Mireia Rodriguez-Zubiri

Stéphane Anguille

Jean-Jacques Brunet

Jean-Claude Daran

Pt-Catalysed Intermolecular Hydroamination of Non-Activated Olefins Using a Novel Family of Catalysts: Arbuzov-Type Phosphorus Metal Complexes †

Keywords: Platinum, phosphorus ligands, Arbuzov, hydroamination, halides

The catalytic system «PtBr 2 (0.3 mol%)/2P(OR) 3 /10nBu 4 PBr» (R = alkyl) discovered recently in our group, allows good to excellent catalytic activities for the intermolecular hydroamination of ethylene and higher α-olefins (1-hexene) with aniline type amines to give the expected N-ethyl-(1) and N,N-diethyl-anilines (2) along with 2-methyl-quinoline (3). A poisoning effect of alkyl and aromatic phosphines has been observed. This effect could be minimized using small amounts of molecular iodide which reacts with phosphorus ligands to form non-coordinating well-described ionic species. Interestingly, beneficial effects of added P(OR) 3 (R = alkyl) have been pointed out and further investigated. In this way, a new potential family of Arbuzov-type phosphorus-metal complexes has been suggested to be responsible for good catalytic activities found when using P(OR) 3 alkyl phosphites rather than PR 3 (R = alkyl, aromatic) and P(OPh) 3 co-catalysts.

INTRODUCTION

Catalytic hydroamination of alkenes is a practical, economical and sustainable alternative for the preparation of amines and its derivatives. This atom-economic process allows the addition of an N-H bond over an unsaturated carbon-carbon bond to yield a large variety of alkylated amines, very important chemicals in industry and everyday's chemistry. Intense efforts have been devoted to the study and optimisation of this reaction in the past 30 years [1]. Nowadays, the hydroamination reaction could be classified in three categories: the intramolecular hydroamination of olefins [START_REF] Hong | For selected reports on intramolecular hydroamination see: a)[END_REF], the intermolecular hydroamination of activated olefins and alkynes [3] and, the most challenging, the intermolecular hydroamination of nonactivated olefins [1][START_REF] Hong | For selected reports on intramolecular hydroamination see: a)[END_REF][3][4]. The latter has known important improvements with the recently discovered Pt and Rh-based catalytic systems [5]. The Pt-based catalysts have shown to be very efficient systems for the intermolecular hydroamination of ethylene (Scheme 1) and 1-hexene (Scheme 2) affording the Markovnikov product with an unprecedented regioselectivity (95%).

Scheme 1. Intermolecular Pt-catalysed hydroamination of ethylene. This Pt-based system results from the association of PtBr 2 with tetrabutylphosphonium salts. Scheme 2. Intermolecular Pt-catalysed hydroamination of 1-hexene.

It is also noteworthy that this system proved to be as efficient when reactions were performed under aerobic conditions [5b,5c]. The discovery of an original Rh III -based system, RhCl 3 •3H 2 O/2PR 3 /65nBu 4 PI/2I 2 , which consists in the association of simple Rh III salts with phosphonium salts and PR 3 ligands (PR 3 = para substituted triarylphosphines, P(OMe)Ph 2 , BINAP, dppe) (Scheme 3) was also described recently [5h]. The latter proved to allow the highest catalytic activity for the intermolecular hydroamination of ethylene, but also 1-butene and 1-hexene, with aniline type amines (0.3 mol% catalytic precursor) to give the expected N-ethyl-(1) and N,N-diethyl-anilines (2) along with 2-methyl-quinoline (3) (Scheme 3). This system is particularly efficient in the presence of 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, BINAP (CE = 460, CE = Catalytic Efficiency = TON (1) +2TON ( 2) +2TON (3) ) and tri- (p-tolyl)phosphine (CE = 528). Good to excellent activities were also found combining the Wilkinson's catalysts (Rh I complexes) with nBu 4 PI and I 2 . Interestingly, the simple association of PPh 3 and I 2 was shown to be an extremely efficient "in situ generated" source of I -promoters able to substitute preformed nBu 4 PI. It is important to note that the performance of this Rh-based system depends upon the combination of both PR 3 /I -promoters [5g,5h]. Scheme 3. Rh-catalysed hydroamination of ethylene.

For many years now, the scientific community has brought special attention to the use of phosphorus ligands in catalysis. This vast family of ligands has extensively been reported in the literature as efficient additives for a large amount of homogeneous catalytic processes, including the hydroamination of olefins, offering a valuable source of chirality [6][7][8][9][10][11][12][13][14][15]. In this area, the past decade has known an important growth in the use of phosphorus ligands for the intermolecular hydroamination of activated alkenes [6] such as styrenes [7], norbornenes [8], dienes [9], allenes [10], and of alkynes [11], as well as for the intramolecular hydroamination reaction [12][13][14]. Nevertheless, studies on the association of a catalyst precursor with a phosphine ligand for the intermolecular hydroamination of non-activated alkenes are very scarce [15]. Pioneering this area, Diamond and co-workers explored, for the first time in 1979, the hydroamination of ethylene by aniline using RhCl 3 /2PPh 3 and PdCl 2 /2PPh 3 systems, although low activities were afforded [15d]. After a long silence, in 2001 Keim et al. used a variety of neutral and cationic phosphine and phosphite containing ruthenium complexes to study the hydroamination of ethylene by piperidine achieving good selectivities but low yields [15c]. Interestingly, the hydroamination of 1-hexene combining a copper halide (5 mol%) and a silver salt (5-10 mol%) in the presence of dppe, reported by Michon and co-workers, allowed up to 90% yield although branched isomers were formed in a ratio 4/6 [15b]. Recently, Widenhoefer and co-workers successfully hydroaminated 1alkenes with very low basicity amines (cyclic ureas) in the presence of chiral AuClPR 3 (PR 3 = P(tBu) 2 o-biphenyl and 2-di-tert-butylphosphino-1,1'-binaphthyl) complexes affording high yields with up to 78% ee. To the best of our knowledge, this is the only existing report on transition-metal catalysed enantiomeric intermolecular hydroamination of non-activated olefins, showing the urgency to further develop this significant area of broad interest for the scientific community [15a]. The development of stereoselective catalysts for the synthesis of chiral alkylamines could be a useful and practical tool for synthetic chemists and industry, and thus, an important scientific and economic challenge, especially when targeting the intermolecular hydroamination of non-activated olefins.

Herein we report the study on the Pt-catalysed intermolecular hydroamination of ethylene and 1-hexene by aniline in the presence of a variety of phosphorus ligands and a potential explanation on the recovery of the catalytic activity upon the addition of I 2 . Unexpectedly, the inhibiting effect shown by aryl and alkyl phosphines disappears in the presence of alkyl phosphites. A new potential family of Arbuzov-type phosphorus-metal complexes has been appointed to be responsible for good catalytic activities obtained when using P(OR) 3 alkyl phosphites rather than other phosphorus (III) ligands. This study could provide a significant insight on compatible ligands as potential chiral vectors. Furthermore, we have found out an important difference in the coordination behaviour of PtBr 2 when reacting with aryl, aryloxy, and alkoxy phosphines leading to a new X-ray structure of a phosphine containing Pt II complex.

EXPERIMENTAL SECTION

Instrumentation

GC analyses were performed on a Hewlett-Packard HP 4890 (FID) chromatograph (HP 3395 integrator) equipped with a 30 m HP1 capillary column. GC-MS analyses were performed on a Hewlett-Packard HP 6890 apparatus equipped with a HP 5973 M ion detector. NMR analyses were performed on Bruker AM 250 and 400 machines. J values are given in Hz. Catalytic experiments were conducted in a 100 mL stainless steel thermoregulated (electric oven) autoclave with a glass liner and a magnetic stirring bar.

