Kinetic or Dynamic Control on a Bifurcating Potential Energy Surface? An Experimental and DFT Study of Gold-Catalyzed Ring Expansion and Spirocyclization of 2-Propargyl-β-tetrahydrocarbolines

Abstract

In classical transition state theory, a transition state is connected to its reactant(s) and product(s). Recently, chemists found that reaction pathways may bifurcate after a transition state, leading to two or more sets of products. The product distribution for such a reaction containing a bifurcating potential energy surface (bPES) is usually determined by the shape of the bPES and dynamic factors. However, if the bPES leads to two intermediates (other than two products), which then undergo further transformations to give different final products, what factors control the selectivity is still not fully examined. This missing link in transition state theory is founded in the present study. Aiming to develop new methods for the synthesis of azocinoindole derivatives, we found that 2-propargyl-β-tetrahydrocarbolines can undergo ring expansion and spirocyclization under gold catalysis. DFT study revealed that the reaction starts with the intramolecular cyclization of the gold-activated 2-propargyl-β-tetrahydrocarboline with a bPES. The cyclization intermediates can not only interconvert into each other via a [1,5]-alkenyl shift, but also undergo ring expansion (through fragmentation/protodeauration mechanism) or spirocyclization (through deprotonation/protodeauration mechanism). Detailed analysis of the complex PESs for substrates with different substituents indicated that the reaction selectivity is under dynamic control if the interconversion of the intermediates is slower than the ring expansion and spirocyclization processes. Otherwise, the chemical outcome is under typical kinetic control and determined by the relative preference of ring expansion versus spirocyclization pathways. The present study may enrich chemist's understanding of the determinants for selectivities on bPESs.

Cryptic post-transition state bifurcations that reduce the efficiency of lactone-forming Rh-carbenoid C–H insertions

“…2–5,25–29,32 In such a case, traditional transition state theory (TST), 33–36 where barriers to formation of two competing products are compared, cannot be used to predict experimental product distributions, because the two products share a TSS for their formation. PTSBs have been reported previously for some Au-catalyzed reactions, 37–46 as well as a Rh-promoted C–H insertion reaction where the PTSB leads to both the direct insertion product and the product of a C–H activation/Cope rearrangement sequence. 4 Examination of structures along the IRC for the fragmentation reaction suggests that the reaction is asynchronous, with hydride transfer preceding C–O bond breaking (see ESI†).…”

“…2), secondary carbocations in terpene-forming cyclization/rearrangements, 3,26 π-complexes in Au-promoted cyclizations. 37–46 One should not only interrogate reactions of interest for the presence of this scenario, but reactions with PTSBs also, in principle, can be designed by looking for (and rationally manipulating) putative intermediates expected to reside in extremely shallow energy wells that can be accessed from high energy TSSs. It is time to stop bumping into bifurcations and instead actively pursue both of these directions.…”

Copper‐Catalyzed Cascade Cyclization of Indolyl Homopropargyl Amides: Stereospecific Construction of Bridged Aza‐[n.2.1] Skeletons

“…[17] Thus,both the metal catalyst and protecting group of the substrate are the key to achieve the desired cascade cyclization. Interestingly,this cascade cyclization was also extended to 3-substituted indole-tethered homopropargyl amides (5), and the desired aza-[3.2.1] skeletons 6a-h were formed in generally good yields,a ss ummarized in Table 4. Initial investigation of N-protecting groups of the amide moiety demonstrated that the reaction proceeded smoothly with different sulfonyl groups to furnish the desired aza-[3.2.1] skeletons 2a-d in 68-84 %yields (entries 1-4), and the Ts-protected homopropargyl amide 1a gave the best result (entry 1).…”

“…[2,3] In particular,there is alack of efficient synthetic methods for their enantioselective synthesis. [4,5] Meanwhile,s uch ac opper-catalyzed cyclization has been far less vigorously investigated, [6] and the internal nucleophiles here are limited to the more nucleophilic electron-rich amines,thus severely limiting their further synthetic applications as the N-protecting groups of the formed products are difficult for removal. [4,5] Meanwhile,s uch ac opper-catalyzed cyclization has been far less vigorously investigated, [6] and the internal nucleophiles here are limited to the more nucleophilic electron-rich amines,thus severely limiting their further synthetic applications as the N-protecting groups of the formed products are difficult for removal.…”

“…[11] Despite these remarkable achievements,t hese intramolecular tandem reactions have so far been limited to the noble-metal catalysts (Aua nd Pt), and initiated by an exo-cyclization pathway in terms of terminal alkynes. [13] However,a chieving this cascade reaction is highly challenging:1 )how do we prevent the competing exo cyclization of the terminal alkyne partner by the highly nucleophilic indole moiety by at ypical Markovnikov addition; [5] and 2) how do we achieve the desired cascade cyclization but not stop at the dihydropyrrole intermediate. [12] Inspired by these results,w ee nvisioned the synthesis of indole-based tropanes might be achieved by such an anti-Markovnikov hydroamination-initiated cascade cyclization of indolyl homopropargyl amides (Scheme 1e).…”