The catalyst may be selected from those known in the art. Additives may be required or preferred in embodiments of particular reaction types. The energy source may be tailored to the needs or facilities available to the practitioner.

In one embodiment of the present invention, the at least one carbon monoxide consuming chamber comprises a reaction mixture suitable for the reaction selected from hydroformylation, reductive carbonylation, Fischer-Tropsch synthesis, aminomethylation, homologation of carboxyiic acid, CO hydrogenation, homologation of alcohols, silylformylation, hydrocarboxylation, hydroesterification, CO copolymerization with olefins, CO terpolymerization with olefins, Reppe carbonylation, oxidative carbonylations of olefins, Pauson-Khand reaction, carbonylative cycloadditions, cyclo-carbonylations, alkoxycarbonylation, aminocarbonylation, carbonylative lactonization, carbonylative lactamization, hydroxycarbonyiation, thiocarbamoyiation, thiocarbonyiation, amidocarbonyiation, oxidative bisoxycarbonylation, oxidative carbonylation of alcohols, oxidative alkoxycarbonylation, oxidative aminocarbonylation, oxidative carbonylation of amines, carbonylative annulations, CO complexation by a metal, acyl-metal complexes generation, acid fluoride synthesis, carbonylation of alcohols, carbonylation of esters, carbonylation of aziridines, carbonylation of aldehydes, carbonylation of epoxides, carbonylation of amines, carbonylative Heck - Mizoroki reaction, carbonylative Suzuki - Miyaura coupling reaction, carbonylative Stille coupling reaction, carbonylative Sonogashira coupling reaction, carbonylative cross-couplings, carbonylative cross coupling reaction with organometallic reagents, CO reduction, CO oxidation, water-gas shift reaction, ring opening carbonylation, ring opening carbonylative polymerization, ring expansion carbonylation, radical carbonylations, carbonylation of organometallic reagents, carbonylation of organolithium reagents, carbonylation of organomagnesium reagents, carbonylation of organoboranes, carbonylation of organomercurials, and carbonylation of organopalladium compounds.

In one embodiment of the present invention, the catalyst used for the

carbonylation reaction in the carbon monoxide consuming chamber can be the same as the solid support. In general, shipment and handling of the carbonylation system is made easier when the reactants are encapsulated.

5 In one embodiment of the present invention, the one or more reactants in the carbon monoxide consuming chamber are encapsulated with an encapsulation material.

In another embodiment of the present invention, the reactants in the carbon 10 monoxide consuming chamber are separately encapsulated with an encapsulation material.

Shipment and handling of the carbonylation system is made even easier when the optional solvent is at solid form before use. When the carbonylation system is

15 prepared for use, the system is heated to the melting point of the one solvent or solvent mixture. Hence, suitable solvents have a melting point as measured with a differential scanning calorimeter (DSC) above -78 degrees Celsius, such as in the range of -75-400 degrees Celsius, e.g. -65 degrees Celsius, such as in the range of -55-400 degrees Celsius, e.g. -45 degrees Celsius, such as in the range of -35-

20 400 degrees Celsius, e.g. -25 degrees Celsius, such as in the range of -15-400 degrees Celsius, e.g. -5 degrees Celsius, such as in the range of 0-400 degrees Celsius, e.g. 5 degrees Celsius, such as in the range of 10-400 degrees Celsius, e.g. 15 degrees Celsius, such as in the range of 20-400 degrees Celsius, e.g. 25 degrees Celsius, such as in the range of 30-400 degrees Celsius, e.g. 35 degrees

25 Celsius, such as in the range of 40-380 degrees Celsius, e.g. 45 degrees Celsius, such as in the range of 50-350 degrees Celsius, e.g. 55 degrees Celsius, such as in the range of 60-300 degrees Celsius, e.g. 65 degrees Celsius, such as in the range of 70-280 degrees Celsius, e.g. 75 degrees Celsius, such as in the range of 80-250 degrees Celsius, e.g. 85 degrees Celsius, such as in the range of 90-180

30 degrees Celsius, e.g. 95 degrees Celsius, such as in the range of 100-150 degrees Celsius, e.g. 125 degrees Celsius. In a preferred embodiment the solvents have a melting point as measured with a differential scanning calorimeter (DSC) above the range of -75-100 degrees Celsius. Non limiting examples of such solvents Paraffin wax (mp 53-57 °C (ASTM D 87)), Paraffin wax (mp 58-62 °C (ASTM D

35 87)), Paraffin wax (mp >65 °C (ASTM D 87)), Paraffin wax (mp 70-80 °C (ASTM D 127)), Poly(ethylene glycol) methyl ether 5,000 (mp = 60-64 °C), Poly(ethylene glycol) methyl ether 2,000 (mp = 52-56 °C).

In still another embodiment of the present invention, the encapsulation material is one or more solvents having a melting point above 25 degrees Celsius.

In one embodiment, the one or more solvents are on solid form at room

temperature to ease the handling of the carbonylation system. Non-limiting examples of such solvents are Paraffin wax (mp 53-57 °C (ASTM D 87)), Paraffin wax (mp 58-62 °C (ASTM D 87)), Paraffin wax (mp >65 °C (ASTM D 87)), Paraffin wax (mp 70-80 °C (ASTM D 127)), Poly(ethylene glycol) methyl ether 5,000 (mp = 60-64 °C), Poly(ethylene glycol) methyl ether 2,000 (mp = 52-56 °C). In another embodiment of the present invention, the reactants for the

carbonylation reaction are coated by the solid solvent. When the solvent melts, the reaction is initiated. In a special embodiment, the solvent may also be one of the reactants, e.g. the base. In still another embodiment of the present invention, the reactants and/or the catalyst are individually coated by the solid solvent, thereby protecting the reactants from the catalyst and/or base prior to heating the system to above room temperature. When the solvent melts, the reaction is initiated. In general, shipment and handling of the carbonylation system is made easier when the reactants are encapsulated.

Encapsulated particles of reactants disclosed herein, such as the the catalyst and the carbonylation reagents, can vary in size from particles commonly known as microcapsules, typically from 25 to 750 microns in size, to those which are commonly referred to as macrocapsules, typically from 1,000 to 3,000 microns in size, or even larger. The maximum size of the encapsulated products of this invention is limited only by the method of the production. Non-limiting examples of solvents with melting points between -25 and rt (room temperature) are:

Benzene (5,5 °C), 1,4-Dioxane (11,8 °C), dimethyl sulfoxide (19 °C), acetic acid (16-17 °C), water (0 °C), tert-butyl alcohol (25.5 °C), cyclohexane (6.6 °C), diethylene glycol (-10 °C), ethylene glycol (-13 °C), glycerin (-18 °C), hexamethyl phosphoramide (7,2 °C), V-methyl-2-pyrrolidine (-24 °C), para-xylene (13.3 °C).

