Access to divergent benzo-heterocycles via a catalyst-dependent strategy in the controllable cyclization of o-alkynyl-N-methoxyl-benzamides

Abstract

A chemo- and regio-selectively controllable approach for construction of diverse benzo-heterocycles is established. A new strategy for using the ligand effect in gold catalysis to control the regioselectivity in the cyclization of o-alkynyl-N-methoxyl-benzamide is successfully achieved. Meanwhile, the chemoselectivity between nitrogen and oxygen nucleophiles is precisely switched by gold and platinum catalysts.

Theoretical Insight into the Mechanism and Origin of Divergent Reactivity in the Synthesis of Benzo-Heterocycles from o-Alkynylbenzamides Catalyzed by Gold and Platinum Complexes

“…Moreover, in the precursors and regioselectivity-determining transition states of the XphosAu­(I)-catalyzed system, the NCI analysis reveals two additional weak interactions between the substrate and ligand: the π – π interaction between the phenyl group in the substrate and the terminal phenyl group in Xphos and the CH···π interaction between the phenyl group in the substrate and the isopropyl group in Xphos. As shown in Figure , these two interactions in O endo - 3b and O endo - TS2b are significantly stronger than those in O exo - 2b and O exo - TS1b , providing further support for the exclusive O -6-cyclization selectivity observed in the experiment . To confirm these noncovalent interactions (NCIs), we calculated and compared the distortion/interaction energies ,,, of two key transition states ( O exo - TS1b and O endo - TS2b ) as shown in Table .…”

“…These two structures are calculated to be less favorable in energy by over 10 kcal/mol in comparison with the O -attack transition states, indicating that the N attack cannot compete with the O attack. This is in agreement with the experimentally observed sole O -attack products …”

“…The above calculated results provide a theoretical support for the observed chemo- and regioselectivities that both the Au­(I) catalysts (ArO) 3 PAuOTf and XphosAuNTf 2 favor the O attack over the N attack with the former giving the O -5- exo-dig cyclization product and the later producing the O -6- endo-dig cyclization product. The higher chemoselectivity to the O attack can be attributed to the following factors: first, the more negative charges on the carbonyl-O than on the amino-N (Figure S2) favor the O attack; and second, the configuration distortion from the precursors to transition states in the O -attack mode is expected to be smaller than that in the N -attack mode.…”

“…o -Alkynylbenzamides are a class of powerful dual-function building blocks synthesizing various N / O -heterocyclic architectures through chemo- and regioselective intramolecular annulations, − including base-mediated 5- exo -azo cyclization, − Lewis acid-catalyzed 6- endo -azo cyclization, , and transitional metal-catalyzed 5- exo - or 6- endo -oxy cyclization. − Excitingly, Jiang et al recently reported a controllable approach for constructing four different heterocyclic compounds from o -alkynyl- N -methoxyl-benzamides, as indicated in Scheme by a representative o -alkynylbenzamide with R 1 = Ph. Both chemo- and regioselectivities were perfectly achieved by tuning the catalyst or ligand.…”

Base-Promoted Chemodivergent Formation of 1,4-Benzoxazepin-5(4H)-ones and 1,3-Benzoxazin-4(4H)-ones Switched by Solvents

“…Chemodivergent reactions are interesting and efficient protocols that form the structurally different heterocyclic compounds from the same starting materials through simple change of reaction conditions [1,2,3,4,5,6,7,8,9,10]. Among them, the solvent-dependent or solvent-controlled chemodivergent reactions have been well applied in the synthesis of heterocyclic compounds [11,12,13,14,15,16,17,18,19,20,21].…”