Reactive intermediates from DMDO oxidation of ynamides. Trapping of a de novo chiral push-pull carbene via cyclopropanation

The reaction profile of DMDO oxidations of ynamides is described. This work illustrates the first examples of highly diastereoselective intramolecular cyclopropanations of a push-pull carbene derived from alkyne oxidation. In addition, the ynamide oxidation provides facile access to ketoimides and reveals mechanistic insights into the chemistry of electronically biased oxirenes.     

Copper(II)-catalyzed amidations of alkynyl bromides as a general synthesis of ynamides and Z-enamides. An intramolecular amidation for the synthesis of macrocyclic ynamides

A general and efficient method for the coupling of a wide range of amides with alkynyl bromides is described here. This novel amidation reaction involves a catalytic protocol using copper(II) sulfate-pentahydrate and 1,10-phenanthroline to direct the sp-C-N bond formation, leading to a structurally diverse array of ynamides including macrocyclic ynamides via an intramolecular amidation. Given the surging interest in ynamide chemistry, this atom economical synthesis of ynamides should invoke further attention from the synthetic organic community.     

Alkyne Versus Ynamide Reactivity: Regioselective Radical Cyclization of Yne‐Ynamides

Ynamides are typically more reactive than simple alkynes and olefins. However, a serendipitous observation revealed a rare case where the reactivity of simple alkynes exceeds that of ynamides. This led to the development of a unique sulfur‐radical‐triggered cyclization of yne‐tethered ynamides, which involves attack of the alkyne by a thiyl radical followed by cyclization with the ynamide. A wide range of novel 4‐thioaryl pyrroles that could tolerate common functional moieties and N‐protecting groups were expediently constructed by this strategy. The current method contrasts with the typical cyclization of yne‐ynamides, which involves the attack of the alkyne moiety by the ynamide core. Control experiments and DFT calculations supported the participation of the sulfur radical in the reaction and the regioselective cyclization. The synthetic potential of the substituted pyrroles is also discussed.     

Irregularities in the effect of potassium phosphate in ynamide synthesis

The yields of ynamides using Hsung's second generation protocol depend substantially on the quality of K(3)PO(4). Samples of K(3)PO(4) from different suppliers were investigated by various techniques, revealing that the use of pure and anhydrous K(3)PO(4) provides higher ynamide yields in comparison to samples contaminated with hydrates (K(3)PO(4) x 1.5 H(2)O and K(3)PO(4) x 7 H(2)O). With high quality K(3)PO(4), a number of ynamides were synthesized in yields of 52-91%. In addition, we report that ynamides can undergo regioselective hydroamination with carbamates.     

Gold-Catalyzed Annulations of N-Propargyl Ynamides with Anthranils with Two Distinct Chemoselectivities

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.     

2+2] Cycloaddition of ketenes with ynamides. A general method for the synthesis of 3-aminocyclobutenone derivatives

Ynamides react with ketenes in [2+2] cycloadditions leading to a variety of substituted 3-aminocyclobut-2-en-1-ones. The ynamides employed in these reactions are readily available via the copper-promoted N-alkynylation of carbamates and sulfonamides with alkynyl bromides and iodides. The scope of the [2+2] cycloaddition with regard to both the ketene and ynamide component is described.     

Click chemistry with ynamides

A series of diversely 1-substituted 4-amino 1,2,3-triazoles were synthesized by [3+2] cycloaddition between azides and ynamides. This copper catalyzed process represents the first examples of a ‘click reaction’ employing ynamides and should expand the scope of the ynamide chemistry both synthetically and industrially. Various azides (even highly functionalized) were allowed to react with N-benzyl, N-tosyl ynamide to give the corresponding triazole adducts in high yield and with very high levels of regioselectivity.     

Copper‐Catalyzed Azide–Ynamide Cyclization to Generate α‐Imino Copper Carbenes: Divergent and Enantioselective Access to Polycyclic N‐Heterocycles

Here an efficient copper‐catalyzed cascade cyclization of azide‐ynamides via α‐imino copper carbene intermediates is reported, representing the first generation of α‐imino copper carbenes from alkynes. This protocol enables the practical and divergent synthesis of an array of polycyclic N‐heterocycles in generally good to excellent yields with broad substrate scope and excellent diastereoselectivities. Moreover, an asymmetric azide–ynamide cyclization has been achieved with high enantioselectivities (up to 98:2 e.r.) by employing BOX‐Cu complexes as chiral catalysts. Thus, this protocol constitutes the first example of an asymmetric azide–alkyne cyclization. The proposed mechanistic rationale for this cascade cyclization is further supported by theoretical calculations.     

