Christophe Michon

Kirsty Macintyre

Yann Corre

Francine Agbossou-Niedercorn

Pentamethylcyclopentadienyl iridium(III) metallacycles applied to homogeneous catalysis for fine chemicals synthesis

Keywords: iridium, metallacycle, half-sandwich, organometallics, homogeneous catalysis

teaching and research institutions in France or abroad, or from public or private research centers.

Introduction

The cyclometallation reaction, discovered in early 1960's, has become a unique synthetic tool in organometallic chemistry. [1,2] Indeed, cyclometallation provides access to original organometallic compounds bearing a metal-carbon  bond. Such complexes are synthesised via C-H (or C-C) bond activation of a ligand which is assisted intramolecularly by coordination of a directing donor atom (N, P, O, C…). Thus, the resulting metallacycle consists of a metal bound to a chelate carboligand which not only provides increased stability to the complex, but also exclusive reactivity. [1,2] Most significantly, transition-metal-catalysed C-H activation has allowed various ortho-selective C-C and C-X bond-forming reactions through insitu generation of metallacycle intermediates. [3] Compared to their ruthenium and rhodium counterparts, iridacycles have been far less studied [4] but have attracted a rising interest these past years.

More specifically, half-sandwich (i.e. pentamethylcyclopentadienyl) iridium(III) metallacycles have demonstrated a great potential in homogeneous catalysis displaying significant activities for a range of organic reactions. Meanwhile, iridacycles have also attracted a great interest in photochemistry due to their photophysical properties. [START_REF] Meggers | For some recent reviews[END_REF] Further applications of iridium(III) metallacycles have been reported in biology as antibacterial and anticancer agents [6] as well as in other reactivity studies. [7,8] Indeed, half-sandwich iridium(III) metallacycles have been recently applied in energy and environmental science to catalyse reactions such as: dehydrogenation and oxidation of formic acid, hydrogenation of carbonates, productions of hydrogen or hydrogen peroxide. [8] All these complementary properties and applications of iridacycles will not be detailed herein. This minireview summarises recently developed homogeneous catalysed organic chemical reactions employing half-sandwich iridium(III) cyclometallated complexes as catalysts in hydrogenation, amine alkylation, dehydrogenation, oxidation and hydrofunctionalization reactions as well as dynamic kinetic resolutions (DKR).

Hydrogenation, transfer hydrogenation, reductive amination

Hydrogenation

In 2013, a series of half-sandwich iridium(III) metallacycles was investigated by Xiao et al. to catalyse the hydrogenation of C=N containing substrates (Scheme 1). [9] After a thorough screening of C-N chelate ligands, the optimized catalyst was applied in the hydrogenation of a large France. E-mail: christophe.michon@ensc-lille.fr, francine.agbossou@ensc-lille.fr [b] ENSCL, UCCS-CCM-CASECO, (Chimie-C7) CS 90108, 59652 Villeneuve d'Ascq Cedex, France scope of imines and N-heterocyclic substrates. The use of 2,2,2trifluoroethanol (TFE) meant effective chloride dissociation without the use of a halide abstraction agent allowing H2 coordination to proceed. The catalyst developed was effective in the chemoselective reduction of various cyclic and acyclic imines as well as N-heteroaromatic substrates like quinoxalines and unprotected indoles.

Scheme 1. Hydrogenation of C=N bonds. [9] More recently, the modification of such iridacycles was reported to facilitate the hydrogenation of imines at low catalyst loadings (Scheme 2). [10] They observed substrates with electron donating groups were hydrogenated more efficiently than those bearing electron withdrawing substituents.

Scheme 2. Hydrogenation of imines. [10] The reaction of a ketimine was scaled up to 2 g using 0.01 mol% of 2, at 85 °C in 2 h and afforded the related amine in 93 % yield.

Transfer hydrogenation

Transfer hydrogenation has been applied by Xiao et al. in the presence of half-sandwich iridium(III) metallacycles for the reduction of imines with formic acid. [11] The mechanistic aspects of the reaction were studied in detail through kinetic experiments and DFT calculations. Two key steps of the mechanism have been particularly scrutinized i.e. formation of the metal hydride (rate determining) and hydride transfer to the substrate (Figure 1). Beside the 3 possible pathways for the synthesis of the Ir-H species, 5 routes were investigated for the hydride transfer step. If the hydride formation may proceed by an ion-pair mechanism, the transfer of the hydride to the iminium shall occur directly through an outer sphere mechanism. Though this route is limited by the hydride formation and facilitated by electrostatic interactions, this pathway is the most favourable to lead to the amine product. Calculations were also performed considering a methanol molecule for both steps. A significant energy drop of the ion pair transition state was shown due to its stabilisation via hydrogen bonding.

Figure 1. Mechanism of imine hydrogenation with formic acid. [11] Half-sandwich iridium(III) metallacycles have also been applied by Xiao et al. to catalyse the transfer hydrogenation of a range of carbonyl compounds for the preparation of relevant functionalised secondary alcohols (Scheme 3). [12] Scheme 3. Transfer hydrogenation of various carbonyl compounds. [12] The attractiveness of this protocol relies on low catalyst loadings, the use of formate as the hydrogen source and of a water medium. Following a ligand screening, two catalysts emerged as the most efficient for the hydrogenation of a wide range of substrates such as -keto ethers, -substituted ketones,  and -keto-esters, and -unsaturated aldehydes, presenting a great application potential for the synthesis of high added value compounds (Scheme 3).

Imino based half-sandwich iridacycle 5 was also versatile when applied under identical catalytic conditions to the transfer hydrogenation of various N-heterocycles in water (Scheme 4). [13] The reaction is applicable to a large scope of N-heterocycles, even on a 35 g scale, and demonstrated excellent functional group compatibility. The mechanism of the reaction was studied through deuterium labelling experiments. Competitive 1,2-and 1,4-hydride addition pathways were observed with stereoelectronic attributes of the substrate and the catalyst affecting their rate. Scheme 4. Transfer hydrogenation of N-heterocycles. [13] Asymmetric transfer hydrogenation of ketones and ketimines has been reported by Pfeffer, De Vries et al. using half-sandwich iridacycle 7 as catalyst (Scheme 5). [14a] Alcohols and amines were obtained in low to high yields with rather high enantioselectivities.

Scheme 5. Asymmetric transfer hydrogenation of alkyl and aryl ketones. [14] Later, Mata et al. reported chiral at metal half-sandwich iridium(III) metallacycles 8 and 9 bearing an N-heterocyclic carbene ligand and a chelated primary (S)-[1-(1naphthyl)ethyl]amine (Scheme 5). [14b] These complexes catalysed the asymmetric transfer hydrogenation of ketones in low to high yields with low to average enantioselectivities depending on the bulkiness of the N-heterocyclic carbene ligand. DFT calculations suggested a concerted one-step mechanism based on a direct hydrogen transfer via a highly ordered transition state centered at the iridium amido group.

Reductive amination

The potential of half-sandwich iridium(III) metallacycles has also been examined to catalyse reductive amination reactions. Under the hydrogen transfer conditions previously described, the first example of production of pyrrolidinones from levulinic acid derivatives was reported by Xiao et al. (Scheme 6). [15] Electron donating methoxy groups on the aryl residues of the ligand promoted reactivity of catalyst 10. The transformations could also be carried out in methanol with HCOOH/Et3N azeotrope as a hydrogen source. 6-membered Nheterocycles could also be obtained by applying this methodology to 5-oxohexanoic acid. Scheme 6. Synthesis of pyrrolidinones from levulinic acid. [15] Reductive amination of simple ketones and aldehydes in water or methanol has also been described under transfer hydrogenation conditions (Scheme 7). [16] Scheme 7. Reductive amination of carbonyl compounds in water. [16] Half-sandwich iridium(III) metallacycle 5 was the most appropriate catalyst for these reactions. Best activities and chemoselectivities were achieved in water when the pH was set to 4.8. It is worth noting all examples given above are also pH dependent with narrow acidic windows for transfer hydrogenation performed in water. The reaction was found to proceed 6 times faster under aqueous conditions than in MeOH. [16] Interestingly, the reduction of β-keto esters was also explored, providing access to the corresponding amino acids. An increased activity was observed with aldehydes by comparison with ketone substrates. By applying catalyst 5 to the reductive amination of benzaldehyde with p-anisidine on a 250 mmol scale, a 95 % yield was obtained in 48 hours achieving a very high Substrate/Catalyst ratio of 1x10 5 . [16] The direct synthesis of primary amines via reductive amination of ketones and aldehydes was also reported using ammonium formate. [16b,17] The latter acted as a source of both ammonia and proton to lead to an iminium intermediate which was then hydrogenated (Scheme 8). [17] Catalyst 5 was used with a large scope of carbonyl compounds to produce various primary amines. It is worth to note the reaction of an α,βunsaturated ketone furnished a saturated amine. The authors suggested a 1,4-reduction pathway occurred first as it has frequently been observed in transfer hydrogenation. The catalytic system was also investigated for use in the synthesis of non-natural α-amino acids from α-keto acids.

Scheme 8. Direct reductive amination of carbonyl compounds for the production of primary amines. [17]

Dehydrogenation

The ability of half-sandwich iridium(III) metallacycles to catalyse hydrogenation and transfer hydrogenation reactions led researchers to examine their potential in dehydrogenation reactions.

Alcohols and formic acid dehydrogenation

Following preliminary investigations, Yamaguchi et al. developed iridium(III) metallacycles based on cooperating 2hydroxy C-N chelate ligands. Complex 11 was shown to catalyse efficiently the oxidant free dehydrogenative oxidation of both primary and secondary alcohols (Scheme 9). [18a,b] An hydrido iridium complex was found to be involved in the catalytic reaction. Subsequently, Albrecht et al. prepared the bimetallic iridacycle 12 based on a bridging triazolylidene ligand to perform such selective reactions using stronger conditions. [18c] A seminal work from Fukuzumi et al. reported the application of a pyrazol based iridium(III) metallacycle as a functional mimic of alcohol dehydrogenase (ADH) to catalyse in water the combined dehydrogenation of alcohols and hydrogenation of oxidized -nicotinamide adenine dinucleotide (NAD + ) (Scheme 10). [19] In a basic aqueous solution, aquo complex 13 was initially shown to be equilibrated with complex 14 and hydroxo complex 15. [19a] Interestingly, complex 15 catalysed the dehydrogenation of alcohols and led to iridium hydrido species 16 which could subsequently reduce NAD + molecules with a turnover frequency (TOF) up to 18 h -1 and regenerate complex 15. [19b] Scheme 9. Dehydrogenation of primary and secondary alcohols. [18] Scheme 10. Dehydrogenation of primary alcohols and hydrogenation of oxidized -nicotinamide adenine dinucleotide (NAD + ). [19]

N-heterocycles dehydrogenation

In 2013, Xiao et al. used half-sandwich iridium(III) metallacycles to catalyse the acceptorless dehydrogenation of a variety of benzofused N-heterocycles in 2,2,2-trifluoroethanol (TFE) (Scheme 11). [20a] Tetrahydroisoquinolines and tetrahydroβ-carbolines which do not easily undergo dehydrogenation due to formation of stable imine intermediates were also tolerated. The catalytic dehydrogenation of a primary alcohol containing substrate (R1 = 2-CH2OH) showed the chemoselective nature of this catalyst. Subsequently, Xiao et al. highlighted the potential of this catalytic system by demonstrating the dehydrogenation process in the synthesis of Harmine, a major -carboline alkaloid. [20a] Following these results, regioselective acceptorless dehydrogenative couplings of 2-Me N-heterocycles were further developed to afford functionalised quinolines, phenanthrolines, and indoles. These reactions generated in-situ nucleophilic enamines which could react with various electrophiles. A further cascade process was developed by combining these dehydrogenative couplings with Friedel-Crafts additions. [20b] Scheme 11. Acceptorless dehydrogenation of N-heterocycles. [20a]

Amine alkylation

Based on results related to imine reduction and dehydrogenation (see above), Xiao et al. reported the application of half-sandwich iridium(III) metallacycles to catalyse the amine alkylation with alcohols or amines under rather mild conditions (Scheme 12). [21] Scheme 12. Alkylation of amines with either alcohols or amines. [21] 2,2,2-trifluoroethanol (TFE) was found to be crucial for the reaction to proceed, as no reaction was observed with any other solvent. Alkylation of anilines and cyclic amines could be performed with various alcohols including methanol. The use of diols allowed the synthesis of several morpholine, piperidine, and pyrrole based heterocycles. Furthermore, under the same reaction conditions, the cross-coupling of amines led to secondary amines in good yields using diisopropylamine and various anilines (Scheme 12).

