Synergistic Action of Ascorbic Acid and Readily Accessible NHC^N Ligands for the Oxidation of Gold(I) With Electron‐Rich Aryldiazonium Salts

ABSTRACT

The synergistic action of ascorbic acid and NHC^N ligands enables the challenging oxidation of Au(I) with electron‐rich aryldiazonium salts in the absence of a cocatalyst and/or irradiation. EPR, NMR, and x‐ray analyses reveal the reaction to be triggered by a radical pathway facilitated by the ligand‐assisted stabilization of the Au(III) center. The utility of this synergistic effect was demonstrated in a catalytic arylative carbocyclization, providing access to a 3,4‐diaryl‐2H‐chromene containing two electron‐rich aryl groups, a substitution pattern inaccessible by previous protocols.

The synergic action of ascorbic acid and NHC^N ligands enables Au(I) oxidation with electron‐rich aryldiazonium salts.

1. Introduction

Gold‐redox chemistry has attracted attention due to its potential to enhance the catalytic activity of a low‐toxicity metal. Interestingly, various studies have shown that the couple Au(I)/Au(III) can yield reaction outcomes or regioselectivities that differ from those observed with transition metals commonly used in catalysis [1, 2, 3]. A key challenge for applying gold in redox catalysis is the high redox potential Au(I)/Au(III) (E°red Au(III/I) = 1.41 V) [4]. To overcome the latter, four main strategies have been employed: (a) the use of stoichiometric external oxidants [5, 6, 7, 8, 9, 10]. (b) designing bidentate ligands capable of satisfying the coordination needs of both Au(I) and Au(III) [11, 12, 13, 14, 15, 16, 17, 18, 19, 20]. (c) employing aryldiazonium salts as electrophiles [21, 22, 23, 24, 25, 26]. and more recently, (d) electrochemical anodic oxidation [27, 28, 29, 30, 31]. In coupling reactions, aryldiazonium salts offer advantages over aryl halides as they are accessible from anilines, compatible with aqueous‐alcoholic media, and their nucleofugic nitrogen makes them highly electrophilic, enabling ligandless conditions and reducing the need for high temperatures [32, 33, 34, 35, 36, 37, 38, 39]. In gold redox chemistry, aryldiazonium salts oxidize gold through a two‐electron transfer (STEP) process, typically requiring a photoredox cocatalyst [21, 22, 23, 24, 25, 26]. Upon irradiation, the cocatalyst becomes excited, generating aryl radicals that add to Au(I), forming Au(II) intermediates, which evolve to Au(III) by reacting with the oxidized form of the photocatalyst (Scheme 1a). In some instances, simply irradiating or the addition of certain bases or ligands is sufficient to facilitate Au(I)/Au(III) oxidation [26, 40, 41, 42, 43]. Our group has evidence that aryldiazonium salts can produce aryl‐Au(III) intermediates thermally or with ascorbic acid [44, 45, 46]. EPR experiments confirmed that catalytic amounts of ascorbic acid increase aryl radical concentrations from aryldiazonium salts. Complementary to this, DFT calculations on the reaction mechanism of aryldiazonium chlorides [46] revealed that once generated, aryl radicals readily add to Au(I) without an energy barrier, resulting in aryl‐Au(II) intermediates that react with another equivalent of the aryldiazonium salt to produce the aryl‐Au(III) complex and an aryldiazonium radical. This step is also barrierless and appears to be assisted by the chloride counter anion (Scheme 1a). Fragmentation of the aryldiazonium radical regenerates an aryl radical; this step is the only one comprising an energy barrier (ΔG = 7.3 Kcal mol⁻¹ for Ar 4‐NO₂‐C₆H₄, and ΔG = 9.5 Kcal mol⁻¹ for Ar 4‐MeO‐C₆H₄) [46] Although energy values are favorable for aryldiazonium salts containing electron‐poor and electron‐rich groups, experimentally, it is observed that aryldiazonium salts substituted with electron‐rich groups show reluctance to react. The last can be attributed to their higher reduction potential.

SCHEME 1.

(a) Mechanism for the oxidation of Au(I) under photoredox catalysis; (b) Mechanism for the oxidation of Au(I) with ascorbic acid.

The diminished reactivity of aryldiazonium salts with electron‐rich groups poses a challenge for their application in gold redox chemistry. This limited scope imposes serious restrictions on the synthesis of complex organic compounds, as electron‐rich aryl motifs are ubiquitous in natural products and pharmaceuticals. Therefore, developing efficient methodologies that facilitate the activation of these reluctant species is crucial. Through our studies on gold‐mediated arylation reactions with aryldiazonium salts [47, 48, 49, 50, 51, 52, 53]. we observed that adding pyridine derivatives as bases or ligands improves the yields. In comparison, phosphines, common ligands in catalysis, typically do not enhance yields. The latter is likely due to their tendency to form azophosphonium salts [54, 55, 56, 57] or undergo SET reactions with aryldiazonium salts, leading to phosphine cation radicals that promote the dediazoniation of the aryldiazonium salt [58, 59, 60]. If the formation of aryl radicals is slow (which depends upon the reduction potential), these secondary reactions may become significant. In line with our observations, other studies have found evidence that pyridine, 2,2'‐bipyridine, and derivatives have a beneficial effect on gold redox catalysis [40]. Bower and Russell have proven that 2,2'‐bipyridine derivatives, especially 5,5'‐difluoro‐2,2'‐bipyridine (I, Figure 1a), enable oxidative addition of aryl, alkenyl, and alkynyl C‐I bonds [14, 61, 62, 63]. By DFT calculations, they demonstrated that the best oxidative addition rates were correlated with a more electron‐poor ligand [62]. The principle underlying the beneficial effect of 2,2'‐bipyridine is related to what the group of Bourissou described for o‐carborane diphosphines (DPCb) [64, 65] or the hemilabile amino‐phosphine Me‐Dalphos [13]. These kinds of ligands are able to coordinate Au(I) in a bent geometry, which preorganizes the square‐planar coordination mode of Au(III), enhances the energy levels of the Au(I) d orbitals, and the π‐back donation [66]. Altogether, these factors favor the coordination of the oxidizing reagent and lower the energy barrier to oxidative addition [12]. In a similar vein, the Hashmi group demonstrated experimentally and by DFT that oxidative addition to Au(I) is favored in the presence of weakened bidentate σ‐donor ligands, such as phenanthroline (II, Figure 1a), or even by the dicoordination of weakened σ‐donor ligands, such as pyridine [67, 68]. Along with bipyridine derivatives, mesoionic carbenes containing a pendant pyridine or pyrimidine moiety (MIC^N) have been shown to facilitate oxidative addition (III and IV, Figure 1a) [69, 70, 71]. The group of X. Ribas demonstrated its ability to catalyze the arylation‐lactonization of γ‐alkenoic acids in excellent yields [70, 71]. Finally, along with carbenes, phosphines have also been used in some instances, in combination with pyridines, in P^N ligands to facilitate the oxidation of Au(I) with aryldiazonium salts [72, 73] and aryliodides [18].

