Catalytic conversion of alkynes to α -vinyl sulfides mediated by carbene-linker-carbene (CXC) rhodium and iridium complexes

The catalytic activity of a set of mono- and bimetallic Rh( I ) and Ir( I ) complexes bearing carbene-linker-carbene (CXC) bis-triazolylidene ligands (with X = O, N) coordinated in a bridging or chelating fashion was evaluated in the hydrothiolation of alkynes. The hydrothiolation of 1-hexyne with thiophenol in the absence of an external base or other additives was selected as a model reaction. All rhodium complexes are highly selective catalysts towards Markovnikov product formation and display superior activity compared to the related iridium derivatives. DFT calculations were carried out to rationalize the reaction mechanism and selectivity of this process. Neutral dinuclear [Rh 2 Cl 2 (cod) 2 ( μ - COC )] was found to be the most effective catalyst for this transformation. Its applicability was further studied towards the hydrothiolation of different alkyl and aryl alkynes using predominantly aryl thiols and proved to be one of the most active and selective catalysts towards the α -vinyl sulfide product to date.


Introduction
The structural pattern of α-vinyl sulfides makes these organic molecules important commodities for multiple synthetic applications. They are valuable building blocks extensively used as Michael acceptors, enolate surrogates, or intermediates towards different ring size heterocycles. [1][2][3][4] They are present in biologically active compounds and pharmaceuticals, and found application in materials science and total synthesis. [5][6][7] Thus, the development of atomeconomical methods for the preparation of alkenyl sulfides such as the catalysed intermolecular functionalisation of alkynes (see Scheme 1, a) has been attracting much interest in recent years.
α-Vinyl sulfides are accessible via different synthetic strategies. [8][9][10] Not surprisingly, the use of transition metal catalysis provides substantial tunable control of the regioselectivity outcomes. 5 Rhodium catalysts are of particular interest. These species are often referred to as "chameleonic species" 8,11 because subtle modifications of the ancillary ligands significantly affect their activity and selectivity towards the Markovnikov (α-vinyl sulfides) or the anti-Markovnikov (E/Z-β-vinyl sulfides) addition products. 5,8,[12][13][14][15] The most generally accepted mechanism involves the oxidative addition of the thiol S-H bond to the Rh(I) metal precursor to generate the corresponding Rh(III) intermediate as a first step (Scheme 1, b). 8,11 Then, the 1,2or 2,1-alkyne insertion into the Rh-S or Rh-H bonds takes place to produce four possible reaction paths. Subsequent reductive elimination generates predominantly the αor β-Evinyl sulfides. For the oxidative addition route, an in-depth analysis by Castarlenas et al. highlighted two important factors that need to be considered when developing new rhodium complexes, 8 (i) the alkyne insertion into the Rh-H bond is energetically favored over the Rh-SR bond insertion, promoting the β-E/Z isomer formation and (ii) the marked trans influence of the hydride in the generation of the α-vinyl sulfide product, i.e. due to the control of the coordination of the acetylene trans to the hydride and favoring the attack of the thiolate cis to the alkyne. Thus, complexes that favor trigonal bipyramidal geometry around the metal center or have low stereochemical control typically favor the anti-Markovnikov addition. 13,[16][17][18] In  21 promote alkyne insertion into the Rh-SR bond giving the Markovnikov product. Interestingly, a switch in the selectivity towards the α-vinyl sulfide was observed for some Rh(I)-NHC based complexes, after incorporating a pyridine ligand trans to the carbene moiety which prevents coordination of the alkyne in this position. 12,21 In some cases the addition of a 10 fold excess of pyridine to the reaction mixture is required to attain higher selectivities. 12,21 Parallel to this, the presence of strongly σ-donating NHC ligands bearing bulky substituents also positively impacted on the catalysis. In this context, our first report in the field involved a rhodium(I)-oxygen adduct featuring an anionic CNC bis(triazolylidene) based on the rigid carbazole framework functionalized with strong electron-donating 1,2,3-triazol-5ylidenes (MICs). [22][23][24] High selectivity towards the Markovnikov product was displayed when alkyl thiols and aliphatic alkynes were used. 15 Encouraged by this result and aiming to study the effect of steric relaxation around the metal center, we prepared a series of monometallic Rh(I)-MIC complexes A [Rh(cod)(C Boc N)] and B [Rh(CO) 2 (C Boc N)] bearing different chelating C-N ligands (Fig. 1). 14 Gratifyingly, neutral dicarbonyl complex B [Rh(CO) 2 (C Boc N)] featuring a hemi-labile tethered-NBoc amido-1,2,3triazolylidene ligand acting as internal base proved to be very selective for the hydrothiolation of different alkynes with thiophenol through a non-oxidative reaction with metalligand cooperation (Scheme 1, c). Shortly after, a related highly selective Rh(I)-NHC complex bearing a N,O-pyridine-2methanolato (N-O) bidentate supporting this mechanism has been reported. 11 More importantly, a series of preconditions that need to be satisfied to prevent the oxidative addition route were defined. These include the presence of an internal base along with a chelating ligand to control the potential equilibrium between mono-and dinuclear species and a π-acceptor ligand. Besides that, few examples of iridium complexes mediating this transformation are known. Only two cationic iridium catalysts featuring P-N bidentate ligands have been reported, 18,26 both displaying complete selectivity towards the β-E/Z vinyl sulfide product. On this basis, we foresaw that the availability of a set of rhodium and iridium complexes offering a palette of different coordination modes and nuclearities could contribute to gain more insight into the prerequisites for a selective catalyst in this transformation. Spurred by the success demonstrated in catalysis by metal complexes containing ancillary aliphatic pincer ligands, [27][28][29][30] we recently described the synthesis of a series of mono and dimetallic Rh(I) and Ir(I) complexes from readily available ether-and amine-bridged bis(triazolium) ligand precursors. 25 With this set of catalysts in hand, we herein evaluate their catalytic properties towards the hydrothiolation of alkynes to discriminate between the effects of (i) Rh(I) vs. Ir(I), (ii) mono-vs. dinuclear complexes and, (iii) chelating vs. non-chelating ligands (Fig. 1).

