Volume 7, Issue 46 e202203582
Research Article
Open Access

Visible-Light Enabled Late-Stage, Room-Temperature Aminocarbonylation of Aryl Iodides with Labeled Carbon Monoxide

Kim S. Mühlfenzl

Corresponding Author

Kim S. Mühlfenzl

Early Chemical Development, Pharmaceutical Sciences AstraZeneca, Pepparedsleden 1, 431 50 Mölndal, Sweden

Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark

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Dr. Malvika Sardana

Dr. Malvika Sardana

Early Chemical Development, Pharmaceutical Sciences AstraZeneca, Pepparedsleden 1, 431 50 Mölndal, Sweden

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Prof. Troels Skrydstrup

Prof. Troels Skrydstrup

Interdisciplinary Nanoscience Center (iNANO) and Department of Chemistry, Aarhus University, Gustav Wieds Vej 14, 8000 Aarhus C, Denmark

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Dr. Charles S. Elmore

Dr. Charles S. Elmore

Early Chemical Development, Pharmaceutical Sciences AstraZeneca, Pepparedsleden 1, 431 50 Mölndal, Sweden

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First published: 08 December 2022
Citations: 2

Graphical Abstract

Herein, a robust method for the isotopic labeling of amides, mediated by visible-light irradiation and palladium catalysis, at room temperature is reported. A broad substrate scope including various (hetero)aryl iodides, primary and secondary amines, and carbon-14 labeled pharmaceuticals for the carbonylation with stochiometric amounts of (labeled) CO is presented.


In recent years, coupling reactions mediated by visible light have been widely studied because such reactions can often be run at significantly lower temperatures. In this work, aryl iodides were coupled with amines at ambient temperature in the presence of stoichiometric amounts of carbon monoxide using visible-light irradiation and palladium catalysis. A wide range of aryl substrates, both electron-deficient and rich, as well as heterocycles, were carbonylated to provide the corresponding amides in moderate to good yields based on CO. In addition, the generality of the amine was investigated, and primary and secondary amines yielded the desired products in moderate to good yields. This methodology was also successfully applied to the synthesis of pharmaceuticals and the incorporation of a carbon-14 label into the carbonyl group, where the use of 9-methyl-fluorene-9-carbonyl chloride (COgen) as the carbon isotope-labeled CO source allowed easy translation between the unlabeled and the labeled transformations.


Before a new active pharmaceutical ingredient (API) can be approved, preclinical and clinical studies are mandatory to disclose the drug metabolism and pharmacokinetic characteristics of the compound. These include detailed adsorption, distribution, metabolism, and excretion studies. The inclusion of isotope labels with radionuclides, i. e. tritium and carbon-14, (3H/14C) is an important tool to investigate the metabolite profiles and to determine pharmacological and toxicological effects.1 Typically, carbon-14 is used in in vivo studies as a structural identification method, wherein the label should be located in a metabolically stable position of the compound in order to provide meaningful results.2 To reduce the amount of radioactive waste and limit the number of steps using radioactive materials, the radiolabel is ideally incorporated as late as possible into the API. As a result, the late-stage labeling of APIs often requires a significant modification of the original synthetic route.

Carboxamides are widely found in bioactive molecules, including pharmaceuticals (Figure 1). Consequently, aminocarbonylation constitutes an important process in the molecular assembly of biologically relevant molecules, and the development of methods for the coupling of aryl halides with amines in the presence of carbon monoxide (CO) has been widely investigated.3 In addition, as a one-carbon synthon, the unlabeled CO can be replaced with 13C or 14C labeled CO to give the often metabolically stable carboxamide, which can be used as an internal standard in pharmacological studies4 and to assess drug metabolites in human ADME studies.5 However, most conventional carbonylation reactions require a large excess of CO and/or high reaction temperatures.6 In particular, the use of a large excess of CO poses a problem for the incorporation of a radiolabel. Labeled CO is not only expensive, but in the case of 14CO, not commercially available, and using an excess would also result in unavoidable radioactive waste.

Details are in the caption following the image

Examples of Biologically Relevant Molecules Containing a Benzamide Moiety.