Methods and Materials

Potassium bromide (Aldrich, +99%), 1-iodobutane (Alfa Aesar, 99%), tri-n-butylphosphine (Acros Organics, 95%), triphenylphosphine (Aldrich, 99%), triphenylphosphite (Acros, 99%), trimethylphosphite (Strem, 97%), methyldiphenylphosphinite (Acros, 99%), tris((4trifluoromethyl)phenyl)phosphine (Avocado, 98%), rac-2,2'-bis(diphenylphosphino)-1,1'binaphthyl (Aldrich, 97%), 1,3-bis(diphenylphosphino)propane (Aldrich, 97%), 1,10phenantroline (Aldrich, +99%), potassium tetrachloroplatinate(II) (Aldrich, 98%) and platinum(II) bromide (Strem Chemicals, 98%) were used as received. Tetra-nbutylphosphonium bromide (Aldrich, 98%) was stored in a desiccator under vacuum prior to use. Molecular iodine was purchased from Acros Organics. Aniline (Acros Organics, 99% for analysis ACS), N-ethylaniline (Acros Organics, 98%), N,Ndi-n-butylaniline (Aldrich, 97%), 1-hexene (Aldrich, 97%), tri-t-butylphosphine (Aldrich, 98%), trimethylphosphine (Aldrich, 97%) tris(dimethylamino)phosphine (Aldrich, 97%) and triethylphosphite (Aldrich, 98%) were distilled before use and stored under argon. Ethylene (N25, +99.5%) was purchased from Air Liquide. Water was deionised and degassed. All other solvents were of HPLC grade and were degassed prior to use.

cis-Dibromobis(trimethylphosphite)platinum(II)

[16a] and cis-Dibromobis(triphenylphosphine)platinum(II) [16b] were prepared according to established methods. Tetra-n-butylphosphonium iodide was prepared from nBu 3 P and nBuI (see below), stored under argon, in a freezer, and protected from light. Tetrabutylphosphonium cis-dibromo(dimethylphosphonato)(trimethylphosphite)platinum(II), 6, was prepared from cis-dibromobis(trimethylphosphite)platinum(II) and tetra-nbutylphosphonium bromide (see below).

Preparation of tetra(n-butyl)phosphonium iodide

Tri(n-butyl)phosphine (38 mL, 0.15 mol) was slowly added to 1-iodobutane (40 mL, 0.35 mol) under argon. The mixture was stirred for 1h at RT and then at 100°C for 20h. After cooling, the resulting precipitate was washed with diethylether (4x50 mL) until a white solid was obtained. Evaporation of residual solvent under vacuum overnight afforded pure nBu 4 PI as a white powder (55.6 g, 96%), mp = 95-96°C. Anal. Found: C, 49.75; H, 9.57. Calc. for C 16 H 36 IP: C, 49.74; H, 9.39. δ H (250 MHz, acetone-d 6 ) 0.96 (3H, t, 3 J 3), 1.55 (2H, m), 1.70 (2H, m), 2.54 (2H, m); δ P (250 MHz, acetone-d 6 ) 33.52 (s).

Preparation of cis-[PtBr 2 (P(OCH 3 ) 3 )(OP(OCH 3 ) 2 )](nBu 4 P), 6

To a vigorously stirred solution of cis-PtBr 2 (P(OMe) 3 ) 2 (243 mg, 0.404 mmol) in acetonitrile (2 mL) placed in to a round-bottom flask at 70°C (oil bath), was dropwise added another solution of nBu 4 PBr (137 mg, 0.404 mmol) in acetonitrile (2 mL). The reaction mixture was stirred for further 2h until completion. Solvent removal afforded cis-[PtBr 2 (P A (OCH 3 ) 3 )(OP B (OCH 3 ) 2 )](nBu 4 P) quantitatively (340 mg). Anal. Found: C, 29.78; H, 6.25. Calc. for C 21 H 51 O 6 P 3 Br 2 Pt: C, 29.76; H, 6.07. δ H (400 MHz, acetone-d 6 ) 0.97 (3H, t, 3 J 3, CH 3 from nBu 4 P) 1.55 (2H, m, CH 2 from nBu 4 P) 1.7 (2H, m, CH 2 from nBu 4 P) 2.54 (2H, m, CH 2 from nBu 4 P) 3.5 (6H, d, 3 J PH 4.9, P B -OCH 3 ); 3.77 (9H, d, 3 J PH 4.9, P A -OCH 3 ); δ P (400 MHz, acetone-d 6 ) 31.06 (m, 1 J PB-Pt 4962, P B ) 33.34 (m, + PBu 4 ) 82.40 (m, 1 J PA-Pt 6631, P A ).

Catalytic reactions

2.5.1. Hydroamination of ethylene: typical procedure. The autoclave was charged with PtBr 2 (46.2 mg, 0.13 mmol), PPh 3 (2 equiv/Pt, 68.0 mg, 0.26 mmol) and nBu 4 PBr (10 equiv/Pt, 441 mg, 1.3 mmol), closed and submitted to several argonvacuum cycles. Distilled and degassed aniline (4.1 mL, 45 mmol) was then syringed into the autoclave. The ethylene pipe was connected to the autoclave, purged, and the ethylene pressure was adjusted to 25 bars at RT (ca. 100 mmol). The temperature was then raised to 150°C. After 10h, the autoclave was allowed to cool to room temperature and slowly vented in a fume cupboard. The reaction mixture was poured into 120 mL of diethylether, stirred for 2h, and then filtered. The external standard (N,N-di(n-butyl)aniline, ca. 0.15 g) was added to the collected ethereal phases and the solution analysed by GC and GC-MS.

Hydroamination of 1-hexene: typical procedure.

The autoclave was charged with PtBr 2 (46.2 mg, 0.13 mmol), and nBu 4 PBr (65 equiv/Pt, 2.88 g, 8.45 mmol), closed and submitted to several argon-vacuum cycles. Distilled and degassed aniline (4.1 mL, 45 mmol) along with P(OMe) 3 (1 equiv/Pt, 15.8 mg, 0.13 mmol) and 1hexene (11.3 mL, 91 mmol) were then syringed sequentially into the autoclave. The temperature was then raised to 150°C. After 10h, the autoclave was allowed to cool down to room temperature and slowly vented in a fume cupboard. The reaction mixture was then poured into 120 mL of diethylether, and stirred for 2h, and then filtered. The external standard (N,N-di(n-butyl)aniline, ca. 0.15 g) was added to the collected ethereal phases and the solution analyzed by GC and GC-MS.

Taking into account the liquid nature of both substrates (aniline and 1-hexene), the hydroamination of 1-hexene by aniline could analogously be carried out using adapted Schlenk glass-ware as follows: A 35 mL Ace Pressure Tube was charged with PtBr 2 (46.2 mg, 0.13 mmol) and nBu 4 PBr (65 equiv/Pt, 2.88 g, 8.45 mmol). Distilled and degassed aniline (4.1 mL, 45 mmol) along with P(OMe) 3 (1 equiv/Pt, 15.8 mg, 0.13 mmol) and 1-hexene (11.3 mL, 91 mmol) were then syringed sequentially into the Ace Pressure Tube. The temperature was then raised to 150°C. After 10h, the reaction mixture was allowed to cool down to room temperature and poured into 120 mL of diethylether. The external standard (N,N-di(nbutyl)aniline, ca. 0.15 g) was added to the collected ethereal phases and the solution analysed by GC and GC-MS.

