Palladium-Catalyzed Alkynylation Research Articles

Palladium-catalyzed alkynylation of allylic gem-difluorides.

Herein, a palladium-catalyzed regioselective alkynylation, esterification, and amination of allylic gem-difluorides via C-F bond activation/transmetallation/β-C elimination or nucleophilic attack has been achieved. This innovative protocol showcases an extensive substrate range and operates efficiently under mild reaction conditions, resulting in high product yields and Z-selectivity. Particularly noteworthy is its exceptional tolerance towards a wide array of functional groups. This developed methodology provides effective and convenient routes to access a diverse array of essential fluorinated enynes, esters and amines.

Palladium-Catalyzed Alkynylation of Enones with Alkynylsilanes via C-C Bond Activation.

We report herein the synthesis of 1,3-enynes via palladium-catalyzed cross-coupling between enone derivatives and alkynylsilanes. The employment of an appropriate pyridine-oxazoline ligand is the key to the C-C cleavage and the high E/Z stereoselectivity. This protocol features broad substrate scope and wide functional-group tolerance, affording the desired products in moderate-to-good yields. Late-stage diversification of natural product β-ionone further demonstrated the synthetic utility of this protocol.

Palladium-catalyzed direct alkynylation of thiophenes with halosilylacetylenes

Silylethynylthiophenes were obtained from palladium-catalyzed alkynylation of various thiophenes with 1-halo-2-silylacetylenes. The α-position of thiophenes was alkynylated with high regioselectivity. The terminal silyl groups of products could be replaced by several functional groups.

Access to Divergent Fluorinated Enynes and Arenes via Palladium-Catalyzed Ring-Opening Alkynylation of gem-Difluorinated Cyclopropanes.

Herein, we describe a palladium-catalyzed alkynylation of gem-difluorinated cyclopropanes via C-C bond activation/C-F bond cleavage, followed by C-C(sp) coupling. The new approach proceeds with broad substrate scope under mild reaction conditions, whereas both 1,1-disubstituted and complex-molecule-modified gem-difluorinated cyclopropanes react smoothly with high stereoselectivity. The developed method provides efficient and convenient ways access to diversity of important fluorinated enynes and arenes by slightly modification of the reaction conditions.

Palladium-catalyzed alkynylation of aromatic amines via in situ formed trimethylammonium salts

A palladium-catalyzed alkynylation of aromatic amines with terminal alkynes via in situ formed trimethylammonium salts is developed. Compared with previous system using ammonium salts as starting materials and high loading of pre-prepared NHC-Pd catalyst (10 mol% Pd), this reaction directly employed amines as the coupling partners and the commercially available Pd2(dba)3/PPh2Cy (1 mol% Pd) as the catalyst, greatly simplifying the manipulation and decreasing the cost.

Switchable Synthesis of Arylalkynes and Phthalides via Controllable Palladium-Catalyzed Alkynylation and Alkynylation-Annulation of Benzoic Acids with Bromoalkynes.

A ligand-promoted palladium(II)-catalyzed synthesis of arylalkynes and phthalides from benzoic acids and bromoalkynes via carboxylate-assisted ortho-C-H activation is reported. A series of phthalides with various functional groups are prepared via ortho-alkynylation and alkynylation-annulation. Moreover, the key ortho-alkynylated products are also obtained by controlling the reaction conditions. In addition, heteroaryl acids could react smoothly to form the corresponding alkynylation and cyclization products.

Palladium-catalyzed direct ortho-alkynylation of aryl acetamides with low catalyst loading

The palladium-catalyzed alkynylation of phenylacetic acid derivatives using 4-CF3C6F4NH2 as the auxiliary is described. The reaction efficiency can be greatly promoted by pyridine ligand, which enables the reaction to proceed at a catalyst loading as low as 1 mol%. Various functional groups are tolerated under the reaction conditions. The kinetic studies show that the rate of the reaction is first order in phenylacetamide and the Pd(OAc)2 in combination of the pyridine ligand provides a highly robust and effective catalyst.

Cyclic Hypervalent Iodine Reagents: Enabling Tools for Bond Disconnection via Reactivity Umpolung.

