Ruthenium -‐ Catalyzed Direct Oxidative Alkenylation of Arenes through Twofold C – H Bond Functionalization in Water : Synthesis of Ethyl ( E ) -‐ 3 -‐ ( 2 -‐ Acetamido -‐ 4 -‐ methylphenyl ) acrylate

A. Ethyl (E)-3-(2-acetamido-4-methylphenyl)acrylate. A 500-mL, two-necked, round-bottomed flask is equipped with a 2.5 cm rod-shaped, Teflon-coated magnetic stirring bar, rubber septum, reflux condenser and nitrogen inlet and outlet at the top of the reflux condenser. The flask is flushed with nitrogen (Note 1) and charged with N-m-tolylacetamide (5.00 g, 33.5 mmol), [RuCl2(p-cymene)]2 (513 mg, 0.84 mmol, 2.5 mol %), KPF6 (1.233 g, 6.70 mmol, 20.0 mol %), Cu(OAc)2·H2O (6.690 g, 33.5 mmol, 1.0 equiv), (Note 2) and H2O (100 mL) (Note 3). The reaction mixture is stirred for 10 min at ambient temperature, then ethyl acrylate (3.39 g, 3.6 mL, 33.86 mmol, 1.0 equiv) is added via syringe in one portion, and the rubber septum is changed to a glass stopper. After stirring for additional 15 min at ambient NH Ac


Notes
1.This operation is performed by opening the nitrogen inlet from the condenser and flushing the vessel for 10 minutes.2. N-m-Tolylacetamide, [RuCl 2 (p-cymene)] 2 , Cu(OAc) 2 •H 2 O, and ethyl acrylate are obtained from Sigma-Aldrich, (97-98% purity).KPF 6 is also obtained from Sigma-Aldrich and used as received.The N-mtolyacetamide should be ground with a mortar and pestle if it is supplied as a hardened solid.3. Water is distilled in a stream of nitrogen prior to its use.4. The initially deep-green color of the reaction mixture is changed to redbrown after 30 min heating, and subsequently becomes dark after additional 2 h of heating.Heating was performed using an Al block heater in place of an oil bath. 5.The consumption of N-m-tolylacetamide is monitored by GC-MS.Small aliquots were withdrawn, worked-up by following the extraction procedures to the final EtOAc extraction, and then studied by a coupled gas chromatography/mass spectrometry instrument 7890A GC-System with mass detector 5975C (Triplex-Axis-Detector) from Agilent Technologies equipped with HP-5MS column (30 m × 0.25 mm, film 0.25 µm).Retention time t ret = 4.65 min with helium flowrate of 3 mL/min, temperature profile T = 70 °C/1 min, then 70-150 °C/2.7 min, then 150 °C/1 min, then 150-250 °C/2.9 min, then 250 °C/3 min.The final conversion of the limiting substrate is 95-100%.6. Technical grade NH 4 Cl and aqueous NH 3 solutions are obtained from Teknova and SAFC respectively.7. The residue is dissolved in CH 2 Cl 2 (60 mL) and then charged onto a column (7 × 20 cm, 300 g of silica gel).The column is eluted with nhexane/EtOAc/CH 2 Cl 2 2:2:1 (5 L) collecting the 200-mL fractions that contain material with R f = 0.22.A total of eighteen 200-mL portions were collected, and the product was identified to be present in fractions 8 through 16.

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Discussion
Conventional palladium-catalyzed 2 cross-coupling reactions have matured to being among the most reliable tools for the formation of C sp 2-C sp 2 bonds for the preparation of styrene derivatives, which present useful intermediates in synthetic organic chemistry.Based on the pioneering studies by Mizoroki 3a and by Heck, 3b regioselective syntheses of styrenes 4 including naturally occurring products 5 -have predominantly exploited palladium catalysts for reactions between prefunctionalized aryl (pseudo)halides and alkenes (Figure 1a).Despite its remarkable importance and the thus achieved considerable advances in organic synthesis, the Mizoroki-Heck reaction is unfortunately accompanied by the formation of stoichiometric amounts of potentially hazardous halide salts which can cause a significant environmental pollution.For this reason, recent research interest has shifted towards the development of more environmentally-friendly halide-free alkenylations.In 1967, Fujiwara and Moritani thus reported the first example of catalyzed direct oxidative coupling of arenes with styrene through a twofold C-H bond activation approach, wherein the C-H bond of the alkene was replaced with the aromatic moiety in the presence of a palladium catalyst. 7his approach is not only advantageous with respect to the overall minimization of by-product formation (atom-economy), 8a,b but also enables a streamlining of organic syntheses by significantly reducing the overall number of required reaction steps (step-economy).8c As a consequence, a plethora of synthetically useful protocols for palladium-catalyzed direct oxidative couplings between arenes and alkenes (Figure 1b) was elaborated during the last decade. 9Furthermore, relatively expensive rhodium catalysts were also developed for oxidative alkenylations in recent years. 10,11onversely, fourteen times less expensive 12 ruthenium 13 complexes have only recently been exploited as catalysts for direct C-H bond alkenylations on arenes. 14