Study on the coordination chemistry of the PtBr 2 /nBu 4 PBr/PR 3 catalytic system.

Typical procedure: PtBr 2 (0.13 mmol, 46.2 mg), nBu 4 PBr (65 equiv/Pt, 45 mmol, 2.87 g) and PPh 3 (2 equiv/Pt, 0.26 mmol, 68.0 mg) were weighted and placed in to a 25 mL round-bottom flask. o-Dichlorobenzene (5 mL) was added and a reflux condenser adapted to the system. The stirred reaction mixture was heated to 150ºC in an oil bath. After 10h, the reaction mixture was allowed to cool down to room temperature, then the solvent was removed under reduced pressure and the crude analysed by 31 P NMR (250 MHz, CDCl 3 , see SI). When PPh 3 and P(OPh) 3 were used, crystals suitable for X-ray diffraction were grown while cooling down the reaction mixture to room temperature (see SI).

X-ray Structure Determination.

Single crystals of 7, 8 and 9 were mounted under inert perfluoropolyether at the tip of glass fibre and cooled in the cryostream of the Oxford-Diffraction XCALIBUR CCD diffractometer. Data were collected using the monochromatic MoK radiation (= 0.71073). The structures were solved by direct methods (SIR97) [START_REF] Altomare | SIR97 a program for automatic solution of crystal structures by direct methods[END_REF] and refined by least-squares procedures on F2 using SHELXL-97 [START_REF] Sheldrick | SHELXL97. Program for crystal structure refinement[END_REF]. All H atoms attached to carbon were introduced in calculation in idealised positions and treated as riding models. The drawing of the molecules was realised with the help of ORTEP32 [START_REF] Farrugia | ORTEP3 for Windows[END_REF]. Crystal data and refinement parameters are shown in Table 3-5 from the SI. Crystallographic data (excluding structure factors) have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC 878731 -878733.

Copies of the data can be obtained free of charge on application to the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: (+44) 1223-336-033; e-mail: deposit@ccdc.cam.ac.uk).

RESULTS AND DISCUSSION

Hydroamination of ethylene by aniline in the presence of phosphorus ligands

Taken the urgency to develop new catalytic systems for the intermolecular hydroamination of non-activated olefins and the consolidated reputation of phosphorus ligands to accomplish this type of task for a large range of catalytic reactions (see introduction), we were prompted to investigate the effect of several classical and simple phosphorus ligands in the intermolecular hydroamination of ethylene by aniline as model reaction (Scheme 4). Aiming to improve the already efficient stable low-loading (0.3 mol%) "one-pot" ready-to-use PtBr 2 /nBu 4 PBr system recently discovered in our team [5b,5c], we carried some studies to identify a compatible class of ligand able to afford good catalytic activities and capable of playing the role of a potential chiral vector. Scheme 4. Pt-catalysed intermolecular hydroamination of ethylene by aniline in the presence of PR 3

In this work, we were led to consider the TON (mol of product formed by mol of catalyst) in order to evaluate the efficiency of the catalyst. In a previous report, it was briefly pointed out that the catalytic efficiency for the hydroamination of ethylene (Scheme 4) could be dramatically affected by the presence of phosphorus ligands [20]. In order to confirm and generalise our observations, it was decided to investigate the influence of the PR 3 /PtBr 2 ratio and the nature of the associated ligand for the hydroamination of ethylene with aniline. For this study, experiments were conducted without acid co-catalyst in order to better observe the role of the phosphorus additives. According to previous studies, the selected reaction time was 10h and the chosen reaction temperature was 150ºC. At first, it must be recalled that, in the absence of PR 3 ligands, the PtBr 2 -based systems exhibit catalytic activity up to TON = 102 (entry 1, Table 1) for the formation of the hydroamination product 1 (Scheme 4). The influence of the nature of the phosphorus ligands was studied using several types of phosphines containing alkyl, aryl, aryloxy or alkoxy substituents and the results are listed in Table 1. These results showed that to the exception of P(OMe) 3 (entries 6-7, Table 1), phosphorus ligands seem to be inhibitors. It seems that this effect is enhanced when using 2 equiv of ligand/Pt mainly due to a lower production of 1.

In the case of PPh 3 (entries 2-3, Table 1) the observed catalytic performance is in contrast with our previous results on the Rh III -catalysed reactions of aniline with ethylene [5g,5h], where aromatic phosphorus ligands such as PPh 3 seemed to allow excellent catalytic activities. In the same way, aryloxy-substituted ligands (triarylphosphites) and trialkylphosphines allow the reaction but are inefficient co-catalysts (entries 4-5, 8-9). Unexpectedly, catalytic activity is fully recovered upon the introduction of alkoxy groups as substituents on the phosphorus atoms. Indeed, results obtained with 2 equiv/Pt of P(OMe) 3 (entries 6-7, Table 1) showed that this ligand does afford higher selectivity (less production of 2 and 3 side-products) and catalytic activity for the formation of the desired product, Nethylaniline 1, than when the reaction is performed in the absence of ligand. Thus, the presence of alkoxy groups in the structure of the phosphorus ligands seems to be a key factor for achieving good catalytic activities. According to results stated in Table 1, alkyl phosphites may represent the only type of phosphorus ligand without an inhibitor effect and thus suitable for the studied reaction.

Hydroamination of higher α-olefins in the presence of phosphorus ligands

In order to potentially widen the scope of this catalytic process, we studied the addition of aniline to higher α-olefins such as 1-hexene in the presence of a variety of phosphorus ligands. The products resulting from these reactions are of great relevance in industry and the transformation of higher α-olefins is itself an important scientific challenge [21,15d]. Literature on the intermolecular hydroamination of higher olefins by simple amines is very scarce and quite recent [2a,5c,15b,22-25]. 22] studied the hydroamination of 1-pentene with n-propylamine and reported to deal with a challenging reaction, the intermolecular hydroamination of non-activated alkenes, in comparison to intramolecular hydroamination, 350x faster, and alkyne hydroamination, 1400x faster. To the best of our knowledge, only four reports have appointed the use of phosphorus ligands for the intermolecular hydroamination of higher non-activated α-olefins. First, He et al. worked on the addition of TosNH 2 to 1-octene with 5 mol% of Ph 3 PAuCl/AgOTf in toluene at 85°C [23]. Later on, Loh and co-workers studied the same reaction in the presence of InBr 3 (20 mol%) in toluene at 120°C [24]. Both groups obtained the desired Markovnikov hydroamination product along with another Markovnikov isomer resulting from the hydroamination of an internal alkene formed by isomerisation of the initial terminal double bond alkene. Next, Agbossou-Niedercorn and Michon (see introduction), used dppe for the hydroamination of 1hexene by TosNH 2 [15b]. Using AuClPR 3 (PR 3 = P(tBu) 2 o-biphenyl and 2-di-tertbutylphosphino-1,1'-binaphthyl) complexes Widenhoefer and co-workers successfully hydroaminated 1-alkenes with very low basicity amines [25]. As may be seen from literature, only group 11 (Au, Cu, Ag) transition metals have been associated with phosphorus ligands to investigate the title reaction. Thus, the addition of aniline to 1-hexene (Scheme 5) was studied using Pt/P-based catalytic systems. Scheme 5. Pt-catalysed intermolecular hydroamination of 1-hexene by aniline in the presence of PR 3 .

