# Enabling Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling of Carbamoyl Fluorides: Mechanism and Scope

Lulu Han, Viktor Boshevski, Yi Yang, Dan Louvel, Margherita Colombo, Gaël

Tran, Emmanuel Lacôte, Abderrahmane Amgoune, Anis Tlili

► To cite this version:

Lulu Han, Viktor Boshevski, Yi Yang, Dan Louvel, Margherita Colombo, et al. Enabling Nickel-Catalyzed Suzuki–Miyaura Cross-Coupling of Carbamoyl Fluorides: Mechanism and Scope. ChemistryEurope, 2025, 3 (5), 10.1002/ceur.202500213. [https://hal.science/hal-05347064v1](https://hal.science/hal-05347064v1)

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# Enabling Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Carbamoyl Fluorides: Mechanism and Scope

Lulu Han,[a] Viktor Boshevski,[a, b+] Yi Yang,[a, +] Dan Louvel,[b] Margherita Colombo,[c] Gaël Tran,[b] Emmanuel Lacôte,[a] Abderrahmane Amgoune,[*b] and Anis Tlili*[a]

[a] L. Han, V. Boshevski, Y. Yang, Dr. E. Lacôte, Dr. A. Tlili
Universite Claude Bernard Lyon 1, CNRS, CNES, ArianeGroup
LHCEP, Villeurbanne F-69622, France
E-mail: anis.tlili@univ-lyon1.fr

[b] Dr. D. Louvel, Dr. G. Tran, Prof. Dr. A. Amgoune
Université Claude Bernard Lyon 1, CNRS, ICBMS, UMR5246
43 Bd du 11 Novembre 1918, 69622 Villeurbanne, France
E-mail: abderrahmane.amgoune@univ-lyon1.fr

[c] M. Colombo
Universite Claude Bernard Lyon 1, CNRS, LMI UMR5615
Villeurbanne F-69622, France

[+] These authors contributed equally.

**Abstract:** We report the first Ni-catalyzed Suzuki cross-coupling amide synthesis using stable carbamoyl fluoride starting materials under mild conditions. Mechanistic studies were carried out to document the reactivity of nickel towards the C-F bond oxidative addition of carbamoyl fluorides and the transmetalation with arylboronic acids. Stoichiometric reactions and isolation of key organometallic intermediates allowed us to identify the transmetalation as the most challenging step of the coupling reaction mechanism. The use of tris(4-methoxyphenyl) phosphine ligands enabled the development of robust and practical catalytic approach for the synthesis of a broad range of amides.

Amides are ubiquitous in chemistry and biology. They are at the origin of life in proteins and play a pivotal role in the structure and function of numerous pharmaceuticals, [1] agrochemicals, [2] (bio)materials, [3] etc. Given their significance, the development of efficient catalytic methods for their preparation remains a critical objective in synthetic chemistry. [4] Among the various strategies explored, the direct functionalization of carbamoyl groups via carbamoyl fluorides represents a promising yet scarcely reported approach. One notable example is the coupling of carbamoyl dihydropyridines with aryl bromides under nickel/photoredox-catalysis. The key step is the capture of the carbamoyl radical formed via a photoredox process by the nickel complex (Scheme 1A). [5] An alternative approach featured carbamoyl silanes. [6] These processes remain however moderately atom-efficient. In this context, carbamoyl fluorides, which would only leave out a fluoride ion, stand as particularly attractive candidates (Scheme 1B). These bench-stable compounds have gained increased attention, especially since straightforward methods for their preparation under mild conditions were introduced. [7] Our group recently reported the deoxyfluorination of carbamates generated from readily available amines and atmospheric CO₂. [8] We believed that a strategy involving an oxidative addition into the C–F bond followed by direct coupling would enable a two-step access to amides from CO₂, an amine and some kind of carbon donor.