Oxydation, racemization, resolution

Before the successful application of half-sandwich iridium(III) metallacycles bearing C-N chelate ligands to hydrogenation and dehydrogenation processes, such catalysts had been successfully applied to alcohol oxidation reactions.

Aerobic alcohol oxidation

Ikariya et al. used amido based half-sandwich iridium(III) metallacycles to catalyse the dehydrogenative oxidation of alcohols with molecular oxygen as the hydrogen acceptor. [22] They observed an amine-hydrido iridacycle was dehydrogenated by O2 from air to lead to the corresponding amido iridacycle and water. This reactivity allowed them to apply, for the first time, chiral bifunctional half-sandwich iridium(III) metallacycles to catalyse the kinetic resolution of racemic alcohols through aerobic oxidation of alcohols (Scheme 13). Catalyst screening showed the crucial role played by the NH moiety in the initiation of O2 activation. The reaction appeared to be sensitive to altering substrates (redox properties), chiral catalyst structure, and small changes in reaction conditions such as solvent and dilution.

Scheme 13. Oxidative kinetic resolution of secondary alcohols. [22] This was the first time aerobic kinetic resolution of racemic secondary alcohols had been performed efficiently using molecular oxygen as the hydrogen acceptor and with defined chiral bifunctional amido half-sandwich iridium(III) metallacycles as catalysts. However, the most selective catalyst was not a metallacycle but an iridium(III) complex based on N-mesyl diphenylethylenediamine ligand (46% recovery, >99% ee), Ikariya et al. proceeded to expand the applications of halfsandwich iridacycles bearing achiral C-N chelate ligands, derived from benzylic amines, to the aerobic oxidation of primary and secondary alcohols (Scheme 14 and 15). [23] Again, the bifunctionality of the catalytic metal-NH unit was shown to enable the dehydrogenation of secondary alcohols to ketones using oxygen as hydrogen acceptor (Scheme 14). Under similar conditions, amine based catalyst 19 allowed oxidation of primary alcohols into esters through an oxidative dimerization pathway (Scheme 15). Scheme 14. Aerobic oxidation of secondary alcohols. [23] Scheme 15. Aerobic oxidation of primary alcohols. [23]

Racemisation of alcohols and amines

Feringa, De Vries et al. applied selected half-sandwich iridacycles to the racemisation of chiral alcohols and amines. [24] Activation of iridium(III) pre-catalyst 21 with a base led to the racemisation of alcohols and some amounts of ketones (Scheme 16), while the non-activated complex 22 was selective for the effective racemisation of amines (Scheme 17).

Scheme 16. Racemisation of alcohols. [24] Scheme 17. Racemisation of amines. [24]

Dynamic Kinetic Resolution of racemic secondary alcohols

In 2008, Feringa, de Vries et al. reported the first direct stereoselective transformation of racemic β-haloalcohols into enantiomerically enriched epoxides via a DKR process in the presence of a half-sandwich iridium(III) metallacycle as the catalyst (Scheme 18). [25] The latter was used in conjunction with a haloalcohol dehalogenase (Hhec) variant possessing two mutations in order to increase enzyme stability towards oxidation (Cys153Ser) and enantioselectivity for aromatic substrates (Trp249Phe). A biphasic medium was required in order to trap the Brønsted acid released during ring closure to the epoxide. Although the bromoalcohol substrates often resulted in higher yields of products, increased enantioselectivities were obtained with the chloride derivatives, as the rate of the uncatalysed ring closure of chloroalcohols was lower than that for bromoalcohols.

Scheme 18. Chiral epoxides via DKR of β-haloalcohols. [25] In 2012, Ikariya et al. explored further the potential of their bifunctional amido-iridium catalysts in a chemo-enzymatic system. The dynamic kinetic resolution (DKR) of racemic alcohols combining 20 with Candida antarctica lipase B (CALB) provided a range of chiral acetates (Scheme 19). [26] Scheme 19. Optically pure acetates through DKR of alcohols. [26] Interestingly, such a catalytic system combined a metalcatalysed racemisation with an enantioselective enzymatic transesterification at room temperature, in the absence of a base and with an equimolar amount of acyl donor. All 8 substrates were converted to acetates with 99 % ee and 7 resulted in yields over 80%. These significant achievements present an interesting route for the synthesis of optically pure acetates from racemic secondary alcohols and highlight the compatibility of such bifunctional iridium catalysts with chemo-enzymatic conditions.

Hydrofunctionalizations

Hydrosilylation

A study on the hydrosilylation of imines employing halfsandwich iridium(III) metallacycles was reported by Michon et al (Scheme 20). [27] Scheme 20. Hydrosilylation of imines. [27] Activation of half-sandwich iridium(III) metallacycle 23 via displacement of the chloride ligand was required and sodium tetrakis [(3,5-trifluoromethyl)phenyl]borate (NaBArF24) proved to be the most effective in displacing the halide and affording an active catalyst. The authors demonstrated the less coordinating the anion was, the higher the yields were. The catalytic activity of the tricarbonyl chromium bound half-sandwich iridium(III) was also monitored in the hydrosilylation of imines, but afforded lower yields. The catalyst appeared to be very active at mild temperatures affording for example 90 % yield of the amine issued from the hydrosilylation of Nphenylethylideneaniline with 0.01 mol % cat. in 24 hours. A broad range of aldimines and ketimines were reduced under mild conditions with low catalyst loading (Scheme 20). Further analysis of the active species showed the in-situ generated iridacycles to be more active than the isolated cationic complexes. In-situ NMR experiments showed several mono-and dihydride iridium species without any coordinated molecular hydrogen.

Tandem hydroamination-hydrosilylation

In 2012, Djukic et al. reported a seminal application of halfsandwich iridium(III) metallacycles to catalyse a tandem hydroamination-hydrosilylation reaction (Scheme 21). [28] Following a study on the stoechiometric insertion of phenylacetylene into C-Ir bonds of some iridacycles, the authors reported the transformation of terminal aromatic alkynes to racemic N-phenyl, 1-arylethylamines in a 'one-pot' reaction using an iridacycle bound by an electron withdrawing tricarbonylchromium. Such half-sandwich iridacycles were shown to catalyse the hydroamination of terminal alkynes into Nphenylimines and the hydrosilylation of the latter into benzylamines, both as two separate reactions and in a tandem 'one-pot' fashion. The efficiency of the catalyst in the hydrosilylation process was attributed to the involvement of an Ir-mono-hydride intermediate. [19,29] Scheme 21. Tandem hydroamination-hydrosilylation. [28]

Conclusion

The application of pentamethylcyclopentadienyl iridium(III) metallacycles in homogeneous catalysis is a rapidly expanding area of research. Through the development of novel catalysts tailored to facilitate a wide range of organic transformations, the potential of such complexes continues to be exposed. Hence, well defined half-sandwich iridacycles have been reported in the production of several related chemical reactions, e.g. mainly hydro-and dehydrofunctionalizations, with broad substrate scopes. These half-sandwich iridacycle catalysts have shown high activities under mild conditions and at low catalyst loadings. In most cases, they offer environmentally and economically beneficial routes towards fine chemicals, since novel and alternative protocols for existing processes have been reported.

While half-sandwich iridium(III) metallacycles are by now clearly well-established homogeneous catalysts, fundamental developments in this area of research are appearing more frequently, and many recent reports predict further promising advancements in the near future. Key studies and modifications of the C-N chelate ligands are needed. They may rationalize and improve catalyst activity, allow metal ligand cooperation and enable the application of recycling methods and processes.

Christophe

  Michon defended PhD in chemistry at Strasbourg Univ. in 2003 (Dr. J. P. Djukic, Dr. M. Pfeffer) and Habilitation in 2014 (Lille Univ.). He occupied several post-doctoral positions in U.S.A (Prof. R. J. Angelici, Ames Lab. U.S.D.O.E./Iowa State Univ.), in Japan (Prof. M. Uemura, Kyoto Pharm. Univ.) and in Switzerland (Prof. J. Lacour, Geneva Univ.). Since 2009, he has been a senior scientist (CR1) at CNRS, UCCS-Lille Univ. France. His research interests are in the field of homogeneous catalysis with a focus on hydrofunctionalizations. Kirsty MacIntyre is a Master student studying chemistry at The University of Edinburgh, Scotland. Since fall 2015, she has been participating in the Chemistry 4MX course taken as the 4th year of the MChem Year Abroad degree program with ERASMUS and the ENSCL. Her present research focusses on the synthesis of chiral N-Heterocyclic Carbene ligands and their organometallic complexes with applications in homogeneous catalysis. Yann Corre is Doctor in Pharmacy from Rennes Univ. After a Master training period at Tohoku Univ. (Japan) within Prof. Y. Yamamoto laboratory, he started his PhD at Lille Univ., working with Dr. F. Agbossou-Niedercorn and Dr. C. Michon on the hydrosilylation of unsaturated carbonheteroatom bonds catalysed by iridium(III) metallacycles. After his defense by fall 2015, he has accepted a post-doctoral position in medicinal chemistry at Grenoble Univ. Francine Agbossou-Niedercorn obtained her PhD in the field of porphyrin chemistry. Afterwards, she took a research fellow position with the CNRS in IRCELYON (Villeurbanne) on Cytochrome P450 models. In 1985, she joined the LCC (Toulouse) and got involved in homogeneous catalysis (hydration, amination, oxidation). After a postdoctoral stay at the University of Utah in Salt Lake City with Prof. J. A. Gladysz, she joined UCCS (Lille) in 1991. Since 2010, she is leader of the Department of Catalysis and Molecular Chemistry of UCCS. Her research interests focus on homogeneous catalysis and asymmetric synthesis.

  [a] Dr. C. Michon, K. MacIntyre, Y. Corre, Dr. F. Agbossou-Niedercorn, Univ. Lille, CNRS, Centrale Lille, ENSCL, Univ. Artois, UMR 8181 -UCCS -Unité de Catalyse et Chimie du Solide, F-59000 Lille,

Acknowledgements

The University of Edinburgh, ENSCL and E.U. are thanked for an Erasmus+ fellowship (K.M.). The Ministère de l'Enseignement Supérieur et de la Recherche and Région Nord-Pas de Calais are acknowledged for a PhD fellowship (Y.C.). CNRS, Chevreul Institute (FR 2638), Ministère de l'Enseignement Supérieur et de la Recherche, Région Nord -Pas de Calais and FEDER are acknowledged for supporting and funding partially this work.


Y Corre

W Iali

M Hamdaoui

X Trivelli

J.-P Djukic

Francine Agbossou-Niedercorn

C Michon

J. -P Djukic

F Agbossou- Niedercorn

Efficient hydrosilylation of imines using catalysts based on iridium(III) metallacycles

published or not. The documents may come

Efficient hydrosilylation of imines using catalysts based on iridium( iii ) metallacycles

Introduction

Amines are ubiquitous in natural products, building blocks or targets for fine chemicals, farming related chemicals and biologically active compounds. 1 Among the several synthetic methods for amine, the transition-metal catalysed reduction of imines is a valuable pathway which can be performed by hydrogenation, 2 hydrogen transfer 3 or hydrosilylation. 4 The latter, which operates in mild reaction conditions without any autoclave pressure, is an interesting alternative to hydrogenation provided inexpensive and abundant hydrosilanes are used. The stereoselective synthesis and reactivity of metallacycles like iridacycle 1 and chromiumtricarbonyl-bound iridacycle 2 have been studied by some of us for several years (Scheme 1). 5 Recently, complexes of type 2 were found to display novel catalytic virtues for the conversion of terminal aromatic alkynes into racemic N-phenyl, 1-arylethylamines by tandem hydroamination and hydrosilylation/protodesilation reactions under mild ''one pot'' conditions. 5a The peculiar efficiency of such catalyst in promoting hydrosilylation was assigned to the intervention of Ir-hydrido intermediate 3, 5a,e a key species for the transfer of the hydritic H atom to the electrophilic imine substrate. In addition, other reports stated on the efficiency of such iridacycles for hydrogenation reactions. 2h-i,3e-h a Université Lille Nord de France, 59000 Lille, France.

Fax : +33-320436585, Email : christophe.michon@ensc-lille.fr b CNRS, UCCS UMR 8181, 59655 Villeneuve d'Ascq, France. Hence, considering the interest of some of us on the synthesis and reactivity of iridacycles, 5 and the complementary research of others on the synthesis of amines using hydroamination reaction, 6 we investigated Ir(III) metallacycles as catalysts for the hydrosilylation of imines. Scheme 1. Studied iridacycles.

