Recent advances in the ruthenium-catalyzed hydroarylation of alkynes with aromatics : synthesis of trisubstituted alkenes

The hydroarylation of alkynes with substituted aromatics in the presence of a metal catalyst via chelationassisted C–H bond activation is a powerful method to synthesize trisubstituted alkenes. Chelationassisted C–H bond activation can be done by two ways: (a) an oxidative addition pathway and (b) a deprotonation pathway. Generally, a mixture of cis and trans stereoisomeric as well as regioisomeric trisubstituted alkenes was observed in an oxidative addition pathway. In the deprotonation pathway, the hydroarylation reaction can be done in a highly regioand stereoselective manner, and enables preparation of the expected trisubstituted alkenes in a highly selective manner. Generally, ruthenium, rhodium and cobalt complexes are used as catalysts in the reaction. In this review, a ruthenium-catalyzed hydroarylation of alkynes with substituted aromatics is covered completely. The hydroarylation reaction of alkynes with amide, azole, carbamate, phosphine oxide, amine, acetyl, sulfoxide and sulphur directed aromatics is discussed.


Introduction
The alkene subunits are present in various natural products, drug molecules and materials.In addition, alkenes are versatile synthetic intermediates which are widely used for various organic transformations. 1 The transition metal-catalyzed coupling of aromatic electrophiles or organometallic reagents with carbon-carbon π-components is a powerful route to synthesize alkene derivatives in a highly regio-and stereoselective manner.Alkenes and alkynes are widely used as carbon-carbon πcomponents in the coupling reaction.Usually, alkenes reacted with aromatic electrophiles or organometallic reagents in the presence of a metal catalyst, providing disubstituted alkenes (Fig. 1) 2 and alkynes reacted with aromatic electrophiles or organometallic reagents, affording trisubstituted alkenes (Fig. 1). 3 Various metal complexes such as palladium, nickel, cobalt, rhodium, iron, etc are widely used as catalysts in this type of alkenylation reaction.Aromatic iodides, aromatic bromides and aromatic triflates are frequently used as electrophiles in the reaction.Similarly, aromatic organometallic reagents such as borane, silane, stannane and magnesium are used as a transmetallating agent.Although this type of coupling reaction is very powerful to synthesize substituted alkenes, a preactivated coupling partner such as a C-X or C-Y is usually required on the aromatic moiety.A preactivated species such as X or Y is wasted at end of the reaction.If a similar type of reaction is carried out directly by the C-H bond of aromatic moiety instead of with a C-X or C-M, it would be more useful in organic synthesis.Because, this method would be highly atomand step economical as well as an environmentally friendly process.(2005-2009).Then, he moved to the Ludwig-Maximilians-Universität, Munich, Germany, for a postdoctoral study with Prof. Paul Knochel supported by Alexander von Humboldt foundation (2009 to 2010).At present, he is working as an assistant professor in Indian Institute of Science Education and Research Pune (2010-till now).He was the recipient of DAE Young Scientist Research Award (2011), Science Academy Medal for a young associate, Indian Academy of Sciences (2012-2015), Science Academy Medal for Young Scientists, Indian National Science Academy (2013), Alkyl Amines -ICT Young Scientist Award by Institute of Chemical Technology Mumbai (2013) and ISCB Award of Appreciation for Chemical Science, CSIR-CDRI (2014), India.His research interest includes the development of new synthetic methods using metal complexes as catalysts, asymmetric synthesis and natural product synthesis.
Alternatively, alkene derivatives can also be prepared by a metal-catalyzed chelation-assisted alkenylation at the C-H bond of substituted aromatics with carbon-carbon πcomponents via C-H bond activation without having any preactivated species on the aromatic moiety (Fig. 2). 4 There are several ways to activate the C-H bond of aromatics in the presence of metal catalysts. 5However, doing the C-H bond activation in a controlled and regioselective manner is a challenging task.This type of regioselective C-H bond activation can be done by a chelation-assisted metalation pathway (Fig. 3).Usually, heteroatom such as nitrogen or oxygen containing directing group is needed on the aromatic moiety to activate the C-H bond in a highly regioselective manner.The heteroatom of directing group coordinates with a metal centre via either σ or π bond and allows bringing the ortho C-H bond of aromatics to close proximity to the active metal centre.During this time, the C-H bond activation takes place very selectively at the ortho position and providing a five membered metalacycle intermediate.There are two pathways such as oxidative addition and deprotonation possible to activate the C-H bond of organic moiety (Fig. 3).In the oxidative addition pathway, a five membered hydrometallacycle intermediate I is formed and in the deprotonation pathway, a five membered metallacycle intermediate without having a hydride species II is formed.It is important to note that in the deprotonation pathway; usually a carbonate or acetate base is required to deprotonate the C-H bond of organic moiety.In the oxidative addition pathway, a metal species undergoes an oxidative addition with a C-H bond of aromatic moiety and providing a hydrometallacycle intermediate I. Generally, M(0) or M(I) active catalysts favour oxidative addition pathway and M(II)(OR) 2 or M(III)(OR) 2 catalysts favours deprotonation pathway.In this context, metal-catalyzed chelation-assisted ortho alkenylation of substituted aromatics with alkenes is well explored in the literature. 4But, an ortho alkenylation of substituted aromatics with alkynes has gained much attention quite recently.In 1993, Murai's group reported a ruthenium-catalyzed chelation-assisted ortho alkylation of aromatic ketones with alkenes via C-H bond activation.In the reaction, aromatic ketones reacted with alkenes in the presence of RuH 2 (CO)(PPh 3 ) 3 , giving ortho alkylated aromatic ketones in a highly regioselective manner.6a The C-H bond activation reaction proceeds via an oxidative addition pathway.Later, the same group demonstrated an ortho alkenylation of aromatic ketones with alkynes, leading to trisubstituted alkenes in the presence of a ruthenium catalyst (Fig. 4).6b The hydroarylation reaction proceeds via a chelation-assisted oxidative addition of ortho C-H bond of aromatic ketone with a ruthenium catalyst providing a five-membered hydrometallacycle intermediate III.
