Deactivation of gold(I) catalysts in the presence of thiols and amines – characterisation and catalysis

Thiols and amines, which are common heteroatom nucleophiles in gold-catalysed reactions, are known to dampen the reactivity of gold catalysts. In this article, the identity and activity of gold( I ) catalysts in the presence of thiols and amines is investigated. In the presence of thioacid, thiophenol and thiol, digold with bridging thiolate complexes [{Au(L)} 2 ( μ -SR)][SbF 6 ] are formed and have been fully characterised by NMR and X-ray crystallography. In the presence of amines and anilines, complexes [LAu-NH 2 R][SbF 6 ] are formed instead. All new isolated gold complexes were investigated for their catalytic activity in order to compare the level of deactivation in each species.


Introduction
In less than a decade, homogenous gold catalysis has undergone a transformation from rarity to an incredibly active and rapidly evolving field of research. 1Its popularity is partly result of the excellent selectivity and efficiency of gold catalysts as π-Lewis acids for activating C-C π bonds, and also the ability to tune gold catalysts in order to vary the reactivity and selectivity of the reactions. 1One of the research efforts within our group is to explore the diverse chemistry of gold-catalysed reactions with cyclopropenes, 2,3 allenes 4 and allylic alcohols. 5ithin this context, we have used alcohols, 2a,b,4,5 amines 2f and thiols 2f as nucleophiles in gold-catalysed reactions, and have observed that the presence of these nucleophiles can dramatically alter the reactivity as well as selectivity of the gold catalysts.For example, we have previously observed that although gold(I)-catalysed reactions can work very well with alcohol nucleophiles 1l (Scheme 1, eqn (1)), 2a,b,4a the equivalent reaction of anilines with cyclopropenes do not proceed to completion (Scheme 1, eqn (2)), 2f presumably due to deactivation of the catalyst by the N-nucleophile.On the other hand, despite the initial assumption that S-nucleophiles would fare worse than N-nucleophiles (as they are known strong coordinators to gold), 6 reactions with thiols do proceed to completion. 7owever, reactions are clearly slower with more nucleophilic S-nucleophiles ( progressively slower from thioacid→thiophe-nol→alkyl thiols, Scheme 1, eqn (3)).2f Furthermore, functionalities such as furans 2c and alcohols, 2a,b which usually react with cyclopropenes within minutes under gold(I)-catalysis, are no longer reactive in the presence of thiols.2f In order to explain these observations, we were keen to elucidate the structure and activity of the actual gold(I) species involved in these reactions. 8,9So far, not much effort has been made to isolate, characterise 10 and investigate the catalytic properties of these species.Nevertheless, heteroatom nucleophiles such as RSH and RNH 2 are commonly used in gold-catalysed reactions, 1a,d so a better understanding of the nature and activity of gold(I) catalysts in the presence of these nucleophiles will be invaluable if we are to better understand the mechanisms of gold-catalysed reactions. 11n a recent publication describing the gold(I)-catalysed reactions of thiols with cyclopropenes, we briefly disclosed that [{Au(L)} 2 (μ-SR)][SbF 6 ] species are likely to be the thiol-deactivated complexes formed in the reaction.2f,12 In this article, we present our full investigations into the nature of the gold-

Results and discussion
2.1 Gold(I) catalyst with thiols, thiophenols and thioacids Our investigations commenced with NMR studies of Echavarren catalyst 13 8 in the presence of sulfur nucleophiles RSH.Catalyst 8 is a commonly used, commercially available Au(I) catalyst and was chosen for our studies because it was previously found to have the best catalytic activity in the presence of thiols.2f The second reason for using 8 is one of practicality: the displacement of the MeCN in the complex by an S-nucleophile can be clearly monitored by 1 H NMR spectroscopy, indicated by the appearance of unbound MeCN in the solution.
When catalyst 8 was subjected to 20 equiv. of an alkyl thiol, thiophenol or thiobenzoic acid (to replicate the ratio which would be present in a typical 5 mol% gold(I)-catalysed reaction), an almost instantaneous conversion to new complexes was observed by 31 P NMR analysis (Fig. 1,top), backed up by the appearance of unbound MeCN in the 1 H NMR spectra (Fig. 1, bottom).
A plausible mechanism for the formation of complexes 6a-c is shown in Scheme 3. Acetonitrile is displaced by RSH to form 9, followed by loss of H + to form 10. Complex 10 is nucleophilic and reacts with 8 to form the observed digold complex 6.Evidence for the reversibility of this process is discussed in section 2.3.

