# Gold(III) Catalysis in Ionic Liquids: The Case Study of Coumarin Synthesis

Francesco Ravera, Marte Sofie Martinsen Holmsen, Paolo Sgarbossa, Didier Bourissou, Andrea Biffis

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Francesco Ravera, Marte Sofie Martinsen Holmsen, Paolo Sgarbossa, Didier Bourissou, Andrea Biffis. Gold(III) Catalysis in Ionic Liquids: The Case Study of Coumarin Synthesis. Advanced Synthesis and Catalysis, In press, 10.1002/adsc.202400706. hal-04849470

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# Gold(III) Catalysis in Ionic Liquids: The Case Study of Coumarin Synthesis

Francesco Ravera,<sup>a, b</sup> Marte Sofie Martinsen Holmsen,<sup>c, d</sup> Paolo Sgarbossa,<sup>b, e</sup> Didier Bourissou,<sup>c,*</sup> and Andrea Biffis<sup>a, b,*</sup>

Manuscript received: June 13, 2024; Revised manuscript received: September 5, 2024;
Version of record online: ■■, ■■

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Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202400706

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© 2024 The Author(s). Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

**Abstract:** Well-defined (P,C)-cyclometalated Au(III) complexes proved to be able to catalyze the synthesis of coumarins by intramolecular hydroarylation of a broad range of aryl propiolates under mild and practical conditions (0.1–2 mol% catalyst, 25–40 °C, 1–24 hours). The use of an ionic liquid as reaction solvent allowed to drastically decrease the amount of Brönsted acid used to unlock the catalyst regeneration step. The effect of the nature of the acid additive and of the ionic liquid anion have been assessed. Preliminary results on the extension of this methodology to the cyclization of aryl propargyl ethers are also presented.

**Keywords:** Hydroarylation; Cyclization; Anion effect; Phenols; Alkynes

## Introduction

In the last two decades, gold chemistry has emerged as a powerful and convenient tool for modern organic synthesis.[1] The high robustness of gold complexes toward moisture and air, together with their compatibility with many different functional groups, were the main promoters for a fast development of gold-catalyzed reactions, particularly those exploiting the carbophilicity of gold to achieve functionalization of unsaturated hydrocarbon substrates.[2] Among these, direct addition of aromatic C–H bonds to unsaturated substrates by π-acidic catalysis (direct hydroarylation) is a fascinating and challenging chemical transformation, due to the high atom economy of the process and

the readily available substrates.[3] Following the pioneering work of Fujiwara on Pd- and Pt-catalyzed hydroarylation of alkynes,[4] important contributions within this field have been made *inter alia* by Hashmi,[5] Echavarren,[6] Reetz[7] and Nolan,[8] who developed a wide range of gold(I) catalysts and methodological approaches to accomplish this transformation. However, those studies are quite limited when turning to species that are based on gold(III) metal centers. Up to now, relevant catalytic applications mainly employ simple gold(III) salts that can be activated by a silver co-catalyst,[9,10] generating complex species among which it is difficult to distinguish the catalytically competent one.[7] Moreover, N-heterocyclic carbene (NHC) complexes with a gold(I) metal

<figure><img src="image_4.png" /></figure>

<footnote><sup>a</sup> Department of Chemical Sciences – DiSC, University of Padova, via Marzolo 1, 35131 Padova, Italy
E-mail: andrea.biffis@unipd.it</footnote>

<footnote><sup>b</sup> Consorzio Interuniversitario per le Reattività Chimiche e la Catalisi (CIRCC), c/o Department of Chemical Sciences – DiSC, University of Padova, via Marzolo 1, 35131 Padova, Italy</footnote>

<footnote><sup>c</sup> Laboratoire Hétérochimie Fondamentale et Appliquée – LHFA UMR5069, CNRS/Université de Toulouse, UPS, 31062 Toulouse Cedex09, France
E-mail: didier.bourissou@univ-tlse3.fr</footnote>

<footnote><sup>d</sup> Centre for Materials Science and Nanotechnology, University of Oslo, N-0316 Oslo, Norway
and
Department of Chemistry, University of Oslo, N-0315 Oslo, Norway</footnote>

<footnote><sup>e</sup> Department of Industrial Engineering, University of Padova, via Marzolo 9, 35131 Padova, Italy</footnote>
center were generally found to be superior in catalytic activity with respect to analogous NHC–Au(III) species.[8c,11]

Gold(III) catalysis from well-defined complexes has attracted increasing attention in recent years and significant progress has been achieved.[12] Of special note, (P,C)-cyclometalated ligands were discovered to unlock the catalytic potential of electrophilic gold(III) complexes, opening a new avenue for gold-catalyzed hydro arylation.[13] A detailed mechanistic study re- vealed a strict similarity between those species and the more traditional gold(I) catalysts.[14,15] An outer-sphere pathway was indeed demonstrated to be the most probable, where the coordination of the alkyne at the metal center precedes the effective C–H bond activa- tion (Scheme 1).[14,15] This mechanistic scenario was supported by kinetic isotope experiments and DFT calculations. Moreover, both the catalytically active species, as well as π-alkyne Au(III) intermediates and an off-cycle Wheland-type Au(III) σ-aryl complex were authenticated experimentally by NMR spectro- scopy and/or mass spectrometry coupled to CID (collision-induced dissociation) analyses. On the other hand, the mechanistic study has not been extended beyond simple electron-rich arenes as substrates; furthermore, the potential role of the catalyst counter- ion on the catalytic performance has not been exhaustively explored, compared to gold(I)-catalyzed