Results and discussion
We initiated a comparative catalytic study for the different Rh(I) complexes towards the hydrothiolation of 1-hexyne with thiophenol in deuterated benzene at 80°C over a period of 24 h. The reaction conditions used during the evaluation of the catalytic properties of A and B were used as a benchmark. 14 Previously, we have shown that when the metal precursor [RhCl(cod)] 2 was combined with 2 equivalents of K 2 CO 3 as the base, a mixture of the thiosubstituted alkene derivatives bis-β-E, β-Z-vinyl sulfide and the related bis-β-Z, Fig. 1 Schematic representation of mono-and dimetallic Rh(I) and Ir(I) complexes used in this study. 14,25 Scheme 1 a) Alkyne hydrothiolation catalysed by group 9 transition metals. b) and c) Rhodium-catalysed alkyne hydrothiolation activation mechanisms.
To compare the performance of dimetallic amine-chelated 4a and 4b with ether-bridged 2a and 2b under the same reaction conditions, their activity was evaluated employing a 0.5 mol% catalyst loading (1 mol% with respect to the metal). Catalyst 4a [Rh 2 (cod) 2 (μ-CNC)](PF 6 ) displayed a moderate 58% conversion, lower than that observed for 2a but Reactions performed in C 6 D 6 (0.5 mL) at 80°C for 24 h using 1,4-di-tert-butylbenzene as internal standard, alkyne : thiol (1 : 1), 1 mol% catalyst (3.5 × 10 −6 mol) for all compounds, as well as 0.5 mol% catalyst (1.75 × 10 −6 mol) for binuclear compounds 2a-b, 4a-b and 5 (for comparison purposes). Conversion and product distribution of the α, β-Z and β-E-vinyl sulfide products were determined as the average of duplicate runs as determined from NMR integration based on 1-hexyne and thiophenol average referenced to 1,4-di-tert-butylbenzene.  Table 1). In contrast, 4b [Rh 2 (CO) 4 (μ-CNC)] (PF 6 ), exhibited a poor 31% conversion (entry 14, Table 1). Finally, we evaluated the activity of the neutral tricarbonyl dimetallic rhodium(I) complex 5 [Rh 2 Cl(CO) 3 (μ-CNC)], by first using 1 mol% catalyst loading (2 mol% with respect to the metal). Despite exhibiting a moderate conversion of 48%, excellent selectivity towards the α-vinyl sulfide product was observed (entry 15, Table 1). The conversion was maintained when catalyst loading was halved to 0.5 mol% (1 mol% with respect to the metal) with only a slight decrease in the observed selectivity towards the α-vinyl sulfide product. Density functional theory (DFT) calculations were carried out at the dispersion corrected PCM(benzene)-B3LYP-D3/def2-SVP level (see computational details in the ESI †) to gain more insight into the reaction mechanism and selectivity of the above transformations. To this end, we selected the process involving the Rh(I) catalyst 3, which bears the C H NC-pincer ligand and leads to an almost complete selective transformation towards the α-vinyl sulfide (see entry 10, Table 1). This system was chosen because, although displayed a lower conversion than the parent system A, allows us to understand the influence of the C H NC-pincer ligand on the process.

