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The hydrofluorination of alkynes is an efficient synthetic route to monofluoroalkenes or difluoroalkanes. Both fluorinated motifs have found applications in medicinal chemistry and beyond. This review explores the recent advances in the hydrofluorination of diverse alkynes through various activation methods, from classical coinage metal catalysis to metal‐free conditions. The range of alkynes goes from the simplest unactivated alkynes to activated ones (ynones and derivatives, ynamides, alkynyl sulfides and sulfones as much as haloalkynes). Regio‐ and stereoselective methods exists, but there is still room for improvement depending on the type of alkyne. [ABSTRACT FROM AUTHOR]

Transition metal‐catalyzed divergent synthesis through alternation of the catalyst is appealing, as it provides an operationally simple way to access different valuable products, while using the same reactants as starting materials. Herein, a gold‐catalyzed cascade reaction of conjugated diynamides with allylic alcohols is described. By variation of the catalysts, substituted allenes and furans could be obtained selectively. Mechanistic studies indicate that, after the addition of allylic alcohol to gold‐activated diynamide, a [3,3]‐sigmatropic rearrangement would take place and lead to the formation of a common reactive intermediate, which would further convert to the final products selectively. Further variation of the structure of diynamides has unveiled an additional reaction sequence involving intramolecular Himbert arene/allene Diels‐Alder cycloaddition to afford a series of dearomatized products bearing bicyclo[2,2,2]octadiene core. [ABSTRACT FROM AUTHOR]

The fully regio‐ and stereoselective Zn‐catalyzed hydrocyanation of ynamides is reported and represents a general access to various trisubstituted E‐α‐enamidonitriles. The catalyst‐free photoisomerization selectively yields the energetically comparable Z‐stereoisomer. Finally, the synthetic potential of these new α‐enamidonitriles was evaluated through the synthesis of original heterocycles. [ABSTRACT FROM AUTHOR]

1,1,4,4‐Tetracyanobutadienes (TCBDs) bearing a large diversity of fluorophores were prepared following a multi‐step synthesis. In a crucial last step, all compounds were obtained from the corresponding ynamides, which were particularly suitable for the formation of the TCBDs in the presence of tetracyanoethylene via a [2+2] cycloaddition/retroelectrocyclization step (CA‐RE). Several fluorenyl derivatives in addition to phenanthrenyl and terphenyl ones provided ynamide‐based TCBDs affording remarkable emission properties covering a large range of wavelengths. Those compounds emit both in solid state and in solution from the visible region to the NIR range, depending on the molecular structures. Quantum yields in cyclohexane reached unforeseen values for such derivatives, up to 7.8 %. A huge sensitivity to the environment of the TCBDs has also been unraveled for most of the compounds since we observed a dramatic fall of the quantum yields when changing the solvent from cyclohexane to toluene, while they are almost non‐emissive in dichloromethane. [ABSTRACT FROM AUTHOR]

A copper‐mediated coupling reaction between ynamides and diazo‐compounds to produce N‐allenamides is reported for the first time. This method enables facile and rapid access to terminal N‐allenamides by using commercially available TMS‐diazomethane with wide functional group compatibility on the nitrogen. Furthermore, the ubiquity of molecules containing a fluorine moiety in medicine, in agricultural, and material science requires the continuous search of new building blocks, including this unique surrogate. The CuI/diazo protocol was successfully applied to the synthesis of fluorine‐substituted N‐allenamides. DFT calculations provided insights in the mechanism involved. [ABSTRACT FROM AUTHOR]

Gold(I)‐catalyzed higher‐order [8+2] cycloadditions of 8‐aryl‐8‐azaheptafulvenes 1 with allenamides 2 and ynamides 3 were studied. 1,8‐Dihydrocycloheptapyrroles 4 were achieved by a regioselective [8+2] cycloaddition of azaheptafulvenes 1 and allenamides 2 in the presence of (2,4‐ditBuC6H3O)3PAuNTf2 as catalyst. Besides, ynamides 3 and 8‐aryl‐8‐azaheptafulvenes 1, undergo a regioselective [8+2] cycloaddition, to give 2‐amido‐1,4‐dihydrocycloheptapyrroles 7 in the presence of JohnPhosAuNTf2 as catalyst. Both reactions take place with good yields and with a variety of substituents. A plausible mechanism hypothesis suggests a nucleophilic attack of the 8‐azaheptafulvene to the gold activated electron rich allene or alkyne moieties of the allenamide and ynamide, respectively. [ABSTRACT FROM AUTHOR]

