Gold(I)-catalysed cyclisation of (E)-ketene-N,O-acetals: a synthetic route toward spiro-oxazole-γ-lactones.

In this study, we developed a cascade 5,5-cyclisation of internal ketene-N,O-acetals utilizing homogeneous Au(I) catalysis. This process involves an initial 5-exo-dig carbocyclisation, followed by a 5-exo-dig heterocyclisation that stereoselectively incorporates the O-atom of a water molecule into an N-tethered propargyl alkyne. This sequential reaction results in the formation of one C-C, two C-O, and two C-I bonds, ultimately leading to the synthesis of spiro-α-iodo-γ-lactone structures featuring oxazole rings in good yields.

Regioselective Twofold Annulation of Propargyl Acetates.

The regioselective annulation of unsymmetrical alkynes has always been a focused research topic. A Pd-catalyzed double annulation of unsymmetrical alkynes (i.e., yne-acetates) with aryl diazonium salts for the synthesis of substituted naphthalene derivatives is developed. The process addresses intrinsic regioselectivity challenges in the annulations of unsymmetrical alkynes. Mechanistic investigations shed light on the crucial role of the acetate-directing groups in determining the regiochemical reaction outcome.

Copper-Catalyzed Regio- and Stereoselective Hydroarylation of Ynamide.

Presented herein is a copper-catalyzed trans-hydroarylation of ynamides. The reaction showcases the assembly of boronic acids across the carbon-carbon triple bond of ynamides. The reaction proceeds under mild conditions offering a complementary approach for the versatile synthesis of multifunctional (E)-α,ß-disubstituted enamides. Moreover, the hydroarylation process is highly regio- and stereoselective. The transformation shows a broad scope (30 examples) and tolerates a wide range of labile functional groups. Control experiments provide substantive evidence supporting the mechanistic cycle and the observed selectivity.

Synthetic manifestation of trinitro-pyrazolo-2H-1,2,3-triazoles (TNPT) as insensitive energetic materials.

This study showcases the design and development of a facile method for synthesizing trinitro-pyrazolo-triazole (TNPT) and its derivatives. The synthesized compounds are analysed using multinuclear NMR [1H, 13C, and 15N] and HRMS analyses. Furthermore, X-ray diffraction studies confirm the structure of some TNPT derivatives. Notably, compounds 8, 9, 11, and 12 exhibit good thermal stability with a decomposition threshold above 250 °C, and show a high level of insensitivity towards impact and friction [impact sensitivity (IS) is more than 25 J and friction sensitivity (FS) is above 180 N]. Compound 12, in particular, displays excellent performance characteristics [density 1.76 g cc-1 (at 298 K), a high detonation velocity (Dv = 8550 m s-1), and good thermal stability (Td = 280 °C), with high insensitivity towards impact and friction (IS = 35 J; FS = 180 N)]. The Hirshfeld surface analysis study provides further insight into the sensitivity of the TNPT derivatives.

Probing Chiral Sulfoximine Auxiliaries in Ru(II)-Catalyzed One-Pot Asymmetric C-H Hydroarylation and Annulations with Alkynes.

Developed herein is a chiral sulfoximine-enabled Ru(II)-catalyzed asymmetric C-H activation/functionalization involving intramolecular hydroarylation and functionalization/annulation of alkynes. This process constructs dihydrobenzofuran- or indoline-fused isoquinolinones having a tertiary or quaternary stereocenter with good yields and enantioselectivities (up to 97:3 enantiomeric ratio). The chiral sulfoxide precursor used in synthesizing the enantiopure sulfoximines is spontaneously eliminated during the reaction. It can be recovered without losing enantiopurity (∼99% enantiomeric excess) and reused.

A Three-Component Arene Difunctionalization: Merger of C(sp3 )/(sp2 )-H Bond Addition.