Later, an alkyne undergoes coordinative insertion into a metalhydride bond of intermediate III followed by reductive elimination, providing a trisubstituted alkene derivative and regenerates a active Ru(0) catalyst for the next catalytic cycle.However, this type of hydroarylation reaction is not completely regio-and stereoselective.Mostly, a mixture of Please do not adjust margins Please do not adjust margins regio-and stereoisomeric trisubstituted alkenes were observed.For example, aromatic ketone reacted with symmetrical alkyne, diphenylacetylene, in the presence of a ruthenium catalyst, yielding a mixture of cis and trans stereoisomeric trisubstituted alkenes.Later, Murai's group has reported the hydroarylation of alkynes with various directing groups such as ester, nitrile and aldehyde substituted aromatics in the presence of a ruthenium catalyst. 6Later, a similar type of hydroarylation of alkynes with heteroatom substituted aromatics has been well explored by using various metal complexes such as rhodium, iridium, palladium, nickel, cobalt and manganese complexes as catalysts.Although it is one of the best methods to synthesize trisubstituted alkenes in one pot, the observation of a mixture of cis and trans stereoisomeric and regioisomeric products limits the synthetic application in organic synthesis.The recent observation clearly revealed that this type of regioand stereoisomeric issues can be easily overcome by doing the hydroarylation reaction via a concerted deprotonation metalation pathway. 7In the reaction, substituted aromatics reacted with alkynes in the presence of a ruthenium catalyst, providing trisubstituted alkene derivatives in a highly regioand stereoselective manner.Notably, the metal oxidant is not needed for the hydroarylation reaction unlike the orthoalkenylation of aromatics with alkenes in the presence of metal catalysts.The catalytic reaction proceeds via a chelation-assisted acetate accelerated deprotonation at the ortho C-H bond of hetero atom substituted aromatic with a metal complex (Rh or Ru), providing a metallacycle intermediate IV.Coordinative insertion of an alkyne into the metal-carbon bond of metallacycle followed by protonation in the presence of organic acid provides trisubstituted alkene derivative in a highly regio-and stereoselective manner (Fig. 4).The regiochemistry of product of this reaction is completely reversed when compared with the regiochemistry of product observed via an oxidative addition pathway.In the oxidative addition pathway, alkynes preferred to insert into Ru-H bond of intermediate III compared with Ru-C bond.In the deprotonation pathway, alkynes preferred to insert into Ru-C bond of metallacycle intermediate IV.
Ruthenium, rhodium and cobalt complexes are widely used as a catalyst in the reaction.In 2010, Fagnou et.al. reported a rhodium-catalyzed amide group assisted hydroarylation of alkynes with substituted indoles (Fig. 5). 8The hydroarylation reaction proceeds via a deprotonation metalation pathway.
The reaction pathway was supported by a deuterium labelling experiment.In this review, we would like to focus on a ruthenium-catalyzed direct C-H bond hydroarylation of substituted aromatics with alkynes via a chelation-assisted deprotonation metalation pathway.