Gold(I) catalyst with amines and anilines
Having evaluated the identity of the gold complexes in the presence of thiols, we next carried out a similar study with N-nucleophiles.With nBuNH 2 , p-MeO-C 6 H 4 NH 2 ( p-anisidine) and aniline, a clear shift in the 31 P NMR peak is observed (Fig. 3), once again, accompanied by the appearance of unbound MeCN in the 1 H NMR spectra (see ESI †).The 31 P NMR shift appears to move more upfield the better the parent

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Dalton Transactions RNH 2 nucleophile, consistent with a progressively more electron rich Au(I) centre.
In order to characterise these species, single crystals were grown by vapour diffusion (CDCl 3 -hexane).In stark contrast to the digold species with thiols, single crystal X-ray crystallography reveals monogold [LAu-NH 2 R][SbF 6 ] species 7a, 7b and 7c (Fig. 4).These species are more than likely to be the cause of dampening of reactivity in some gold(I)-catalysed reactions with amines and anilines (e.g.eqn (2), Scheme 1). 17The intermolecular Au-Au distances are 7.5686(4), 8.1290(3) and 7.6009(4) Å respectively for 7a, 7b and 7c, showing that there are no significant aurophilic interactions.Weak Au-arene stabilisation of the Au centre by the ligand is once again evident in all of these structures (Au-arene distances of 3.154, 3.162 and 3.172 Å in 7a, 7b and 7c respectively).This interaction is thought to render extra stability to the gold complexes in this study, and allows them to be stable (e.g.7c is air stable >6 months upon standing on the bench) and isolable for characterisation.In contrast, subsequent attempts to grow the corresponding NHC (IPr) versions of these complexes in the same manner led to decomposition.
Fig. 3 31 P and 1 H NMR analysis of a 1 : 1 mixture of 8 and RNH 2 .

Dalton Transactions Paper
[SbF 6 ] in solution, the equilibrium firmly lies towards 8 (in Scheme 4). 18This observation is as expected as it reflects the catalytic activity of gold(I) in the presence of N-nucleophiles: protected amines such as Boc-and Ts-amines are more commonly used nucleophiles.] have never been studied in the context of catalysis, so it will be useful to know whether these complexes are completely inactive or whether they can competently release active catalyst in situ.For example, in related work, formation of carbon bridged digold species have been shown to be inhibitory to catalysis as they are in competition with the product yielding protodeauration step. 19Related [{Au(L)} 2 (μ-OH)][X] complexes have also been reported and utilised as active catalysts. 20In addition, we were also keen to investigate the degree of deactivation in 6a-c and 7a-c relative to each other.
Firstly, [{Au(L)} 2 (μ-SR)][SbF 6 ] was investigated in a reaction with RSH as a nucleophile, in order to ascertain whether it could be the actual catalytically active species in these reactions.When complex 6b was used as a catalyst in a reaction of a cyclopropene 21,22 with thiophenol, 2f the production of the gold(I) catalysed product 12 is nowhere near as good as with the parent catalyst 8 (Table 1, entry 3 vs. 1).Instead, the background (non gold(I)-catalysed) addition reaction to form cyclopropane 13 dominates.This initially suggests that 6b is most likely not the active catalyst in the reaction shown in entry 1, Table 1, and is instead a deactivation pathway in gold(I)-catalysed reactions with thiols.
However, this result was initially rather puzzling as the procedure in entry 1 involves pre-mixing catalyst 8 with PhSH in CH 2 Cl 2 before addition to cyclopropene substrate 11: this forms 6b in situ almost instantaneously (see section 2.1).One difference between using isolated 6b (entry 3) and 6b made in situ from 8 (entry 1) is the presence of H + , released upon formation of 6b from 8 (Scheme 3). 23If the formation of 6 from 8 is indeed reversible, then the presence of H + may allow for more active catalyst to be in solution for catalysis, whereas the absence of residual H + (entry 3) causes the equilibrium to be towards inactive 6.Indeed, when 6b is used with added H + , the gold(I)-catalysed product 12 is once again the major product (entry 4).A control reaction using Brønsted acid alone (entry 5) Scheme 4 Formation of complex 7.  shows that the reaction to form 12 in entry 4 is gold(I)catalysed.
Next, [LAu-NH 2 R][SbF 6 ] complex 7b was investigated in a reaction where RNH 2 is a nucleophile.When complex 7b was used as a catalyst in a reaction of a cyclopropene with p-anisidine, the conversion to 15 is 15% with 7b compared to 27% using catalyst 8 (entries 1-2, Table 2).As expected, addition of acid does not improve the conversion to desired product (entry 3, Table 2 vs. entry 4, Table 1) as this time it does not affect the equilibrium between 8 and 7 (Scheme 4). 31P NMR analysis of a 1 : 1 : 1 ratio of 8 : 7b : p-anisidine in CD 2 Cl 2 clearly shows immediate formation of 7b in situ, which persists after 2 hours.
Finally, the gold(I)-catalysed reaction of alcohols with cyclopropenes (eqn (1), Scheme 1) was used to compare the catalytic activities (or rather, the amount of dampening of catalytic activity) of complexes 6a-c and 7a-c.We have previously shown that this reaction goes to full conversion with a variety of commercial gold(I) catalysts.2a,b In comparison, complexes 6a-c do not produce full conversions to product 16 (entries 1-3, Table 3).The conversions are moderate to low: 47%, 25% and <5% respectively for 6a, 6b, and 6c.This observed trend neatly reflects the Lewis basicity of the original RSH thiol employed to form the complexes 6a-c.The increasing Lewis basicity going from thioacid→thiophenol→alkyl thiol to form 6a, 6b, and 6c respectively is likely to push the equilibrium towards 6 (Scheme 3), resulting in a lower concentration of active catalyst in the reaction.Complexes 7a-c show a similar trend (entries 4-6).The conversions, reflecting the catalytic activity, also decrease going from 7a→7b→7c, reflecting the increasing Lewis basicity of the parent aniline→ anisidine→amine.