A tandem three-component C-H bond addition involving the activation of an inert C(sp3 )-H bond is reported. The process enables the direct regioselective synthesis of 1,2-difunctionalized arenes with the formation of C(sp3 )- and C(sp2 )-C(arene) bonds. 2-Iodobenzoic acid derivatives behave as masked bifunctional reagent (BFR) and react with 2-pyridyl-methyl sulfoximine (MPyS) protected aliphatic acids bearing α,α-disubstituted groups, and alkenes to produce ß-aryl-δ-alkenyl amide derivatives in a single operation. The transformation involves Pd(II)/Pd(IV) and Pd(II)/Pd(0) catalytic systems. Detailed mechanistic studies, including density functional theory (DFT) calculations, reveal the formation of large T-shaped palladacycles and the onset of a 1,2-palladium migration via decarboxylation.

Sulfoximine Assisted C-H Activation and Annulation via Vinylene Transfer: Access to Unsubstituted Benzothiazines.

In this study, we report the synthesis of unsubstituted 1,2-benzothiazines through a redox-neutral Rh(III)-catalyzed C-H activation and [4+2]-annulation of S-aryl sulfoximines with vinylene carbonate. Notably, the introduction of an N-protected amino acid ligand significantly enhances the reaction rate. The key aspect of this redox-neutral process is the utilization of vinylene carbonate as an oxidizing acetylene surrogate and an efficient vinylene transfer agent. This vinylene carbonate enables the cyclization with the sulfoximine motifs, successfully forming a diverse array of 1,2-benzothiazine derivatives in moderate to good yields. Importantly, this study highlights the potential of Rh(III)-catalyzed C-H activation and [4+2]-annulation reactions for the synthesis of optically pure 1,2-benzothiazines with high enantiomeric purity.

Two-component symmetrical diarylation of ynamides.

The present study describes a method for the dicarbofunctionalization of ynamide via a palladium-catalyzed two-component diarylation with aryl boronic acids. The reaction involves a consecutive transmetalation of the aryl boronic acids with a Pd(II)-complex making the transformation stereoselective. Importantly, the reaction proceeds under mild conditions and tolerates a broad range of functional groups. Control experiments validate the role of the oxidant (useful for catalyst regeneration) in the reaction mechanism.

Regioselective Difunctionalization and Annulation of Ynamide.

The use of ynamides in organic synthesis has gained significant attention due to their ability to provide access to complex molecular structures through transformations such as 1,2-difunctionalization and annulation reactions. These reactions enable the formation of highly functionalized N-bearing olefins and unusual N-bearing heterocycles. In this minireview, we present a systematic overview of the regioselective difunctionalization and annulation reactions of ynamides. We discuss the multi-component reactions, and radical-triggered functionalizations across the ynamides carbon-carbon multiple bonds and the use of bifunctional reagents in annulation of ynamides, highlighting their potential in expanding the substrate scope. Furthermore, we provide insights into the mechanistic breakthroughs that have been achieved in recent years in the development of these reactions. Finally, we emphasize the promising future prospects of ynamides as versatile building blocks for the synthesis of complex molecular architectures.

Three Component syn-1,2-Arylmethylation of Internal Alkynes.

A Pd-catalyzed three-component syn-1,2-arylmethylation of internal alkynes (ynamides/yne-acetates/alkynes) is described. The readily available and bench stable coupling partners iodo-arenes, and methyl boronic acid are successfully used in this coupling strategy to access the methyl-containing tetra-substituted olefins; the scope is broad showing excellent functional-group tolerance. Notably, the transformation is regio- as well as stereoselective. The biologically relevant motifs (BRM) bearing iodo-arenes and ynamides are also used for the late-stage syn-1,2-arylmethylation of alkynes. Aryl-alkylation, aryl-trideuteriomethylation, alkynyl-methylation, and alkenyl-methylation of ynamides are also presented. The Me-substituted alkenes are further transformed into synthetically important ß-amino-indenones and α-fluoro-α'-methyl ketones.

A 6-endo-dig Thiolative Cyclization of Yne-Ynamides: Access to Thiodihydropyridin-2-ones.