In 2012, Miura's group reported a highly regio-and stereoselective hydroarylation of alkynes with substituted benzamides, providing trisubstituted alkenes in a highly regioand stereoselective manner.9a-b When N,N-dimethylbenzamide (1a) was treated with symmetrical diphenylacetylene (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5.0 mol %), AgSbF 6 (20 mol %) and acetic acid (4.0 equiv) in 1,4-dioxane at 100 C for 5 h, a trisubstituted alkene 3a was observed in 82% yield (Scheme 1).It is important to note that the product 3a was observed only in 43% yield without acetic acid under similar reaction conditions.In the meantime, no hydroarylation product 3a was observed in the presence of acetate base, KOAc, instead of acetic acid.In the reaction, acetic acid acts as a proton donor as well as base to activate the C-H bond of benzamide.The hydroarylation reaction was compatible with various substituted alkynes.Particularly, unsymmetrical alkynes such as 1-phenyl-1-propyne (2b) and 1-phenyl-1-butyne (2c) regioselectively reacted with benzamide (1a), yielding This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins trisubstituted alkenes 3b-c in 77% and 68% yields, respectively, in a highly regio-and stereoselective manner.In the reaction, alkyl groups such as Me and n-Bu substituted carbon of alkynes connected at the ortho carbon of 1a.Similarly, 1phenyl-2-(trimethylsilyl)acetylene (2d) provided disubstituted alkene 3d in 63% yield along with trisubstituted alkene 3d' in 17% yield, respectively.During the reaction, silyl group was cleaved in product 3d.Apart from internal alkyne, the reaction was also examined with terminal alkyne, tris(isopropyl)silylacetylene (2e).However, only 19% of disubstituted alkene 3e was observed.Under similar reaction conditions, substituted benzamides and cyclic benzamides also nicely participated in the reaction with diphenylacetylene (2a), yielding ortho alkenylated products 3f-h in good yields.The alkenylation reaction was also compatible with substituted phenyl azoles (Scheme 2).Treatment of 1-phenylpyrazole (4a) with diphenylacetylene (2a) under similar reaction conditions gave bis alkenylated pyrazole derivative 5a in 85% yield.Similarly, substituted 1-phenylpyrazole 5 reacted with various symmetrical alkynes 2, providing the corresponding bis alkenylated pyrazole derivatives 5 in good yields.The alkenylation reaction was also examined with 2phenylimidazoles.
2-Phenylimidazole (6a) underwent hydroarylation with 2a, yielding the corresponding mono alkenylated phenylimidazole derivative 7a in 79% yield.But, Nmethyl-2-phenylimidazole (6b) provided mono alkenylated phenylimidazole 7b only in 65% yield.This is most likely due to the intramolecular steric hindrance of N-Me group into an alkene moiety of compound 7b.It is believed that the C-H bond activation proceeds via a deprotonation metalation pathway (Scheme 4).To confirm the deprotonation pathway, deuterated benzamide 1a' was taken and treated with alkyne 2a under similar reaction conditions.If the C-H bond activation proceeds via an oxidative addition pathway, ortho deuterium of benzamide 1a' should be transferred into one of the alkene carbons of the expected product.Whereas, if the C-H bond activation reaction proceeds via a deprotonation pathway, deuterium incorporation should not take place and could be formed AcOD as a side product.In the product, deuterium incorporation was not observed at the alkene carbon of product 3a'-d4.Thus, the C-H bond activation proceeds via a deprotonation metalation pathway.Later, an intermolecular competitive reaction of deuterated benzamide 1a' with a simple benzamide 1a was conducted.A considerable primary isotope effect of 1:2 ratios of products 3a'-d4 and 3a were observed.This result suggested that the ortho C-H(D) bond cleavage is the rate-determining step as well as the cleavage proceeds via a deprotonation metalation pathway.
Scheme 4 Competitive reaction of benzamide with deuterated benzamide.
In the same year, Li's group reported a ruthenium-catalyzed hydroarylation of alkynes with isoquinolone derivatives in the presence of acetic acid (Scheme 5). 10 Treatment of N-methyl isoquinolone (10a) with diphenylacetylene (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5 mol %), AgSbF 6 (20 mol %) and acetic acid (4.0 equiv) in 1,4-dioxane at 100 C for 18 h gave the expected alkenylated isoquinolone derivative 11a in 96% yield.The same reaction was also examined with other catalysts such as [RhCp*Cl 2 ] 2 and [IrCp*Cl 2 ] 2 under similar reaction conditions.In the iridium-catalyzed reaction, product 11a was observed in 86% yield and in the rhodium-catalyzed reaction, product 11a was observed only in 45% yield.This Please do not adjust margins Please do not adjust margins result clearly reveals that a ruthenium catalyst is suitable for the reaction.The hydroarylation reaction was also examined with N-H free isoquinolone (10b).However, in the reaction, the expected product 11b was observed only in 43% yield.
Scheme 5 The hydroarylation of alkynes with isoquinolone derivatives.
The hydroarylation reaction was examined with various symmetrical and unsymmetrical alkynes 2. In all cases, the hydroarylation reaction worked very well and gave the corresponding hydroarylation products in good yields.
Particularly, 1-pheny-1-propyne (2b) reacted with 10a providing the expected alkenylated product 11c in 83% yield in a highly regio-and stereoselective manner.In the reaction, Me attached carbon of alkyne 2b connected at the C-8 position of isoquinolone derivative.Interestingly, in the reaction of 1phenyl-1-silylacetylene with 10a, the expected hydroarylation product 11e was observed in 85% yield without silyl cleavage.However, in the previous Miura's reaction, the silyl group was cleaved (Scheme 1, product 3d).
Scheme 6 The hydroarylation of diphenylacetylene with N-methyl benzamide.
In the reported hydroarylation of alkynes with benzamides, only N,N-disubstituted benzamides was examined.In 2011, Ackermann's group reported an oxidative cyclization of Nmethyl benzamides with alkynes, providing substituted isoquinolone derivatives (Scheme 6). 11In the reaction of Nmethyl benzamide (12) with diphenylacetylene (2a) in the presence of ruthenium catalyst and Cu(OAc) 2 .H 2 O in ether solvent, a minor amount of ortho alkenylated benzamide 13 was observed in 15% yield along with isoquinolone derivative 14 in 27% yield, respectively.This result clearly reveals that the N-methyl benzamides prefer cyclization reaction with alkynes rather than the hydroarylation reaction.