For the late-stage labeling of complex drug-like molecules, the palladium-catalyzed carbonylation is a well-known method to incorporate carbon-14, using labeled 14CO. In this reaction, advanced intermediates, such as aryl or vinyl halides, are coupled with 14CO in the presence of an appropriate nucleophile to afford the corresponding carbonyl-labeled product.7 Since 13CO/14CO is typically more valuable than the aryl/vinyl halide, it is used as the limiting reagent. To ensure a controlled release of (labeled) carbon monoxide, a carbon monoxide surrogate, COgen (9-methyl-9H-fluorene-9-carbonyl chloride), can be used. Since COgen can be obtained in both its unlabeled and labeled forms, a straightforward transfer between the unlabeled and labeled reactions is possible.

Typical procedures use 1 equiv. of labeled CO and an equal molar amount of the aryl/vinyl halide with a catalytic amount of a palladium complex at a reaction temperature between 80–120 °C.8 However, methods with milder reaction conditions are desirable for radiolabeling. These ideally include neither high temperature nor pressure. Furthermore, the use of strong acids or bases should be avoided. In the last decade, visible light-mediated photocatalysis has gained significant attention in the chemical community. It has been shown that it can be used in many transformations that are normally performed at elevated temperatures using traditional transition metal catalysis. In those cases, visible light enables radical generation from abundant functional groups under mild and catalytic conditions.

In 2019, a method for the aminocarbonylation of unactivated alkyl iodides using COgen as a CO surrogate was reported.9 This catalytic protocol enables aminocarbonylations to be performed at ambient temperatures by visible light and palladium catalysis in the presence of stoichiometric amounts of unlabeled and labeled CO. It was found that this palladium-catalyzed method also worked well for the carbonylation of aryl iodides at ambient temperature.

In the following year, Arndtsen and coworkers reported a palladium and visible light-enabled carbonylative coupling of aryl halides with nucleophiles applying 4 atm of CO. In this context, the role of visible light in carbonylation reactions at ambient temperature was investigated and a radical mechanism was proposed.10

In this paper, we report on the scope of a palladium-catalyzed and visible-light mediated aminocarbonylation of aryl iodides at ambient temperature in the presence of stoichiometric amounts of unlabeled and carbon-labeled carbon monoxide, itself derived from COgen with and without a carbon label. The high functional group tolerance and mild reaction conditions make this robust aminocarbonylation method a valuable addition to the toolbox for carbon isotope labeling methods and enable the carbonylative coupling of thermally sensitive substrates. The carbon-labeled substrates thus obtained can then be used to support ADME studies in the drug approval process.

Results and Discussion

4-Iodoanisole (1) and morpholine (2) were used as model substrates to perform the initial control and screening experiments. The limiting reagent for all reactions was unlabeled CO derived from COgen. Using COgen allowed the release of stoichiometric amounts of CO and thus an easy translation between unlabeled and labeled transformations. Since the 12C/14C isotope effect is very small and to keep the costs and generation of radioactive waste relatively low, 12CO was used as a surrogate for 14CO for investigating the substrate scope. (Scheme 1)

Details are in the caption following the image

Reaction Conditions for Screening.

A two-chamber system (COware8c) was used to keep the release and consumption of CO separate. For each set of reactions, a fresh batch of COgen was synthesized.11 The CO-releasing chamber (Chamber A) was placed into a heating block which was surrounded by a photoreactor equipped with blue light-emitting diodes (15 V, 15 W/meter, λ=465.2 nm). To keep the CO-consuming chamber (Chamber B) at room temperature, a fan was placed on top of the reactor. (see Supporting Information)

While it was found that the presence of Pd(PPh3)4 (Table 1, entry 2) is essential to obtain the product in a high yield, small quantities of the product were observed in the absence of light (entry 3). Carrying out the reaction without the addition of a base (entry 4) gave similar results to those obtained under the optimized conditions. However, the presence of potassium carbonate was expected to be beneficial for amines with low nucleophilicity. When the radical trapping reagent TEMPO is added to the reaction mixture, no formation of the desired product was observed (entries 5 and 6).

Table 1. Control Experiments.[a]


Deviation from Standard Conditions

Yield [%][b]





No Pd(PPh3)4



No light



No K2CO3



With TEMPO (1.0 equiv)



With TEMPO (1.0 equiv), no CO


  • [a] All reactions were set up using COware on a 0.6 mmol scale. Ex-situ CO release: COgen (1.0 equiv), Pd(dba)2 (5 mol%), DIPEA (1.5 equiv) in PhMe (5 mL) at 70 °C. [b] Determined by 1H NMR using benzyl benzoate as internal standard. [c] Masses of TEMPO-quenched aryl and acyl radical in LCMS observed. [d] Mass of TEMPO quenched aryl radical in LCMS observed.

