Synthesis of Highly Substituted Pyridines via [4 + 2] Cycloadditions of Vinylallenes and Sulfonyl Cyanides.

A convergent strategy for the synthesis of multisubstituted pyridines is described. Vinylallenes combine with commercially available arylsulfonyl cyanides in Diels-Alder cycloadditions to generate isopyridine cycloadducts that are converted to pyridines upon further heating or addition of a base. The 2-sulfonylpyridine products undergo nucleophilic aromatic substitution reactions with oxygen and carbon nucleophiles to provide access to a variety of highly substituted pyridines.

Formal Bimolecular [2 + 2 + 2] Cycloaddition Strategy for the Synthesis of Pyridines: Intramolecular Propargylic Ene Reaction/Aza Diels-Alder Reaction Cascades.

Two methods for the synthesis of multisubstituted pyridines are described. In each strategy, a highly reactive vinylallene is generated via an intramolecular propargylic ene reaction in the presence of an azadienophile. Reactions employing ethyl N-(tosyl)iminoacetate furnish an intermediate that undergoes elimination and isomerization upon the addition of DBU. The reaction of the intermediate vinylallene with TsCN leads to the isolation of a 2-sulfonylpyridine that serves as a versatile intermediate undergoing substitution reactions with oxygen and carbon nucleophiles.

Furo[2,3- g]thieno[2,3- e]indole: Application of an Ynamide-Based Benzannulation Strategy to the Synthesis of a Tetracyclic Heteroaromatic Compound.

The first synthesis of the tetracyclic aromatic compound furo[2,3- g]thieno[2,3- e]indole ("FTI") is described. The synthetic strategy features a photochemical benzannulation based on the reaction of an α-diazo ketone and ynamide which assembles a benzothiophene equipped with substituents that enable subsequent cyclizations to generate the nitrogen and oxygen heterocyclic rings.

Aza Diels-Alder Reactions of Nitriles, N,N-Dimethylhydrazones, and Oximino Ethers. Application in Formal [2 + 2 + 2] Cycloadditions for the Synthesis of Pyridines.

Metal-free, formal [2 + 2 + 2] cycloaddition strategies for the synthesis of polycyclic pyridine derivatives are described. The overall transformation proceeds via a two-stage pericyclic cascade mechanism. In the first step, an intramolecular propargylic ene reaction generates a vinylallene that is necessarily locked in the s-cis conformation. This vinylallene exhibits exceptional reactivity as a Diels-Alder reaction partner and engages in [4 + 2] cycloadditions with normally unreactive azadienophiles including unactivated cyano groups and heterosubstituted imine derivatives such as dimethylhydrazones and oximino ethers. Few examples of oximino ether Diels-Alder reactions have been reported previously, and normal electron-demand [4 + 2] cycloadditions of unactivated dialkylhydrazones are unprecedented. Overall, this metal-free formal [2 + 2 + 2] cycloaddition provides access to polycyclic pyridine derivatives and complements transition-metal-catalyzed [2 + 2 + 2] strategies.

Reproducibility in Chemical Research.

"… To what extent is reproducibility a significant issue in chemical research? How can problems involving irreproducibility be minimized? … Researchers should be aware of the dangers of unconscious investigator bias, all papers should provide adequate experimental detail, and Reviewers have a responsibility to carefully examine papers for adequacy of experimental detail and support for the conclusions …" Read more in the Editorial by Robert G. Bergman and Rick L. Danheiser.

Synthesis of Highly Substituted Quinolines via a Tandem Ynamide Benzannulation/Iodocyclization Strategy.

A two-stage "tandem strategy" for the regiocontrolled synthesis of very highly substituted quinolines is described. Benzannulation based on the reaction of cyclobutenones or diazo ketones with N-propargyl-substituted ynamides proceeds via a cascade of several pericyclic reactions to generate multiply substituted aniline derivatives. In the second stage of the tandem strategy, triflate derivatives of the phenolic benzannulation products undergo Larock cyclization upon exposure to iodine to form products that are further elaborated by methods such as palladium-catalyzed coupling to generate quinolines that can be substituted at every position of the bicyclic system.