1,4-dioxane, pivalic acid (5.0 equiv) 100 °C, 16 h 22 examples 64-89% yield The scope of the hydroarylation reaction was examined with various sensitive functional groups such as I, Br, Cl, F and OMe substituted aromatic carbamates.In all reactions, the expected hydroarylation product was observed in good to moderate yields.The hydroarylation reaction was further examined with various unsymmetrical aromatic carbamates.For example, 3methoxyphenyl diethylcarbamate (15b) reacted with ethyl but-2-ynoate (2e) at a less hindered C6-H under similar reaction conditions, yielding trisubstituted alkene derivative 16b in 79% yield.Sesamol carbamate 15c reacted with 2b at the sterically This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins hindered C-H bond, providing 16c in 86% yield in a highly regioselective manner.
The hydroarylation reaction was also examined with unsymmetrical alkynes such as hex-2-ynoate, methyl oct-2ynoate, 1-phenyl-1-propyne, 1-phenyl-1-butyne and 1-phenyl-1-hexyne.In all reactions, alkyl group substituted carbon of alkyne connected at the ortho carbon of aromatic carbamates.But, methyl 3-phenylpropiolate (2f) reacted with 15c providing a mixture of regioisomeric products 16d and 16d' in 89% combined yield in approximately a 1:1 ratio.Later, the ester group of trisubstituted alkene 16f was converted into the carboxylic acid derivative 17a in the presence of LiOH (2.0 equiv) (Scheme 8).Whereas, 10.0 equiv. of LiOH cleaved both ester and carbamate moieties of compound 16g, giving phenol derivative 17b in 87% yield.In the alkyne, if two coordinating groups are there, both prefer to stay near to the ruthenium metal and thus a mixture of regioisomeric products was observed.
Scheme 9 Proposed reaction mechanism of aromatic carbamates with alkynes.
It is believed that the C-H bond activation proceeds via an acetate assisted deprotonation pathway instead of an oxidative addition pathway.The coupling reaction of sesamol carbamate 15c with ethyl but-2-ynoate (2e) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5 mol %) , AgSbF 6 (20 mol %) and CD 3 COOD (5.0 equiv) in 1,4-dioxane at 100 C for 16 h was examined (Scheme 9).In the reaction, instead of pivalic acid, CD 3 COOD (5.0 equiv) was used.In the coupling product 16h, 75% of deuterium incorporation was observed in an alkene C-H bond.This deuterium study clearly revealed that the present reaction proceeds via the deprotonation pathway.
To show the C-H activation proceeds via a deprotonation metalation pathway and the corresponding metalation is a rate determining and reversible step, the reaction of deuterated 2-aminobiphenyl 20a-d 5 with 2a under similar reaction conditions for 30 min was carried out (Scheme 12).In the reaction, alkenylated product 21a-d n was observed in 9% yield without any deuterium incorporation at the alkene C-H bond.This observation clearly indicates that the C-H bond activation proceeds via a deprotonation pathway.
Thus, apart from 26a, other ortho alkenylated products were also observed.Interestingly, the expected product 26a in 82% yield was observed exclusively without any other ortho alkenylated products in the presence of an excess amount of triphenylphosphine oxide (5.0 equiv).Pivalic acid, 2,6dimethylbenzoic acid and AcOH were also equally effective for the reaction.Further, the hydroarylation reaction was examined with Me, OMe, F, Cl and CF 3 substituted triphenyl phosphine oxides 25.In these substrates, the expected hydroarylation products were observed in good yields 26.Particularly, meta methyl substituted triphenyl phosphine oxide 25c, the C-H bond activation takes place at the less hindered side (product 26c).The hydroarylation reaction was also compatible with alkyl(diphenyl) and dialkyl(phenyl)phosphine oxides 25d-e (see, products 26d-e).The hydroarylation reaction also worked very well with various symmetrical alkynes 2. Unsymmetrical alkyne 2h reacted efficiently with 25a under similar reaction conditions providing the expected hydroarylation product 26f in 58% yield in a highly regio-and stereoselective manner.Later, ortho alkenylated triphenylphosphine oxide 26g was converted into ortho alkenylated triphenylphosphine 27a in 66% yield in the presence of (4-NO 2 C 6 H 4 O) 2 P(O)OH and (EtO) 2 MeSiH.