Based on the previously reported mechanisms of both palladium and visible-light catalysis12 together with the observation of the acyl radical trapping with TEMPO, we propose a radical-based mechanism.

As shown in Scheme 2, photoexcitation of the Pd0 complex I furnishes excited *[Pd0] (II). Abstraction of the iodine from the aryl iodide results in a [PdI]-aryl radical species III. This is followed by CO insertion to give IV and the attack by the nucleophile (HNRR’) to afford [PdII]-complex V. Subsequent reductive elimination regenerates I and provides amide VI.

Details are in the caption following the image

Proposed Mechanism for the Role of Visible Light in Catalysis.

However, further mechanistic studies to confirm the proposed mechanism have not been performed.

First, a catalyst screening was performed with several Pd(0)-catalysts (SI, Table 1). Although Pd(PPh3)4 was shown to be the most effective catalyst for the aminocarbonylation of alkyl iodides9, the mechanism is likely to be different for aryl iodides and may therefore benefit from a different catalyst. However, monodentate Pd(0) catalysts and Pd(II) catalysts (entries 2–4) performed worse than Pd(PPh3)4 (entry 1) as did Pd(II) catalysts with bidentate ligands (entries 5 and 6).

Next, various solvent systems were investigated for the CO-consuming chamber, while the solvent system for the CO-releasing chamber remained unchanged. The effect of water as a co-solvent on the different solvent systems was investigated. 2-Methyltetrahydrofuran with water (SI, Table 2, entry 1) proved to be the most effective and resulted in a 79 % yield of the desired amide product 3. For the water-miscible solvents (entries 9, 11 and 13), a significant decrease in yield was observed and in some cases no product formed when the reaction proceeded in a homogeneous but aqueous medium. Since 2-MeTHF performed well with and without water as a co-solvent and since it is a more environmentally friendly solvent compared to the other solvent systems that also gave good results, 2-MeTHF was chosen for the procedure.

Furthermore, both the concentration and scale of the CO-consuming and CO-releasing chambers were investigated. It was shown that with decreased concentration and higher solvent levels, slightly higher yields were obtained (SI, Table 3, entries 1–4). Thus, it could be concluded that the reaction on a small scale is only slightly dependent on the concentration of the CO-consuming chamber and the overall pressure in the two-chamber system. Keeping the solvent levels unchanged in both chambers while increasing the scale also led to slightly higher yields (entries 4–7). Both contrast with the results of Sardana and coworkers9, where a significant drop in yield was observed at a larger scale and higher pressure. However, to avoid solubility issues and facilitate substrate purification and isolation, a 0.6 mmol-scale was chosen as the standard scale for the aminocarbonylation.

With the optimized reaction conditions in hand, the reaction scope was explored. First, the generality of the aryl iodide substrate in the aminocarbonylation with 2 was investigated (Scheme 3). The aminocarbonylation of unsubstituted iodobenzene and 1-iodonaphthalene provided the desired products 4 and 5 in good yields. Aryl iodides bearing electron-donating groups, such as amine (6), ether (3, 79), alkyl (1012), or hydroxy (1315) group also provided the corresponding product in good to moderate yields. However, comparing the yields of ortho-, meta- and para- substitution, a decreased yield is observed in all cases for ortho substitution. Substrates 1315 were obtained in higher yields by carrying out the reaction in anhydrous 2-MeTHF. Due to the increased polarity, iodophenols tend to dissolve in the aqueous phase rather than the organic phase, thereby hindering the reaction.

Details are in the caption following the image

Scope of Aminocarbonylation of (Hetero)Aryl Iodides.[a]

Carboxamides featuring electron-withdrawing substituents, such as ketone 16, ester 17, and halogens 18 and 19, were also obtained in good to moderate yields. The substitution with the electron-withdrawing group p-CF3 led to the formation of 20 with moderate yield, while substitution with p-CN and p-NO2 resulted in low yields of 21 and 22.

A notable feature of this method is the tolerance of heterocyclic aryl iodides. Interestingly, the reaction with 2-iodothiophene provided the desired product 24 in good yield. Iodopyridines were tolerated only partially, and amides 2527 were obtained in moderate yield. The reaction with 6-iodoquinoline afforded the corresponding amino carbonylation product 28 in good yield. However, the method tolerated less 1-iodoisoquinoline and 7-iodo-1H-indole as the corresponding amides 29 and 30 were obtained in lower yields.