FIGURE 1.

(a) Previously developed Au(I) complexes undergoing oxidative addition based on pyridine and/or carbene coordination; (b) This work: (NHC^N)Au(I) complexes undergoing oxidative addition with cooperative assistance of ascorbic acid.

Considering the aforementioned challenges, and to enhance the reactivity of aryldiazonium salts containing electron‐rich groups, we became interested in studying the effect of incorporating ligands that position pyridine and 2,2'‐bipyridine near the gold center (Figure 1b). We chose NHC carbenes as a platform to link the pendant pyridine moiety because they permit the introduction of different fragments in an accessible, modular manner and strongly stabilize the metal [74, 75, 76, 77, 78, 79]. Indeed, NHC carbene ligands can stabilize Au(III) even in water [80, 81, 82], and recently, CCC‐NHC pincer ligands have been used to stabilize elusive Au(III) species [83]. On the other hand, hemilabile ligands containing dimethyl amino groups and NHC carbenes (V, Figure 1a) have been shown to catalyze the 1,2‐oxyarylation of alkenes and the C‐C coupling of arenes with aryliodides [84, 85]. The cooperative effect of bidentate NHC^N ligands and a readily accessible reducing agent in the context of gold‐redox chemistry remains unexplored. In this study, we report the synergistic action of readily available NHC^N ligands and ascorbic acid for the oxidation of Au(I) with electron‐rich aryldiazonium salts, providing a sustainable protocol that avoids the need for photoredox catalysts.

2. Results and Discussion

We envisioned the synthesis of NHC carbenes bearing pyridine or bipyridine moieties at the imidazole‐2‐ylidene nitrogen to benefit from a potential bent coordination mode. For the latter, we began by synthesizing the imidazolium salt precursors of the desired carbene ligands (Scheme 2). First, we focused on the synthesis of imidazolium salts 2a‐c, which would permit us to compare the stereo‐electronic properties of a carbene containing two pyridine fragments (σ donor and π‐acceptor character, 2a), versus a carbene containing a pyridine in combination with a sterically stabilizing group such as mesityl (Mes, 2b), or a strong σ donor such as isopropyl (iPr, 2c). Their synthesis was accomplished by heating the corresponding N‐substituted‐1H‐imidazoles (1a‐c) and 2‐bromopyridine at 180°C for 18 h in a J. Young tube (42%–63% yield) [84, 85]. With the aim to compare the effect imparted by pyridine with 2,2'‐bipyridine, imidazolium salt 2d containing a 3‐(2,2'‐bipy) fragment and a mesityl, was synthesized by reaction of 6‐bromo‐2,2'‐bipyridine with 1‐mesityl‐1H‐imidazole (1b) at 180°C for 4 h (34% yield). Additionally, we prepared imidazolium salts 2e and 2f substituted with a small donor group (methyl) by heating 2‐(1H‐imidazol‐1yl)pyridine (1a) and 6‐(1H‐imidazol‐1‐yl)‐2,2'‐bipyridine (1d) with MeI in THF at 180°C (2e 72%, 2f yield 49%). The alternative synthesis of these salts from 1‐methylimidazole and either 2‐bromopyridine or 6‐bromo‐2,2'‐bipyridine afforded lower yields. All imidazolium salts were purely obtained by direct filtration and washing of the crude reaction mixture, or by precipitation with diethyl ether. The signals of the more acidic imidazolium protons were observed in the ¹H NMR spectra between 10.04 ppm and 11.57 ppm.

SCHEME 2.

Synthesis of imidazolium salts (2a‐f) precursors of carbene ligands.

With imidazolium salts 2a‐2f in hand, we proceeded to prepare the corresponding Au(I) complexes (Scheme 3). The best yields were obtained following the “weak base route” developed by Gimeno [86, 87] and Nolan [88, 89, 90], either by deprotonation with (n‐Bu)₄NOAc in CH₂Cl₂ or K₂CO₃ in acetone. Thus, complexes 3a, 3b, and 3d were synthesized by mixing a solution of [AuCl(SMe₂)] in CH₂Cl₂ with imidazolium salts 2a, 2b, and 2d, in the presence of (n‐Bu)₄NOAc as a base for 4 h. To ensure the isolation of the mono‐carbene Au(I) species, an excess of NaBr (2 equiv) was added at the end of the reaction [91]. The desired complexes were purely isolated in 52%–55% yield, after filtration of the crude reaction mixture through a pad of celite and silica. On the other hand, complexes 3c, 3e, and 3f were prepared by treating a solution of [AuCl(SMe₂)] in acetone with imidazolium salts 2c, 2e, and 2f in the presence of K₂CO₃ as a base, under reflux for 10 h. Complexes 3c and 3f were purely isolated as mono‐carbene NHC‐Au(I)Br complexes after filtration through a pad of celite and silica in 65% and 46% yield, respectively. Complex 3e was isolated as a bis‐carbene cationic complex in 47% yield; attempts to displace the equilibrium to the mono‐carbene complex (by addition of NaX salts) were unsuccessful. The coordination of imidazolium salts 2a‐f to Au(I) was corroborated by the disappearance of the more acidic proton of the imidazolium salt in the ¹H NMR of 3a‐f complexes, along with ¹³C NMR and HRM (FAB⁺) analyses. In the case of 3e, the elemental analysis agreed with the formula [(NHC)₂Au][AuI₂], indicating (AuI₂)⁻ as the counteranion. Suitable crystals of 3a, 3b, and 3d for X‐ray diffraction analyses were obtained by slow diffusion of Et₂O in CH₂Cl₂, further confirming their structure (Figure 2).