Results and discussion

Screening of catalysts, additives and reaction conditions was performed on the hydrosilylation of N-phenylethylideneaniline 4a and we rapidly noticed the use of an additive was critical to displace the iridium chloride ligand and afford an active cationic catalyst (Table 1). Iridacycle 1 proved to be the most active catalyst as compared to chromiumtricarbonyl bound iridacycle 2 (entries 1-4). Dichloromethane and 1,1',2,2'-tetrachloroethane led to good yields and were the most interesting solvents considering their polarity or high boiling point (entries 3-6). The use of toluene and tetrahydrofuran implied lower yields (entries 7-9). By changing the couteranion of the Ir(III) catalyst, we confirmed the less coordinating the anion was, the higher were the yields (entries 10-15). The activity increased according to the following order: Table 1. Screening of catalysts, additives, solvents, times and temperatures.

Entry

Cat. (mol%) Additive (mol%) Solvent Time (h) T (°C) Yield (%) [a] 1 2) [e] CH2Cl2 0.25 25 100 15 2 (1) NaBArF24 (2) CH2Cl2 0.25 25 [a] Measured by 1 H NMR after work-up. [b] TCE: 1,1',2,2'-tetrachloroethane. [c] THF: tetrahydrofuran. [d] % yield in 40 h. [e] NaBArF24: sodium tetrakis[(3,5-trifluoromethyl)phenyl]borate.

Table 2. Effects of catalyst and additive loadings.

Entry Cat. 1 (mol%) NaBArF24 (mol%)

[4a] (mmol.l -1 ) Time (h) Temperature (°C) Yield (%) [a] TON [b] 1 [a] Measured by 1 H NMR after work-up. [b] TON, turnover number (mol product / mol catalyst).

BF4 -< PF6 -< SbF6 -<< BArF24 -. Hence, sodium salts with specific anions were efficient to displace chlorides and afford an active catalyst (entries [11][12][13][14][15]. Indeed, the use of tetrakis [(3,5trifluoromethyl)phenyl]borate, e.g BArF24 anion, proved to be critical in drastically reducing reaction times from 20 to 0.25 hour, that is to say a hundred fold decrease. Interested by such an effect, we studied in detail the activity of our catalytic system in order to find the best loadings in catalyst 1 and NaBArF24 additive (Table 2). When the catalyst loading was reduced from 1 to 0.5 mol%, 2 hours were needed to complete the hydrosilylation of imine 4a at room temperature but catalyst activity, i.e. turnover number (TON), increased (entries 1-4). By operating at 0.1 mol% of 1, the yield in 5a was still high within 2 hours and a 24 hour reaction time allowed quantitative yields and TONs of 1000 (entries 5-10). When we decreased further the catalyst loading, we noticed a higher concentration of the reaction medium could decrease the yield of 10 to 20% as well as the catalyst activity (entries 1, 2, 5, 6, 8, 9). At 0.05 mol% loading, catalyst 1 remained quite active at room temperature affording 88% yield of 5a and 1760 TON within 24 hours (entries [11][12][13]. Finally, using a 0.01 mol% catalyst loading resulted in an important decrease of 5a yield at room temperature (entry 14). However, by increasing the reaction temperature to 40°C or even 60°C, high yields and up to 9000 TON could be achieved (entries 15, 16). To the best of our knowledge, species 1 is among the most active Ir(III) catalysts for hydrosilylation reactions. 7 Morever, by using 1.2 equivalents of reducing agent, iridacycle 1 appeared to be sustainable as compared to catalysts requiring 3 equivalents of silane. Various silane reagents could be used for the hydrosilylation of 4a (Table 3). Whereas triethoxysilane reagent afforded 5a in a poor yield, triethylsilane proved to be an efficient hydrosilylation agent for a moderate cost (entries 1-2). The use of expensive phenyl-, diphenyl-and triphenylsilane led also to good yields (entries 3-5). Sterically hindered 1,1,1,3,5,5,5heptamethyltrisiloxane afforded 5a in a poor yield and so did the electron-poor trichlorosilane (entries 6-7). Finally, among the inexpensive and green hydrosilylation reagents, polymethylhydroxysiloxane (PMHS) led to poor results but we were glad to reach a quantitative yield using tetramethyldisiloxane reagent (entries 8-9). We next studied the hydrosilylation of a series of ketimines. Iridacycle catalyst 1 was used with selected reaction conditions in order to perform fast and straightforward reductions (Table 4). The hydrosilylation of N-phenylethylideneaniline 4a and related para-substituted ketimines 4b-c could be performed readily and afforded the corresponding amines in high isolated yields (entries 1-3). We noticed the substrate reactivity could be influenced by ortho-substituents as hydrosilylation of brominated reagent 4d required much more time to be completed (entrie 4). However, ortho-alkylated substrate 4e reacted as well as ketimines 4a-c (entrie 5). Interestingly, halogenated substrates 4c-d were reduced without any dehalogenation. Whereas the hydrosilylation of triarylimine 4g was easily performed (entry 7), the reduction of N-phenylpropylideneaniline 4f required 2 hours to be completed (entry 6). Aliphatic imines which are challenging substrates 2-4 could be also reduced efficiently. Cyclic reagent 4h reacted easily (entry 8) and dialkylimines 4i-j required only one hour of reaction to be reduced (entries 9, 10). As already noticed with other catalysts, 8 hydrosilylation of Ncyclohexyl imines like 4k proved to be difficult, most likely because of reagent steric hindrance (entry 11). Indeed, the switch to N-butylimine 4l led in our case to a much more efficient reduction (entry 12). Table 3. Screening of silane reagent.

Entry

silane Cost [a] (€/mmol) Time (h)

Yield [b] (%) [c] 0.11 0.25 100 9 PMHS [d] 0.01 0.25 17 5 13 [a] according 4 and www.sigmaaldrich.com. [b] Measured by 1 H NMR after work-up. [c] 1,1,3,3-tetramethyldisiloxane. [d] PMHS: Polymethylhydroxysiloxane.

The reaction scope was further studied with the hydrosilylation of a series of aldimines. Iridacycle catalyst 1 and selected conditions were applied for fast and straightforward reactions (Table 5). The hydrosilylation of N-benzylidene aniline 6a and related ortho-and para-substituted aldimines 6b-g could be performed readily and afforded the corresponding amines in high isolated yields independently of the reagent substitution (entries 1-7). Indeed, halogenated substrates 6b,d,f were reduced without any dehalogenation. Regarding the hydrosilylation of N-alkylaldimines 6h and 6i, reactions were slower but good yields were obtained after 1 to 2 hours of reaction (entries 8-9). Other aryl-, heteroaryl-and alkylaldimines 6j-l could be reduced in high yields (entries 10-12). Finally, the hydrosilylation of conjugated aldimine 6m led to 7m1 as the major product through a 1,2-reduction of the imine function. The doubly reduced product 7m2 was isolated as a minor product arising from the additional reduction of the C=C bond (entry 13).

Table 4. Hydrosilylation of ketimines catalysed by cycloiridated complex 1.

Entry

Reagent Time (h) Yield [a] (isolated yield %) [b] 1 37) [c] 9 1 5i 100 ( 85) 10 1 5j 70 (68) 11 24 5k 34 (-) 12 2 5l 100 (88) [a] Measured by 1 H NMR after workup. [b] Isolated yield after flash chromatography. [c] Decomposition of product.

It was worth noting the use of an excess of triethylsilane allowed most of product 7m1 to be reduced into 7m2 within 18 hours (entry 14).

As a preliminary study regarding the possible active species involved in the catalytic process and the mechanism of such hydrosilylation reaction, 9,10 we performed an analysis by electrospray ionization mass spectroscopy on the reaction mixture issued from the hydrosilylation of ketimine 4b (Table 4). We could unambiguously characterized dechlorinated Ir(III) complex 1, i.e. cationic species 8, along with its BArF24 anion and the hydrolysed reaction product 5b (Figure 1 and the Supporting Information). Hence, though the reaction mixture was not quenched, the simple use of methanol for the solvation of the mass analysis sample led to the hydrolysis of the hydrosilylated reaction product and afforded amine 5b. In addition, the mass analysis conditions didn't allow any hydride complex like 3 to be observed, probably because of the Table 5. Hydrosilylation of aldimines catalysed by cycloiridated complex 1.

Entry

Reagent Time (h) Yield [a] (isolated yield %) [b] 0.25 0.25 0.25 0.5 0.5 0.25 0.25 100 (7m1 87 + 7m2 13) [c] 100 (7m1 20 + 7m2 80) [d] [a] Measured by 1 H NMR after workup. [b] Isolated yield after flash chromatography. [c] 7m1 is issued from the imine reduction; 7m2 is the doubly reduced product. [d] With 2.2 equivalents of triethylsilane. possible ionization of such species during the analysis or because of reaction with alcoholic solvents and air atmosphere.

7a
In order to compare in-situ generated and isolated catalysts, cationic iridacycle 8a was isolated. Whereas 8a could be characterized by elemental analysis and HRMS, 1 H and 13 C NMR spectra proved to suffer from strong dynamic effects. The latter were induced by the rapid switch of the pentamethylcyclopentadienyl fragment from endo to exo positions as respect to the 2-phenyl pyridine ligand. That phenomenon was already observed on related iridacycles and predicted by calculations by some of us. 5b Complex 8b could also be synthesized and its molecular structure confirmed by X-ray diffraction analysis, two iridacycle entities being bridged by a chloride and with a single BArF24 anion (Table 5 and Figure S1 in the Supporting Information). Iridacycles 8a-b were then tested on the hydrosilylation of N-phenylethylideneaniline 4a (Table 5). Though the in-situ prepared catalyst involving chlorinated iridacycle 1 and NaBArF24 afforded amine 5a quantitatively, moderate yields of 27% and 39% were observed using respectively catalyst 8a and 8b (entries 1-3). In addition, cationic acetonitrile iridacycles 9a-d were prepared using a related procedure 11 (see Table 5 and the Supporting Information). Coordination of the acetonitrile to the iridium was confirmed unambiguously at the liquid state by DOSY 1 H and 2 D-15 N-HMBC NMR experiments (see Figures S2 andS3 in the Supporting Information). Acetonitrile BArF24 complex 9a proved to catalyse the hydrosilylation of ketimine 4a in a fair 82% yield (Table 5, entry 4). However, complexes 9b-d bearing respectively SbF6, PF6 and BF4 anion led to much lower yields (Table 5, entries 5-8). Hence, we showed in-situ generated catalysts were more active as compared to isolated cationic iridacycles. In both cases, the catalyst activity and productivity were strongly depending on the counterion and noncoordinative BArF24 anion proved to be the most suitable. Interestingly, such anion effect was already observed for iridium catalysed hydrogenations of alkenes and imines 12a-b and the nature of the cation was previously shown to influence the catalytic activity of ruthenium catalysed hydrogenation of ketones. 12c Regarding the reaction mechanism and on the basis of the bibliography, two pathways may be considered for the hydrosilylation reaction catalysed by iridium (III) (see Schemes S1 and S2 in the Supporting Information). A first one is based on the Chalk-Harrod mechanism which implies an iridium activation of the silane reagent by oxidative addition. 9

Table 5. Hydrosilylation of imine 4a by catalysts 8a-b, 9a-d.

Entry

Cat. (mol%) Additive (mol%) Time (h) T (°C) Yield (%) [a] 1 1 (1) NaBArF24 (2) [b] 0 [a] Measured by 1 H NMR after work-up. [b] NaBArF24: sodium tetrakis[(3,5-trifluoromethyl)phenyl]borate.

A second reaction pathway consideres the activation of the substrate through a silane-iridium adduct whereas another silane molecule participates in the hydride transfer. 10 When complex 8a was allowed to react with a stoechiometric amount of triethylsilane, the 1 H NMR analysis of the resulting mixture showed several mono and dihydride species without any coordinated hydrogen according T1 measurements. 13 Unfortunately, additional 29 Si INEPT and DEPT45 NMR experiments didn't provide significant informations (see Figures S4-S7 in the Supporting Information). Hence, at this stage, further investigations of the reaction mechanism proved to be difficult.

Conclusions

The combined use of an Ir(III) metallacycle and NaBArF24 was successfully applied as catalyst for the hydrosilylation of various ketimines and aldimines. By using a slight excess of an affordable organosilane reagent, reactions proceeded rapidly and efficiently, at low catalyst loadings and in very mild reaction conditions. Several examples of cationic Ir(III) catalysts could be synthesized, characterized and tested for the hydrosilylation of imines. In-situ generated catalysts proved to be more active as compared to isolated ones and non-coordinative BArF24 anion was the most adapted in order to reach high catalytic activities. Considering the high efficiency of such cationic cyclometallated Ir(III) catalyst, further applications and developments can be reasonably foreseen. Other studies from our laboratories will be reported soon.

