[8+2] vs [4+2] Cycloadditions of Cyclohexadienamines to Tropone and HeptafulvenesMechanisms and Selectivities

• Published in: Journal of the American Chemical Society Vol. 143; no. 2; pp. 934 - 944
• Main Authors: Chen, Xiangyang, Thøgersen, Mathias Kirk, Yang, Limin, Lauridsen, Rune F, Xue, Xiao-Song, Jørgensen, Karl Anker, Houk, K. N
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 20.01.2021; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Physical Sciences; Science & Technology; CATALYSIS; MOLECULAR-ORBITAL METHODS; DIELS-ALDER REACTION; CONSTRUCTION; ORGANOCATALYSIS; BUTADIENE; GAUSSIAN-TYPE BASIS
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.0c10966

The cinchona-alkaloid-catalyzed cycloaddition reactions of 2-cyclohexenone with tropone and various heptafulvenes give [8+2] or [4+2] cycloadducts, depending on the substituents present on the heptafulvene. We report the results of new experiments with heptafulvenes, containing diester and barbiturate substituents, which in combination with computational studies were performed to elucidate the factors controlling [8+2] vs [4+2] cycloaddition pathways, including chemo-, regio-, and stereo­selectivities of these higher-order cycloadditions. The protonated cinchona alkaloid primary amine catalyst reacts with 2-cyclohexenone to form a linear dienamine intermediate that subsequently undergoes a stepwise [8+2] or [4+2] cycloaddition. Both tropone and the different heptafulvenes initially form [8+2] cycloadducts. The final product is ultimately decided by the reversibility of the [8+2] cycloaddition and the relative thermal stability of the [4+2] products. The stereoisomeric transition states are distinguished by the steric interactions between the protonated catalyst and tropone/heptafulvenes. The [8+2] cycloaddition of barbiturate-heptafulvene afforded products with an unprecedented trans-fusion of the five- and six-membered rings, while the [8+2] cycloadducts obtained from cyanoester-heptafulvene and diester-heptafulvene were formed with a cis-relationship. The mechanism, thermodynamics, and origins of stereo­selectivity were explained through DFT calculations using the ωB97X-D density functional.