A straightforward regioselective intramolecular 6-endo-dig cyclization of yne-tethered ynamide is herein developed. The reaction involves an intramolecular enolate attack of ketene-N,O-acetals, generated in situ from yne-ynamide and methanesulfonic acid, to the alkyne moiety activated by a sulfonium cation. The transformation enables access to structurally diverse 5-(arylthio)-3,6-dihydropyridin-2(3H)-ones with broad functional group compatibility. The recovery of S-protecting groups and synthetic applications of the products make the transformation useful.

Polynitro-N-aryl-C-nitro-pyrazole/imidazole Derivatives: Thermally Stable-Insensitive Energetic Materials.

A wide array of methoxy-substituted-polynitro-aryl-pyrazole/imidazoles with readily oxidizable -NH2/NO2/NHNO2/diazo functional groups is synthesized. Single crystal X-ray diffraction (XRD) analysis confirms the molecular structure of the compounds. Energetic properties of the synthesized compounds are determined by theoretical and experimental studies. Most of the compounds are thermally stable and insensitive to impact and friction. Some of the molecules possess better detonation velocity and detonation pressure over TNT.

Multiple annulations of inert C(sp2)-H bonds with alkynes.

Transition-metal catalyzed directing group (DG) assisted annulation of inert C-H bonds leads to the formation of complex molecular frameworks from readily accessible substrates. Thus, multiple annulation of less functionalized substrates with unsaturated species leads to the construction of structurally diverse fused poly(hetero)cycles. The directed inert C(arene)-H bond activation and the mode of TM-migration in this process could enabled obatining L-type [involves DG heteroatom, o-C(arene)-H bond, and C(arene)-H bond of aryl-motif in alkyne], Y-type [involves two heteroatoms of the DG and o-,o'-C(arene)-H bonds], and B-type [involves o-C(arene)-H bond and m-C(arene)-H bond] π-extended annulation products. The coordination preference of the DG heteroatom makes the transformation chemo- and regio-selective. This article underlines the conceptual development of unsymmetrical multiple annulation of arene C(sp2)-H bonds with alkynes, which is exceedingly appealing and highly important.

Cationic-palladium catalyzed regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes.

π-Extended tetrasubstituted olefins are widely found motifs in natural products, leading drugs, and agrochemicals. Thus, development of modular strategies for the synthesis of complex all-carbon-substituted olefins always draws attention. The difunctionalization of unsymmetrical alkynes is an attractive approach but it has remained faced with regioselectivity issues. Here we report the discovery of a regio- and stereoselective syn-1,2-dicarbofunctionalization of unsymmetrical internal alkynes. A cationic Pd-catalyzed three-component coupling of aryl diazonium salts, aryl boronic acids (or olefins) and yne-acetates enables access to all-carbon substituted unsymmetrical olefins. The transformation features broad scope with labile functional group tolerance, building broad chemical space of structural diversity (94 molecules). The value of this synthetic method is demonstrated by the direct transformation of natural products and drug candidates containing yne-acetates, to enable highly substituted structurally complex allyl acetate analogues of biologically important compounds. Synthetic versatility of the carboxylate bearing highly substituted olefins is also presented. The reaction outcome is attributed to the in situ formation of stabilized cationic aryl-Pd species, which regulates regioselective aryl-palladation of unsymmetrical yne-acetates. Control experiments reveal the synergy between the carboxylate protecting group and the cationic Pd-intermediate in the regioselectivity and reaction productivity; density functional theory (DFT) studies rationalize the selectivity of the reaction.

Palladium-Catalyzed Regioselective Arylalkenylation of Ynamides.

A cationic palladium-catalyzed arylalkenylation of ynamides is presented. The putative keteniminium arylpalladium intermediate likely dictates the regioselective carbopalladation of the ynamide to form a vinylpalladium species. The capture of this complex by the olefin yields linear conjugated ß-alkenyl aminodienes (especially with trans selectivity). The transformation features a broad scope with labile functional group tolerance and makes 42 unusual molecular scaffolds with structural diversity. DFT studies provide valuable insights into the reaction mechanism.