Experimental Section

General procedure for the catalysis In a glovebox, imine reagent (0.15 mmol, 1 eq.), selected iridium(III) catalyst (x mol%) and additive (2x mol%) were introduced in a Schlenk tube. Under nitrogen, solvent (2 mL) was added followed by silane reagent (0.18 mmol, 1.2 eq.). The reaction mixture was then heated at 25°C under stirring. In order to follow the progress of the reaction, aliquots (0.1 mL) were taken at defined times, filtered through Celite with a CH2Cl2 wash (3 mL), evaporated under vacuum and analysed by 1 H NMR. At the end of the reaction, solvent was evaporated under vacuum and the crude product was directly purified by flash chromatography or by preparative TLC.

Figure 1 .

 1 Figure 1. ESI(+)-MS analysis in methanol of the crude mixture resulting from the hydrosilylation of reagent 4b.

  Institut de Chimie de Strasbourg, UMR 7177, Université de Strasbourg, 4 rue Blaise Pascal, F-67000 Strasbourg, France.

	d UGSF CNRS, UMR 8576, Université Lille Nord de France, 59655
	Villeneuve d'Ascq Cedex (France).
	e ENSCL, UCCS-CCM-CCCF UMR 8181, (Chimie-C7) CS 90108, 59652
	Villeneuve d'Ascq Cedex, France.
	Electronic Supplementary Information (ESI) available: [experimental
	procedures, analytical data, NMR spectra, HRMS spectra]. See the web
	(free of charge).

c

Acknowledgements

The French Ministry of Research and Higher Education and Région Nord-Pas de Calais are acknowledged for a PhD fellowship (Y. C.). The University of Strasbourg is thanked for a PhD funding (W. I.) and the LABEX Chimie des Systèmes Complexes is thanked for a PhD funding (M. H). Support from CNRS is warmly acknowledged. Partial fundings from Région Nord-Pas de Calais and FEDER are also appreciated. Ms Charlotte Denneulin is thanked for her help with some experiments. Mrs C. Delabre and C. Méliet (UCCS) are warmly thanked for GC, GC-MS and elemental analyses. Lydia Brelot-Karmazin (Institut de Chimie Strasbourg) is thanked for X-ray analysis of compound 8b. Mrs N. Duhal and C. Lenglart (CUMA, Univ. of Lille) are thanked for HRMS analyses.

Notes and references


Dr Christophe Michon
email: christophe.michon@ensc-lille.fr

Marc-Antoine Abadie

Dr Florian Medina

Francine Agbossou-Niedercorn

Mononuclear gold

Keywords: hydroamination, alkenes, amines, gold, N-heterocycles

come

Along the past years, the usefulness of gold [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF] was pointed out on various C-C multiple bond substrates like alkynes, [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Wang | Examples on gold catalysed hydroamination of alkynes[END_REF] alkenes, [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF] allenes, [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Zhang | Examples of gold catalysed hydroamination of allenes[END_REF] and dienes [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Shapiro | Examples of gold catalysed hydroamination of dienes[END_REF] for both intra-and intermolecular hydroamination reactions as well as for diaminations. These results may be quite surprising because gold(I) can be considered as a challenging metal for asymmetric catalysis. [11] First, it is stressed gold(I) privileges a linear-dicoordination geometry [12] which positions the ligand and the activated substrate in a trans fashion restricting thus the asymmetric induction. Tri and tetracoordination of gold(I) proved to be less common. [12,13] Second, though the reaction mechanism appears to depend on the nature of the nucleophile, [14,15] gold(I) catalyzed reactions are considered to be outer-sphere in most cases, the metal coordinating the substrate pi-system and the nucleophile attacking from the back side which is far away from the chiral ligand. However, some gold amide complexes were recently shown to be unreactive for the amination of alkynes suggesting that the inner sphere mechanism for addition to pi-bonds may not be preferred with some strong nucleophiles. [16a] In addition, it was also recently demonstrated that pi-bonds do not insert into the related gold-carbon bonds. [16b] Regarding the mechanisms of acid and gold catalyzed hydroamination of alkenes and dienes, Ujaque et al. have performed interesting calculations. [17] Whereas the acid-catalyzed process was shown as concerted, the gold-catalyzed reaction was found to be stepwise for the nucleophile-assisted and counterion-assisted pathways. Indeed, a proton-transfer agent, i.e the nucleophile or the counterion, was crucial to lower the energy barrier for the proton transfer step. Toste, Goddard et al. studied through calculations and experiments the intramolecular aminoauration of unactivated alkenes providing evidence of an anti-addition mechanism for alkene aminoauration. [18] However, once prepared, such assumed catalytic intermediates didn't allow the hydroamination reaction to proceed leading only to the unreacted alkenes. The authors concluded that was due to the high energy barrier calculated for the protodeauration step. [18]. Finally, the reversibility of C-Nuc bond formation was evidenced and may play an important role in the stereoselectivity of gold(I) catalyzed hydrofunctionalization. [18,19] To date, 3 strategies have been developed in gold(I) catalyzed asymmetric catalysis and to some extent to hydroamination reactions. The first one implies the use of chiral phosphate anions like TRIP in combination with a gold(I) complex to create a tight ion pair. The resulting chiral binding pocket proved to be highly efficient for some asymmetric intramolecular hydroamination of allenes. [9ac, 9ad] The chiral phosphate counterion was shown to act as a ligand bonded to the gold species all along the hydroamination reaction. [20] The second concept implies the use of chiral dinuclear gold(I)-phosphine complexes. Due to the broad choice of bisphosphine ligands, this approach has been versatile for some inter-and intramolecular asymmetric hydroamination of allenes and alkenes. [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF][START_REF] Zhang | Examples of gold catalysed hydroamination of allenes[END_REF] Surprisingly, little has been reported on the role of the second gold atom and the importance of gold-gold interactions in the catalytic course and therefore in the asymmetric

induction. [8e]

The third strategy developed in gold(I) catalyzed asymmetric catalysis implies the use of mononuclear gold(I) complex relying mainly on chiral phosphoramidite and diaminocarbene ligands. Though that approach has been efficient for various asymmetric organic reactions, [6b, [START_REF] Muñoz | Phosphoramidite ligands in asymmetric gold catalysis[END_REF][START_REF] Corberan | Diaminocarbene ligands in asymmetric gold catalysis[END_REF]23] it has until recently not been applied to hydroamination reactions and remains promising. [8a, 9i, 11, 24] Though gold was shown to be active for intra-and inter-molecular hydroamination of alkenes, [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF] high temperatures and long reaction times are generally required. Hence, asymmetric gold catalyzed hydroamination of alkenes has been scarcely studied with, to the best of our knowledge, only three specific reports published so far. First, Widenhoefer et al. reported on gold(I) catalyzed intermolecular hydroamination of ethylene and 1alkenes with cyclic ureas with good yields and enantioselectivities. [8a] Interestingly, the authors studied their gold pre-catalysts by Xray diffraction analyses and identified a weak gold-π interaction between the Au atom and one of the ligand aromatic ring. Presumably, such interaction might also occur with the gold cationic catalyst and influence the course of the reaction.

According to the previous statements, the achievement of efficient and highly selective gold catalyzed hydroamination of alkenes is still a challenging field. Hence, following our interest on hydroamination and aza-Michael reactions [24,25] and considering the inadequacy of applications of chiral mononuclear gold(I) species to asymmetric hydroamination, [8a, 9f, 11, 24] we would like to report herein our own results on asymmetric intramolecular hydroamination of alkenes using mononuclear gold catalysts.

Results and discussion

First, we performed preliminary studies on the racemic intramolecular hydroamination of alkene with amine substrates 1a-i using Ph3PAuCl as pre-catalyst along with 5 mol% AgOTf (Table 1). Whereas electron rich amine substrates (entries 1-2) didn't afford any product, some electron poor substrates did. Indeed, N-alkenyl tosylate, benzylcarbamate and urea worked quite well (entries 3, 6, 10). The use of pre-catalyst IPrAuCl instead of Ph3PAuCl increased significantly the product yield provided the alkene was not functionalized by any substituent (entries [START_REF] Wang | Examples on gold catalysed hydroamination of alkynes[END_REF][START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF][START_REF] Zhang | Examples of gold catalysed hydroamination of allenes[END_REF]. Other N-alkenyl carboxamides proved to be non-reactive (entries 4, 5). Hence, a strong substituent effect appeared controlling the intramolecular hydroamination reaction.

A first study on asymmetric intramolecular hydroamination of alkenes using mononuclear gold catalysts was then achieved by screening various chiral ligands and complexes for the reaction of reagent 1f (Table 2 andFigure 1). A catalytic amount of AgOTf was used along with each gold complex in order to generate in situ the cationic active species. As already reported, N-alkenyl carbamates proved to be privileged substrates when gold(I) catalysts were used. [START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF] In addition, as highlighted in the introduction of the present work, the carbamate function was shown to participate in a low barrier mechanistic hydroamination pathway through carbamate tautomerization assisted by a triflate anion acting as a proton shuttle. [17] Table 1. Amine substitution effect on reactivity. Our screening started with mononuclear gold(I) complexes 3 and 5 based on diaminocarbene ligands [23] but poor conversions and enantioselectivities were obtained (Figure 1 and Table 2 entries 1,3). Gold(III) diaminocarbene complexes 4 and 6 [24] didn't afford any reaction (Scheme 1 and Table 2,entries 2,[START_REF] Crimmin | For examples of asymmetric intramolecular hydroamination with main-group metals[END_REF]. We next switched to mononuclear gold(I) complexes issued from phosphoramidite ligands (Figure 1, table 2). First, L1 based on BINOL and the Whitesell amine was used affording product 2f in good conversions and moderate enantioselectivities (Table 2, entries 5-7). The stereoselectivity as well as the catalyst activity proved to strongly depend on the ligand configuration. Indeed, the chirality of the BINOL scaffold and of the amine needed to be opposite to afford the best results, (R,S,S) and (S,R,R) being the configurations of choice. Next, as shown by the use of phosphoramidite ligands L2-L5, any change on the chiral amine fragment proved to have a negative effect on the enantioselectivity (table 2, entries 8-11). Moreover, the switch from ligand Monophos L5 to L6, that is to say the change from a BINOL scaffold to a partially hydrogenated one, led to a severe decrease of the conversion (entries 11-12). Hence, an increase of the ligand dihedral angle had a negative effect on the reactivity. In addition, the change to ligand L8 based on a biphenyl scaffold resulted in a decrease of the enantioselectivity (entrie 14). Such a trend was also observed when the ligand BINOL backbone was Table 2. Screening of mononuclear gold(I) and (III) catalysts.

Entry

Entry

Ligand (Lx) or complex (Y) By comparison to mononuclear gold(I) catalysts, dinuclear gold(I) catalysts didn't afford better conversions and enantioselectivities within the same experimental conditions (Table 3 andFigure 2). A maximum of 70% conversion was reached with biphep ligand L15 along with a poor enantioselectivity (Table 3, entry 1). Surprisingly, the change for L16 with a Segphos backbone led to complete loss of reactivity (entry 2). The use of trans-ligands L17 and L18 (entries 3-4) or P-chiral phosphines L19 and L20 (entries 5-6) afforded 2f in low conversions with no enantioselectivity.

Conversion a (%) Ee (%) b Configuration c 1 d (R,R)-3 5 4 (S) 2 e,f (R,R)-4 0 0 - 3 g (R,R)-5 9 5 (S) 4 (S,S)-6 0 0 - 5 (S,R,R)-L1 75 15 (R) 6 (S,S,S)-L1 <5 - - 7 (R,S,S)-L1 62 19 (S) 8 (S,R)-L2 70 5 (S) 9 (S,R,R)-L3 85 4 (R) 10 (R,R,R)-L4 >95 7 (S) 11 (R)-L5 90
We next checked the anion influence on the conversion and enantiomeric excess (Table 4). Among the various silver salts screened (entries 1-10), tetrafluoroborate and perchlorate anions appeared to be the most appropriate (entries 3, 6). Hence, in our reaction conditions, a strong ion-pairing implied a good conversion and a higher enantioselectivity for product 2f. Moreover, when no ligand and gold were used, silver tetrafluoroborate was not catalysing the hydroamination of 1a (entrie 4). Gold(I) catalyst based on L1 proved to be non-reactive when associated with chiral TRIP phosphate anion, even if stronger reaction conditions were used (entries 9-10).