Next, the scope of the aminocarbonylation with respect to the nature of the amine was investigated. As shown in Scheme 4, 1-iodo-4-methoxybenzene performed well with a range of amines. Good yields were obtained for primary amines 3135. In addition, a secondary amine was also tolerated by the method and provided 36 in a good yield. However, the reaction was shown to be sensitive to steric hindrance, with tert-butyl and diisopropyl substitution, providing the corresponding products 37 and 38 in relatively low yields. In addition, amines with low nucleophilicity were shown to be challenging to the method.

Details are in the caption following the image

Scope of Amines for the Aminocarboylation. [a]

To further demonstrate synthetic utility, pharmaceutical-relevant compounds 3941 were isolated with good yields (Scheme 5). Procainamide (42) was obtained in moderate yield, although 6 and 33 have been previously synthesized in good yields. Imatinib (43) was synthesized in a moderate yield as a result of the low nucleophilicity of the corresponding amine and solubility issues. Unfortunately, due to the ortho-substituent of the aryl iodide, the synthesis of olaparib (44) was not optimal.

Details are in the caption following the image

Last- and Late-Stage Aminocarbonylation of Pharmaceutically Relevant Compounds. [a]

Lastly, the reaction conditions were applied to carbon-14 labeling (Scheme 6). Carbon-labeled COgen was prepared by replacing the CO2 with labeled 14CO2.8b To reduce the radioactive waste from the aminocarbonylation, a dilution of 5 % 14COgen in unlabeled COgen was used (to give a final specific activity of 0.11 TBq/mmol). First, the reaction was carried out using the established model substrates 1 and 2. The corresponding product [14C]-3 was obtained in 52 % radiochemical yield (RCY) (34 MBq, SA: 0.09 TBq/mmol), which is in good agreement with the results from the unlabeled aminocarbonylation. Next, labeled Imatinib [14C]-38 was isolated in 47 % RCY (31 MBq, SA: 0.12 TBq/mmol). Furthermore, [14C]-41 was successfully synthesized in 20 % RCY (13 MBq, SA: 0.12 TBq/mmol). The specific activities were, in all cases, within the expected margin.13

Details are in the caption following the image

Scheme 14C-labeling of Amides. [a]


Using visible-light irradiation and palladium catalysis, the late-stage aminocarbonylation of aryl iodides and carbon isotope incorporation into the carbonyl group were achieved. Noteworthy, this method works with carbon monoxide as a limiting reagent at ambient temperature. This methodology provides an alternative for late-stage labeling of amides, especially temperature-sensitive compounds. The conditions tolerate a wide range of functional groups, including electron-deficient and -rich aryl iodides as well as amines with varying nucleophilicity, and provide the substrates with moderate to good yields. In the same manner, 14C labeled substrates were synthesized successfully. The reaction conditions were less tolerated by less nucleophilic amines and sterically hindered aryl iodides, which resulted in lower yields.

Experimental Section

General Information

Reagents and Solvents. All commercial reagents were purchased and used as received without further purification unless mentioned otherwise. Anhydrous solvents were purchased from Sigma-Aldrich and stored under a nitrogen atmosphere. 9-Methyl-9H-fluorene-9-carbonyl chloride and 9-methylfluorene-9-[14C]-carbonyl chloride (COgen and 14COgen, respectively) were prepared according to the procedure of Skrydstrup et al.8b.

Experimental Procedures. All reactions were carried out under a nitrogen atmosphere using Teflon-coated stir bars. Air and moisture-sensitive liquids were transferred via syringe through rubber septa. Solids were added under inert gas or were dissolved in the appropriate solvent and added via syringe. Reactions that were run above room temperature were heated using electric heating plates and DrySyn® heating blocks, and a stated temperature corresponds to the external DrySyn® temperature. Low-temperature reactions were carried out using a Dewar flask filled with acetone/dry ice (−78 °C) or water/ice (0 °C). Reactions were monitored by TLC, gas chromatography-mass spectroscopy (GCMS), or liquid chromatography-mass spectroscopy (LCMS). Thin-layer chromatography was carried out using E. Merck silica glass plates (60F-254) with UV light (254 nm) and/or potassium permanganate as the visualization agent. Crude reaction mixtures were purified by preparative reversed-phase high-performance liquid chromatography (HPLC) using a Waters 2545 Quaternary Gradient Module equipped with a Waters 2489 UV/Vis detector with an Xbridge Prep C-18 10 μm OBD, 30×250 mm column. Yields are based on the limiting reagent and refer to a purified, isolated, homogeneous product and spectroscopically pure material unless stated otherwise.