Ruthenium-catalyzed hydroarylation of alkynes with anilides
In 2014, we have reported a ruthenium-catalyzed hydroarylation of alkynes with acetanilides. 15The catalytic reaction provides ortho-alkenylated anilides in good to excellent yields in a highly regio-and stereoselective manner.The reaction of 4-hydroxy anilide (28a) with 1-phenyl-1propyne (2b) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5.0 mol This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins %), AgSbF 6 (20 mol %) and pivalic acid (5.0 equiv) in iso-PrOH at 100 C for 12 h gave ortho alkenylated anilide (29a) in 78% yield (Scheme 14).The hydroarylation reaction is highly stereoselective, the ortho C-H bond of 28a coupled with the methyl substituted carbon of alkyne 2b.It is known that the acetanilides underwent oxidative cyclization with alkynes in the presence of rhodium or ruthenium catalysts and acetate base providing indole derivatives (Fig. 6).But, in the presence of organic acid RCOOH source instead of a base, orthoalkenylated anilides were observed.It is noteworthy to note that the organic acid favours hydroarylation reaction and base favours oxidative cyclization reaction.The hydroarylation reaction was compatible with various functional groups such as OH, OMe, F, Cl, Br, I, CN and ester substituted anilides (Scheme 14).Treatment of ester substituted anilide 28f with 2b gave trisubstituted alkene 29f in 71% yield.In the substrate 28f, directing groups such as NHCOMe and ester were present.However, alkenylation takes place chemoselectively at the ortho carbon to NHCOMe of 28f.The hydroarylation reaction was also examined with unsymmetrical acetanilides 28g-h.2-Naphthyl acetamide 28g reacted with 2a, providing trisubstituted alkene derivative 29g in excellent 82% yield, in which C-H bond activation takes place at the C3-H of 28g.In contrast, 3,4-(methylenedioxy)anilide (28h) reacted with 2a, yielding product 29h in 81% yield in which hydroarylation takes place at a sterically hindered C-H bond of 28h.
The scope of the hydroarylation reaction was further examined with various unsymmetrical alkynes such as 1phenyl-1-butyne, 1-phenyl-1-hexyne, 1-phenyl-2-(trimethylsilyl) acetylene, ethyl 2-butynoate, methyl hex-2ynoate and methyl oct-2-ynoate (Scheme 15).In these reactions, the expected hydroarylation product was observed in good to excellent yields.In all these alkynes, alkyl substituted carbon of alkynes was regioselectively connected at the ortho carbon of acetanilide.Methyl phenyl propiolate (2g) which having two coordinating groups such as Ph and ester on the alkyne provided a mixture of hydroarylation products 29l and 29l' in 81% combined yields in a 60:40 ratio.Interestingly, 2-thienyl substituted alkyne 2h provided hydroarylation products 29m and 29m' in 75% combined yields in a 3:1 ratio.Surprisingly, alkyne 2i which having Ph and CH 2 Ph provided a single coupling product 29n in 62% yield.To know the coordinating ability of Ph and ester groups, anilide 28i was treated with 2b (1.0 equiv) and 2f (1.0 equiv) under similar reaction conditions.In the reaction, alkyne 2b coupling Please do not adjust margins Please do not adjust margins product 29a was observed in a major 59% yield and alkyne 2f coupling product 29i in a less 32% yield, respectively.This result clearly reveals that the Ph coordinates with a Ru metal better than ester.Later, ortho-alkenylated acetanilides 29a and 29d were efficiently converted into ortho-alkenylated anilines 30a and 30b in 93% and 91% yields, respectively, in the presence of a 1:1 mixture of 17% HCl and THF at 100 C for 17 h.Further, the hydroarylation reaction was tested with a weak ester directing group substituted aromatic moiety.Treatment of methyl piperonate (31) with diphenylacetylene (2a) under similar reaction conditions provided the hydroarylation product 32 in 71% yield in a highly regioselective manner.

Scheme 17
The hydroarylation of diphenylacetylene with methyl piperonate.A possible reaction mechanism was proposed to account for the hydroarylation of alkynes with anilides (Scheme 18 In the reaction, initially ortho alkenylated anilide 29 was formed as described in the mechanism in Scheme 18.Under the reaction conditions, ortho alkenylated anilide 29 was converted into 2-quinolinone derivative 36.To confirm that the ortho alkenylated anilide is a key intermediate, product 29i was prepared separately and treated with pivalic acid in iso-PrOH solvent at 130 C for 24 h without a ruthenium catalyst (Scheme 19).As expected, 2-quinolinone derivative 36 was observed in 75% yield.This result clearly reveals that the carboxylic acid or solvent iso-PrOH accelerates trans-cis isomerization of the double bond of compound 28i via Michael addition.Intramolecular nucleophilic addition of NHCOMe to the ester moiety followed by a loss of acetyl group leads to 2quinolinone 36.In the reaction, organic acid plays multiple roles such as acting as a proton source, the corresponding acetate anion deprotonates the C-H bond, accelerating cistrans isomerization and deacylation of anilide to aniline.

