WO2012079583A1

WO2012079583A1 - System providing controlled delivery of gaseous co for carbonylation reactions

Info

Publication number: WO2012079583A1
Application number: PCT/DK2011/050480
Authority: WO
Inventors: Troels Skrydstrup; Anders Thyboe Lindhardt; Philippe Hermange; Rolf Hejle Taaning; Stig Düring FRIIS
Original assignee: Aarhus Universitet
Priority date: 2010-12-15
Filing date: 2011-12-14
Publication date: 2012-06-21

Abstract

A carbonylation system comprising at least one carbon monoxide producing chamber and at least one carbon monoxide consuming chamber forming an interconnected multi-chamber system, said interconnection allowing carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber, said at least one carbon monoxide producing chamber containing a reaction mixture comprising a carbon monoxide precursor and a catalyst, said at least one carbon monoxide consuming chamber being suitable for carbonylation reactions, said interconnected multi- chamber system being sealable from the surrounding atmosphere during carbonylation.

Description

System providing controlled delivery of gaseous CO for carbonylation reactions

Technical field of the invention

The present invention relates to carbonylation reactions. In particular the present invention relates to a system providing controlled delivery of gaseous CO for carbonylation reactions.

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.

The synthetic industries also take advantage of CO as a cost efficient CI building block, transforming alkenyles into aldehydes, carboxylic acid derivatives or alcohols by way of carbonylation reactions. Furthermore, these industrial processes are performed on bulk scale, thus providing straightforward access to valuable intermediates in polymer synthesis and other consumables.

The majority of the work published on palladium catalyzed carbonylations, require CO at elevated pressures and reactions performed at pressures of 30-50 bars is not uncommon. The high pressure is required to overcome the low solubility of CO in almost any organic or inorganic solvent. However, lately several pioneering protocols developed by the groups of Buchwald, Beller, Hartwig and others have provided the possibility to perform carbonylations at near atmospheric pressure using only a syringe connected balloon as CO-reservoir for the reaction or autoclaves pressurized in the range of 2-5 bar.

Despite the advantages of CO gas as a reagent, its everyday use is compromised by the obvious safety reasons. CO is a highly toxic gas excluding oxygen from binding to haemoglobin in the blood stream leading to asphyxiation. Furthermore, CO is invisible, odourless and tasteless and side effects of CO only appear at late stage exposure. This in turn requires that CO is handled with extreme caution, including storage and transport, and its use is often accompanied with CO detectors and other specialized high-pressure equipment.

In order to overcome the dangers involved using CO gas, Larhed and others (Morimoto, T. ; KakiuChi, K. ; Angew. Chem. Int. Ed. 2004, 43, 5580-5588). have developed CO-equivalents that allow in situ carbonyl transfer to afford safe alternatives to a pressurized CO-bottle. These equivalents include in situ CO- release from alkyl formate, formamides, formic anhydride, chloroform, aldehydes etc. which generally require the presence of a transition metal catalyst and strong base in combination with high temperatures (> 100 °C) to release or activate the CO equivalent. Although interesting, compatibility issues between the CO- producing and CO-consuming reaction severely limits the degree of overall molecular complexity.

Another approach to overcome the dangers involved using CO gas, is to trap carbondioxide using a suited nucleophile, typically organolithium, organozinc or Grignard reagents, and subsequently transforming the formed acid into the desired product. The latter method compromises the functional group tolerance of the system due to the presence of highly basic or nucleophilic reagents and requires the carbonyl moiety to be installed early in the synthesis.

The search for alternatives to CO-gas from a pressurized bottle is further of great importance since they address another subject often disregarded in carbonylative chemistry, namely stoichiometricy. Traditionally this subject has not been discussed, probably due to the relatively low price of CO from a pressurized bottle compared to the synthetic cost of the additional reagents. It is though surprising that the only field actually operating with sub-stoichiometric loadings of CO on all reactions is within positron emission tomography (PET). One obvious problem emerge when a sub-stoichiometric amount of CO is to be applied in carbonylation chemistry; how to quantify and deliver an exact amount of CO with high efficiency? A general strategy with a broad range of functional group tolerance is still needed. Furthermore, only few of the already existing CO- equivalents are actually suitable for efficient isotope labelling, due to their synthesis and CO-releasing capabilities.

Hence, an improved system for carbonylation reactions would be advantageous, and in particular a more efficient and controllable system would be advantageous.

Summary of the invention

An object of the present invention relates to the application of CO as the limiting reagent or applied in slight excess in carbonylation reactions. For this purpose, a new highly efficient decarbonylative protocol was developed so as to release carbon monoxide from a CO precursor ex situ from the CO consuming reaction. The combination of the CO producing reaction with a CO consuming reaction in an isolated multichamber-chamber system afforded high capture of the CO

generated.

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 at least one carbon monoxide producing chamber and at least one carbon monoxide consuming chamber forming an interconnected multi-chamber system, said interconnection allowing carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber, said at least one carbon monoxide producing chamber containing a reaction mixture comprising a carbon monoxide precursor and a catalyst, said at least one carbon monoxide consuming chamber being suitable for carbonylation reactions, said interconnected multi-chamber system being sealable from the surrounding atmosphere during carbonylation. Brief description of the figures

Figure 1 show examples of a carbonylation system where one chamber is situated within the other,

Figure 2 shows examples of a carbonylation system where one chamber is alligned with the other,

Figure 3 shows an example of a carbonylation system with six chambers,

Figure 4 shows the conversion of pivaloyl chloride with 5 mol% of Pd(dba)₂/P^tBu₃ over time compared to an internal standard; figure 4A shows NMR spectra taken at 0, 15, 30, 60, 105 and 165 min for the decarbonylation of pivaloyl chloride versus an internal standard ; figure 4B shows a schematic representation of the Η NMR, and figure 4C shows a schematic representation of a rough gas-volumetric study, and

Figure 5 shows a schematic representation of different gas-volumetric studies of the course of decarbonylation of pivaloyl chloride under different reaction conditions,

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

The carbonylation system

An object of the present invention relates to the application of CO as the limiting reagent or applied in slight excess in carbonylation reactions. For this purpose, a new highly efficient decarbonylative protocol was developed so as to release carbon monoxide from a CO precursor ex situ from the CO consuming reaction. The combination of the CO producing reaction with a CO consuming reaction in an isolated multichamber system afforded high capture of the CO generated. The at least one carbon monoxide producing chamber is wherein the carbon monoxide is produced, and the at least one carbon monoxide consuming chamber is wherein the carbon monoxide is consumed. The carbon monoxide producing chamber and the carbon monoxide consuming chamber are connected in a manner as to allow only the produced carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber without contamination of the individual reactions in the individual chambers. The figures 1-3 show non- limiting examples of such multichamber systems.

Hence, one aspect of the invention relates to a carbonylation system comprising at least one carbon monoxide producing chamber and at least one carbon monoxide consuming chamber forming an interconnected multi-chamber system, said interconnection allowing carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber, said at least one carbon monoxide producing chamber containing a reaction mixture comprising a carbon monoxide precursor and a catalyst, said at least one carbon monoxide consuming chamber being suitable for carbonylation reactions, said interconnected multi-chamber system being sealable from the surrounding atmosphere during carbonylation.

Figures la and lb show an example wherein the carbon monoxide producing chamber (1) is situated within the carbon monoxide consuming chamber (2). This could easily be the other way around, such that the carbon monoxide consuming chamber (2) is situated within the carbon monoxide producing chamber (1).

In one embodiment of the present invention, the carbon monoxide producing chamber (1) is situated within the carbon monoxide consuming chamber (2).

In another embodiment of the present invention, the carbon monoxide consuming chamber (2) is situated within the carbon monoxide producing chamber (1). The multi-chamber system is sealable from the surrounding atmosphere during carbonylation. In one embodiment, and as shown in figures 1 and 2, this may be done by a cap or plug (3). In another embodiment, to avoid contamination of the individual reactions in the individual chambers, the system is build with a filter or membrane (4) between the chambers (1) and (2), as 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 another embodiment of the present invention, a transfer tube may be in a center portion of the membrane or filter 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.

In one embodiment of the present invention, the carbon monoxide producing chamber (1) and the carbon monoxide consuming chamber (2) is connected by one or more connecting units (5), as exemplified in figure 2. The connecting unit (5) allows carbon monoxide to pass from the at least one carbon monoxide producing chamber (1) to the at least one carbon monoxide consuming chamber (2). The connecting unit (5) may comprise a filter or membrane (4), as

exemplified in figure 2b. In another embodiment of the present invention, the connecting unit (5) is a filter or membrane.

In yet another embodiment of the present invention, the carbonylation system comprises multiple carbon monoxide producing chambers and/or multiple carbon monoxide consuming chambers, such as in the range of 1-1000 carbon monoxide producing chambers and 1-1000 carbon monoxide consuming chambers, e.g. 500 carbon monoxide producing chambers and 400 carbon monoxide consuming chambers, such as in the range of 2-50 carbon monoxide producing chambers and 1-300 carbon monoxide consuming chambers, e.g. 25 carbon monoxide producing chambers and 150 carbon monoxide consuming chambers, such as in the range of 5-15 carbon monoxide producing chambers and 2-100 carbon monoxide consuming chambers, e.g. 10 carbon monoxide producing chambers and 2 carbon monoxide consuming chambers. An example of a multiple carbon monoxide producing chambers and multiple carbon monoxide consuming chambers is shown in figure 3.

In still another embodiment of the present invention, the carbonylation system comprises multiple carbon monoxide producing chambers and/or multiple carbon monoxide consuming chambers, wherein the carbon monoxide producing chamber (1) is situated within the carbon monoxide consuming chamber (2).

In another embodiment of the present invention, the carbonylation system comprises multiple carbon monoxide producing chambers and/or multiple carbon monoxide consuming chambers, wherein the carbon monoxide consuming chamber (2) is situated within the carbon monoxide producing chamber (1).

Constituents of the carbon monoxide producing chamber

The carbon monoxide precursor

In one embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (I) :

M_n(CO)o Formula I, wherein M is one or more metals selected from the transition metals or mixtures thereof; n is an integer between 1 and 12; o is an integer between 2 and 40 and o being greater than n.

The metal carbonyl, M_x(CO)_y may comprise of transitions elements, Group I, II, III, IV, V, VI; VII or Group VIII metals (M), preferably transition metals, and may be tailored to the nature of the reaction, the reagents and/or any catalyst comprising the reaction mixture. Typically, the metal (M) of said metal carbonyl is selected from the group comprising of Mo, Fe, W, Mn, Cr, and Co or mixtures thereof, preferably Mo, Fe and Cr, most preferably Mo.

The metal carbonyl may exist as a complex of one or more metals complexed with one or more carbon monoxide molecules. Accordingly, in the formula M_x(CO)_y, x may be any integer, depending on the level of the complex. Typically, x is selected from 1 to 10, such as 1 to 6, preferably selected from an integer from 1 to 4, such as 1, 2, 3, and 4.

Similarly, y is an integer whose value depends on the size of the metal carbonyl complex. Typically, y is selected from 2 to 40, such as 2 to 24, preferably selected from an integer from 2 to 12. The integer y is greater than x.

The metal carbonyl may be selected from those known to the person skilled in the art. The metal carbonyl may be selected from the non-limiting group comprising of Mo(CO)₆, W(CO)₆, Fe(CO)₅, Fe₂(CO)₉, Fe₃(CO)i₂, Mn₂(CO)i₀, Cr(CO)₆, Ni(CO)₄ , and Co₂(CO)₈ or derivatives thereof, preferably Mo(CO)₆, W(CO)₆ and Ca(CO)₆, preferably Mo(CO)₆.

Preferably, the metal-carbonyl complex is of low toxicity.

In one embodiment, the metal carbonyl, when exposed to an energy source, affords liberation of carbon monoxide in its gaseous form from said metal carbonyl, into the carbon monoxide producing chamber.

In another embodiment, the metal carbonyl, when exposed to an energy source and a base, affords liberation of carbon monoxide in its gaseous form from said metal carbonyl, into the carbon monoxide producing chamber. Preferably, one equivalent of base liberates one equivalent of carbon monoxide.

In another embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (II) :

HCONF^R² Formula II, wherein R¹, R² are independently of one another being selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, and heteroaryl; R¹ and R², optionally linked 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, S(0)i_₂ or carbonyl, and wherein n is an integer between 1 and 12.

Form a ring means that the atoms mentioned are connected through a bond such that the ring structure is formed. The term "ring" is used synonymously with the term "cyclic".

Alkyl group: the term "alkyl" means a saturated linear, branched or cyclic hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like. Preferred alkyls are lower alkyls, i.e. alkyls having 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. A cyclic alkyl/cycloalkyl means a saturated carbocyclic compound consisting of one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyi, hydroxyalkyi, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, aryl- aminosulfonyl,

alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylamino- carbonyl, alkylcarbonylamino and arylcarbonylamino. The alkyl group may also be understood as a heteroalkyl. A heteroalkyl is a saturated linear, branched or cyclic hydrocarbon group (including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like) wherein one or more carbon atoms are substituted for a heteroatom selected from N, O, S, S(0)i_₂, Si or P and which can optionally be substituted with one or more substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyi, hydroxyalkyi, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or arylcarbonylamino. Heteroalkyls of the present invention may be branched or unbranched or forming a ring and may range from one (1 ) to fifty (50) carbon atoms in length wherin 50% or less, of said carbon atoms may be substituted for N, NH(Q-4), O, S, S(0) i_₂, Si, P, CI, Br. A cyclic heteroalkyl/heterocyclyl means a saturated cyclic compound or part of a compound, consisting of one to more rings, of three to eight atoms per ring, incorporating one, two, three or four ring heteroatoms, selected from N, O or S(0) i-2, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro,

alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, arylaminocarbonyl, alkylcarbonylamino, or arylcarbonylamino. Examples of common heterocyclyls of the present invention include, but are not limited to piperazine and piperidine which may thus be heterocyclyl substituents as defined herin. Such substituents may also be denoted piperazino and piperidino

respectively. A further heterocyclyl of the present invention is thiophene.

If the radical (R) is an alkyl group, in which, in addition, one CH₂ group (alkoxy or oxaalkyl) may be replaced by an O atom, it may be straight-chain or branched. It preferably has 2, 3, 4, 5, 6, 7, 8, 9 or 12 carbon atoms and accordingly is preferably ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, ethoxy, propoxy, butoxy, pentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy, furthermore also undecyl, dodecyl, undecyloxy, dodecyloxy, 2-oxapropyl (=2- methoxymethyl), 2-oxabutyl (=methoxyethyl) or 3-oxabutyl (=2-ethoxymethyl), 2-, 3- or 4-oxapentyl, 2-, 3-, 4- or 5-oxahexyl, or 2-, 3-, 4-, 5- or 6-oxaheptyl. Particular preference is given to hexyl, pentyl, butyl, n-butyl, propyl, i-propyl, methyl and ethyl, in particular propyl and pentyl; particularly preferred alkoxy groups are hexyloxy, pentoxy, n-butoxy, propoxy, i-propoxy, methoxy and ethoxy, in particular ethoxy and n-butoxy.

Preferred branched radicals are isopropyl, 2-butyl (= l-methylpropyl), isobutyl (=3-methylpropyl), tert-butyl, 2-methylbutyl, isopentyl (=3-methylbutyl), 2- methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-ethylhexyl, 5-methylhexyl, 2- propylpentyl, 6-methylheptyl, 7-methyloctyl, isopropoxy, 2-methylpropoxy, 2- methylbutoxy, 3-methylbutoxy, 2-methylpentoxy, 3-methylpentoxy, 2- ethylhexyloxy, 1-methylhexyloxy, 1-methylheptyloxy, 2-oxa-3-methylbutyl and 3- oxa-4-methylpentyl. The radical R may also be an optically active organic radical containing one or more asymmetrical carbon atoms. Halogen preferably represents chlorine, but may also be bromine, fluorine or iodine.

Alkenyl group: the term "alkenyl" means a non-saturated linear, branched or cyclic hydrocarbon group including, for example, methylene or ethylene. Preferred alkenyls are lower alkenyls, i.e. alkenyls having 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5 or 8 carbon atoms. A cyclic alkenyl/cycloalkenyl means a non-saturated carbocyclic compound consisting of one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyi, hydroxyalkyi, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, aryl- aminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylamino- carbonyl, alkylcarbonylamino and arylcarbonylamino. The alkenyl group may also be understood as a heteroalkenyl. A heteroalkenyl is a non-saturated linear, branched or cyclic hydrocarbon group (including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like) wherein one or more carbon atoms are substituted for a heteroatom selected from N, O, S, S(0)i-2, Si or P and which can optionally be substituted with one or more substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyi, hydroxyalkyi, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl,

alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or

arylcarbonylamino. Heteroalkenyls of the present invention may be branched or unbranched or forming a ring and may range from one (1 ) to fifty (50) carbon atoms in length wherein 50% or less, of said carbon atoms may be substituted for N, NH(Q-4), O, S, S(0)i-2, Si, P, CI, Br. A cyclic heteroalkenyl means a non- saturated cyclic compound or part of a compound, consisting of one or more rings, of three to eight atoms per ring, incorporating one, two, three or four ring heteroatoms, selected from N, O or S(0)i_₂, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,

arylsulfonylamino, alkylaminofarbonyl, arylaminocarbonyl, alkylcarbonylamino, or arylcarbonylamino.

Alkynyl group: the term "alkynyl" means a non-saturated linear or branched hydrocarbon group including, for example, ethynyl or propynyl. Preferred alkynyls are lower alkynyls, i.e. alkynyls having 1 to 10 carbon atoms, such as 1, 2, 3, 4, 5 or 9 carbon atoms.

The acyl radical has the formula RCO, where R represents an alkyl group that is attached to the CO group with a single bond. Examples of acyl radicals are alkanoyi, aroyl, lower alkoxycarbonyl, or N,N-di-lower alkylcarbamoyi, preferably lower alkanoyi.

Acyl in acyloxy represents lower alkanoyi, aroyl, lower alkoxycarbonyl, or N,N-di- lower alkylcarbamoyi, preferably lower alkanoyi.

Lower alkanoyi is preferably acetyl, propionyl, butyryl, or pivaloyl, especially acetyl.

Aroyl is preferably benzoyl; and also e.g. benzoyl substituted by one or two of lower alkyl, lower alkoxy, halogen or trifluoromethyl; aroyl is also e.g. thienoyl, pyrroloyl, 2-, 3- or 4-pyridylcarbonyl, advantageously nicotinoyl.

Lower alkanoyloxy is preferably acetoxy; and also e.g. pivaloyloxy or

propionyloxy.

Aroyloxy is preferably benzoyloxy; and also e.g. benzoyloxy substituted on the benzene ring by one or two of lower alkyl, lower alkoxy, halogen or

trifluoromethyl. Heteroaroyloxy is preferably 2-, 3- or 4-pyridylcarbonyloxy, advantageously nicotinoyloxy.

Aryl represents a hydrocarbon comprising at least one aromatic ring, and may contain from 5 to 18, preferably from 6 to 14, more preferably from 6 to 10, and most preferably 6 carbon atoms. Typical aryl groups include phenyl, naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenylenyl, and fluorenyl groups. Particularly preferred aryl groups include phenyl, naphthyl and fluorenyl, with phenyl being most preferable. Hence, aryl represents a carbocyclic or heterocyclic aromatic radical comprising e.g. optionally substituted phenyl, naphthyl, pyridyl, thienyl, indolyl or furyl, preferably phenyl, naphthyl, pyridyl, thienyl, indolyl or furyl, and especially phenyl. Non-limiting examples of substituents are halogen, alkyl, alkenyl, alkoxy, cyano and aryl. A carbocyclic aromatic radical represents preferably phenyl or phenyl substituted by one or two substituents selected from lower alkyl, lower alkoxy, hydroxy, acyloxy, nitro, amino, halogen, trifluoromethyl, cyano, carboxy, carboxy functionalized in form of a pharmceutically acceptable ester or amide, lower alkanoyl, aroyl, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyi and N,N-di- lower alkylsulfamoyi; also 1- or 2-naphthyl, optionally substituted by lower alkyl, lower alkoxy, cyano or halogen.