Catalytic results have revealed that, to the exception of alkyl phosphites (P(OEt) 3 and P(OMe) 3 , entries 7-10, Table 1 from SI), the catalytic activity of this reaction seems, once more, inhibited in the presence of phosphorus ligands. As in the case of ethylene, this is true for aromatic phosphines, alkyl phosphines and aromatic phosphites (see Table 1 from SI for further details), confirming our hypothesis on the need of a P-O-C bond in the structure of the ligand to obtain a good catalytic performance. These results seem to confirm a strong coordination mode between the metal centre and the ligands, completely deactivating the catalytic system by blocking its active sites. This is somehow confirmed by the results obtained (TON = 1.5) for the hydroamination of 1hexene (1.6 mL, 12.73 mmol, 150ºC, 144h) by aniline (4.1 mL, 45 mmol) in the presence of preformed cis-PtBr 2 (PPh 3 ) 2 (0.114 g, 0.13 mmol) and nBu 4 PBr (6.62 g, 19.5 mmol).

On the basis of previous results on the platinum-catalysed hydroamination of alkenes [5c], the possible role of molecular iodine was also considered. The association of the reported inhibitor systems, nBu 4 PBr/dppp (dppp = 1,2-bis(diphenylphosphino)propane) and nBu 4 PI/PPh 3 , with molecular iodine allows to recover the catalytic activity in the presence of PtBr 2 (see Table 2 from SI for further details). These results may be understood as I 2 being an antidote for the poisoning effect of aromatic phosphines by forming [R 3 PX] + X -salts (Scheme 6) as described in the literature [26]. Scheme 6. Formation of [R 3 PX] + X -salts from PR 3 and I 2

To confirm this hypothesis, we have studied the 31 P NMR (under inert atmosphere) of the reaction mixture of a typical catalytic run in the presence of triphenylphosphine. Two signals were identified: the expected signal corresponding to the phosphonium salt, nBu 4 PI, at δ P = 33.1 ppm, along with another signal (δ P = 26.9 ppm, major product) that could be attributed to iodotriphenylphosphonium iodide, [R 3 PI] + I -, by correlation with the 31 P NMR data obtained from the in situ NMR reaction (at room temperature in acetone-d 6 ) between PPh 3 and I 2 .

A more detailed discussion about the obtained catalytic results along with literature data for the hydroamination of 1-hexene in the presence of phosphorus ligands and/or I 2 is available in the supporting information (SI).

It is premature to speculate about the exact role of these phosphorus-containing ligands and mechanistic studies are required to gain full insight into these phenomena. A full mechanistic study on the title reaction is out of the scope of this article and will be addressed in future publications. Although the NMR monitoring of the catalytic process could have provided some important insights on the active catalytic species and on possible intermediates of the catalytic cycle, this study could not be done due to technical difficulties (high temperature, 150 °C, during 10h, and high pressure, 25 bar, in the case of ethylene as starting olefin). As a preliminary alternative we have tried to recover the catalyst at the end of the reaction in order to evaluate, by 195 Pt NMR, the absence/presence of phosphorus containing platinum complexes that could explain the observed catalytic results. Decomposition of the active platinum species to black Pt 0 (black precipitate at the end of the catalytic process) did not allow us to observe any platinum containing species by the NMR technique.

Hydroamination in the presence of Arbuzov-type phosphorus containing Ptcomplexes

On the basis of the good catalytic results obtained with the association of PtBr 2 with nBu 4 PI and alkylphosphites, our next efforts were aimed at investigating the particularly beneficial effect of this unique type of phosphorus ligands in the intermolecular Pt-catalysed hydroamination of ethylene by aniline. For this study we addressed an important question concerning the fact that alkylphosphites allow high catalytic activities whereas alkyl-and arylphosphines, and even arylphosphites, behave as inhibitors. Our first hypothesis was based on chemical structural differences between phosphorus promoters and inhibitors: alkylphosphites are the only ones to have O-alkyl substituents on the phosphorus atom. Thus we were prompted to consider an "in situ" transformation, under the catalytic conditions, of metal-coordinated alkylphosphites into somehow more active species according to a Michaelis-Arbuzov type reaction. As described by Odinets et al [27], the Michaelis-Arbuzov reaction allows the formation of a P=O bond by reaction of an alkylphosphite with an alkylhalide (Scheme 7).

Scheme 7. Michaelis-Arbuzov reaction

Taking a look into literature data we could find several reports on a special type of Michaelis-Arbuzov reaction where, similarly, a metallic complex containing one or more halogen ligands allows the reaction (Scheme 8) [28]. Interestingly, authors report this reaction to take place at moderate to high temperatures when reaction times are prolonged, as in our case.

Scheme 8. Michaelis-Arbuzov reaction in metallic complexes

Roundhill and co-workers reported an interesting study on successive Michaelis-Arbuzov reactions on various alkoxy groups from the phosphorus ligand. They succeeded in the formation of transition metal complexes containing different type of phosphorus ligands in equilibrium, when several equivalents of alkylphosphite reacted with a chosen metallic complex (Scheme 9) [29]. Scheme 9. Transition-metal Michaelis-Arbuzov reaction described by Roundhill and coworkers [29].

Taking into account the state of the art, and in order to confirm our hypothesis on the Michaelis-Arbuzov reaction to be responsible of the particular catalytic effect of alkylphosphites, further catalytic experiments were conducted in the presence of a preformed Pt-complex containing a Michaelis-Arbuzov type phosphorus ligand. Thus, the complex cis-[PtBr 2 (P(OCH 3 ) 3 )(OP(OCH 3 ) 2 )](nBu 4 P) (6) (Scheme 10) was synthesised (see experimental section) and used along with nBu 4 PBr for the catalytic hydroamination of ethylene by aniline (Scheme 11). Results in this area were particularly interesting. Indeed, TON up to 127 towards the production of 1 (TON1 = 127, TON2 = 5, TON3 = 4) were obtained using the association of cis-[PtBr 2 (P(OCH 3 ) 3 )(OP(OCH 3 ) 2 )](nBu 4 P) (6) (0.3 mol%, 0.13 mmol, 0.110 g) with nBu 4 PBr (10 equiv/Pt, 0.4412 g, 1.30 mmol), a particularly efficient system for the hydroamination of ethylene (25 bar, ca.100 mmol, 150°C and 10h) by aniline (4.1 mL, 45.5 mmol) and even more active and selective towards the formation of 1, under comparable conditions, than the platinum system PtBr 2 /10nBu 4 PBr/2P(OMe) 3 (entry 7, Table 1). It is important to note that no black Pt(0) has been observed at the end of the reaction when performing the catalytic tests in the presence of cis-[PtBr 2 (P(OCH 3 ) 3 )(OP(OCH 3 ) 2 )](nBu 4 P). This seems to point out an important feature of this system: a high stability of the catalytically active species even at high temperature and in a reductive media. A mechanistic study on the Pt-catalysed hydroamination reaction in the presence of P containing ligands will be addressed in future works.