Ruthenium-catalyzed [2+2] cycloadditions of bicyclic alkenes and ynamides

Ruthenium-catalyzed [2+2] cycloadditions between bicyclic alkenes and ynamides were investigated. The ynamide moiety was found to be compatible with the ruthenium-catalyzed cycloaddition conditions giving the corresponding cyclobutene cycloadducts in moderate to good yields (up to 97%). Diastereoselective cycloaddition utilizing chiral cyclic ynamides were also examined and a low to moderate level of asymmetric induction was observed.     

Synthesis of 3-(arylmethylene)isoindolin-1-ones from ynamides by Heck-Suzuki-Miyaura domino reactions. Application to the synthesis of lennoxamine

Substituted 3-(arylmethylene)isoindolin-1-ones can be efficiently synthesized from various ynamides and boronic acids by palladium-catalyzed Heck-Suzuki-Miyaura domino reactions. This methodology has been applied to the total synthesis of lennoxamine and a concise route to this isoindolobenzazepine alkaloid was achieved in eight steps from 2,3-dimethoxybenzoic acid via a key intermediate ynamide.     

Ruthenium-catalyzed [2 + 2] cycloadditions of ynamides

Ruthenium-catalyzed [2 + 2] cycloadditions between norbornene and ynamides were investigated. The ynamide moiety was found to be compatible with the ruthenium-catalyzed cycloaddition conditions, giving the corresponding cyclobutene cycloadducts in moderate to good yields (up to 97%). [reaction: see text]     

Umpolung Reactivity of Ynamides: An Unconventional [1,3]‐Sulfonyl and [1,5]‐Sulfinyl Migration Cascade

A regioselective sulfonyl/sulfinyl migration cycloisomerization cascade of alkyne‐tethered ynamides is developed in the presence of XPhosgold catalyst. This reaction is the first example of a general [1,3]‐sulfonyl migration from the nitrogen center to the β‐carbon atom of ynamides, followed by umpolung 5‐endo‐dig cyclization of the ynamide α‐carbon atom to the gold‐activated alkyne, and final deaurative [1,5]‐sulfinylation. This process allows the synthesis of peripherally decorated unconventional 4‐sulfinylated pyrroles with broad scope from N‐propargyl‐tethered ynamides. In contrast, N‐homopropargyl‐tethered ynamides undergo intramolecular tetradehydro Diels–Alder reaction to provide 2,3‐dihydro‐benzo[f]indole derivatives. Control experiments and density‐functional theory studies were used to study the reaction pathways.     

Synthesis of Aminopyridines and Aminopyridones by Cobalt‐Catalyzed [2+2+2] Cycloadditions Involving Yne‐Ynamides: Scope,Limitations, and Mechanistic Insights

An in‐depth study of the cobalt‐catalyzed [2+2+2] cycloaddition between yne‐ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal‐catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron‐deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne‐ynamide allows the regioselectivity to be switched toward 3‐ or 4‐aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne‐ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3‐aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4‐aminopyridines arise from an insertion pathway.     

Gold(I)-Catalyzed [8+2]-Cycloaddition of 8-Aryl-8-azaheptafulvenes with Allenamides and Ynamides: Regioselective Synthesis of Dihydrocycloheptapyrrole Derivatives

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.     

Copper sulfate-pentahydrate-1,10-phenanthroline catalyzed amidations of alkynyl bromides. Synthesis of heteroaromatic amine substituted ynamides

A practical cross-coupling of amides with alkynyl bromides using catalytic CuSO(4).5H(2)O and 1,10-phenanthroline is described here. This catalytic protocol is more environmentally friendly than the use of CuCN or copper halides and provides a general entry for syntheses of ynamides including various new sulfonyl and heteroaromatic amine substituted ynamides. Given the interest in ynamides, this N-alkynylation of amides should be significant for the future of ynamides in organic synthesis.     

Structures and properties of zirconia-supported ruthenium oxide catalysts for the selective oxidation of methanol to methyl formate