To pursue our study on the influence of reaction parameters, various solvents were screened (Table 5). Except for tetrachloroethane and dioxane (entries 1, 7), reaction was not running in polar solvents (entries [START_REF] Zhang | Examples of gold catalysed hydroamination of allenes[END_REF][START_REF] Shapiro | Examples of gold catalysed hydroamination of dienes[END_REF][11][12]. Though reactions needed to be heated, apolar aromatic solvents afforded 2f in better conversions and enantiomeric excesses (entries [START_REF] Giardello | For examples of asymmetric intramolecular hydroaminations with lanthanide complexes[END_REF][START_REF] Gribkov | For examples of asymmetric intramolecular hydroamination with group 4 complexes, see[END_REF][START_REF] Crimmin | For examples of asymmetric intramolecular hydroamination with main-group metals[END_REF][START_REF] Lutete | For examples of asymmetric intramolecular hydroamination with late transition metals[END_REF][START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Sun | Examples of gold catalysed hydroamination of alkenes[END_REF]. On that basis, we confirmed tight ion pairs were critical to allow the reaction to proceed enantioselectively. Moreover, the reaction outcome remained unchanged upon removal of AgCl by filtration through Celite TM of the phosphoramidite mononuclear gold(I) cationic species prepared prior to the catalysis (entry 2). Hence, no "silver effect" was observed in our gold catalysed hydroamination reactions. [26, 26d] d Done with (S,R,R)-L1. e Same result using a catalyst purified by filtration over Celite TM .

f 1 equivalent of water was added as soon as the reaction was started.

In addition, because all experiments were carried out under nitrogen and strict conditions (see experimental part), our gold-triflate catalysts were unlikely to form any hydrate or hydroxide species along the hydroamination reactions.

[26c] We noticed the voluntary addition of 1 equivalent of water to the reaction mixture resulted in a conversion decrease without any change on the enantioselectivity (Table 5, entry 3).

Next, using selected experimental conditions, we reinvestigated the substituent effect on amine reactivity (Table 6). All reactions afforded good to high conversions in 20 h at 50 °C or below. However, mononuclear gold(I) catalyst based on phosphoramidite ligand L1 appeared to be sensitive to alkene substituents, because substrate 1g didn't react even when the reaction was heated at 100 °C (entry 4). Regarding the enantioselectivity, N-alkenyl CBz and urea were by far the most appropriate substrates with values respectively of 23 and 30% ee provided the reaction temperature was set to 50 °C and the solvent was toluene (entries 1- [START_REF] Gribkov | For examples of asymmetric intramolecular hydroamination with group 4 complexes, see[END_REF]13,14). The N-tosyl and Boc substrates reacted only in tetrachloroethane and led to no enantioselectivity (entries 9-12). The change of substituents at the C2 position of the alkenyl chain had even a more critical effect on the reactivity and stereochemical outcome of the hydroamination reaction. Indeed, conversions and enantioselectivities were very low for methyl and cyclohexyl substituents (entries [START_REF] Lutete | For examples of asymmetric intramolecular hydroamination with late transition metals[END_REF][START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF][START_REF] Wang | Examples on gold catalysed hydroamination of alkynes[END_REF]15). Such trend was also observed for substrate 1l with a 5-hexenyl chain (entry 8). phosphoramidite ligands related to L1 was foreseen. Based on the Whitesell amine and on BINOL, these ligands would carry bulky substituents at the 3,3' positions of the BINOL scaffold (see Figure 3 and Table 7). [27] As illustrated by some MM2 calculations, we were confident such phosphoramidite ligands would afford an enhanced steric hindrance around the gold(I) catalytic center and would lead to a better enantioselectivity (see supporting information). All the 3,3'-substituted phosphoramidite ligands of defined configurations (Figure 3) were prepared according reported procedures (see supporting information). Catalytic tests were performed on substrates 1f, 1i-k and 1n performing first the reactions with our best experimental conditions, in toluene at 50 °C for 20 h using AgClO4 (Table 7, Figure 3). The use of phosphoramidite ligand L1 confirmed the enhanced ee previously obtained (entry 1). We next studied the four stereoisomers of phosphoramidite ligand L11 bearing phenyl substituents. Conversions were almost quantitative but enantioselectivities highly depended on the ligand configuration, values being quite disparate (entries 2-5). With a 95% conversion and a 28% ee, ligand (S,R,R)-L11 afforded the best result (entry 4).

Lowering the temperature to 0 °C didn't improve 2f enantioselectivity and reduced significantly the conversion (entry 6). It was worth noting the chirality of L11 BINOL fragment was the key factor controlling the stereochemistry of the product 2f. Indeed, both were shown to display the same configuration. However, this trend could not be observed for other phosphoramidite ligands L12, L13 and L14 (entries 7-13). Ligand L12 bearing biphenyl substituents afforded product 2f in high 95% conversions and average 29% ee provided (R,S,S)-L12 was used (entries 7, 8). Phosphoramidite ligand L13 functionalized by anthracenyl substituents led also to high conversions (95%) but lower ee (16-18%) were obtained (entries 9, 10). Finally, phosphoramidite ligand L14 bearing benzhydryl substituents afforded 2f in good to high conversions (68-95%) along with low to average ee (2-32%), configuration (R,S,S) being the best (entries 11-13). Otherwise, modifications of the reagent substituents at the C2 position of the alkenyl chain lead to critical changes of the product enantiomeric excess. By offering a 40% ee of 2k in a 95% conversion, reagent 1k bearing a cyclohexyl group was reactive and quite selective when ligand (S,R,R)-L11 was used (entry 14). The ligand (R,S,S)-L14 led also to 2k in high conversion though a much lowered enantiomeric excess was reached (entry 15). This result outlined the importance of a match pair [28] between selected N-alkenyl reagents and catalysts to reach high ee.

Moreover, the steric hindrance at the C2 position of the substrate appeared also to be the key factor to control in order to avoid any Thorpe-Ingold effect [START_REF] Zulys | For examples of Thorpe-Ingold effect in hydroamination of alkenes[END_REF] which significantly lowered the conversion or even prevented the reaction (see entries [START_REF] Crimmin | For examples of asymmetric intramolecular hydroamination with main-group metals[END_REF]14,16). The N-alkenyl urea substrate 1i led to good conversions (95%) and average enantiomeric excesses (29-30%) when ligands (S,R,R)-L1 and (R,S,S)-L14 were used (entries 17, 18). However, the use of ligand (R,S,S)-L12 resulted in a complete loss of enantioselectivity for 2i (entry 19). Hence, no improvement of the asymmetric induction could be reached on substrate 1i using all the prepared substituted phosphoramidites. Finally, N-alkenyl urea reagent 1n bearing methyl substitutents at the C2 position afforded average yield and lower ee when ligand (R,S,S)-L14 was used (entry 20). By comparison to binuclear gold(I) catalysts, mononuclear gold(I) catalysts appeared slightly less active and selective for N-alkenyl urea substrates.

[8e]

Conclusion.

The gold catalyzed asymmetric intramolecular hydroamination of alkenes was studied screening a series of mononuclear gold (I) and (III) complexes in combination with silver salts. Among the various chiral monophosphine and diaminocarbene ligands tried, the best catalysts arose from mononuclear gold(I) complexes built on BINOL based phosphoramidite ligands. The latest were improved by addition of bulky substituents at the specific 3,3'-positions of the BINOL scaffold. The resulting gold (I) complexes were combined with selected silver salts to afford efficient catalysts for intramolecular hydroamination of alkenes at mild temperatures, with good conversions and average enantioselectivities. Hence, such phosphoramidite based mononuclear gold(I) catalysts appeared as valuable alternatives to binuclear gold(I) catalysts for the hydroamination of alkenes.

Experimental

General remarks.

All solvents were dried using standard methods and stored over molecular sieves (4 Å). Karl-Fischer titrations were performed to guarantee a water content below 5 ppm. All silver salts were weighted in a glovebox. All reactions were carried out under a dry nitrogen atmosphere and were repeated at least twice. Analytical thin layer chromatography (TLC) was performed on Merck pre-coated 0.20 mm silica gel Alugram Sil 60 G/UV254 plates.

Flash chromatography was carried out with Macherey silica gel (Kielselgel 60). 1 H (300 MHz), 13 C (75 MHz) and 31 P (121 MHz) spectra were acquired on a Bruker Avance spectrometer. Chemical shifts (δ) are reported downfield of Me4Si in ppm and coupling constants are expressed in Hz. 1,3,5-trimethoxybenzene and1,2,4,5-tetrachlorobenzene were used as internal standards when needed. Infrared spectra were recorded on a ThermoScientific-Nicolet 6700 spectrometer; the samples being prepared with KBr powder. HPLC was performed on an equipement Hitachi LaChromElite with a micropump, a Peltier oven and a DAD detector. HRMS-ESI analyses were performed at CUMA-Pharm. Dept.-University Lille Nord de-France. Elemental analyses were performed at UCCS, University Lille Nord de France. AuS(Me)2Cl was prepared following related procedures. [30] BARF and TRIP silver salts were prepared as reported. [31,32] Gold diaminocarbene complexes 3-6 were prepared according to reported procedures. [23,25] See supporting informations for other details.

General procedures.

General Procedure (Ligand screening). In a glovebox, AuS(Me)2Cl (0.01 mmol, 2.95 mg) and the corresponding ligand (0.01 mmol) are disposed in a first Schlenk flask. Dry dichloromethane (1 mL) is added under a nitrogen atmosphere and the resulting mixture is stirred at room temperature for 2 hours. Afterwards, the solvent is evaporated under vacuum and the resulting solid is dried 30 minutes before addition of AgOTf (0.009 mmol, 2.31 mg) in a glovebox. Dry tetrachloroethane (1 mL) is added under nitrogen and the resulting solution is stirred for 30 minutes before being transferred to a second Schlenk containing amino-alkene substrate 1f (0.18 mmol, 66.9 mg). After 20 hours of stirring at 30 °C, the solution is filtered through a pad of silica gel using dichloromethane as solvent. After evaporation of solvent under vacuum, the resulting oil is analyzed by 1 H NMR and HPLC.

General procedure (Silver salt screening). In a glovebox, AuS(Me)2Cl (0.01 mmol, 2.95 mg) and (R,S,S)-L1 (0.01 mmol, 5.40 mg) are disposed in a first Schlenk flask. Dry dichloromethane (1 mL) is then added under a nitrogen atmosphere and the resulting mixture is stirred for two hours at room temperature. Afterwards, the solvent is evaporated under vacuum and the resulting solid is dried 30 minutes before addition of the corresponding silver salt reagent AgX (0.009 mmol) in a glovebox. Dry toluene (1 mL) is added under nitrogen atmosphere and the resulting solution is stirred for 30 minutes before being transferred in a second Schlenk flask containing amino-alkene substrate 1f (0.18 mmol, 66.9 mg). After 20 hours under stirring at 50 °C, the solution is filtered through a pad of silica gel using dichloromethane as solvent. After evaporation of solvents under vacuum, the resulting oil is analyzed by 1 H NMR and HPLC.

General procedure (Solvent screening). In a glovebox, AuS(Me)2Cl (0.01 mmol, 2.95 mg) and (R,S,S)-L1 (0.01 mmol, 5.40 mg) were added to a Schlenk flask. Dry dichloromethane (1 mL) is then added under a nitrogen atmosphere and the resulting mixture is stirred for two hours at room temperature. Afterwards, the solvent is evaporated under vacuum and the resulting solid is dried 30 minutes before addition of AgOTf (0.009 mmol, 2.31 mg) in a glovebox. The corresponding dry solvent (1 mL) is added under a nitrogen atmosphere and the resulting solution is stirred for 30 minutes before being transferred in a second Schlenk flask containing amino-alkene substrate 1f (0.18 mmol, 66.9 mg). After 20 hours under stirring at 30 or 50 °C, the solution is filtered through a pad of silica gel using dichloromethane as solvent. After evaporation of solvents under vacuum, the resulting oil is analyzed by 1 H NMR and HPLC.

4.3.Physical and spectra data for compounds.

Benzyl (5-methyl-2,2-diphenylhex-4-en-1-yl)carbamate 1g

The corresponding primary amine was prepared according reported procedures. [33] That reagent (10 mmol, 2.51 g) was then allowed to react with benzylchloroformate (12 mmol, 2.05 g, 1.71 ml) in an ethanol / water (3:2) mixture (50 mL) at room temperature for 12 hours. The resulting mixture was extracted with diethylether and the organic phases washed with brine. After drying over MgSO4, the solvents were evaporated to lead to an oily residue which was further purified by flash chromatography on silica gel using a 4:1 mixture of petroleum ether and ethylacetate (Rf= 0.45). Compound was recovered as a colorless oil which crystallized slowly to afford a white solid (1. 65 g, 4.3 mmol, 43% yield). 1 H NMR (300 MHz, CDCl3): δ = 1.38 (s, 3H), 1.60 (s, 3H), 2.81 (d,J= 7.1 Hz,2H),3.93 (d,J= 6.0 Hz,2H),4.39 (m,1H),4.91 (m,1H),5.05 (s,2H),7.30 (m,6H),7.60 (m,9H). 3291,1706,1497,1403,1364,1069,1034,976,749,695.