## A. Carbamoyl radical approach

<figure><img src="image_2.png" /></figure>

## B. Carbamoyl fluorides as electrophile: C-F bond activation

<figure><img src="image_3.png" /></figure>

## This work

<figure><img src="image_4.png" /><figcaption>**Scheme 1.** Nickel catalyzed carbamoylation strategies for the synthesis of amide.</figcaption></figure>
Nickel-catalyzed C–F bond activation of acyl fluorides has proven to be a powerful tool for the construction of valuable carbon-carbon or carbon-heteroatom bonds.[9] The Sanford group successfully implemented a decarbonylative strategy for C(sp²)–C(sp²) bond formation toward biaryls using benzoyl fluoride and various aryl boronic acid derivatives.[10] Alternatively, the decarbonylation can be prevented, leading to the synthesis of benzophenone derivatives.[11] In contrast, the application of carbamoyl fluorides as valuable building blocks under transition metal catalysis remains largely unexplored.[12a] So far, C–F bond activation of carbamoyl fluorides has only been successful when assisted by a pyridine-based directing group, using a catalyst system of Pd(Cl₂(PPh₃)₂) in conjunction with triphenylphosphine oxide.[12b] Only one example has been reported of a successful nickel-catalyzed intermolecular coupling of carbamoyl fluorides, with alkynylsilanes.[13] It is particularly striking that nickel catalyzed Suzuki-Miyaura coupling has not been applied to the synthesis of amides using carbamoyl fluorides. We endeavored to fill that gap.

Several challenges must be addressed to achieve successful direct cross-couplings of carbamoyl fluorides with boronic acid derivatives. First, catalysts capable of selectively activating the C-F bond but keeping the resulting fluoro-nickel complexes reactive enough for the fundamental cross-coupling steps must be found. The low reactivity of Ni-carbamoyl fluoride intermediates toward transmetalation presents a significant limitation that must be overcome. Indeed, recent work by Luan, Ye, and co-workers showed that cyclization via insertion of alkenes into the Ni-carbamoyl moiety bests direct transmetalation with aryl boronic acids in homoallyl carbamoyl fluorides (Scheme 1B).[14]

A second pitfall involves the selectivity of the coupling process vis-à-vis decomposition pathways. For aroyl fluorides, the decarbonylative process has been shown to be highly favorable in Ni catalyzed Suzuki-Miyaura couplings. With carbamoyl fluorides the decarbonylation would lead to undesired amine by-products. Ensuring selective coupling without decarbonylation is essential for the successful application of this method.

We initiated our study by examining the nickel-catalyzed cross-coupling of carbamoyl fluoride 1 with boronic acid 2 using the Ni(COD)₂/PCy₃ catalytic system as reported for the SM cross-coupling of aroyl fluorides.[10, 15] The reaction resulted in a very low yield of the desired amide 3 (<15% spectroscopic yield), along with the formation of urea (likely arising from the degradation of carbamoyl fluoride) and biphenyl (which is formed via coupling of phenylboronic acid). (Scheme 2A). This observation is in line with that reported by the group of Ye.[14] indicating a very difficult coupling of carbamoyl fluorides with arylboronic acids using Ni(0)/PCy₃. Gratifyingly, screening of a selection of phosphine ligands reported for Ni mediated SM couplings (Scheme 2A), showed that tris(4-methoxyphenyl)phosphine delivered a more promising 58% yield.[16]

The contrasting catalytic performance of P(4-OMePh)₃ and PCy₃, as well as reactivity difference with boronic acids of Ni(COD)₂/PCy₃ toward aroyl fluoride vs. carbamoyl fluoride prompted us to further compare their stoichiometric reactivity. It is also worthy of note that while nickel carbamoyl fluorides have logically been proposed as catalytic intermediates in cross-coupling reactions, they have never been isolated, let alone characterized. Stoichiometric studies were thus conducted to get more insight into the structure and reactivity of the putative nickel carbamoyl fluoride intermediates (Scheme 2B).

The reaction of carbamoyl fluoride 1 with Ni(COD)₂/2 P(4-OMePh)₃ was first carried out in toluene-d₈ at room temperature. NMR monitoring indicated slow formation of a new species (74% NMR yield after 48 h), with ³¹P{¹H} (d, 12.4 ppm, *J* = 47 Hz) and ¹⁹F{¹H} (t, -322.7 ppm, *J* = 48 Hz) signals fully consistent with the desired *trans* square planar oxidative addition complex **A**. Importantly, ¹³C{¹H} NMR confirmed the presence of the carbonyl group in the complex. However, all attempts to obtain X-ray quality crystals of **A** were unsuccessful. In comparison, when PCy₃ was used, ³¹P and ¹⁹F NMR monitoring indicated more rapid formation of the desired oxidative addition complex **B** (³¹P{¹H}: d, 19.2 ppm, *J* = 45 Hz; ¹⁹F{¹H}: t, -352.1 ppm, *J* = 46 Hz). The complex was isolated in 70% yield and fully characterized.