Coordination Chemistry of the PtBr 2 /nBu 4 PBr/PR 3 catalytic systems

As stated above, one of the advantages of the catalytic strategy used in the present study was the possibility to add in a "one-pot" manner the components of the catalytic system. Nevertheless, in order to better understand the coordination abilities of the metal centre towards the added phosphine ligands, we decided to explore a few more experiments on the reactivity of PtBr 2 with some of the phosphine and phosphites used for the hydroamination reaction. Surprisingly, literature data on this subject are still scarce [30]. For this purpose, PtBr 2 was reacted with 1 and 2 equiv/Pt of three different phosphorus ligands (PPh 3 , P(OEt) 3 and P(OPh) 3 ), in the presence of nBu 4 PBr. Surprisingly, the reactivity of PtBr 2 towards aromatic phosphines, aromatic phosphites and alkyl phosphites was found to be quite different under the same reaction conditions. As expected, the reaction of PtBr 2 with 1 equiv/Pt of PPh 3 gave a new binuclear complex trans-[PtBr 2 (PPh 3 ) 2 ] 2 7 (Figure 1) while 2 equiv/Pt of PPh 3 gave the already known mononuclear complex cis-PtBr 2 (PPh 3 ) 2 8 (Figure 2). Interestingly, the same reaction under the same conditions but using 1 or 2 equiv/Pt of P(OPh) 3 gave only the mononuclear complex cis-PtBr 2 (P(OPh) 3 ) 2 9 (Figure 3) as stated by a very clean 31 P NMR spectra. Concerning P(OEt) 3 ligand, its coordination chemistry with PtBr 2 seems less straight forward and we tentatively propose the formation of cis-PtBr 2 (P(OEt) 3 ) 2 along with, as expected, platinum complexes containing several Arbuzov-type phosphorus ligand according to related literature data. Single crystals suitable for X-ray diffraction were obtained for compounds 7-9 while cooling down the reaction mixture to room temperature (see experimental section and SI for further details).

A more detailed discussion about the obtained results along with experimental, spectroscopic and crystallographic data for 7-9 complexes and related compounds is available in the supporting information (SI).

CONCLUSIONS

An important effect of phosphorus co-catalysts on the intermolecular Pt-catalysed hydroamination of ethylene and 1-hexene by aniline has been evidenced. Indeed, although alkyl-and arylphosphines, as well as arylphosphites, inhibit the reaction, alkylphosphites showed to be a unique class of ligands suitable for the title reaction. We have investigated this particular effect of alkylphosphites and found that the association PtBr 2 (P(OMe) 3 )(OP(OMe) 2 )/10nBu 4 PBr is a very efficient catalytic system allowing even higher TON than the PtBr 2 /10nBu 4 PBr/2P(OMe) 3 catalyst studied in this work and the previously reported PtBr 2 /10nBu 4 PBr system [5b]. These results give access to a new broad family of efficient Arbuzov-type ligands for homogeneous catalytic processes. Modulation of their structural properties could provide a large range of new Arbuzov-like phosphoranes. Even more important, these phosphorus containing co-catalysts may represent the first family of ligands suitable for the intermolecular Pt-catalysed hydroamination of ethylene and higher α-olefins and thus become an important option when considering the enantioselective version of this reaction; an important scientific challenge (see introduction). Indeed, a new series of chiral catalysts could be considered combining, in the coordination sphere of a transition metal centre, different phosphonites P(OR 1 ) 2 R 2 and/or phosphinites P(OR 1 )R 2 R 3 bearing a chiral R 2 and/or R 3 group or, alternatively, 2 different R 2 and R 3 groups. Furthermore, we have been able to evidence a preventing effect of I 2 towards the poisoning effect of phosphines and arylphosphites on the studied reactions by the formation of [R 3 PI] + I - type salts. Investigations on the coordination chemistry of PtBr 2 with PPh 3 , P(OPh) 3 and P(OEt) 3 have revealed an interesting behaviour when using phosphites (only monomers are formed) and provide a new X-ray structure for the dimer complex trans-[PtBr 2 (PPh 3 )] 2 .

SUPPORTING INFORMATION

A detailed discussion about the obtained results on i) the hydroamination of 1-hexene in the presence of phosphorus ligands and/or I 2 along with literature data, and ii) the coordination chemistry of the PtBr 2 /nBu 4 PBr/PR 3 catalytic systems along with experimental, spectroscopic and crystallographic data for 7-9 complexes and related compounds, is available in the Supporting Information (SI). This material is available free of charge via the Internet.

  (4.1 mL, 45.5 mmol), C 2 H 4 (25 bar, ca.100 mmol), 150°C, 10h. b N-ethylaniline (1), N,N-diethylaniline (2), 2-methyl-quinoline (3).

Scheme 10 .

 10 Scheme 10. Preparation of compound cis-[PtBr 2 (P(OCH 3 ) 3 )(OP(OCH 3 ) 2 )](nBu 4 P) (6)

Figure 1 .

 1 Figure 1. Molecular view of compound 7 trans-[PtBr 2 (PPh 3 )] 2 with the atom-labelling scheme.

Figure 2 .

 2 Figure 2. Molecular view of compound cis-PtBr 2 (PPh 3 ) 2 , 8, with the atom-labelling scheme.

Figure 3 .

 3 Figure 3. Molecular view of compound cis-PtBr 2 (P(OPh) 3 ) 2 , 9, with the atom-labelling scheme.Concerning P(OEt) 3 ligand, its coordination chemistry with PtBr 2 seems less straight forward and we tentatively propose the formation of cis-PtBr 2 (P(OEt) 3 ) 2 along with, as expected, platinum complexes containing several Arbuzov-type phosphorus ligand according to related literature data. Single crystals suitable for X-ray diffraction were obtained for compounds 7-9 while cooling down the reaction mixture to room temperature (see experimental section and SI for further details).

Table 1 .

 1 Effect of the amount and nature of the phosphorus ligands used on the PtBr 2catalysed hydroamination of ethylene by aniline. a PtBr 2 (46.1 mg, 0.13 mmol), PR 3 , nBu 4 PBr (0.4412 g, 1.30 mmol), PhNH 2

	Entry	Ligand (equiv/Pt) TON 1 b TON 2 b TON 3 b
	1	-	102	5	15
	2	PPh 3 (1)	18	-	23
	3	PPh 3 (2)	11	-	19
	4	nBu 3 P (1)	31	-	6
	5	nBu 3 P (2)	5	-	4
	6	P(OMe) 3 (1)	98	4	10
	7	P(OMe) 3 (2)	112	6	8
	8	P(OPh) 3 (1)	24	-	-
	9	P(OPh) 3 (2)	<1	-	-
	a Conditions:

ACKNOWLEDGMENTS

We are grateful to The Centre National de la Recherche Scientifique (CNRS, France) and the FSE (post-doctoral grant to SA) for funding. Dr. J.-J. Bonnet and Dr. D. Neibecker are acknowledged for academic support and Prof. F.-X. Felpin and Dr. F. Malbosc (Solvionic) for fruitful discussions.


Dr Marina E Trusova

Mireia Rodriguez-Zubiri

Dr Ksenia V Kutonova

Dr Nicole Jung

Stefan Braese

Francois-Xavier Felpin
email: fx.felpin@univ-nantes.fr

Dr Pavel S Postnikov
email: postnikov@tpu.ru

Dr Mireia Rodríguez-Zubiri

Prof Xavier François-

Felpin

Prof Stefan Bräse

A A Bondarev

Stefan Bräse

François-Xavier Felpin

Ultra-fast

come

Introduction

Arenediazonium salts are a class of powerful electrophiles allowing for a plethora of organic transformations. 1 For instance, the use of arenediazonium salts as aryl halide surrogates in palladium-catalyzed reactions allowing C-C bond formation is certainly one of the most intriguing applications.