The regioselective anti‐carboindation of ynamides by using InBr3 and silylated nucleophiles was developed to synthesize (Z)‐β‐(carbonylamino)alkenylindiums. The X‐ray crystallographic analysis of an alkenylindium suggested that the reaction proceeded in an anti‐addition fashion. In contrast to reported syn‐carbometalations of ynamides by using organometallics, a cooperation of InBr3 and silylated nucleophiles to ynamides achieved an anti‐addition, which was supported by DFT calculations. The scope of substrates included various ynamides and silylated nucleophiles, such as silyl ketene acetals and silyl ketene imines. The transformation of synthesized alkenylindiums by iodination, radical coupling, and Pd‐catalyzed cross‐coupling successfully afforded trisubstituted enamines with high regio‐ and stereoselectivities. [ABSTRACT FROM AUTHOR]

Activated amide bonds have been attracting intense attention; however, most of the studied moieties have twisted amide character. To add a new strategy to activate amide bonds while maintaining its planarity, we envisioned the introduction of an alkynyl group on the amide nitrogen to disrupt amide resonance by nN→Csp conjugation. In this context, the conformations and properties of N‐ethynyl‐substituted aromatic amides were investigated by DFT calculations, crystallography, and NMR spectroscopic analysis. In contrast to the cis conformational preference of N‐ethyl‐ and vinyl‐substituted acetanilides, N‐ethynyl‐substituted acetanilide favors the trans conformation in the crystal and in solution. It also has a decreased double bond character of the C(O)−N bond, without twisting of the amide. N‐Ethynyl‐substituted acetanilides undergo selective C(O)−N bond or N−C(sp) bond cleavage reactions and have potential applications as activated amides for coupling reactions or easily cleavable tethers. [ABSTRACT FROM AUTHOR]

Amide‐substituted diynes were cyclized in the presence of a cationic gold catalyst and an external nucleophile leading to 1‐indenones and 1‐iminoindenones. The electron‐donating features of the nitrogen atom enable the formation of a reactive ketene iminium ion, which can be trapped by either diphenyl sulfoxide or anthranil as nucleophiles in a subsequent oxidation step, providing substituted inden‐1‐on‐3‐carboxamides. [ABSTRACT FROM AUTHOR]

The alkylative carboxylation of ynamides and allenamides with CO2 and alkylzinc halides catalyzed by a copper catalyst was developed. A variety of alkylzinc halides bearing functional groups were used for this transformation to afford α,β‐unsaturated carboxylic acids, which contain the α,β‐dehydroamino acid skeleton, introducing the corresponding alkyl group and CO2 across the carbon–carbon triple or double bond. This alkylative carboxylation formally consists of Cu‐catalyzed carbozincation of ynamides or allenamides with alkylzinc halides and the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO2. This protocol would be a useful method for the synthesis of α,β‐dehydroamino acid derivatives possessing a functionalized alkyl group due to the high regio‐ and stereoselectivity, simple one‐pot procedure as well as the use of CO2 as a starting material. [ABSTRACT FROM AUTHOR]

Gold‐catalyzed annulation of N‐propargyl ynamides with anthranils can proceed by two distinct mechanisms. In the case of a terminal N‐propargyl ynamide, its resulting α‐imino gold carbene reacts with a tethered alkyne to generate a vinyl cation to enable hydrolysis, which ultimately yields a pyrrolo[2,3‐b]quinoline derivative after treatment with p‐toluenesulfonic acid. For an internal alkyne, its α‐imino gold carbene reacts with a tethered alkyne via either a vinyl cation or an alkenylgold carbene; both paths ultimately lead to a 4‐ketone‐2‐aminopyrrole derivative. Our mechanistic analysis indicates that water is a better nucleophile than anthranil for terminal ynamides, whereas water and anthranils are equally reactive for internal ynamides. Intramolecular reaction of metal carbenes with alkynes: Gold‐catalyzed annulation of N‐propargyl ynamides with anthranils are described to proceed through two distinct mechanisms (see scheme). [ABSTRACT FROM AUTHOR]

Gold‐catalysed oxidative cyclisation reactions of ynamides offer great promise in γ‐lactam synthesis but are limited by preferential over‐oxidation to form α‐keto imides. Evaluating the factors that might limit N‐cyclisation pathways led to effective gold‐catalysed conditions that allow access to different fused γ‐lactams on changing the ynamide N‐substituent and accommodate previously incompatible substitution patterns. New and efficient methods for the synthesis of functionalised 3‐aryl indoles and cyclohepta[c]pyrrol‐1‐one derivatives are presented. These conditions illustrate the complementarity of gold catalysis to other metals. OxidativeN‐cyclisations of ynamides provide efficient access to a variety of fused γ‐lactams including oxindoles and cyclohepta[c]pyrrol‐1‐one derivatives. A model is proposed to rationalise the reactivity challenges and show how previously dominant over‐oxidation pathways can be overcome to access the desirable reactivity patterns of gold carbenes. [ABSTRACT FROM AUTHOR]