A heterocyclic aromatic radical represents particularly thienyl, indolyl, pyridyl, furyl; and also e.g. a said heterocyclic radical monosubstituted by lower alkyl, lower alkoxy, cyano or halogen.

Thienyl represents 2- or 3-thienyl, preferably 2-thienyl.

Pyridyl represents 2-, 3- or 4-pyridyl, preferably 3- or 4-pyridyl advantageously 3- pyridyl.

Furyl represents 2- or 3-furyl, preferably 3-furyl.

Indolyl represents preferably 3-indolyl. Heteroaryl means an aromatic cyclic compound or part of a compound having one or more rings, of four to eight atoms per ring, incorporating one, two, three or four heteroatoms (selected from nitrogen, oxygen, or sulfur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl,

alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonlamino and arylcarbonylamino.

Substituted lower alkyl means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol. The term "lower" referred to above and hereinafter in connection with organic radicals or compounds respectively preferably defines such with up to and including 10, preferably up to and including 7 and advantageously one or two carbon atoms. A lower alkyl group preferably contains 1-4 carbon atoms and represents for example ethyl, propyl, butyl or advantageously methyl.

A lower alkenyl group preferably contains 2-4 carbon atoms and represents for example allyl or crotyl.

A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example methoxy, propoxy, isopropoxy or advantageously ethoxy.

In one embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (III) :

Formula (III)

wherein, R¹, R², R³, and R⁴ are independently of one another being selected from hydrogen, alkyl, acyl, aryl, heteroaryl, and heteroatom;

R⁵ being selected from hydrogen or OCOR¹;

R⁶ being selected from halide, OR⁷, OCOR⁷, SR⁷, 0^"M, (OM)⁺ⁿX^"n, N(R⁷)(R⁸), (N(R⁷)(R⁸)(R⁹))⁺X^", P(R⁷)(R⁸), (P(R⁷)(R⁸)(R⁹))⁺X^~, PO(R⁷)(R⁸), OB(OR⁷)(OR⁸), OCSR⁷; R⁸, R⁹ and R⁹ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴, R⁵ , R⁶, R⁷, R⁸ and/or R⁹ individually or in conjunction are optionally linked to R¹, R², R³, R⁴, R⁵ , R⁶, R⁷, R⁸ and/or R⁹ 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.

In one embodiment of the present invention, M is selected from Na⁺, K⁺, Cs⁺, Cu⁺, Ag⁺, Mg²⁺, Ca²⁺, Mn²⁺'³⁺, Fe²⁺'³⁺, Cu²⁺, Ni²⁺, Zn²⁺, Mo⁶⁺, Al³⁺, Si⁴⁺, B³⁺, Ti⁴⁺ and Zr⁴⁺, and n being an integer having a value from 1-10.

In a preferred embodiment of the present invention, R¹ and R² are independently of one another being selected from aryl and heteroaryl, such as e.g. Formula IV or Formula V, wherein individually or in conjunction the aromatic rings are optionally substituted by one or more substituents selected from lower alkyl, lower alkoxy, hydroxy, acyloxy, nitro, amino, halogen, trifluoromethyl, cyano, carboxy, carboxy functionalized in form of a pharmceutically acceptable ester or amide, lower alkanoyl, aroyl, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyi and N,N-di- lower alkylsulfamoyi; also 1- or 2-naphthyl, optionally substituted by lower alkyl, lower alkoxy, cyano or halogen. Formula (IV)

Formula (V)

In another embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (Ilia)

Formula (Ilia)

R⁵ being selected from halide, OR⁶, OCOR⁶, SR⁶, 0^"M, (OM)⁺ⁿX^"n, N(R⁶)(R⁷),

(N(R⁶)(R⁷)(R⁸))⁺X^~, (PR⁶)⁺X^~; R⁶, R⁷ and R⁸ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴, R⁵ , R⁶, R⁷ and/or R⁸ individually or in conjunction are optionally linked to R¹, R², R³, R⁴, R⁵ , R⁶, R⁷ and/or R⁸ 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.

In one embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (VI) : Formula (VI)

wherein, R¹, R², R³, R⁴ and R⁵ are independently of one another being selected from hydrogen, alkyl, acyl, aryl, heteroaryl, and heteroatom;

R⁶ being selected from halide, OR⁷, OCOR⁷, SR⁷, 0^"M, (OM)⁺ⁿX^~n, N(R⁷)(R⁸), (N(R⁷)(R⁸)(R⁹))⁺X^", P(R⁷)(R⁸), (P(R⁷)(R⁸)(R⁹))+X-, PO(R⁷)(R⁸), OB(OR⁷)(OR⁸), OCSR⁷; R⁷, R⁸ and R⁹ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴, R⁵ , R⁶, R⁷, R⁸ and/or R⁹ individually or in conjunction are optionally linked to R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and/or R⁹ 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. In another embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (VII) :

Formula (VII)

wherein, R¹, R² and R³ are independently of one another being selected from hydrogen, alkyl, acyl, aryl, heteroaryl, and heteroatom;

R⁴ being selected from halide, OR⁵, OCOR⁵, SR⁵, 0^"M, (OM)⁺ⁿX^"n, N(R⁵)(R⁶), (N(R⁵)(R⁶)(R⁷))⁺X^", P(R⁵)(R⁶), (P(R⁵)(R⁶)(R⁷))⁺X^~, PO(R⁵)(R⁶), OB(OR⁵)(OR⁶), OCSR⁵; R⁵, R⁶ and R⁷ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl; M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴, R⁵ , R⁶ and/or R⁷ individually or in conjunction are optionally linked to R¹, R², R³, R⁴, R⁵ , R⁶ and/or R⁷ with a bridge member Y_n, thereby forming one or more rings;

In yet another embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (VIII) :

Formula (VIII) wherein, R¹ is selected from hydrogen, alkyl, acyl, aryl, heteroaryl, and

heteroatom;

R² being selected from halide, OR³, OCOR³, SR³, 0^"M, (OM)⁺ⁿX^"n, N(R³)(R⁴), (N(R³)(R⁴)(R⁵))⁺X^", P(R³)(R⁴), (P(R³)(R⁴)(R⁵))⁺X^~, PO(R³)(R⁴), OB(OR³)(OR⁴),

OCSR³; R³, R⁴ and R⁵ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴ and/or R⁵ individually or in conjunction are optionally linked to R¹, R², R³, R⁴ and/or R⁵ 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. In one embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (IX) :

Formula (IX)

wherein, R¹, R², R³, and R⁴ are independently of one another being selected from alkyl, acyl, aryl, heteroaryl, and heteroatom;

R⁶ being selected from halide, OR⁷, OCOR⁷, SR⁷, 0^"M, (OM)⁺ⁿX^"n, N(R⁷)(R⁸), (N(R⁷)(R⁸)(R⁹))⁺X^", P(R⁷)(R⁸), (P(R⁷)(R⁸)(R⁹))⁺X^~, PO(R⁷)(R⁸), OB(OR⁷)(OR⁸), OCSR⁷; R⁷, R⁸ and R⁹ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², and/or R⁶ individually or in conjunction are optionally linked to R¹, R², and/or R⁶ with a bridge member Y_n, thereby forming one or more rings;

In one embodiment of the present invention, M is selected from Na⁺, K⁺, Cs⁺, Cu⁺, Ag⁺, Mg²⁺, Ca²⁺, Mn²⁺'³⁺, Fe²⁺'³⁺, Cu²⁺, Ni²⁺, Zn²⁺, Mo⁶⁺, Al³⁺, Si⁴⁺, B³⁺, Ti⁴⁺ and Zr⁴⁺, and n being an integer having a value from 1-10. In a preferred embodiment of the present invention, R¹ and R² are independently of one another being selected from aryl and heteroaryl.

In a preferred embodiment of the present invention, the residue of the CO precursor not being CO should not be volatile.

In another embodiment of the present invention, the carbonylation system comprises a carbon monoxide precursor of formula (X) Formula (X)

wherein, Z are being selected from Si, Ge, and Sn.

R¹, R², and R³ are independently of one another being selected from hydrogen, alkyl, acyl, aryl, heteroaryl, alkoxy and heteroatom;

R⁴ being selected from halide, heteroaryl, OR⁵, OCOR⁵, SR⁵, SCSR⁵, OCSR⁵, 0^"M, (OM)⁺ⁿX^"n, N(R⁵)(R⁶), (N(R⁵)(R⁶)(R⁷))⁺X^~, P(R⁵)(R⁶), (P(R⁵)(R⁶)(R⁷))⁺X^~,

PO(R⁵)(R⁶), OB(OR⁵)(OR⁶); R⁵, R⁶ and R⁷ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

wherein R¹, R², R³, R⁴, R⁵ , R⁶, and/or R⁷ individually or in conjunction are optionally linked to R¹, R², R³, R⁴, R⁵ , R⁶, and/or R⁷ 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 catalyst

In one embodiment of the present invention, the catalyst in the at least one carbon monoxide producing 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 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-ter^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( V-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[2.2.1]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-21H,23H- 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(n⁶-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- cymene)ruthenium(II) dimer, Hexaammineruthenium(II) chloride,

Pentaamminechlororuthenium(III) chloride,

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

Pentamethylcyclopentadienyltris (acetonitrile)ruthenium(II) hexafluorophosphate, 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,

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- 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,

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),

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) 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. l]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, Iron(O) 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 R²R³ 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:

^R^p1 ^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 heteroalkyl comprising 1 to 12 heteroatoms selected from the group consisting of N, 0, S(O)₀-2 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 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/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:

R N N^2R3

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/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 heteroalkyl 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 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 ligands:

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

tributylphosphonium tetrafluoroborate, tri-tert-butyl phosphine, tri-teri- butylphosphonium tetrafluoroborate, Di-tert-butylmethylphosphine, Di-tert- butylneopentylphosphine, Di-te/t-butylneopentylphosphonium tetrafluoroborate, Di-tert-butylcyclohexylphosphine, diadamantyl-butylphosohine, diadamantyl- benzylphosphine, di-tert-butyl-ferrocenylphosphine, di-tert-butyl- ferrocenylphosphonium tetrafluoroborate, X-Phos, te/t-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'-dipyndyl, 2-(2-pyridinyl)quinoline, 3,3'-Bis-isoquinoline, 4-4'-Dimethoxy-2-2'-bipyndine, 4,4'-Di-tert-butyl-2,2'- dipyridyl, 4,4'-Diphenyl-2,2'-dipyndyl, 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 liqands 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 liqands 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). In one embodiment of the present invention, the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more bases selected from the group consisting of inorganic bases and organic bases or mixtures thereof.

In one embodiment of the present invention, the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more solvents.

The term "solvent" refers to a liquid, solid, or gas that dissolves another solid, liquid, or gaseous solute, resulting in a solution wherein the solute is soluble in a certain volume of the solvent at a specified temperature.

In another embodiment of the present invention, the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more non-polar organic solvents. The non-polar organic solvent may also be made up of two or more non-polar organic solvents, i.e. being a mixture of such solvents.

In one embodiment, the non-polar organic solvent is hexane. In another embodiment the non-polar organic solvent is selected from the group consisting of benzene, toluene, dioxane, and xylene.

In one embodiment of the invention, the non-polar organic solvent is both non- polar and aprotic, e.g. the non-polar organic solvent has a dielectric constant of less than 15 and a pKa of 5 or more, such as a dielectric constant of less than 15 and a pKa of 6 or more, such as a dielectric constant of less than 15 and a pKa of 7 or more, such as a dielectric constant of less than 15 and a pKa of 8 or more, such as a dielectric constant of less than 15 and a pKa of 10 or more, such as a dielectric constant of less than 10 and a pKa of 5 or more, such as a dielectric constant of less than 10 and a pKa of 6 or more, such as a dielectric constant of less than 10 and a pKa of 7 or more, such as a dielectric constant of less than 10 and a pKa of 8 or more, such as a dielectric constant of less than 10 and a pKa of 10 or more, such as a dielectric constant of less than 5 and a pKa of 5 or more, such as a dielectric constant of less than 5 and a pKa of 6 or more, such as a dielectric constant of less than 5 and a pKa of 7 or more, such as a dielectric constant of less than 5 and a pKa of 8 or more, such as a dielectric constant of less than 5 and a pKa of 10 or more. Examples of non-polar, aprotic solvents in accordance with the invention are hexane, benzene, toluene, diethyl ether, chloroform and ethyl acetate. In still another embodiment the non-polar aprotic organic solvent is selected from the group consisting of 2-methylbutane, n-hexane, 2,3-dimethylbutane, n- heptane, 2-methylhexane, 2,2,3-trimethylbutane, n-octane, 2,4-dimethylhexane, 2,2,4-trimethylpentane, 2-methyloctane, 3-methyloctane, 2,6-dimethylheptane, 2,7-dimethyloctane, n-hexadecane, 7,8-dimethyltetradecane, cyclopentane, methylcyclopentane, ethylcyclopentane, isopropylcyclopentane, n- butylcyclopentane, n-hexylcyclopentane, 2-cyclopenyloctane, 1,4- dicyclopentylbutane, cyclohexane, decalin, benzene, toluene, ethylbenzene, m- xylene, isopropylbenzene, 1,3,5-trimethylbenzene, n-butylbenzene, sec- butylbenzene, tert-butylbenzene, l-methyl-4-isopropylbenzene, dimethylbenzene, l,3,5-trimethyl-2-ethylbenzene, l,3,5-trimethyl-2-propylbenzene, 1,3,5- trimethyl-2-allylbenzene, 2-phenyl-2,4,6-trimethylheptane, l-methyl-2- phenylcyclopentane, l-ethyl-2-phenylcyclopentane, naphtalene, alfa- methylnaphtalene, 2-methylbut-2-ene, hexene-1, 2,3-dimethylbut-l-ene, heptene-1, diisobutylene. The aprotic non-polar organic solvent may also be made up of two or more aprotic non-polar organic solvents, i.e. being a mixture of such solvents.

In another embodiment, the aprotic non-polar organic solvents are selected from the group of solvents of similar structure as hexane, such as aliphatic unbranched hydrocarbons, for example pentane, heptane, octane, nonane and undecane, such as small branched aliphatic hydrocarbons of 6-20 carbons, for example 2- methylhexane, 2,2,3-trimethylbutane, 2,4-dimethylhexane, 2,2,4- trimethylpentane, 2-methyloctane, 3-methyloctane, 2,6-dimethylheptane, 2,7- dimethyloctane, 7,8-dimethyltetradecane.

In yet another embodiment, water is poorly soluble in the non-polar organic solvent or in the non-polar aprotic organic solvent, such as a solubility of less than 1% w/w of water at 20 degrees Celsius, such as in the interval of 0-0.9% w/w, more preferably in the interval of 0-0.8% w/w, such as 0-0.7% w/w, such as 0- 0.6% w/w, such as 0-0.5% w/w, such as 0-0.4% w/w, such as 0-0.3% w/w, such as 0-0.2% w/w, such as 0-0.25% w/w, such as 0-0.1% w/w, more preferably in the interval of 0-0.09% w/w, such as 0-0.08% w/w, such as 0-0.07% w/w, such as 0-0.06% w/w, such as 0-0.05% w/w, such as 0-0.04% w/w, such as 0-0.03% w/w such as 0-0.02% w/w, such as 0-0.01% w/w, such as a solubility of 0% w/w of water at 20 degrees Celsius.

In another embodiment of the present invention, the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more polar organic solvents.

In another embodiment of the present invention, the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more ionic liquids, such as 3-(Triphenylphosphonio)propane-l-sulfonate, 3- (Triphenylphosphonio)propane-l-sulfonic acid tosylate, Tetrabutylphosphonium methanesulfonate, Tetrabutylphosphonium p-toluenesulfonate,

Tributylhexadecylphosphonium bromide, Tributylmethylphosphonium dibutyl phosphate, Tributylmethylphosphonium methyl sulfate,

Triethylmethylphosphonium dibutyl phosphate, Trihexyltetradecylphosphonium bis(2,4,4-trimethylpentyl)phosphinate, Trihexyltetradecylphosphonium

bis(trifluoromethylsulfonyl)amide , Trihexyltetradecylphosphonium bromide, Trihexyltetradecylphosphonium chloride, Trihexyltetradecylphosphonium decanoate, Triisobutylmethylphosphonium tosylate,

Benzyldimethyltetradecylammonium chloride, Tetrabutylammonium

methanesulfonat, Tetraheptylammonium bromide, Tributylmethylammonium chlorid, Tributylmethylammonium methyl sulfate , 1,2,3-Trimethylimidazolium methyl sulfate, l-Butyl-3-methylimidazolium acetate, l-Butyl-3- methylimidazolium chloride, l-Butyl-3-methylimidazolium methyl sulfat, tetradecyl(trihexyl)phosphonium bromide, tetradecyl(trihexyl)phosphonium chloride, tetradecyl(trihexyl)phosphonium decanoate,

triisobutyl(methyl)phosphonium tosylate, tributyl(methyl)phosphonium

methylsulfate, tributyl(hexadecyl)phosphonium bromide. An ionic liquid is a salt in the liquid state.

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 CO precursor is coated by the solid solvent, thereby protecting it from the catalyst or base prior to heating the system to above room temperature. When the solvent melts, the reaction is initiated.

In still another embodiment of the present invention, the base and/or the catalyst are individually coated by the solid solvent, thereby protecting the precursor 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. In one embodiment of the present invention, the one or more reactants in the carbon monoxide producing chamber are encapsulated with an encapsulation material.

In another embodiment of the present invention, the reactants in the carbon monoxide producing 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 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 25 degrees Celsius, such as in the interval of 30-400 degrees Celsius, e.g. 35 degrees Celsius, such as in the interval of 40-380 degrees Celsius, e.g. 45 degrees Celsius, such as in the interval of 50- 350 degrees Celsius, e.g. 55 degrees Celsius, such as in the interval of 60-300 degrees Celsius, e.g. 65 degrees Celsius, such as in the interval of 70-280 degrees Celsius, e.g. 75 degrees Celsius, such as in the interval of 80-250 degrees Celsius, e.g. 85 degrees Celsius, such as in the interval of 90-180 degrees Celsius, e.g. 95 degrees Celsius, such as in the interval of 100-150 degrees Celsius, e.g. 125 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 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.

Encapsulated particles of reactants disclosed herein, such as the CO precursor and the catalyst, 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.

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

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. Technol. 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. Technol. 1996, 48, 189-297; 2: Khodakov, A. Y. ; Chu, W. ; Fongarland, P. Chem. Rev. 2007, 107, 1692-1744), 5 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

10 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),

15 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- 20 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

25 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), double carbonylation (Barnard, C. F. J. Organometallics 2008, 27, 5402-5422), carbonylative lactonization,

30 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- 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. ; 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, 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. 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 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. 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, 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 and a nucleophile, 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

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 specie 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 wxamples 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 bars. 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 bars. 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 bars. 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 (HSiR₃), 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 (HSiR₃), 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

regenerates the active catalyst by re-oxidization of the metal center.

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

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.

Double carbonylation (type V)

Type V reactions involve an activated substrate (as described for type I reactions) and a nucleophile reacting with two carbon monoxide units mediated by a metallic or organometallic catalyst. In such reactions as reviewed by Salaun et al, Dalton Trans., 2003, 1041-1052, a bond is formed between the activated substrate and the first carbonyl unit, between the first CO and a second carbon monoxide and between the second CO and the nucleophile to obtain an -ketocarbonyl compound.