The efficient synthesis of organic compounds is an important field of research, which sets the basis for numerous applications in medicine or materials science. Based on the polarity induced by functional groups, logical bond disconnections can be deduced for the elaboration of organic compounds. Nevertheless, this classical approach makes synthesis rigid, as not all bond disconnections are possible. The concept of Umpolung has been therefore introduced: by inverting the normal polarity of functional groups, new disconnections become possible. Among the tools for achieving Umpolung, hypervalent iodine reagents occupy a privileged position. The electrophilicity of the iodine atom and the reactivity of the hypervalent bond allow access to electrophilic synthons starting from nucleophiles. Nevertheless, some classes of hypervalent iodine reagents can be too unstable for many applications, in particular involving metal catalysis. In this context, cyclic hypervalent iodine reagents, especially benziodoxolones (BXs), have been known for a long time to be more stable than their acyclic counterparts, yet their synthetic potential had not been fully exploited. In this Account, we report our efforts since 2008 on the use of BX reagents in the development of new transformations in organic synthesis, which showed for the first time their versatility as synthetic tools. Our work started with electrophilic alkynylation, as alkynes are one of the most important functional groups in organic chemistry, but are usually introduced as nucleophiles. We used ethynylbenziodoxolones (EBXs) in the direct alkynylation of nucleophiles, such as keto esters, thiols, or phosphines. The reagents could then be applied to the gold- and palladium-catalyzed alkynylation of C-H bonds on (hetero)arenes, leading to a more efficient alternative to the Sonogashira reaction. More complex reactions were then developed with formations of several bonds in a single transformation. Gold- and platinum-catalyzed cyclization/alkynylation domino processes gave access to new types of alkynylated heterocycles. Multifunctionalization of olefins became possible through intramolecular oxy- and amino-alkynylations. (Enantioselective) copper-catalyzed oxy-alkynylation of diazo compounds led to stereocenters with perfect atom economy. Finally, EBXs were also used for the alkynylation of radicals generated under photoredox conditions. Since 2013, we then extended the use of BX reagents to other transformations. Azidobenziodoxol(on)ess (ABXs) were used in the azidation of keto esters, enol silanes, and styrenes. New more stable derivatives were introduced. Cyanobenziodoxolones (CBXs) enabled the cyanation of stabilized enolates, thiols, and radicals. Finally, new BX reagents were developed for the Umpolung of indoles and pyrroles. They could be used in metal-catalyzed directed C-H functionalizations, as well as in Lewis acid mediated oxidative coupling to give functionalized bi(hetero)arenes. In the past decade, our group and others have shown that BX reagents are not only "structural beauties", but also extremely useful reagents in synthetic chemistry. A toolbox of cyclic hypervalent iodine reagents is now available to achieve Umpolung-based disconnections. We are convinced that the field is still in its infancy, and many new reagents and transformations still remain to be discovered.

Palladium-Catalyzed Synthesis of 2,3-Diaryl- N-methylindoles from ortho-Alkynylanilines and Aryl Pinacol Boronic Esters.

A palladium-catalyzed synthesis of 2,3-diaryl- N-methylindoles from o-alkynylanilines and aryl pinacol boronic esters was developed. The system possesses high functional group tolerance and a broad substrate scope with a variety of aryl pinacol boronic esters to provide valuable 2,3-diaryl- N-methylindoles in moderate to good yields. Remarkably, the sequential reaction controlled by iridium-catalyzed C-H borylation or palladium-catalyzed alkynylation followed by the present palladium-catalyzed C3 arylation reaction provided functionalized 2,3-diaryl- N-methylindoles in good yields.

Regioselective Palladium-Catalyzed Alkynylation of Enallenes

Regioselective Palladium-Catalyzed Alkynylation of Enallenes

ChemInform Abstract: Silver‐Free Palladium‐Catalyzed sp3 and sp2 C—H Alkynylation Promoted by a 1,2,3‐Triazole Amine Directing Group.

AbstractA triazolylamine is proved to be an effective directing group in promoting both sp3 and sp2 C—H alkynylations under Pd‐catalysis.

Palladium-Catalyzed Alkynylation

Palladium-Catalyzed Alkynylation

ChemInform Abstract: Privilege Ynone Synthesis via Palladium‐Catalyzed Alkynylation of “Super‐Active Esters”.

A neat palladium-catalyzed alkynylation reaction was developed with “super-active ester” as the carbonyl electrophile, which provides a clean and efficient synthetic protocol for a broad array of ynone compounds under CO-, Cu-, ligand-, and base-free conditions. The superior activity of triazine ester was rationalized by the strong electron-withdrawing ability and the unique affinity of triazine on palladium. A mechanistic experiment clearly demonstrated that the N–Pd coordination of triazine plays a crucial role for the highly efficient C–O activation.

Privilege Ynone Synthesis via Palladium-Catalyzed Alkynylation of "Super-Active Esters".

A neat palladium-catalyzed alkynylation reaction was developed with "super-active ester" as the carbonyl electrophile, which provides a clean and efficient synthetic protocol for a broad array of ynone compounds under CO-, Cu-, ligand-, and base-free conditions. The superior activity of triazine ester was rationalized by the strong electron-withdrawing ability and the unique affinity of triazine on palladium. A mechanistic experiment clearly demonstrated that the N-Pd coordination of triazine plays a crucial role for the highly efficient C-O activation.