reactions.[16] For example, Zuccaccia and co-workers recently reported an in-depth study on the role of the counterion X⁻ (Cl⁻, BF₄⁻ or OTf⁻) in the alkyne hydration reaction catalyzed by [(2-phenylpyridine)Au(NHC)X]X complexes by a computational approach coupled to NMR studies.[17] Overall, gold(III) π-acid catalysis appears to hold much potential in direct hydroarylation reactions, but its study and application remain preliminary at this stage.

Being of our interest to develop new approaches for efficient and more sustainable gold-based processes, we became involved in applying the hydroarylation of alkynes to the direct synthesis of coumarins and performed a comprehensive study of this catalytic transformation with (P,C)-cyclometalated Au(III) com- plexes. Coumarins find broad application in diverse fields because of their fluorescence and medicinal properties.[18] They are conveniently and efficiently prepared by intra- or intermolecular metal-catalyzed hydroarylation processes,[19] with only very few prece- dents involving Au(III) catalysis to date.[7,9,13] As reported hereafter, the (P,C)-cyclometalated Au(III) complexes proved very efficient catalysts for the synthesis of coumarins by intramolecular hydroaryla- tion. Systematic screening of the reaction variables enabled us to achieve high yields (> 90%) using low amounts of gold catalyst (0.1–2 mol%) under mild and practical conditions (25–40 °C, 1–24 hours). In partic- ular, ionic liquids[20] were employed to limit the amount of Brönsted acid used to unlock the catalyst regeneration step, substantiating for the first time the interest and potential of these attractive solvents in catalysis by well-defined Au(III) complexes.[21] The impact of the acidic additive strength and of the ionic liquid have been preliminarily assessed.

**Results and Discussion**

The direct reaction of ethyl phenylpropiolate with sesamol was selected as model reaction to access coumarins. Direct comparison with the benchmark compound 1,3,5-tri-methoxybenzene (TMB) was con- ducted under the standard conditions developed by Fujiwara: dichloromethane/trifluoroacetic acid 1:4 as solvent and an alkyne/arene molar ratio 1:2.[4,22]

The (iPr₂P,C)Au<sup>III</sup> complex I (Table 1) yielded as expected 99% of product with TMB at 1 mol% loading after only 1 h at 25 °C (entry 1). However, changing the aromatic substrate to sesamol completely switched off catalysis (entry 2). Further attempts with increased loadings of gold complex or at higher temperatures were also unsuccessful (entries 3 and 4). Direct analysis of the reaction mixture by <sup>31</sup>P NMR {<sup>1</sup>H} spectroscopy (entry 3) revealed the presence of two main peaks at 90.5 and 79.5 ppm, which are both upfield compared to the signal of the isolated complex I (107.8 ppm in CDCl₃). This result suggested the

<figure><img src="image_5.png" /><figcaption>**Scheme 1.** Mechanism proposed to account for the intermolec- ular hydroarylation of alkynes catalyzed by (P,C)-cyclometa- lated gold(III) complexes.</figcaption></figure>

<figure><img src="image_6.png" /></figure>
<figure><img src="image_7.png" /><figcaption>**Table 1.** Direct hydroarylation of ethyl phenylpropiolate with TMB and sesamol.[a]</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Substrate</th><th>Time [h]</th><th>Yield 2a<sup>[b]</sup> [%]</th><th>Yield 2b<sup>[b]</sup> [%]</th></tr></thead><tbody><tr><td>1</td><td>TMB</td><td>0.5</td><td>&gt; 99</td><td>-</td></tr><tr><td>2</td><td>Sesamol</td><td>2</td><td>-</td><td>Traces</td></tr><tr><td>3<sup>[c]</sup></td><td>Sesamol</td><td>2</td><td>-</td><td>Traces</td></tr><tr><td>4<sup>[d]</sup></td><td>Sesamol</td><td>3</td><td>-</td><td>Traces</td></tr><tr><td>5<sup>[e]</sup></td><td>Sesamol + TMB</td><td>1 (24)</td><td>5 (8)</td><td>- (-)</td></tr></tbody></table>

[a] Reaction conditions: [Alkyne] = 1 M, 2 eq. arene:

[b] Yields were calculated by ¹H NMR spectroscopy using hexamethylbenzene as internal standard:

[c] 5 mol% catalyst:

[d] Reaction performed at 40 °C:

[e] 2 eq. sesamol + 2 eq. TMB.

presence of inactive resting states of the catalyst. To further support this view, a competitive test (entry 5) revealed that the presence of sesamol inhibits the catalytic coupling with TMB. Imputing this phenomenon to the presence of the hydroxyl moiety of the phenolic substrate and its possible interaction with the catalyst, other aimed tests were performed in order to establish a deactivation path. No evidence for such an interaction was recorded placing **I** and sesamol in ratio 1:2 under Fujiwara's conditions; however, partial conversion of the catalyst was recorded after 1 equiv.

