RESUMEN
A nucleopalladation-triggered cascade transformation of internal alkynes bearing an amino nucleophile and an electrophilic enone was investigated under unconventional microwave-assisted conditions. Among the three possible pathways, the chloropalladation-triggered domino process proceeded selectively to furnish 3-chloro-1H-indenes in good to excellent yields. The reactions under microwave irradiation were completed in 30 min, and the conventional heating required 3-5 h for completion. The yields obtained under nonclassical heating using microwave irradiation are marginally higher (71-97%) than those of the conventional heating conditions (67-96%). The mechanism of this domino process involves chloropalladation of alkynes to deliver σ-vinylpalladium intermediates, intramolecular carbopalladation via Heck-type olefin insertion, and protodepalladation steps. The other two competitive intramolecular aminopalladation-initiated cascades via 7-endo-dig or 6-exo-dig cyclizations leading to oxazepine or benzoxazine scaffolds were not observed.
RESUMEN
Palladium-catalyzed regiocontrolled intramolecular oxypalladation-initiated cascades of multifunctional internal alkyne bearing an N-tosyl tether deliver functionalized benzazepine as an exclusive product via 6-endo-dig pathway in 1,4-dioxane solvent and tetrahydroquinoline scaffold as a major product via the 5-exo-dig pathway in the DMSO solvent. The role of the solvent in controlling the regioselectivity is still unknown which can be a major hurdle for further reaction development. Moreover, the reaction in DMSO suffered from having a mixture of products, and no exclusive formation of tetrahydroquinoline was achieved. Herein, we report a concerted computational and experimental study, revealing the role of the solvent in controlling the reaction outcome. DFT study revealed that the formation of the σ-vinylpalladium intermediate is reversible for the 5-exo-dig pathway while it is irreversible for the 6-endo-dig mechanism in 1,4-dioxane and consequently, the 5-exo-dig pathway is difficult to proceed. In contrast, both the 5-exo-dig and 6-endo-dig pathways are irreversible in DMSO. We predicted an exclusive formation of isobenzofuranone-fused chromane via the 5-exo-dig pathway when the N-tosyl tether is replaced by the O-tether in the internal alkyne in DMSO. The experimental study confirms the theoretical hypothesis and provides a highly chemo-divergent approach for the synthesis of biologically significant chromane with a large substrate scope and up to 95% yield at room temperature.
RESUMEN
Palladium-catalyzed, solvent-dependent intramolecular oxypalladation-triggered domino sequences of internal alkynes bearing tethered nucleophilic carboxylic ester and electrophilic enone functionalities were developed for the chemodivergent synthesis of two completely distinct biologically significant complex molecules including isochromenone-fused benzazepines and isobenzofuranone-fused tetrahydroquinolines/chromanes in a single synthetic operation.
RESUMEN
A microwave-assisted, palladium(II)-catalyzed cascade reaction of 2-alkynylanilines tethered with an α,ß-unsaturated carbonyl moiety was established to access 5,10-dihydroindeno[1,2-b]indoles in high yields (up to 84%) in a short reaction time. This operationally simple cascade process shows 100% atom economy and allows the construction of two new five-membered rings and two new (1 C-C and 1 C-N) bonds in a single synthetic attempt. The mechanistic pathway of this reaction is visualized involving intramolecular aminopalladation (5-endo-dig) followed by carbopalladation (olefin insertion) and protonolysis steps. A systematic comparison between microwave irradiation and conventional heating methods was also performed to demonstrate the supremacy of the microwave-assisted approach. This domino reaction requires no protecting groups for the amino group and the palladium catalyst needs no ligands. To the best of our knowledge, this is the first report on microwave-assisted nucleopalladation-initiated cascade transformation.
RESUMEN
A highly efficient microwave-assisted copper(II)-catalyzed cyclization cascade was established starting from readily accessible O/N-propargylated 2-hydroxy or 2-aminobenzaldehydes and o-phenylenediamines to synthesize densely functionalized imidazo[1,2-d][1,4]oxazepines and imidazo[1,2-d][1,4]diazepines in high yields (up to 93%). This one-pot two-step process was found to be highly atom economical (-H2O, -H2) and operationally simple and enabled the generation of two new heterocycle rings (seven- and five-membered) and three new C-N bonds in a single synthetic operation. These reactions well tolerated a variety of substituents including electron-donating and electron-withdrawing groups and furnished the desired fused heterocycles in high yields under microwave irradiation in a very short reaction time. The mechanism of the established protocol involves sequential imine formation-intramolecular cyclization-air oxidation followed by 7-exo-dig cyclization steps. A comparative study between the microwave-assisted approach and conventional heating was also performed to demonstrate the advantages of the microwave-assisted protocol in terms of high yield and shorter reaction time.