Suitable nucleophiles are for examples 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. As examples, alcohol, thiol, or amine may suitably be used as nucleophile so as to provide a-ketoester, -ketothioester, or a-ketoamide, respectively. 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 1 and 10 bars. The metal catalyst is typically a metal suitable for type I carbonylation (Fe, Ni, Co, Pd,...), preferentially Pd and Co, more preferentially Pd. Palladium sources and ligands if needed may be introduced from the same precursor like Pd(P^tBu₃)₂ or from two different source. The palladium source can be a palladium(II) species, such as Pd(OAc), Pd(CI)₂ and PdCI₂(CH₃CN)₂, or a palladium(O) species, such as Pd(dba)₂ and Pd₂(dba)₃. Ligands are preferably phosphine ligands, such as PPh₃ and Ρ'Β^. Double carbonylations are typically run with a base present in order to abstract the excess proton arriving with the nucleophile and to ensure proper regeneration of Pd(0), or the nucleophile is delivered to the reaction mixture as its

corresponding base. 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 (1,8- diazabicyclo[5.4.0]undec-7-ene).

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 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, double carbonylation, 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 catalyst and ligand used for the carbonylation reaction in the carbon monoxide consuming chamber can be the same as the ones used in the carbon monoxide producing chamber.

Labelling

In cases where labelled CO is applied, and hence may become the 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 are ideally suited for the synthesis of carbon-14-labeled compounds. This is most prominently expressed by the ability to easily handle and incorporate small quantities of CO, even in substoichiometric amounts. Moreover incorporation of the isotope label at a late stage in the synthesis is facilitated because CO is typically joined with the parent molecule using conditions involving transition metal catalysis which represents notably milder conditions than the anionic and strongly basic reaction conditions usually applied for C0₂ derived reagents. Compounds labeled with carbon-14 have been used for decades as important and unparalleled tools in a broad range of applications, particularly in metabolism and environmental fate of novel pharmaceuticals and crop protection agents respectively. Carbon-14-labeled compounds are unmatched for the study of their metabolism in vitro, e.g. with hepatocytes, cytochrome P450 subtypes and other enzyme or subcellular tissue preparations, or for in vivo determination of their absorption, distribution, metabolism and excretion (ADME) both in animals and in humans. One of the newer methods for detection is accelerator mass spectrometry (AMS), which allows for detection of even smaller amounts of carbon-14, hence providing better safety margin when conducting ADME studies on humans. Carbon-14-labeled compounds have also contributed with important discoveries for biochemistry, biosynthetic pathways, enzyme mechanisms, organic reaction mechanisms and environmental sciences (Voges, R. ; Heys, J. R. ;

Moenius, T. "Preparation of Compounds Labeled with Tritium and Carbon-14" 2009, John Wiley & Sons, Ltd, The Atrium, Southern Gate, Chichester, West Sussex, P019 8SQ, United Kingdom). Moreover carbon-14-labeling is an unparalleled tool for studying the environmental fate of crop protection agents (e.g. degradation, mobility and metabolism).

The carbon monoxide kits presented herein are ideally suited for the synthesis of carbon-13-labeled compounds, which complement carbon-14-labeled compounds nicely, in particular for in vivo studies (Berliner, L. 1 ; Robitaille,P.-M. "Biological Magnetic Resonance 15, In Vivo Carbon-13 NMR" 1998, Kluwer Academic / Plenum Publishers, New York 233 Spring Street, New York, N.Y. 10013). Where carbon-14-labeled compounds are ideal for whole body uptake and excretion, carbon-13-labeled compounds are exceptional for monitoring the labeled compound in tissues either in vivo or in biopsy because carbon-13 unlike its carbon-12 and carbon-14 counterparts can be detected in a NMR spectrometer. It is fairly straightforward to determine the specific position of the carbon-13-label in a given molecule because each carbon possesses a unique chemical shift and further has spectral patterns which are dictated by its immediate environment (i.e. direct covalently bonded atoms and through space interactions), hence at the same time providing structural information about the molecule. Carbon-13-labeled compounds are also key tools for the determination of protein structure, in the elucidation of biosynthetic pathways and reaction mechanisms in organic synthesis, for analysis of polymer dynamics and polymer degradation and as internal standards for GC-MS analysis in e.g., forensic medicine and

environmental studies. Tracers labelled with short-lived positron emitting radionuclides (e.g. ⁿC, ti_/2 = 20.3 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, ¹³C and ¹⁴C labelled precursors. 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. 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. Hence, in one embodiment of the present invention, the carbon-isotope of the carbon monoxide precursor is ⁿC-, ¹³C-, ¹⁴C or mixtures thereof.

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

The following examples show a combination of ex situ palladium catalysed decarbonylation with palladium catalysed carbonylation in an interconnected multi-chamber system. The ex situ palladium catalysed decarbonylation is performed in one chamber, while the palladium catalysed carbonylation is performed in another chamber connected to the former chamber. A controlled, smooth and highly efficient palladium catalysed CO releasing reaction combined with aminocarbonylation of heteroaryltosylates is achieved in very good yields with only 1.5 equivalents of the CO precursor. Furthermore, the inventors demonstrate that the system of the present invention is useful for [13C] labelling of various compounds of medicinal interest.

Decarbonylation of pivaloyl chloride

Investigations were started on pivaloyl chloride 1 to ensure the suppression of the ketene pathway. Decarbonylation was achieved by reacting pivaloyl chloride 1 with 5 mol% Pd(dba)₂/P^tBu₃ at 80°C for 20 hours. However, the conversion was less than 10 percent. A complete conversion was observed by the addition of one equivalent of diisopropylethylamine (DIPEA), favouring the reductive elimination of HCI (Scheme 1). Scheme 1 : Decarbonylation of pivaloyl chloride.

Pd(dba)₂ (5 mol%)

80°C, 20h Full conversion

( H NMR)

Analysis of the crude reaction mixture by H NMR in CDCI₃ showed only

hydrochloride salt of DIPEA left and specific shifts of partially solubilised

isobutene, observed at 4.64 ppm (sept, 2H, J = 1.2 Hz) and 1.71 ppm (t, 6H, J = 1.2 Hz), confirming the starting hypothesis mechanism. The course of the reaction was studied by H NMR by monitoring the conversion of pivaloyl chloride 1 over time compared to an internal standard (Figure 4A-C). It was observed that the reaction ran to completion within three hours at 80°C when 5 mol % of Pd(dba)₂ and P^lBu₃ were used. The almost linear aspect of the curve (figure 4B) clearly indicates that the carbon monoxide was generated in a controlled manner. Gas-volume measurements (figure 4C) show that the gas evolution correlates roughly with the consumption of 1. The production of CO appears from gas-volumetric studies to be dependent on temperature and catalyst loadings (Figure 5). In order to find easy-to-handle and air-stable carbon monoxide precursors, a screening of the catalytic system was performed by meassuring Η NMR conversions after 1.5 and 4 hours for various palladium sources, ligands, bases and acyl chlorides (Table 1).

Table 1 : Screening of the catalytic system for decarbonylation.

- HCI

Conversion

Acyl Pd (%)^a

Entry Ligand Base

Chloride Source 1 h

4 h

30

1 1 PdCI₂ P'Bus DIPEA 60 100

2 1 PdCI₂ / DIPEA 27 77^b

3 1 Pd(dba)₂ P^lBu₃ ^c DIPEA 66 100

4 1 Pd(dba)₂ PPh₃ DIPEA 25 35

5 1 Pd(dba)₂ P(o-tol)₃ DIPEA 59 67

6 1 Pd(dba)₂ IPr^d DIPEA 39 43

P^lBu₃.

7 Pd(dba)₂ DIPEA 70 100

HBF₄

8 1 Pd(dba)₂ P^lBu₃ NEt₃ 63 100

9 1 Pd(dba)₂ P^lBu₃ DABCO^e 93 100

10 2 Pd(dba)₂ P^lBu₃ DIPEA 100^f 100^f

11 4 Pd(dba)₂ P^lBu₃ DIPEA 100⁹ 100⁹ ^a Determined by ¹H NMR compared to m-xylene as internal standard. More complex ^ NMR of the crude. ^c 10 mol %. ^d 1,3-Bis(2,6- diisopropylphenyl)imidazol-2-ylidene. ^e l,4-Diazabicyclo[2.2.2]octane. ^f Only traces of 3 were detected in the crude Η NMR. ⁹ 94% Η NMR yield of 5 was determinate compared to internal standard.

Changing the palladium source from Pd(dba)₂ to a palladium(II) source (i.e.

palladium dichloride) didn't affect the course of the reaction. Both identical kinetic and conversion was observed (Table 1, entry 1, compared to Figure 4), which means that the in situ reduction is probably faster than the decarbonylation process. Interestingly, consumption of the pivaloyl chloride 1 is also observed at 80°C with PdCI₂ without any phosphine ligand despite a slower rate and the appearance of other unidentified by-products (entry 2).

The use of 10 mol % of tert-butylphosphine for the reaction didn't lead to dramatic changes in the results (entry 3) in contrary to what was observed for the double bond migration studies where the reaction rate was significantly lowered. However, reacting excess isobutyryl chloride with the commercially available complex Pd[P^lBu₃]₂ released 1 equiv of free P^lBu₃ at room temperature in THF. This suggests that monophosphine palladium complexes are the major specie and excess phosphine stays free in the reaction mixture. When taking price of the ligand into consideration, tri-(tert-butyl)phosphine appears so far to be the optimal for this reaction as tri-phenylphosphine and tri-(o-tolyl)phosphine provided lower conversions (entry 4 and 5). Comparable Tolman's cone angles for P(o-Tol)₃ (0 = 194°) and P^lBu₃ (0 = 182°), as well as the poor result obtained with an hindered carbene (IPr, entry 6), indicates that electronic effects probably also play an important role in this reaction. Using the air stable HBF₄ salt of the phosphine ligand didn't affect the course of the decarbonylation (entry 7) which was also compatible with various tertiary amine like triethylamine or 1,4- diazabicyclo[2.2.2]octane (entry 8 an 9). Finally, uses of other acyl chlorides were investigated and the -trisubstituted center showed to be crucial. Indeed, octanoyl chloride 2 only provided traces of the decarbonylation products 3 despite a full conversion in less than 1 h 30 which suggests a high competition of the ketene pathway in this case, generating unidentified by-products. Moreover, with conditions similar to the ketene formation in the Staudinger reaction, this process may even be non-metal catalysed.

The solid acyl chloride 4 was employed successfully forming the residue 5 with an excellent H NMR yield of 94% in less than 1 h 30. The high reactivity to undergo decarbonylation could be attributed to higher steric hindrance effects in this case. The inventors of the present invention have shown that the decarbonylation reaction occurred in a controlled manner and could with proper optimisation also be performed with the easy-to-handle and air-stable solids (i. e. PdCI₂,

P^lBu₃.HBF₄, 4 and DABCO).

Experimental procols for "Decarbonylation of pivaloyl chloride" Decarbonylation of pivaloyl chloride

In the glovebox under an argon atmosphere, to Pd(dba)₂ (14.4 mg, 25 μηηοΙ) ) in 1 ml_ dioxane in a 8 ml_ vial, were added successively distilled pivaloyl chloride 1 (61,6 μΙ_, 500 μηιοΙ), P(ⁱBu)₃ from a 0.02 mg. L ¹ stock solution in dioxane (253 μΙ_, 25 Mmol) and distilled diisopropylethylamine (87.1 μΙ_, 500 Mmol). The vial was sealed with a Teflon screwcap and a 10 ml_ syringe put through. The mixture was stirred for 20 hours at 80°C. Slow expansion of the syringe was observed and ending volume was superior to 12 mL of gas. H NMR analysis of the crude showed complete conversion of the pivaloyl chloride 1 and traces of solubilised isobutene (4.64 ppm (sept, 2H, J = 1.2 Hz), 1.71 ppm (t, 6H, J = 1.2 Hz)).

Excess pressure needed to move the piston of the syringe was measured around 100 mbars.

Course of the decarbonylation reaction

In the glovebox under an argon atmosphere, to Pd(dba)₂ (86.3 mg, 150 Mmol) in a 10 mL volumetric flask, were added successively P(^fBu)₃ from a 0.02 mg.ML ¹ stock solution in dioxane (1.52 mL, 150 Mmol), distilled pivaloyl chloride 1 (370 pL, 3.0 mmol), distilled diisopropylethylamine (523 MU 3.3 mmol), m-xylene (363 ML, 3.0 mmol) and dioxane to complete to a total volume of 10 mL. Six times 1 mL of this freshly-shake mother solution were introduced in six 5-mL vials that were sealed with a Teflon screwcap with a 10 mL syringe put through. All vials were stirred simultaneously out of the glovebox at 80°C. Gas creation was roughly monitored by measuring syringes expansion and H NMR analysis of the crude allowed determining conversion of pivaloyl chloride 1 compared to m-xylene. Table 2: Conversions and gas evolution observed.

Volumes as observed on syringe. ^a ^-NMR conversion of pivaloyl chloride 1 compared to m-xylene

Effect of temperature and catalyst loading on the rate of the expected

decarbonylation

1 mol % Pd: In the glovebox under an argon atmosphere were added successively in the external tube of SI (SI is depicted in figure 1A) Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (432 μί, 7.5 μηιοΙ), P(ⁱBu)₃ from a 0.02 mg. L ¹ stock solution in dioxane (75.9 μί, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μί, 750 μηιοΙ), distilled diisopropylethylamine (131 μί, 750 μηιοΙ) and 2.25 mL of dioxane to obtain a total volume around 3 mL. 2 mL of dioxane were introduced in the internal tube which was carefully placed in the external tube. System was sealed with a teflon coated microwave cap and a 20mL-syringe was put through the cap. The system was heated at the desired temperature. Created volume was determined by expansion of the syringe. 3.3 mol % Pd: In the glovebox under an argon atmosphere were added successively in the external tube of SI Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (1.44 ml_, 25 μηηοΙ), P(^fBu)3 from a 0.02 mg. L ¹ stock solution in dioxane (253 μί, 25 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (131 μί, 750 μηιοΙ) and 1.3 mL of dioxane to obtain a total volume around 3 mL. 2 mL of dioxane were introduced in the internal tube which was carefully placed in the external tube. System was sealed with a teflon coated microwave cap and a 20mL-syringe was put through the cap. The system was heated at 80°C. Created volume was determined by expansion of the syringe.

Screening of the CO-releasing system

- HCI

Scheme 2: Reaction setup for screening of the CO-releasing system.

In a glovebox under an argon atmosphere in two 5 mL vial, twice of a palladium source (5 mol%, 15 μηηοΙ, solid or from a 0.01 mg. L^"1 stock solution in dioxane), phosphine (5 mol%, 15 μηηοΙ, solid or from a 0.02 mg. L^"1 stock solution in dioxane), acyl chloride (1 eq, 0.3 mmol), base (1.1 eq, 0.33 mol), m-xylene (36.7 μί, 0.3 mmol) and dioxane to complete to a total volume of 1 mL were added. Both vials were sealed with a Teflon screwcap and a 10 mL syringe put through. Mixtures were stirred at 80°C for 1 h 30 or 4 h and conversions determined by Η NMR of the crude compared to m-xylene. Optimization of the aminocarbonylation of heteroaryl tosylates

Hexylamine and 2-pyridyl tosylate 6 were chosen as test system to develop the reaction conditions. Screening of palladium source, ligand, base, solvent and temperature allowed to determine that a combination of Pd(dba)₂, 1,1'- bis(diisopropylphosphino)ferrocene (D'PrPF), DIPEA and dioxane at 80°C were the best conditions to give the desired product 7 in 87% isolated yield as depicted in scheme 3. Scheme 3: Optimized conditions for aminocarbonylation of 2-pyridyl tolyslate 6 with gaseous CO.

5 Reproducible results were achieved with a triple balloon (three standard balloons inside each other providing a measured 1.1 atm pressure) without CO flushing. As this procedure showed to be optimal for allowing a slow diffusion of CO in the reaction atmosphere, the inventors suspected that the catalytic species involved were highly sensitive to the level of carbon monoxide. This may be explained by a 10 CO backbonding effect that deplete the reaction mixture of palladium complexes able to undergo oxidative addition. Such procedure is sufficient for a system screening but too rough for substrate scope. Furthermore, all attempts with Mo(CO)6 gave maximum yields around 60% (results not shown). Hence, the possibility of using the CO releasing system as previously described was studied.

15

Controlled CO delivery

All in situ combinations of the CO generating and CO consuming reactions depicted in Scheme 2 and 3 failed. Acylation of the hexylamine being the only product observed, even with slow addition of the amine over hours and directly at 20 80°C. Attention was then paid to realize the decarbonylation process of 1 ex situ in parallel to the aminocarbonylation of 2-pyridyl tosylate 6, hypothesising that gas diffusion between the two mixtures would result in the transfer of the carbonyl group.

A first generation of glassware (Figure 1A) was designed for optimal heat

25 exchange and stirring, as well as for maintaining the maximal partial pressure of CO below one atmosphere in order to minimize pressure effects. The glassware is composed of an internal tube where the aminocarbonylation occurs (the CO consuming chamber) and of an external wall containing the CO releasing mixture (the CO producing chamber); this sealed two-chamber system was heated at 30 80°C for 20 h with various catalyst loadings.

Scheme 4: Tests of the two-chamber system.

1 1 .5 equiv

A first experiment was conducted with 5 mol% of Pd(dba)₂ and D'PrPF in the inner chamber to ensure presence of the catalytic specie until completion of the reaction, and with 5 mol% (i. e. 3.3 mol% compared to 1) of Pd(dba)₂ and P^lBu₃ in the external reactor. This last change didn't seem to affect the completion of the decarbonylation of 1 by considering the obtained result. Not only was the isolated yield of 7 equivalent to the value obtained with a CO loaded balloon (87 %, scheme 4), but this procedure also proved its high efficiency by the low amount of CO precursor needed (only 1.5 equivalent of pivaloyi chloride 1). The amount of CO in a balloon was typically 0.5 L, i.e. roughly 40 equivalents, for a reaction on a 0.5 mmol scale. Moreover, even if partially solubilised isobutene was detected by Η NMR in the crude of the aminocarbonylation reaction; this disubstituted alkene was probably too unreactive to interfere in the catalytic cycle. Varying tosylate substrates and amines have been tested and are shown in Scheme 5.

Scheme 5 : Scope of the aminocarbonylation of heteroaryltosylates using a two- chamber system (Figure 1A).

Pd(dba)₂ (3 mol%)

a 5 mol% catalyst in the external tube (i.e. 3.3 mol % to 1). ^b Isolated in mixture with 17% tosylhexylamine.^c 5 mol% catalyst in the internal tube. ^d 93/7 mixture of isomers. ^e In THF. ^f 3 days at 95°C. ^a 10 mol% catalyst in the internal tube, 2 eq of ₄-fluoroaniline, 2 eq of 1 , 7days at 95°C. ^h On 0.25 mmol, diastereoselectivity > 95/5 determined by ¹H NMR The reaction thus proved to be easily extendable to 2-pyridyl tosylates bearing classical substitutions like methyl groups or chlorine atoms as demonstrated by the good yields (from 82% to 85%) obtained for products 8, 9 and 10. However, more active substrates towards the oxidative addition like 2-pyrimidyl tosylate or 2-(5-trifluoromethyl)pyridyl tosylate were subjected to important competitive direct amination and amine tosylation - the last one, leading to isolated yield of the aminocarbonylation product under 50%. This problem was partially solved by increasing the Pdidba^P'Bus amount in the external chamber to accelerate the CO release, thus affording desired compounds in improved yields from 62% to 77% (11, 12 and 13).

Furthermore, the reaction was compatible with both primary and secondary amines, bearing various functionalities like ethers (14), triple bounds (15) or even free phenols (16). In all these cases, excellent yields of 87% and 88% were obtained. In order to push the reaction to its limits, highly functionalized substrates have been used, like (-)-pseudoephedrine (17), a dipeptide (18) or an acetylated sugar (19). Very decent yields for this kind of molecules (48% to 67%) were observed and none or only little epimerization was detected by H NMR, even at the anomeric carbon of 19.

Aminocarbonylation of heteroarylstosylates with aromatic amines was also investigated but afforded lower yield (20, 48%) due to high competition by the amination reaction. However, even if the use of the deactivated 4-fluoroaniline needed hasher conditions reactions (21, 50%), the kilo-scale-employed pesticide 22 (picolinafen) could be obtained in an isolated yield of 57%.