N-tosyl-3-azacyclohexyne. Synthesis and chemistry of a strained cyclic ynamide.

The first synthesis of a strained six-membered cyclic ynamide is described. N-Tosyl-3-azacyclohexyne is generated via fluoride-promoted 1,2 elimination under conditions that allow trapping of the strained heterocyclic alkyne in a variety of addition, insertion, and [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions.

Batch and flow photochemical benzannulations based on the reaction of ynamides and diazo ketones. Application to the synthesis of polycyclic aromatic and heteroaromatic compounds.

Highly substituted polycyclic aromatic and heteroaromatic compounds are produced via a two-stage tandem benzannulation/cyclization strategy. The initial benzannulation step proceeds via a pericyclic cascade mechanism triggered by thermal or photochemical Wolff rearrangement of a diazo ketone. The photochemical process can be performed using a continuous flow reactor which facilitates carrying out reactions on a large scale and minimizes the time required for photolysis. Carbomethoxy ynamides as well as more ketenophilic bis-silyl ynamines and N-sulfonyl and N-phosphoryl ynamides serve as the reaction partner in the benzannulation step. In the second stage of the strategy, RCM generates benzofused nitrogen heterocycles, and various heterocyclization processes furnish highly substituted and polycyclic indoles of types that were not available by using the previous cyclobutenone-based version of the tandem strategy.

Benzannulation via the reaction of ynamides and vinylketenes. application to the synthesis of highly substituted indoles.

A two-stage "tandem strategy" for the synthesis of indoles with a high level of substitution on the six-membered ring is described. Benzannulation based on the reaction of cyclobutenones with ynamides proceeds via a cascade of four pericyclic reactions to produce multiply substituted aniline derivatives in which the position ortho to the nitrogen can bear a wide range of functionalized substituents. In the second stage of the tandem strategy, highly substituted indoles are generated via acid-, base-, and palladium-catalyzed cyclization and annulation processes.

Why nature eschews the concerted [2 + 2 + 2] cycloaddition of a nonconjugated cyanodiyne. Computational study of a pyridine synthesis involving an ene-Diels-Alder-bimolecular hydrogen-transfer mechanism.

An intramolecular formal metal-free intramolecular [2 + 2 + 2] cycloaddition for the formation of pyridines has been investigated with M06-2X and B3LYP density functional methods, and compared to the experimentally established three-step mechanism that involves ene reaction-Diels-Alder reaction-hydrogen transfer. The ene reaction of two alkynes is the rate-determining step. This is considerably easier than other possible mechanisms, such as those involving an ene reaction of an alkyne with a nitrile, a one-step [2 + 2 + 2] cycloaddition, or a 1,4-diradical mechanism. The relative facilities of these processes are analyzed with the distortion-interaction model. A bimolecular hydrogen-transfer mechanism involving a radical-pair intermediate is proposed rather than a concerted intramolecular 1,5-hydrogen shift for the last step in the mechanism.

Synthesis of 2-iodoynamides and regioselective [2+2] cycloadditions with ketene.

The first synthesis of 2-iodoynamides is described as well as the first [2+2] cycloadditions of ketene with iodo alkynes.

Synthesis of polycyclic benzofused nitrogen heterocycles via a tandem ynamide benzannulation/ring-closing metathesis strategy. Application in a formal total synthesis of (+)-FR900482.

A two-stage "tandem strategy" for the synthesis of benzofused nitrogen heterocycles is described that is particularly useful for the construction of systems with a high level of substitution on the benzenoid ring. The first stage in the strategy involves a benzannulation based on the reaction of cyclobutenones with ynamides. This cascade process proceeds via a sequence of four pericyclic reactions and furnishes a multiply substituted aniline derivative which can bear a variety of functionalized substituents at the position ortho to the nitrogen. In the second stage of the tandem strategy, ring-closing metathesis generates the nitrogen heterocyclic ring. This two-step sequence provides efficient access to highly substituted dihydroquinolines, benzazepines, benzazocines, and related benzofused nitrogen heterocyclic systems. The application of this chemistry in a concise formal total synthesis of the anticancer agents (+)-FR900482 and (+)-FR66979 is described.