Non-limiting examples of ionic liquids as solvent, having a melting point range 0- 200 °C are:

l,2-Dimethyl-3-propylimidazolium bis(trifluoromethylsulfonyl)imide, l-Ethyl-3- methylimidazolium bis(trifluoromethylsulfonyl)imide, l,3-Dihydroxy-2- methylimidazolium bis(trifluoromethylsulfonyl)imide, l,3-Dimethoxy-2- methylimidazolium bis(trifluoromethylsulfonyl)imide, 1,3-Dimethoxyimidazolium hexafluorophosphate, Tetrabutylphosphonium p-toluenesulfonate,

Tetrapentylammonium thiocyanate, l,3-Bis(cyanomethyl)imidazolium

bis(trifluoromethylsulfonyl)imide, l-Butyl-4-methylpyridinium

hexafluorophosphate, l-Ethyl-3-methylimidazolium

bis(pentafluoroethylsulfonyl)imide, l-Ethyl-3-methylimidazolium nitrate, 1-Ethyl- 3-methylimidazolium tosylate, 3-Methyl-l-propylpyridinium

bis(trifluormethylsulfonyl)imide, Methyltrioctylammonium thiosalicylate,

Tetrabutylammonium nonafluorobutanesulfonate, Tetrabutylphosphonium methanesulfonate, l-Ethyl-3-methylimidazolium hexafluorophosphate, 1-Methyl- 3-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)imidazolium hexafluorophosphate, l-Butyl-l-(3, 3,4,4,5,5, 6,6,7, 7, 8, 8,8-tridecafluorooctyl)imidazolium

hexafluorophosphate, l,3-Dimethoxy-2-methylimidazolium hexafluorophosphate, l-(3-Cyanopropyl)pyridinium chloride, 5-Hydroxy-2-methylpyridine.

In the present context, the terms "solvent" and "ionic liquid" may be used interchangeably.

In yet another embodiment of the present invention, the encapsulation material for the reactants in the carbon monoxide consuming chamber and the carbon monoxide consuming chamber are of different type.

The catalyst In one embodiment of the present invention, the catalyst in the at least one carbon monoxide consuming chamber is selected from the group consisting of Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Co, Ir, Ru, Ta, W, Fe, Re, and Os or mixtures thereof.

In another embodiment of the present invention, the one or more of the catalysts in the at least one carbon monoxide consuming chamber comprises an atom selected from the group consisting of Se, Pd, Pt, Rh, Ni, Cu, Cd, Zn, Ti, Sr, Co, Ir, Ru, Ta, W, Fe, Re, and Os or mixtures thereof.

In another embodiment of the present invention, the catalyst is a palladium/ligand complex. In a preferred embodiment, the palladium/ligand complex is

characterized in that the molar ratio between palladium and ligand is from 1: 1 to 1 : 5 in the case of monodentate ligands and from 1 : 1 to 1 :4 in the case of bidentate ligands.

The palladium component of the catalyst complex herein can be zero-valent palladium, a palladium-containing composition which will provide zerovalent palladium, i.e., will undergo reduction, under the conditions of the reaction and/or a palladium (II) salt, with or without the additional presence of a reducing agent such as alkali metal alkoxide, alkali metal acetate and/or alkali metal borohydride. Among such palladium-containing compositions are included palladium (II) acetate, palladium (II) formate, palladium (II) octanoate, palladium (II) propionate, palladium acetylacetonate, palladium (II) bis (.pi.-allyl), palladium (II) nitrate, palladium sulfate, palladium (II) halides such as palladium chloride and palladium bromide, PdCI₂(MeCN)₂, and PdCI₂(PhCN)₂.

Non-limiting examples of catalysts are: Palladium catalysts

(l,3-Bis(diphenylphosphino)propane)palladium(II) chloride, (1,5-

Cyclooctadiene)bis(trimethylsilylmethyl)palladium(II), (2,2'-

Bipyridine)dichloropalladium(II), (2-Butenyl)chloropalladium dimer, (2-

Dicyclohexylphosphino-2',6'-diisopropyl-l, -biphenyl)[2-(2- aminoethyl)phenyl)]palladium(II), (2-Methylallyl)palladium(II) chloride dimer, (Bicyclo[2.2.1]hepta-2,5-diene)dichloropalladium(II),

(Ethylenediamine)palladium(II) chloride, (n,⁵-2,4-Cyclopentadien-l-yl)[(l,2,3-n,)- l-phenyl-2-propenyl]-palladium, l,l'-Bis(di-cyclohexylphosphino)ferrocene palladium dichloride, l,l'-Bis(di-isopropylphosphino)ferrocene palladium

dichloride, l,l'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride, 1,2- Bis(phenylsulfinyl)ethane palladium (II), l,3-Bis(2,4,6-trimethylphenyl)imidazol-2- ylidene (l,4-naphthoquinone)palladium(0) dimer, 1,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene(l,4-naphthoquinone)palladium(0) dimer, l,4-Bis(diphenylphosphino)butane-palladium(II) chloride, 2'-(Dimethylamino)-2- biphenylyl-palladium(II) chloride Dinorbornylphosphine complex,

2,3,7,8,12,13,17,18-Octaethyl-21tf,23tf-porphine palladium(II), 2-(2'-D\-tert- butylphosphine)biphenylpalladium(II) acetate, 2-(Dimethylaminomethyl)ferrocen- l-yl-palladium(II) chloride Dinorbornylphosphine Complex, 2- [Bis(triphenylphosphine)palladium(II)bromide] benzyl alcohol, 2-[Bis(2,4-di-tert- butyl-phenoxy)phosphinooxy]-3,5-di(tert-butyl)phenyl-palladium(II) chloride dimer, Allyl[l,3-bis(mesityl)imidazol-2-ylidene]chloropalladium(II), Allyl[l,3- bis(2,6-diisopropylphenyl)imidazol-2-ylidene]chloropalladium(II),

Allylpalladium(II) chloride dimer, Bis(3,5,3',5'- dimethoxydibenzylideneacetone)palladium(O),

Bis(acetonitrile)dichloropalladium(II), Bis(benzonitrile)palladium(II) chloride, Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II),

Bis(dibenzylideneacetone)palladium(0), Bis(tri-tert-butylphosphine)palladium(0), Bis(triphenylphosphine)palladium(II) diacetate,

Bis(triphenylphosphine)palladium(II) dichloride,

Bis(triphenylphosphine)palladium(II) dichloride, Bis[(dicyclohexyl)(4- dimethylaminophenyl)phosphine] palladium(II) chloride, Bis[l,2- bis(diphenylphosphino)ethane]palladium(0), Bis[di-(tert-butyl)(4- trifluoromethylphenyl)phosphine] palladium (II) chloride, Bis[tris(2- methylphenyl)phosphine] palladium, Bis[tris(3-(1 - , 1/- ,2Η,2Η- perfluorodecyl)phenyl)phosphine]palladium(II) dichloride, Bis[tris(3-

(heptadecafluorooctyl)phenyl)phosphine] palladium (II) dichloride, Bis[tris(4- (l ,l ,2 ,2 -perfluorodecyl)phenyl)phosphine]palladium(II) dichloride,