Palladium-Catalyzed Alkynylation of Morita-Baylis-Hillman Carbonates with (Triisopropylsilyl)acetylene on Water.

Direct alkynylation of Morita-Baylis-Hillman carbonates with (triisopropylsilyl)acetylene catalyzed by a Pd(OAc)2-NHC complex was developed "on water" to give the corresponding 1,4-enynes. The significant effects of water amount in the solvent on further transformations of 1,4-enynes were investigated.

Synthesis of β-alkynyl α-amino acids via palladium-catalyzed alkynylation of unactivated C(sp3)-H bonds

β-Di-substituted α-amino acids (AAs) contain adjacent carbon stereogenic centers and pose considerable synthetic challenge. Complementary to the conventional synthesis strategies based on the transformation of existing functional groups, we envisioned these molecules could be quickly accessed via selective functionalization of sp3 hybridized C-H bonds on the side chains of common α-AA precursors. We report a readily applicable method to prepare β-alkynyl α-amino acids via Pd-catalyzed diastereoselective C(sp3)-H alkynylation of common α-amino acids precursors with acetylene bromide.

Synthesis of 1,3-bis(tetracyano-2-azulenyl-3-butadienyl)azulenes by the [2+2] cycloaddition-retroelectrocyclization of 1,3-bis(azulenylethynyl)azulenes with tetracyanoethylene.

1,3-Bis(azulenylethynyl)azulene derivatives 9-14 have been prepared by palladium-catalyzed alkynylation of 1-ethynylazulene 8 with 1,3-diiodoazulene 1 or 1,3-diethynylazulene 2 with the corresponding haloazulenes 3-7 under Sonogashira-Hagihara conditions. Bis(alkynes) 9-14 reacted with tetracyanoethylene (TCNE) in a formal [2+2] cycloaddition-retroelectrocyclization reaction to afford the corresponding new bis(tetracyanobutadiene)s (bis(TCBDs)) 15-20 in excellent yields. The redox behavior of bis(TCBD)s 15-20 was examined by using CV and differential pulse voltammetry (DPV), which revealed their reversible multistage reduction properties under the electrochemical conditions. Moreover, a significant color change of alkynes 9-14 and TCBDs 15-20 was observed by visible spectroscopy under the electrochemical reduction conditions.

Synthesis, Properties, and Redox Behavior of Tetracyanobutadiene and Dicyanoquinodimethane Chromophores Bearing Two Azulenyl Substituents

Acetylene derivatives with an azulenyl group at both terminals have been prepared by palladium-catalyzed alkynylation under Sonogashira-Hagihara conditions. These alkynes reacted with tetracyanoethylene and 7,7,8,8-tetracyanoquinodimethane in a formal [2 + 2] cycloaddition-retroelectrocyclization reaction to afford the corresponding new tetracyanobutadienes (TCBDs) and dicyanoquinodimethanes (DCNQs), respectively, in excellent yields. Intramolecular CT absorption bands were found in the UV-vis spectra of the novel chromophores, and CV and DPV showed that they exhibited a reversible two-stage reduction wave, due to the electrochemical reduction of TCBD and DCNQ moieties. Color changes were also observed during the electrochemical reduction.

Synthesis of 2‐Azulenyl‐1,1,4,4‐tetracyano‐3‐ferrocenyl‐1,3‐butadienes by [2+2] Cycloaddition of (Ferrocenylethynyl)azulenes with Tetracyanoethylene

1-, 2-, and 6-(Ferrocenylethynyl)azulene derivatives 10-16 have been prepared by palladium-catalyzed alkynylation of ethynylferrocene with the corresponding haloazulenes under Sonogashira-Hagihara conditions. Compounds 10-16 reacted with tetracyanoethylene (TCNE) in a [2+2] cycloaddition-cycloreversion reaction to afford the corresponding 2-azulenyl-1,1,4,4,-tetracyano-3-ferrocenyl-1,3-butadiene chromophores 17-23 in excellent yields. The redox behavior of the novel azulene chromophores 17-23 was examined by using cyclic voltammetry (CV) and differential pulse voltammetry (DPV), which revealed their multistep electrochemical reduction properties. Moreover, a significant color change was observed by visible spectroscopy under electrochemical reduction conditions.

Microwave-Enhanced Cross-Coupling Reactions Involving Alkynyltrifluoroborates with Aryl Bromides

Palladium-catalyzed alkynylation has emerged as one of the most reliable methods for the synthesis of alkynes which are often used in natural product syntheses and material science. An efficient method for coupling alkynyltrifluoroborates with various aryl bromides in the presence of a palladium catalyst has been developed using microwave irradiation. The microwave reactions are rapid and efficient.