Gold(III) NHC Complexes for Catalyzing Dihydroalkoxylation and

Sep 21, 2017 - An Au(III) complex of an N-heterocyclic carbene based hemilabile ligand with two pendant pyrazole arms is an excellent catalyst for pro...
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Gold(III) NHC Complexes for Catalyzing Dihydroalkoxylation and Hydroamination Reactions Ashwin G. Nair, Roy T. McBurney, Mark R. D. Gatus, Samantha C. Binding, and Barbara A. Messerle* Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney 2109, Australia

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ABSTRACT: A gold(III) complex of an N-heterocyclic carbene based hemilabile ligand with two pendant pyrazole arms (1,3-bis((1H-pyrazol-3-yl)methyl)-2,3-dihydro-1H-imidazole, LH) was synthesized. Complex [LAu(III)Cl3] is an excellent catalyst for promoting dihydroalkoxylation at room temperature, even catalyzing this reaction at 0 °C. [LAu(III)Cl3] is one of the most efficient catalysts reported to date for the spirocyclization of alkynyl diols. Furthermore, [LAu(III)Cl3] catalyzed intra- and intermolecular hydroamination reactions, achieving good to excellent conversions. [LAu(III)Cl3] is a more efficient catalyst than a gold(I) analogue, [LAu(I)Cl]. The dependence of the quantity of weakly coordinating anion [BArF4]− ((3,5-trifluoromethyl)phenyl borate) present on catalysis efficiency was probed for the dihydroalkoxylation reaction. X-ray diffraction analysis of single crystals demonstrated the solid-state structure of gold complexes [LAu(III)Cl3] and [LAu(I)Cl], which displayed the expected square-planar and linear coordination geometries, respectively.

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bond,14g,j or bidentate N,O-donor17 or N,N′-donor ligands,14d,f,h see Figure 1. However, in designing and selecting Au(III) complexes as catalysts, a balance needs to be struck between stability and catalytic activity. Highly efficient Au(III) catalysts offering good stability that operate across a range of reactions would be welcome. We reasoned that a ligand with a strong σ-donor to act as an anchor for gold(III) in combination

INTRODUCTION Gold catalysis1 is a vitally important area with many reported examples of gold(I)-catalyzed reactions including C−O2 and C−N3 bond formations, C−C bond forming cyclization reactions,4 applications to total synthesis,5 and photocatalysis.6 Conversely, gold(III)-catalyzed reactions are still in their infancy. The vast majority of reports use inorganic gold(III) salts, typically AuCl3, primarily for promoting hydroaminations,7 hydroalkoxylations,8 intramolecular hydroarylation,9 oxidations,10 rearrangements,11 and C−C bond forming cyclizations.8g,12 There are a growing number of reports using organometallic Au(III) complexes13 as catalysts,14 aided by Hashmi’s method for oxidizing Au(I) to Au(III).14b Organometallic gold(III) complexes have been used for catalyzing isomerizations,14b,c hydroaminations,14d C−C couplings,14e−k hydrations,14l and three component couplings.14m,n A recent communication by Toste highlighted the need to further develop the area of gold(III) catalysis.15 Increasing the scope of organogold(III) catalysis is important to enable a greater level of regio-, chemo-, and enantioselectivity over the products generated, to achieve vastly increased reaction rates and to avoid in situ reduction of Au(III) by substrates, intermediates, or products. The choice of ligand to support gold(III) is crucial for achieving optimal catalytic activity. Common structural motifs found in the ligands of reported organogold(III) catalysts include a central N-heterocyclic carbene (NHC);14k,16 some feature a biphenyl ligand coordinated through a gold-aryl © 2017 American Chemical Society

Figure 1. Gold(III) catalysts featuring (a−d) strong and (e) hemilable coordination motifs; (f) our design features both. Received: August 22, 2017 Published: September 21, 2017 12067