Bromo(tri-tert-butylphosphine)palladium(I) dimer, Bromo[(2-(hydroxy- KO)methyl)phenylmethyl-KC](triphenylphosphine)palladium (II), Chloro(l,5- cyclooctadiene)methylpalladium(II), Chloro(2-dicyclohexylphosphino-2',4',6'- triisopropyl-l,l'-biphenyl)[2- (2-aminoethyl)phenyl)] palladium (II), Chloro(n²-P,C- tris(2,4-di-tert-butylphenyl)phosphite)(tricyclohexylphosphine)palladium(II), Chloro[(l,2,5,6-n)-l,5-cyclooctadiene](2,2-dimethylpropyl)-palladium, Di-μ- chlorobis[2-[(dimethylamino)methyl]phenyl-C,N]dipalladium(II), Di- -chlorobis[5- chloro-2-[(4-chlorophenyl)(hydroxyimino-KN)methyl]phenyl-KC] palladium dimer, Di- -chlorobis[5-hydroxy-2-[l-(hydroxyimino-KN)ethyl]phenyl-KC] palladium (II) dimer, Di- -chlorodimethylbis(triphenylphosphine)dipalladium, Dichloro(l,10- phenanthroline)palladium(II), Dichloro(l,5-cyclooctadiene)palladium(II),

Dichloro( V_/ V_/ V'_/A '-tetramethylethylenediamine)palladium(II), Dichloro[2-(4,5- dihydro-2-oxazolyl)quinoline] palladium (II),

Dichlorobis(methyldiphenylphosphine)palladium(II), Dichlorobis(tri-o- tolylphosphine)palladium(II), Dichlorobis(tricyclohexylphosphine)palladium(II),

Dichlorobis(triethylphosphine)palladium(II), PEPPSI -IPr catalyst, PEPPSI -SIPr, PEPPSI^™-SONO-sp², PEPPSI^™-SONO-sp3, Palladium pivalate, Palladium(II) acetate, Palladium(II) acetylacetonate, Palladium(II) bromide, Palladium(II) chloride, Palladium(II) cyanide, Palladium(II) hexafluoroacetylacetonate,

Palladium(II) iodide, Palladium(II) nitrate dihydrate, Palladium(II) oxide,

Palladium(II) potassium thiosulfate monohydrate, Palladium(II) propionate, Palladium(II) sulfate, Palladium(II) sulfide, Palladium(II) trifluoroacetate,

Palladium (II) [1, 3-bis(diphenylphosphino)propane]-bis(benzonitrile)-bis- tetrafluoroborate, Palladium(n-cinnamyl) chloride dimer,

Tetraamminepalladium(II) bromide, Tetraamminepalladium(II) acetate,

Tetraamminepalladium(II) chloride monohydrate, Tetraamminepalladium(II) tetrachloropalladate(II), Tetrakis(acetonitrile)palladium(II) tetrafluoroborate, Tetrakis(triphenylphosphine)palladium(0), Tris(3,3',3"- phosphinidynetris(benzenesulfonato)palladium(0) nonasodium salt nonahydrate, Tris(dibenzylideneacetone)dipalladium chloroform complex,

Tris(dibenzylideneacetone)dipalladium(0),

Tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, Tris[M-[(l,2-r| :4,5- n)-(lE,4E)-l,5-bis(4-methoxyphenyl)-l,4-pentadien-3-one]]di-palladium, [1,1 - Bis(diphenylphosphino)ferrocene]dichloropalladium(II), [1,2,3,4- Tetrakis(methoxycarbonyl)-l,3-butadiene-l,4-diyl] palladium (II), [1,2- Bis(diphenylphosphino)ethane]dichloropalladium(II), [1,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene]chloro[3-phenylallyl]palladium(II), [1,3- Bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidene]chloro][3- phenylallyl]palladium(II), trans-

Benzyl(chloro)bis(triphenylphosphine)palladium(II), irans-Bis(acetato)bis[o-(di-o- tolylphosphino)benzyl]dipalladium(II), trans-Bis(dicyclohexylamine)palladium(II) acetate, trans-Bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II), trans- Dibromobis(triphenylphosphine)palladium(II), Palladium hydroxide on activated charcoa, Palladium hydroxide on carbon, Palladium nanoparticles, Palladium on activated charcoal, Palladium on activated alumina, Palladium on barium

carbonate, Palladium on barium sulfate, Palladium on calcium carbonate,

Palladium on strontium carbonate, Palladium black, Palladium nanopowder, Palladium wire and supported catalyst :

Bis[(diphenylphosphanyl)methyl]amine palladium(II) acetate, polymer-bound 70- 90 mesh particle size, extent of labeling : 0.5-1.0 mmol/g Pd loading, 1 % cross- linked with divinylbenzene

Bis[(diphenylphosphanyl)methyl]amine palladium(II) dichloride, polymer-bound 70-90 mesh, extent of labeling : 0.5-1.5 mmol/g N loading, 1 % cross-linked Di(acetato)dicyclohexylphenylphosphinepalladium(II), polymer-bound FibreCat^® Pd ~5 %, extent of labeling : 0.4-0.6 mmol/g PPH₃ ligand content loading

Diacetobis(triphenylphosphine)palladium(II), polymer-bound 200-400 mesh particle size, extent of labeling : 1.0-1.5 mmol/g Pd loading, 1 % cross-linked with divinylbenzene

Dichlorobis(triphenylphosphine)palladium(II), polymer-bound 200-400 mesh, extent of labeling : 1.0-2.0 mmol/g loading, 2 % cross-linked with divinylbenzene /V-Methylimidazolium palladium(II), polymer-bound 50-100 mesh particle size, extent of labeling : 0.5-1.5 mmol/g Pd loading, 1 % cross-linked with

divinylbenzene

Tetrakis(triphenylphosphine)palladium, polymer-bound 200-400 mesh, extent of labeling : 0.5-0.9 mmol/g loading, 2 % cross-linked with divinylbenzene.

Rhodium catalysts

(l,5-Cyclooctadiene)bis(triphenylphosphine)rhodium(I) hexafluorophosphate dichloromethane complex (1 : 1), (Acetylacetonato)(l,5-cyclooctadiene)rhodium(I), (Acetylacetonato)(norbornadiene)rhodium(I),

(Acetylacetonato)dicarbonylrhodium(I), (Bicyclo[2.2.1]hepta-2,5-diene)[l,4- bis(diphenylphosphino)butane]rhodium(I) tetrafluoroborate,

Acetylacetonatobis(ethylene)rhodium(I), Bicyclo[2.2. l]hepta-2,5-diene- rhodium(I) chloride dimer, Bis(l,5-cyclooctadiene)rhodium(I)

hexafluoroantimonate, Bis(l,5-cyclooctadiene)rhodium(I) tetrafluoroborate, Bis(l,5-cyclooctadiene)rhodium(I) tetrakis[bis(3,5-trifluoromethyl)phenyl] borate, Bis(l,5-cyclooctadiene)rhodium(I) trifluoromethanesulfonate, Bis(2,2- dimethylpropanoato)(4-methylphenyl)bis[tris[4-

(trifluoromethyl)phenyl]phosphine] rhodium, Bis(acetonitrile)(l,5- cyclooctadiene)rhodium(I)tetrafluoroborate, Bis(norbornadiene)rhodium(I) tetrafluoroborate, Bis(norbornadiene)rhodium(I) trifluoromethanesulfonate, Bis(triphenylphosphine)rhodium(I) carbonyl chloride, Bis[rhodium(a,a,a',a'- tetramethyl-l,3-benzenedipropionic acid)], Chloro(l,5-cyclooctadiene)rhodium(I) dimer, Chloro(l,5-hexadiene)rhodium(I) dimer, Chlorobis(2- phenylpyridine)rhodium(III) dimer, Chlorobis(cyclooctene)rhodium(I),dimer, Chlorotris[(3,3',3"-phosphinidynetris(benzenesulfonato)]rhodium(I) nonasodium salt hydrate, Dicarbonyl(pentamethylcyclopentadienyl)rhodium(I), Dicarbonyl- acetylacetonato-rhodium(I), Dirhodium tetracaprolactamate, Hexarhodium(O) hexadecacarbonyl, Hydridotetrakis(triphenylphosphine)rhodium(I),