of the alkyne was added to the mixture, together with the formation of the coumarin **2b**. The reaction was protracted by further additions of the two substrates to determine almost complete consumption of the gold complex **I** after 5 turnovers. It was then clear that the deactivation mechanism involves the alkyne as well, which should initially π-coordinate to the metal center. The cleavage of a trifluoroacetate ligand by AcF OH is needed to start this process, since no reaction of the gold complex **I** with the substrates was observed in pure CD2Cl2. The addition of as little as 2% v/v of AcF OH (compared to 80% v/v under Fujiwara conditions) was enough to initiate the process, and enabled us to follow it by ¹H and ³¹P NMR spectroscopies. Slow conversion of **I** toward a well-defined species with ³¹P NMR signal at 90.1 ppm was detected, affording 93% conversion after 24 h. This reaction mixture was subjected to complete characterization by multinuclear NMR spectroscopy and MS spectrometry, to authenticate the newly formed species as the gold-vinyl complex **I-2b**' that is expected to form in the course of the catalytic cycle, with the vinyl group *trans* to P (Scheme 2).

Interestingly, when we attempted to purify complex **I-2b**' upon layering the concentrated reaction solution with *n*-hexane, we isolated a solid containing sesamol and the corresponding coumaryl complex **I-2b** (Scheme 2) with ³¹P NMR signal at 79.5 ppm. Remarkably, complex **I-2b** is much more easily protonolyzed than **I-2b**' (Scheme 2; complete experimental and characterization details are given in the Supplementary Information). The inertness of complex **I-2b**' toward protonolysis recalls previously reported results by Tilset and co-workers on the addition of AcF OH to acetylene, catalyzed by N,C-cyclometallated gold(III) complexes.[23] In that case as well, the gold-vinyl intermediate with the vinyl group *trans* to the group of

<figure><img src="image_8.png" /><figcaption>**Scheme 2.** Deactivation pathway authenticated for the intermolecular hydroarylation of alkynes with sesamol catalyzed by the (P,C)-cyclometalated gold(III) complex **I**.</figcaption></figure>

<figure><img src="image_9.png" /></figure>
the chelating ligand with lower *trans* influence was found to be inert towards protonolysis by Ac⁸OH.

The results of our mechanistic investigation pointed out that the synthesis of coumarins by gold(III) catalyzed hydroarylation could be carried out much more efficiently in an intramolecular fashion, since in this case protonolysis of the resulting coumaryl intermediate should be much faster. Consequently, we started to examine the reactivity of preformed aryl propiolic esters as substrates. The model compound **1b** (Table 2) was readily synthetized *via* condensation of sesamol with phenylpropiolic acid, assisted by N,N'-di-cyclohexyl-carbodiimide and 4-(dimethylamino)-pyridine as Brønsted-base catalyst (the full procedure is described in the Experimental Section).

At 0.5 mol% loading, complex **I** was found to efficiently catalyze the cyclization of this substrate, affording the desired product **2b** in 98% yield within only 1 h at 25 °C (Table 2, entries 1 and 3). No trace of the regioisomeric product **2'b** was observed. Operating at 40 °C, the catalytic loading could be lowered to 0.1 mol% without compromising the efficiency of the **1b** to **2b** cyclization (entry 3). In line with previous observations,[13] the (Ph₂P,C)-cyclometalated complex **II** demonstrated to be superior in catalytic performance, enabling complete conversion of **1b** within 30 minutes at 25 °C and 0.1 mol% loading (entry 4). At this point, the (P,C)-cyclometalated complexes fulfilled our expectations in terms of activity, ease-of-process and robustness of the transformation. However, the high amount of trifluoroacetic acid cosolvent and the volatility of the organic mixture are not ideal practically. To further upgrade the catalytic system, we thus looked for conditions that would maintain similar

reaction efficiencies but would at the same time improve the process sustainability and applicability.

In this respect, we considered the use of Ionic Liquids (ILs) as a very interesting perspective. The low vapor-pressure and reduced operating risks of ILs make them appealing candidates to substitute the more traditional Ac⁸OH/DCM mixtures and other common organic solvents (e. g. dichloroethane, toluene, etc.) as reaction media. Moreover, the use of ILs in gold(I) catalysis was already reported to be beneficial both for catalytic activity and stability of the active complex.[20e,f] Butyl-methyl-imidazolium bis(trifluoromethanesulfonyl)imide [BMIM][NTf₂] was selected for process optimization. *In-situ* activation of the bis-iodo-(P,C)Au³I complexes **III** and **IV** (Table 3) was achieved by anion exchange with 2 equivalents of silver hexafluoroantimonate to ensure removal of coordinating iodide anions. Complete formation of the di-cationic species was confirmed by ESI-MS analyses (see the Supporting Information for a detailed discussion). Moreover, former kinetic studies by Blons *et al.* have excluded a possible silver effect[24] in the observed catalysis.[13]

Experimental results accounting for the effect of different acid additives (HA) on the hydroarylation of **1b** are disclosed in Table 3. The presence of a co-catalyst is indeed mandatory to overcome the energy barrier for protonolysis of the Au–C bond and unlock