To conclude, many relevant compounds can be prepared in good yields by this method. For example, 23 can provide lazabemide (a selective inhibitor of monoamine oxidase B used in the treatment against Parkinson's disease) after removal of the Boc- protecting group. 24 was developed by Trost et al for transition-metal-catalysed allylic alkylation, and 25 is a precursor to the interesting bis(oxazolinyl)pyridine ligand (Pybox family). The inventors of the present invention thus proved that 2-pyridyl tosylates are very useful starting materials for the creation of molecules with medicinal and synthetic interest.

Moreover, this new system of CO generation showed its high efficiency, with good to excellent yields obtained with typically only 1.5 equivalent of pivaloyl chloride 1 as CO precursor, as well as its tuning ability via the catalyst loading parameter to overcome side reactions. One coupling reaction between n-hexylamine and 2-pyridyl tosylate 6 was also conducted with limiting pivaloyl chloride 1 (0.75 equivalents compared to 2- pyridyl tosylate 6). This resulted in a 79% isolated yield based on the pivaloyl chloride 1 (Scheme 6).

0.75 mmol

Scheme 6. Aminocarbonylation applying substoichiometric CO. Experimental protocols for "Optimization of the aminocarbonylation of heteroaryl tosylates" and "Controlled CO delivery"

General Methods

Unless otherwise noted, all reactions were carried out under inert atmosphere of argon. Solvents were dried according to standard procedures. Reactions were monitored by thin-layer chromatography (TLC) analysis. All other chemicals were used as received from the appropriate suppliers unless mentioned. Stock solutions were freshly prepared in the glovebox. Flash chromatography was carried out on Merck silica gel 60 (230-400 mesh). The ^ NMR, ¹³C NMR and ¹⁹F NMR spectra were recorded at 400 MHz, 100 MHz and 376 MHz, respectively, on a Varian Mercury 400 spectrometer. The chemical shifts are reported in ppm downfield to TMS (δ = 0) and referenced using the residual CHCI₃ resonance (δ = 7.26), DMSO-d₆ (δ = 2.50) and CD₃CN (δ = 1.94) for ^ NMR and the central CDCI₃ resonance (δ = 77.16), DMSO-d₆ (δ = 39.51), CD₃CN (δ = 206.68 and 29.92) for ¹³C NMR. NMR spectra are reported as follows (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintuplet, hep = heptet, m = multiplet, br = broad; coupling constant(s) in Hz; integration). MS and HRMS were performed on a LC TOF (ES). Optical rotations were measured at the sodium line at ambient temperature (22°C) in acetone solutions.

Optimization of the aminocarbonylation of heteroaryls tosylates

2-pyridinyl tosylate 6 (124.6 mg, 500 pmol), hexylamine (99.2 μΙ_, 750 pmol), palladium source (5 mol %, 25 pmol), ligand (5 mol%, 25 pmol) and base (2 eq, 1.0 mmol) were dissolved in solvent (3 ml_). The sample vial was fitted with a teflon sealed screwcap, removed from the glovebox and equipped with a triple balloon containing CO gas. The reaction was stirred for 18 h at 80 °C and then allowed to cool to 20 °C. Conversion was determined by Η NMR. The reaction mixture was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel using Et₂0/CH₂Cl₂ 5:95 as eluant to afford 7 (Table 3).

Table 3: Optimization of the aminocarbonylation of heteroaryl tosylates.

Temperature Yield³ %

Entry Pd source Ligand (mol %) Base Solvent

(°C) (Conversion¹¹ °/

1 Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 70°C 68 % (73%)

2 Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 80°C 88 % (96%)

3 Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 90°C 81 % (93%)

4 Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 100°C 44 % ( 100%)

5 Pd(dba)₂ D'BuPF (5) DIPEA Dioxane 80°C (6%)

6 Pd(dba)₂ DPPF (5) DIPEA Dioxane 80°C (66%)

7 Pd(dba)₂ DPPE (5) DIPEA Dioxane 80°C (48%)

8 Pd(dba)₂ DPPP (5) DIPEA Dioxane 80°C (82%)

9 Pd(dba)₂ DPPpentyl (5) DIPEA Dioxane 80°C (40%)

10 Pd(dba)₂ XantPhos (5) DIPEA Dioxane 80°C (40%)

11 Pd(dba)₂ Phenanthroline (5) DIPEA Dioxane 80°C (0%)

12 Pd(dba)₂ XPhos ( 10) DIPEA Dioxane 80°C (0%)

13 Pd(dba)₂ P(o-tol)₃ ( 10) DIPEA Dioxane 80°C (0%)

14 Pd(dba)₂ P('Bu)₃HBF₄( 10) DIPEA Dioxane 80°C (0%)

15 Pd(dba)₂ D'PrPF (5) Cy₂NMe Dioxane 80°C 84 % (91%)

16 Pd(dba)₂ D'PrPF (5) Et₃N Dioxane 80°C 88 ( 100%)

17 Pd(dba)₂ D'PrPF (5) DBU Dioxane 80°C (55%)

18 Pd(dba)₂ D'PrPF (5) K3PO4 Dioxane 80°C (64%) 19 Pd(dba)₂ D'PrPF (5) Na₂C0₃ Dioxane 80°C (68%)

20 Pd(dba)₂ D'PrPF (5) Cs₂C0₃ Dioxane 80°C 40 ( 100%)

21 Pd(OAc)₂ D'PrPF (5) DIPEA Dioxane 80°C 87 % ( 100%)

22 PdBr₂ D'PrPF (5) DIPEA Dioxane 80°C (51%)

23 PdClz D'PrPF (5) DIPEA Dioxane 80°C (62%)

24^c Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 80°C 86 % ( 100%)

25 Pd(dba)₂ D'PrPF (5) DIPEA Toluene 80°C 66 % ( 100%)

26 Pd(dba)₂ D'PrPF (5) DIPEA DMF 80°C 77 % ( 100%)

27^d Pd(dba)₂ D'PrPF (5) DIPEA Dioxane 80°C 83 % (97%)

28^e Pd(dba)₂ D'PrPF (3) DIPEA Dioxane 80°C 87 % (96%) isolated yields after column chromatography. Conversions determined by 1H NMR analysis of the crude mixture. ^cl equivalent of hexylamine, 1.5 equivalent of 6. ^dVial flushed with CO prior to heating. ^e 3 mol% Pd(dba)₂. Aminocarbonylation of heteroaryls tosylates with two-chamber system (Figure 1A) General procedure: In the glovebox under an argon atmosphere were added successively in the external tube of the two-chamber system (Figure 1A) Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane, P(^fBu)3 from a 0.02 mg. L ¹ stock solution in dioxane, distilled pivaloyi chloride 1, distilled diisopropylethylamine and dioxane to obtain a total volume around 3 ml_. To the 2-pyridyl tosylate in the internal tube of SI were added Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane, D'PrPF from a 0.02 mg. L ¹ stock solution in dioxane, a primary or secondary amine, diisopropylethylamine and dioxane to obtain a total volume around 2 ml_. The internal tube was carefully placed in the external tube which was then sealed with a teflon coated microwave cap. The system was heated at 80°C for 20 h and unsealed after releasing the excess pressure with a needle. Mixture from the inner tube was evaporated under reduced pressure and purification of the residue by column chromatography on silica gel provided the desired aminocarbonylation product.

/V-Hexyl-picolinamide 7

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ),

P(^fBu)3 from a 0.02 mg. L ¹ stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyi chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled

diisopropylethylamine (131 μΙ_, 750 μηιοΙ) and 2.25 ml_ of dioxane in the external chamber and 2-pyridinyl tosylate 6 (124.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (863 μΙ_, 15 μηιοΙ), D'PrPF from a 0.02 mg. L ¹ stock solution in dioxane (314 μΙ_, 15 μηιοΙ), hexylamine (99.2 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH₂Cl₂/EtOAc (100/3) provided compound 7 as a colorless solid (96%, 99.0 mg). ^ NMR (400 MHz, CDCI₃) δ 8.51 (d, J = 4.8 Hz, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.04 (br s, 1H), 7.83 (td, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.40 (ddd, J = 7.6 Hz, J = 4.8 Hz, J = 1.2 Hz, 1H), 3.46 (q, J = 7.2 Hz, 2H), 1.62 (quin, J = 7.6 Hz, 2H), 1.42-1.29 (m, 6H), 0.88 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 164.1, 150.0, 147.9, 137.2, 125.9, 122.1, 39.4, 31.4, 29.6, 26.6, 22.5, 13.9. HRMS (ESI) Ci₂Hi₈N₂0 [M+Na⁺]; calculated 229.1314, found 229.1317.

Limiting pivaloyl chloride experiment: The general procedure was followed using Pd(dba)₂ from a 0.01 mg^L ¹ stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ), P(^fBu)3 from a 0.02 mg^L ¹ stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 from a 1.0 mmol.mL ¹ stock solution in dioxane prepared in a volumetric flask (750 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (196 μΙ_, 1.13 mmol) and 1.5 mL of dioxane in the external chamber and 2-pyridinyl tosylate 6 (249.2 mg, 1.0 mmol), Pd(dba)₂ from a 0.01 mg^L ¹ stock solution in dioxane (1.73 mL, 30 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in dioxane (628 μΙ_, 30 μηιοΙ), hexylamine (198 μΙ_, 1.5 mmol) and diisopropylethylamine (348 μΙ_, 2.0 mmol) in the internal chamber. Purification of the residue by column

chromatography on silica gel using CH₂CI₂ to CH^I^EtOAc (100/3) provided compound 7 as a colorless solid (79%, 122.0 mg). yv-Hexyl-6-methylpicolinamide 8

procedure was followed using Pd(dba)₂ from a 1 stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ),

a 0.02 mg^L ¹ stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled

diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 mL of dioxane in the external chamber and 2-(6-methyl)pyridinyl tosylate (131.7 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg^L ¹ stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in dioxane (314 μΙ_, 15 μηιοΙ), hexylamine (99.2 μΙ_, 750 μηηοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to ChbCI^EtOAc (100/5) provided compound 8 as a colorless oil (82%, 90.1 mg). ^ NMR (400 MHz, CDCI₃) δ 8.11 (br s, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.69 (t, J = 7.6, 1H), 7.24 (d, J = 7.8, 1H), 3.44 (q, J = 6.9 Hz, 2H), 2.55 (s, 3H), 1.62 (quin, J = 7.4 Hz, 2H), 1.42- 1.28 (m, 6H), 0.90-0.85 (m, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 164.3, 156.9, 149.4, 137.4, 125.6, 119.1, 39.4, 31.5, 29.6, 26.7, 24.2, 22.5, 14.0. HRMS (ESI) Ci₃H₂₀N₂O [M + Na⁺]; calculated

243.1473, found 243.1478. yv-Hexyl-3-methylpicolinamide 9

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. pL ¹ stock solution in dioxane (432 μΙ_, 7.5 pmol),

mg. pL ¹ stock solution in dioxane (75.9 μΙ_, 7.5 pmol), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 pmol), distilled diisopropylethylamine (131 μΙ_, 750 pmol) and 2.25 ml_ of dioxane in the internal chamber and 2-(3- methyl)pyridinyl tosylate (131.7 mg, 500 pmol), Pd(dba)₂ from a 0.01 mg. pL ¹ stock solution in dioxane (863 pl_, 15 pmol), D'PrPF from a 0.02 mg. pL ¹ stock solution in dioxane (314 pl_, 15 pmol), hexylamine (99.2 pl_, 750 pmol), diisopropylethylamine (174 pl_, 1.0 mmol) and 750 μΙ_ of dioxane in the external chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH₂Cl2 EtOAc (100/5) provided compound 9 as a pale yellow oil (82%, 90.2 mg). ^XW NMR (400 MHz, CDCI₃) δ 8.34 (dd, J = 4.7 Hz, J = 1.4 Hz, 1H), 8.11 (br s, 1H), 7.53 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 7.25 (dd, J = 8.0 Hz, J = 1.4 Hz, 1H), 3.38 (q, J = 6.8 Hz, 2H), 2.71 (s, 3H), 1.59 (quin, J = 7.4 Hz, 2H), 1.38- 1.26 (m, 6H), 0.85 (t, J = 7.0 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 165.8, 147.4, 145.3, 140.7, 135.2, 125.4, 39.2, 31.5, 29.6, 26.7, 22.5, 20.5, 14.0. HRMS (ESI) Ci₃H₂₀N₂O [M+Na⁺]; calculated 243.1473, found 243.1469.

5-Chloro-yv-hexylpicolinamide 10

P(^fBu)₃ from a 0.02 mg. pL ¹ stock solution in dioxane (75.9 μΙ_, 7.5 pmol), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 pmol), distilled

diisopropylethylamine (131 μΙ_, 750 pmol) and 2.25 ml_ of dioxane in the external chamber and 2-(5-chloro)pyridinyl tosylate (141.9 mg, 500 pmol), Pd(dba)₂ from a 0.01 mg. pL ¹ stock solution in dioxane (863 pL, 15 pmol), D'PrPF from a 0.02 mg. L ¹ stock solution in dioxane (314 μΙ_, 15 μηιοΙ), hexylamine (99.2 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to ChbCI^EtOAc (100/3) provided compound 10 as a pale yellow 5 oil (85%, 102 mg). ^ NMR (400 MHz, CDCI₃) δ 8.46 (d, J = 2.3 Hz, 1H), 8.13 (d, J = 8.3 Hz, 1H), 7.89 (br s, 1H), 7.79 (dd, J = 8.3 Hz, J = 2.3 Hz, 1H), 3.43 (q, J = 6.9 Hz, 2H), 1.60 (quin, J = 7.2 Hz, 2H), 1.41- 1.24 (m, 6H), 0.87 (t, J = 6.3 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 163.2, 148.2, 146.9, 137.0, 134.7, 123.1, 39.5, 31.4, 29.5, 26.6, 22.5, 14.0. HRMS (ESI) Ci₂Hi₇CIN₂0 [M + Na⁺]; calculated 10 263.0927, found 263.0935. yv-Hexyl-5-(trifluoromethyl)picolinamide 11

The general procedure was followed using Pd(dba)₂ ne (1.44 stock

lled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 1.3 ml_ of dioxane in the internal chamber and 2-(5- trifluoromethyl)pyridinyl tosylate (158.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01

20 mg^L ¹ stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in dioxane (314 μΙ_, 15 μηιοΙ), hexylamine (99.2 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using pentane/CH₂CI₂ (1/1) to pure CH₂CI₂ provided compound 11 (64%, 87.7 mg)

25 contaminated by tosylhexylamine (17%, 21.8 mg). Second purification by column chromatography on silica gel using pentane/CH₂CI₂ (2/3) provided pure compound 11 (14%, 18.5 mg) as a colorless oil. ^ NMR (400 MHz, CDCI₃) δ 8.81 (d, J = 1.7 Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.09 (dd, J = 8.1 Hz, J = 1.7 Hz, 1H), 8.02 (br s, 1H), 3.48 (q, J = 6.8 Hz, 2H), 1.64 (quin, J = 7.4 Hz, 2H), 1.44- 1.30 (m, 6H),

30 0.89 (t, J = 6.9 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 162.8, 152.8, 145.1 (q, J = 4.1 Hz), 134.7 (q, J = 3.3 Hz), 128.6 (q, J = 33.4 Hz), 123.2 (q, J = 273.1 Hz), 122.0, 39.6, 31.5, 29.5, 26.6, 22.5, 14.0. ¹⁹F NMR (377 MHz, CDCI₃) 5(ppm) : -63. HRMS (ESI) Ci₃Hi₇F₃N₂0 [M + Na⁺]; calculated 297.1191, found 297.1190.

35 yv-Benzyl-5-(trifluoromethyl)picolinamide 12

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (1.44 ml_, 25 μηηοΙ), P(^fBu)3 from a 0.02 mg. L ¹ stock solution in dioxane (253 μΙ_, 25 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 1.3 mL of dioxane in the external chamber and 2-(5-trifluoromethyl)pyridinyl tosylate (158.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (863 μΙ_, 15 μmol), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (314 μΙ_, 15 μηηοΙ), benzylamine (81.9 μΙ_, 750 μmol), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH₂Cl₂/EtOAc (100/3) provided compound 12 as a colorless solid (77%, 108.5 mg). ^ NMR (400 MHz, CDCI₃) δ 8.80 (d, J = 1.8 Hz, 1H), 8.38 (d, J = 8.1 Hz, 1H), 8.35-8.31 (m, 1H), 8.11 (dd, J = 8.5 Hz, J = 1.8 Hz, 1H), 7.39-7.28 (m, 5H), 4.69 (q, J = 6.0 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 162.8, 152.7, 145.2 (q, J = 3.7 Hz), 137.8, 134.8 (q, J = 3.4 Hz), 128.8 (q, J = 33.0 Hz), 128.8 (2C), 127.8 (2C), 127.6, 123.1 (q, J = 271.9 Hz), 122.2, 43.7. ¹⁹F NMR (377 MHz, CDCI₃) 5(ppm) : -63. HRMS (ESI)

Ci₄HiiF₃N₂0 [M+Na⁺]; calculated 303.0721, found 303.0721.

/V-Cyclohexyl-2,6-dimethylpyrimidine-4-carboxamide 13

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (1.44 mL, 25 μηηοΙ), P(^fBu)₃ from a 0.02 mg. L^"1 stock solution in dioxane (253 μΙ_, 25 μηιοΙ),

distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 1.3 mL of dioxane in the external chamber and 2,6-dimethylpyrimidin-4-yl tosylate (139.2 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (314 μΙ_, 15 μηηοΙ), cyclohexylamine (76.9 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH^I^EtOAc (3/1) provided compound 13 as a pale brown solid (62%, 72.1 mg). ^ NMR (400 MHz, CDCI₃) δ 7.88 (br d, J = 8.0 Hz, 1H), 7.74 (s, 1H), 3.96-3.86 (m, 1H), 2.68 (s, 3H), 2.53 (s, 3H), 1.99-1.94 (m, 2H), 1.73 (dt, J = 13.3 Hz, J = 3.3 Hz, 2H), 1.62 (dt, J = 13.3 Hz, J = 3.3 Hz, 1H), 1.44-1.15 (m, 5H). ¹³C NMR (100 MHz, CDCI₃) δ 169.5, 166.9, 162.1, 156.4, 114.8, 48.3, 32.9 (2C), 25.8, 25.5, 24.8 (2C), 24.4. Ci₃Hi₉N₃0 [M + Na⁺]; calculated 256.1420, found 256.1424.

/V-(3',4'-Dimethoxyphenethyl)picolinamide 14

P(^fBu)3 from a 0.02 mg. L ¹ stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled

diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 mL of dioxane in the external chamber and 2-pyridinyl tosylate 6 (124.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (1.44 mL, 25 μηηοΙ), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (523 μΙ_, 25 μmol), 2-(3,4-dimethoxyphenyl)ethanamine (135.9 mg, 750 μηηοΙ) and diisopropylethylamine (174 μΙ_, 1.0 mmol) in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH₂Cl₂/Et₂0 (9/1) provided compound 14 as a yellow oil (88%, 151.1 mg). ^ NMR (400 MHz, CDCI₃) δ 8.48 (d, J = 4.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.13 (br s, 1H), 7.81 (dt, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.39-7.36 (m, 1H), 6.79-6.76 (m, 4H), 3.84 (s, 3H), 3.82 (s, 3H), 3.69 (q, J = 6.4 Hz, 2H), 2.86 (t, J = 7.2 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 164.3, 150.0, 149.0, 148.1, 147.7, 137.4, 131.6, 126.1, 122.2, 120.7, 112.1, 111.5, 56.0, 55.8, 40.9, 35.6. Ci₆Hi₈N₂03 [M+Na⁺]; calculated 309.1215, found 309.1321. yv-(3'-Phenylprop-2'-ynyl)picolinamide 15

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ), P(^fBu)₃ from a 0.02 mg. L^"1 stock solution in dioxane (75.9

μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηηοΙ), distilled diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 mL of dioxane in the external chamber and 2-pyridinyl tosylate (124.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (314 μΙ_, 15 μηιοΙ), 3-phenylprop-2-yn- l- amine (98.4 mg, 750 μηηοΙ) dissolved in 750 μΙ_ of dioxane and

diisopropylethylamine (174 μΙ_, 1.0 mmol) in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂CI₂ to CH^I^EtOAc (100/3) provided compound 15 as a brown solid (87%, 102.3 mg). H NMR (400 MHz, CDCI₃) δ 8.57 (ddd, J = 4.6 Hz, J = 1.6 Hz, J = 1.0 Hz, 1H), 8.28 (br s, 1H), 8.21 (dt, J =7.8 Hz, J = 1.0 Hz, 1H), 7.84 (td, J = 7.8 Hz, J = 1.6 Hz, 1H), 7.46- 7.42 (m, 3H), 7.33-7.27 (m, 3H), 4.50 (d, J = 5.5 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 163.9, 149.4, 148.1, 137.3, 131.7 (2C), 128.3, 128.2 (2C), 126.3, 122.6, 122.3, 39.4, 84.7, 83.3, 29.9. HRMS (ESI) Ci₅Hi₂N₂0 [M + Na⁺]; calculated 259.0847, found 259.0849.