Catalysis Science & Technology Paper
According to the computed reaction profile shown in Fig. 2, the process begins with the oxidative addition reaction of PhSH to Rh(I) leading to the corresponding Rh(III)intermediate INT1.
The computed barrier of this step (ΔG ≠ = 31.5 kcal mol −1 , via TS1) and endergonicity of the process (ΔG R = 13.6 kcal mol −1 ) are compatible with the relatively high temperature required for the transformation (80°C, see above). Alternatively, a dissociative mechanism involving the initial release of the CO ligand followed by a similar oxidative addition can be also envisaged. However, our calculations indicate that this alternative pathway via TS1′ is not competitive from both kinetic (ΔG ≠ = 34.7 kcal mol −1 ) and thermodynamic (ΔG R = 26.0 kcal mol −1 ) points of view. Intermediate

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our calculations indicate that the analogous Rh-S insertion reaction from the isomer INT2-iso, which would produce the corresponding β-sulfide via TS2-iso, proceeds with a higher activation barrier (ΔG ≠ = 24.2 kcal mol −1 ) than the process involving INT2. The computed barrier energy difference (ΔΔG ≠ = 2.7 kcal mol −1 ) is consistent with the observed almost complete selectivity towards the formation of the α-vinyl sulfide (95 : 5 see Table 1, entry 10). Strikingly, a lower energy barrier difference of ΔΔG ≠ = 2.4 kcal mol −1 was computed at 378 K (the temperature used in the experiments), which is translated into a 96 : 4 selectivity, therefore nearly matching the observed experimental ratio. Thus, it can be concluded that the origin of the selectivity of this transformation is mainly found in the alkyne insertion into the Rh-S bond. 32 Finally, the process ends up with a protonolysis reaction mediated by a new molecule of PhSH followed by coordination of the previously released CO ligand, which would produce the observed Markovnikov α-sulfide and INT1, the latter entering into a new catalytic cycle. Next, we explored the performance of the six Ir(I) complexes (Table 2), for comparison to the rhodium(I) derivatives in the same transformation. Initially, we studied the two cationic diolefinic 6a [Ir(cod)(COC)](PF 6 ) and dicarbonyl 6b [Ir(CO) 2 (COC)](PF 6 ) mononuclear Ir I complexes, bearing the (COC) ligand acting as chelate (Fig. 1). In this case, 6a displayed a 91% conversion, using 1 mol% catalyst loading, slightly lower than the 94% observed for the neutral Rh(I) complex A [Rh(cod)(CN)] bearing the less bulky (CN) ligand (Fig. 1), but higher than the 68% registered for the cationic Rh(I) analogue 1a [Rh(cod)(COC)](PF 6 ) bearing the (COC) ( Table 1, entries 2 and 4 respectively). In contrast, the related dicarbonyl derivative 6b, [Ir(CO) 2 (COC)](PF 6 ), exhibited a moderate 51% conversion albeit higher than that found for the neutral Rh(I) complex B [Rh(CO) 2 (CN)] featuring the bidentate (CN) ligand or the Rh(I) counterpart 1b [Rh(CO) 2 (COC)](PF 6 ) containing the (COC) ligand (Table 1, entries 3 and 5 respectively). The selectivity of the dicarbonyl complex Ir(I) 6b is markedly higher than that observed for the diolefinic Ir(I) 6a (Table 2, entries 1 and 2 respectively), and slightly higher than that found for the dicarbonyl Rh(I) complex 1b (Table 1, entry 5). However, this species displays a lower selectivity when compared to the diolefinic Rh(I) complex 1a, inferior selectivity to the 96% α-isomer product distribution obtained for diolefinic Rh(I) complex 1a [Rh(cod) (COC)](PF 6 ) is indicated. Next, we assessed the performance of the corresponding neutral dimetallic derivatives 7a [Ir 2 -Cl 2 (cod) 2 (μ-COC)] and 7b [Ir 2 (CO) 4 (μ-COC)] containing the (COC) ligand acting as bridge. First, we used a catalyst loading of 1 mol% (2 mol% metal content). As a result, the dinuclear tetraolefinic Ir(I) catalyst 7a [Ir 2 Cl 2 (cod) 2 (μ-COC)] displayed 81% conversion ( Moreover, in addition to the lower conversion observed in comparison with the Rh(I) analogue 2a, catalyst 7a also proved to exhibit a poor selectivity. The related tetracarbonyl Ir(I) derivative 7b [Ir 2 (CO) 4 (μ-COC)] (1 mol% catalyst loading, 2 mol% Ir(I) content), exhibited a low conversion of 38% (Table 2, entry 5) and matching the selectivity to its rhodium(I) counterpart 2b [Rh 2 (CO) 4 (μ-COC)] ( Table 1, entry  8).
In order to compare the performance of the neutral and bimetallic 7a, b with cationic and monometallic 6a and 6b under the same conditions, we assessed their activity using a 0.5 mol% catalyst loading (1 mol% Ir(I) content). Neutral catalyst 7a [Ir 2 Cl 2 (cod) 2 (μ-COC)] displayed a 59% conversion, much lower than the 91% conversion observed for cationic 6a and showing a similar poor selectivity. In the case of the related tetracarbonyl derivative 7b [Ir 2 (CO) 4 (μ-COC)], the lower catalyst loading (0.5 mol%) resulted in a similar conversion to that found for a 1 mol% catalyst loading of the same catalyst (Table 2, entry 6), although it negatively impacted the selectivity. Finally, we evaluated the Table 2 Hydrothiolation of 1-hexyne and thiophenol catalysed by iridium(I) mono-and dimetallic complexes 6a-b, 7a-b, and 8a-b a