Kinetic resolution of sulfur-stereogenic sulfoximines by Pd(ii)-MPAA catalyzed C-H arylation and olefination.

A direct Pd(ii)-catalyzed kinetic resolution of heteroaryl-enabled sulfoximines through an ortho-C-H alkenylation/arylation of arenes has been developed. The coordination of the sulfoximine pyridyl-motif and the chiral amino acid MPAA ligand to the Pd(ii)-catalyst controls the enantio-discriminating C(aryl)-H activation. This method provides access to a wide range of enantiomerically enriched unreacted aryl-pyridyl-sulfoximine precursors and C(aryl)-H alkenylation/arylation products in good yields with high enantioselectivity (up to >99% ee), and selectivity factor up to >200. The coordination preference of the directing group, ligand effect, geometry constraints, and the transient six-membered concerted-metalation-deprotonation species dictate the stereoselectivity; DFT studies validate this hypothesis.

Sulfur and Nitrogen Modulated One-Pot Double Annulation of Arenes.

The sulfur and nitrogen moieties of methylphenyl sulfoximine (MPS)-enabled aryl thioamides are independently involved in annulation with unactivated alkynes to construct the unusual 6,6-fused thiopyranoisoquinoline skeletons. The MPS directing group plays a vital role in making this unprecedented Ru-catalyzed one-pot double annulation of aryl thioamides with alkynes chemo- and regioselective. Both the o,o'-C-H bonds of the aryl motif are sequentially functionalized to form four bonds [C-C, C-S and C-C, C-N] in a single operation by overcoming the undisputed challenges, viz. the "S" poisoning effect on the transition-metal catalyst and the susceptibility of S to oxidation. The novel isothiochromene-1-one skeletons are successfully constructed, as the annulation is initiated with S in preference over the N motif of thioamides with alkynes. The preliminary photophysical properties of the thiopyrano-isoquinoline derivatives are also discussed.

Gold-Catalyzed Transformation of Ynamides.

Ynamide, a unique species with inherited polarization of nitrogen lone pair electron to triple bond, has been largely used for the developement of novel synthetic methods and the construction of unusual N-bearing heterocycles. The reaction versatility of ynamide on umpolung reactivity, radical reactions and asymmetric synthesis have been recently reviewed. This review provides an overall scenic view into the gold catalyzed transformation of ynamides. The ynamides reactivity towards nitrogen-transfer reagents, such as azides, nitrogen ylides, isoxazoles, and anthranils; oxygen atom-transfer reagents, like nitrones, sulfoxides, and pyridine N-oxides; and carbon nucleophiles under gold catalysis are herein uncovered. The scope as well the mechanistic insights of each reaction is also briefed.

Yb(iii)-catalysed syn-thioallylation of ynamides.

Reported herein is a syn-thioallylation of ynamides incorporating a sulfide moiety at the α-position and an allyl group at the ß-position of the ynamide. The transformation is successful under ytterbium(iii)-catalysis, providing access to highly substituted thioamino-skipped-dienes with broad substrate scope. Thus, tetrasubstituted olefins (with four different functional groups: amide, phenyl, thioaryl/alkyl, and allyl on the carbon centers) are made in a single step from readily accessible ynamides, preserving complete atom economy. The reaction can be extended to the synthesis of selenoamino dienes by ynamide syn-selenoallylation. DFT studies and control experiments provide insight into the reaction mechanism.

Harnessing sulfur and nitrogen in the cobalt(iii)-catalyzed unsymmetrical double annulation of thioamides: probing the origin of chemo- and regio-selectivity.

An unconventional cobalt(iii)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o'-C-H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse 'S' coordination over a more conventional 'N' coordination of thioamides to the Co-catalyst specifically regulates the formation of four [C-C and C-S at first and then C-N and C-C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, the late-stage annulation of biologically relevant motifs and drug candidates is disclosed (17 examples). The preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6π-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation process.