Hydroxy(cyclooctadiene)rhodium(I) dimer, Methoxy(cyclooctadiene)rhodium(I) dimer, Nitrosyltris(triphenylphosphine)rhodium(I),

Pentamethylcyclopentadienylrhodium(III) chloride dimer, Rhodium nanoparticles, Rhodium on activated alumina, Rhodium on activated charcoal, Rhodium(II) acetate dimer dihydrate, Rhodium(II) heptafluorobutyrate dimer, Rhodium(II) hexanoate dimer, Rhodium(II) octanoate dimer, Rhodium(II) trifluoroacetate dimer, Rhodium(II) trimethylacetate, dimer, Rhodium(III) acetylacetonate, Rhodium(III) bromide hydrate, Rhodium(III) chloride, Rhodium(III) oxide, Tetrarhodium dodecacarbonyl, Trichloro[l,l,l- tris(diphenylphosphinomethyl)ethane] rhodium (III),

Trichlorotris(ethylenediamine)rhodium(III) trihydrate,

Tris(triphenylphosphine)rhodium(I) carbonyl hydride,

Tris(triphenylphosphine)rhodium(I) chloride, [1,4- Bis(diphenylphosphino)butane](l,5-cyclooctadiene)rhodium(I) tetrafluoroborate, [Tris(dimethylphenylphosphine)](2,5-norbornadiene)rhodium(I)

hexafluorophosphate, j_/-Dichlorotetracarbonyldirhodium(I), μ- Dichlorotetraethylene dirhodium(I), Triphenylphosphine(2,5- norbornadiene)rhodium(I) tetrafluoroborate, polymer-bound Fibre-cat^®. Ruthenium catalysts

(Bicyclo[2.2. l]hepta-2,5-diene)dichlororuthenium(II) polymer, 1- Hydroxytetraphenyl-cyclopentadienyl(tetraphenyl-2,4-cyclopentadien-l-one)-M- hydrotetracarbonyldiruthenium(II), 2,3,7,8,12,13,17,18-Octaethyl-21tt,23tt- porphine ruthenium(II) carbonyl, 5,10,15,20-Tetraphenyl-21 ,23 -porphine ruthenium(II) carbonyl, Benzeneruthenium(II) chloride dimer, Bis(2,2'- bipyridine)-(5-aminophenanthroline)ruthenium bis(hexafluorophosphate), Bis(2,4- dimethylpentadienyl)ruthenium(II), Bis(2-methylallyl)(l,5- cyclooctadiene)ruthenium(II), Bis(cyclopentadienyl)ruthenium(II),

Bis(cyclopentadienylruthenium dicarbonyl) dimer,

Bis(ethylcyclopentadienyl)ruthenium(II),

Bis(pentamethylcyclopentadienyl)ruthenium(II),

Bis(trifluoroacetato)carbonylbis(triphenylphosphine)ruthenium(II) methanol adduct, Bis(triphenylphosphine)ruthenium(II) dicarbonyl chloride,

Carbonylchlorohydridotris(triphenylphosphine)ruthenium(II),

Carbonyldihydridotris(triphenylphosphine)ruthenium(II),

Chloro(cyclopentadienyl)[bis(diphenylphosphino)methane] ruthenium (II),

Chloro(indenyl)bis(triphenylphosphine)ruthenium(II),

Chloro(pentamethylcyclopentadienyl)(cyclooctadiene)ruthenium(II),

Chloro(pentamethylcyclopentadienyl)ruthenium(II) tetramer,

Chloro[hydrotris(pyrazol-l-yl)borato] ruthenium (II)-dichloromethane/ethanol adduct, Chlorocyclopentadienylbis(triphenylphosphine)ruthenium(II),

Chlorodicarbonyl(l,2,3,4,5-pentaphenylcyclopentadienyl)ruthenium(II),

Chlorodicarbonyl(l-(isopropylamino)-2, 3,4,5- tetraphenylcyclopentadienyl)ruthenium(II), Chloropentaammineruthenium(II) chloride, Cyclopentadienyl(n,⁶-napthalene)ruthenium(II) hexafluorophosphate, Cyclopentadienyl(p-cymene)ruthenium(II) hexafluorophosphate, Dichloro(l,5- cyclooctadiene)ruthenium(II), Dichloro(mesitylene)ruthenium(II) dimer,

Dichloro(p-cymene)ruthenium(II) dimer,

Dichloro(pentamethylcyclopentadienyl)ruthenium(III) polymer, Dichloro[(2,6,10- dodecatriene)-l,12-diyl]ruthenium(IV), Dichlorobis(2-(diisopropylphosphino)- ethylamine)ruthenium(II), Dichlorobis(2- (diphenylphosphino)ethylamine)ruthenium(II), Dichlorobis(3- (diphenylphosphino)propylamine)ruthenium(II), Dichlorobis[2-(di-tert- butylphosphino)ethylamine]ruthenium(II), Dichlorodi-p-chlorobis[(l,2,3,6,7,8-/7- 2,7-dimethyl-2,6-octadiene- l,8-diyl]diruthenium(IV),

Dichlorotetrakis(triphenylphosphine)ruthenium(II),

Dihydridotetrakis(triphenylphosphine)ruthenium(II), Diiodo(p- 5 cymene)ruthenium(II) dimer, Hexaammineruthenium(II) chloride,

Pentaamminechlororuthenium(III) chloride,

Pentamethylcyclopentadienylbis(triphenylphosphine)ruthenium(II) chloride, Pentamethylcyclopentadienylruthenium(III) chloride polymer,

Pentamethylcyclopentadienyltris (acetonitrile)ruthenium(II) hexafluorophosphate,

10 Ruthenium on activated charcoal, Ruthenium on alumina, Ruthenium(III)

acetylacetonate, Ruthenium(III) bromide, Ruthenium(III) chloride, Ruthenium(III) iodide hydrate, Ruthenium(III) nitrosyl chloride hydrate, Ruthenium(IV) oxide, Tetraethylammonium bis(acetonitrile)tetrachlororuthenate(III),

Tricarbonyldichlororuthenium(II) dimer, Triruthenium dodecacarbonyl,

15 Tris(acetonitrile)cyclopentadienylruthenium(II) hexafluorophosphate.

Nickel catalysts

2,3,7,8, 12, 13, 17, 18-Octaethyl-21tf,23tf-porphine nickel(II), 2,3-Bis(2,6- diisopropylphenylimino)butane nickel(II) dibromide, 5, 10, 15,20-Tetraphenyl-

20 21 ,23 -porphine nickel(II), Ammonium nickel(II) sulfate hexahydrate, Bis(l,5- cyclooctadiene)nickel(O), Bis(cyclopentadienyl)nickel(II),