SCHEME 3.

Synthesis of (NHC^N)Au(I) complexes 3a‐3f.

FIGURE 2.

Solid‐state molecular structures of 3a, 3b, and 3d with thermal ellipsoids drawn at 50% probability level. Selected bond lengths (Å) and angles (deg): 3a, C2‐N 1.345, Au‐C2 1.99, Au‐Br 2.392(1), C2‐Au‐Br 175.4; 3b, C2‐N1 1.359(7), C2‐N3 1.346(7), Au‐C2 1.980(7), Au‐Br 2.389(1), C2‐Au‐Br 178.4(2); 3d, C2‐N1 1.352(7), Au‐C2 1.995(5), Au‐Br 2.3778(6), C2‐N3 1.342(7), C2‐Au‐Br 175.2(2).

The solid‐state structures of 3a, 3b, and 3d display Au(I) with a typical linear coordination mode with a small deviation from linearity, with an angle C2‐Au‐Br: 175.4(3)° in 3a, 178.4(2)° in 3b, and 175.2(2)° in 3d. The C2‐Au distances are in the range reported for NHC‐Au(I) complexes: [92] 1.99(1) Å in 3a, 1.980(7) Å in 3b, and 1.995(5) Å in 3d, whereas the bond distance Au‐Br is 2.389(1) Å in 3a, 3b, and 3d.

The tendency of imidazolium salt 2e to form the bis‐carbene complex 3e inspired us to synthesize bis‐imidazolium salts 2g and 2h, where two imidazolium fragments are linked to a pyridine as a connector (Scheme 4a). The last, because this architecture has the potential to generate pincer Au(I) or Au(III) complexes, which may facilitate oxidative addition through the stabilization afforded by tridentate chelation [83, 93]. In Au(I)‐catalyzed reactions, the presence of two NHC ligands hampers catalysis because it is difficult to create a vacant site around the gold coordination sphere [94]. However, [Au(NHC)₂]X complexes are good precursors of Au(III) complexes [91, 95, 96, 97], and it is expected that after oxidative addition, the square planar coordination mode of the generated [Au(III)Ar(NHC‐Py‐NHC)]⁺ complex enables a catalytic process [83]. The synthesis of imidazolium salts 2g and 2h was made by heating 2,6‐dibromopyridine with either 1b or 1e in a Young tube at 180°C, for 3 days in the case of 2g (53% yield), and 3 h for 2h (66% yield) [98, 99].

SCHEME 4.

(a) Synthesis of bis‐imidazolium salts 2g and 2h. (b) Synthesis of bimetallic bis‐carbene complexes 3g and 3h.

Treating a solution of imidazolium salt 2g with [AuCl(SMe₂)] and nBu₄NOAc for 16 h at room temperature afforded complex 3g, which was isolated after filtration, washing with CH₂Cl₂, and evaporation of volatiles as a white powder with enough purity in 26% yield. Conversely, the same protocol applied to imidazolium salt 2h resulted in decomposition. Satisfactorily, heating a solution of 2h and [AuCl(SMe₂)] with K₂CO₃ in acetone under reflux for 10 h allowed the isolation of 3h in 25% yield after recrystallization from chloroform.

The structures of 3g and 3h were assigned by NMR, FAB⁺, and elemental analysis, and were consistent with bimetallic neutral Au(I) complexes rather than the potential monometallic cationic bis‐carbene Au(I) complexes. In the ¹H NMR, the more acidic protons of the imidazolium fragments (at 11.84 ppm in 2g and 10.67 ppm in 2h) disappeared, whereas in the ¹³C NMR carbenic carbon atoms were identified at 173.40 ppm in 3g and 172.14 ppm in 3h. The FAB⁺ spectra showed mass peaks corresponding to a bimetallic species [M‐Br]⁺ at m/z: 922 for 3g and m/z: 714 for 3h. Additionally, elemental analyses of 3g and 3h agreed with the formula [Au₂Br₂(NHC‐Py‐NHC)]. Fortunately, suitable crystals for single X‐ray diffraction of 3g were obtained by slow diffusion of Et₂O into CH₂Cl₂, thereby allowing further confirmation of its structure (Figure 3). The solid‐state molecular structure of 3g corroborates that it is a neutral bimetallic Au(I) complex that crystallizes in the orthorhombic chiral space group P2₁2₁2₁, with a Flack parameter of 0.016(4). The angle between the carbene plane C8‐N9‐C10‐C11‐N7 and pyridine is 43.096(3)°, whereas the angle between the second carbene plane C22‐N23‐C24‐C25‐N21 and pyridine is 48.49(3)°. The planes of the two carbenes are twisted by 53.7°. There is no aurophilic contact, the Au1‐Au2 distance being 7.3313(5) Å. Each Au(I) atom adopts a linear geometry with slight deviations. The angle C8‐Au1‐Br1 is 178.9(2)°, and the angle C22‐Au2‐Br2 is 177.3(2)°. NHC‐Au(I) distances are in the range for Au(I) complexes,⁹⁴ C8‐Au1 is 1.990(8) Å, and C22‐Au2 is 1.986(7) Å. The Au‐Br distances are also similar: Au1‐Br1 is 2.397(1) Å, and Au2‐Br2 is 2.3958(9) Å. Based on this structure, data from mass spectrometry, NMR, elemental analyses, and a similar complex containing chloride instead of bromide [100], we propose that the solid‐state molecular structure of 3h is similar to that of 3g. Bis‐imidazolium salts connected by a pyridine and substituted with alkyl chains at the imidazole‐2‐ylidene nitrogen have been reported to form dimeric dinuclear Au(I) complexes [101]. Although such dimers may exist in equilibrium in solution, they were not detected in FAB⁺ analyses.

