Efficient synthesis of trisubstituted alkenes in an aqueous-organic system using a versatile and recyclable Rh/m-TPPTC catalyst

We have found that the use of [Rh(cod)OH]₂ associated with the water-soluble ligand m-TPPTC was highly efficient for the Rh-catalyzed arylation of alkynes. Aryl and alkyl alkynes were transformed to alkenes using 3 mol % rhodium catalyst and 2.5 equiv of boronic acid at 100 °C in a biphasic water/toluene system in 80-99% yield. The reaction was found to be totally regioselective for alkyl arylalkynes and alkyl silylated alkynes. The Rh/m-TPPTC system was for the first time recycled with no loss of the activity and with excellent purity of the desired alkene.     

Recent advances in the synthetic and mechanistic aspects of the ruthenium-catalyzed carbon-heteroatom bond forming reactions of alkenes and alkynes

The group’s recent advances in catalytic carbon-to-heteroatom bond forming reactions of alkenes and alkynes are described. For the C-O bond formation reaction, a well-defined bifunctional ruthenium-amido catalyst has been successfully employed for the conjugate addition of alcohols to acrylic compounds. The ruthenium-hydride complex (PCy₃)₂(CO)RuHCl was found to be a highly effective catalyst for the regioselective alkyne-to-carboxylic acid coupling reaction in yielding synthetically useful enol ester products. Cationic ruthenium-hydride catalyst generated in-situ from (PCy₃)₂(CO)RuHCl/HBF₄·OEt₂ was successfully utilized for both the hydroamination and related C-N bond forming reactions of alkenes. For the C-Si bond formation reaction, regio- and stereoselective dehydrosilylation of alkenes and hydrosilylation of alkynes have been developed by using a well-defined ruthenium-hydride catalyst. Scope and mechanistic aspects of these carbon-to-heteroatom bond forming reactions are discussed.     

A regioselective synthesis of 3-benzazepinones via intramolecular hydroamidation of acetylenes

Synthesis of 3-benzazepinones by palladium-catalyzed intramolecular addition of amides to alkynes is achieved. Phenyl acetylenes substituted in the ortho-position with tethered amide functionality were prepared in a few steps from readily available starting materials. It was found that 5% Pd(OAc)₂(PPh₃)₂ and KOH most effectively promoted cyclization. When the tethered group is an acetamide and an alkyl substituent is on the acetylene unit, regioselective 3-benzazepinone synthesis could be achieved in good yields.     

Rh2(S-PTAD)4-catalyzed asymmetric cyclopropenation of aryl alkynes

Rh₂(S-PTAD)₄ is an effective catalyst for the asymmetric cyclopropenation of aryl alkynes using a siloxyvinyldiazoacetate as the carbenoid precursor. Upon deprotection of the silyl protecting group, highly enantioenriched cyclopropenes bearing geminal acceptor groups can be accessed. These cyclopropenes undergo regioselective rhodium(II)-catalyzed ring expansion to furans.     

Inorganic base-mediated stereoselective hydroamination of arylalkynes with imidazole: An efficient access to N-vinylimidazoles

A metal-free inorganic base-mediated highly stereoselective hydroamination of arylalkynes with imidazoles has been developed, and the corresponding N-vinylimidazoles were obtained in good yields and with moderate to excellent stereoselectivities (up to 99:1). For the electron rich alkynes, the reaction system of CsOH·H₂O/NMP/140?°C led to the predominant formation of E-addition products, while the reaction system of KOH/NMP/90?°C afforded the Z-isomers as the major product. The electron deficient alkynes furnished predominantly the E-addition products in both reaction systems. This study essentially provides a general and an efficient protocol for the synthesis of E-isomer of the N-vinylimidazoles.     

Regioselective single-step synthesis of 2-aminoimidazole derivatives

A convenient single-step strategy for the regioselective assembly of 2-aminoimidazole derivatives is herein described. Through a transition metal-free domino addition/cyclization process, the reactions of unsymmetrical carbodiimides with propargylic amines mediated by Cs₂CO₃ selectively afforded the corresponding polysubstituted 2-aminoimidazoles in moderate to good yields under very mild conditions. The regioselectivity was reversed in the presence of TEA at a higher temperature. The obtained 2-(o-iodoaryl)amino imidazoles could be easily converted to 2-(2-biphenyl)amino imidazole, 2-(o-alkynylphenyl)amino imidazole, benzoimidazo[1,2-a]imidazole and N-(imidazol-2-yl)indole derivatives.     