Bis(isopropylcyclopentadienyl)nickel, Bis(methylcyclopentadienyl)nickel(II), Bis(pentamethylcyclopentadienyl)nickel(II), Bis(tricyclohexylphosphine)nickel(II) dichloride, Bis(triphenylphosphine)dicarbonylnickel,

25 Bis(triphenylphosphine)nickel(II) dichloride, Bis[(2-dimethylamino)phenyl]amine nickel(II) chloride, Bis[5-[[4-(dimethylamino)phenyl]imino]-8(5 )- quinolinone]nickel(II) diperchlorate,

Chloro(cyclopentadienyl)(triphenylphosphine)nickel(II),

Chloro(ethylcyclopentadienyl)(triphenylphosphinenickel(II),

30 Dibromobis(tributylphosphine)nickel(II),

Dibromobis(triphenylphosphine)nickel(II), Dichlorobis(tributylphosphine)nickel(II), Dichlorobis(trimethylphosphine)nickel(II), Hexaamminenickel(II) bromide, Ν,Ν'- Bis(salicylidene)ethylenediaminonickel(II), Nickel carbonate, Nickel foil, Nickel on silica, Nickel oxide, Nickel wire, Nickel(II) acetate tetrahydrate, Nickel(II)

35 acetylacetonate, Nickel(II) bromide 2-methoxyethyl ether complex, Nickel(II) bromide, Nickel(II) bromide ethylene glycol dimethyl ether complex, Nickel(II) chloride, Nickel(II) chloride ethylene glycol dimethyl ether complex, Nickel(II) fluoride, Nickel(II) hexafluoroacetylacetonate hydrate, Nickel(II) iodide, Nickel(II) nitrate hexahydrate, Nickel(II) stearate, Nickel(II) sulfate hexahydrate, Potassium hexafluoronickelate(IV), Potassium tetracyanonickelate(II),

Tetrakis(triphenylphosphine)nickel(0), Tetrakis(triphenylphosphite)nickel(0), [l,l'-Bis(diphenylphosphino)ferrocene]dichloronickel(II), [1,2- Bis(diphenylphosphino)ethane]dichloronickel(II), [1,3- Bis(diphenylphosphino)propane]dichloronickel(II).

Molybdenum catalysts

(Bicyclo[2.2.1]hepta-2,5-diene)tetracarbonylmolybdenum(0), Ammonium molybdate, Ammonium phosphomolybdate hydrate, Ammonium

tetrathiomolybdate, Barium molybdate,

Bis(acetylacetonato)dioxomolybdenum(VI), Bis(cyclopentadienyl)molybdenum(IV) dichloride, Calcium molybdate, Cyclopentadienylmolybdenum(II) tricarbonyl dimer, Cyclopentadienylmolybdenum(V) tetrachloride,

Dicarbonyl(pentamethylcyclopentadienyl)molybdenum(V) dimer, Lithium molybdate, Magnesium molybdate, Molybdenum boride, Molybdenum(III) chloride, Molybdenum(IV) oxide, Molybdenum(VI) oxide, Molybdenum(VI) tetrachloride oxide, Molybdenumhexacarbonyl, Molybdic acid, Potassium

molybdate, Silicomolybdic acid hydrate, Sodium molybdate, Sodium

phosphomolybdate hydrate, Triamminemolybdenum(O) tricarbonyl,

Tris(triphenylsilyloxy)molybdenum nitride pyridine complex, [1,1'- Bis(diphenylphosphino)ferrocene]tetracarbonylmolybdenum(0).

Iron catalysts

Ammonium iron(II) sulfate hexahydrate, Ammonium iron(III) sulfate

dodecahydrate, Benzenecyclopentadienyliron(II) hexafluorophosphate,

Cyclopentadienyl iron(II) dicarbonyl dimer,

Dicarbonylcyclopentadienyliodoiron(II), Diironnonacarbonyl, Disodium

tetracarbonylferrate dioxane complex, Ferric chloride, Ferrocene, Ferrocenium hexafluorophosphate, Ferrocenium tetrafluoroborate, Iron powder, Iron foil, Iron wire, lron(0) pentacarbonyl, Iron(II) bromide, Iron(II) chloride, Iron(II) ethylenediammonium sulfate tetrahydrate, Iron(II) fluoride tetrahydrate, Iron(II) lactate hydrate, Iron(II) sulfate, Iron(II) trifluoromethanesulfonate, Iron(III) acetylacetonate, Iron(III) bromide, Iron(III) chloride, Iron(III) nitrate

nonahydrate, Iron(III) p-toluenesulfonate hexahydrate, Iron(III) sulfate hydrate, Iron(III) trifluoromethanesulfonate, Potassium ferrate(VI), Potassium

hexacyanoferrate(II) trihydrate, Sodium hexafluoroferrate(III), Tricarbonyl(2- methoxycyclohexadienylium) iron hexafluorophosphate,

Tricarbonyl(cyclooctatetraene)iron(II), [FeCI₂bis(dpbz)].

The use of phosphine ligands is necessary for nearly all homogeneous catalysis with metal catalysts. The choice of the right ligand can influence

• the solubility of the active species

• the shielding and sterical properties of the catalyst

• the electron-density at the metal atom

· the reactivity of the catalyst in the catalytic cycle

• the lifetime and turnover-numbers of the catalyst

• the enantioselectivity of the reaction (with chiral ligands)

A bulkier phosphine ligand (with large cone-angle) tends to have a higher dissociation rate than smaller ligands and electron-rich metal-centers tend to accelerate the "oxidative addition", a key-step in the catalytic cycle.

Preferred monodentate phosphine ligands of the present invention are of the type: PR^R³ where R¹, R² and R³ are independently of one another being selected from hydrogen, alkyl, cycloalkyl, acyl, aryl, heteroaryl, ferrocenyl and heteroatom. Wherein R¹, R² and R³ individually or in conjunction are optionally linked to R¹, R² and/or R³ with a bridge member Y_n, thereby forming one or more rings;

Y_n being a bond or a CI -12 alkyl or an aryl, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)₀-₂ or carbonyl, and wherein n is an integer between 1 and 12.

The phosphine atom may come as its corresponding phosphonium chloride, bromide, iodide, tetrafluoroborate, hexafluorophosphate or carboxylate salt precursors. Preferred bidentate phosphine ligands of the present invention are of the type:

^R1-- _PI ^L - _P2 ^R3

R² R⁴

wherein R¹, R², R³ and R⁴ are independently of one another being selected from hydrogen, alkyl, cycloalkyl, acyl, aryl, heteroaryl, ferrocenyl and heteroatom. wherein R¹, R², R³ and R⁴ individually or in conjunction are optionally linked to R¹, R²' R³ and/or R⁴ with a bridge member Y_n, thereby forming one or more rings; Y_n being a bond or a Cl-12 alkyl or an aryl, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1-3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyi comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(0)o-2 or carbonyl, and wherein n is an integer between 1 and 12; where P¹ and P² are linked with a bridge member L;

L being a bond or a CI -12 alkyl or an aryl, a carbocyclic, a heterocyclic, a ferrocenyl or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyi comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)₀-₂ or carbonyl, and wherein n is an integer between 1 and 12.