FIGURE 3.

Solid‐state molecular structure of 3g drawn at 50% probability level. Solvent molecules are omitted for clarity. Selected bond lengths (Å) and angles (deg): C8‐N9 1.355(9), C8‐N7 1.356(9), Au1‐C8 1.990(8), Au1‐Br1 2.397(1), C8‐Au1‐Br1 178.9(2), C22‐N21 1.350(9), C22‐N23 1.354(9), Au2‐C22 1.986(7), Au2‐Br2 2.3958(9), C22‐Au2‐Br2 177.3(2).

We next initiated reactivity studies by monitoring the reaction of complex 3a with a well‐known, very reactive aryldiazonium salt, 4‐NO₂‐C₆H₄N₂Cl, using ¹H NMR. Previous studies from our laboratory have shown that the reaction of this salt with [AuCl(SMe₂)] in DMSO‐d₆ at 50°C takes 3 h to complete, whereas the addition of ascorbic acid at 10 mol% reduces the reaction time to 30 min at room temperature [44, 46]. With this information, we prepared a sample of 3a with 4‐NO₂‐C₆H₄N₂Cl in DMSO‐d₆ in the presence of ascorbic acid (10 mol%) and DSS (sodium 3‐(trimethylsilyl)propanesulfonate) as internal standard. However, the high reactivity of the aryldiazonium salt under these conditions prevents following the reaction by ¹H NMR. Replacing Cl⁻ with BF₄ ⁻ as the counter anion slightly reduced the reactivity of the aryldiazonium salt. After 10 min, the two doublets at 8.89 and 8.69 ppm, corresponding to the aromatic protons of 4‐NO₂‐C₆H₄N₂BF₄, completely disappeared, and three sets of doublets appeared at higher fields. After 16 h at room temperature, the ¹H NMR spectrum showed signals attributable to the ligand and two sets of doublets at 8.54/8.12 ppm and 7.25/6.84 ppm (Figure S1) [102]. To get more insights about the species being formed, we analyzed the crude reaction mixture by FAB⁺, observing a peak at m/z 620 that corresponds to the [M]⁺ fragment of the expected 3aa complex [Au(III)(Br)(C₆H₄‐NO₂)(Py‐NHC‐Py)]BF₄ (Figure S2) [102]. Fortunately, we were able to isolate crystals suitable for single‐crystal X‐ray diffraction analysis of the elusive Au(III) complex 3aa by slow diffusion of Et₂O in CH₂Cl₂ (Figure 4a). In the solid state, C,N‐chelation is observed, Au(III) adopts a slightly distorted square‐planar geometry, where the carbene is in trans configuration to the bromide (C2‐Au = 2.014(3) Å, Au‐Br = 2.4227(5) Å), whereas the pyridine remains trans to the aryl group (N7‐Au = 2.134(2) Å, Au‐C18 = 2.016(2) Å). The angle N7‐Au‐C2 is 78.4 (1)°, it is highly strained compared to angles Br‐Au‐N7 = 96.34 (7)°, C2‐Au‐C18 = 96.9 (1)° and Br‐Au‐C18 = 88.25 (7)°. The value of 78.4 (1)° for the angle N7‐Au‐ C2 is very similar to the angle found by Bower and Russell in Au(III)‐alkenyl complexes ligated to 5,5'‐difluoro‐2,2'‐bipyridine (N1‐Au‐N2 78.65(14)) [61]. Additionally, the pendant pyridine and the C₆H₄‐NO₂ planes are separated by 3.505 Å, suggesting a π‐π stacking interaction. The unambiguous confirmation of 3aa formation by single‐crystal X‐ray diffraction provides definitive structural validation of our ligand design hypothesis. High‐valent aryl‐Au(III) intermediates are notably unstable and prone to undergo decomposition via reductive elimination or proto‐deauration. However, the molecular structure of 3aa in the solid state highlights the exceptional stabilizing ability of the NHC^N ligand. It satisfies the coordination requirements of Au(III), providing a rigid square‐planar geometry in which one of the pyridine fragments stabilizes the electron‐poor C₆H₄‐NO₂ fragment through π‐π interactions, while the other coordinates efficiently to the metal center. Furthermore, the strained angle N7‐Au‐C2 (78.4 (1)°) in 3aa, confirms that introducing coordinating groups in positions that force Au(I) to adopt a bent coordination mode, successfully assists oxidative addition, significantly increasing the reaction rate relative to [AuCl(SMe₂)].

FIGURE 4.

Solid‐state molecular structures of 3aa (a) and 5 (b) with thermal ellipsoids drawn at 50% probability. Selected bond lengths (Å) and angles (deg): 3aa: C2‐Au 2.014(3), Au‐Br 2.4227(5), N7‐Au 2.134(2), Au‐C18 2.016(2), N7‐Au‐ C2 78.4, Br‐Au‐N7 96.34 (7), C2‐Au‐C18 96.9 (1), Br‐Au‐C18 88.25; 5: C2‐C18 1.475(5), C2‐N1 1.345(4), C2‐C3 1.383(4), N3‐C2‐N1 107.0 (3).