Ruthenium-catalyzed hydroarylation of alkynes with aromatic sulfoxides
Recently, we have reported a regio-and stereoselective hydroarylation of alkynes with aromatic sulfoxides in the presence of a less expensive ruthenium catalyst. 17In the This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins reaction, terminal metal oxidant was not used and only Ru(II) species was involved in the complete catalytic cycle without changing the metal oxidation state.It is important to note that, Miura's group reported the hydroarylation of alkynes with aromatic sulfoxides in the presence of a highly expensive rhodium complex (Scheme 20).However, Cu(OAc) 2 was used as an terminal metal oxidant to regenerate the active rhodium catalyst.Treatment of methyl phenyl sulfoxide (37a) with 1phenyl-1-propyne (2b) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5 mol %) , AgSbF 6 (20 mol %) and pivalic acid (5.0 equiv) in 1,4dioxane at 100 C for 24 h gave the expected hydroarylation product 38a in 75% yield.The hydroarylation reaction was highly regioselective and the methyl group substituted carbon of alkyne 2b was connected at the ortho C-H bond of 37a.The hydroarylation reaction was also highly stereoselective giving only E-stereoisomeric trisubstituted alkene derivative 38a.The hydroarylation reaction was compatible with various functional groups such as Br, Cl and CHO substituted aromatic sulfoxides.Particularly, electron-deficient CHO substituted aromatic sulfoxide 37d reacted with 2b providing the corresponding hydroarylation product 38d in 51% yield.Unsymmetrical meta methoxy phenyl sulfoxide 37e reacted regioselectively with alkyne 2b, yielding product 38e in 57% yield in which the ortho C-H bond activation takes place at a less hindered C-H bond of 37e.

Scheme 20
The hydroarylation of alkynes with aromatic sulfoxides.
The scope of hydroarylation reaction was further examined with various unsymmetrical and symmetrical alkynes.In all reactions, the expected hydroarylation product was observed in good to moderate yields in a highly regio-and stereoselective manner.Particularly, bromo substituted alkyne 2i reacted regioselectively with 37a, affording the corresponding alkene derivative 38f in 63% yield (Scheme 20).In the reaction, n-butyl substituted alkyne carbon connected at the ortho C-H bond of 37a.When compound 38g was treated with acetic anhydride (10.0 equiv) at 140 C for 1 h, α-acyloxy-thioether 39 was observed in 87% yield (Scheme 21).Subsequently, ortho alkenylated phenyl sulfoxide 38h was treated with CF 3 SO 3 H at room temperature for 24 h followed by an addition of a 9:1 ratio of water/pyridine, affording 2,3-disubstituted benzothiophene derivative 40 in 67% yield.
To show the role of organic acid in the hydroarylation reaction, the reaction of 37g with 2b in the presence of CD 3 COOD instead of pivalic acid was tested under similar reaction conditions (Scheme 22).In the reaction, deuterium incorporation was observed at the alkene carbon of hydroarylation product d-38g.This result clearly reveals that the AcOH acts as a proton donor in the reaction.

Scheme 22
The hydroarylation of alkyne with phenyl sulfoxide in CD 3 COOD.

AgSbF 6 controlled E to Z stereoselective transformation of trisubstituted alkenes
Very recently, Hong's group reported a ruthenium-catalyzed Z stereoselective hydroarylation of alkynes with substituted aromatics. 18Generally, E stereoselective alkene derivatives can be prepared efficiently in the hydroarylation proceeds via a deprotonation pathway.In the oxidative addition pathway, a stereoisomeric mixture of E and Z alkene derivatives was prepared.In the Hong's method, Z stereoselective alkene derivatives were prepared efficiently in the presence of an excess amount of AgSbF 6 .This hydroarylation reaction also proceeds via a deprotonation pathway.Initially, in the reaction, E stereoselective alkene derivatives were observed.But, in the presence of an excess AgSbF 6 catalyst, E stereoselective alkene derivatives were converted into Z stereoselective alkene derivatives.When chromone (41a) was treated with diphenylacetylene (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (5 mol %) , AgSbF 6 (16 mol %), Cu(OAc) 2 (10 mol %) and acetic acid (2.0 equiv) in 1,2-dichloroethane at 100 C for 6 h, a stereoisomeric mixture of alkenylated product 42a was observed in 94% yield in a 91:9 E/Z ratio (Scheme 23).If the same reaction was done in the presence of an excess amount of AgSbF 6 (20 mol %) under the same reaction conditions, the stereoisomer of alkene derivative was reversed and producing product 43a in 87% yield in an 8:92 E/Z ratio.AgSbF 6 plays an important role for Please do not adjust margins Please do not adjust margins the stereoselective isomerization of an alkene derivative.In the reaction, alkenylation takes place at the C-5 position of chromone (41a).The alkenylation reaction was examined with various substituted chromone derivatives and alkynes.In all these reactions, the expected trisubstituted alkene derivatives were observed in good to excellent yields.To prove the role of AgSbF 6 , E-stereoisomeric alkene derivative 42d was prepared separately and treated with AgSbF 6 in acetic acid at 100 C for 2 h.In the reaction, the reversed stereoisomeric chromone derivative 43d was observed in 87% yield in a 9:91 E:Z ratio.In was proposed that the isomerization process takes place through the formation of the alkyl cation 44 followed by the bond rotation to drive the transformation of E-alkenyl into the thermodynamically more stable Z-isomer in the presence of AgSbF 6 catalyst.Recently, Liu's group reported a ruthenium-catalyzed 1,2,3triazole directed hydroarylation of alkynes with aromatics. 