The phosphine/phosphines atom/atoms may come as its/their corresponding phosphonium chloride, bromide, iodide, tetrafluoroborate, hexafluorophosphate or carboxylate salt precursors.

Other preferred bidentate nitrogen-nitrogen ligands are of the type:

wherein R¹, R², R³ and R⁴ are independently of one another being selected from hydrogen, alkyl, cycloalkyl, acyl, aryl, heteroaryl, ferrocenyl and heteroatom. wherein R¹, R², R³ and/or R⁴ individually or in conjunction are optionally linked to R¹, R², R³ and/or R⁴ with a bridge member Y_n, thereby forming one or more rings; Y_n being a bond or a CI -12 alkyl or an aryl, a carbocyclic, a heterocyclic or a heteroaromatic structure having 1 -3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyi comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)₀-₂ or carbonyl, and wherein n is an integer between 1 and 12; where N¹ and N² are linked with a bridge member L; L being a bond or a CI -12 alkyl or an aryl, a carbocyclic, a heterocyclic, a ferrocenyl or a heteroaromatic structure having 1-3 rings, 3-8 ring members in each and 0 to 4 heteroatoms, or a heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, O, S(O)₀-₂ or carbonyl, and wherein n is an integer between 1 and 12.

A non-limiting list of such ligand types are:

Monodentate phosphine/phosphonium liqands:

triphenylphosphine, tri-o-tolylphosphine, tri-furyl-phosphine, tri- cyclohexylphosphine, tri-cyclohexylphosphonium tetrafluoroborate, tert-butyl- diisopropylphosphine, triisopropylphosphine, tributylphosphine,

tributylphosphonium tetrafluoroborate, tri-tert-butyl phosphine, tri-tert- butylphosphonium tetrafluoroborate, Di-tert-butylmethylphosphine, D -tert- butylneopentylphosphine, Di-tert-butylneopentylphosphonium tetrafluoroborate, Di-tert-butylcyclohexylphosphine, diadamantyl-butylphosohine, diadamantyl- benzylphosphine, di-tert-butyl-ferrocenylphosphine, di-tert-butyl- ferrocenylphosphonium tetrafluoroborate, X-Phos, tert-butyl-X-Phos, S-Phos, Ru- Phos, John-Phos, Cyclohexyl-John-Phos, BrettPhos, tert-butyl-BrettPhos,

TrixiePhos, DavePhos, MePhos, Q-Phos, 2-(Di-tert-butyl-phosphino)-l-phenyl-l - pyrrole, 2-(Di-tert-butylphosphino)-l-(2-methoxyphenyl)-l -pyrrole, 2-

(Dicyclohexylphosphino)-l-phenyl-l -pyrrole, 2-(Dicyclohexylphosphino)-l-(2- methoxyphenyl)-l -pyrrole, 2-(Di-tert-butylphosphino)-l-phenylindole, 2- (Dicyclohexylphosphino)-l-phenylindole, Bidentate Phosphine/phosphonium liqands:

bis(diphenylphosphino)methane, l,2-bis-(diphenylphosphino)ethane, 1,3-bis- (diphenylphosphino)propane, l,4-bis-(diphenylphosphino)butane, 1,5-bis- (diphenylphosphino)pentane, l,6-bis-(diphenylphosphino)hexane, 1,1- Bis(diphenylphosphino)ethylene, 2-Bis(dicyclohexylphosphino)ethane, 2- Bis(dicyclohexylphosphino)propane, l,3-Bis(dicyclohexylphosphino)propane bis(tetrafluoroborate),2-Bis(dicyclohexylphosphino)butane, l,3-Bis(di-tert- butylphosphinomethyl)benzene, 1,1 -bis(diphenylphosphino)ferrocene, 1,1 - bis(disopropylphosphino)ferrocene, 1,1 -bis(di-tert-butylphosphino)ferrocene, (Oxydi-2,l-phenylene)bis(diphenylphosphine), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene, 4,6-Bis(diphenylphosphino)phenoxazine, 2,2'-Bis(di-p- tolylphosphino)- l,l'-binaphthyl, Bis(diphenylphosphino)- l, l'-binaphthyl.

Bidentate N,N-liqands:

2,2'-Dipyridyl, 6,6'-Dimethyl-2,2'-dipyndyl, 6-Methyl-2,2'-dipyridyl, 4,4'- Dimethyl-2,2'-dipyridyl, 5,5'-Dimethyl-2,2'-dipyridyl, 2-(2-pyridinyl)quinoline, 3,3'-Bis-isoquinoline, 4-4'-Dimethoxy-2-2'-bipyridine, 4,4'-Di-tert-butyl-2,2'- dipyridyl, 4,4'-Diphenyl-2,2'-dipyridyl, 1, 10-Phenanthroline, 4-Methyl- l,10- phenanthroline, 4,7-Dimethyl- l, 10-phenanthroline, 2,9- dimethyl[ l, 10]phenanthroline, 4,7-Dihydroxy- l, 10-phenanthroline, Ν,Ν,Ν',Ν'- Tetramethylethylenediamine, Ν,Ν,Ν',Ν'- tetramethylethylenediamine

dihydrochloride.

Other relevant classes of ligands are:

NHC-Carbene ligands and precursors thereof, such as:

l,3-Bis-(2,6-diisopropylphenyl)imidazolinium chloride, 1,3-Bis(2,4,6- trimethylphenyl)imidazolinium chloride, 1,3-Di-tert-butylimidazolinium

tetrafluoroborate, 1,3-Diisopropylimidazolium tetrafluoroborate, 1,3-Bis(l- adamantyl)imidazolium tetrafluoroborate.

P-N bidentate ligands such as:

Ken-Phos, (R,S)- V-PINAP, (R,R)-0-PINAP. It is likewise possible to use mixtures of the different types of ligands, or mixtures of ligands within the same class.

Palladium is generally employed as a palladium compound, from which the corresponding catalyst is prepared by addition of ligands. It is likewise possible to employ palladium as a complex having the correct stoichiometric composition of palladium to ligand.

Suitable palladium compounds employed in the presence of the excess of ligand are preferably the following : Tetrakis(triphenylphosphine)palladium(0), dibenzylidenepalladium(O) complexes, palladium on carbon (preferably 5%), PdCI₂dppf, palladium acetate/tri-O-tolylphosphine complex, Pd(0)(P(tBu)₃)₂, Pd(0)(tri-O-tolylphosohine)₂, Pd(0)*dppe, Pd(0)*dppp, Pd(0)*dppm, Pd(COD)CI₂, PdCI₂, PdCI₂(MeCN)₂, PdCI₂(PhCN)₂, Pd(OAc)₂ and PdBr₂. In the events where a base is included either as a mandatory or as an optional constituent, such a base is preferably selected from alkali or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, and calcium hydroxide, alkali or alkaline earth metal carbonates, alkali or alkaline earth metal bicarbonates, alkali or alkaline earth metal phosphates, alkali or alkaline earth metal pyrophosphates, ammonia, and organic amines, such as primary, secondary, and tertiary amines, e.g., methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, and anilines, such as aniline, methylaniline and dimethylaniline. Preferably, the one or more bases are tertiary amines, such as DIPEA, TEA, and Cy₂NMe (N,N-dicyclohexylmethylamine). In a preferred embodiment, the one or more bases are on solid form at room temperature to ease the handling of the carbonylation system, such as DABCO (l,4-diazabicyclo[2.2.2]octane) and HMTA (hexamethylenetetramine).