<table><caption>**Table 3.** Influence of the Brønsted acid additive on the gold(III)-catalyzed intramolecular hydroarylation of **1b** in [BMIM][NTf₂].[a]</caption><thead><tr><th>Entry</th><th>HA</th><th>Cat.</th><th>Time [h]</th><th>Yield 2b[b] [%]</th></tr></thead><tbody><tr><td>1[c]</td><td>-</td><td><b>IV</b></td><td>24</td><td>NR[d]</td></tr><tr><td>2</td><td>HNTf<sub>2</sub></td><td><b>III</b></td><td>1 (3)</td><td>31 (&gt; 99)</td></tr><tr><td>3</td><td>HBF<sub>4</sub>·Et<sub>2</sub>O</td><td><b>III</b></td><td>1 (3)</td><td>28 (&gt; 99)</td></tr><tr><td>4</td><td>TfOH</td><td><b>III</b></td><td>1 (3)</td><td>20 (&gt; 99)</td></tr><tr><td>5[c]</td><td>HBF<sub>4</sub>·Et<sub>2</sub>O</td><td><b>IV</b></td><td>1</td><td>&gt; 99</td></tr><tr><td>6</td><td>Ac<sup>F</sup>OH</td><td><b>IV</b></td><td>1 (24)</td><td>25 (48)</td></tr><tr><td>7[e]</td><td>HBF<sub>4</sub>·Et<sub>2</sub>O</td><td><b>IV</b></td><td>1 (3)</td><td>24 (57)</td></tr><tr><td>8[e]</td><td>HBF<sub>4</sub>·Et<sub>2</sub>O</td><td>-</td><td>3</td><td>Traces</td></tr></tbody></table>

[a] Reaction conditions: 0.5 mmol **1b** in 0.75 ml [BMIM][NTf₂];

[b] Yields were calculated by ¹H NMR spectroscopy with 1,2-dimethoxyethane as internal standard:

[c] 5 mol% **IV**, no acid co-catalyst:

[d] NR: no reaction:

[e] Analogous results were collected with HNTf₂ and TfOH:

[f] CH₂Cl₂ instead of [BMIM][NTf₂] and 4 mol% AgNTf₂ as catalyst activator.

<table><caption>**Table 2.** Intramolecular hydroarylation of **1b** under Fujiwara's conditions.[a]</caption><thead><tr><th>Entry</th><th>Cat. (mol%)</th><th>Time[h]</th><th>Yield 2b[b][%]</th></tr></thead><tbody><tr><td>1</td><td>I (0.5)</td><td>1</td><td>98</td></tr><tr><td>2</td><td>I (0.1)</td><td>3</td><td>16</td></tr><tr><td>3[c]</td><td>I (0.1)</td><td>1</td><td>99</td></tr><tr><td>4</td><td>II (0.1)</td><td>1</td><td>&gt; 99</td></tr><tr><td>5</td><td>-</td><td>3</td><td>Traces</td></tr></tbody></table>

[a] Reaction conditions: [1b] = 1 M:

[b] Yields were calculated by ¹H NMR spectroscopy using hexamethylbenzene as internal standard:

[c] Reaction performed at 40 °C.

<figure><img src="image_10.png" /></figure>
catalysis (entry 1 vs 5). Three different strong acids were tested (entries 2–4). Very similar results were obtained (20–31% yield after 1 h, >99% after 3 h using 20 mol% of HA), indicating minimal impact of the related conjugated base (A=NTf₂, BF₄, OTf). Swapping to precatalyst IV (entry 5) enabled to achieve quantitative yields within only 1 h with the three strong acid additives. On the other hand, employing trifluoroacetic acid (Ac⁵OH), i.e. the same acid employed in Fujiwara's conditions, resulted in a significant drop in activity, which can be interpreted in terms of the lower acid strength of this additive and/or of the higher tendency of its conjugated base to coordinate to gold(III).[25]

To support our observations, we can recall that Gagné and co-workers already described the reactivity of a cationic diaurated alkenyl intermediate toward different strong acids and recorded the inability of Ac⁵OH to perform demetallation of this species.[26,27] As a further example, even more similar to our case, Blum and Roth confirmed that a net positive charge at the metal complex can strongly affect its kinetic relative acidity, enabling only strong acids such as TfOH, to cleave Au–C bonds.[28] On the other hand, the basicity of the phosphine seems to have only a minor role on this step.

Furthermore, substituting [BMIM][NTf₂] with dichloromethane as solvent led to lower activities (entry 7), which highlights once more the positive role played by ILs over more traditional organic solvents in this reaction. It is also important to note that a control experiment performed with HBF₄ (20 mol%) but without gold complex resulted in only traces of coumarin 2b after 3 hours (entry 8).[29]

The effect of the anion of the IL was then investigated using different ionic liquids [BMIM][X] (Table 4) with 0.5 mol% gold(III) complex IV. The acid co-catalyst HBF₄·Et₂O was kept as standard additive. Its pKₐ is lower than that of the conjugated acids of most of the other anions X⁻, with the only exception of OAc⁵. In the latter case, the actual co-catalyst is Ac⁵OH.[30,31]

Because of this, and because of the large excess of Ac⁵O⁻ over gold complex, leaving no available coordination site for substrate coordination, no catalytic activity was recorded over 24 h in [BMIM][OAc⁵] (entry 5).

