1121-10-4Relevant articles and documents
Modular Entry to Functionalized Tetrahydrobenzo[ b]azepines via the Palladium/Norbornene Cooperative Catalysis Enabled by a C7-Modified Norbornene
Dong, Guangbin,Liu, Xin,Wang, Jianchun
, p. 9991 - 10004 (2021)
Tetrahydrobenzo[b]azepines (THBAs) are commonly found in many bioactive compounds; however, the modular preparation of functionalized THBAs remains challenging to date. Here, we report a straightforward method to synthesize THBAs directly from simple aryl iodides via palladium/norbornene (Pd/NBE) cooperative catalysis. Capitalizing on an olefin-tethered electrophilic amine reagent, an ortho amination followed by 7-exo-trig Heck cyclization furnishes the seven-membered heterocycle. To overcome the difficulty with ortho-unsubstituted aryl iodide substrates, we discovered a unique C7-bromo-substituted NBE (N1) to offer the desired reactivity and selectivity. In addition to THBAs, synthesis of other benzo-seven-membered ring compounds can also be promoted by N1. Combined experimental and computational studies show that the C7-bromo group in N1 plays an important and versatile role in this catalysis, including promoting β-carbon elimination, suppressing benzocyclobutene formation, and stabilizing reaction intermediates. The mechanistic insights gained could guide future catalyst design. The synthetic utility has been demonstrated in a streamlined synthesis of tolvaptan and forming diverse pharmaceutically relevant THBA derivatives. Finally, a complementary and general catalytic condition to access C6-substituted THBAs from ortho-substituted aryl iodides has also been developed.
Influence of carbocation stability in the gas phase on solvolytic reactivity: Beyond bridgehead derivatives
Abboud, Jose-Luis M.,Alkorta, Ibon,Davalos, Juan Z.,Mueller, Paul,Quintanilla, Esther,Rossier, Jean-Claude
, p. 3786 - 3796 (2007/10/03)
The intrinsic gas-phase stability of bicyclic secondary carbocations has been determined by Dissociative Proton Attachment of chlorides and alcohols, respectively. From these data, Gibbs free energies for hydride transfer relative to 1-adamantyl (ΔrG°(8,exp)) are derived after application of appropriate leaving group corrections, and good agreement with theoretical values, (ΔrG°(8,comp)), calculated at the G2(MP2) or MP2/6-311G(d,p) level, is reached (Table 1). The relative rate constants for solvolysis (log(k/k0)) of the bicyclic secondary derivatives correlate with the stabilities of the respective carbocations in the same manner as tertiary bridgehead derivatives, but simple monoderivatives and acyclic derivatives solvolyze faster than predicted on the grounds of the ion stabilities. The corresponding stabilities of cyclopropyl- and benzyl-substituted carbocations have been obtained by a combination of experimental and computational data available in the literature with computational methods. Correlation of the rate constants for solvolysis vs ion stabilities for these compounds reveals a trend similar to that observed for bridgehead derivatives, but with much more scatter, which is attributed to nucleophilic solvent participation and/or nucleophilic solvation.
