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

Abstract

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.

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

“…The application of tosyl cyanide as an azadienophile was pioneered by van Leusen in the 1970s, and the utility of this commercially available reagent in hetero Diels–Alder reactions has since been demonstrated in a number of laboratories. , Unfortunately, the reactions of tosyl cyanide with acyclic dienes were found by van Leusen to be complicated by the generation of significant amounts of lactam byproducts. These side products result from hydrolysis of the intermediate dihydropyridines, a process that is autocatalytic in water, which is generated by disproportionation of the sulfinic acid formed in the hydrolysis …”

“…Initial attempts to extend these fully intramolecular processes to the more challenging synthesis of pyridines via “bimolecular” [2 + 2 + 2] strategies were not successful. Unactivated nitriles did not prove reactive enough to efficiently trap vinylallenes in intermolecular cycloadditions, but we did discover that ethyl N -(tosyl) iminoacetate and commercially available tosyl cyanide do react and form intermediates that undergo elimination and isomerization to furnish pyridines (Scheme C) . The products obtained from reactions of TsCN proved particularly useful since they react with carbon and heteroatom nucleophiles via addition/elimination pathways to provide products with a variety of new substituents at C2 (vide infra).…”

Palladium-Catalyzed Cross-Coupling, Divergent Allene Generation, and Cycloadditions toward Cyclobuta[b]naphthalen-3(1H)-ones and 11H-Benzo[b]fluoren-11-ones

“…During the course of this project, we discovered that the cross-coupling intermediates from ortho -iodophenyl-ynones and propargylic substrates undergo divergent isomerizations to generate two types of allene species, i.e., ynone-allene II–1 via propargyl-allenyl isomerization (involving 1,3-hydrogen transfer) and enone-allene III via propargylic Alder ene-type − (involving 1,8-hydrogen transfer), depending on heteroatoms at the propargyl carbon (Scheme b). The two different types of allenic intermediates then fulfill formal [2 + 2] and [4 + 2] cycloadditions with high selectivity to provide polycyclic compounds of cyclobuta­[ b ]­naphthalen-3­(1 H )-one and 11H-benzo­[ b ]­fluoren-11-one backbones, respectively (this finding, Scheme b).…”

Polyarylquinone Synthesis by Relayed Dehydrogenative [2 + 2 + 2] Cycloaddition

“…Efforts toward constructing high order molecular polyarenes have led to multistep synthetic plans involving key transformations such as the Diels–Alder cycloaddition, cyclotrimerization, or cross-coupling . It can be noted that mostly cycloadditions using Pd, Rh, Ru, Re, Co, or Mn catalysts have been used to install individual benzene/heteroarene rings by reactions between alkynes and alkenes, alkynes and benzynes or allenes, alkynes and ketones or β-keto esters, alkynes and enol ethers, alkynes and imines, alkynes and nitriles, and between alkenes . Alternatively, the benzene ring formation has also been achieved by transition metal-catalyzed decarboxylative C–H bond functionalization with alkenes and alkynes .…”