Benzyl (2,2-diphenylhex-4-en-1-yl)carbamate 1h

The corresponding primary amine was prepared according reported procedures. [34] That reagent (10 mmol, 2.65 g) was then allowed to react with benzylchloroformate (12 mmol, 2.05 g, 1.71 ml) in an ethanol / water (3:2) mixture (50 mL) at room temperature for 12 hours. The resulting mixture was extracted with diethylether and the organic phases washed with brine. After drying over MgSO4, the solvents were evaporated to lead to an oily residue which was further purified by flash chromatography on silica gel using a 4:1 mixture of petroleum ether and ethylacetate (Rf= 0.55). Compound was recovered as a colorless oil which crystallized slowly to afford a white solid (1.84 g, 4.6 mmol, 45% yield). 1 H NMR (300 MHz, CDCl3, ratio of trans / cis isomers (4:1)): δ = 1.25 (d, J= 6.2 3433,1706,1495,1445,1362,1217,1051,968,776,700.

Benzyl 2-methyl-4,4-diphenylpyrrolidine-1-carboxylate 2f [8v]

Isolated after flash chromatography with petroleum ether/EtOAc (9:1), Rf = 0.5, as a colorless oil. 1 H NMR (300 MHz, CDCl3, ratio of rotamers (1:1)): δ = [1.29 (d, J = 6.0 Hz), 1.36 (d, J = 6 Hz), (1:1), 3H], [2.26 (dd, J = 9.6 Hz and J = 12.8 Hz), 2.31 (dd, J = 9.6 Hz and 12.4 Hz), (1:1), 1H], 2.80-2.86 (m, H), 3.65-3.81 (m, 2H), [4.58 (dd, J = 1.6 Hz and J = 11.6 Hz), 4.74 (dd, J = 2.0 Hz and J = 11.6 Hz), (1:1), 1H], [5.18 (d,J = 12.4 Hz), (1:1), 1H], [5.09 (d,J = 12.4 Hz),5.31 (d,J = 12.4 Hz), (1:1), 1H], 7.11-7.40 (m, 15H). 13 C NMR (75 MHz, CDCl3, ratio of rotamers (1:1)): δ = [20.4, 21.5 [137.3, 137.4, (1:1), C], [145.3, 145.5, (1:1), C], [146.0, 146.0, (1:1), C], [154.9, 155.7, (1:1), CO]. [α]D 20 = +35 (CH2Cl2, c 0.67 g / 100 mL, at 28% ee). Enantiopurity was determined by HPLC using Daicel Chiralpak TM IA column (at 25°C) with (90/10) n-hexane/iPrOH, 1.0 mL/min, λ = 200 nm.

2-Methyl-4,4-diphenyl-pyrrolidine-1-carboxylic acid phenylamide 2i [8u,8w]

Isolated after flash chromatography with petroleum ether/EtOAc (8:2), Rf = 0.37, as yellow solid.

1 H NMR (300 MHz, CDCl3) : δ = 7.44 (d,J = 7.7 Hz,2 H),[START_REF] Wang | Examples on gold catalysed hydroamination of alkynes[END_REF]12 H),7.01 (tt,J = 1.2,7.3 Hz, 1 H), [START_REF] Rudolph | Reviews on gold catalysis with C-C multiple bond substrates[END_REF].54 (br s, 1 H), 4.60 (d,J = 10.6 Hz,1 H),1 H),3.75 (d,J =10.8 Hz,1 H),2.84 (ddd,J = 1.4,6.3,12.3 Hz,1 H),2.35 (dd,J = 9.2,12.3 Hz, 1 H), 1.34 (d, 3 H). 13 C NMR (75 MHz, CDCl3): δ = 154. 2, 145.6, 145.2, 139.2, 128.9, 128.7, 128.5, 126.8, 126.6, 126.4, 122.9, 119.8, 56.2, 52.8, 52.1, 46.6, 20.8. [α]D 20 = +30 (CH2Cl2, c 0.26 g / 100 mL, at 29% ee). Enantiopurity was determined by HPLC using Daicel Chiralpak TM IA CSP (at 25°C) with (90/10) n-hexane/iPrOH, 1.0 mL/min, λ = 200 nm.

Benzyl 3-methyl-2-azaspiro[4.5]decane-2-carboxylate 2k [8v]

Isolated after flash chromatography with petroleum ether/EtOAc (9:1), Rf = 0.5, as a colorless oil. 1 H NMR (300 MHz, CDCl3, ratio of rotamers (1:1)): δ = 1.31 (m, 14H), 2.02 (ddd, J = 1.2, 7.5, 12.9 Hz, 1H), 3.00 (d, J = 10.8 Hz, 1H), 3.59 (bs, 1H), 3.90 (m, 1H), 5.11 (m, 2H), 7.29 (m, 5H). 13 C NMR (75 MHz, CDCl3, ratio of rotamers (3:2)): δ = 20.7 (major), 21.8 (minor), 22.9 (major), 23.8 (minor), 26.1, 34.7, 36.6, 40.9 (minor), 41.2 (major), 45.5 (major), 46.4 (minor), 51.9 (minor), 52.6 (major), 56.7, 66.3 (major), 66.6 (minor), 127.6, 127.7, 128.3, 137.1 (minor), 137.2 (major), 154.9 (major), 155.3 (minor). [α]D 20 = +17 (CH2Cl2, c 0.144 g / 100 mL, at 40% ee). Enantiopurity was determined by HPLC using Regis Whelk01 TM CSP (at 25°C) with (98/02) nhexane/iPrOH, 1.0 mL/min, λ = 200 nm.

2-Methyl-4,4-dimethyl-pyrrolidine-1-carboxylic acid phenylamide 2n

Isolated after flash chromatography with petroleum ether/EtOAc (8:2), Rf = 0.25, as a pale yellow solid.

1 H NMR (300 MHz, CDCl3) : δ = 7.39 (d; J = 7.5 Hz, 2 H), 7.27 (t, J = 7.4 Hz, 2 H), 7.00 (t, J = 7.7 Hz, 1 H), 6.15 (bs, 1H), 4.07 (m, 1H), 3.30 (d, J = 9.3 Hz, 1 H), 3.17 (d,J = 9.3 Hz,1 H),1.96 (dd,J = 7.1,5.4 Hz, 1 H), 1.42 (dd, J = 8.9, 3.9 Hz, 1 H), 1.35 (s, 3H), 1.33 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H). 13 C NMR (75 MHz, CDCl3): 21.3, 26.5, 26.8, 37.8, 48.4, 53.1, 59.6, 119.5, 122.8, 128.9, 139.3, 154.4. HMRS (ESI) m/z calcd for C14H21N2O : 233.16484 [MH+], found : 233.16367. IR (neat, cm -1 ): 3266, 2363, 1641, 1530, 1443, 1371, 1059, 1029, 750, 692. [α]D 20 = -6 (CH2Cl2, c 0.116 g / 100 mL, at 12% ee). Enantiopurity was determined by HPLC using Daicel Chiralpak TM IA CSP (at 25°C) with (90/10) n-hexane/iPrOH, 1.0 mL/min, λ = 200 nm.

δ =

  [8l] Second, Mikami et al. published on gold(I) catalyzed intramolecular hydroamination of N-alkenyl ureas at room temperature with good yields and average enantioselectivities. [8e] Strikingly, these two studies relied on chiral dinuclear gold(I)-phosphine based catalysts. Mikami et al. assumed such species highly accelerated intramolecular hydroamination of N-alkenyl ureas via proximal and bimetallic activation of alkene and urea. According to the authors, rigid dinuclear gold complexes having Au-Au interactions helped providing higher enantioselectivities. While the present work was nearing completion, a third report was published by Shi et al. about the preparation and the use of several monodentate axially-chiral N-heterocyclic carbene and phosphine ligands for mononuclear gold(I) catalyzed intramolecular hydroamination of N-alkenyl tosylates. Moderate yields and enantioselectivities were obtained at quite high temperatures and reaction times.

  substituted at the 3,3'-positions by two methyl substituents (L7) (entries 11,13). The spiro phosphoramidite ligand L9 and the taddol based ligand L10 afforded high conversions but low ee (entries 15-16).

Figure 1 .

 1 Figure 1. Ligands and complexes used for the screening of mononuclear gold(I) and (III) catalysts.

Figure 2 .

 2 Figure 2. Ligands used for the screening of binuclear gold(I) catalysts.

Figure 3 .

 3 Figure 3. Tuned phosphoramidite ligands used for the screening of mononuclear gold(I) catalyst.

  13 C NMR (75 MHz, CDCl3): δ = 17.7 (CH3), 26.0 (CH3), 35.8 (CH2), 47.9 (CH2), 50.7 (C), 66.7 (CH2), 119.1 (CH), 126.4 (CH), 128.1 (CH), 128.2 (CH), 128.5 (CH), 134.9 (C), 136.5 (C), 145.5 (C), 156.3 (CO). HMRS (ESI) m/z calcd for C27H29NO2Na : 422.20910 [MH+], found : 422.20835. IR (neat, cm -1 ):

Reagent 1a-h R 1 R 2 R 3 Product 7a-h conversion (%) a

  Measured by NMR 1 H. b Same result at 120 °C. c with 5 mol% IPrAuCl instead of Ph3PAuCl.

	1 b	1a	Bn	H	H	0 (2a)
	2 b	1b	CH2Cy	H	H	0 (2b)
	3	1c	Ts	H	H	>95 (2c)
	4	1d	Ac	H	H	0 (2d)
	5	1e	Bz	H	H	0 (2e)
	6	1f	CBz	H	H	50 (2f)
	7 c	1f	CBz	H	H	90 (2f)
	8 c	1g	CBz	Me	H	0 (2g)
	9 c	1h	CBz	Me	Me	0 (2h)
	10	1i	CONHPh	H	H	>95 (2i)

a

Table 3 .

 3 Screening of binuclear gold(I). Measured by 1 H NMR. b Measured by HPLC at 204 nm. c Determined from HPLC by comparison with previous work (see supporting information).

	Entry	Ligand (Lx)	Conversion a (%) Ee (%) b Configuration c
	1 d	(S)-L15	70	5	(R)
	2	(S)-L16	5	-	-
	3	(S)-L17	5	-	-
	4 d	(R,R)-L18	35	5	(S)
	5 e	(R,R)-L19	20	0	-
	6 e	(R,R)-L20	25	0	-
		a

d

Performed at 80 °C. e Performed with 2.5 mol% ligand and 5 mol% (Me)2SAuCl.

Table 4 .

 4 Silver salt screening.

	Entry	AgX	Conversion (%) a	Ee (%) b Configuration c
	1	AgOTf	75	23	(S)
	2	AgOTs	10	-	-
	3	AgBF4	>95	27	(S)
	4 d	AgBF4	0	-	-
	5	AgSbF6	>95	18	(S)
	6	AgClO4	>95	27	(S)
	7	AgNTf2	10	11	(S)
	8 e	AgBARF	<5	-	-
	9 e	(R)-AgTRIP	<5	-	-
	10 e	(S)-AgTRIP	<5	-	-

a Measured by 1 H NMR. b Measured by HPLC at 204 nm. c Determined from HPLC by comparison with previous work (see supporting information). d Performed without any ligand and gold source. e Done with (S,R,R)-L1.

Table 5 .

 5 Solvent screening.

	Entry	Solvent	T	Conversion
			(°C)	(%

) a Ee (%) b Configuration c

  Measured by 1 H NMR. b Measured by HPLC at 204 nm. Determined from HPLC by comparison with previous work (see supporting information).

	1 d	TCE	30	75	15	(S)
	2 e	Toluene	50	75	23	(S)
	3 f	Toluene	50	50	23	(S)
	4	Toluene	30	0	-	-
	5	Toluene	70	95	20	(S)
	6	Benzene	50	0	-	-
	7	1,4-dioxane	50	20	19	(S)
	8	m-xylene	50	<10	-	-
	9	THF	50	<5	-	-
	10	CH2Cl2	30	<5	-	-
	11	CF3CH2OH	50	<5	-	-
	12	CH3CN	50	<5	-	-
	a

c

Table 6 .

 6 Substituent effects on enantioselectivity. Measured by 1 H NMR. b Measured by HPLC at 204 nm. c Same result at 100 °C for 20 h. d Done at 50 °C for 87 h.

