On the regiochemical differences between Pd-catalyzed heterocyclization–allylation and –arylation reactions of alkynylbenzamides: preparation of 4-allyl-isochromen-1-imines and computational study

Abstract

The Pd(0)-catalyzed cyclization-allylation reactions of 2-alkynylbenzamides proceed with high regioselectivity to afford the 6-endo-cyclization-derived products 4-allyl-isochromen-1-imines. DFT calculations have been performed on this and the related arylation reaction, that has been reported to afford the products corresponding to an exo-cyclization under similarly Pd(0)-catalyzed conditions. Under the reaction conditions, these cyclizations are presumed to be triggered by activation of the C-C triple bond with either an allyl- or an aryl palladium complex, generated by oxidative addition of an allyl- or aryl halide to the Pd(0) catalyst. For reactions promoted by allylpalladium species, calculations predict a reversible cyclization, followed by a regioselectivity-determining endo-selective reductive elimination. In contrast, according to calculations, the corresponding arylations would proceed through irreversible exo-selective cyclization and reductive elimination steps. These predictions are consistent with the experimental observations. The divergent regiochemical outcome appears to have its origin in the differences caused on the intermediate palladium complexes by the groups derived from the coupling agents (allyl or aryl) and by the reaction conditions (solvent and ligands) through a subtle interplay of polarity and coordinative effects.

Regioselective Palladium-Catalyzed Heterocyclization–Sonogashira Coupling Cascades from 2-Alkynylbenzamides and Terminal Alkynes: Experimental and DFT Studies

“…Two pathways are then possible depending on whether alkyne C–H palladation precedes or follows the heterocyclization event. For example, pathway A, where cyclization precedes the C–H palladation step, has been reported to be followed by the aminocyclization–alkynylation reactions of 2-alkynyldimethylaniline derivatives, whereas pathway B would be reminiscent of the mechanism followed by typical Pd(0)-catalyzed reactions such as arylations, where the initial oxidative addition of an aryl halide provides the Pd­(II) species needed to activate the C–C triple bond and trigger heterocyclization. ,− ,, Interestingly, we have recently found that, in the particular case of arylations (and allylations) of 2-alkynylbenzamides, the final regiochemical outcome is partially determined by the character of the R group (aryl or allyl) in the organopalladium­(II) RPdY σ complex intermediate …”

“… a wB97XD/LANL2DZ/6-31G*//wB97XD-SMD (DMF)/LANL2DZ/6-31G*. b Data taken from ref . c Agostic interaction with C–H from AcO Me group. …”

“…One representative example of palladium-catalyzed heterocyclization–coupling is provided by the reactions of 2-alkynylbenzamides. These substrates have been shown to undergo palladium-catalyzed O-cyclization–coupling reactions with aryl and allyl halides, alkenes, − carbon monoxide, and 2-alkynyldimethylanilines, as well as oxidative homocoupling, in all cases with good control of the regiochemistry (exo/endo) of cyclization (Scheme ).…”

“… a Conditions: (a) Pd­(PPh 3 ) 4 , 2,6-lutidine, MeCN, reflux, Ar; (b) Pd 2 (dba) 3 , DIPEA, toluene, 120 °C, Ar; (c) PdCl 2 (PPh 3 ) 2 , KI, DMF, air, 80 °C; − (d) Pd­(OAc) 2 , PPh 3 , KI, DMAP, DMF, air, 35 °C; (e) PdI 2 , KI, MeOH; (f) Pd­(OAc) 2 , Cu­(OAc) 2 , n Bu 4 NI, HOAc, DMSO, air, 80 °C; (g) Pd­(OAc) 2 , Cu­(OAc) 2 , K 2 CO 3 , MeCN, air, 100 °C …”

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

“…Intrigued by these interesting chemo-and regioselectivities, we here performed a comparative theoretical study on the four reactions shown in Scheme 2, aiming at a better understanding of the intrinsic molecular mechanism of catalyst-dependent divergent reactivities. It is noted that Aurrecoechea and coworkers 26,27 have reported two excellent theoretical works on the origin of the chemo-and regioselectivity of intramolecular annulations of o-alkynylbenzamides, which are very enlightening for the present mechanism study. In this work, we calculated the reactions catalyzed by all four catalysts shown in Scheme 2; however, the results for the Na 2 CO 3 -catalyzed system are shown in the Supporting Information (pages S9− S12) due to the intrinsically different mechanism by base from that by transition metals.…”