The molecular structure of **B** was unambiguously confirmed by single crystal X-ray diffraction analysis (Scheme 2B). The nickel center adopts a slightly distorted square planar environment (D₄h symmetry) as confirmed by SHAPE calculations. It is ligated by two phosphorus atoms and a carbamoyl and fluoride ligands. As told, complex **A** is the first structurally characterized carbamoyl nickel fluoride complex. Its formation provides direct evidence for the NCO–F bond oxidative addition to Ni(0).[17]
A. Evaluation of effective phosphine ligands in Ni catalyzed SM coupling

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /></figure>

<table><thead><tr><th>Ligand</th><th>Yield (%)</th></tr></thead><tbody><tr><td>PCy<sub>3</sub></td><td>15%</td></tr><tr><td>PPPh<sub>3</sub></td><td>48%</td></tr><tr><td>P(4-MeOPh)<sub>3</sub></td><td>58%</td></tr><tr><td>P(4-NMe<sub>2</sub>Ph)<sub>3</sub></td><td>32%</td></tr><tr><td>DPPP</td><td>12%</td></tr></tbody></table>

B. Stoichiometric investigations

C-F bond oxidative addition of carbamoyl fluoride 1 to Ni(0)

<figure><img src="image_7.png" /></figure>

A (PR<sub>3</sub> = P(4-OMePh)<sub>3</sub>: 70 % yield

B (PR<sub>3</sub> = PCy<sub>3</sub>) : 74 % yield

<figure><img src="image_8.png" /></figure>

Reactivity of complex A and B with p-CF<sub>3</sub>phenylboronic acid

<figure><img src="image_9.png" /></figure>

From A: 75% yield
From B: 53% yield

Scheme 2. Investigations of SM type coupling with Ni(COD)<sub>2</sub>/PR<sub>3</sub>

Complex B demonstrated complete stability in toluene at room temperature. Interestingly, the stability of B toward decarbonylation starkly contrasts with the analogous benzoyl fluoride oxidative addition complex reported by Sanford *et al.*, which spontaneously decarbonylate over a few hours.

We next investigated the reactivity of complexes A and B in the transmetalation step with Ar-B(OH)<sub>2</sub> in the presence of CsF (Scheme 2B). When the reaction was performed at room temperature, only low yields of cross-coupled product was observed. However, at 90 °C, both complexes delivered the cross-coupled product 3 in 76% and 53% spectroscopic yield, respectively.

At first sight, these observations seem to be in contradiction with the observed catalytic yields obtained with P(4-OMePh)<sub>3</sub> and PCy<sub>3</sub> (58% and 15% respectively). However, a closer look at the species formed in the stoichiometric reactions revealed that (COD)<sub>2</sub>Ni(PCy<sub>3</sub>)<sub>2</sub>[15] was a major product when PCy<sub>3</sub> was used, indicating that decarbonylation proceeded at higher temperature. The formation of this well-known cross-coupling thermodynamic sink suggests that Ni(0)/PCy<sub>3</sub> is an inefficient catalyst for the coupling of carbamoyl fluoride with arylboronic acids. This may originate from the reluctance of the fluorocarbamoyl nickel(II) intermediate to undergo rapid transmetalation with boronic acids, in line with that previously reported.[14-15, 18]

Taken together, the stoichiometric experiments support the relevance of carbamoyl nickel(II) fluoride intermediates in the catalytic cycle. The concurrent unproductive decarbonylation process is more prominent with PCy<sub>3</sub>, leading to the large variation in yields observed between PCy<sub>3</sub> and P(4-OMePh)<sub>3</sub>. It also highlights the considerable differences in reactivity and stability between complexes derived from aroyl and carbamoyl fluorides.

We retained P(4-OMePh)<sub>3</sub> as ligand for the catalytic optimization studies (Table 1). Our initial tests focused on the impact of reaction solvent on the outcome (entries 2–6). Using THF led to a decrease to 34% (entry 2), while performing the reaction in DMF resulted in only 18% yield of the desired product 3 (entry 3). No product was obtained in either MeCN or 1,4-dioxane (entries 4 and 5), while iPrOH led to only traces of 3 (entry 6). Varying the temperature between 80 °C and 120 °C did not produce any noticeable impact on the reaction outcome (entries 7 and 8).

We then examined the influence of the external base. Without Cs<sub>2</sub>CO<sub>3</sub>, only 13% of the desired product was obtained. Using K<sub>2</sub>CO<sub>3</sub> resulted in a modest yield of 27% (entry 10), while potassium fluoride achieved a slightly better yield of 39% (entry 11). The best results were obtained with CsF base (79% yield, entry 12). The strong influence of the base again differs from the Suzuki-Miyaura coupling of aroyl fluorides.[9c] The reaction could be carried out using a reduced catalyst loading of 10 mol% Ni(COD)<sub>2</sub> and 20 mol% P(4-MeOC<sub>6</sub>H<sub>4</sub>)<sub>3</sub>, affording the desired product in 55% yield.