	Entry	Reagent N	R 1	R 2	R 3 Solvent	T (°C)	Conversion	Ee
									(%) a	(%) b
	1 c	1f	1	CBz	Ph	H	toluene	50	2f 75	23
	2	1f	1	CBz	Ph	H	TCE	30	2f 75	15
	3	1f	1	CBz	Ph	H	toluene	30	2f 75	15
	4 c	1g	1	CBz	Ph	Me toluene	100	2g 0	-
	5 d	1j	1	CBz	Me	H	TCE	50	2j 20	0
	6 e,f	1j	1	CBz	Me	H	toluene	50	2j 0	-
	7 e	1k	1	CBz	-(CH2)4-	H	toluene 50 (20 h)	2k 10	-
	8 c	1l	2	CBz	Ph	H	toluene	100	2l 0	-
	9 e,f	1c	1	Tos	Ph	H	toluene	50	2m 0	-
	10	1c	1	Tos	Ph	H	TCE	80	2m >95	0
	11 e,f	1m	1	Boc	Ph	H	toluene	50	2n 0	-
	12 e	1m	1	Boc	Ph	H	TCE	50	2n 23	1
	13 e	1i	1	CONHPh	Ph	H	toluene	50	2i >95	30 g
	14 e	1i	1	CONHPh	Ph	H	TCE	50	2i >95	18
	15 e,h	1n	1	CONHPh	Me	H	toluene	50	2o 75	12
	a

e

Performed with (S,R,R)-L1. f Same result at 80 or 100 °C. g Same result at 0 °C. h Done with AgClO4.

Table 7 .

 7 Screening of mononuclear gold(I) catalyst based on tuned phosphoramidite ligands. Measured by 1 H NMR. b Measured by HPLC at 204 nm. c Determined from HPLC by comparison with previous work (see supporting information). d Performed at 0 °C.

	Entry Reagent	R 1	R 2	Ligand	Conversion a	Ee	Configuration c
					(Lx)	(%)	(%) b
	1	1f	CBz	Ph	(S,R,R)-L1	2f >95	21	(R)
	2	1f	CBz	Ph	(S,S,S)-L11	2f >95	11	(S)
	3	1f	CBz	Ph	(R,R,R)-L11	2f >95	7	(R)
	4	1f	CBz	Ph	(S,R,R)-L11	2f >95	28	(S)
	5	1f	CBz	Ph	(R,S,S)-L11	2f >95	15	(R)
	6 d	1f	CBz	Ph	(R,S,S)-L11	2f 35	14	(R)
	7	1f	CBz	Ph	(R,S,S)-L12	2f >95	29	(R)
	8	1f	CBz	Ph	(R,R,R)-L12	2f >95	3	(S)
	9	1f	CBz	Ph	(R,R,R)-L13	2f >95	16	(R)
	10	1f	CBz	Ph	(R,S,S)-L13	2f >95	18	(R)
	11	1f	CBz	Ph	(S,S,S)-L14	2f >95	13	(S)
	12	1f	CBz	Ph	(S,R,R)-L14	2f >95	2	(S)
	13	1f	CBz	Ph	(R,S,S)-L14	2f 68	32	(S)
	14	1k	CBz	-(CH2)4-	(S,R,R)-L11	2k >95	40	-
	15	1k	CBz	-(CH2)4-	(R,S,S)-L14	2k >95	16	-
	16	1j	CBz	Me	(S,R,R)-L11	2j 0	-	--
	17 d	1i	CONHPh	Ph	(S,R,R)-L1	2i >95	30	-
	18	1i	CONHPh	Ph	(R,S,S)-L14	2i >95	29	-
	19	1i	CONHPh	Ph	(R,S,S)-L12	2i >95	1	-
	20	1n	CONHPh	Me	(R,S,S)-L14	2n 64	16	-
	a

  Hz, 3H) (cis), 1.46(d, J= 6.3 Hz, 3H) (trans), 2.70(d, J= 7.7 Hz, 2H) (trans), 2.78(d, J= 7.3 Hz, CH, trans), 126.5 (CH, trans), 126.6 (CH, cis), 127.3 (CH, cis), 128.1 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 129.4 (CH, trans), 136.5 (C, cis), 136.6 (C, trans), 145.3 (C, cis), 145.4 (C, trans), 156.2 (CO, trans), 156.3 (CO, cis). HMRS (ESI) m/z calcd for C26H28NO2 : 386.21146 [MH+], found : 386.02192. IR (neat, cm -1 ):

	2H) (cis), 3.83 (m, 2H), 4.12 (m, 1H) (cis), 4.26 (m, 1H) (trans), 4.96 (s, 3H), 5.28 (m, 1H) (trans), 5.41 (m, 1H)
	(cis), 6.95 (m, 6H), 7.17 (m, 9H). 13 C NMR (75 MHz, CDCl3): δ = 12.8 (CH3, cis), 18.0 (CH3, trans), 34.4 (CH2,
	cis), 40.7 (CH2, trans), 47.7 (CH2, trans), 48.0 (CH2, cis), 50.4 (C, trans+cis), 66.7 (CH2, trans+cis), 125.3 (CH,
	cis), 125.9 (

Acknowledgements

This work is first financed by the French National Research Agency with project ANR-09-BLAN-0032-02 (with a PhD fellowship to F.M). The French "Ministère de la Recherche et des Nouvelles Technologies" is gratefully acknowledged for a PhD fellowship to M.A.A. Support from CNRS is warmly acknowledged. Partial funding from Région Nord-Pas de Calais with "Projet Prim: Etat-Région" and "Fonds Européen de Développement Régional (FEDER)" is also appreciated. Mrs C. Méliet (UCCS) is thanked for elemental analyses on organic samples. Mrs C. Delabre (UCCS) is thanked for assistance with GC and HPLC analyses. Mrs N. Duhal (CUMA, Université Lille 2) is thanked for HRMS analyses. The authors are grateful to the reviewers for their helpful comments and advices.


Yann Corre

Christophe Werlé

Lydia Brelot-Karmazin

Jean-Pierre Djukic

Francine Agbossou-Niedercorn

Christophe Michon
email: christophe.michon@ensc-lille.fr

Regioselective hydrosilylation of terminal alkynes using pentamethylcyclopentadienyl iridium(III) metallacycle catalysts

Keywords: iridium, metallacycles, half-sandwich, hydrosilylation, alkynes

Pentamethylcyclopentadienyl iridium(III) metallacycles catalyse the hydrosilylation of alkynes using triethylsilane and no additive. The reactions proceed rapidly and efficiently at low catalyst loadings and under mild reaction conditions. If catalyses starting from terminal alkynes lead selectively to (Z)-alkenylsilanes in high yields, reactions are less efficient and selective starting from internal alkynes due to steric hindrance and the possible formation of isoquinolinium salts. Mass spectrometry highlights up to two consecutive 1,2-insertions of alkynes could take place into the catalyst iridium-carbon bond.

Introduction

Selective reduction of alkynes to alkenes is an important reaction in organic and polymer chemistry [1]. If semihydrogenation of alkynes has been successfully studied mainly by Lindlar reduction [2], the metal-catalysed hydrosilylation of alkynes is an interesting direct and atom-economic reaction which provides versatile alkenylsilanes [3]. However, the control of the reaction's stereoand regiochemistry remains challenging depending on several factors like the structure of the catalyst, the nature of reagents (e.g. alkyne and silanes) and reaction parameters (e.g. solvent and temperature). The hydrosilylation of terminal alkynes shall lead to -(E)and less frequent -(Z)-linear vinylsilanes, through respectively anti-Markovnikov syn-addition and anti-Markovnikov anti-addition [3n,v]. Futhermore, the synthesis of branched -vinyl silanes through Markovnikov addition is rare [3a,o,u].

The stereoselective synthesis and reactivity of metallacycles like iridium(III) complex 1 and chromiumtricarbonylbound iridacycle 2 have been studied by some of us for several years (Scheme 1) [4]. Complexes of type 2 were found to display novel catalytic properties for the conversion of terminal aromatic alkynes into racemic N-phenyl, 1-arylethylamines by tandem hydroamination and hydrosilylation/protodesilation reactions under mild "one pot" conditions (Scheme 2 a) [5]. Scheme 1.

Scheme 2.

The peculiar efficiency of such catalysts in promoting hydrosilylation was assigned to the intervention of iridium-hydrido intermediate 3 (Scheme 1) [4e, 5,6], a key species for the transfer of the hydritic H atom to the electrophilic imine substrate. Recently, we showed the combination of iridacycle 1 with sodium tetrakis (3,5-trifluoromethyl)phenyl]borate, NaBArF24, as an additive could catalyse the hydrosilylation of various ketimines and aldimines at low catalyst loadings and under mild reaction conditions (Scheme 2 b) [7].

Finally, other reports stated the efficiency of such iridacycles for other reactions [8] like hydrogenation [9] and transfer hydrogenation [10]. Regarding the reactivity of iridacycles with alkynes, we and others demonstrated complexes of type 4 could be obtained from a double 1,2-insertion of a terminal aromatic alkyne like phenylacetylene (Scheme 1) [5,11]. A recent report have revealed such 1,2-alkyne insertion could compete with a vinylidene rearrangement/1,1-insertion depending the nature of the iridium(III) metallacycle. Indeed, the reaction of fluorinated iridacycles with diphenylacetylene derivatives was shown to afford ninemembered metallacycle complexes of type 5 by way of a sequential vinylidene rearrangement, 1,1-insertion of the vinylidene ligand, and the 1,4-iridium migration to the Ar group (Scheme 1) [11a]. Considering our previous results on hydrosilylation of imines as well as on tandem hydroamination-hydrosilylation reactions, we investigated iridium(III) metallacycles as catalysts for the hydrosilylation of alkynes.

Results and discussion

Screening of reaction conditions (e.g. solvent, temperature, time) and catalysts was performed on the hydrosilylation of phenylacetylene 6a with triethylsilane (Table 1). Among the various solvents screened, tetrahydrofuran (THF) led to a moderate yield and a poor selectivity (entry 1). If the use of toluene and 1,4-dioxane afforded higher yields and a selectivity for (E)-product 8a (entries 2-4), acetonitrile allowed the reaction to proceed well in favor of the (Z)-product 7a provided the reaction temperature was kept at 80°C for 20 hours, yields being barely not improved at 100°C (entries 5,6). By comparison, chlorinated solvents had to be preferred considering reactions proceeded well at 40°C in favor of (Z)-product 7a. If dichloromethane led to an almost quantitative yield and a fair selectivity for 7a in 20 hours without the use of AgBF4 or NaBArF24 (entries 7, 8, 9), 1,1',2,2'-tetrachloroethane gave better results in only 2 hours (entry 10). Finally, alcohols could not be used because of their spontaneous reactivity with silanes. Hence, as already noticed in our previous studies [4,5,7], a strong polar solvent had to be preferred to activate the catalyst by dissociation of the Ir-Cl bond. Though the use of acetonitrile, a greener solvent, afforded fair yields and selectivities at 80°C and 20 hours of reaction, the non-coordinating dichloromethane and 1,1',2,2'tetrachloroethane led to better results in only few hours. In presence of our iridium(III) catalysts, nitrile solvents had another drawback due to their reactivity with silane reagents at high temperatures (entries 5,6) [5,7]. Within the most efficient and selective reaction conditions, catalyst 1 proved to be slightly more active than catalyst 2 (entries 10, 11). Yield and selectivity were also high using 1 mol% of catalyst 1 though the reaction time had to be extended to 3 hours (entries 12, 13). A preliminary kinetic study performed at 40°C and 1 mol% catalyst loading allowed us to determine a half-life of 1.6 hour (94 minutes) along with a turnover number (TON) of 50 and a turnover frequency (TOF) of 31. However, the data could not be fitted with any simple kinetic law. A further decrease of the catalyst loading to 0.1 mol% led to a much slower reaction with a slightly reduced yield and a significant increase of TON and TOF values (entry 14). However, decreasing the amount of catalyst to 0.01 mol% resulted in a very low yield and showed the catalyst limits (entry 15).

Table 1: hydrosilylation of phenylacetylene 6a -effects of solvent, temperature and time.

Entry

Cat.

(%)

Solvent T (°C) t (h) Yield (%) [a]
Selectivity [a] (Z) / (E) / (gem) TON [b] TOF [c] 1 [a] determined by 1 H NMR using 1,3,5-trimethoxybenzene as an internal reference. [b] Turnover number = mol of product/mol of catalyst. [c] Turnover frequency = mol of product/mol of catalyst/hour. [d] 1,4-dioxane. [e] reaction with 5 mol% of AgBF4 or NaBArF24, sodium tetrakis (3,5trifluoromethyl)phenyl]borate. [f] 10 mL solvent and 0.1 eq. of 1,3,5-trimethoxybenzene.