DOI: 10.1021/acs.inorgchem.7b02161 Inorg. Chem. 2017, 56, 12067−12075

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Inorganic Chemistry

[LAu(I)Cl] and gold(III) square planar in [LAu(III)Cl3], see Figure 2. In both structures the gold ion is coordinated to the

with hemilabile pendant arms to stabilize intermediates/ transition states during the catalytic cycle should be a promising catalyst. Given our past success with complexes based on such ligands,18 an NHC-based ligand with two pyrazole pendant arms was selected. These ligands were specifically targeted because of the range of coordination modes accessible, as well as the known stability of NHC−gold(III) complexes.13c,14g Herein, we report the synthesis and catalytic activity of a novel Au(III) complex containing a hemilabile bis-pyrazole carbene ligand (1,3-bis((1H-pyrazol-3-yl)methyl)-2,3-dihydro1H-imidazole, LH).18 Ligand LH has accommodated a range of transition metals including Rh(I) and Ir(I),18a Ru(II),18b and Ni(II).18c We were interested to discover if gold(III) catalyst [LAu(III)Cl3] could be stabilized by its pendant pyrazole arms after addition of a halide abstraction agent. Catalyst [LAu(III)Cl3] was found to efficiently catalyze the dihydroalkoxylation of a series of alkynyl diols at room temperature under mild conditions. [LAu(III)Cl3] also catalyzed intra- and intermolecular hydroamination reactions. The catalytic efficiency of [LAu(III)Cl3] was compared against that of a related Au(I) catalyst, [LAu(I)Cl].

Figure 2. X-ray crystal structures of (a) [LAu(I)Cl] and (b) [LAu(III)Cl3]. Nitrogen atoms are shown in purple, carbons gray, gold yellow, and chloride green; hydrogens are omitted for clarity. Selected bond lengths (Å) and angles (deg): [LAu(I)Cl], C1−Au(I) 1.973, (C2−C3)centroid−C1−Au(I) 175.57; [LAu(III)Cl3], C1−Au(III) 2.007, (C2−C3)centroid−C1−Au(III) 178.7.

carbenic atom in the NHC unit (∼2 Å) and the (C2− C3)centroid−C1−Au angle is close to linear. The pendant pyrazole groups were uncoordinated (N−Au distances are all greater than 3.1 Å), though in the Au(III) example the nitrogen in the pyrazole ring would be available for coordination upon displacement of a chloride ion by a suitable weakly coordinating counterion such as [BArF4]− (tetrakis[3,5-bis(trifluoromethyl)phenyl]borate). Dihydroalkoxylation Catalysis. Dihydroalkoxylations are atom efficient C−O bond forming reactions between two alcohols and an alkyne, affording ethers as the final product. Dihydroalkoxylations lead to spiroketals, which are important structural motifs found in many natural products.19 We examined the dihydroalkoxylation spirocyclization of alkynyl diol containing substrates, specifically 2-(5-hydroxypent-1ynyl)benzyl alcohol 1 (Scheme 2).

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RESULTS AND DISCUSSION Synthesis and Characterization. Ligand 1,3-bis((1Hpyrazol-3-yl)methyl)-2,3-dihydro-1H-imidazole, LH, was synthesized according to our previous report, see Scheme 1.18a,b Scheme 1. Synthesis of [LAu(III)Cl3] and [LAu(I)Cl]

Scheme 2. Conversion of 1 to 2a and 2b

The dihydroalkoxylation reactions were first attempted at 70 °C in C2D2Cl4 with a catalyst loading of 1 mol % to which Na[BArF4] (1.1 mol %) was added and the substrate alkynyl diol, 1. The reaction was monitored at regular intervals using 1 H NMR spectroscopy. The Au(III) catalyzed reaction reached completion (>98% conversion) in less than 1 min, with the Au(I) catalyzed reaction completing soon after (Figure 3a). Given the excellent reaction progress at 70 °C, we repeated the reactions at room temperature (25 °C). The Au(III) catalyst was significantly faster than the Au(I) catalyst for this reaction, achieving completion within 9.3 min. Pleasingly, [LAu(III)Cl3] still gave excellent conversion of 1 to 2a and 2b at 0 °C, albeit over a much longer time frame (>170 min). We did not test [LAu(I)Cl] at 0 °C as we expected the reaction to take significantly longer than [LAu(III)Cl3] did at 0 °C. Lowering the gold(III) catalyst loading to 0.1 mol % resulted in a significant decrease of reaction progress, with only 30% conversion of substrate 1 to 2a and 2b after 2.2 min, Figure 3b. Further decreasing to 0.01 mol % resulted in just 10% conversion of substrate after 3.3 min. The time conversion