Conclusions
In conclusion, we found that thiols deactivate Au(I) catalysts by forming digold with bridging thiolate complexes [{Au(L)} 2 -(μ-SR)][SbF 6 ] (e.g.6a-c, which have now been fully characterised).These species are in equilibrium with the active gold catalysts (Scheme 3) and the presence of residual H + in situ is required for enough active catalyst to be in solution for catalysis, whereas the absence of residual H + causes the equilibrium to shift towards the inactive complex 6.In addition, the more nucleophilic the parent thiol (RSH), the less active the resulting gold(I) complex, presumably because this pushes the equilibrium increasingly towards the inactive complex The difference in behaviour between gold(I) complexes in thiols and amines is possibly due to the difference in acidity of the proton in 9 vs. 7.We hope that these results shed some light on the identity as well as activity of gold(I) catalysts when thiols and amines are used as nucleophiles in gold(I)-catalysed reactions.

General experimental section
All reactions were carried out in air without the need for predried solvents, in order to replicate the reaction conditions in gold(I) catalysed reactions, which are typically carried out in air. 1 H NMR spectra were recorded on Bruker AV 300 and AV 400 spectrometers at 300 and 400 MHz respectively and referenced to residual solvent. 13C NMR spectra were recorded using the same spectrometers at 75 and 100 MHz respectively.Chemical shifts (δ in ppm) were referenced to tetramethylsilane (TMS) or to residual solvent peaks (CDCl 3 at δ = 7.26).For 31 P NMR, chemical shifts were referenced against H 3 PO 4 at δ 0 ppm.J values are given in Hz and s, d, dd, t, q and m abbreviations correspond to singlet, doublet, doublet of doublet, triplet, quartet and multiplet.Mass spectrometry data was acquired at the EPSRC UK National Mass Spectrometry Facility at Swansea University.Infrared spectra were obtained on Perkin-Elmer Spectrum 100 FT-IR Universal ATR Sampling Accessory, deposited neat or as a chloroform solution to a diamond/ZnSe plate.Elemental analyses were determined by the departmental service (HWU).Flash column chromatography was carried out using Matrix silica gel 60 from Fisher

Dalton Transactions Paper
Chemicals and TLC was performed using Merck silica gel 60 F254 precoated sheets and visualised by UV (254 nm) or stained by the use of aqueous acidic ceric ammonium molybdate.Petrol ether refers to petroleum ether (40-60 °C).Dichloromethane (DCM) was purchased from Fisher and used without further purification.All nucleophiles were purchased from Sigma-Aldrich or Acros, and used without further purification.
4.2 General experimental procedure for crystals 6a-c and 7a-c Catalyst 8 and the nucleophile RSH or RNH 2 (1 equiv.)were added to an NMR tube, and dissolved in CDCl 3 (0.75 mL). 1 H and 31 P NMR were obtained from the resulting crude mixture.