Hydroxyphenyl)piperazin-l'-yl)picolinamide 16

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ), P(ⁱBu)₃ from a 0.02 mg. L ¹ stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μmol), distilled

diisopropylethylamine (131 μΙ_, 750 μηιοΙ) and 2.25 mL of dioxane in the external chamber and 2-pyridinyl tosylate 6 (124.6 mg, 500 μηηοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (1.44 ml_, 25 μηηοΙ), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (523 μΙ_, 25 μmol), 2-

(piperazin-l-yl)phenol (133.7 mg, 750 μηιοΙ) and diisopropylethylamine (174 μΙ_, 1.0 mmol) in the internal chamber. Purification of the residue by column chromatography on silica gel using pure EtOAc provided compound 16 as a yellow oil (70%, 100.3 mg). ^ NMR (400 MHz, CDCI₃) δ 8.60 (d, J = 4.8 Hz, 1H), 7.82 (td, J = 7.6 Hz, J = 2.0 Hz, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.36 (ddd, J = 7.6 Hz, J = 4.8 Hz, J = 1.2 Hz, 1H), 7.14 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.10-7.07 (m, 1H), 7.00 (br s, 1H), 6.96 (dd, J = 8.4 Hz, J = 1.6 Hz, 1H), 6.86 (td, J = 6.4 Hz, J = 1.6 Hz, 1H), 3.98-3.96 (m, 2H), 3.78-3.76 (m, 2H), 3.00-2.98 (m, 2H), 2.91- 2.88 (m, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 167.7, 153.9, 151.4, 148.4, 138.4, 137.3, 127.0, 124.8, 124.2, 121.6, 120.3, 114.5, 53.0, 52.5, 48.0, 43.2.

Ci₆Hi₇N₃0₂ [M+Na⁺]; calculated 306.1218, found 306.1215. yv-((l' ?,2' ?)-l'-Hydroxy-l'-phenylpropan-2'-yl)-yv-methylpicolinamide 17

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (432 μΙ_, 7.5 μηιοΙ), P(^fBu)₃ from a 0.02 mg. L^"1 stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ),

distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled

diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 mL of dioxane in the external chamber and 2-pyridinyl tosylate (124.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg. L^"1 stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg. L^"1 stock solution in dioxane (314 μΙ_, 15 μηιοΙ), (l£,2£)-(-)-pseudoephedrine (123.9 mg, 750 pmol), diisopropylethylamine (174 μί, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using CH₂Cl2/EtOAc (1/1) to pure EtOAc provided compound 17 as a colorless solid (67%, 90.6 mg). A diastereoselectivity of 93/7 was determined by ^ NMR. [a]²⁰D - 106.4 (c 1.0, acetone). ^ NMR (400 MHz, CDCI₃) δ 8.65 (dt, J = 4.8 Hz, J = 1.4 Hz, 1H), 7.88 (td, J = 7.7 Hz, J = 1.6 Hz, 1H), 7.80 (dt, J = 7.7, J = 1.4 Hz, 1H), 7.45 (ddd, J = 7.7 Hz, J = 4.8 Hz„ J = 1.4 Hz, 1H), 7.31-7.21 (m, 5H), 7.14 (d, J = 8.4 Hz, 1H), 4.55 (dd, J = 10.0 Hz, J = 8.4 Hz, 1H),. 4.19-4.11 (m, 1H), 3.13 (s, 3H), 0.90 (d, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ

168.5, 153.7, 146.6, 143.0, 138.3, 128.4 (2C), 127.6, 126.7 (2C), 125.5, 125.1, 75.2, 58.9, 27.2, 16.3. HRMS (ESI) Ci₆Hi₈N₂0₂ [M + Na⁺]; calculated 293.1266, found 293.1263.

2-Pyridinocarbonyl-Phe-Leu-OMe 18

The general procedure was followed using Pd(dba)₂ from a 0.01 mg. L ¹ stock solution in dioxane (432 μΙ_, 7.5 Mmol), P(^fBu)₃ from a 0.02 mg. L ¹ stock solution in dioxane (75.9 μΙ_, 7.5

Mmol), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 Mmol), distilled diisopropylethylamine (131 μΙ_, 750 Mmol) and 2.25 mL of dioxane in the external chamber and 2-pyridinyl tosylate 6 (124.6 mg, 500 Mmol), Pd(dba)₂ from a 0.01 mg. ML ¹ stock solution in dioxane (1.44 mL, 25 Mmol), D'PrPF from a 0.02 mg. ML ¹ stock solution in dioxane (523 μί, 25 Mmol), Phe-Leu-OMe (208.8 mg, 500 Mmol) and diisopropylethylamine (174 \JI L, 1.0 mmol) in the internal chamber.

Purification of the residue by column chromatography on silica gel using pentane/EtOAc (7/3 to 6/4) provided compound 18 as a yellow oil (48%,

95.4mg). [a]²⁰ _D +47.9 (c 1.0, acetone). ^ NMR (400 MHz, CDCI₃) δ 8.59 (d, J = 8.0 Hz, 1H), 8.55 (d, J = 4.8 Hz, 1H), 8.14 (dd, J = 8.0 Hz, J = 1.2 Hz, 1H), 7.82 (tt, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.44-7.40 (m, 1H), 7.29-7.23 (m, 4H), 7.22-7.19 (m, 1H), 6.59 (d, J = 8.4 Hz, 1H), 4.93-4.87 (m, 1H), 4.45 (dd, J = 8.8 Hz, J = 5.2 Hz, 1H), 3.68 (s, 3H), 3.21 (d, J = 6.8 Hz, 2H), 2.12-2.04 (m, 1H), 0.83-0.79 (m, 6H). ¹³C NMR (100 MHz, CDCI₃) δ 171.7, 170.7, 164.3, 149.0, 148.2, 137.2, 136.6, 129.3 (3C), 128.5 (2C), 126.7, 126.4, 122.2, 57.3, 54.6, 52.0, 38.1, 31.0, 18.7, 17.7. C₂₂H₂₇N₃0₄ [M + Na⁺]; calculated 406.1743, found 406.1747. /V-2-(2'-pyridinocarbonyl)-0-l,3,4,6-tetraacetyl-/S-D-glucosamine 19

500 μηιοΙ), Pd(dba)₂ from a 0.01 mg^L^"1 stock solution in THF (1.44 ml_, 25 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in THF (523 μΙ_, 25 μηηοΙ), 1,3,4,6-tetraacetyl-yS-D-glucosamine (259.0 mg, 750 μηιοΙ) and

diisopropylethylamine (174 μΙ_, 1.0 mmol) in the internal chamber. Purification of the residue by column chromatography on silica gel using pure EtOAc provided compound 19 as a colorless solid (55%, 119.1 mg. [a]²⁰ _D -9.6 (c 1.0, acetone). ^XW NMR (400 MHz, CDCI₃) δ 8.56 (m, 1H), 8.16 (dt, J = 7.6 Hz, J = 1.2 Hz, 1H), 8.12 (d, J = 9.6 Hz, 1H), 7.85 (td, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.45 (ddd, J = 7.6 Hz, J = 4.8 Hz, J = 1.2 Hz, 1H), 5.89 (d, J = 8.8 Hz, 1H), 5.39 (dd, J = 10.4 Hz, J = 9.2 Hz, 1H), 5.20 (t, J = 9.6 Hz, 1H), 4.43 (td, J = 10.0 Hz, J = 8.8 Hz, 1H), 4.34 (dd, J = 12.8 Hz, J= 4.8 Hz, 1H), 4.16 (dd, J = 12.4 Hz, J = 2.4 Hz, 1H), 3.90 (ddd, J = 9.6 Hz, J = 4.4 Hz, J = 2.0 Hz, 1H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.94 (s, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 170.7, 170.5, 169.5, 169.4, 164.6, 148.9, 148.2, 137.4, 126.6, 122.4, 92.5, 72.9, 72.4, 68.2, 61.8, 52.9, 20.9, 20.8, 20.7, 20.6. C₂oH₂₄N₂Oio [M+Na⁺]; calculated 475.1329, found 475.1325. yv-Phenylpicolinamide 20

wed using Pd(dba)₂ from a 0.01 e (432 μΙ_, 7.5 μηηοΙ), P(^fBu)₃ from

dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyi chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 ml_ of dioxane in the external chamber and 2- pyridinyl tosylate 6 (124.6 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg^L ¹ stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in dioxane (314 μΙ_, 15 μηιοΙ), aniline (68.5 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. A first purification of the residue by column chromatography on silica gel using pentane/CH₂CI₂ (1/1) to pure CH₂CI₂ followed by a second purification by preparative TLC on silica gel using pentane/CH₂CI₂ (3/7) afforded pure 20 as a colorless solid (48%, 47.8 mg). ^ NMR (400 MHz, CDCI₃) δ 10.03 (br s, 1H), 8.61 (d, J = 4.7 Hz, 1H), 8.30 (d, J = 7.7 Hz, 1H), 7.90 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 7.7 Hz, J = 4.8 Hz, 1H), 7.42-7.37 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H). ¹³C NMR (100 MHz, CDCI₃) δ 162.1, 149.9, 148.1, 137.9, 137.8, 129.2 (2C), 126.6, 124.4, 122.5, 119.8 (2C). HRMS (ESI) Ci₂H₁₀N₂O

[M+Na⁺]; calculated 259.0847, found 259.0849. yv-(4'-fluorophenyl)-6-methylpicolinamide 21

The general procedure was followed using Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (1.44 mL, 25 pmol), P(^fBu)₃

from a 0.02 mg.pL ¹ stock solution in dioxane (253 pL, 25 pmol), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 pmol), distilled

diisopropylethylamine (131 μΙ_, 750 pmol) and 1.3 mL of dioxane in the external chamber and 2-(6-methyl)pyridinyl tosylate (131.7 mg, 500 pmol), Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (1.44 mL, 25 pmol), D'PrPF from a 0.02 mg.pL ¹ stock solution in dioxane (523 pL, 25 pmol), 4-fluoroaniline (71.0 pL, 750 pmol) and diisopropylethylamine (174 pL, 1.0 mmol) in the internal chamber and reacted at 95°C for 3 days. A first purification of the residue by column

chromatography on silica gel using pentane/CH₂CI₂ (1/1) to pure CH₂CI₂ followed by a second purification by column chromatography on silica gel using

pentane/CH₂CI₂ (1/3) afforded pure 21 as a colorless solid (50%, 57.7 mg. H NMR (400 MHz, CDCI₃) δ 10.05 (br s, 1H), 8.08 (d, J = 7.8 Hz, 1H), 7.78-7.72 (m, 3H), 7.31 (d, J = 7.8 Hz, 1H), 7.06 (t, J = 8.6 Hz, 2H), 2.61 (s, 3H). ¹³C NMR (100 MHz, CDCI₃) δ 162.3, 159.4 (d, J = 242.8 Hz), 157.3, 149.0, 137.9, 134.0, 126.4, 121.5 (d, J = 7.7 Hz, 2C), 119.6, 115.8 (d, J = 22.3 Hz, 2C), 24.4. ¹⁹F NMR (377 MHz, CDCI₃) 5(ppm) : -119. MS (ESI) Ci₃HnFN₂0 [M + Na⁺]; calculated 253.1, found 253.0. yv-(4'-Fluorophenyl)-6-(3"-(Trifluoromethyl)phenoxy)picolinamide 22

(picolinafen)

The general procedure was followed using Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (1.44 mL, 25 pmol), P(^fBu)₃ from a 0.02 mg.pL ¹ stock solution in dioxane (253

μΙ_, 25 μηιοΙ), distilled pivaloyl chloride 1 (123.2 μΙ_, 1.00 mmol), distilled diisopropylethylamine (174 μΙ_, 1.0 mmol) and 1.3 mL of dioxane in the external chamber and 6-(3'-(trifluoromethyl)phenoxy)pyridin-2-yl 4-tosylate (204.7 mg, 500 pmol), Pd(dba)₂ (28.8 mg, 50 μηιοΙ), D^jPrPF (20.9 mg, 50 μηιοΙ) dissolved in dioxane (1 mL), 4-fluoroaniline (94.8 μΙ_, 1.0 mmol), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 1 mL dioxane in the internal chamber and reacted at 95°C for 7 days. Purification of the residue by column chromatography on silica gel using pentane/CH₂CI₂ (4/1 to 1/1) provided compound 22 contaminated by others products. Trituration with pentane afforded pure 22 as a colorless solid (57%, 107.9 mg). ^ NMR (400 MHz, CDCI₃) δ 9.25 (br s, 1H), 8.03 (dd, J = 7.4 Hz, J = 0.8 Hz, 1H), 7.95 (dd, J = 8.2 Hz, J = 7.4 Hz, 1H), 7.63-7.54 (m, 3H), 7.51-7.46 (m, 2H), 7.40 (dt, J = 7.4 Hz, J = 2.3 Hz, 1H), 7.18 (dd, J = 8.2 Hz, J = 0.8 Hz, 1H), 7.02 (t, J = 8.6 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 161.5, 161.1, 159.5 (d, J = 243.4 Hz), 153.7, 147.5, 141.7, 133.6, 132.3 (q, J = 32.3 Hz), 130.5, 125.1, 122.0 (q, J = 3.7 Hz), 121.1 (d, J =7.7 Hz, 2C), 121.0 (q, J = 273.6 Hz), 118.9 (q, J = 3.7 Hz), 117.9, 115.8 (d, J =22.4 Hz, 2C), 115.1. ¹⁹F NMR (377 MHz, CDCI₃) 5(ppm) : -63, -119. HRMS (ESI) CigH^F^C^ [M + Na⁺]; calculated 399.0733, found 399.0739. f- Butyl (2-(5-chloropyridine-2-carboxamido)ethyl)carbamate 23

followed using Pd(dba)₂ from a in dioxane (432 μΙ_, 7.5 μηιοΙ),

stock solution in dioxane (75.9 μΙ_, 7.5 μηιοΙ), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 μηιοΙ), distilled

diisopropylethylamine (131 μΙ_, 750 μηηοΙ) and 2.25 mL of dioxane in the external chamber and 2-(5-chloro)pyridinyl tosylate (141.9 mg, 500 μηιοΙ), Pd(dba)₂ from a 0.01 mg^L ¹ stock solution in dioxane (863 μΙ_, 15 μηηοΙ), D'PrPF from a 0.02 mg^L ¹ stock solution in dioxane (314 μΙ_, 15 μηηοΙ), /V-Boc-ethylenediamine (118.7 μΙ_, 750 μηιοΙ), diisopropylethylamine (174 μΙ_, 1.0 mmol) and 750 μΙ_ of dioxane in the internal chamber. Purification of the residue by column

chromatography on silica gel using CH₂CI₂ to CH₂Cl₂/EtOAc (4/1) provided compound 23 as a colorless solid (66%, 99.3 mg). ^ NMR (400 MHz, CDCI₃) δ 8.45 (d, J = 2.2 Hz, 1H), 8.22 (br s, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.78 (dd, J = 8.1 Hz, J = 2.2 Hz, 1H), 5.09 (t, J = 6.0 Hz, 1H), 3.56 (q, J = 6.0 Hz, 2H), 3.37 (q, J = 6.0 Hz, 2H), 1.38 (s, 9H). ¹³C NMR (100 MHz, CDCI₃) δ 164.3, 156.5, 147.9, 147.2, 137.1, 135.1, 123.3, 79.6, 40.5, 40.2, 28.4 (3C). HRMS (ESI) Ci₃Hi₈CIN₃03 [M+Na⁺]; calculated 263.0927, found 263.0935.

/V,/V'-((lS,2S)-cyclohexane-l,2-diyl)dipicolinamide 24 The general procedure was followed using Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (432 pL, 7.5 pmol), P(^fBu)₃

from a 0.02 mg.pL ¹ stock solution in dioxane (75.9 pL, 7.5 pmol), distilled pivaloyl chloride 1 (92.4 μΙ_, 750 pmol), distilled

diisopropylethylamine (131 μΙ_, 750 pmol) and 2.25 ml_ of dioxane in the external chamber and 2-pyridinyl tosylate (137.1 mg, 550 pmol), Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (863 pL, 15 pmol), D'PrPF from a 0.02 mg.pL ¹ stock solution in dioxane (314 pL, 15 pmol), (lS,2S)-(+)-l,2-diaminocyclohexane (28.5 mg, 250 pmol) dissolved in dioxane (750 pL) and diisopropylethylamine (174 pL, 1.0 mmol) in the internal chamber. Purification of the residue by column chromatography on silica gel using to CH₂Cl₂/EtOAc (9/1) to pure EtOAc provided compound 24 as a colorless solid (73%, 59.2 mg). [a]²⁰ _D +112.7 (c 1.0, acetone). ^ NMR (400 MHz, CDCI₃) δ 8.48 (d, J = 4.7 Hz, 2H), 8.22 (d, J = 6.9 Hz, 2H), 8.03 (d, J = 7.7 Hz, 2H), 7.69 (td, J = 7.7 Hz, J = 1.7 Hz, 2H), 7.30 (ddd, J = 7.7 Hz, J = 4.7 Hz, J = 1.0 Hz, 2H), 4.07-4.01 (m, 2H), 2.22-2.15 (m, 2H), 1.84-1.77 (m, 2H), 1.50-1.40 (m, 4H). ¹³C NMR (100 MHz, CDCI₃) δ 164.6 (2C), 149.9 (2C), 148.1 (2C), 137.1 (2C), 126.0 (2C), 122.1 (2C), 53.3 (2C), 32.7 (2C), 24.9 (2C). HRMS (ESI) Ci₈H₂oN₄0₂ [M + Na⁺]; calculated 347.1484, found 347.1478. /V,/V-bis(( ?)-2'-hydroxy-l'-phenylethyl)pyridine-2,6-dicarboxamide 25

The general procedure was followed using Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (432 pL, 7.5 pmol), P(^fBu)₃ from a 0.02 mg.pL ¹ stock solution in dioxane (75.9 pL, 7.5 pmol), distilled pivaloyl chloride 1 (92.4 pL, 750 pmol), distilled diisopropylethylamine (131 pL, 750 pmol) and 2.25 ml_ of dioxane in the external chamber

and pyridine-2,6-diyl bistosylate (104.9 mg, 250 pmol), Pd(dba)₂ from a 0.01 mg.pL ¹ stock solution in dioxane (863 pL, 15 pmol), D'PrPF from a 0.02 mg.pL ¹ stock solution in dioxane (314 pL, 15 pmol), (#)-(-)- phenylglycinol (343 mg, 625 pmol), diisopropylethylamine (174 pL, 1.0 mmol) and 750 pL dioxane in the internal chamber. Purification of the residue by column chromatography on silica gel using to CH₂Cl₂/EtOAc (9/1) to pure EtOAc provided compound 25 as a colorless solid (84%, 85.8 mg). [a]²⁰ _D + 118.6 (c 1.0, acetone). ^ NMR (400 MHz, CDCI₃) δ 8.59 (d, J = 7.4 Hz, 2H), 8.32 (d, J = 7.9 Hz, 2H), 8.01 (t, J = 7.9 Hz, 1H), 7.41-7.35 (m, 8H), 7.34-7.30 (m, 2H), 5.24 (dt, J = 7.4 Hz, J = 4.7 Hz, 2H), 4.00 (d, J = 4.7 Hz, 4H), 2.74 (s, 2H). ¹³C NMR (100 MHz, CDCI₃) δ 163.8 (2C), 148.6 (2C), 139.1 (2C), 139.0, 128.8 (4C), 127.8 (2C), 126.8 (4C), 125.1 (2C), 65.8 (2C), 55.8 (2C). HRMS (ESI) C₂₃H₂₃N₃0₄

[M+Na⁺]; calculated 428.1586, found 428.1581.