[LAu(I)Cl] was prepared by stirring a suspension of chloroauric acid in the presence of triethylamine, dichloromethane, methanol, and LH at room temperature for 16 h. The resulting reduced gold(I) complex, [LAu(I)Cl], was precipitated from a dichloromethane solution by addition of pentane and isolated as a white/gray solid. [LAu(III)Cl3] was prepared via a transmetalation from [L2Ag(I)][BPh4]18b using chloroauric acid in dichloromethane and ethanol. Precipitation from pentane produced [LAu(III)Cl3] as a yellow solid. The 1H NMR spectra (see Figure S6 and Figure S8) show that [LAu(I)Cl] and [LAu(III)Cl3] are symmetrical species; each has a plane of symmetry passing through an axis defined by the carbene−gold bond. There are clear differences in the 1H NMR spectra of complexes [LAu(III)Cl3] and [LAu(I)Cl], indicating that the different oxidation states and number of chloride coligands present have a clear effect on the chemical environment of the ligand backbone. Crystals suitable for crystallographic analysis were obtained, and X-ray crystallography demonstrated that the coordination environments were as expected, with gold(I) being linear in 12068

DOI: 10.1021/acs.inorgchem.7b02161 Inorg. Chem. 2017, 56, 12067−12075

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Inorganic Chemistry

Figure 3. Comparison of Au(III) and Au(I) catalysts, loadings, and additives for the conversion of 1 to 2a and 2b. (a) Reagents and conditions: gold catalyst (1 mol %), Na[BArF4] (1.1 mol %), substrate 1, C2D2Cl4. (b) Reagents and conditions: [LAu(III)Cl3], substrate 1, Na[BArF4] or Ag[SbF6] (1.1 equiv wrt [LAu(III)Cl3]), C2D2Cl4, 25 °C. Conversion was determined by integration of the product resonances relative to the substrate resonances using 1H NMR spectroscopy. Empty columns denote that experiment was not performed.

Figure 4. Effect of increasing equivalents of added Na[BArF4]− (from 0 to 4 equiv) on catalytic efficiency. Catalytic efficiency was measured by the TOF (h−1) calculated from the first data point after >50% conversion of substrate 1 to product (2a + 2b), as the amount of product formed by one mole of catalyst per hour.

reach completion. This increase in catalysis rate with increase in counterion concentration was expected when coordinated chloride ions are replaced by hemilabile pyrazole arms and weakly coordinating anions. Furthermore, the catalyst remains stable and active under these conditions. As a control experiment, we have shown that Na[BArF4] alone will not catalyze dihydroalkoxylation reactions of 1.22 Separate from the catalysis reactions, 1H NMR spectra of [LAu(III)Cl3] on addition of counterion in tetrachloroethaned4 were obtained (Scheme 3 and Figure S10). Addition of just 1

graphs for these reactions (see Figure S2) show that the conversion to product essentially plateaued after the first 1H NMR spectrum was recorded, although good turnover numbers of over 1000 were achieved when using [LAu(III)Cl3] at 0.1 mol % catalyst loading. The use of different counterions has been found to have an impact on the efficiency of a number of charged catalysts, and in particular gold catalysts.20 Our use of [SbF6]− as a counterion at 1 mol % catalyst loading of [LAu(III)Cl3] catalyst resulted in a 4-fold decrease in reaction rate and a lower conversion (Figure 3b). At 0.1 mol % catalyst loading using Ag[SbF6] no conversion to spiroketal products was observed. We therefore did not attempt any lower catalyst loading reactions with Ag[SbF6]. These results would indicate that for this specific reaction [BArF4]− clearly outperforms [SbF6]−. Screenings of other weakly coordinating anions were deemed unnecessary given the excellent performance of [BArF4]−. When using any silver halide abstraction agent, it is necessary to consider any potential effect that silver may have on the reaction. Zhdanko and Maier reported a detailed study on the effects of silver on gold(I) catalyzed hydroalkoxylations where silver was found to be innocent with regard to the catalytic cycle but either decreased or increased catalysis rate.21 We thus deemed any silver effect to be negligible. Our catalyst design features hemilabile pendant pyrazole arms that can coordinate to the gold ion. Progressively stripping Cl− from the gold(III) ion in [LAu(III)Cl3] should allow these pyrazole arms to coordinate, thereby stabilizing the complex, and the removal of coordinated Cl− should improve substrate access to the gold ion, increasing the rate of catalysis. Focusing on the reaction shown in Scheme 2, for the conversion of 1 to 2a and 2b using 1 mol % of catalyst [LAu(III)Cl3] at room temperature, we gradually increased the equivalents of Na[BArF4] relative to [LAu(III)Cl3] and observed the resulting effect on the reaction rate (Figure 4). As more equivalents of Na[BArF4] were added, the reaction rate increased and time to completion (>98% conversion) shortened considerably. The reaction promoted using [LAu(III)Cl3] and 3 equiv of Na[BArF4] was complete after just 5 min, whereas when no Na[BArF4] was present it took 68 min to