The effects of RuO(x) structure on the selective oxidation of methanol to methyl formate (MF) at low temperatures were examined on ZrO(2)-supported RuO(x) catalysts with a range of Ru surface densities (0.2-3.8 Ru/nm(2)). Their structure was characterized using complementary methods (X-ray diffraction, Raman and X-ray photoelectron spectra, and reduction dynamics). The structure and reactivity of RuO(x) species change markedly with Ru surface density. RuO(x) existed preferentially as RuO(4)(2-) species below 0.4 Ru/nm(2), probably as isolated Zr(RuO(4))(2) interacting with ZrO(2) surfaces. At higher surface densities, highly dispersed RuO(2) domains coexisted with RuO(4)(2-) and ultimately formed small clusters and became the prevalent form of RuO(x) above 1.9 Ru/nm(2). CH(3)OH oxidation rates per Ru atom and per exposed Ru atom (turnover rates) decreased with increasing Ru surface density. This behavior reflects a decrease in intrinsic reactivity as RuO(x) evolved from RuO(4)(2-) to RuO(2), a conclusion confirmed by transient anaerobic reactions of CH(3)OH and by an excellent correlation between reaction rates and the number of RuO(4)(2-) species in RuO(x)/ZrO(2) catalysts. The high intrinsic reactivity of RuO(4)(2-) structures reflects their higher reducibility, which favors the reduction process required for the kinetically relevant C-H bond activation step in redox cycles using lattice oxygen atoms involved in CH(3)OH oxidation catalysis. These more reactive RuO(4)(2-) species and the more exposed ZrO(2) surfaces on samples with low Ru surface density led to high MF selectivities (e.g. approximately 96% at 0.2 Ru/nm(2)). These findings provide guidance for the design of more effective catalysts for the oxidation of alkanes, alkenes, and alcohols by the synthesis of denser Zr(RuO(4))(2) monolayers on ZrO(2) and other high surface area supports.     

Keteniminium-Driven Umpolung Difunctionalization of Ynamides

A three-component Pd-catalyzed coupling of ynamides, aryl diazonium salts, and aryl boronic acids for the synthesis of novel triaryl-substituted enamides is described. This transformation represents the first example of an umpolung regioselective unsymmetrical syn-1,2-diarylation/aryl-olefination of ynamides. The aryl moieties of the diazonium salt (electrophile) and boronic acid (nucleophile) are explicitly incorporated in the electrophilic α- and nucleophilic β-position, respectively, of the ynamide, resulting in a single isomer of the N-bearing tetrasubstituted olefin. The scope is broad (68 examples), showing excellent functional-group tolerance. DFT calculations substantiate the rationale of the mechanistic cycle and the regioselectivity. The chemoselectivity and synthetic potential of the enamide products were also studied.     

Ruthenium-catalyzed oxidative cleavage of olefins to aldehydes.

Three oxidation protocols have been developed to cleave olefins to carbonyl compounds with ruthenium trichloride as catalyst (3.5 mol %). These methods convert olefins that are not fully substituted to aldehydes rather than carboxylic acids. While aryl olefins were cleaved to aromatic aldehydes in excellent yields by using the system of RuCl3-Oxone-NaHCO3 in CH3CN-H2O (1.5:1), aliphatic olefins were converted into alkyl aldehydes with RuCl3-NaIO4 in 1,2-dichloroethane-H2O (1:1) in good to excellent yields. It is noteworthy that terminal aliphatic olefins were cleaved to the corresponding aldehydes in excellent yields by using RuCl3-NaIO4 in CH3CN-H2O (6:1).     

Keteniminium‐Driven Umpolung Difunctionalization of Ynamides

A three‐component Pd‐catalyzed coupling of ynamides, aryl diazonium salts, and aryl boronic acids for the synthesis of novel triaryl‐substituted enamides is described. This transformation represents the first example of an umpolung regioselective unsymmetrical syn‐1,2‐diarylation/aryl‐olefination of ynamides. The aryl moieties of the diazonium salt (electrophile) and boronic acid (nucleophile) are explicitly incorporated in the electrophilic α‐ and nucleophilic β‐position, respectively, of the ynamide, resulting in a single isomer of the N‐bearing tetrasubstituted olefin. The scope is broad (68 examples), showing excellent functional‐group tolerance. DFT calculations substantiate the rationale of the mechanistic cycle and the regioselectivity. The chemoselectivity and synthetic potential of the enamide products were also studied.     

NMR studies on epoxidations of allenamides. Evidence for formation of nitrogen-substituted allene oxide and spiro-epoxide via trapping experiments

Two epoxidations of chiral allenamides are described here. While treatment with m-CPBA led to highly stereoselective formation of an alpha-keto aminal that can be useful synthetically, DMDO oxidation led to conclusive evidence for both nitrogen-substituted allene oxide (via mono-epoxidation) and spiro-epoxide (via bis-epoxidation) using intramolecular nucleophilic trapping experiments. NMR studies provide reliable evidence for a 3-oxetanone that can be derived from the spiro-epoxide and also suggest the presence of an allene oxide. Despite a facile second epoxidation as evidenced by the predominant formation of the 3-oxetanone, in the presence of furan, [4 + 3] cycloaddition of the nitrogen-substituted allene oxide or oxyallyl cation with furan occurs faster than the second epoxidation efficiently leading to cycloadducts. This rate difference plays an invaluable role for the success of a stereoselective sequential epoxidation-[4 + 3] cycloaddition reaction via DMDO epoxidations of chiral allenamides.