Various silane reagents [12] could be used for the hydrosilylation of phenylacetylene 6a (Table 2). Interestingly, reactions using affordable triethylsilane could be run in 2 hours and at 40°C affording (Z)-product in good yield, selectivity, TON and TOF (entry 1).

However, an increase of temperature and time resulted in the partial isomerization of (Z)product 7a into (E)-product 8a (entry 2). Within the same reaction conditions (e.g. 2 hours and 40°C), the reaction with triphenylsilane allowed also the selective hydrosilylation of 6a into (Z)-product 7a but in lower yield, TON and TOF. An increase of the reaction time and temperature led to the complete isomerization of 7a into (E)-product 8a (entries 3, 4). If sterically hindered 1,1,1,3,5,5,5-heptamethyltrisiloxane afforded selectively (Z)-product 7a at 60°C in 20 hours, a double reaction time led exclusively to the (E)-product 8a (entries 5, 6).

Otherwise, the use of triethoxysilane required a stronger heating and showed only the (E)product formation (entries 7, 8). Finally, inexpensive hydrosilylation reagents like tetramethyldisiloxane (TMDS) and polymethylhydroxysiloxane (PMHS) led to complex mixtures (entries 9, 10).

The reaction scope was then studied using the best silane reagent and reaction conditions (Table 3). The hydrosilylation of phenylacetylene 6a proceeded in fair yields at 40°C with high selectivities for (Z)-product 7a using triethyl-or triphenylsilane. If the use of triethylsilane led to the (Z)-alkenylsilane 7b from para-fluorinated reagent 6b in good yield and selectivity, triphenylsilane afforded only the (E)-product 8b in a modest yield. [b] Selectivity [b] (Z) / (E) / (gem) TON [c] TOF [d] 1 [e] unidentified products --10 PMHS 0.01 60 40 100 [e] --

[a] According to ref. 12 and www.sigmaaldrich.com. [b] determined by 1 H NMR using 1,3,5trimethoxybenzene as an internal reference. [c] Turnover number = mol of product/mol of catalyst. [d] Turnover frequency = mol of product/mol of catalyst/hour. [e] determined by GC and GC-MS.

The same tendency could be observed with para-methoxy and meta-methyl derivatives 6c and 6d with higher yields and reduced selectivities. By comparison, dimethylamino substrate 6e led to an opposite trend. Indeed, whereas the use of triethylsilane led to the (E)-alkenylsilane 8e in fair yield and selectivity, triphenylsilane afforded both (Z)-and (E)-products, 7e and 8e, in a good yield. We could also notice alkyl substrates 6f and 6g displayed poor reactivities. [a] determined by 1 H NMR using 1,3,5-trimethoxybenzene as an internal reference and by GC. [b] same result in 20h and 14% yield of (E)-selectivity if 80°C during 20h. [c] mixture of -(E)and -(Z)-products as respect to phenyl substituent. [d] in CH3CN. [e] mixture of and -(E)-products as respect to phenyl substituent.

Indeed, no reaction was observed with reagent 6g and the hydrosilylation of 6f proceeded only with the use of triethylsilane to lead to the (E)-product 8f in a low yield. Ethylpropiolate 6h displayed also a poor reactivity independently of the reaction time and temperature.

Finally, the hydrosilylation of internal alkynes 6i and 6j was investigated. If no reactions were observed while using triphenylsilane, modest to average yields were obtained with triethylsilane and the use of acetonitrile as a solvent resulted also in lower reactivities.

Reagent 6i led to both (Z)-and (E)-products, 7i and 8i, in a fair yield, and substrate 6j afforded exclusively (E)-products 8j in a modest yield.

As a preliminary study regarding the possible active species involved in the catalytic process of such alkyne hydrosilylation reactions [3s, 13, 14], we performed an analysis by electrospray ionization mass spectrometry on the reaction mixture obtained from the quantitative reaction of phenylacetylene 6a and complex 2 (Scheme 3, Figure 1).

Along this study, complex 2 had to be preferred to 1 because of its higher stability when analysed in methanol by mass spectrometry. Species 10 and 11 could be characterized unambiguously along with complexes 12 and 13a. Hence, if complex 10 resulted from a single 1,2-insertion of terminal alkyne 6a into the iridium-CAr bond of complex 2, species 11 was issued from a double 1,2-insertion of 6a and no vinylidene rearrangement/1,1-insertion could be evidenced. Our previous studies on tandem hydroamination and hydrosilylation/protodesilylation reactions demonstrated complex 11, once isolated, had no catalytic activity [5]. Hence, single and double 1,2-insertion of terminal alkyne 6a proved to compete, one leading to an active catalyst and the other to an inert species. Otherwise, complex 13a and complex 12 which had been previously linked to the catalyst resting state [7] were also observed.

Scheme 3.

Figure 1. ESI(+)-MS analysis in methanol of the crude mixture resulting from the catalytic hydrosilylation of reagent 6a.

Another analysis by electrospray ionization mass spectrometry was performed on the crude mixture resulting from the quantitative reaction of iridium(III) complex 2 with internal alkyne 6i (Scheme 4, Figure 2). The use of silver tetrafluoroborate was shown to be critical to stabilize the formed species. If complex 13b appeared as the first reaction intermediate linked to the catalyst resting state [7], the main species observed at m/w 656 was likely to be complex 14 and/or 15 as the result of a single 1,2-insertion of internal alkyne 6i into complex 2 iridium-CAr bond.

Scheme 4. Reaction of complex 2 with AgBF4 and phenylpropiolate. On the whole, if isoquinolinium salt 17 could be synthesised to the detriment of the catalytic hydrosilylation of alkynes, its characterization confirmed a single 1,2-insertion of internal alkyne into the catalyst iridium-CAr bond was likely to occur. However, we could not find evidences of a double 1,2-insertion of internal alkynes or of a vinylidene rearrangement/1,1insertion. Hence, the reaction mechanism shall start by the insertion of alkyne reagent into the iridium-CAr bond of the dechlorinated species A (Scheme 5). for the hydrosilylation of internal alkynes may be related to their implicit steric hindrance and the possible formation of isoquinolinium salts, the selective synthesis of (Z)-alkenylsilanes from terminal alkynes proved to depend on both electronic and steric parameters of the substrates as well as on the reaction temperature (Tables 2 and3, Scheme 5). According previous studies on iridium and rhodium catalysts [13c-e], (Z)-alkenylsilanes 7a-j shall be the kinetic products formed through anti-additions leading to intermediates D (Scheme 5).

Isomerization appeared privileged by high reaction temperature and time (Table 1). It may occur through  2 -vinyl species F or zwitterionic carbenes G to generate intermediates E which shall then react with iridium hydride 3 and afford (E)-alkenylsilanes 8a-j as the thermodynamic products (Scheme 5).

Conclusion

Pentamethylcyclopentadienyl iridium(III) metallacycles were shown to catalyse the hydrosilylation of alkynes using triethylsilane and no additive. The reactions could proceed rapidly and efficiently at low catalyst loading and under mild conditions. If the catalyses starting from terminal alkynes led selectively to (Z)-alkenylsilanes in high yields, reactions were less efficient and selective starting from internal alkynes due to steric hindrance and the possible formation of isoquinolinium salts. Isomerization from (Z)-to (E)-alkenylsilanes appeared privileged by high reaction temperature and time. A study by mass spectrometry showed single and double alkyne 1,2-insertion could take place into the catalyst iridiumcarbon bond but no vinylidene rearrangement/1,1-insertion could be evidenced. Whereas a single insertion was observed for internal alkynes, a double 1,2-insertion was possible using terminal alkynes but led to an inert catalytic species.

Experimental section

General data

All solvents were dried using standard methods. All commercial reagents were used as received unless otherwise stated. Unless stated, all reactions were carried out under a dry nitrogen atmosphere. 1 H (300 MHz) and 13 C (75 MHz) spectra were acquired on a Bruker Avance spectrometer. Chemical shifts are reported downfield of Me4Si in ppm and coupling constants are expressed in Hz. Gas chromatography analyses were done on GC Shimadzu

Figure 2 .

 2 Figure 2. ESI(+)-MS analysis in methanol of the crude mixture resulting from the stoechiometric hydrosilylation of reagent 6i.

Figure 3 .

 3 Figure 3. Ortep plot of 17 in the solid state. Thermal ellipsoids are drawn at a 50% probability level. Hydrogen atoms are omitted for clarity. CCDC 1473938 [16].

Scheme 5 .

 5 Scheme 5. Proposed reaction mechanism.

Table 2 :

 2 hydrosilylation of phenylacetylene 6a -effects of silanes and temperature.

	Entry	Silane	Cost [a]	T	t	Yield
			(€/mmol)	(°C)	(h)	(%)

Table 3 :

 3 substrate scope.

	Entry		R1	R2	Silane	T	t	Yield	Selectivity
						(°C)	(h)	(%) [a]	7a-j / 8a-j / 9a-j
									(Z) / (E) / (gem)
	1	6a	Ph	H	Et3SiH	40	2	91	92	6	2
	2	6a	Ph	H	Ph3SiH 40	2	80	100	0	0
	3	6b	p-F-(C6H4)	H	Et3SiH	40	2	74	93	5	2
	4	6b	p-F-(C6H4)	H	Ph3SiH 40	2	22	0	100 0
	5	6c	p-MeO-(C6H4)	H	Et3SiH	40	2	86	69	30	1
	6	6c	p-MeO-(C6H4)	H	Ph3SiH 40	2	85	0	98	2
	7	6d	m-Me-(C6H4)	H	Et3SiH	40	2	93	93	5	2
	8	6d	m-Me-(C6H4)	H	Ph3SiH 40	2	100	0	95	5
	9	6 e	p-NMe2-(C6H4)	H	Et3SiH	40	2	81	19	81	0
	10	6 e	p-NMe2-(C6H4)	H	Ph3SiH 40	12	86	55	41	4
	11	6f	n-pentyl	H	Et3SiH	40	2	33	0	100 0
	12	6f	n-pentyl	H	Ph3SiH 40	2	0	-	-	-
	13	6g	cyclopropyl	H	Et3SiH	40	2	0	-	-	-
	14	6g	cyclopropyl	H	Ph3SiH 40	2	0	-	-	-
	15	6h	CO2Et	H	Et3SiH	40	2	13 [b]	100	0	0
	16	6h	CO2Et	H	Ph3SiH 40	2	0	-	-	-
	17	6i	Ph	CO2Et Et3SiH	80	20	62 [c]	42	58	-
	18	6i [d]	Ph	CO2Et Et3SiH	80	20	6	100	0	0
	19	6i	Ph	CO2Et Ph3SiH 80	20	0	-	-	-
	20	6j	Ph	Me	Et3SiH	80	20	35 [e]	0	100 0
	21	6j [d]	Ph	Me	Et3SiH	80	20	8	50	50	0
	22	6j	Ph	Me	Ph3SiH 80	20	0	-	-	-

Acknowledgements

The Université Lille 1 and Région Nord-Pas de Calais are acknowledged for a PhD fellowship (Y. C.). The Agence Nationale de la Recherche (project ANR-10-BLAN-0736 administered by the University of Strasbourg) is thanked for a PhD funding (C. W.). The CNRS, the Chevreul Institute (FR 2638), the Ministère de l'Enseignement Supérieur et de la Recherche, the Région Nord -Pas de Calais and the FEDER are acknowledged for supporting and funding partially this work. Mrs C. Delabre (UCCS) is thanked for GC and GC-MS analyses. Mrs N. Duhal and C. Lenglart (CUMA, Lille University) are thanked for HRMS analyses.

2010+ with FID detectors using Supelco SPB-5 column (30 m, 0.25 mm, 0.25 μm) and with nitrogen as gas carrier. GC-MS analyses were performed on a Shimadzu QP2010+ (EI mode) using Supelco column SLBTM-5ms (30 m, 0.25 mm, 0.25 μm). Analytical thin layer chromatography (TLC) was performed on Merck pre-coated 0.20 mm silica gel Alugram Sil 60 G/UV254 plates. Flash chromatography was carried out with Macherey silica gel (Kielselgel 60). MS-ESI and HRMS-ESI analyses were performed at CUMA-University Lille Nord de-France.

General procedure for the catalysis

Under nitrogen, alkyne reagent (0.15 mmol, 1 eq.) and selected iridium(III) catalyst (x mol%) were introduced in a Schlenk tube along with internal reference 1,3,5trimethoxybenzene (1 eq.). TCE solvent (2 mL) was added followed by silane reagent