Scheme 3. Addition of Na[BArF4] to [LAu(III)Cl3]

equiv of Na[BArF4] resulted in a complicated spectrum, with contributions from the original complex [LAu(III)Cl3], and additional species where one or more chlorides have been removed resulting most likely in one pyrazole arm coordinating to the gold ion. This mixture could also contain a bridged auro−chloro dimer species.23 Upon of addition of 3 equiv of Na[BArF4] the spectrum is composed of one species (>95%), presumably a species where all chlorides have been removed, the two pyrazole arms coordinate the gold ion, and one vacant site is available at the gold(III) center. This assumption is backed up by a related study from Miqeu, Amgoune, and Bourissou, who used detailed NMR investigations to prove a cationic gold(III) species, which was later used for insertion of olefins into gold−aryl bonds.14j Control studies were performed to assess substrate conversion (1 to 2a and 2b) using gold salts to promote the reactions. Chloroauric acid (HAuCl4) led to no conversion of substrate at room temperature, with or without Na[BArF4] present. However, AuCl3 has been reported to catalyze the dihydroalkoxylation of a similar substrate, proceeding to 41% yield with a 5 mol % catalyst loading after 30 min.8a Au(I)Cl(SMe2) catalyzed the reaction of 1 to 2a and 2b at 25 °C, which was greatly accelerated in the presence of 1 equiv of Na[BArF4] (Figure S1). Au(I)Cl(SMe2) proved a much 12069

DOI: 10.1021/acs.inorgchem.7b02161 Inorg. Chem. 2017, 56, 12067−12075

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Inorganic Chemistry

substrate 9 proceeded to a greater level of conversion to product than substrate 7. Hydroamination Catalysis. Having established that gold(III) catalyst [LAu(III)Cl3] was an excellent catalyst for dihydroalkoxylation reactions, we set out to investigate other potential heterobond-forming applications. Hydroamination reactions involve the addition of an N−H bond across an unsaturated C−C bond and are atom economical processes for the formation of C−N bonds.27 A few organometallic gold(III) catalyzed hydroaminations have been reported including intramolecular cyclizations onto alkyne,14d,28 alkene,29 and allene30 acceptors, and also intermolecular additions to allenes.31 The activity of catalysts [LAu(I)Cl] and [LAu(III)Cl3] was assessed for the intramolecular cyclization of 4pentyne-1-amine, 11, to 2-methyl-1-pyrroline, 12 (Scheme 5a).

more efficient catalyst than [LAu(I)Cl]. On undertaking the catalysis of the conversion of 1 to 2a and 2b using [LAu(III)Cl3] as a catalyst, nanoparticles were observed as a broad peak between 260 and 340 nm in the UV/vis spectra (Figure S5). However, a mercury drop test ruled out any nanoparticle contribution to the catalysis reaction forming 2a and 2b.24 Spirocyclization of substrate 1 leads to a pair of isomeric spiroketal products 2a and 2b. Previous reports have shown that it is difficult to achieve regioselectivity between these two spiroketal isomers.22,25 Here, using both gold(I) and gold(III) catalysis we found that the product distributions were uniformly 3:1. We had hoped that reducing the reaction temperature to 0 °C may have an effect on selectivity by favoring formation of one ring size over the other. However, this was not fruitful, with the same ratio of isomers of the spiroketal being observed as at elevated temperatures. We also investigated the gold catalyzed cyclizations of substrates with varying lengths of alkyl chain between the alkyne and the aliphatic alcohol. Using catalyst [LAu(III)Cl3] the substrate 2-(4-hydroxybut-1-ynyl)benzyl alcohol (3) with a shorter alkyl chain was cyclized to give the 5,5-spiroketal product, 4, with >99% conversion to product observed after 15 min (Scheme 4a). In comparison, when using catalyst