On the other hand, anions that interact more weakly with the gold center, such as PF₆⁻ B and BF₄⁻ C, express the highest activity. The coumarin product is obtained in almost 90% yield within 1 h (entries 2 and 3). The anion NTf₂⁻ A provides somewhat lower activity, but still allows full conversion of the substrate in 3 h (entry 1). Conversely, much lower activity was observed with the anion TfO⁻ D (entry 4), 24 h being needed in this case to obtain 85% of product. This result is likely the consequence of the higher affinity of

<table><caption>**Table 4.** Effect of the ionic liquid anion on the gold(III)-catalyzed intramolecular hydroarylation of 1b.[a]</caption><thead><tr><th>Entry</th><th>[X]<sup>-</sup></th><th>Time [h]</th><th>Yield 2b<sup>[b]</sup> [%]</th></tr></thead><tbody><tr><td>1</td><td><b>A</b></td><td>1 (3)</td><td>34 (&gt; 99)</td></tr><tr><td>2</td><td><b>B</b></td><td>1 (3)</td><td>90 (&gt; 99)</td></tr><tr><td>3</td><td><b>C</b></td><td>1 (3)</td><td>90 (&gt; 99)</td></tr><tr><td>4</td><td><b>D</b></td><td>3 (24)</td><td>28 (85)</td></tr><tr><td>5</td><td><b>E</b></td><td>24</td><td>NR<sup>[c]</sup></td></tr></tbody></table>

[a] Reaction conditions: 0.5 mmol 1b in 0.75 ml [BMIM][X]:

[b] Yields were calculated by ¹H NMR spectroscopy with 1,2-dimethoxyethane as internal standard:

[c] NR: no reaction.

D for the gold(III) metal center. Thus, the recorded differences in reactivity with different anions of the IL seem to correlate well with the coordinating ability of the anion, which in case of gold(I) catalysis has been expressed through the GAI (gold affinity index) of the anion itself.[16b] In spite of these findings, we chose to employ the ionic liquid [BMIM][NTf₂] for practical reasons, since it is easier to work with ionic liquids containing NTf₂⁻ compared to BF₄⁻ and PF₆⁻ due to the higher stability of the former. Aging of ILs, caused in particular by the absorption of water and consequent hydrolysis of the BF₄⁻ or PF₆⁻ anions,[32] is indeed an issue potentially causing poorly reproducible results when these solvents are employed in our reactions.

After having examined the effects of the acid additive and of the ionic liquid anion, the substrate scope of the intramolecular reaction was assessed under the above optimized conditions: complex IV (2 mol%), AgSbF₆ (4 mol%), HBF₄·Et₂O (20 mol%), IL [BMIM][NTf₂] (Table 5).

In the first stage, we evaluated the substituent effect at the alkyne. Keeping constant the sesamol moiety, products were obtained in quantitative yields within 1 h for the internal alkynes (with phenyl and *n*-propyl substituents) as well as terminal alkynes (> 94% yield in 0.5 h, entries 1 to 3). The presence of substituents at the 3–5 positions of the arene moiety showed no steric influence on the conversion to the coumarin products (entries 4 and 5). Conversely, substrates 1g and 1h with an unsubstituted phenyl react significantly slower, high cyclization yields requiring 24 h (entries 6 and 7). Introducing a 4-tert-butyl substituent is enough to restore high catalytic activity, allowing to obtain 90%

<figure><img src="image_11.png" /></figure>
<figure><img src="image_12.png" /><figcaption>**Table 5.** Scope of the gold(III)-catalyzed cyclization of aryl alkynoates in ionic liquids.[a]</figcaption></figure>

[a] Conditions: 0.5 mmol of **1** in 0.75 ml [BMIM][NTf₂]:

[b] Yields were calculated by ¹H NMR vs internal standard 1,2-dimethoxyethane (reaction time is reported in parenthesis):

[c] Isolated yield:

[d] [BMIM][BF₄] instead of [BMIM][NTf₂], 5 mol% **IV** at 60°C.

**2i** and 82% **2j** in high yields within only 5 h (88% of **2j** was isolated after 24 h reaction). The cyclization of biphenyl-4-yl propiolate **11** proceeded slowly but quantitatively under standard conditions (entry 11), while for the related substrate **1k**, turning to [BMIM][BF₄] as IL and heating to 60°C proved necessary to obtain the corresponding coumarin **2k** in good yield, 71% at best (entry 10). Attempts to extend the reaction to the bromide-substituted substrate **1m** gave modest results (entry 12). For substrates with electron-depleted aryl moieties such as **1k** and **1m**, byproducts deriving from the hydrolysis of the ester moiety were consistently detected. The best obtained yields are however comparable to those reported by He and Shi with the AuCl₃/AgOTf system, which are the best achieved so far with these substrates upon gold catalysis.[9]