Entry
Cat.
In the case of the best performing catalyst from this study, Rh(I) 2a-b, and the most selective Ir(I) catalyst 8a-b, the decrease in the π-basicity of the metal centre for carbonyl coligands (b) vs. cod-substituted complexes (a), accompanied by a loss in selectivity could be indicative of a decrease in the ease of oxidative addition in a catalytic cycle that differs from that of A/B (and includes oxidative addition of the thiol substrate). It was concluded that the best performing catalyst is 2a [Rh 2 Cl 2 (cod) 2 (μ-COC)] at 80°C and 24 h using a 0.5 mol% catalyst loading (see Table S1, † entry 7). Following the identification of 2a [Rh 2 Cl 2 (cod) 2 (μ-COC)] as the catalyst of choice, the substrate scope of both aliphatic and aryl substrates for the base-free hydrothiolation of terminal alkynes, under the optimized reaction conditions, was expanded (Table 3). Catalyst 2a revealed good functional group tolerance with no coupled bis-β-, β-vinyl sulfide products detectable. By examination of the results gathered in Table 3, we can confirm that the neutral dimetallic complex 2a [Rh 2 Cl 2 (cod) 2 (μ-COC)] proved to be very selective towards the branched α-vinyl sulfide product when aliphatic alkynes and both aryl and alkyl thiols were used as substrates in the absence of an internal base or hemilabile ligand function (Table 3, entries 1-7). In contrast, only moderate selectivities were obtained for aryl alkynes (Table 3, entries [8][9], especially in the case where both the alkyne and thiol contain an aryl group (entry 8). Finally, we evaluated the catalytic activity of complex 2a [Rh 2 Cl 2 (cod) 2 (μ-COC)] in the base-free hydrothiolation of an internal alkyne such 3-hexyne with thiophenol under the same reaction conditions (Table 3, entry 10). A lower conversion of 26% was observed with preferential formation of (E)-3-phenylsulfanyl-3-hexene, in comparison with the high yield reported for the formation of this E-isomer. 13

Conclusions
The catalytic activity of a series of mono-and dimetallic rhodium(I) and iridium(I) complexes bearing carbene-linkercarbene (CXC) bis-triazolylidene ligands (with X = O, N) ligands were assessed in the hydrothiolation model reaction of the terminal 1-hexyne with thiophenol. The catalytic studies revealed that, in general, the Rh(I) complexes outperformed the related Ir(I) derivatives, both in terms of activity and selectivity. Among them, the rhodium complexes bearing the (COC) ether bridged bis-triazolylidene ligand have shown superior activity and selectivity towards the sought after branched α-vinyl sulfide product, in comparison with related Rh(I) counterparts featuring the (CNC) amino bridged derivative. Finally, the neutral dimetallic rhodium(I) complex 2a containing the carbene-ether-carbene (COC) ligand proved to be the best catalyst in terms of activity and selectivity for a series of aliphatic alkynes and different thiols, demonstrating good functional group tolerance. Notably, the identified best-performing rhodium catalyst 2a and selective iridium catalyst 8a employed in this study, the absence of a basic, hemilabile coordinating moiety and the selectivity improvement observed for cod co-ligands instead of stronger π-acidic carbonyl ligands, point to an alternative catalytic mechanism for these complexes, compared to the non-oxidative route exemplified by catalysts A/B. Indeed, DFT calculations carried out for the transformation involving the Rh(I) catalyst 3 suggest that the process involves an initial oxidative addition step followed by a selectivity-determining step consisting of the alkyne insertion into the Rh-S bond.

Conflicts of interest
There are no conflicts to declare.