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.

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.

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.

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.

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.

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.

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

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 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.

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.

Acyl-Pictet–Spengler cyclizations can be achieved in scCO2/CO2-expanded liquid media via the in situ formation of carbamate derivatives of β-arylethylamines.