<figure><img src="image_10.png" /><figcaption>Table 1. Reaction optimization</figcaption></figure>
<table><tr><td>3</td><td>DMF instead of toluene</td><td>18</td></tr><tr><td>4</td><td>MeCN instead of toluene</td><td>0</td></tr><tr><td>5</td><td>1,4-dioxane instead of toluene</td><td>0</td></tr><tr><td>6</td><td>iPrOH instead of toluene</td><td>19</td></tr><tr><td>7</td><td>80 °C instead of 100 °C</td><td>53</td></tr><tr><td>8</td><td>120 °C instead of 100 °C</td><td>58</td></tr><tr><td>9</td><td>Without base</td><td>13</td></tr><tr><td>10</td><td>K<sub>2</sub>CO<sub>3</sub> instead of Cs<sub>2</sub>CO<sub>3</sub></td><td>27</td></tr><tr><td>11</td><td>KF instead of Cs<sub>2</sub>CO<sub>3</sub></td><td>39</td></tr><tr><td>12</td><td>CsF instead of Cs<sub>2</sub>CO<sub>3</sub></td><td><b>79</b></td></tr><tr><td>13</td><td>10 mol% Ni(COD)<sub>2</sub>/20 mol% ligand</td><td>55</td></tr><tr><td>14</td><td>1eq of 1 and 1.5eq of 2</td><td>73</td></tr></table>

[a] All reactions were performed with **1** (0.15 mmol, 1.5 equiv.), **2** (0.1 mmol), Ni(cod)<sub>2</sub> (20 mol%), P(4-MeOPh)<sub>3</sub> (40 mol%), base (0.2 mmol, 2 equiv.) and PhMe (1 mL). Unless otherwise noted, the reaction was stirred at 100 °C for 16h. [b] Yields determined by <sup>19</sup>F NMR with PhOCF<sub>3</sub> as an internal standard.

<figure><img src="image_11.png" /></figure>

**Scheme 3.** [a] All reactions were performed with carbamoyl fluorides (0.3 mmol, 1.5 equiv.), **2** (0.2 mmol), Ni(cod)<sub>2</sub> (20 mol%), P(4-MeOPh)<sub>3</sub> (40 mol%), CsF (0.2 mmol, 2 equiv.) and PhMe (2 mL), at 100 °C for 16 h. All yields in brackets were determined by <sup>19</sup>F NMR spectroscopy with PhOCF<sub>3</sub> as an internal standard.
With the optimal conditions in hands, we probed the reaction scope. Our initial efforts centered on the applicability of various carbamoyl fluoride derivatives. Overall, good to excellent reactivities were observed with a variety of cyclic and benzylic, carbamoyl fluorides. In contrast, a reduced yield was observed with aromatic derivative **12** (25%).

On the aryl boronic side, both electron-donating and electron-withdrawing groups were compatible and successfully converted to the desired products, showcasing the efficiency of the catalytic system.[19] For example, aryl boronic acids substituted with methyl, methoxy, ethoxy, and benzyloxy derivatives were smoothly converted. Substituents in the *ortho* position were tolerated under our protocol, as the desired products were obtained in yields of up to 80% (product 14, **Scheme 3**). When starting with 4-fluorophenylboronic acid, the catalytic system exhibited exclusive selectivity toward the C–F bond of the carbamoyl fluoride. A similar observation was achieved with *para*-substituted OCF₃ boronic acid derivatives. Interestingly, pyridine derivatives were converted to the corresponding amide product in a synthetically useful yield of 50% (product 28, **Scheme 3**).

In summary, we have developed an efficient nickel-catalyzed cross-coupling between carbamoyl fluorides and arylboronic acids. The use of these bench-stable, readily available substrates, provides an alternative strategic disconnection for the synthesis of widely useful amides. Stoichiometric organometallic studies revealed transmetalation as the most challenging step of the coupling reaction mechanism, while also highlighting the unique behavior of carbamoyl fluoride-derived nickel complexes in the elementary steps.

## Supporting Information

The authors have cited additional references within the Supporting Information.

## Acknowledgements

We acknowledge financial support from ANR (grants ANR-20-CE07-0002, CDI-DEOX and ANR-22-CE07-0004, Polyazanes), université Claude Bernard Lyon 1, CNRS, CNES and ArianeGroup. Y. Y. and L. H. Thank the China Scholarship Council for a scholarship. V. B. thanks CNES and CNRS for a Ph. D. stipend.

**Keywords:** Nickel Catalysis • Carbamoyl Fluorides • Cross Coupling • Amides

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