After these encouraging results, we proceeded to examine the reaction of 3a with 4‐MeO‐C₆H₄N₂BF₄. The reluctance of this salt to react necessitated heating the reaction to 50°C. In this case, 3a evolved cleanly over time into a unique second species (Figure 5, left). The set of doublets at 8.65 and 7.49 ppm of 4‐MeO‐C₆H₄N₂BF₄ (Figure 5B, left) evolved after 2 h and 35 min to a new set of doublets at 7.33 and 6.96 ppm (Figure 5C, left). The intensity of the new set of doublets reached a maximum after 3 h and 45 min (31% of conversion) and did not evolve further. It seems that after this time, the newly formed compound remains in equilibrium with 3a and the unreactive 4‐MeO‐C₆H₄N₂BF₄. Attempts to isolate the second species were unsuccessful. Following the reaction by FAB,⁺ after 30 min, we detected a peak at m/z 329 (Figure S4) [102], whose intensity increased with time, and that matches the mass of imidazolium salt 4, which is expected to be formed from the reductive elimination of [Au(III)(Br)(C₆H₄‐4‐MeO)(Py‐NHC‐Py)]⁺. Apparently, in this case, the aryl‐Au(III) is too unstable and directly evolves by reductive elimination. For comparison, a mixture of [AuCl(SMe₂)] and 4‐MeO‐C₆H₄N₂BF₄ under the same conditions showed less than 5% conversion after 3 h 45 min (Figure 5, right).

FIGURE 5.

Top: Oxidation of complex 3a with 4‐MeO‐C₆H₄N₂BF₄ in the presence of ascorbic acid. Bottom: Left: (A) ¹H NMR of 4‐MeO‐C₆H₄BF₄ in DMSO‐d₆; (B) ¹H NMR of the reaction of 3a with 4‐MeO‐C₆H₄BF₄ and asc. acid (1 mol%) in DMSO‐d₆ at 50°C after 5 min; (C) after 2 h 45 min; (D) after 3 h 45 min. Right: A) ¹H NMR of 4‐MeO‐C₆H₄BF₄ in DMSO‐d₆; B) ¹H NMR of the reaction of [AuCl(SMe2)] with 4‐MeO‐C₆H₄BF₄ and asc. acid (1 mol%) in DMSO‐d₆ at 50°C after 5 min; C) after 2 h 45 min; D) after 3 h 45 min.

Replacing 4‐MeO‐C₆H₄N₂BF₄ with 4‐Me‐C₆H₄N₂BF₄ led to a more complex ¹H NMR spectrum, in which several sets of doublets were observed (Figure S7) [102]. Mass analysis by FAB⁺, showed after 15 min, a peak at m/z 589 that corresponds to the expected mass of the cationic fragment of the complex [Au(III)(Br)(C₆H₄‐4‐Me)(Py‐NHC‐Py)] (3ab) along with a peak at m/z 313, that matches with the mass of a imidazolium salt, resulting from reductive elimination of the complex [Au(III)(Py‐NHC‐Py)(C₆H₄‐Me)] (Figure S8) [102]. In this case, we succeeded in obtaining crystals suitable for X‐ray diffraction analysis of this salt (5, Figure 4b), by slow diffusion of Et₂O into CH₂Cl₂. The solid‐state molecular structure of 5 unveils the formation of a bond between the NHC fragment and the aryl group. The distance between C2 and C18 is 1.475(5) Å, typical of Csp2‐Csp2 bonds, whereas the distances C2‐N1 and C2‐C3 are 1.345(4) Å and 1.383(4) Å, and the angle N3‐C2‐N1 is 107.0 (3)°. Curiously, in this structure, the imidazolium core equilibrates its cationic charge in the unit cell with a half negative charge from an AuBr₂ ⁻ anion, and a half negative charge from BF₄ ⁻, and the symmetry code (−x+2, −y+1, −z+1) is necessary to complete the structure.

The isolation of 5 suggests that gold underwent oxidative addition followed by rapid reductive elimination. Imidazolium salts have also been observed as a byproduct by Valdés, Guisado‐Barrios, and Ribas in reactions with [Au(I)(MIC^N)Cl] complexes [70]. The fast reductive elimination suggests that in the intermediate Au(III) complex, the carbene ligand and the aryl group must be placed in cis position, as confirmed by the molecular structure of the Au(III) complex 3aa. The results derived from the analysis of the reactions of 4‐MeO‐C₆H₄N₂BF₄ and 4‐Me‐C₆H₄N₂BF₄ with 3a and [AuCl(SMe₂)] altogether indicate that the carbene ligand containing two pyridine fragments facilitates oxidative addition. However, the [Au(III)(Br)Ar(Py‐NHC‐Py)]BF₄ complexes formed when the aryl contains an electron‐rich group are unstable and tend to decompose by reductive elimination to form imidazolium salts and an aurate AuBr₂ ⁻.