Moving to **1n** and **1o** featuring 4-methoxy substituted aryl moieties revealed an interesting selectivity issue. Indeed, with these substrates the *ipso* position is activated and may compete with the *ortho* positions for nucleophilic attack to the alkyne, giving spirocyclic lactones instead of coumarins. This side process has been already reported by Vadola *et al.*, who showed that the gold(I) catalytic system (Ph₃P)AuCl + AgOTf affords the spiro lactone with high selectivity in the

presence of 1 equivalent of water.[33] In our case, only traces of water are present in the [BMIM][NTf₂] ionic liquid, which probably favor the formation of the coumarin over the corresponding spirocyclic lactone. The hydroarylation proceeds faster from **1o** than **1n**, which limits the formation of spirocycle **3o** to 13% (entry 14). The competition between these two cyclization pathways prompted us to take a closer look at the effect of the reaction conditions on product selectivity, using (Ph₂P·C)-cyclometalated Au(III) complexes **II** and **IV** (Table 6).

Fujiwara's conditions were tested first. Interestingly, operating at 2 mol% catalytic loading, low activity but exclusive selectivity towards **3n** were recorded (entry 2). Increasing the catalytic loading to 5 mol% enabled to achieve complete conversion of **1n** after 24 h and to obtain the spirolactone **3n** in 89% isolated yield (entry 3).

The ability of the AcF·O⁻ anion to assist O-demethylation probably plays a major role in the observed chemoselectivity. The crude mixture actually displays a ¹H NMR signal at δ 3.99 ppm accounting for the concomitant formation of the trifluoroacetate methyl ester. As for the IL conditions, it was also possible to obtain **3n** in high yield (97%) using [BMIM][OTf] and 5 mol% of complex **IV** (entry 5). The TfO⁻ anion is

<figure><img src="image_13.png" /></figure>
<table><caption>**Table 6.** Impact of the reaction conditions on the coumarin vs spirolactone formation from **1n**.</caption><thead><tr><th>Entry</th><th>Conditions<sup>[a,b]</sup></th><th>Cat. (mol%)</th><th>Time [h]</th><th>Conv. 1n<sup>[c]</sup> [%]</th><th>Yield 2n<sup>[c]</sup> [%]</th><th>Yield 3n<sup>[c]</sup> [%]</th></tr></thead><tbody><tr><td>1</td><td>IL, [X] = [NTf<sub>2</sub>]</td><td><b>IV</b> (2)</td><td>5</td><td>&gt; 99</td><td>66</td><td>34</td></tr><tr><td>2</td><td>Fujiwara's</td><td><b>II</b> (2)</td><td>24</td><td>37</td><td>-</td><td>37</td></tr><tr><td>3</td><td>Fujiwara's</td><td><b>II</b> (5)</td><td>24</td><td>98</td><td>Traces</td><td>92 (89)<sup>[d]</sup></td></tr><tr><td>4</td><td>IL, [X] = [OTf]</td><td><b>IV</b> (2)</td><td>24</td><td>30</td><td>-</td><td>29</td></tr><tr><td>5</td><td>IL, [X] = [OTf]</td><td><b>IV</b> (5)</td><td>24</td><td>&gt; 99</td><td>-</td><td>97</td></tr></tbody></table>

[a] IL conditions: 0.5 mmol **1n** in 0.75 ml [BMIM][X], 20 mol% HBF₄ Et₂O, 40 °C:

[b] Fujiwara's conditions: DCM/AcF OH 1:4 v/v, [**1n**] = 1 M at 25 °C:

[c] Yields and conversions were calculated by ¹H NMR spectroscopy using hexamethylbenzene (Fujiwara's conditions) or 1,2-dimethoxyethane (IL conditions) as internal standards:

[d] Isolated yield.

more nucleophilic than the NTf₂⁻ anion in the commonly employed IL [BMIM][NTf₂] and may better assist the O-demethylation; it also makes the IL more hygroscopic, which may explain the complete selectivity for the dearomative spirocyclization.

Finally, to probe the impact of the aryl group (phenyl vs naphthyl) on the hydroarylation/spirocyclization competition, we prepared and tested substrates **1p** and **1q**. Here, the corresponding coumarins were quantitatively obtained within 3 h whatever the position of the methoxy group (entries 15 and 16, Table 5). Moreover 92% of **2q** could be isolated after complete conversion of the alkynoate (entry 16).

The last part of the work was focused on the activation of more electron-rich alkynes. Aryl propargyl ethers were selected to explore a further application of our system to the synthesis of chromenes (Table 7).

Remarkably rapid conversion of substrates **4h** and **4o** was observed under the same conditions developed for coumarin synthesis (entries 1 and 2). However, complex mixtures were obtained due to the fast degradation of the obtained chromenes under reaction conditions. Chromene **5o** accumulated in the reaction mixture and its consumption was monitored over-time (entries 4 and 5). Fujiwara's conditions allowed to reach 67% of **5o**, stopping the reaction after 30 minutes (entry 4). On the other hand, any attempt to expand the scope to substrates **4h** (entry 3) and **4c** (entries 6 to 8) produced much poorer results, due to the fast degradation of the chromenes with respect to cyclization rates.