Synthesis and characterization of a free phenylene bis(N-heterocyclic carbene) and its di-Rh complex: Catalytic activity of the di-Rh and CCC–NHC Rh pincer complexes in intermolecular hydrosilylation of alkynes

1,3-Bis(3-butylimidazolium-1-yl)benzene diiodide (1) was reacted with Li(2,2,6,6-tetramethylpiperidine) yielding the free bis-carbene, 1,3-bis(3-butylimidazol-2-ylidene-1-yl)benzene (3), which has been spectroscopically characterized. Combining the free bis-carbene with [Rh(COD)Cl]₂ yielded the corresponding di-Rh bis(N-heterocyclic carbene) complex (4) that was structurally characterized. The di-Rh bis-carbene complex was found to exhibit complex solution ¹³C and ¹H NMR spectra that have been assigned as a mixture of diastereomers. The crystal structure of the di-Rh bis-carbene compound 4 was composed of a pair of enantiomeric atropisomers. The diastereomeric atropisomers were assigned as the source of the spectral complexities. The di-Rh di-carbene complex 4 and the CCC–NHC Rh pincer complex 2 were applied as catalysts in hydrosilylation reactions of terminal and internal alkynes. Both catalysts are highly active, regioselective, stereoselective, and chemoselective: terminal alkynes give predominantly the β-(Z) isomer and internal alkynes afford the β-(E) isomer in chloroform or benzene. One of the strongest attributes of the catalyst systems is that the results were achieved without exclusion of air and without purification of commercially available reagents.     

Highly regioselective hydroselenation and double-bond isomerization of terminal alkynes with benzeneselenol catalyzed by bis(triphenylphosphine)palladium(II) dichloride

Bis(triphenylphosphine)palladium(II) dichloride (PdCl₂(PPh₃)₂) catalyzes regioselective addition of benzeneselenol to terminal alkynes and the subsequent double-bond isomerization to afford the corresponding internal alkenyl selenides in good yields.     

InCl3 and ZrCl4 catalyzed regioselective reaction of 2,2′-dihydroxybiphenyl with terminal alkynes: synthesis of new dibenzo[d,f][1,3]dioxepines

The regioselective reaction of 2,2′-dihydroxybiphenyl with terminal alkynes was found to be rapidly catalyzed by InCl₃ and ZrCl₄. The chemoselectivity of catalysts and alkynes for biphenol over water, together with the reaction mechanism are discussed in details.     

Reaction of hydrosilanes with alkynes catalyzed by gold nanoparticles supported on TiO2

Gold nanoparticles supported on TiO₂ (0.8–1.4 mol %) catalyze the β-(E) regioselective hydrosilylation of a variety of functionalized terminal alkynes with alkylhydrosilanes in 1,2-dichloroethane (70 °C). The product yields are excellent, and the reaction times relatively short, while almost equimolar amounts of alkynes and hydrosilanes can be used. Minor side-products in up to 35% relative yield of cis-oxidative (dehydrogenative) disilylation, an unprecedented reaction pathway, are formed in the cases of the less hindered hydrosilanes and alkynes. Triethoxysilane reacts faster and affords apart from β-(E) addition products, minor α-hydrosilylation regio-isomers in upto 15% relative yield. Internal alkynes are generally less reactive or even unreactive. It is proposed that cationic Au(I) species stabilized by the support are the reactive catalytic sites, forming in the presence of hydrosilanes either silyl–Au(III)–H (hydrosilylation pathway) or Au(III)–disilyl species (dehydrogenative disilylation pathway). Regarding the mechanism of hydrosilylation, kinetic experiments are in agreement with silyl carbometallation of the triple bond in the rate determining step of the reaction.     