With the aim of stabilizing and isolating more challenging Au(III) intermediates bearing electron‐rich aryl groups, we next analyzed the reaction of complex 3b, which contains a bulky mesityl group, with 4‐MeO‐C₆H₄N₂BF₄. An analysis of the reaction after 20 min by FAB⁺ showed a peak at m/z 646 that corresponds to the expected [Au(III)(Br)(C₆H₄‐4‐OMe)(Py‐NHC‐Mes)]⁺ (3ba) complex, along with a peak at 370 that can be attributed to the imidazolium salt coming from reductive elimination (Figure S10) [102]. This time, we successfully isolated a 3ba crystal suitable for X‐ray diffraction analysis by slowly diffusing Et₂O into CH₂Cl₂, thus providing unambiguous crystallographic evidence of Au(I)/Au(III) oxidation by an electron‐rich aryldiazonium salt. The solid‐state molecular structure of 3ba validates the high stabilization imparted by the NHC^N ligand in the Au(III) complex (Figure 6). The Au(III) center adopts a slightly distorted square‐planar geometry featuring C,N‐chelation, with the carbene in trans configuration to the bromide (C8‐Au = 2.014(4) Å, Au‐Br = 2.4292 (5) Å), and the pyridine moiety remaining trans to the aryl group (N1‐Au = 2.144(3) Å, Au‐C21 = 2.014 (3) Å). The geometric strain observed in 3aa is preserved in this system; the acute N1‐Au‐C8 angle of 78.7 (1) ° remains compressed compared to the complementary angles around the coordination sphere (Br‐Au‐N1 = 95.68 (9)°, C8‐Au‐C21 = 96.4 (1)°, and Br‐Au‐C21 = 89.2 (1)°). Most notably, in this structure, the ancillary mesityl ring and the 4‐OMe‐C₆H₄ fragment are aligned in a parallel fashion at a tight distance of 3.306 (6) Å. This close contact indicates an important stabilizing intramolecular π‐π stacking interaction. The latter provides enhanced stabilization relative to pyridine stacking in 3aa, thereby decelerating reductive elimination and rendering this highly reactive, electron‐rich Au(III) species isolable.

FIGURE 6.

Solid‐state molecular structures of 3ba with thermal ellipsoids drawn at 50% probability. C8‐Au 2.014(4), Au‐Br 2.4292 (5), N1‐Au 2.144(3), Au‐C21 2.014(3), N1‐Au‐C8 78.7 (1), Br‐Au‐N1 95.68 (9), C8‐Au‐C21 96.4 (1), Br‐Au‐C21 89.2 (1).

Efforts in isolating these highly elusive high‐valent intermediates aryl‐Au(III) complexes demonstrated that the geometric strain imposed by the chelating pyridine moiety and stabilization of the newly introduced aryl group through intramolecular π‐π stacking interactions, either by pyridine or the bulky mesityl scaffolds, enable Au(I)/Au(III) oxidation.

Next, we turn our attention to the role of ascorbic acid in the system. Although we previously established the capacity of ascorbic acid as a radical promoter that facilitates the oxidation of Au(I) by aryldiazonium salts [46], to validate the necessity of adding it in the presence of NHC^N ligands, we conducted NMR and EPR experiments. First, we monitored the reaction of 3b with 4‐MeO‐C₆H₄N₂BF₄ by ¹H NMR in the absence of ascorbic acid in DMSO‐d₆ . After heating at 50°C for 24 h, the signals from the Au(I) complex and the aryldiazonium salt (8.66 ppm d and 7.51 ppm d) remained without change (Figure 7). The latter indicates that ascorbic acid is needed to promote oxidation.

FIGURE 7.

(a) ¹H NMR of the reaction of 3b with 4‐MeO‐C₆H₄BF₄ without asc. acid, in DMSO‐d₆ at 50°C using DSS as internal standard after 5 min; (b) after 30 min; (c) after 1 h; (d) after 24 h.

Subsequently, we performed EPR experiments to determine whether 4‐MeO‐C₆H₄N₂BF₄ generates radical species in the presence of ascorbic acid and Au(I) complexes 3a and 3b, and whether these species differ from those generated by the reaction of ascorbic acid with 4‐MeO‐C₆H₄N₂BF₄. For these studies, we selected a mixture of acetone:THF (50:50) as the solvent (to avoid interference from DMSO methyl radicals) and added 5,5‐dimethyl‐1‐pyrroline N‐oxide (DMPO) as a spin trap [103]. Figure 8 shows the EPR spectra of: a) asc. acid (green), b) 4‐MeO‐C₆H₄N₂BF₄ (orange), c) asc. acid and 4‐MeO‐C₆H₄N₂BF₄ (magenta), d) complex 3a, asc. acid and 4‐MeO‐C₆H₄N₂BF₄ (red). All EPR spectra were recorded in the presence of DMPO and after 5 min of solution preparation. From these spectra, the following can be observed: 1) for asc. acid, a doublet was obtained with g = 2.0056 and a_H = 1.8 G, consistent with an ascorbyl radical [104], 2) the 4‐MeO‐C₆H₄N₂BF₄ solution is EPR silent, 3) the solution of asc. acid and 4‐MeO‐C₆H₄N₂BF₄ generates a radical signal as a major triplet, consistent with a nitrogen‐centered radical a_N = 13.8 G and g = 2.0060, this signal may be due to DMPO ring opening, 4) the solution of complex 3a, asc. acid and the 4‐MeO‐C₆H₄N₂BF₄ with DMPO generates a mixture of radicals. At least two systems can be identified: a minor system with g = 2.0059, a_N = 14.3 G, and a_H = 20.6 G, consistent with the DMPO‐C adduct [105, 106], and a major system with g = 2.0061, a_N = 13.0 G, and a_H = 8.42 G, which has not yet been identified. These experiments demonstrate the role of asc. acid as an inducer of radical species in the presence of complex 3a. Clearly, the signals generated solely with asc. acid and 4‐MeO‐C₆H₄N₂BF₄ are different.

FIGURE 8.

EPR of: (a) Green line: asc. acid, (b) orange line: 4‐MeO‐C₆H₄N₂BF₄, ₍c) magenta line: asc. acid, 4‐MeO‐C₆H₄N₂BF₄ and DMPO, (d) red line: complex 3a, asc. acid, 4‐MeO‐C₆H₄N₂BF₄ and DMPO. All spectra were recorded in a mixture of acetone:THF (50:50) after 5 min of solution preparation.

Figure 9 shows the same comparative analysis for the reaction with complex 3b, which exhibited the same behavior as complex 3a. The red line shows the EPR spectrum of a solution containing complex 3b, asc. acid, 4‐MeO‐C₆H₄N₂BF₄, and DMPO after a 5‐minute reaction. Similarly, a complex signal is observed, indicating the generation of radicals that do not correspond to the DMPO/4‐MeO‐C₆H₄ adduct.