Scheme 5. Gold Catalyzed Intra- and Intermolecular Hydroamination Reactions

Scheme 4. Au(III) Catalyzed Dihydroalkoxylation Spirocyclizations of Alkynyl Diols

Given the slower progress of hydroamination reactions, a catalyst loading of 2 mol % was used and the reaction was conducted in toluene-d8 at 100 °C; the conversions were determined by integration of the product resonances relative to the substrate resonances. The gold(III) catalyst led to a maximum conversion to product 12 of 97% after 15 min, outperforming the gold(I) catalyst. The substrate containing an internal alkyne 5-phenyl-4-pentyn-1-amine, 13, also gave complete conversion to 14 after 24 min no matter what catalyst was used, Scheme 5b. The performance of both gold catalysts matches our fastest reports for the cyclizations of pentynamine and phenylpentynamine using Rh(I) and Ir(I) catalysts.32 The gold-catalyzed intermolecular hydroamination reactions between either phenylacetylene or pentyne and either aniline or benzylamine were investigated. The only combination of substrates that gave rise to any reaction when using our gold catalysts was phenylacetylene 15 with aniline 16 to give imine 17 (Scheme 5c). While both gold catalysts gave low conversions (approximately 30%) to the imine product, it was notable that gold(III) outpaced gold(I). Extended reaction times at 100 °C did not improve the conversions. Lowering the reaction temperature to 70 °C and lengthening reaction times did not lead to improved conversions. Catalyst [LAu(III)Cl3] also promoted the intermolecular hydroamination between phenylacetylene, 15, and sterically hindered mesitylamine, 18,

[LAu(I)Cl] the reaction took almost 2 h to reach near completion (96% conversion) for the cyclization of 3. The catalyzed cyclization of 2-(6-hydroxyhex-1-ynyl)benzyl alcohol (5) using [LAu(III)Cl3] required heating at 40 °C and gave just 38% conversion to the 6,6-spiroketal product 6 after 3 min (Scheme 4b). The conversion did not increase with longer reaction times. No reaction was observed when using [LAu(I)Cl] at 40 °C with substrate 5. The differing rates of 5- and 6-membered ring closure have been noted for Rh(I) and Ir(I) catalysts previously by us.26 The results here would indicate that Au-catalyzed sequential 6-exo and 6-endo spirocyclizations are much slower than 5-membered cyclizations resulting in lower yields of the 6,6-spiroketal product 6. The catalyzed cyclization of symmetric alkynyl diols 7 and 9 gave excellent conversion to products 8 and 10 using [LAu(III)Cl3] (Scheme 4c,d). Unsurprisingly, less hindered 12070

DOI: 10.1021/acs.inorgchem.7b02161 Inorg. Chem. 2017, 56, 12067−12075

Inorganic Chemistry giving a good conversion to 19 of 61% (Scheme 5d). This was unexpected given the steric hindrance around the amino site. The reaction between phenylacetylene, 15, and 4(trifluoromethyl)aniline, 20, gave only 49% conversion to 21 (Scheme 5e). Clearly the electron withdrawing CF3 group decreases the reactivity of the aniline. Our gold NHC-based catalysts proved more efficient for intra- than intermolecular hydroaminations. Catalyst Investigations. Our results in the dihydroalkoxylation and hydroamination catalysis reactions demonstrated the high levels of reaction efficiency achieved using catalyst [LAu(III)Cl3]. It was also evident that, despite our attempt at creating a stable gold(III) catalyst based on a hemilabile NHC ligand, the catalysis results were quite mixed. To further our understanding of the shortcomings of our gold(III) catalyst we revisited the dihydroalkoxylation reaction of substrate 1, Scheme 2. We ran the reaction at 25 °C using [LAu(III)Cl3] (1 mol %) and Na[BArF4] (1.1 mol %) in C2D2Cl4. After the reaction was complete (