Scheme 3. Ruthenium(II)-catalyzed oxidative alkenylations with electrondonating coordinating substituents
Until recently, ruthenium-catalyzed oxidative alkenylations through twofold C-H bond functionalizations have proven to be limited to (hetero)arenes bearing electron-withdrawing groups (vide supra).Challenging oxidative olefinations with electron-rich arenes 10a, on the contrary, were elaborated very recently with [RuCl 2 (p-cymene)] 2 , KPF 6 and Cu(OAc) 2 •H 2 O as the catalytic system in water as the reaction medium (Scheme 3). 19Moreover, a cationic ruthenium (II) catalyst derived from [RuCl 2 (p-cymene)] 2 and AgSbF 6 enabled highly efficient oxidative alkenylations of electron-rich aryl carbamates with weakly coordinating and removable directing groups. 23These catalytic conditions allowed for highly productive cross-dehydrogenative C-H bond functionalizations of 10b in a highly chemo-, diastereo-and site-selective fashion, affording diversely decorated phenol derivatives 12 (Scheme 3). 23oreover, ruthenium-catalyzed oxidative alkenylations of arenes Narylpyrazoles 13, 2-aryl-1H-imidazoles, 2-aryl-1H-benzo[d]imidazoles, 2arylbenzo[d]thiazoles 14 and 2-aryl-4,5-dihydrooxazoles 15 (Figure 2a) with heterocyclic directing groups have recently been reported by Dixneuf and coworkers 24 as well as Satoh, Miura and coworkers.16a,18 Hence, substrates 13 were directly alkenylated with acrylates and acrylamides 2 employing Ruthenium catalysts for oxidative C-H/C-H alkenylation reactions of heteroarenes have hitherto been less explored as compared to palladium-or rhodium-catalyzed analogous transformations.22b,25 In summary, ruthenium(II) complexes allowed for challenging direct double C-H/C-H bond alkenylations of arenes with ample scope.Considering the practical importance of atom-and step-economical C-H bond alkenylations for natural product synthesis, drug discovery and crop protection, along with the unique features of the robust and selective ruthenium catalysts, significant further progress is expected in this rapidly evolving research area.
LutzAckermann (1972) studied Chemistry at the Christian-Albrechts-University Kiel, Germany, and received his Ph.D. from the University of Dortmund in 2001 for research under the supervision of Alois Fürstner at the Max-Plank-Institut für Kohlenforschung in Mülheim /Ruhr.He was a postdoctoral coworker in the laboratory of Robert G. Bergman at the UC Berkeley before initiating his independent career in 2003 at the Ludwig-Maximilians-University München.In 2007, he became Full Professor at Georg-August-University Göttingen, and serves as the Dean at the Georg-August-University Göttingen since 04.2011.His recent awards and distinctions include a JSPS visiting professor fellowship (2009), an AstraZeneca Excellence in Chemistry Award (2011) and an ERC Consolidates Grant (2012).The development of novel concepts for sustainable catalysis and their application to organic synthesis constitute his major current research interests.William Trieu received his B.S in chemical engineering in 2007 at the University of California, Berkeley where he worked for Prof. Jay Keasling on the production of an antimalarial drug precursor.He worked at Merck supporting Gardasil fermentation operations prior to joining Amgen in 2008.At Amgen he has worked on a number of projects in which he has optimized chemical processes by utilizing chemical engineering principles.He received his M.S in chemical engineering in 2012 at the University of Southern California.