Crystal data
Single crystal X-ray diffraction data were collected on crystals 6a, 6c, 7a-7c which were coated in Paratone-N oil and mounted on an X8 Apex2 diffractometer with a MiTiGen Micromount.Diffraction data were collected at 100 K with graphite monochromated MoKα radiation from a sealed X-ray tube set at 50 kV and 35 mA.Diffraction data for 6b were collected on an Agilent SuperNova, Dual, Atlas diffractometer using Cu Kα radiation (1.5418 Å) with mirror optics.The crystal was kept at 120.01 (10) K during data collection.Using Olex2, 24 the structure was solved with the XS 25 structure solution program using Direct Methods and refined with the XL 25   Dalton Transactions Paper refinement package using least squares minimisation.All non hydrogen atoms were refined anisotropically.All H atoms including water were constrained to idealised geometries apart from N bound H atoms in 7a-7c.CCDC 914704 (6a), 896069 (6b), 914705 (6c), 914706 (7a), 914707 (7b), and 914708 (7c), contain the supplementary crystallographic data for this paper (see Table 4 for crystal data and structure refinements).
The solution was then filtered through a plug of silica with diethyl ether, and concentrated under reduced pressure.The reaction mixture was analysed by 1 H NMR in CDCl 3 to determine 12 : 13 ratio by comparison with literature known spectra.2f General procedure for Table 2 Catalyst (5 mol%) was added to a stirred solution of cyclopropene 14 (1.2 equiv.)and p-anisidine (1 equiv.) in CH 2 Cl 2 (0.1 M).The resulting solution was stirred for 18 h at 25 °C, filtered through a silica plug with ether and concentrated under reduced The reaction mixture was then analysed by 1 H NMR in CDCl 3 to determine reaction conversion by comparison with literature known spectra.2f General procedure for Table 3 Catalyst (5 mol% with respect to gold) was added in one portion to a stirred solution of cyclopropene 11 (1 equiv.)and phenethyl alcohol (1 equiv.) in CH 2 Cl 2 (0.48 M).The resulting solution was stirred for 19 h at 20 °C, the mixture was then filtered through a silica plug with ether and concentrated under reduced pressure.The reaction mixture was then analysed by 1 H NMR in CDCl 3 to determine reaction conversion by comparison with spectra of isolated 16 (see ESI †).
species formed in the presence of thiols, and compare these with species formed in the presence of amines.Solution state NMR studies are presented, along with the isolation and characterisation of the thiol-deactivated species [{Au(L)} 2 -(μ-SR)][SbF 6 ] 6a-c and amine-deactivated species [LAu-NH 2 R]-[SbF 6 ] 7a-c by NMR spectroscopy and X-ray crystallography (Scheme 2).Complexes of type [{Au(L)} 2 (μ-SR)][SbF 6 ] and [LAu-NH 2 R][SbF 6 ] have never been studied in the context of catalysis, so 6a-c and 7a-c were investigated for their catalytic activity in an effort to compare the level of deactivation in each of these species.

Fig. 1
Fig. 1 31 P and 1 H NMR analysis of a 20 : 1 mixture of 8 and RSH.

Scheme 3
Scheme 3 Plausible mechanism for the formation of 6a-c.
1a,d 2.3 Catalytic studies with 6a-c and 7a-c Having established, isolated and characterised the gold(I) species in the presence of RSH and RNH 2 (6a-c and 7a-c respectively), we set out to study the catalytic activity of these species.Complexes of type [{Au(L)} 2 (μ-SR)][SbF 6 ] and [LAu-NH 2 R][SbF 6

Table 1
Comparison of the reaction of cyclopropene 11 with thiophenol in the presence of 8 and 6b; and control reactions a Determined by 1 H NMR analysis of crude reaction mixture.b 8 is premixed with PhSH in CH 2 Cl 2 before addition to 11.

Table 2
Comparison of the reaction of cyclopropene 14 with p-anisidine in the presence of 8 and 7b a Determined by 1 H NMR of crude reaction mixture.

Table 3
Comparison of catalytic activity of 6a-c and 7a-c a 5 mol% with respect to gold, i.e. 2.5 mol% for digold species 6a-c.b Determined by 1 H NMR analysis of crude reaction mixture.