Abstract: Ynamides, as versatile synthetic precursors, have attracted much attention from synthetic chemists and sparked the development of a number of methodologies for the construction of various structures. 1H‐Pyrrolo[2,3‐d]carbazole is a core scaffold of a series of monoterpene indole alkaloids found in Kopsia, Strychnos, and Aspidosperma, for example. In this study, 1H‐pyrrolo[2,3‐d]carbazole derivatives were synthesized by a Brønsted acid‐catalyzed tandem cyclization starting from tryptamine‐based ynamides. This strategy prevented Wagner–Meerwein rearrangement by instantaneous intramolecular nucleophilic trapping of the indoleninium to afford a tetracyclic indoline via an in situ‐formed enol species induced by the formation of a more stable conjugate diene moiety. The functional group tolerances were investigated by using a series of readily available substrates. A plausible mechanism has been proposed based on the evidence of the capture of the hemiaminal intermediate. Lastly, a Büchi ketone, which is the pivotal intermediate in the synthesis of the indole alkaloid vindorosine, was synthesized by utilizing our newly developed methodology. [ABSTRACT FROM AUTHOR]

Abstract: An intramolecular catalytic dearomatization of phenols via gold carbene species proceeded to provide 2‐azaspiro[4.5]decan‐3‐ones. The use of NHC ligand and water as a co‐solvent was critical for achieving high reactivity. This reaction did not require hazardous diazo compounds as carbene sources and proceeded even under air. The obtained spirocyclic product could be readily transformed into a gabapentin derivative by hydrogenation and deprotection. [ABSTRACT FROM AUTHOR]

Abstract: Organic synthesis boasts a wide array of reactions involving either radical species or ionic intermediates. The combination of radical and polar species, however, has not been explored to a comparable extent. Herein we present the hydrative aminoxylation of ynamides, a reaction which can proceed by either a polar‐radical crossover mechanism or through a rare cationic activation. Common to both processes is the versatility of the persistent radical TEMPO and its oxidised oxoammonium derivative TEMPO+. The unique mechanisms of these processes are elucidated experimentally and by in‐depth DFT‐calculations. [ABSTRACT FROM AUTHOR]

Abstract: Using ynamides as readily available starting materials, a single step can generate highly reactive ketenimines, which can then undergo a variety of transformations. The choice of the method for generating the ketenimine dictates the outcome of the reaction that can, moreover, be precisely steered through minor variations of the starting material. This Concept gives an overview of the different existing methodologies for this objective, showcasing the diverse nitrogen‐containing frameworks that can be obtained by this highly versatile strategy. [ABSTRACT FROM AUTHOR]

Ynamides were used as precursors for the in situ generation of highly reactive ketenimines that could be trapped with imines in a [2+2] cycloaddition. This imino-Staudinger synthesis led to a variety of imino-analogs of β-lactams, namely azetidinimines (20 examples), that could be further functionalized through a broad range of transformations. [ABSTRACT FROM AUTHOR]

A facile thermal cyclization of ynamide-tethered 1,3,8-triynes to form a 3,5,6,7-tetrahydro-1 H-pyrano[3,4- c]pyridine skeleton is described. Although the mechanism of this unusual reaction has yet to be defined, the formation of either a strained keteniminium or a biradical intermediate followed by a 1,5-hydride or -hydrogen shift is tentatively proposed as the key elementary steps in the reaction sequence. Appropriate electronic activation at the carbon center donating a hydride or hydrogen is crucial for successful cyclization. [ABSTRACT FROM AUTHOR]

The treatment of readily available N-alkynyl-5-iodo-6-sulfamido-pyrimidines with iPrMgCl⋅LiCl followed by a transmetalation with CuCN⋅2 LiCl produces, after intramolecular carbocupration, metalated py rrolo[2,3- d]pyrimidines. Quenching of these pyrimidines with allylic halides or acid chlorides results in polyfunctional pyrrolo[2,3- d]pyrimidines. Further reaction with ICl and a Negishi cross-coupling, using PEPPSI- iPr as the catalyst, furnishes fully substituted N-heterocycles. A formal synthesis of the marine alkaloid rigidin A has been achieved as well as the preparation of a derivative of 7-azaserotonine, related to the natural hormone serotonin. [ABSTRACT FROM AUTHOR]