No improvements were recorded operating under IL conditions rather than Fujiwara's ones. However, an interesting result was obtained from **4b**, leading to the formation of the chromane **6b** as major product (72% yield, entry 9). Overreduction of chromenes was al-

ready reported by Sames *et al.* as a side-process in the intramolecular hydroarylation of aryl propargyl ethers using Pd(OAc)₂ under Fujiwara's conditions.[34] Assuming that the acid conditions play a role in the reduction of the initially formed chromene, we performed some blank tests reacting **5b** along with HBF₄ and [BMIM][NTf₂] as reaction medium (see the Supporting Information for details). Formation of chromane **6b** was observed, along with the corresponding benzopyrilium salt **7b**, which was unambiguously authenticated by ¹H NMR spectroscopy. To our knowledge, this disproportionation process was never reported before in the case of chromenes, while a similar acid-initiated process is known for 1,2-dihydronaphthalene and quinoline derivatives.[29,35,36] This new reactivity could be usefully applied for synthetic purposes. Benzopyrilium salts are indeed valuable intermediates for the synthesis of 4H-chromenes or 2-substituted chromenes, upon nucleophilic attack at 4 or 2 position, respectively.[37,38] Moreover, taking as an example the work conducted by Chang and coworkers[29] we successfully synthesized **7b** directly from **4b** by addition of 1 equivalent of HNTf₂ in dichloromethane (details are reported in the Supporting Information).

Whereas formation of **7b** seems to require acid conditions, formation of the chromane **6b** was recorded also under neutral conditions in the presence of gold complex **IV** after 1 day of reaction (entry 10). It is clear that the gold catalyst also contributes to consume the chromene product over time (entries 8 and 10). More studies are needed to clarify what is the nature of those secondary processes.

<figure><img src="image_14.png" /></figure>
<figure><img src="image_15.png" /><figcaption>**Table 7.** Synthesis of chromenes.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Conditions<sup>[a,b]</sup></th><th>Substrate</th><th>Cat. (mol%)</th><th>Time [h]</th><th>Conv. 4<sup>[c]</sup> [%]</th><th>Yield 5<sup>[c]</sup> [%]</th></tr></thead><tbody><tr><td>1</td><td>IL</td><td><b>4h</b></td><td><b>IV (2)</b></td><td>1</td><td>94%</td><td>n.d.<sup>[d]</sup></td></tr><tr><td>2</td><td>IL</td><td><b>4o</b></td><td><b>IV (2)</b></td><td>1</td><td>&gt; 99</td><td>n.d.<sup>[d]</sup></td></tr><tr><td>3</td><td>Fujiwara's</td><td><b>4h</b></td><td><b>II (0.5)</b></td><td>3 (24)</td><td>15 (47)</td><td>n.d.<sup>[d]</sup></td></tr><tr><td>4</td><td>Fujiwara's</td><td><b>4o</b></td><td><b>II (0.5)</b></td><td>0.5 (6)</td><td>&gt; 99</td><td>67 (&lt; 5)</td></tr><tr><td>5<sup>[e]</sup></td><td>IL</td><td><b>4o</b></td><td><b>IV (2)</b></td><td>0.5 (1)</td><td>&gt; 99</td><td>30 (12)</td></tr><tr><td>6<sup>[e]</sup></td><td>IL</td><td><b>4c</b></td><td><b>IV (2)</b></td><td>0.5</td><td>&gt; 99</td><td>n.d.<sup>[d]</sup></td></tr><tr><td>7</td><td>Fujiwara's</td><td><b>4c</b></td><td><b>II (0.5)</b></td><td>0.5</td><td>&gt; 99</td><td>n.d.<sup>[d]</sup></td></tr><tr><td>8<sup>[f]</sup></td><td>IL</td><td><b>4c</b></td><td><b>IV (2)</b></td><td>1 (4)</td><td>75 (&gt; 99)</td><td>21 (Traces)</td></tr><tr><td>9</td><td>IL</td><td><b>4b</b></td><td><b>IV (2)</b></td><td>5</td><td>95</td><td>n.d.<sup>[d,g]</sup></td></tr><tr><td>10<sup>[f]</sup></td><td>IL</td><td><b>4b</b></td><td><b>IV (2)</b></td><td>1 (24)</td><td>40 (84)</td><td>30 (13)<sup>[h]</sup></td></tr></tbody></table>

## Conclusion

In this work, we presented a practical methodology to access coumarins employing (P,C)-cyclometalated Au-(III) complexes as hydroarylation catalysts in ILs. Direct cyclization of aryl alkynoates was demonstrat-edly operated at low loading of gold (0.1–2 mol%) employing sub-stoichiometric quantities of Brønsted acid additive (20 mol%).

The reaction scope showed good compatibility toward different propiolate fragments. The transformation works best when the aromatic ring bears electron donating groups, with the exception of *para*-methoxy substituents due to competitive dearomative spirocyclization. Conversely, we found that it is possible to obtain the spirolactone with complete selectivity under both Fujiwara's and IL conditions. In general, the gold(III)-based catalytic system proved to be competitive with other gold(I)-based systems previously described in the literature,

Attempts to further extend the application of the gold(III) catalyst system to the cyclization of aryl

propargyl ethers were difficult due to the instability of the ensuing chromenes under the employed reaction conditions. However, an acid-mediated disproportionation process leading to chromanes and benzopyrilmum salts was disclosed.