It should be noted that embodiments and features described in the context of one of the aspects of the present invention also apply to the other aspects of the invention.

All patent and non-patent references cited in the present application, are hereby incorporated by reference in their entirety.

The invention will now be described in further details in the following non-limiting examples.

Examples

Cyclotron production of [ⁿC]carbon monoxide and its incorporation in Palladium catalysed [ⁿC]carbonylation reactions

[ⁿC]Carbon dioxide was produced by the ¹⁴N(p, a)ⁿC nuclear reaction using a nitrogen gas target (containing 1% oxygen) pressurized at 150 psi and bombarded with 16MeV protons using the General Electric Medical Systems PETtrace 200 cyclotron. Typically, the irradiation time was 30 minutes using a 40μΑ beam current. After irradiation [ⁿC]carbon dioxide was trapped and concentrated on 5A molecular sieves (from Alltech) in a stream of Helium

(30ml/min). [ⁿC]C0₂ was then released from the trap by heating it at 350°C and was then reduced on-line to [ⁿC]carbon monoxide after passing through a quartz tube filled with molybdenum wire (Strem chemicals) heated at 800°C.

[ⁿC]Carbon monoxide was then transferred with a flow of Helium (30 mL/min) into chamber 2 of our reaction 2-chamber system cooled at -196°C (liquid nitrogen) and trapped on molecular sieves. After 10 min of delivery, a

radioactivity maximum was reached. The inlet and outlet tubings or needles were then closed and the reaction 2-chamber system was heated at 120°C for 10 min in order for the carbonylation reaction to occur. After cooling of the reaction vial, the excess of unreacted [ⁿC]CO was flushed out before measurement of the radioactivity of the crude product. A small aliquot was taken for analysis on an analytical radio HPLC.

Analytical HPLC was performed using a Dionex system (Summit HPLC system), equipped with a Dionex HPLC pump (Model P680A LPG) with a 20 μΙ injection loop connected in series with an analytical HPLC column, a variable Dionex UV detector (UVD 170U) and a sodium iodide radiodetector of in-house design.

The desired radioactive product was identified by co-injection with a nonradioactive reference.

The given yields of the products are based on the final radioactivity measured in the reaction vial at EOS (End Of Synthesis).

Synthesis of [ⁿC]Phthalide:

Preparation of a stock-solution :

In a glovebox under an argon atmosphere, 2-bromobenzyl alcohol (93.5 mg, 0.5 mmol), tetrakis(triphenylphosphine)palladium(0) (57.8 mg, 0.05 mmol) and TEA (140 μΙ, 1.0 mmol) were added to a 8 mL vial and dissolved in 5 mL dioxane. Reaction 1 :

In the glovebox, 250 μΙ of the stock solution was transferred to the vial called chamber 2 of our two-chambers system and 250 μΙ of dioxane was added. Then a vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 178 MBq of crude product was isolated after flushing of the 2- chamber system. Analytical HPLC was run on an aliquot of the crude

(Phenomenex Luna 5μ C18(2) 100A, 150x4.6 mm 5 micron, 30%

Acetonitrile:70% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired [ⁿC]phthalide was 98.3% radiochemically pure.

Reaction 2:

In the glovebox, 100 μΙ of the stock solution was transferred to the vial called chamber 2 of our two-chambers system and 400 μΙ of dioxane was added. Then a vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 453 MBq of crude product was isolated after flushing of the 2- chamber system. Analytical HPLC was run on an aliquot of the crude

(Phenomenex Luna 5μ C18(2) 100A, 150x4.6 mm 5 micron, 30%

Acetonitrile:70% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired [ⁿC]phthalide was 96% radiochemically pure.

Reaction 3:

In the glovebox, 100 μΙ of the stock solution was transferred to the vial called chamber 2 of our two-chambers system and 400 μΙ of dioxane was added. Then a vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 735 MBq of crude product was isolated after flushing of the 2- chamber system. Analytical HPLC was run on an aliquot of the crude

(Phenomenex Luna 5μ C18(2) 100A, 150x4.6 mm 5 micron, 30%

Acetonitrile:70% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired [ⁿC]phthalide was 92% radiochemically pure.

Synthesis of [ⁿC]Raclopride:

Preparation of a stock-solution : In a glovebox under an argon atmosphere, 2-bromo-4,6-dichloro-3- methoxyphenol (134 mg, 500 μηιοΙ), Pd(dba)2 (28.8 mg, 50 μηιοΙ), Xantphos (28.9 mg, 50 μηιοΙ) and sodium acetate (164 mg, 2.0 mmol) were added to a 8 ml_ vial and dissolved in 5 ml_ dioxane. The mixture was stirred 5 min at room temperature then acetic acid (85.1 μΙ_, 1.5 mmol) and (S)-(-)-2-aminomethyl-l- ethylpyrrolidine (139.5 μΙ_, 1.0 mmol) were added. The mixture was stirred another 5 min at room temperature.

Reaction 4:

In the glovebox, 500 μΙ of the stock solution was transferred to the vial called chamber 2 of our two-chambers system. Then a vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 671 MBq of crude product was isolated after flushing of the 2-chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 5μ C18 100A, 250x4.6 mm 5 micron, 35% Acetonitrile 65% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired

[ⁿC]raclopride was 7% radiochemical^ pure.

Reaction 5:

In the glovebox, 500 μΙ of the stock solution was transferred to the vial called chamber 2 of our 2-chamber system. Then an injection vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 307 MBq of crude product was isolated after flushing of the 2-chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 5μ C18 100A, 250x4.6 mm 5 micron, 35% Acetonitrile 65% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired

[ⁿC]raclopride was 11% radiochemically pure.

Reaction 6:

In the glovebox, 500 μΙ of the stock solution was transferred to the vial called chamber 2 of our 2-chamber system. Then an injection vial with the 5A MS (750 mg) was installed in the chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol. 345 MBq of crude product was isolated after flushing of the 2-chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 5μ C18 100A,

250x4.6 mm 5 micron, 35% Acetonitrile 65% NaH₂P0₄ 70mM, 2 mL/min). The HPLC chromatogram from the radio-channel showed that the desired

[ⁿC]raclopride was 8% radiochemically pure.

Synthesis of [ⁿC] V-(2-(Diethylamino)ethyl)nicotinamide:

Preparation of a stock-solution :

In a glovebox under an argon atmosphere, 5-iodopyridine (103 mg, 500 pmol), Pd(dba)₂ (14.4 mg, 25 pmol) and triphenylphosphine (13.1 mg, 50 pmol) was dissolved in 5 mL dioxane in an 8 mL vial, followed by addition of N^N¹- diethylethane-l,2-diamine (141 pL, 1.0 mmol) and triethylamine (139 pL, 1.0 mmol). The stock solution was stirred 5 min at room temperature to ensure homogeneity.