The [2+2] cycloaddition of ynamides with the highly polarized reagent Tf2C=CH2 has been developed to regioselectively afford bis(triflyl)aminocyclobutenes in the absence of catalyst under mild conditions. Incidentally, with the ynamides bearing electron-rich aromatic rings at the C-terminal, an interesting reactivity switch was observed; a cyclization/hydroxylation sequence yielded 2-amino-3-(triflyl)cyclobut-2-enols. Aminocyclobutene construction with addition of alcohols resulted in the formation of aminocyclobutenyl ethers through a cyclization/hydroalkoxylation process. Moreover, the utility of functionalized aminocyclobutenes as precursors for further elaboration was demonstrated with the preparation of α-amino-β,γ-unsaturated ketones and 3-(triflyl)buta-1,3-dien-2-amines through 4 π-electrocyclic ring opening. [ABSTRACT FROM AUTHOR]

A novel method for metal-free oxothiolation of ynamides to construct oxazolidine-2,4-diones bearing sulfur-substituted quaternary carbon atoms has been developed. It represents a rare C−O bond cleavage of ynamides, as well as a facile and tandem approach for the formation of C−O, C−S, and C−Cl bonds. This redox-neutral protocol can be applied to the synthesis of multisubstituted oxazolidine-2,4-diones with good chemoselectivity and good yields of isolated products under mild conditions. [ABSTRACT FROM AUTHOR]

Alkylative carboxylation of ynamides with CO2 and dialkylzinc reagents using a N-heterocyclic carbene (NHC)-copper catalyst has been developed. A variety of ynamides, both cyclic and acyclic, undergo this transformation under mild conditions to afford the corresponding α,β-unsaturated carboxylic acids, which contain the α,β-dehydroamino acid skeleton. The present alkylative carboxylation formally consists of Cu-catalyzed carbozincation of ynamides with dialkylzinc reagents with the subsequent nucleophilic carboxylation of the resulting alkenylzinc species with CO2. Dialkylzinc reagents bearing a β-hydrogen atom such as Et2Zn and Bu2Zn still afford the alkylated products despite the potential for β-hydride elimination. This protocol would be a desirable method for the synthesis of highly substituted α,β- dehydroamino acid derivatives due to its high regio- and stereoselectivity, simple one-pot procedure, and its use of CO2 as a starting material. [ABSTRACT FROM AUTHOR]

Bromoenynamides represent precursors to a diversity of azacycles by a cascade sequence of carbopalladation followed by cross-coupling/electrocyclization, or reduction processes. Full details of our investigations into intramolecular ynamide carbopalladation are disclosed, which include the first examples of carbopalladation/cross-coupling reactions using potassium organotrifluoroborate salts; and an understanding of factors influencing the success of these processes, including ring size, and the nature of the coupling partner. Additional mechanistic observations are reported, such as the isolation of triene intermediates for electrocyclization. A variety of hetero-Diels-Alder reactions using the product heterocycles are also described, which provide insight into Diels-Alder regioselectivity. [ABSTRACT FROM AUTHOR]

Gold-catalyzed cycloadditions of ynamides with azidoalkenes or 2 H-azirines give [3+2] or [4+3] formal cycloadducts of three classes. Cycloadditions of ynamides with 2 H-azirine species afford pyrrole products with two regioselectivities when the Cβ-substituted 2 H-azirine is replaced from an alkyl (or hydrogen) with an ester group. For ynamides substituted with an electron-rich phenyl group, their reactions with azidoalkenes proceed through novel [4+3] cycloadditions to deliver 1 H-benzo[ d]azepine products instead. [ABSTRACT FROM AUTHOR]

Highly enantioselective catalytic asymmetric [2+2] cycloadditions of cyclic α-alkylidene β-oxo imides with ynamides are described. The high reactivity of the cyclic α-alkylidene β-oxo imide allows the [2+2] cycloadditions of a hindered substrate with unreactive ynamides at low temperature. The X-ray crystallographic analysis of the product suggests that the enantioselectivity of the [2+2] cycloaddition can be well explained by the chelate model comprising the intramolecular hydrogen bond, wherein the cyclic α-alkylidene β-oxo imide coordinates with CuII through the two imide carbonyls. The imide group in the product can be transformed to amide, nitrile, and ester groups; moreover, it is removable. [ABSTRACT FROM AUTHOR]