Future work will aim at further exploring and developing gold(III) catalysis in ILs. In particular, ligand design will be optimized in order to overcome catalyst deactivation currently hampering efficient coumarin synthesis by intermolecular direct alkyne hydroarylation with phenols.

## Experimental Section

### General Procedures for Catalytic Tests

#### Fujiwara's Conditions (Intermolecular Hydroarylation)

The arene (2.0 mmol) was placed in a flame-dried Schlenk tube under argon atmosphere along with 0.8 ml of AcF OH. Gold

<figure><img src="image_16.png" /></figure>

<footnote>[a] IL conditions: 0.5 mmol **1**n in 0.75 ml [BMIM][NTf₂], 20 mol% HBF₄•Et₂O or HNTf₂ at 40 °C.</footnote>

<footnote>[b] Fujiwara's conditions: DCM/AcF OH 1:4 v/v, [4] = 1 M at 25 °C.</footnote>

<footnote>[c] Yields and conversions were calculated by ¹H NMR using hexamethylbenzene (Fujiwara's conditions) or 1,2-dimethoxyethane (IL conditions) as internal standards:</footnote>

<footnote>[d] n.d.: not detected:</footnote>

<footnote>[e] Reaction performed at 25 °C:</footnote>

<footnote>[f] No acid co-catalyst was employed:</footnote>

<footnote>[g] **6b** was detected with 72% yield:</footnote>

<footnote>[h] **6b** was detected in traces and then with 20% yield respectively at 1 h and 24 h reaction time.</footnote>
complex I (6.7 mg, 0.01 mmol)<fnref n="1" /> and hexamethylbenzene (25.0 mg, 0.15 mmol) were dissolved in 0.2 ml of DCM and added to the flask. A t₀ NMR check was performed after taking an aliquot of the reaction mixture in 0.5 ml CDCl₃. The flask was then cooled down to 0°C and ethyl phenyl-propiolate (0.17 ml, 1.0 mmol) was added. After 5 min stirring at 0°C, the mixture was placed in a 25°C thermostatic bath and the reaction monitored by ¹H NMR using hexamethylbenzene as internal standard, as for the t₀ NMR check.

## Fujiwara's Conditions (Intramolecular Hydroarylation)

The substrate (1 mmol) and hexamethylbenzene (25.0 mg, 0.15 mmol) were placed in a flame-dried Schlenk tube under argon atmosphere along with 0.9 ml of a solution 1:4 v/v DCM/ AcF OH. A t₀ NMR check was performed after taking an aliquot of the reaction mixture in 0.5 ml CDCl₃. Then the gold complex I or II (0.001 mmol or 0.005 mmol) in 0.1 ml of the DCM/ AcF OH mixture was added to the mixture. The flask was then placed in a thermostatic bath at 25 or 40°C, and the reaction monitored by ¹H NMR using hexamethylbenzene as internal standard, as for the t₀ NMR check.

### IL conditions

The substrate (0.5 mmol) and the gold complex III or IV (0.01 mmol)<fnref n="2" /> were placed in a flame-dried Schlenk tube under argon atmosphere. A freshly prepared solution of the silver salt AgSbF₆ (6.9 mg, 0.02 mmol) in [BMIM][X] (0.75 ml) and 1,2-dimethoxyethane (0.05 ml, 0.48 mmol) were added to the flask and the mixture was stirred for 5 min at room temperature. A t₀ NMR check was performed after taking an aliquot of the reaction mixture in 0.5 ml CDCl₃. The acid co-catalyst HA (0.1 mmol) was then added to the mixture and the flask was placed in a thermostatic bath at 40°C. The reaction was monitored by ¹H NMR using 1,2-dimethoxyethane as internal standard, as for the t₀ NMR check.

Compounds 2b-g, 2j, 2k, 2m, and 2q were synthesized by the same procedure and isolated as follows:

The reaction crude was taken-up in DCM (15 ml) and the resulting organic phase was quenched with a saturated NaHCO₃ aqueous solution. The aqueous phase was then counter-extracted with DCM (3×10 ml) and the whole combined organic phases were dried over Na₂SO₄ before removing all volatiles under reduced pressure. The obtained residue was subjected to flash chromatography over silica gel to obtain the pure products upon collecting and evaporating the relevant fractions.

## Acknowledgements

F.R. wish to thank the Erasmus Traineeship program for the award of a scholarship. This study is a part of the FRINATEK project 315004 funded by the Research Council of Norway (stipend to M.S H.). Open access publishing facilitated by Universita degli Studi di Padova, as part of the Wiley – CRUI-CARE agreement.

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<figure><img src="image_17.png" /></figure>
# Gold(III) Catalysis in Ionic Liquids: The Case Study of Coumarin Synthesis

*Adv. Synth. Catal.* **2024**, *366*, 1–11

<figure><img src="image_18.png" /></figure>

F. Ravera, M. S. Martinsen Holmsen, P. Sgarbossa, D. Bourissou*, A. Biffis*

<figure><img src="image_19.png" /></figure>