Iron-catalyzed hydroaminocarbonylation of alkynes: Selective and efficient synthesis of primary α,β-unsaturated amides

α,β-Unsaturated primary amides are important intermediates and building blocks in organic synthesis. Herein, we report a ligand-free iron-catalyzed hydroaminocarbonylation of alkynes using NH₄HCO₃ as the ammonia source, enabling the highly efficient and regioselective synthesis of linear α,β-unsaturated primary amides. Various aromatic and aliphatic alkynes are transformed into the desired linear α,β-unsaturated primary amides in good to excellent yields. Further studies show that using NH₄HCO₃ as the ammonia source is key to obtain good yields and selectivity. The utility of this route is demonstrated with the synthesis of linear α,β-unsaturated amides including vanilloid receptor-1 antagonist TRPV-1.     

Catalytic CN Bond Alkynylation of N‐Benzylic Sulfonamides with Terminal Alkynes

A new cross‐coupling reaction of N‐benzylic sulfonamides with terminal alkynes for the synthesis of internal alkynes is reported. In the presence of 5 mol% of (Tf)₂NH/Bi(OTf)₃ (1:1), a broad range of N‐benzylic sulfonamides react smoothly with arylacetylenes to afford structurally diverse internal alkynes in moderate to excellent yields. We reasoned that vinyl cations could be formed by the regioselective attack of terminal alkynes with benzyl cations generated in situ from N‐benzylic sulfonamides under acidic conditions, which then eliminated to form a carbon‐carbon triple bond.     

Synthesis and biological evaluation of novel imidazole-containing macrocycles

A new family of compounds made of a 5-aryl-1H-imidazole motif included in a macrocycle has been designed and synthesized. The synthesis of the imidazole core makes use of our previously developed method for the regioselective preparation of 1,2,5-trisubstituted imidazoles while the construction of the macrocycle is based on a three steps sequence: S_NAr, Suzuki coupling, and RCM reaction. Biological evaluation of synthesized imidazole-containing macrocycles revealed that they display actual binding activity toward A₃ adenosine (h) receptor, dopamine D₁ (h) receptor, chloride channel (GABA-gated), and choline transporter (h) CHT1.     

Tandem versus single C-C bond forming reaction under palladium-copper catalysis: regioselective synthesis of α-pyrones fused with thiophene

We herein report a highly convenient protocol for rapid construction of α-pyrone fused with thiophene. This includes one-pot and regioselective synthesis of 4,5-disubstituted and 5-substituted thieno[2,3-c]pyran-7-ones, 6,7-disubstituted and 6-substituted thieno[3,2-c]pyran-4-ones. The synthesis of thieno[2,3-c]pyran-7-ones involves palladium mediated cross coupling of 3-iodothiophene-2-carboxylic acid with terminal alkynes in a simple synthetic operation. The coupling-cyclization reaction was initially studied in the presence of Pd(PPh₃)₂Cl₂ and CuI in a variety of solvents. 5-Substituted 4-alkynylthieno[2,3-c]pyran-7-ones were isolated in good yields when the reaction was performed in DMF. Similarly, 6-substituted 7-alkynylthieno[3,2-c]pyran-4-ones were synthesized via palladium-catalyzed cross coupling of 2-bromothiophene-3-carboxylic acid with terminal alkynes. A tandem C-C bond forming reaction in the presence of palladium catalyst rationalizes the formation of coupled product in this apparently three-component reaction. The cyclization step of this coupling-cyclization-coupling process occurs in a regioselective fashion to furnish products containing six-membered ring only. This sequential C-C bond forming reaction however, can be restricted to the formation of single C-C bond by using 10% Pd/C-Et₃N-CuI-PPh₃ as catalyst system in the cross coupling reaction. 5-Substituted thieno[2,3-c]pyran-7-ones were obtained in good yields when the coupling reaction was performed under this condition. Some of the compounds synthesized were tested in vitro for their anticancer activities.     

Rhodium(III)-catalysed,redox-neutral C(sp2)-H alkenylation using pivalimide as a directing group with internal alkynes

In the presence of [RhCp¹Cl₂]₂, N-pivaloyl anilines react with internal alkynes to give the corresponding 2-alkenylpivalimides under redox neutral conditions through C-H activation. This redox neutral hydroarylation, which does not require an external organic acid, unlocks a regioselective synthetic route to 2-alkenyl anilines and is generally applicable to diversely substituted electron rich and electron poor pivalimides.     