A gold-catalyzed cycloisomerization of 1,6-diynes containing an ynamide propargyl ester or carbonate moiety has been developed that provides an attractive route to a diverse-substituted 3-acyloxy-1,4-dihydrocyclopenta[ b]indoles. Mechanistic studies indicate that the reaction likely proceeds through a competitive 1,2-OAc migration followed by [3+2] cycloaddition of the vinyl gold-carbenoid intermediate with the pendant triple bond. The synthetic utility of the obtained cyclopenta[ b]indole products was demonstrated by their efficient transformations by deprotection or double-bond isomerization reactions. [ABSTRACT FROM AUTHOR]

A high-yielding sequence of [2+2] cycloaddition-retroelectrocyclization of ynamides with tetracyanoethylene (TCNE) is described. The reaction provided tetracyanobutadiene (TCBD) species, which were characterized by various techniques. DFT and TD-DFT calculations were also performed to complement experimental findings. [ABSTRACT FROM AUTHOR]

A new synthetic route to the privileged 1,2-dihydroisoquinolines is reported. This method, which relies on a gold-catalyzed formal [4+2] cycloaddition between ynamides and imines, provides a new retrosynthetic disconnection of the 1,2-dihydroisoquinoline core by installing the 1,8a CC and 2,3 CN bonds in one step. Both aldimines and ketimines can be used as substrates. In addition, one example of dihydrofuropyridine synthesis is also demonstrated. [ABSTRACT FROM AUTHOR]

Unique α-hemiaminal ether gold carbene intermediates were accessed by a gold-catalysed 1,1-carboalkoxylation strategy and evolved through a highly selective 1,2- N-migration. This skeletal rearrangement gave functionalised indenes, and isotopic labelling confirmed the rare CN bond cleavage of the ynamide moiety. The effect of substituents on the migration has been explored, and a model is proposed to rationalise the observed selectivity. [ABSTRACT FROM AUTHOR]

A series of arylynamides with alkyloxy groups at the ortho position of the aryl group was prepared through a short alkylation/cross-coupling/amidation sequence. The gold-catalyzed conversion of these substrates combined both CO and CC formation steps, thus providing benzofurans with amine functionalities at the 2-position and alkyl groups at the 3-position. Cross-over experiments showed that the alkyl-migration step was an intermolecular process. X-ray crystal-structure analysis of two of the products supported our structural assignment. In some cases, the corresponding benzofurans without the alkyl group at the 3-position were obtained as side-products, which were formed through a competing protodeauration process. [ABSTRACT FROM AUTHOR]

Hydrate your chemistry! Hydrative cyclization of 5‐yne‐ynamides in the presence of Echavarren's catalyst and p‐toluenesulphonic acid (PTSA)⋅H2O at room temperature affords an array of 1,6‐dihydropyridin‐2(3H)one derivatives. Isomerization, epoxidation, and hydrogenation of the double bond and insertion of an extended π‐conjugate system into the pyridinone skeleton have been successfully accomplished (see scheme; Ts=tosyl). [ABSTRACT FROM AUTHOR]

Highlights from the article: Cover Feature: N-Ethynylation of Anilides Decreases the Double-Bond Character of Amide Bond while Retaining trans-Conformation and Planarity (Chem. Eur. J. 43/2019) B N-Alkynylated anilides b can retain a I trans i conformation as secondary amides, in contrast with I N i -alkyl and vinyl derivatives, which exist in I cis i conformation. This amide activation strategy is apparent from the planarity of its amide bonds, because the majority of known activation methods destroy amide planarity.

Highlights from the article: B The cover picture b provided by Alexander Ahrens from the group of A. S. K. Hashmi presents the results of their work on the gold-catalysed cyclisation of amide-substituted 1,5-diynes leading to functionalised 1-indenones. This conversion was achieved by a 1,4-dioxidation utilising diphenyl sulfoxide as oxidant, which is illustrated by the two skyrockets in the cover picture. Referring to the 20th IUPAC International Symposium on Organometallic Chemistry Directed Towards Organic Synthesis (OMCOS 20), which will be held in Heidelberg in July 2019, its two symbols, the Heidelberg castle and the old bridge, are shown on the cover picture.

Ynamides were used as precursors for the in situ generation of highly reactive ketenimines which were trapped with imines in a [2+2] cycloaddition under microwave irradiation. Twenty novel azetidinimines have been prepared in this straightforward and operationally simple manner. Furthermore, the products arising from this imino‐Staudinger synthesis were functionalized using a wide range of protocols that leave the four‐membered amidine ring intact. (Illustration by E. Menneteau, CNRS‐PRC 2017). More information can be found in the Communication by R. H. Dodd, K. Cariou et al. on page 12991. [ABSTRACT FROM AUTHOR]