Analytical Instrumentation. Nuclear magnetic resonance (NMR) spectra were obtained on Bruker Avance III HD 500 MHz and Bruker Avance NEO NanoBay 400 MHz instruments at room temperature. Chemical shifts of the NMR spectra are reported relative to residual signals of CDCl3 (1H NMR: δ=7.26 ppm, 13C NMR: δ=77.16 ppm) or DMSO-d6 (1H NMR: δ=2.50 ppm, 13C NMR: δ=39.52 ppm). Signals are listed in ppm, and multiplicity was identified as s=singlet, br=broad, d=doublet, dt=doublet of a triplet, t=triplet, tt=triplet of a triplet, q=quartet, quin=quintet, h=hextet, and m=multiplet; coupling constants in Hz; integration. Benzyl benzoate was used as an internal standard for quantitative NMR (qNMR). GCMS (EI) analysis was performed on an Agilent 7890 A GC system and Agilent 5975 C inert MSD system equipped with an Agilent 19091S-433 L (30 m×250 μ×0.25 μm) capillary column and electron impact ionization at 70 eV. LCMS analysis was performed on a Waters Acquity UPLC using an Acquity BEH C18 column (1.7 μm, 50 mm×2.1 mm).Radiochemical purity was determined on a Waters Acquity UPLC equipped with a Waters Xbridge C18 (3.5 μm, 4.6×100 mm) column and Perkin-Elmer TRI-CARB 2500 liquid scintillation analyzer with Ultima Gold cocktail. High-resolution mass spectra (HRMS) were recorded on a Waters Xevo Q-TOF mass spectrometer with an electrospray ion source in positive mode.

General Procedures. General Procedure i) for Chamber A: CO-releasing Chamber. To a solution of Pd(dba)2 (17.5 mg, 0.03 mmol, 5 mol%) in toluene (3 mL), tri-tert-burtylphosphine (30 μL, 0.03 mmol, 5 mol%) and N, N-diisopropylethylamine (160 μL, 0.90 mmol, 1.5 equiv) were added. The chamber was sealed with a Teflon-lined PTFE septum and a stabilizing disc after which it was purged with N2 for 5 min. A solution of COgen (2 mL, 0.60 mmol in toluene, 1 equiv) was added and the chamber was stirred and heated to 70 °C.

General Procedure ii) for Chamber A: 14CO-releasing Chamber. To a solution of Pd(dba)2 (17.5 mg, 0.03 mmol, 5 mol%) in toluene (3 mL) tri-tert-burtylphosphine (30 μL, 0.03 mmol, 5 mol%) and N, N-diisopropylethylamine (160 μL, 0.90 mmol, 1.5 equiv) were added. The chamber was sealed with a Teflon-lined PTFE septum and a stabilizing disc after which it was purged with N2 for 5 min. A solution of 14COgen (65.7 MBq, 0.03 mmol, 0.05 equiv) and 12COgen (138.0 mg, 0.57 mmol, 0.95 equiv) in toluene (2 mL) was added and the chamber was stirred and heated to 70 °C.

General Procedure iii) for Chamber B: CO-consuming Chamber. Pd(PPh3)4 (34.7 mg, 0.03 mmol, 5 mol%), K2CO3 (85.0 mg, 0.61 mmol, 1.02 equiv), aryl iodide (0.60 mmol, 1 equiv), amine (1.80 mmol, 3 equiv) were dissolved in 2-MeTHF (3.5 mL) and water (1.5 mL). The chamber was sealed with a Teflon-lined PTFE septum and a stabilizing disc after which it was purged with N2 for 5 min. The chamber was irradiated with blue LEDs for 24 h.

Supporting Information Summary

General information, optimization and experimental details, characterization data and copies of 1H and 13C NMR spectra, and radioHPLC chromatograms are provided in the Supporting Information.


This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 859910.

    Conflict of interest

    T.S. is co-owner of SyTracks A/S, which commercializes the two-chamber system (COware).

    Data Availability Statement

    The data that support the findings of this study are available in the supplementary material of this article.