Design of a new solid CO-precursor and its application in substoiciometric labelling studies.

Although, pivaloyl chloride 1 is an obvious choice as the CO-equivalent, with regards to commercial availability, cost and overall atom economy, it may fall short of being a universal CO-precursor. It is a volatile liquid with a boiling point of 105 °C at atmospheric pressure. Hence, the risk of hampering the overall small- scale synthesis may be considerable. Furthermore, the isobutene by-product formed from this acid derivative may induce some problems. The presence of isobutene gas in the CO-consuming chamber did apparently not influence the outcome of the above studied aminocarbonylation, but this trend cannot be expected in general. The inherent high reactivity of olefins under a wide variety of different reaction conditions would severely limit the diversity of reactions performable in the CO-consuming chamber. Finally, the formation of isobutene ads to the overall pressure formed inside the closed multi-chamber system during CO-release, rendering pivaloyl chloride 1 an imperfect choice for further studies. The inventors report a CO-releasing system based on a solid CO-source which fulfils other desired properties e.g., the by-product formed upon CO-release is non-volatile in order to avoid cross-contamination to the CO-consuming chamber. The strategy of activating the acid precursor by its acid chloride is maintained, since this transformation is straightforward and attainable in quantitative yields using known literature protocols. With the desire to apply the new precursor for isotope labelling, it would be useful to introduce the labelled carbonyl group at a late stage in the synthesis. Ideally, the final CO-precursor would be easy to synthesize on large scale, a stable solid, easily handled and stored and with the < / / Ο^ Ι_υ ±

77 ability to be regenerated preserving a reasonable atom economy. 4 was selected for subsequent studies (Scheme 7). The synthesis of 4 starts from commercially available 9-fluorenone, which is methylated using MeMgl forming 26. This compound was then converted into 9-methyl-9W-fluorene by acid catalyzed dehydration in refluxing glacial acetic acid followed by overnight reduction using Pd/C and H₂ (1 atm - balloon) in a one pot procedure. 9-Methyl-9W-fluorene was obtained in a 67% yield (2 steps) starting from 20 grams of 9-fluorenone ( 111 mmol). 9-Methyl-9AY-fiuorene was subsequently used to capture gaseous C0₂ after deprotonation using n-BuLi in cold THF. Using excess C0₂ resulted in a total isolated yield of 91% of the acid precursor 27 after recrystallization . 9-Methyl-9H- fluorene was also used for the capture of [¹³C]-C0₂ applied as limiting reagent, resulting in a 73% isolated yield of *27. 27 and *27 was then transformed quantitatively into their acid chloride derivatives 4 and *4 using oxalyl chloride and a ca DMF in CH₂CI₂ at 30 °C.

MeMgl

9-Fluorenone 26 - 91% yield 9-Methyl-9H-fluorene recrystallization 74%

silica-plug filtration

Scheme 7. Preparation of 4 and

Both 4 and *4 are stable and easy to handle solids at room temperature which can be recrystallized from CH^I^pentane or Et₂0/pentane mixtures if needed.

4 or *4 Methylene-fluorene

9-Methyl-9H-fluorene

58%

Scheme 8. CO-Release and regeneration of 4 and *4.

Upon CO-release 4 and *4 forms non volatile 9-methylene-fluorene which upon hydrogenation using Pd/C regenerated 9-Methyl-9 -fluorene in 58% isolated yield (average of 9-methylene-fluorene formed from 43 reactions), the common precursor for 4 and *4 (Scheme 8).

The aminocarbonylation between 4-iodoanisole and n-hexylamine using Pd(dba), PPh₃ and TEA in dioxane at 80 °C proved highly capable in capture of the formed CO from 4 in combination with a second generation sealed two-chamber system (Figure 2A) (Scheme 9).

Scheme 9. Aminocarbonylation performed in two-chamber system (Figure 2A) using 4 as CO-precursor. The solid CO-precursor 4 did prove to deliver the CO required for the

aminocarbonylation and ^-NMR analysis of the crude reaction mixture in the CO- producing chamber showed full conversion of 4 into 9-methylene-fluorene after 20 hours. To our surprise, the coupling product 28 was not only formed but also isolated in a near quantitative yield (97%) based on the limiting 4 and hence the CO formed for the reaction. The high yield of isolated 28 indicates a near stoichiometric and clean conversion of the 4 precursor into 9-methylene-fluorene. In comparison, 28 was isolated in an 84% isolated yield when pivaloyl chloride 1 was applied as the CO-source. Whether this difference in yield is due to the rate at which the two different CO-precursors release the CO for the subsequent palladium-catalyzed aminocarbonylation in the CO-consuming chamber or if the conversion of pivaloyl chloride 1 into CO is less efficient compared to 4 remains to be explored. Finally, the labelled *4 was applied and *28 was secured in a comparable 95% isolated yield with >95% incorporation of [¹³C]-CO as measured by ^-NMR proving the concept of this labelling technique. The reactions depicted in scheme 9 clearly indicates that CO can be thought of as any other reagent, and hence, can be applied as the limiting reagent. Furthermore, gas-equilibriums between the two reaction chambers and mixtures are seemingly fast and non- problematic.

Various aryl halides and amine substrates were then investigated with both 1 (pivaloyl chloride), 4 or 4* as the carbon monoxide source leading to compounds with high medicinal relevance as summarized in Table 2. The CO-precursors 1 (pivaloyl chloride), 4 or 4* in combination with the two-chamber system (Figure 2A) was applied in the synthesis of a variety of biologically relevant structures (Table 4).

Table 4: Palladium-Catalyzed Carbonylations using 1 (pivaloyl chloride), 4 or 4* as the CO-source.

Chamber 1 :

Entry (Het)Ar-X Product

5 46

47 48

a Isolated yields based on CO precursor 1.5 equivalent of CO precursor, isolated yields based on the aryl halide

The synthesis outline for the compounds in Table 4 were constructed with the aim of performing the aminocarbonylation in the final step or on a late stage intermediate in order to obtain maximum utilization of the labelled precursor. All iodide electrophiles were aminocarbonylated using the Pd(dba)2/PPh₃ catalytic system in dioxane developed in scheme 9 (Table 4, Entries 1-6). This furnished the structurally related Metaclopramide (34) and Bromopride (36) in 63% and 65% isolated yield (Entries 3 and 4). Together with Itopride (32 - Entry 2) they represent gastroprokinetic drugs used in the treatment of irritable bowel syndrome, acid reflux disease, gastroparesis among others. Gratifyingly, by using *4 their [¹³C]-CO labelled analogues were isolated in yields ranging from 62-89% (Entries 2-4). Two other iodides were tested against both a primary and a secondary amine affording V-(2-(diethylamino)ethyl)nicotinamide (40), and the piperazine derivative (30), a compound patented by GlaxoSmithKline for its effect on histamine h3 receptor, in excellent 83% and 86% isolated yields respectively (Entries 1 and 1). Once again was their [¹³C]-CO labelled counterpart obtained in near 90% isolated yield, simply by changing the CO-precursor in the CO- producing chamber (Entries 6 and 2). Aryl bromides were also tested in these aminocarbonylation but preliminary studies required a change in catalytic conditions for the aminocarbonylation. Modified conditions of those reported by Buchwald and Beller using XantPhos or CatacXium A in toluene at 80 °C proved useful. In order to avoid a solvent exchange between the two chambers toluene was also applied as solvent in CO-producing chamber. Applying these new conditions compound 42, belonging to the Ampakine-class of compounds, was synthesized in an 83% isolated yield. An excellent yield of 95% was obtained of labelled 42 when applying *4 (Entry 7). Differences in isolated yield between these two reactions could be related to the stability of the catalyst in the aminocarbonylation. Towards the end of the reaction, when nearly all CO has been consumed, the stability of the palladium complex formed after oxidative addition must be high in order to avoid catalyst decomposition. Despite the relative low partial pressure of CO applied in the palladium catalyzed

aminocarbonylations reported above the catalysts seemed to stay reasonable active. At the same time electron donating ligands have been proved essential in carbonylation chemistry at high partial CO pressure in order to avoid the formation of palladium-carbonyl clusters and palladium black, an issue that is clearly not important when operating with substoichiometric CO. However, since several different protocols have been applied for the aminocarbonylations performed in this manuscript this topic will not be discussed in further detail. It should though be noted that since an execellent 95% isolated yield of *42 was secured a near quantitative CO-release in the CO-producing chamber occurs despite the change in solvent from dioxane to toluene.

Two intramolecular aminocarbonylations where also attempted affording 44, core of the PARP familiy, and 46, a precursor for Loxapine, in 84% (75% of *44) and 79% (80% of *46) isolated yields respectively. Finally, an alkoxycarbonylation was attempted applying 2-(diethylamino)ethanol as the nucleophilic counterpart and DMAP as the acyl transfer reagent. This afforded Butoxycaine (48), a local anesthetic, in a good 89% isolated yield. Once again, simply by changing to *4 in the CO-generating chamber afforded 91% isolated yield of [¹³C]-Butoxycaine. The reactions presented in Table 4, Entries 2-8 were also conducted using pivaloyl chloride 1 as the CO-source and limiting reagent and afforded the corresponding product of aminocarbonylation in poor to excellent yields (25-98%). Moreover for selected substrates it was shown that the aminocarbonylation could be run with an excess of CO-source 4 (Table 4, Entries 1-3, 6, 7 and 9) in good yields although in the case of the loxapine precursor (Table 4, Entry 9) resulting in a decreased yield based on the aryl halide.

During the aminocarbonylations using 4 visual inspection of the reactions suggested that the CO-release from this precursor initiated at a lower

temperature when compared to pivaloyl chloride, which did not initiate CO-release below 50 °C. Formation of bubbles even occurred at room temperature although at a slower rate which really startled us, since palladium-catalyzed

decarbonlyations usually requires temperatures well above 100 °C. Two room temperature aminocarbonylations were performed using protocols developed by Kondo and Lizuka in order to capture any CO formed at this unusual low temperature (Scheme 10). Pd(dba)₂ (5 mol%)

0.5 mmol - 1 equiv 1.25 equiv 86% - 28

0.

Scheme 10: Decarbonylation of 4 at room temperature. Applying DBU as the base afforded an 86% isolated yield of 28 whereas DABCO, favoring double carbonylation at room temperature, provided 68% isolated yield of 49 accompanied by 7% of 28. To the best of our knowledge this is the first time efficient palladium-catalyzed decarbonylation of an acid chloride is reported at room temperature. This in combination with the fact that CO-release from pivaloyl chloride, 4 and *4 could be performed in all solvents tested so far including toluene, dioxane and THF thereby proving the broad utility of this new method. Again, it must be stressed that the high levels of CO-capture is attributed to the reactions being performed in a sealed two-chamber system. Experimental protocols for "Design of a new solid CO-precursor and its application in substoiciometric labelling studies"

General Methods

Unless otherwise noted all reactions were carried out under inert atmosphere of argon. Solvents were dried according to standard procedures. Reactions were monitored by thin-layer chromatography (TLC) analysis. All other chemicals were used as received from the appropriate suppliers unless mentioned. Stock solutions were freshly prepared in the glovebox. Flash chromatography was carried out on Merck silica gel 60 (230-400 mesh). The ^ NMR, ¹³C NMR and ¹⁹F NMR spectra were recorded at 400 MHz, 100 MHz and 376 MHz, respectively, on a Varian Mercury 400 spectrometer. The chemical shifts are reported in ppm downfield to TMS (δ = 0) and referenced using the residual CHCI₃ resonance (δ = 7.26), DMSO-d₆ (δ = 2.50) and CD₃CN (δ = 1.94) for ^ NMR and the central CDCI₃ resonance (δ = 77.16), DMSO-d₆ (δ = 39.51), CD₃CN (δ = 206.68 and 29.92) for ¹³C NMR. NMR spectra are reported as follows (s = singlet, d = doublet, t = triplet, q = quartet, quin = quintuplet, hep = heptet, m = multiplet, br = broad; coupling constant(s) in Hz; integration). MS and HRMS were performed on a LC TOF (ES).

9-methyl-9H-fluorene-9-carboxylic acid (27). 9-methyl-9 -fluorene (5.60 g, 31.1 mmol) was dissolved in THF (40 mL) under an inert atmosphere of argon. The solution was cooled to -78 °C, nBuLi (1.6 M in hexane, 20.4 mL, 32.6 mmol) was added dropwise and left stirring for 10 min. The resulting red solution was purged with C0₂ for 10 min and left under an atmosphere of C0₂ using a balloon while the reaction mixture was allowed to reach room temperature. Upon reaching room temperature the reaction mixture gradually looses the red coloration. THF was subsequently removed in vacuo, 4 M aqueous HCI (100 mL) was added and extracted with Et₂0 (3 x 100 mL). The combined organic phases were washed with brine, dried over MgS0₄, filtered and evaporated in vacuo. The residue was recrystallized from EtOAc/pentane to afford the title compound 27 as colorless crystals (6.359 g, 28.4 mmol, 91%). ^ NMR (400 MHz, CDCI₃) δ (ppm) 7.74

(ddd, J = 7.6, 1.2, 0.8 Hz, 2H), 7.56 (ddd, J = 7.6, 1.2, 0.8 Hz, 2H), 7.41 (td, J = 7.2, 1.2 Hz, 2H), 7.34 (td, J = 7.6, 1.2 Hz, 2H), 1.77 (s, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 180.8, 146.6 (2C), 140.4 (2C), 128.4 (2C), 127.7 (2C), 124.4 (2C), 120.3 (2C), 57.0, 23.7. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

[13C]-9-methyl-9H-fluorene-9-carboxylic acid (*27). 9-methyl-9 -fluorene (9.66 g, 53.6 mmol) was dissolved in THF (90 mL) under an inert atmosphere of argon. The solution was cooled to -78 °C, nBuLi (1.6 M in hexane, 33.5 mL, 53.6 mmol) was added dropwise and left stirring for 15 min to afford a red solution. C0₂ from pressurized container (ISOTEC®, loading pressure 2.42 atm, loading temperature 300 K, cylinder volume 451 mL, 43.76 mmol) was transferred to the reaction mixture via a cannula, which was left in place while allowing the mixture to reach room temperature overnight. The red coloration of the solution persisted until quenching of the reaction mixture with 4 M aqueous HCI (100 mL). The water phase was extracted with Et₂0 (3 x 100 mL). The combined organic phases were washed with brine, dried over MgS0₄, filtered and evaporated in vacuo. The residue was recrystallized from EtOAc/pentane and the filtrate was evaporated in vacuo and subjected to column chromatography (CH₂CI₂, then Et₂0 as eluent) to afford the title compound *27 as colorless crystals (7.39 g, 32.8 mmol, 75% from ¹³C0₂). H NMR (400 MHz, CDCI₃) δ (ppm) 7.74 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.41 (td, J = 7.2, 0.8 Hz, 2H), 7.33 (td, J = 7.2, 1.2 Hz, 2H), 1.76 (d, J = 4.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 180.5 (¹³C-enriched), 146.7 (2C), 140.4 (d, J = 6.4 Hz, 2C), 128.4 (2C), 127.8 (2C), 124.4 (2C), 120.3 (2C), 57.0 (d, J = 54.8 Hz), 23.8. HRMS C₂oH₃₇N0₄ [M+Na⁺]; calculated : , found : .

9-methyl-9H-fluorene-9-carbonyl chloride (4). 9-methyl-9 -fluorene-9- carboxylic acid 27 (2.680 g, 11.95 mmol) was dissolved in CH₂CI₂ (20 mL) under an inert atmosphere of argon. To this was added oxalyl chloride (3.03 mL, 35.9 mmol) and one drop of DMF (~0.01 mL, 0.13 mmol). The reaction mixture was heated to 30 °C until bubbling subsides (3 hours) and excess oxalyl chloride was removed in vacuo to afford the title compound 4 in quantitative yield as a pale yellow solid, which was used without further purification. H NMR (400 MHz, CDCI₃) 5 (ppm) 7.82-7.78 (m, 2H), 7.52-7.46 (m, 4H), 7.42-7.36 (m, 2H), 1.82 (s, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 176.8, 145.6 (2C), 141.2 (2C), 129.3 (2C), 128.3 (2C), 124.1 (2C), 120.8 (2C), 66.3, 22.7. HRMS C₂₀H₃7NO₄ [M + Na⁺]; calculated : , found : .

[13C]-9-methyl-9H-fluorene-9-carbonyl chloride (*4). [13C]-9-methyl-9H- fluorene-9-carboxylic acid *27 (2.00 g, 8.88 mmol) was dissolved in CH2CI2 (20 ml_) under an inert atmosphere of argon. To this was added oxalyl chloride (2.25 ml_, 26.6 mmol) and one drop of DMF (~0.01 ml_, 0.13 mmol). The reaction mixture was heated to 30 °C until bubbling subsides (3 hours) and excess oxalyl chloride was removed in vacuo to afford the title compound *27 in quantitative yield as a pale yellow solid, which was used without further purification. H NMR (400 MHz, CDCI₃) 5 (ppm) 7.82-7.78 (m, 2H), 7.52-7.46 (m, 4H), 7.42-7.36 (m, 2H), 1.81 (d, J = 6.0 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 176.8 (¹³C- enriched), 145.5 (d, J = 1.6 Hz, 2C), 141.2 (d, J = 1.9 Hz, 2C), 129.3 (2C), 128.3 (2C), 124.0 (d, J = 1.0 Hz, 2C), 66.3 (d, J = 51.3 Hz), 22.7. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

General protocol for aryl iodides (Chamber 1)

In a glovebox under argon, to chamber 1 of two-chamber system (Figure 2A) was added Pd(dba)₂ (14.4 mg, 0.025 mmol), PPh₃ (13.1 mg, 0.05 mmol), aryl iodide (0.5 mmol), dioxane (3 ml_), amine (1.0 mmol), TEA (139 μΙ_, 1.0 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated to 80 °C overnight (typically between 16 and 20 hours). The crude reaction mixture was evaporated on silica gel and directly subjected to column chromatography.

General protocol for aryl bromides (Chamber 1)

In a glovebox under argon, to chamber 1 of two-chamber system (Figure 2A) was added Pd(dba)₂ (14.4 mg, 0.025 mmol), cataCXium® A (17.9 mg, 0.05 mmol), Na₂C0₃ (159 mg, 1.5 mmol), aryl bromide (0.5 mmol), amine (1.0 mmol) and toluene (3 ml_) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated to 80 °C overnight (typically between 16 and 20 hours). The crude reaction mixture was evaporated on silica gel and directly subjected to column chromatography.

General protocol for CO release from pivaloyl chloride 1 (Chamber 2)

In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added Pd(dba)₂ (9.6 mg, 0.017 mmol), pivaloyl chloride 1 (from stock solution, 0.1 mg μΙ_^_1, 402 μΙ_, 0.333 mmol), solvent (same as the solvent in the reaction chamber, chamber 1) (2 ml_), P(tBu)₃ (from stock solution, 0.01 mg μΙ_ ^_1, 337 μΙ_, 0.0167 mmol) and DIPEA (87 μΙ_, 0.50 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated at the temperature described for the CO consuming chamber.