Zinc‐Catalysed Hydroboration of Terminal and Internal Alkynes

A regioselective hydroboration of alkynes has been developed by using commercially available zinc triflate as a catalyst, in the presence of catalytic amount of NaBHEt₃. The reaction tolerates a wide range of terminal alkynes having several synthetically useful functional groups and proceeds regioselectively to furnish hydroborated products in moderate to excellent yields. This system shows moderate chemoselectivity towards terminal C≡C bond over terminal and internal C=C bond and internal C≡C bond.     

One pot Pd(OAc)2-catalysed 2,5-diarylation of imidazoles derivatives

The regioselective 2- or 5-arylation of imidazole derivatives with aryl halides using palladium catalysts has been described in recent years; whereas the arylation at both C2 and C5 carbons of imidazoles in high yields has not been performed. We found conditions allowing the access to these 2,5-diarylimidazoles via a one pot reaction. The choice of the base was found to be crucial to obtain these products in high yields. Using CsOAc as the base, DMA as the solvent and only 2 mol % of the phosphine-free Pd(OAc)₂ the catalyst, the target 2,5-diarylated imidazoles were obtained in moderate to good yields with a wide variety of aryl bromides. Substituents such as fluoro, trifluoromethyl, formyl, acetyl, propionyl, ester, nitro or nitrile on the aryl bromide were tolerated. Sterically congested aryl bromides or heteroaryl bromides can also be employed. Surprisingly the nature of the substituent at position 1 on the imidazole derivative exhibits a huge influence on the reaction.     

Homogeneous hydrogenation of alk-1-enes and alkynes catalyzed by the 1-[Ir(CO)(PhCN)(PPh3)]-7-C6H5-1,7-(σ-C2B10H10) complex

The complex [Ir(σ-carb)(CO)(PhCN)(PPh₃)], where carb = -7-C₆H₅-1,2C₂B₁₀H₁₀, was found to be an effective catalyst for homogeneous hydrogenation of terminal olefins and acetylenes at room temperature and atmospheric or subatmospheric hydrogen pressure. Internal olefins are not hydrogenated, but simple alk-1-enes are readily converted into the corresponding alkanes. Isomerization of the double bond catalyzed by the metal complex occurs at very small extent. Catalytic hydrogenation of olefins having carboxylate substituents on the unsaturated carbon atoms is prevented by the formation of thermally stable chelate hydridoalkyl complexes of the type I$\text{(H)}$(σ-CHRCHR′C(O)OR″) (σ-carb)(CO)(PPh₃)]. Acetylenes are hydrogenated to alkenes. The alk-1-enes formed in the hydrogenation of the alkynes HCCR in turn undergo the more slow reactions either of hydrogenation to alkanes or isomerization to internal olefins which cannot be further hydrogenated. Hydrogenation of alkynes of the type RCCR′ is stereospecifically cis, yielding cis- olefins. Catalyzed cis → trans isomerization reaction of these internal olefins occurs only to a negligeable extent.     

Annulation of internal alkynes through a hydroamination/aza-Heck reaction sequence for the regioselective synthesis of indoles

Highly regioselective annulation reactions of unsymmetrically substituted alkynes by primary 2-bromo or 2-chloroanilines are achieved with an efficient one-pot protocol, which relies on a regioselective TiCl₄-catalyzed intermolecular hydroamination and a subsequent palladium-catalyzed intramolecular aza-Heck reaction. The use of unsymmetrically substituted alkynes in this strategy enables the synthesis of diversely functionalized indoles, with a regioselectivity that is complementary to the one obtained when employing Larock's annulation reaction.     

Insertion of activated acetylenes into the metal-hydride bond of [(η5-C5H5)2M(CO)H] (M = Nb,Ta)

Reactions of [Cp₂M(CO)H] (M = Nb, Ta; Cp = η⁵-C₅H₅) with various acetylenes RCCR having electron-withdrawing groups were investigated. They give the σ-al- kenyl complexes [Cp₂M(CO)(CRCHR)] via insertion of the alkyne into the MH bond. On the basis of ¹H and ¹⁹F NMR data the reactions were shown to be: (i) regioselective, monosubstituted alkynes giving only the α-R metallated complex; (ii) stereoselective, exclusive formation of the Z-isomer being observed with hexafluorobut-2-yne. The Z isomer has been shown to exist as two conformers, the steric requirements of the ligands creating a barrier to rotation of the alkenyl group around the MC σ bond.