19In the reaction, bis alkenylated aromatics were observed and the alkenylation takes place at the both ortho C-H bonds of phenyl group.Please do not adjust margins Please do not adjust margins well in all cases and the expected bis alkenylated aromatics were observed in good to excellent yields 48b-f.The reaction was compatible with F, Cl, CF 3 , NO 2 and OMe substituents on the aromatic ring of substituted 1,2,3-triazole derivatives.The hydroarylation reaction was also examined with various symmetrical alkynes.In all cases, the expected bis alkenylated products were observed in good yields.Unsymmetrical alkynes such as 1-phenyl-1-propyne and 1-phenyl-1-hexyne reacted efficiently with 47a, yielding the expected bis alkenylated aromatics 48g and 48h in a highly regio-and steteroselective manner.Methyl as well as hexyl substituted carbon of alkynes were connected at the ortho C-H bond of phenyl group.In 2014, Zeng's group reported a ruthenium-catalyzed 2pyridyl directed hydroarylation of alkynes with indoles.20a The reaction of N-(2-pyridyl)indole (49a) with diphenylacetylene (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (7 mol %), AgSbF 6 (20 mol %) and pivalic acid (1.0 equiv) in 1,4-dioxane solvent at 110 C for 24 h gave C2-alkenylated N-(2-pyridyl)indole (50a) in 54% yield (Scheme 26).Later, the yield of the reaction was increased up to 98% by changing the solvent 1,4-dioxane into dimethylformamide.In the reaction, 2-pyridyl acts as a directing group to activate the C2-H of indole.As 2-pyridyl is a strong chelating group, the catalytic reaction can proceed efficiently with a neutral ruthenium species and the cationic ruthenium species was not needed.

Ruthenium
The hydroarylation reaction was examined with various sensitive functional groups such as OMe, F, Cl, Br, NO 2 , CN and CO 2 Me substituent on the aromatic ring of indole derivatives.In all these substrates, the hydroarylation reaction worked very nicely and yielding the expected alkene derivatives in good to excellent yields 50b-f.Next, the hydroarylation reaction was examined with various unsymmetrical alkynes.
Particularly, 3-phenylprop-2-yn-1-ol reacted nicely with 52a giving the corresponding alkene derivative 50g in 89% yield, in which, CH 2 OH group substituted carbon of alkyne was connected at the C2-position of indole.Meanwhile, the hydroarylation reaction was examined with diyne and enyne (products 50j and 50k).Interestingly, the hydroarylation reaction was compatible with terminal alkynes.However, in the reaction, a mixture of 1,1-disubstituted alkene and 1,2disubstituted alkene derivatives were observed.The hydroarylation reaction was also nicely worked with N-(2pyridyl)pyrrole (49m).However, in the reaction, a mixture of diene derivatives 50m and 50m' were observed.Later, 2pyridyl group of alkene derivative 50a was cleaved in the presence of MeOTf and a free N-H indole derivative 51a was observed in 90% yield (Scheme 27).
Very recently, the same group reported a ruthenium-catalyzed carbamide directed Z-stereoselective hydroarylation of alkynes with indole derivatives.20b In the previous report, by employing 2-pyridyl group, alkenylation was done at the C2-position of indole in a highly E-steroselective manner.In the present work, by employing carbamide group, alkenylation was done at the C2-position of indole in a highly Z-steroselective manner.It is important to note that during the reaction, carbamide group was cleaved and only providing Z-stereoselective alkene derivatives.When N-benzyl-1H-indole-1-carboxamide (52a) was treated with diphenylacetylene (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (10 mol %), Cu(OAc) 2 (0.5 equiv) and acetic acid (1.0 equiv) in 1,2-dichloroethane at 100 C for 24 h, a Z-stereoselective C2-alkenylated indole derivative 53a was observed in 80% yield (Scheme 28).The optimization studies clearly revealed that the AcOH is crucial to increase the yield of the product 53a.
The scope of hydroarylation reaction was examined with OMe, F, Br, Cl and CO 2 Me substituted indole derivatives and Ncarbamide substituted pyrrole.In all these reactions, Zstereoselective alkene derivatives were observed in good to excellent yields 53b-g.The hydroarylation reaction was also Please do not adjust margins Please do not adjust margins examined with various unsymmetrical alkynes.Interestingly, 1phenyl-1-propyne, 1-phenyl-1-butyne and 4-methoxylphenyl phenyl alkynes reacted regioselectively with 52a providing C2alkenylated indole derivatives 53h-k in good yields in a highly Z-regioselective manner.

Ruthenium-catalyzed sulfur assisted hydroarylation of alkynes with benzylthioethers
Scheme 30 The hydroarylation of alkyne with benzylthioethers.