General protocol for CO release from XCI/*XCI (Chamber 2)

In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added Pd(dba)₂ (9.6 mg, 0.017 mmol), acid chloride (9-methyl-9tt-fluorene-9- carbonyl chloride 4 or [13C]-9-methyl-9 -fluorene-9-carbonyl chloride *4) (81.0 mg, 0.333 mmol), solvent (same as the solvent in the reaction chamber, chamber 1) (3 ml_), P(tBu)₃ (from stock solution, 0.01 mg μΙ_^_1, 337 μΙ_, 0.0167 mmol) and DIPEA (87 μΙ_, 0.50 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated at the temperature described for the CO consuming chamber.

General protocol for the release of excess CO from XCI (Chamber 2)

In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added Pd(dba)₂ (4.3 mg, 0.0075 mmol), 9-methyl-9tt-fluorene-9-carbonyl chloride 4 (182 mg, 0.750 mmol), solvent (same as the solvent in the reaction chamber, chamber 1) (3 ml_), P(tBu)₃ (from stock solution, 0.01 mg μΙ_ ^_1, 151 μΙ_, 0.00746 mmol) and DIPEA (196 μΙ_, 1.13 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated at the temperature described for the CO consuming chamber.

yv-hexyl-4-methoxybenzamide (28). The reaction chambers of S2 was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 4-iodoanisole (117 mg) and n- hexylamine (132 μΙ_). The title compound 28 was obtained after flash

chromatography (30% EtOAc in pentane as eluent) as a pale yellow solid (75.0 mg, 0.319 mmol, 96% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 7.73 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 9.2 Hz, 2H), 6.49 (br s, 1H), 3.79 (s, 3H), 3.37 (td, J = 7.2, 6.0 Hz, 2H), 1.55 (quintet, J = 6.8 Hz, 2H), 1.36-1.21 (m, 6H), 0.85 (t, J = 6.4 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 167.1, 162.0, 128.7 (2C), 127.2, 113.6 (2C), 55.4, 40.1, 31.6, 29.7, 26.8, 22.6, 14.1. HRMS C₂₀H₃₇NO₄ [M + Na⁺]; calculated : , found : .

CO-release from pivaloyi chloride 1 : The title compound 28 was obtained in a 84% isolated yield from pivaloyi chloride 1 when loading the reaction chambers of S2 according to "General protocol for aryl iodides (Chamber 1)" except solvent used was THF (3 mL) and "General protocol for CO release from pivaloyi chloride 1 (Chamber 2)".

CO-release from Mo(CO)e'- In a glovebox under argon, to chamber 1 of two- chamber system (Firgure 2A) was added Pd(dba)₂ (14.4 mg, 0.025 mmol), PPh₃ (13.1 mg, 0.050 mmol), 4-iodoanisole (117 mg, 0.50 mmol), THF (3 mL), n- hexylamine (132 μί, 1.0 mmol), TEA (139 μί, 1.0 mmol). The chamber was sealed with a screwcap fitted with a Teflon® seal. In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added Mo(CO)₆ (132 mg, 0.50 mmol), THF (3 mL) and pyridine (201 μί, 2.5 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated to 70 °C for 21 hours. The crude reaction mixture was evaporated on silica gel and the title compound 28 was obtained after flash chromatography (increasing polarity from 20% to 25% EtOAc in pentane as eluent) as a pale yellow solid (113.8 mg, 0.484 mmol, 97%).

Room temperature experiment to form 28: In a glovebox under argon, to chamber 1 of two-chamber system (Figure 2A) was added Pd(dba)₂ (5.8 mg, 0.01 mmol), tBu₃P-HBF₄ (5.8 mg, 0.02 mmol), 4-iodoanisole (117 mg, 0.50 mmol), THF (3 mL), n-hexylamine (132 μί, 1.0 mmol), DABCO (112 mg, 1.0 mmol). The chamber was sealed with a screwcap fitted with a Teflon® seal. In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added

Pd(dba)₂ (7.2 mg, 0.013 mmol), 9-methyl-9 -fluorene-9-carbonyl chloride 4 (152 mg, 0.625 mmol), THF (3 mL), P(tBu)₃ (from stock solution, 0.01 mg μί^_1, 253 μ\-, 0.013 mmol) and DIPEA (163 μί, 0.94 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was held at 25 °C for 48 hours. The crude reaction mixture was

evaporated on silica gel and the title compound 28 was obtained after flash chromatography (increasing polarity from 10% to 40% EtOAc in pentane as eluent) as a pale yellow solid (101.0 mg, 0.429 mmol, 86%).

CO-release from dimethylphenylsilanecarboxylic acid: One camber of the two- chamber system (Figure 2A) is loaded according to "General protocol for aryl iodides (Chamber 1)". The other is loaded with dimethylphenylsilanecarboxylic acid (65.0 mg, 0.36 mmol) in THF (3ml_) and sealed with a teflon coated microwave cap. Tetrabutylammonium fluoride in THF (1.0 M, 0.40 mL, 0.40 mmol) is added to the CO producing chamber and the two-chamber system is heated to 70°C overnight. The crude reaction mixture of the carbonylation chamber is concentrated in vacuo and purified by column chromatography (20% EtOAc in pentane as eluent) to give a brown solid (77.5 mg, 0.329 mmol, 91% from dimethylphenylsilanecarboxylic acid). H NMR (400 MHz, CDCI₃) δ (ppm) 7.72 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.24 (br s, 1H), 3.83 (s, 3H), 3.40 (td, J = 7.2, 6.0 Hz, 2H), 1.58 (quintet, J = 7.2 Hz, 2H), 1.38- 1.27 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 167.1, 162.0, 128.7 (2C), 127.2, 113.7 (2C), 55.5, 40.1, 31.6, 29.8, 26.8, 22.7, 14.1.

CO-release from methyl methyldiphenylsilanecarboxylate: One camber of the two- chamber system (Figure 2A) is loaded according to "General protocol for aryl iodides (Chamber 1)". The other is loaded with methyl

methyldiphenylsilanecarboxylate (175.0 mg, 0.68 mmol) in THF (3mL) and sealed with a teflon coated microwave cap. Tetrabutylammonium fluoride in THF (1.0 M, 0.50 mL, 0.50 mmol) is added to the CO producing chamber and the two-chamber system is heated to 70°C overnight. The crude reaction mixture of the

carbonylation chamber is concentrated in vacuo and purified by column

chromatography (20% EtOAc in pentane as eluent) to give a brown solid (110.5 mg, 0.470 mmol, 94% from 4-iodoanisole). NMR (400 MHz, CDCI₃) δ (ppm) 7.73 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.28 (br s, 1H), 3.82 (s, 3H), 3.40 (td, J = 7.2, 6.0 Hz, 2H), 1.57 (quintet, J = 7.2 Hz, 2H), 1.38- 1.26 (m, 6H), 0.87 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 167.1, 162.0, 128.7 (2C), 127.2, 113.7 (2C), 55.5, 40.1, 31.6, 29.8, 26.8, 22.7, 14.1. HRMS

Ci₄H₂iN0₂ [M+Na⁺] ; calculated : 258.1465, found : 258.1468.

[ 13C]-/V-hexyl-4-methoxybenzamide (*28). The reaction chambers of S2 was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 4-iodoanisole (117 mg) and n-hexylamine (132 μΙ_). The title compound *28 was obtained after flash chromatography (25% EtOAc in pentane as eluent) as a pale yellow solid (75.4 mg, 0.319 mmol, 96% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 7.76- 7.70 (m, 2H), 6.86 (d, J = 8.4 Hz, 2H), 6.45 (br s, 1H), 3.80 (s, 3H), 3.41-3.34 (m, 2H), 1.56 (quintet, J = 6.8 Hz, 2H), 1.37-1.22 (m, 6H), 0.85 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 167.1 (¹³C-enriched), 162.0, 128.7 (d, J = 2.4 Hz, 2C), 127.2 (d, J = 65.7 Hz), 113.7 (d, J = 4.3 Hz, 2C), 55.4, 40.1, 31.6, 29.8 (d, J = 0.9 Hz), 26.8, 22.6, 14.1. HRMS C₂₀H₃₇NO₄ [M + Na⁺];

calculated : , found : .

(4-isopropylpiperazin-l-yl)(4-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)methanone (30). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 4-(4-iodophenoxy)tetrahydro- 2 -pyran 29 (152 mg) and 1-isopropylpiperazine (203 μΙ_). The title compound 30 was obtained after flash chromatography (increasing polarity from 0% to 2% MeOH in a mixture of TEA/CH^I^E^O (1 : 50: 50) as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (92.1 mg, 0.277 mmol, 83% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 7.35 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 4.54-4.46 (m, 1H), 3.99-3.92 (m, 2H), 3.84-3.38 (m, 6H), 2.70 (sept, J = 6.8 Hz, 1H), 2.60-2.40 (m, 4H), 2.04-1.96 (m, 2H), 1.82-1.72 (m, 2H), 1.02 (d, J = 6.4 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 170.1, 158.4, 129.3 (2C), 128.3, 115.7 (2C), 71.7, 65.1 (2C), 54.6, 48.8 (br, 2C), 42.7 (br, 2C), 31.8 (2C), 18.5 (2C). HRMS

C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

Excess CO: The title compound 30 was obtained in a 97% isolated yield from 29 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for the release of excess CO from 4 (Chamber 2)".

[13C]-(4-isopropylpiperazin-l-yl)(4-((tetrahydro-2H-pyran-4- yl)oxy)phenyl)methanone (*30). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 4-(4-iodophenoxy)tetrahydro- 2 -pyran 29 (152 mg) and 1-isopropylpiperazine (203 μΙ_). The title compound *30 was obtained after flash chromatography (increasing polarity from 0% to 2% MeOH in a mixture of TEA/CH₂Cl₂/Et₂0 (1 : 50: 50) as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (99.8 mg, 0.299 mmol, 90% from *4). ^ NMR (400 MHz,

CDCI₃) δ (ppm) 7.40-7.33 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H), 4.55-4.48 (m, 1H), 4.00-3.93 (m, 2H), 3.84-3.38 (m, 6H), 2.71 (sept, J = 6.4 Hz, 1H), 2.61-2.40 (m, 4H), 2.06-1.97 (m, 2H), 1.83-1.73 (m, 2H), 2.07 (d, J = 6.4 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm). 170.0 (¹³C-enriched), 158.3, 129.2 (d, J = 2.3 Hz, 2C), 128.2 (d, J = 67.6 Hz), 115.6 (d, J = 4.2 Hz, 2C), 71.6, 65.0 (2C), 54.5, 48.7 (br, 2C), 42.7 (br, 2C), 31.7 (2C), 18.4 (2C). HRMS C₂₀H₃₇NO₄ [M + Na⁺]; calculated : , found : .

Itopride (32). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 4-Iodoveratrole 31 (132 mg) and 2-(4- (aminomethyl)phenoxy)- V, V-dimethylethanamine (194 mg). The title compound 32 was obtained after flash chromatography (increasing polarity from 60% to 20% EtOAc in a mixture of MeOH/CH₂CI₂ (1 : 1) as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (111.7 mg, 0.312 mmol, 94% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 7.45 (d, J = 2.0 Hz, 1H), 7.29-7.25 (m, 3H), 6.90 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.4 Hz, 6.35 (br s, 1H), 4.56 (d, J = 5.6 Hz, 2H), 4.06 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.73 (t, J = 5.6 Hz, 2H), 2.34 (s, 6H). ¹³C NMR (100 MHz, CDCI3) δ (ppm) 166.9, 158.1, 151.5, 148.8, 130.6, 129.1 (2C), 127.0, 119.5, 114.6 (2C), 110.6, 110.1, 65.9, 58.2, 55.9, 55.9, 45.8 (2C), 43.4. HRMS C20H37NC [M+Na⁺] ; calculated : , found : .

CO-release from pivaloyi chloride 1 : The title compound 32 was obtained in a 98% isolated yield from pivaloyi chloride 1 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyi chloride 1 (Chamber 2)".

Excess CO: The title compound 32 was obtained in a 91% isolated yield from 31 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for the release of excess CO from 4 (Chamber 2)".

[ 13C]-Itopride (*32). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 4-Iodoveratrole 31 (132 mg) and 2-(4- (aminomethyl)phenoxy)- V, V-dimethylethanamine (194 mg). The title compound *32 was obtained after flash chromatography (increasing polarity from 60% to 20% EtOAc in a mixture of MeOH/CH₂Cl2 (1 : 1) as eluent) and subsequent washing of a CH2CI2 solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (106.4 mg, 0.296 mmol, 89% from *4). ^ NMR (400 MHz,

CDCI3) δ (ppm) 7.46 (dd, J = 4.0 Hz, J = 2.0 Hz, 1H), 7.30-7.25 (m, 3H), 6.90 (d, J = 8.8 Hz, 2H), 6.84 (dd, J = 8.4 Hz, 0.8 Hz), 6.45-6.38 (m, 1H), 4.56 (dd, J = 5.6, 3.2, 2H), 4.05 (t, J = 5.6 Hz, 2H), 3.92 (s, 3H), 3.91 (s, 3H), 2.72 (t, J = 6.0 Hz, 2H), 2.33 (s, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 166.9 (¹³C-enriched), 158.2, 151.6, 148.8 (d, J = 3.2 Hz), 130.7, 129.1 (2C), 127.1 (d, J = 66.1 Hz), 119.5 (d, J = 2.4 Hz), 114.7 (2C), 110.6, 110.2. HRMS C₂₀H₃₇NO₄ [M + Na⁺] ;

calculated : , found : .

Metoclopramide (34). The reaction chambers of S2 was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 2-chloro-4-iodo-5-methoxyaniline 33 (142 mg) and /V^A^-diethylethane-l^-diamine (141 μΙ_). The title compound 34 was obtained after flash chromatography (increasing polarity from 5% to 80% MeOH in CH₂CI₂ as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (63.2 mg, 0.211 mmol, 63% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.21 (br t, 1H), 8.09 (s, 1H), 6.28 (s, 1H), 4.44 (br s, 2H), 3.85 (s, 3H), 3.47 (q, J = 6.0 Hz, 2H), 2.60 (t, J = 6.2 Hz, 2H), 2.55 (q, J = 7.1 Hz, 4H), 1.02 (t, J = 7.1 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.5, 157.7, 146.8, 132.9, 112.7, 111.4, 98.0, 56.0, 51.7, 46.8, 37.6, 12.2. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated : , found : .

CO-release from pivaloyl chloride 1 : The title compound 34 was obtained in a 53% isolated yield from pivaloyl chloride 1 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyl chloride 1 (Chamber 2)".

Excess CO: The title compound 34 was obtained in a 41% isolated yield from 33 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for the release of excess CO from 4 (Chamber 2)".

[13C]-Metoclopramide (*34). The reaction chambers of S2 was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 2-chloro-4-iodo-5-methoxyaniline 33 (142 mg) and /V^A^-diethylethane-l^-diamine (141 μΙ_). The title compound *34 was obtained after flash chromatography (increasing polarity from 5% to 20% MeOH in CH2CI2 as eluent) and subsequent washing of a CH2CI2 solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (61.8 mg, 0.205 mmol, 62% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.20 (br s, 1H), 8.07 (d, J = 4.8 Hz, 1H), 6.29 (d, J = 1.6 Hz, 1H), 4.52 (br s, 2H), 3.83 (s, 3H), 3.48-3.41 (m, 2H), 2.58 (t, J = 6.0 Hz, 2H), 2.53 (q, J = 7.2 Hz, 4H), 1.01 (t, J = 6.8 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.5 (¹³C-enriched), 157.7, 146.8, 132.9, 112.8 (d, J = 65.8 Hz), 111.4 (d, J = 3.3 Hz), 98.0 (d, J = 3.2 Hz), 55.9, 51.7, 46.8 (2C), 37.6, 12.2 (2C), 3 peaks in the carbonyl region (168-163 ppm) likely resulting from alternative carbonylation reactions with ¹³CO (~2% relative to ¹³C peak at 164.5 ppm).. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

Bromopride (36). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 2-bromo-4-iodo-5-methoxyaniline 35 (164 mg) and /V^A^-diethylethane-l^-diamine (141 μΙ_). The title compound 36 was obtained after flash chromatography (increasing polarity from 5% to 100% MeOH in CH₂CI₂ as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (74.7 mg, 0.217 mmol, 65% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.23 (br s, 1H), 8.22 (s, 1H), 6.29 (s, 1H), 4.51 (br s, 2H), 3.85 (s, 3H), 3.51 (q, J = 5.6 Hz, 2H), 2.66 (t, J = 6.0 Hz, 2H), 2.61 (q, J = 7.2 Hz, 4H), 1.06 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.5, 158.4, 147.9, 136.2, 113.2, 100.6, 97.8, 56.0, 51.7, 47.0, 37.4, 11.8. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated : , found : .

CO-release from pivaloyi chloride 1 : The title compound 36 was obtained in a 73% isolated yield from pivaloyi chloride 1 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyi chloride 1 (Chamber 2)".

[13C]-Bromopride (*36). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 2-bromo-4-iodo-5-methoxyaniline 35 (164 mg) and /V^-diethylethane-l^-diamine (141 μΙ_). The title compound *36 was obtained after flash chromatography (increasing polarity from 5% to 20% MeOH in CH2CI2 as eluent) and subsequent washing of a CH2CI2 solution of the compound with saturated aqueous Na₂C0₃, as a colorless solid (75.6 mg, 0.219 mmol, 66% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.23 (d, J = 4.4 Hz, 1H), 8.19 (br s, 1H), 6.29 (d, J = 1.2 Hz, 1H), 4.54 (br s, 2H), 3.83 (s, 3H), 3.48-3.42 (m, 2H), 2.58 (t, J = 6.4 Hz, 2H), 2.53 (q, J = 7.2 Hz, 4H), 1.01 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.4 (¹³C-enriched), 158.3 (d, J = 0.8 Hz), 147.9, 136.2 (d, J = 1.3 Hz), 113.3 (d, J = 65.9 Hz), 100.6 (d, J = 5.2 Hz), 97.8 (d, J = 3.1 Hz), 55.9, 51.7 (d, J = 2.0 Hz), 46.8 (2C), 37.6, 12.2 (2C), 6 peaks in the carbonyl region (170-163 ppm) likely resulting from alternative carbonylation reactions with ¹³CO (~4% relative to ¹³C peak at 164.4 ppm). HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

Raclopride (38). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyl chloride 1 (Chamber 2)". 4,6-dichloro-2-iodo-3- methoxyphenol 37 (159 mg) and (S)-(l-ethylpyrrolidin-2-yl)methanamine (140 μΙ_). The title compound 38 was obtained after flash chromatography (5% MeOH in CH2CI2 as eluent) as a brown oil (28.9 mg, 0.083 mmol, 25% from pivaloyl chloride 1). ^ NMR (400 MHz, CD₃CN) δ (ppm) 10.61 (br s, 1H), 9.02 (br s, 1H), 7.56 (s, 1H), 3.92 (s, 1H), 3.81 (dt, J = 14.4, 4.8 Hz, 1H), 3.69 (dt, J = 14.0, 3.2 Hz, 1H), 3.52-3.45 (m, 1H), 3.36-3.28 (m, 1H), 3.18 (dq, J = 12.4, 7.2 Hz, 1H), 2.78-2.64 (m, 2H), 2.16-2.05 (m, 1H), 1.93-1.73 (m, 3H), 1.25 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CD₃CN) δ (ppm) 170.1, 158.9, 155.0, 134.5, 119.2, 117.5, 111.0, 65.5, 62.9, 54.2, 49.9, 40.9, 28.8, 23.1, 12.3. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

CO-release from Mo(CO)e'- In a glovebox under argon, to chamber 1 of two- chamber system S2 was added Pd(dba)₂ (19.9 mg, 0.0347 mmol), PPh₃ (18.2 mg, 0.0693 mmol), 4,6-dichloro-2-iodo-3-methoxyphenol 37 (221 mg, 0.693 mmol), THF (3 ml_), (S)-(l-ethylpyrrolidin-2-yl)methanamine (193 μΙ_, 1.39 mmol), TEA (194 μΙ_, 1.39 mmol). The chamber was sealed with a screwcap fitted with a Teflon® seal. In a glovebox under argon, to chamber 2 of two-chamber system S2 was added Mo(CO)₆ (183 mg, 0.693 mmol), THF (3 ml_) and pyridine (280 μΙ_, 3.47 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was heated to 70 °C for 19 hours. The crude reaction mixture was evaporated on silica gel and the title compound 38 was obtained after flash chromatography (5% MeOH in CH₂CI₂ as eluent) as brown oil (153.7 mg, 0.443 mmol, 64% from 37).