FIGURE 9.

EPR of: (a) Green line: asc. acid, (b) orange line: 4‐MeO‐C₆H₄N₂BF₄, (c) magenta line: asc. acid and 4‐MeO‐C₆H₄N₂BF₄ and DMPO, (d) red line: complex 3b, asc. acid, 4‐MeO‐C₆H₄N₂BF₄ and DMPO. All spectra were recorded in a mixture of acetone:THF (50:50) after 5 min of solution preparation.

Altogether, the results from NMR and EPR data demonstrate that the oxidation of (NHC^N)Au(I) complexes with 4‐MeO‐C₆H₄N₂BF₄ occurs via a radical pathway driven by a cooperative effect. Specifically, ascorbic acid activates the aryldiazonium salt, promoting the generation of transient radical species, while the NHC^N carbene ligand provides the optimal electronic and steric environment to facilitate oxidative addition at the gold center.

2.1. Catalytic Studies

After establishing the efficacy of ascorbic acid and NHC^N ligands bearing a pendant pyridine in promoting the oxidation of Au(I) with 4‐MeO‐C₆H₄N₂BF₄, we envisioned evaluating the ability of complexes 3a‐h to act as catalysts. We aimed to explore whether the designed ligands achieve an optimal balance between stabilizing the high valent aryl‐Au(III) intermediates and maintaining sufficient reactivity to permit catalytic turnover. These catalytic studies were conceived as a preliminary proof of concept to gain insights into how competitive pathways, such as the reductive elimination leading to imidazolium salts observed in stoichiometric reactions, might affect the stability and turnover of the synthesized complexes and interfere with their activity under catalytic conditions. As a model reaction, we selected the arylative carbocyclization of 1‐methoxy‐4‐(3‐phenoxy‐1‐propyn‐1‐yl)‐benzene (6) with 4‐MeOC₆H₄N₂BF₄ (Table 1). Previous works from our laboratory on the arylative carbocyclization of arylpropargyl ethers showed that the complex [AuCl(PPh₃)] is able to catalyze the reaction, delivering 3,4‐diaryl‐2H‐chromenes with yields from moderate to excellent when employing aryl diazonium salts containing electron‐poor groups. However, [AuCl(PPh₃)] failed to catalyze the reaction for aryldiazonium salts substituted with electron‐rich groups [47]. To test the catalytic activity of the synthesized complexes, we used the optimized reaction conditions established for the [AuCl(PPh₃)]‐catalyzed reaction [47]. When 6 was treated with 1.5 equiv of 4‐MeO‐C₆H₄N₂BF₄ in the presence of 3a (10 mol%) as a catalyst, ascorbic acid (0.5 mol%), and 2,6‐di‐tert‐butylpyridine (2,6‐DTBPy) as a base (1 equiv), in acetonitrile at 50°C, 9 was isolated in 13% yield after 16 h (entry 1). Replacing 2,6‐DTBPy with Li₂CO₃ (which also proved to give good yields in the reaction catalyzed by [AuCl(PPh₃)]), the yield increased to 18% (entry 2). Extending the reaction time to 36 h raised the yield to 22%. We selected the reaction conditions of entry 3, that is, Li₂CO₃ as a base, 36 h of reaction, and 50°C of temperature, to test the catalytic performance of complexes 3b‐3 h. Complex 3b that contains a pyridine and a mesityl onto the nitrogen of the imidazole‐2‐ylidene core, delivered 9 in 22% yield (entry 4). Comparatively, complex 3c bearing an isopropyl and a pyridine reacted only in 8% yield (entry 5). On the other hand, complex 3d bearing a mesityl and a 3‐(2,2'‐bipy) fragment afforded 9 in 40% yield. The bis‐carbene Au(I) complex 3e did not catalyze the reaction (entry 7), whereas 3f, containing a methyl and a 3‐(2,2'‐bipy) fragment, catalyzed the reaction in less than 5%. Regarding bimetallic NHC‐Au(I) complexes 3g and 3h, 3g afforded 9 in 23%, whereas 3h in 30%. From these results, the best catalyst for the arylative carbocyclization of 6 with 4‐MeO‐C₆H₄N₂BF₄ was 3d. A direct comparison of the catalytic activities of 3b and 3d indicates that bipyridine increases the catalytic activity compared to pyridine. It was also observed that mesityl increases reactivity relative to isopropyl, so complex 3b is a better catalyst than 3c. The lack of reactivity of complexes 3e and 3g can be attributed to the presence of iodide. The nature of the halogen attached to gold in Au(III) complexes strongly affects their tendency to undergo reductive elimination. In fact, according to accurate studies on the mechanism of reductive elimination from Au(III) by the Toste group, iodide is the halide that most accelerates undesired C_aryl‐I reductive elimination, due to the highest lability of the Au(III)‐I bond [107]. The latter could justify the low reactivity of 3e and 3g. Regarding the bimetallic NHC‐Au(I) complexes, 3g, which can be viewed as the bimetallic counterpart of 3b, afforded 9 in a yield similar to that of 3b (23% vs. 22%). Comparatively, 3h reached 30%, supporting the idea that the lack of reactivity of complexes 3e and 3f is not due to the methyl group but to iodide. In all the experiments, along with 9, the other observed compounds were 4,4'‐dimethoxy‐1,1'‐biphenyl, derived from the homocoupling of the arildiazonium salt 7, along with some colored degradation products, which were not possible to identify and variable amounts of unreactive 6. The latter was difficult to quantify due to the close Rf value of 6 relative to 9. Finally, to gain deeper mechanistic insights and better understand the electronic factors that govern our system, we turned our attention to an electron‐deficient variant. Since we were previously able to isolate and characterize the aryl‐Au(III) intermediate 3aa (Figure 4) derived from 3a and 4‐NO₂‐C₆H₄N₂BF₄, we evaluated the catalytic activity of 3a in the arylative carbocyclization of 6 with this salt. Under the conditions of entry 2, the corresponding 2H‐chromene 10 was isolated in a higher 71% yield (entry 11). In our previous computational studies on this transformation [47], DFT calculations showed that the energy barrier of the carbocyclization step remains nearly the same for aryl‐Au(III) intermediates bearing either electron‐donating or electron‐withdrawing groups. According to this, the observed difference in efficiency (71% for ─NO₂ vs 22% for ─OMe using catalyst 3a) strongly indicates that the generated aryl‐Au(III) intermediate is significantly less prone to deactivation pathways when electron‐poor groups are present. In summary, after scrutinizing the catalytic activity of 3a‐h in the arylative carbocyclization of arylpropargyl ethers with 4‐MeO‐C₆H₄N₂BF₄, it can be concluded that the framework benefits from the presence of the mesityl group (which can stabilize the aryl‐Au(III) intermediate by π‐π interactions) and the bipyridine fragment. The lower yields achieved with the aryldiazonium salt 4‐MeO‐C₆H₄N₂BF₄ can probably be attributed to competing reactions such as homocoupling, and deactivation of the catalyst by reductive elimination that forms very stable imidazolium salts, as observed in our stoichiometric experiments. Another possible pathway for catalyst deactivation could be the formation of less reactive bis‐carbene species during the course of the reaction.