2 Indeed, the high polarization of the C-N 2 + bond allows facile oxidative additions of Pd(0) complexes in mild conditions at moderate temperature, usually ranging from 25 to 60 °C, and most often under base-, ligand-and additive-free conditions. 3 The peculiar properties of these super-electrophiles are salient advantages for the development of palladium-catalyzed sustainable processes since they allow working under experimentally simple conditions, reducing both energy expenses and waste generation. 4 By contrast, exploiting the high reactivity of arenediazonium salts with Pd(0) complexes has been mostly overlooked for the development of ultra-fast reactions speeding up the productivity. 5 With no doubt, the Heck and Suzuki coupling reactions are the most popular palladium-catalyzed transformations in the toolbox of synthetic chemists. Under traditional conditions, when using aryl halide as electrophiles, these reactions usually require extensive reaction times (>>1 hour), mostly under heating, especially for the more demanding Heck reaction although few catalysts systems allowing high turnover frequencies (TOFs) have been reported. 6 Developing ultra-fast palladium-catalyzed coupling reactions, completed within minutes or even seconds, would be of great interest to speed up processes, either in multi-step synthesis where reactions times contribute to a large extent to the global time required for the synthesis of complex architectures, or with unstable products not supporting extended stirring and heating. In this contribution, we report our findings on catalyst systems allowing ultra-fast palladiumcatalyzed coupling reactions by taking advantage of the high reactivity of arenediazonium salts. Our efforts have culminated with the synthesis of highly sensitive styrenes within seconds through the coupling of arenediazonium salts with vinyl potassium trifluoroborate. Further studies allowed the preparation of symmetrical and asymmetrical stilbenes within minutes through sequential Suzuki-Heck reactions under microwave heating. This journal is © The Royal Society of Chemistry 20xx

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Results and discussion

The development of ultra-fast reactions is particularly relevant for the preparation of highly sensitive architectures which are prone to degradation upon exposure to external stimuli such as light, oxygen or high temperature. In this regard, we reasoned that the synthesis of styrenes, which are intermediates of utmost importance in medicinal and polymer chemistry, could serve as illustrative examples for showing the potential of ultra-fast reactions. Our approach for the synthesis of styrene consists in the coupling of arenediazonium salts with potassium vinyltrifluoroborate 1. While this process could be hastily considered as trivial, it required a fine tuning of experimental conditions since the ambivalent properties of vinyltrifluoroborate could lead to divergent reaction outcomes with either a Suzuki (pathway A) or Heck coupling (pathway B), eventually followed by a second coupling (pathway C and D) as depicted in Scheme 1. However, we anticipated that pathway A would be favored since Suzuki couplings are usually much less demanding processes than Heck reactions.

We studied these different reaction outcomes on a benchmark reaction involving the coupling of bench-stable 4nitrobenzenediazonium tosylate 2 with a slight excess of potassium vinyltrifluoroborate 1 (1.5 eq.) using 1 mol% of Pd(OAc) 2 as a catalyst. While most Pd-catalyzed coupling reactions have been described with diazonium salts having a tetrafluoroborate counterion, we recently highlighted the benefits of diazonium tosylates since they usually display a higher reactivity and stability and do not produce highly harmful HF as by-product. We initially carried out the reaction in water and at room temperature without any additive such as base or ligand (entry 1). Under these conditions styrene 3a was isolated as the major product, although significant amounts of stilbene 4a, resulting from a sequential Suzuki-Heck process (pathways A -> C), were also isolated. We reasoned that the increase of hydroxyl ion concentration with the use of NaOAc as a base, could favor the Suzuki coupling through the formation of palladium hydroxo intermediates 7 , but unfortunately, our hypothesis was invalidated since the distribution of products 3a/4 was unchanged under these conditions (entry 2). Suspecting that the low selectivity for 3a could be due to solubility issues, we switched the reaction solvent from H 2 O to MeOH and CH 3 CN. While MeOH is usually an excellent solvent for Pd-catalyzed reactions involving arenediazonium salts, 3, 8 it proved to be unsuitable for our methodology since 3a was isolated in only 23% (entry 3). Actually, nitrobenzene, resulting from the reduction of 2, was the main side-product formed with 63% yield. By contrast, when the reaction was carried out in CH 3 CN the selectivity and the reaction rate were notably improved since the expected styrene 3a was formed as the only isolable product with 95% yield after only 80 seconds (entry 5). While these results were already impressive on their own, we discovered that the reaction time could be reduced to 25 seconds, allowing a remarkable turn over frequency (TOF) of 14 000 h -1 , in a CH 3 CN/H 2 O (1/1) co-solvent media and still with a complete selectivity for 3a (entry 6). The process efficiency was highly dependent on the source of palladium since the switch of Pd(OAc) 2 for PdCl 2 (Ph 3 P) 2 considerably slowed down the reaction rate (entry 7). The very high reaction rates observed on this benchmark reaction significantly differ from literature precedents. 5b,c We attribute this impressive feature to the higher solubility of arenediazonium tosylates with respect to traditional arenediazonium tetrafluoroborates and the increased reactivity of potassium vinyltrifluoroborate 1 with respect to potassium arytrifluoroborates. 9 As background reaction, we carried out the coupling between potassium vinyltrifluoroborate 1 and 4nitrobenzenediazonium tetrafluoroborate under optimized conditions. The results reveals that the cross-coupling requires 120 seconds to reach completion, corresponding to a disappointing TOF of 2550 h -1 (entry 8). Moreover, the process is notably plagued by the formation of the undesired stilbene 4a with 6% yield.

Scheme 1. Divergent pathways for the coupling of arenediazonium salts with vinyltrifluoroborate

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With an optimized procedure in hands, we demonstrated the robustness of our methodology through the screening of variously decorated arenediazonium tosylates (Table 2). We were pleased to find that both para-and ortho-substituted arenediazonium salts were coupled with vinyltrifluoroborate 1 with very high rates corresponding to reaction times ranging from ca. 20 to 60 seconds. These ultra-fast reaction times correspond to remarkably high TOF from 4 800 h -1 up to 16 200 h -1

. The only exception to our survey was observed for styrene 3k, bearing a carboxylate group in ortho position, which required 7.5 minutes of reaction time (TOF = 600 h -1

). This behavior was likely associated to an internal chelation between the carboxylate group and the cationic palladium atom after the oxidative addition which slowed down the reactivity of palladium intermediates. The reaction also proved to be sensitive to steric hindrance when ortho-ortho' positions were substituted by bromine atoms (compound 3m). However, while the reaction time increased to 3.5 hours, the steric hindrance was not prohibitive for producing 3m in a synthetically useful yield. It should be noted, that described methodology is fully compatible with heterocycle-and azo-containing diazonium salts (compounds 3g-i). For instance, we were able to prepare 4-vinyluracyl 3i with a good yield (62%) in only 5.5 minutes (TOF = 660 h -1

); 3i has unique electronic properties and can be used for the preparation of labeled nucleosides.

7,8b

Table 2. Reaction scope for the preparation of styrenes and vinylheterocycles a,b a Reaction conditions: diazonium salt (0.2 mmol), potassium vinyltrifluoroborate 1 (0.3 mmol) and Pd(OAc)2 (1 mol%) were mixed in CH3CN/H2O (1/1 : v/v, 5 ml) and stirred at room temperature. The reaction was stopped after full conversion of arenediazonium tosylate determined by probe with β-naphtol. b Isolated yield. c NaOAc (0.2 mmol) was added to the reaction mixture.