Very recently, Villuendas and Urriolabeitia reported a ruthenium-catalyzed hydroarylation of alkynes with benzylthioethers leading to ortho alkenylated benzylthioethers in good to moderate yields. 21Treatment of thioether 58a with hex-3-yne (2a) in the presence of [{RuCl 2 (p-cymene)} 2 ] (10 mol %) , KPF 6 (10 mol %) and Cu(OAc) 2 . H 2 O (1.0 equiv) in electron deficient HFIP solvent at 100 C for 0.5 h under the microwave irradiation (150 W) gave a mixture of mono as well as bis alkenylated benzylthioether 59a in 78% yield.To avoid the bis alkenylation, one of the ortho carbons of benzylthioether was blocked by Me, CF 3 , Cl and NO 2 groups and treated with 2a under similar reaction conditions.In the reaction, only mono alkenylated benzylthioethers 59b-e were observed in good to moderate yield.The hydroarylation reaction was examined with various S substituted benzylthioethers.In these reactions also, the expected alkenylated product was observed in good yields 59f-h.Later, the hydroarylation reaction was examined with unsymmetrical alkynes.However, in the reaction, a mixture of regio-as well as stereoisomeric products was observed 59i-k.

Conclusions
In the present review, a ruthenium-catalyzed hydroarylation of alkynes with substituted aromatics providing trisubstituted This journal is © The Royal Society of Chemistry 20xx Please do not adjust margins Please do not adjust margins alkene derivatives in a highly regio-and stereoselective manner was discussed elaborately.The hydroarylation reaction was explored with amide, azole, carbamate, phosphine oxide, amine, acetyl and sulfoxide directed aromatics with alkynes.The hydroarylation reaction was examined with various symmetrical and unsymmetrical alkynes.In all these reactions, the expected alkene derivatives were observed in a highly regio-and stereoselective manner.
In the alkyne, if coordinating group such as aryl or ester is present in one of the carbons and non-coordination alkyl group in the another carbon, the C-H bond of aromatic moiety prefers to connect at the alkyl substituted carbon of alkyne and the coordinating group of alkyne and aromatic moiety are trans to each other.In the unsymmetrical alkyne, if both carbons having coordinating groups such as Ph and ester, a mixture of regioisomeric products were observed.A possible reaction mechanism of these reactions was proposed and the proposed mechanism was strongly supported by experimental evidence.Particularly, deuterium labelling and kinetic studies clearly revealed that the C-H bond activation step is a rate determining step and the C-H bond activation proceeds via a deprotonation pathway.
There are still several challenges in a ruthenium-catalyzed hydroarylation reaction.Mostly, a higher reaction temperature is needed for the C-H bond functionalization.We believe that it can be done at room temperature by designing the new ruthenium catalysts or to find out the proper reaction conditions with the existing catalysts.The hydroarylation reaction can be explored with a weak chelating group substituted aromatics.Apart from sp 2 C-H bond functionalization, sp 3 C-H bond functionalization should also be explored.In addition, in the hydroarylation reaction, only alkyne carbon-carbon π-component is used.It can also be extended with other carbon-carbon π-components such as alkenes and allenes.We believe that these issues could be easily overcome in the future investigations.

Fig. 2
Fig. 2 Synthesis of alkenes by C-H bond activation.

Scheme 8
Scheme 8 Synthesis of phenol derivatives.
To support the role of organic acid, 28i was treated with 2b in the presence of CD 3 COOD instead of pivalic acid under similar reaction conditions.In the reaction, product d-29i was observed in 40% yield with 76% of deuterium incorporation at the alkene carbon.Meanwhile, 67% deuterium incorporation was observed at the ortho carbon of anilide in product d-29i.
insertion of alkyne 2 into the Ru-carbon bond of intermediate 34 provides intermediate 35.Protonation at Ru-C bond of intermediate 35 in the presence of RCOOH affords the hydroarylation product 29 and regenerates the active ruthenium species 33 for the next catalytic cycle.O Scheme 19 Cyclization of substituted anilides with propiolates.
Scheme 24 Silver-catalyzed stereoisomerization of trisubstituted alkenes.The alkene isomerization reaction was further examined with ortho alkenylated anilides, aromatic carbamates, esters, sulfoxides and phosphonates in the presence of AgSbF 6 and acetic acid (Scheme 24).In all these reactions, a mixture of stereoselective alkene derivatives 46 were observed in a major amount of >92% of Z stereoisomer.The representative examples of these reactions were shown in Scheme 24.
-triazole substituted aromatics.The reaction worked very This journal is © The Royal Society of Chemistry 20xx Scheme 28 Z-Stereoselective C-2 alkenylation of indoles with alkynes.Scheme 29 Proposed mechanism for the hydroarylation of alkynes with indoles.A possible reaction mechanism was proposed to account for the present Z-stereoselective alkenylation reaction (Scheme 29).The ortho C-H bond of indole group was deprotonated by an acetate species of ruthenium catalyst providing a metalacycle intermediate 54.Later, the nucleophilic attack of amide nitrogen 54 into an alkyne 2 with the assistance of Cu(OAc) 2 forms an alkenylated intermediate 55 and isocyanate 56 as a byproduct.Later, acetate anion undergoes nucleophilic attack with isocyanate 56 forming amide 57 with the release of CO 2 .In the same time, an alkenylated metal intermediate 55 could be further isomerized followed by protonation produces the final free (N−H) (Z)-alkenyl indoles 53 and regenerates the active catalyst.