TABLE 1.

Catalytic activity of complexes 3a‐h in the arylative carbocyclization of 6.

Entries a	salt	[Au]	Base	t (h)	Yield (%) b
1	7	3a	2,6‐DTBPy	16	13
2	7	3a	Li2CO3	16	18
3	7	3a	Li2CO3	36	22
4	7	3b	Li2CO3	36	22
5	7	3c	Li2CO3	36	8
6	7	3d	Li2CO3	36	40
7	7	3e	Li2CO3	36	ND
8	7	3f	Li2CO3	36	<5
9	7	3g	Li2CO3	36	23
10	7	3h	Li2CO3	36	30
11	8	3a	Li2CO3	36	71

Abbreviation: 2,6‐DTBPy = 2,6‐di‐tert‐butylpyridine, ND = not detected.

^a Reaction conditions: 6 (0.1 mmol, 1.0 equiv), 4‐OMe‐C₆H₄NBF₄ (0.15 mmol, 1.5 equiv), [Au] (10 mol%), asc. acid (1 mol%), base (0.1 mmol, 1.0 equiv) in CH₃CN (1 mL) under a N₂ atmosphere.

^b Isolated yield.

3. Conclusion

In this work, we have studied the interplay of ascorbic acid and NHC^N carbenes with a pendant pyridine or bipyridine and NHC bis‐carbenes connected by a pyridine fragment, to facilitate the challenging oxidation of Au(I) with highly reluctant, electron‐rich aryldiazonium salts. The corresponding Au(I) complexes were synthesized using readily accessible, practical methodologies that are easy to implement. NMR and FAB+ analyses evidenced that the presence of these ligands accelerates oxidation. Notably, we were able to unambiguously substantiate the formation of the elusive intermediate [Au(III)(Br)(C₆H₄‐4‐OMe)(Py‐NHC‐Mes)]BF₄ complex by single‐crystal X‐ray diffraction. Analysis of the molecular structure in the solid‐state reveals the explicit coordination of the pyridine moiety to the Au(III) center, confirming that its coordinating ability facilitates the oxidation step. Furthermore, EPR and NMR analyses established that the ligand alone is insufficient to promote oxidation and that the addition of ascorbic acid is essential for oxidation to proceed. Preliminary catalytic studies with the synthesized complexes on the arylative carbocyclization of 1‐methoxy‐4‐(3‐phenoxy‐1‐propyn‐1‐yl)‐benzene with 4‐MeO‐C₆H₄N₂BF₄ and 4‐NO₂‐C₆H₄N₂BF₄ showed that the combination of ascorbic acid and (NHC^N)Au(I) enables arylation processes with electron‐rich and electron‐poor aryldiazonium salts. Although the yields with 4‐MeO‐C₆H₄N₂BF₄ are modest, it is important to note that these electron‐rich salts are completely inert toward other commonly used Au(I) complexes, such as [AuCl(PPh₃)], under identical conditions in the absence of a cocatalyst and/or irradiation. The lower yields observed with 4‐MeO‐C₆H₄N₂BF₄ (40% with 3d) can be attributed to competitive deactivation pathways, such as the formation of highly stable imidazolium salts via undesired reductive elimination, as supported by stoichiometric experiments, or the potential formation of less reactive bis‐carbene species during the reaction. To reduce these deactivation pathways, several ligand design strategies will be explored in the future. For instance, the nature of the halogen attached to Au(I) appears to directly affect catalyst efficiency, as lower yields were obtained with iodide. Since the halide in the Au(I) precursor is determined by the starting aryl halide or alkyl halide used, modifications to the synthetic protocols would allow us to analyze the impact of this factor. Additionally, tuning the chelating ligand size is expected to influence the performance of the catalyst. In summary, we have shown that the synergistic interplay between ascorbic and NHC^N ligands enables Au(I) oxidation by electron‐rich aryldiazonium salts. This breakthrough represents a paradigm shift in the generation of high‐valent gold intermediates under mild, sustainable conditions, opening the door for the design of novel, sustainable gold‐catalyzed cross‐coupling methodologies with a broad scope in organic synthesis.

Conflicts of Interest

The author declare no conflicts of interest

Supporting information

Deposition numbers for crystallographic structures [108]. The authors have cited additional references within the Supporting Information [109, 110, 111, 112, 113, 114, 115, 116].

Supporting file: chem71247‐sup‐0001‐SuppMat.pdf.

Data Availability Statement

The data that support the findings of this study are available in the Supporting Information of this article.