As discussed above, the formation of symmetrical stilbene 4a as side-product was observed in some circumstances during our optimization studies due to the ambivalent properties of vinyltrifluoroborate 1 (table 1, entry 1-3, 5). Therefore, we wondered if the use of an excess of the diazonium salt with respect to vinyltrifluoroborate 1 could allow an ultra-fast preparation of symmetrical stilbenes through a sequential Suzuki/Heck process. While similarities in reaction conditions for conducting Suzuki and Heck couplings with diazonium salts would help us for succeeding in developing an ultra-fast sequential process, we reasoned that the demanding nature of the Heck reaction might require to fine tune experimental conditions. With this objective in mind, we explored the coupling of two equivalents of 4-nitrobenzenediazonium salt 2 with one equivalent of vinyltrifluoroborate 1 in aqueous acetonitrile in the presence of 1 mol% of Pd(OAc) 2 as a catalyst. The double coupling reached completion after being stirred for 56 minutes, giving the expected symmetrical stilbene 4a with 89% yield. Since the Suzuki cross-coupling occurred in a matter of seconds, we clearly identified the Heck coupling as the rate limiting reaction. In order to speed-up the sequential process and especially the Heck reaction, we stirred the reaction mixture under microwave heating at 70 °C. Under these conditions it was gratifying to record a striking decrease of the reaction time to only 1 minute for achieving 4a with an excellent yield (86%, TOF = 2 600 h -1

). With these conditions in hand we prepared a collection of representative structures. The results depicted in Table 3 deserve few comments.

As discussed above, the formation of symmetrical stilbene 4a as First, all symmetrical stilbenes prepared in this study required less than 9 minutes of reaction time corresponding to remarkable TOF ranging from 570 to 5 500 h -1 for both sequential chemical reactions, in order to achieve completion with the exception of stilbene 4e which required 132 minutes. While steric considerations might explain, at least in part, this behavior, the preparation of 4f in only 1 minute (TOF = 930 h - 1), suggests that electronic factors might also be involved. Reaction conditions: diazonium salt (0.4 mmol), potassium vinyltrifluoroborate 1 (0.2 mmol) and Pd(OAc)2 mol%) were mixed in CH3CN/H2O (1/1 : v/v, 5 ml) and immediately placed in microwave reactor (70 °C, 30 bars). The reaction was stopped after full conversion of arenediazonium tosylate determined by probe with β-naphtol. b Isolated yield. c 2 mol % of Pd(OAc)2 were used. d 3 mol % of Pd(OAc)2 were used.

Secondly, bromine atoms of stilbene 4c remarkably survived to the microwave heating and no evidence for a competing coupling at the bromine atom was detected. The high chemoselectivity for the diazonium group allows to envisage further orthogonal functionalizations of stilbene 4c under standard organometallic chemistry. Thirdly, the methodology is remarkably efficient for synthetizing highly conjugated stilbenes that might find applications in material chemistry for the preparation of optoelectronic devices. From these studies, we learned that the temperature was the only experimental parameter that differed for carrying out Suzuki and Heck couplings. Therefore, we wondered if we could prepare unsymmetrical stilbenes following sequential Suzuki-Heck reactions using two different arenediazonium salts. From a practical point of view, we reasoned that after mixing an equimolar amount of an This journal is © The Royal Society of Chemistry 20xx

Please do not adjust margins Please do not adjust margins arenediazonium salt with potassium vinyltrifluoroborate 1 for achieving ultra-fast Suzuki cross-couplings, the resulting styrene could be involved in a subsequent microwave-triggered Heck coupling upon addition of a second equivalent of another arenediazonium salt. We explored the synthetic usefulness of this promising strategy through the preparation of several representative examples depicted in Table 4. Pleasingly, unsymmetrical stilbenes could be prepared in high yields with reaction times ranging from 60 to 240 seconds corresponding to TOF ranging from 2 600 to 5 300 h -1

. As already noticed for the preparation of symmetrical stilbenes, heterocycles and heteroatom-containing diazonium salts were tolerated for this process. As a relevant feature, we also noticed that switching the order of addition of arenediazonium salts did not affect the reaction outcome as exemplified by the preparation of compound 4h. Table 4. Preparation of unsymmetrical stilbene through a sequential Suzuki-Heck process.

a,b a Reaction conditions: diazonium salt (0.2 mmol), potassium vinyltrifluoroborate 1 (0.2 mmol) and Pd(OAc) 2 (1 mol%) were mixed in CH 3 CN/H 2 O (1/1 : v/v, 5 ml) and stirred at room temperature, then the second diazonium salt was added and the mixture was stirred at 70 °C under microwave irradiation. The reaction was stopped after full conversion of arenediazonium tosylate determined by probe with β-naphtol.

b Isolated yield.

Conclusions

In summary, we exploited the super-electrophilic properties of arenediazonium salts for establishing ultra-fast Pd-catalyzed methodologies. Highly sensitive styrenes were prepared in seconds with TOF up to 16 200 h -1 through Suzuki cross-couplings while a collection of symmetrical and unsymmetrical stilbenes were synthetized through sequential Suzuki-Heck reactions requiring only a couple of minutes to reach completion for most examples. As highlights of this work, it can be argued that these methodologies (i) were conducted under extremely simple experimental conditions without any additives such as base and ligand, (ii) allowed remarkable high TOF for such simple conditions, (iii) provided styrenes and (un)symmetrical stilbenes in high yields. We believe that this contribution, highlighting the usefulness of arenediazonium salts, could inspire chemists involved in process intensification and should be of practical interest for synthetic chemists.

Experimental

General procedure for preparation of styrenes from potassium vinyltrifluoroborate 1 and ADT.

To a mixture of ADT (2a-m) (0.2 mmol) and potassium vinyltrifluoroborate (0.3 mmol, 0.040 g) in 5 ml water/acetonitrile (1/1) was added 1 mol % Pd(OAc) 2 (0.002 mmol, 0.0005 g). The end of the nitrogen evolution and the formation of Pd(0) indicated the reaction completion. Brine (10 ml) was added to the reaction mixture and the organic layer was extracted with pentane (3×50 mL). The organic layers were dried over anhydrous MgSO 4 . The solvent was removed in vacuo to give the corresponding styrene without further purification (3a-m).

5-vinyluracil (3i

General Procedure for preparation of symmetric stilbenes from potassium vinyltrifluoroborate 1 and ADT.

To a mixture of ADT (0.4 mmol) and potassium vinyltrifluoroborate (0.2 mmol, 0.027 g) in water/acetonitrile (5 mL, 1/1) was added Pd(OAc) 2 (1 mol %). The reaction vessel was immediately placed into a microwave reactor (70 °C, 30 bars). After completion, brine was added, the reaction mixture was extracted with CHCl 3 (3×50 mL) and dried over anhydrous MgSO 4 . The solvent was removed in vacuo to give the corresponding stilbenes without further purification.

(E)-1,2-bis(4-((E)-phenyldiazenyl)phenyl)ethene

4d. The reaction of (E)-4-(phenyldiazenyl)benzenediazonium tosylate 2h (0.4 mmol, 0.124 g) and potassium vinyltrifluoroborate (0.2 mmol, 0.027 g) according to the general procedure during 5 min afforded compound 4d (0.067 g, 86 % yield) as an red solid mp = 199-201 °C. General Procedure for preparation of unsymmetric stilbenes from potassium vinyltrifluoroborate 1 and ADT.