Reaction 7:

In the glovebox, 100 pL of the stock solution and 400 pL of dioxane were transferred to the vial called chamber 2 of our two-chamber system. Then a vial with the 5A MS (750 mg) was installed in chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol with an added precooling to -196°C of the [ⁿC]Carbon monoxide/Helium gas mixture. 738 MBq of crude product was isolated after flushing of the two- chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 3p CN 100A column, 150x3.0 mm 3 micron, 25% Acetonitrile 75% NaH₂P0₄ 70mM, 0.5 mL/min). The HPLC chromatogram from the radio- channel showed that the desired [ⁿC] V-(2-(diethylamino)ethyl)nicotinamide was 74% radiochemically pure.

Reaction 8:

In the glovebox, 150 pL of the stock solution and 600 pL of dioxane were transferred to the vial called chamber 2 of our two-chamber system. Then a vial with the 5A MS (750 mg) was installed in chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol with an added precooling to -196°C of the [ⁿC]Carbon monoxide/Helium gas mixture. 238 MBq of crude product was isolated after flushing of the two- chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 3μ CN 100A column, 150x3.0 mm 3 micron, 25% Acetonitrile 75% NaH₂P0₄ 70mM, 0.5 mL/min). The HPLC chromatogram from the radio- channel showed that the desired [ⁿC] V-(2-(diethylamino)ethyl)nicotinamide was 80% radiochemically pure.

Reaction 9:

In the glovebox, 150 μί of the stock solution and 600 μί of dioxane were transferred to the vial called chamber 2 of our two-chamber system. Then a vial with the 5A MS (750 mg) was installed in chamber 2 and the system was sealed with a crimp-cap (Aluminium Cap 20mm, silicone/PTFE). Palladium catalysed [ⁿC]carbonylation reactions was then run following the previous described protocol with an added precooling to -196°C of the [ⁿC]Carbon monoxide/Helium gas mixture. 303 MBq of crude product was isolated after flushing of the two- chamber system. Analytical HPLC was run on an aliquot of the crude (Phenomenex Luna 3μ CN 100A column, 150x3.0 mm 3 micron, 25% Acetonitrile 75% NaH₂P0₄ 70mM, 0.5 mL/min). The HPLC chromatogram from the radio- channel showed that the desired [ⁿC] V-(2-(diethylamino)ethyl)nicotinamide was 71% radiochemically pure.

Claims

1. A carbonylation system comprising

- an enclosure sealed from the surrounding atmosphere, the enclosure comprising

- at least one solid support arranged for ⁿCO being sorped thereto, and

- at least one carbon monoxide consuming chamber comprising

carbonylation reagents, wherein said at least one carbon monoxide consuming chamber is arranged for performing carbonylation reactions in a gas-diffusion process between ⁿCO from the solid support and said carbonylation reagents to form a reaction product, wherein the solid support is arranged within the enclosure so as to allow an external application of heat to warm up the solid support in order to free ⁿCO therefrom and drive the ⁿCO into contact with the carbonylation reagents by means of diffusion.

2. A carbonylation system according to claim 1, with the proviso that said carbonylation system does not comprise a liquid pump.

3. A carbonylation system according to any one of claims 1-2, wherein the enclosure is arranged for providing an inlet and an outlet to allow a flow of a gas to pass the solid support in order to allow ⁿCO contained in the gas to be sorped to the solid support.

4. A carbonylation system according to any one of claims 1-3, wherein the enclosure is arranged for providing a reaction product outlet to allow removal of the reaction product from the carbon monoxide consuming chamber.

5. A carbonylation system according to any one of claims 3-4, wherein a boundary of a part of the enclosure is formed by a barrier arranged for penetration of a needle so as to provide said inlet or outlets.

6. A carbonylation system according to any one of claims 1-5, wherein the pressure within the enclosure is within the range of 1-10 atm during

carbonylation.

7. A carbonylation system according to any one of claims 1-6, wherein the carbonylation reagents are encapsulated with one or more solvents having a melting point as measured with a differential scanning calorimeter (DSC) within the range of -75-100 degrees Celsius.

8. A carbonylation system according to any one of the claims 1-7, wherein the at least one carbon monoxide consuming chamber further comprises one or more catalysts.

9. A carbonylation system according to any one of the claims 1-8, wherein the at least one carbon monoxide consuming chamber comprises a reaction mixture of carbonylation reagents suitable for the reaction selected from the group consisting of hydroformylation, reductive carbonylation, Fischer-Tropsch synthesis, aminomethylation, homologation of carboxylic acid, CO hydrogenation,

homologation of alcohols, silylformylation, hydrocarboxylation, hydroesterification, CO copolymerization with olefins, CO terpolymerization with olefins, Reppe carbonylation, oxidative carbonylations of olefins, Pauson-Khand reaction, carbonylative cycloadditions, cyclo-carbonylations, alkoxycarbonylation, aminocarbonylation, carbonylative lactonization, carbonylative lactamization, hydroxycarbonylation, thiocarbamoylation, thiocarbonylation, amidocarbonylation, oxidative bisoxycarbonylation, oxidative carbonylation of alcohols, oxidative alkoxycarbonylation, oxidative aminocarbonylation, oxidative carbonylation of amines, carbonylative annulations, CO complexation by a metal, acyl-metal complexes generation, acid fluoride synthesis, carbonylation of alcohols, carbonylation of esters, carbonylation of aziridines, carbonylation of aldehydes, carbonylation of epoxides, carbonylation of amines, carbonylative Heck - Mizoroki reaction, carbonylative Suzuki - Miyaura coupling reaction, carbonylative Stille coupling reaction, carbonylative Sonogashira coupling reaction, carbonylative cross-couplings, carbonylative cross coupling reaction with organometallic reagents, CO reduction, CO oxidation, water-gas shift reaction, ring opening carbonylation, ring opening carbonylative polymerization, ring expansion carbonylation, radical carbonylations, carbonylation of organometallic reagents, carbonylation of organolithium reagents, carbonylation of organomagnesium reagents, carbonylation of organoboranes, carbonylation of organomercurials, and carbonylation of organopalladium compounds.

10. A carbonylation system according to any one of claims 1-9, wherein the solid support has a specific surface area of at least 1 m²/g, measured by BET surface area technique.

11. A carbonylation system according to any one of claims 1-10, wherein the solid support is selected from the group consisting of molecular sieve, silica, active charcoal, palladium on charcoal 5%, palladium on charcoal 10%, Pd(OH)₂ on charcoal, celites, zeolites, GC packaging materials, such as carbospheres, and metal-organic frameworks (MOFs).

12. A carbonylation system according to any one of claims 1-11, wherein the solid support comprises molecular sieves with a pore size in the range of 1-15 angstrom.

13. A carbonylation system according to any one of the claims 1-12, wherein the enclosure is constituted by an element forming the carbon monoxide consuming chamber and a carbon monoxide releasing chamber containing the at least one solid support, wherein said chambers are operationally connected by a passage allowing diffusion of ⁿCO from the carbon monoxide releasing chamber to the carbon monoxide consuming chamber.

14. A carbonylation system according to any one of claims 1-12, wherein the enclosure is constituted by an element forming the carbon monoxide consuming chamber, and wherein the solid support is arranged within the carbon monoxide consuming chamber.

15. A carbonylation system according to any one of claims 1-14, for use in carbon-isotope labelling.