A New Route to Silyl-substituted Cyclobutenones and Silylketenes.

2-Silyl-cyclobutene(di)ones are obtained by an addition/substitution approach on dimethyl squarate using silyl anions. The acetal and in particular the thioacetal derivatives readily undergo electrocyclic ring opening to reactive silyl(vinyl)ketenes.

A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles based on intramolecular cycloadditions of conjugated enynes.

A [4 + 4] annulation strategy for the synthesis of eight-membered carbocycles is reported that proceeds via a cascade involving two pericyclic processes. In the first step, the [4 + 2] cycloaddition of a conjugated enyne with an electron-deficient cyclobutene generates a strained six-membered cyclic allene that isomerizes to the corresponding 1,3-cyclohexadiene. In the second step, this bicyclo[4.2.0]octa-2,4-diene intermediate undergoes thermal or acid-promoted 6-electron electrocyclic ring opening to furnish a 2,4,6-cyclooctatrienone. The latter transformation represents the first example of the promotion of 6-electron electrocyclic ring opening reactions by acid.

Cyano Diels-Alder and cyano ene reactions. Applications in a formal [2 + 2 + 2] cycloaddition strategy for the synthesis of pyridines.

Two metal-free, formal [2 + 2 + 2] cycloaddition strategies for the construction of polycyclic pyridine derivatives are described that proceed via pericyclic cascade mechanisms featuring the participation of unactivated cyano groups as enophile and dienophile cycloaddition partners.

Formal [2 + 2 + 2] cycloaddition strategy based on an intramolecular propargylic ene reaction/Diels-Alder cycloaddition cascade.

A formal, metal-free, [2 + 2 + 2] cycloaddition strategy is described based on a cascade of two pericyclic processes. The first step involves an intramolecular propargylic ene reaction of a 1,6-diyne to generate a vinylallene, which then reacts in an inter- or intramolecular Diels-Alder reaction with an alkenyl or alkynyl dienophile. Reactions involving unsymmetrical alkenyl and alkynyl dienophiles proceed with good to excellent regioselectivity, and the diastereoselectivity in the Diels-Alder step is also high, with endo cycloadducts produced as the exclusive products of the reaction. In the case of alkynyl dienophiles, [4 + 2] cycloaddition initially generates an isotoluene-type intermediate that isomerizes to the isolated aromatic product upon exposure to a catalytic amount of DBU at room temperature. The mechanism of several earlier fully intramolecular related transformations have been shown to involve an analogous process rather than the diradical-mediated pathways proposed previously.

Synthesis of amides and lactams in supercritical carbon dioxide.

Supercritical carbon dioxide can be employed as an environmentally friendly alternative to conventional organic solvents for the synthesis of a variety of carboxylic amides. The addition of amines to ketenes generated in situ via the retro-ene reaction of alkynyl ethers provides amides in good yield, in many cases with ethylene or isobutylene as the only byproducts of the reaction. Reactions with ethoxy alkynes are performed at 120-130 degrees C, whereas tert-butoxy derivatives undergo the retro-ene reaction at 90 degrees C. With the exception of primary, unbranched amines, potential side reactions involving addition of the amines to carbon dioxide are not competitive with the desired C-N bond-forming reaction. The amide synthesis is applicable to the preparation of beta-hydroxy and beta-amino amide derivatives, as well as amides bearing isolated carbon-carbon double bonds. Preliminary experiments aimed at developing an intramolecular variant of this process to afford macrolactams suggest that the application of CO(2)/co-solvent mixtures may offer advantages for the synthesis of large-ring compounds.

A benzannulation strategy for the synthesis of phenols and heteroaromatic compounds based on the reaction of (trialkylsilyl)vinylketenes with lithium ynolates.

(Trialkylsilyl)vinylketenes react with lithium ynolates to generate 3-(oxido)dienylketenes which undergo rapid 6π-electrocyclization. The ultimate products of this benzannulation are highly substituted resorcinol monosilyl ethers which are formed via a [1,3] carbon to oxygen silyl group shift. Further transformations of the benzannulation products are described providing efficient access to ortho-benzoquinones and benzofuran, benzoxepine, and benzoxocine ring systems.