N-(2-(diethylamino)ethyl)nicotinamide (40). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from XCI/*XCI (Chamber 2)". 3- Iodopyridine 39 (103 mg) and /V^/V^diethylethane-l^-diamine (141 μΙ_). The title compound 40 was obtained after flash chromatography (increasing polarity from 20% to 100% MeOH in EtOAc as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless oil (63.1 mg, 0.285 mmol, 86% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.95 (d, J = 1.6 Hz, 1H), 8.66 (dd, J = 4.8, 1.2 Hz, 1H), 8.09 (dt, J = 8.0, 2.0 Hz, 1H), 7.34 (ddd, J = 8.0, 4.8, 0.8 Hz, 1H), 7.20 (br s, 1H), 3.45 (q, J = 5.2 Hz, 2H), 2.62 (t, J = 6.0 Hz, 2H), 2.52 (q, J = 7.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 165.4, 152.1, 148.0, 135.1, 130.4, 123.5, 51.2, 46.7 (2C), 37.3, 12.0 (2C). HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

CO-release from pivaloyi chloride 1 : The title compound 40 was obtained in a 85% isolated yield from pivaloyi chloride 1 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyi chloride 1 (Chamber 2)".

Excess CO: The title compound 40 was obtained in a 56% isolated yield from 39 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for the release of excess CO from 4 (Chamber 2)".

[13C]-N-(2-(diethylamino)ethyl)nicotinamide (*40). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl iodides

(Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 3- Iodopyridine 39 (103 mg) and /V^/V^diethylethane-l^-diamine (141 μΙ_). The title compound *40 was obtained after flash chromatography (increasing polarity from 20% to 100% MeOH in EtOAc as eluent) and subsequent washing of a CH₂CI₂ solution of the compound with saturated aqueous Na₂C0₃, as a colorless oil (64.5 mg, 0.290 mmol, 87% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.95-8.93 (m, 1H), 8.67 (dd, J = 4.8, 1.2 Hz, 1H), 8.11-8.06 (m, 1H), 7.34 (ddt, J = 8.0, 4.8, 0.8 Hz, 1H), 7.13 (br s, 1H), 3.48-3.42 (m, 2H), 2.62 (t, J = 6.4 Hz, 2H), 2.52 (q, J = 7.2 Hz, 4H), 0.99 (t, J = 7.2 Hz, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 165.5 (¹³C-enriched), 152.2, 148.1 (d, J = 3.3 Hz), 135.3, 130.6 (d, J = 64.8 Hz), 123.7 (d, J = 2.8 Hz), 51.3, 46.9 (2C), 37.5, 12.2 (2C). HRMS

C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)(piperidin-l-yl)methanone (42).

The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine 41 (108 mg) and piperidine (99 μΙ_). The title compound 42 was obtained after two times flash chromatography (1^st: increasing polarity from 5% to 30% EtOAc in CH₂CI₂ as eluent, 2^nd: increasing polarity from 5% to 30% Et₂0 in CH₂CI₂ as eluent) as a colorless oil (68.1 mg, 0.275 mmol, 83% from 4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 6.90 (d, J = 2.0 Hz, 1H), 6.87-6.80 (m, 2H), 4.23 (s, 4H), 3.74-3.26 (m, 4H), 1.68-1.44 (m, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 169.8, 144.6, 143.3, 129.6, 120.4, 117.1, 116.5, 64.5, 64.3, 49.0 (br), 43.4 (br), 26.4 (br, 2C), 24.7. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated : , found : . CO-release from pivaloyi chloride 1 : The title compound 42 was obtained in a 86% isolated yield from pivaloyi chloride 1 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl iodides (Chamber 1)" and "General protocol for CO release from pivaloyi chloride 1 (Chamber 2)".

Excess CO: The reaction chamber 1 of the two-chamber system (Figure 2A) was loaded with 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine 41 (108 mg, 0.50 mmol), piperidine (99 μΙ_, 1.0 mmol), Na₂C0₃ (159 mg, 1.5 mmol), Xantphos (14.5 mg, 0.025 mmol), Pd(OAc)₂ (5.6 mg, 0.025 mmol) and toluene (3 ml_) and the CO- releasing chamber 2 (Figure 2A) was loaded according to "General protocol for the release of excess CO from 4 (Chamber 2)" in a glovebox under argon. The title compound 42 was obtained after flash chromatography (increasing polarity from 50% to 100% Et₂0 in pentane as eluent) as a yellow oil (121.5 mg, 0.491 mmol, 98% from 41).

[13C]-(2,3-dihydrobenzo[b] [l,4]dioxin-6-yl)(piperidin-l-yl)methanone (*42). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". 6-bromo-2,3-dihydrobenzo[b][l,4]dioxine 41 (108 mg) and piperidine (99 μΙ_). The title compound *42 was obtained after two times flash chromatography (1^st: increasing polarity from 10% to 40% EtOAc in CH₂CI₂ as eluent, 2^nd: increasing polarity from 5% to 30% Et₂0 in CH₂CI₂ as eluent) as a colorless oil (78.3 mg, 0.315 mmol, 95% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm) 6.90 (dd, J = 4.0, 2.0 Hz, 1H), 6.88-6.80 (m, 2H), 4.23 (s, 4H), 3.75-3.20 (m, 4H), 1.68-1.44 (m, 6H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 169.8 (¹³C- enriched), 144.7 (d, J = 0.6 Hz), 143.3 (d, J = 5.6 Hz), 129.7 (d, J = 67.2 Hz), 120.5 (d, J = 1.9 Hz), 117.1 (d, J = 4.9 Hz), 116.5 (d, J = 2.6 Hz), 64.5, 64.3, 48.9 (br), 43.4 (br), 26.3 (br, 2C), 24.7. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated : , found : .

3,4-dihydroisoquinolin-l(2H)-one (44). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 2-(2- bromophenyl)ethanamine 43 (100 mg). The title compound 44 was obtained after flash chromatography (increasing polarity from 40% to 100% EtOAc in pentane as eluent) as a colorless oil (41.0 mg, 0.279 mmol, 84% from 4). H NMR (400 MHz, CDCI₃) δ (ppm) 8.05 (dd, J = 7.6, 1.2 Hz, 1H), 7.43 (td, J = 7.6, 1.6 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.31 (br s, 1H), 7.20 (dt, J = 7.6, 0.4 Hz, 1H), 3.59-3.54 (m, 2H), 2.98 (t, J = 6.4 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 166.8, 139.0, 132.2, 129.1, 127.9, 127.3, 127.1, 40.2, 28.4. HRMS C₂₀H₃7NO₄ [M + Na⁺];

calculated : , found : .

[13C]-3,4-dihydroisoquinolin-l(2H)-one (*44). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 2-(2- bromophenyl)ethanamine 43 (100 mg). The title compound *44 was obtained after flash chromatography (increasing polarity from 40% to 100% EtOAc in pentane as eluent) as a colorless oil (36.9 mg, 0.249 mmol, 75% from *4). H NMR (400 MHz, CDCI₃) δ (ppm) 8.05 (dd, J = 7.2, 3.6 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.38 (br s, 1H) 7.34 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 3.59-3.53 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 166.8 (¹³C-enriched), 139.0, 132.2, 129.1 (d, J = 61.4 Hz), 127.9, 127.3 (d, J = 3.0 Hz), 127.1 (d, J = 4.0 Hz). HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

2-chlorodibenzo[b,f] [l,4]oxazepin-ll(10H)-one (46). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 2-(2-bromophenyl)ethanamine 45 (149 mg). In addition DMAP (15.3 mg, 0.125 mmol) was added to chamber 1. The title compound 46 was obtained after flash chromatography (increasing polarity from 0% to 10% Et₂0 in CH₂CI₂ as eluent) as a colorless solid (64.7 mg, 0.263 mmol, 79% from 4).¹H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.68 (br s, 1H), 7.72 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 8.8, 2.8 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 7.6, 1.2 Hz, 1H), 7.23- 7.12 (m, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.4, 157.6, 150.1, 134.0, 130.8, 130.6, 129.4, 127.3, 126.2, 125.4, 122.8, 121.8, 121.3. HRMS C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

Excess CO: The title compound 46 was obtained in a 43% isolated yield from 45 when loading the reaction chambers of (Figure 2A) according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for the release of excess CO from 4 (Chamber 2)". In addition DMAP (15.3 mg, 0.125 mmol) was added to chamber 1.

[13C]-2-chlorodibenzo[b,f] [l,4]oxazepin-ll(10H)-one (*46). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With 2-(2-bromophenyl)ethanamine 45 (149 mg). In addition DMAP (15.3 mg, 0.125 mmol) was added to chamber 1. The title compound *46 was obtained after flash chromatography (increasing polarity from 0% to 10% Et₂0 in CH₂CI₂ as eluent) as a colorless solid (66.0 mg, 0.268 mmol, 80% from *4). H NMR (400 MHz, DMSO-d₆) δ (ppm) 10.69 (br s, 1H), 7.73-7.69 (m, 1H), 7.66 (ddd, J = 8.8, 2.8, 1.6 Hz, 1H), 7.41-7.36 (m, 1H), 7.36-7.31 (m, 1H), 7.23-7.11 (m, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 164.4 (¹³C-enriched), 157.6, 150.1, 134.0, 130.7, 130.6 (d, J = 1.0 Hz), 129.4 (d, J = 5.0 Hz), 127.3 (d, J = 63.7 Hz), 126.2, 125.4, 122.8 (d, J = 2.6 Hz), 121.8 (d, J = 3.1 Hz), 121.3. HRMS C₂₀H₃₇NO₄

[M+Na⁺]; calculated :, found : .

Stadacaine (48). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4(Chamber 2)". With l-bromo-4-butoxybenzene 47 (115 mg) and 2-(diethylamino)ethanol (265 μΙ_, 2.0 mmol). In addition DMAP (15.3 mg, 0.125 mmol) was added to chamber 1. The title compound 48 was obtained after flash chromatography (increasing polarity from 0% to 5% MeOH in EtOAc as eluent) as a colorless oil (87.4 mg, 0.298 mmol, 89% from 4). H NMR (400 MHz, CDCI₃) δ (ppm) 7.97 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz), 4.36 (t, J = 6.4 Hz, 2H), 4.01 (t, J = 6.4 Hz, 2H), 2.84 (t, J = 6.4 Hz, 2H), 2.63 (q, J = 7.2 Hz, 4H), 1.82-1.74 (m, 2H), 1.50 (sextet, J = 7.6 Hz, 2H), 1.07 (t, J = 7.2 Hz, 6H), 0.98 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 166.4, 163.0, 131.6 (2C), 122.6, 114.1 (2C), 67.9, 63.2, 51.2, 47.9 (2C), 31.2, 19.3, 13.9, 12.2 (2C).

HRMS C₂₀H₃7NO₄ [M+Na⁺]; calculated : , found : .

[13C]-Stadacaine (*48). The reaction chambers of (Figure 2A) was loaded according to "General protocol for aryl bromides (Chamber 1)" and "General protocol for CO release from 4/*4 (Chamber 2)". With l-bromo-4-butoxybenzene 47 (115 mg) and 2-(diethylamino)ethanol (265 μΙ_, 2.0 mmol). In addition DMAP (15.3 mg, 0.125 mmol) was added to chamber 1. The title compound *48 was obtained after flash chromatography (EtOAc as eluent) as a colorless oil (90.0 mg, 0.306 mmol, 92% from *4). ^ NMR (400 MHz, CDCI₃) δ (ppm). 7.98-7.93 (m, 2H), 6.90-6.85 (m, 2H), 4.33 (td, J = 6.4, 3.2 Hz, 2H), 3.98, (t, J = 6.4 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H), 2.60 (q, J = 7.2 Hz, 4H), 1.80-1.71 (m, 2H), 1.47 (sextet, J = 7.6 Hz, 2H), 1.04 (t, J = 7.2 Hz, 6H), 0.95 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 166.4 (¹³C-enriched), 163.0 (d, J = 0.5 Hz), 131.6 (d, J = 2.8 Hz, 2C), 122.6 (d, J = 76.6 Hz), 114.1 (d, J = 4.8 Hz . HRMS

C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : .

yv-hexyl-2-(4-methoxyphenyl)-2-oxoacetamide (49). In a glovebox under argon, to chamber 1 of two-chamber system (Figure 2A) was added Pd(dba)₂ (5.8 mg, 0.01 mmol), tBu₃P-HBF₄ (5.8 mg, 0.02 mmol), 4-iodoanisole (117 mg, 0.50 mmol), THF (3 ml_), n-hexylamine (132 μΙ_, 1.0 mmol), DBU (149 μΙ_, 1.0 mmol). The chamber was sealed with a screwcap fitted with a Teflon® seal. In a glovebox under argon, to chamber 2 of two-chamber system (Figure 2A) was added

Pd(dba)₂ (14.4 mg, 0.025 mmol), 9-methyl-9 -fluorene-9-carbonyl chloride 4 (303 mg, 1.25 mmol), THF (3 ml_), P(tBu)₃ (from stock solution, 0.01 mg μΙ_ ^_1, 506 μΙ_, 0.025 mmol) and DIPEA (327 μΙ_, 1.88 mmol) in that order. The chamber was sealed with a screwcap fitted with a Teflon® seal. The loaded two-chamber system was held at 25 °C for 48 hours. The crude reaction mixture was

evaporated on silica gel and the title compound 49 was obtained after flash chromatography (increasing polarity from 5% to 30% EtOAc in pentane as eluent) as a colorless oil (90.4 mg, 0.343 mmol, 69%). ^ NMR (400 MHz, CDCI₃) δ (ppm) 8.38 (d, J = 8.8 Hz, 2H), 7.20 (br s, 1H), 6.91 (d, J = 9.2 Hz, 2H), 3.85 (s, 3H), 3.34 (q, J = 6.4 Hz, 2H), 1.57 (quintet, J = 6.8 Hz, 2H), 1.39-1.24 (m, 6H), 0.86 (t, J = 6.8 Hz, 3H). ¹³C NMR (100 MHz, CDCI₃) δ (ppm) 186.0, 164.7, 162.4, 134.0 (2C), 126.5, 113.8, 55.6, 39.5, 31.5, 29.3, 26.6, 22.6, 14.1. HRMS

C₂₀H₃₇NO₄ [M+Na⁺]; calculated :, found : . 28 (7.0 mg, 0.030 mmol, 6%) was also isolated.

Claims

1. A carbonylation system comprising at least one carbon monoxide producing chamber and at least one carbon monoxide consuming chamber forming an interconnected multi-chamber system, said interconnection allowing carbon monoxide to pass from the at least one carbon monoxide producing chamber to the at least one carbon monoxide consuming chamber, said at least one carbon monoxide producing chamber containing a reaction mixture comprising a carbon monoxide precursor and a catalyst, said at least one carbon monoxide consuming chamber being suitable for carbonylation reactions, said interconnected multi- chamber system being sealable from the surrounding atmosphere during carbonylation.

2. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (I) :

3. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (II) : HCONF^R² Formula II, wherein R¹, R² are independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl.

4. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (III) : Formula (III)

R⁵ being selected from hydrogen or OCOR¹;

R⁶ being selected from halide, OR⁷, OCOR⁷, SR⁷, 0^"M, (OM)⁺ⁿX^~n, N(R⁷)(R⁸), (N(R⁷)(R⁸)(R⁹))⁺X^", P(R⁷)(R⁸), (P(R⁷)(R⁸)(R⁹))⁺X^~, PO(R⁷)(R⁸), OB(OR⁷)(OR⁸), OCSR⁷; R⁷, R⁸ and R⁹ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

5. A carbonylation system according to claim 4, wherein, R¹ and R² are

independently of one another being selected from aryl and heteroaryl.

6. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (VI) :

Formula (VI)

M being a positively charged counterion;

X being a negatively charged counterion;

7. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (VII) :

Formula (VII)

R⁴ being selected from halide, OR⁵, OCOR⁵, SR⁵, 0^"M, (OM)⁺ⁿX^"n, N(R⁵)(R⁶),

(N(R⁵)(R⁶)(R⁷))⁺X^", P(R⁵)(R⁶), (P(R⁵)(R⁶)(R⁷))⁺X^~, PO(R⁵)(R⁶), OB(OR⁵)(OR⁶),

OCSR⁵; R⁵, R⁶ and R⁷ independently of one another being selected from hydrogen, alkyl, acyl, aryl, and heteroaryl;

M being a positively charged counterion;

X being a negatively charged counterion;

8. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (VIII) :

heteroatom;

M being a positively charged counterion;

X being a negatively charged counterion;

9. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of formula (IX) :

Formula (IX)

M being a positively charged counterion;

X being a negatively charged counterion;

10. A carbonylation system according to claim 1, comprising a carbon monoxide precursor of (X) Formula (X)

wherein, Z are being selected from Si, Ge, and Sn.

M being a positively charged counterion;

X being a negatively charged counterion;

11. A carbonylation system according to any one of claims 1-10, wherein the catalyst in the at least one carbon monoxide producing 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.

12. A carbonylation system according to any one of claims 1-10, wherein the catalyst is a palladium-ligand complex.

13. A carbonylation system according to any one of claims 1-12, wherein the reaction mixture in the at least one carbon monoxide producing chamber further comprises one or more bases selected from the group consisting of inorganic bases and organic bases or mixtures thereof.

14. A carbonylation system according to any one of claims 1-13, wherein the carbon-isotope of the carbon monoxide precursor is ⁿC-, ¹³C- or ¹⁴C.

15. A carbonylation system according to any one of claims 1-14, wherein one or more of the reactants in the carbon monoxide producing chamber are

encapsulated with an encapsulation material.

16. A carbonylation system according to any one of claims 1-15, wherein the reactants in the carbon monoxide producing chamber are separately encapsulated with an encapsulation material.

17. A carbonylation system according to any one of claims 15-16, wherein the encapsulation material is one or more solvents having a melting point above 25 degrees Celsius.

18. A carbonylation system according to any one of claims 1-17, wherein 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 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, double carbonyiation, carbonyiative lactonization,

carbonyiative lactamization, hydroxycarbonylation, thiocarbamoylation, thiocarbonylation, amidocarbonylation, oxidative bisoxycarbonylation, oxidative carbonyiation of alcohols, oxidative alkoxycarbonylation, oxidative

aminocarbonylation, oxidative carbonyiation of amines, carbonyiative annulations, CO complexation by a metal, acyl-metal complexes generation, acid fluoride synthesis, carbonyiation of alcohols, carbonyiation of esters, carbonyiation of aziridines, carbonyiation of aldehydes, carbonyiation of epoxides, carbonyiation of amines, carbonyiative Heck - Mizoroki reaction, carbonyiative Suzuki - Miyaura coupling reaction, carbonyiative Stille coupling reaction, carbonyiative

Sonogashira coupling reaction, carbonyiative cross-couplings, carbonyiative cross coupling reaction with organometallic reagents, CO reduction, CO oxidation, water-gas shift reaction, ring opening carbonyiation, ring opening carbonyiative polymerization, ring expansion carbonyiation, radical carbonylations,

carbonyiation of organometallic reagents, carbonyiation of organolithium reagents, carbonyiation of organomagnesium reagents, carbonyiation of organoboranes, carbonyiation of organomercurials, and carbonyiation of organopalladium compounds.

19. A carbonyiation system according to any one of claims 1-18, wherein one or more of the reactants in the carbon monoxide consuming chamber are

encapsulated with an encapsulation material.

20. A carbonyiation system according to any one of claims 1-19, for use in combinatorial chemistry, parallel synthesis, chemical library, and/or carbon- isotope labelling.