To a solution of ADT (0.2 mmol) and potassium vinyltrifluoroborate (0.3 mmol, 0.040 g) water/acetonitrile (5 mL, 1/1) was added Pd(OAc) 2 (1 mol%). The reaction mixture was stirred until the cessation of the nitrogen evolution, then the second (0.2 mmol) was added to reaction mixture. The reaction vessel was placed into a microwave reactor (70 °C, 30 bars). After completion, brine was added, the reaction mixture was extracted with CHCl 3 (3×50 mL) and dried over anhydrous MgSO 4 . The organic extracts were filtered through short silica pad. The solvent was removed in vacuo to give the corresponding stilbenes without further purification.

Please do not adjust margins Please do not adjust margins (d, J = 8.4 Hz, 2H), 7.98-7.93 (m, 4H), 7-72-7.67 (m, 4H), 7.56-7.49 (m, 3H), 7.34 (d, J = 16.4 Hz, 1H), 7.25 (d, J = 16.0 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 152. 8; 152.6; 147.1; 143.6; 138.9; 132.5; 131.4; 129.3; 127.9; 127.2; 124.4; 123.7; 123.1. HRMS (TOF MS ESI+): calcd for C20H16N3O2 (M+H+) 330.1243; found 330.1246.

All experimental details as well as NMR spectra for all compounds is provided in ESI.

Table 1 .

 1 Optimization studies

	Entry a	Solvent		Base (eq.)	Reaction time (seconds)	Yield 3a/4a (%) b
	1	H2O		-	900		54 / 20
	2	H2O		NaOAc (1)	1920		52 / 18
	3	MeOH		-	540		23 / 5 c
	4	CH3CN		-	80		95 / 0
	5	CH3CN		NaOAc (1)	80		93 / 1
	6	CH3CN/H2O	d	-	25		97 / 0
	7 e	CH3CN/H2O	d	-	2220		95 / 0
	8 f	CH3CN/H2O		-	120		85 / 6
							4-
	nitrobenzenediazonium	tetrafluoroborate	was	used	instead	4-
	nitrobenzenediazonium tosylate.

a Reaction conditions: 4-nitrobenzenediazonium tosylate 2 (0.2 mmol), potassium vinyltrifluoroborate 1 (0.3 mmol) and Pd(OAc)2 (1 mol%) were stirred in the solvent (5 ml) at room temperature. The progress was monitored by TLC analysis. b Isolated yield.

c

Nitrobenzene was isolated with 63% yield. d A 1/1 ratio of starting materials was used. e Pd(PPh3)2Cl2 (1 mol%) was used as catalyst.

f

Table 3 .

 3 Preparation of symmetrical stilbene through a sequential Suzuki-Heck process

a,b

  The reaction of 4-nitrobenzenediazonium tosylate 2a (0.2 mmol, 0.064 g), (E)-4-(phenyldiazenyl)benzenediazonium tosylate 2h (0.2 mmol, 0.076 g) and potassium vinyltrifluoroborate (0.2 mmol, 0.0268 g) afforded compound 4i (0.057 g, 87 % yield) as a white solid mp 238 °C (decomp.).

	1 H NMR (400 MHz, CDCl 3 ):
	δ 8.25

(E)-1-(4-((E)-4-nitrostyryl)phenyl)-2-phenyldiazene 4i.

This journal is © The Royal Society of Chemistry 20xx J. Name.,2013, 00, 1-3 | 3

This journal is © The Royal of Chemistry 20xx J. Name., 2013, 00, 1-3 | 5

Acknowledgements

This work was supported by the Tomsk Polytechnic University (project VIU-316/2017), the University of Nantes (France) and the "Centre National de la Recherche Scientifique" (CNRS). FXF is member of the "Institut Universitaire de France, IUF." SB acknowledges funding through the DFG (SFB 1176, TRR 88). The authors greatly acknowledge the Laboratory of physicalchemical analytical methods of Tomsk State University for the NMR and HRMS analysis.


F Brunet-Possenti
email: forence.brunet-possenti@aphp.fr

L Deschamps

H Colboc

A Somogyi

K Medjoubi

D Bazin

V Descamps

 Further studies are needed to confirm this potential link.

Detection of titanium nanoparticles in the hair shafts of a patient with frontal fibrosing alopecia

Editor Frontal fibrosing alopecia (FFA) is a lymphocyte-mediated primary cicatricial alopecia closely related to lichen planopilaris. [START_REF] Poblet | Frontal fibrosing alopecia versus lichen planopilaris: a clinicopathological study[END_REF] Over time, the number of FFA reports has increased continuously, suggesting the implication of yet unidentified environmental factors. Several studies based on questionnaires have pointed out that leave-on facial skin care products, especially sunscreens, could be implicated in FFA. [START_REF] Kidambi | Frontal fibrosing alopecia in men: an association with facial moisturizers and sunscreens[END_REF] Here, we report the detection of titanium dioxide (TiO 2 ) along the hair shafts of a patient presenting FFA.

The patient was a 73-year-old woman who presented with typical FFA characterized by a frontotemporal hairline regression and eyebrow loss (Fig. 1a,b). There was no manifestation of nail, mucosal or cutaneous lichen planus. A biopsy was per-formed in an active area of the temporal frontline, showing ostial hyperkeratosis and perifollicular fibrosis with gigantocellular reaction, as well as a reduced number of hair follicles. Her past medical history was unremarkable, but she reported the application on a daily basis of a sunscreen containing nanoparticles of TiO 2 during the last ten years to prevent skin photoageing.

A physicochemical characterization of the patient's hair was performed with scanning electron microscopy (SEM) coupled with energy-dispersive X-ray spectroscopy (EDX). Two plucked hairs were analysed using SEM, which showed the presence of micrometre scale abnormal deposits on the hair surface (Fig. 1c,d). The EDX analysis of these deposits pointed out the presence of silicium, sulphur, chlorine, calcium and titanium (Fig. 1e,f). These findings are in line with the literature, [START_REF] Majewska | X-ray fluorescence techniques in medical applications: reference values of elements in human serum, urine and hair[END_REF] except for the presence of titanium. In a second phase, a finer analysis of the particles containing titanium was performed with micro-X-ray fluorescence spectroscopy. This technique evidenced a large aggregate of 0.5-to 1-lm-sized titanium particles associated with smaller (<=0.5 lm) titanium particles on the hair surface. The EDX microanalysis confirmed the presence of a fluorescence peak corresponding to exogenous titanium in these abnormal deposits (Fig. 1g). The strong intensity of this peak (up to 200 counts/50 ms) reflects a high concentration of titanium along the patient's hair shafts. TiO 2 is the most widely used white pigment in the world. It has a wide range of applications, from paint to food colouring, and is also used in cosmetics and skin care. Due to its properties of UV

Figure 1

 1 Figure 1 Clinical features and physicochemical analysis. Clinical features of the patient (a, b). Typical frontal fibrosing alopecia characterized by a hairline regression (a) associated with eyebrows loss (b). (c, d) Conventional SEM images of a patient's plucked hair showing the presence of micrometre scale abnormal deposits, scale bar 20 lm (c) and 10 lm (d). (e, f) The EDX data (black support, red abnormal deposit) identify the presence of silicium (EK a = 1.740 keV), sulphur (EK a = 2.305 keV), chlorine (EK a = 2.622 keV), calcium (EK a = 3.694 keV) and titanium (EKa = 4.511 keV) in the abnormal deposit present at the hair surface (g). Micro-X-ray fluorescence spectroscopy: high 500 nm resolution distribution maps of Ti within the two measured hair samples.