Studies on the Himbert Intramolecular Arene/Allene Diels–Alder Cycloaddition. Mechanistic Studies and Expansion of Scope to All-Carbon Tethers

Abstract

The unusual intramolecular arene/allene cycloaddition described thirty years ago by Himbert permits rapid access to strained polycyclic compounds that offer great potential for the synthesis of complex scaffolds. To more fully understand the mechanism of this cycloaddition reaction, and to guide efforts to extend its scope to new substrates, quantum mechanical computational methods were employed in concert with laboratory experiments. These studies indicated that the cycloadditions likely proceed via concerted processes; a stepwise biradical mechanism was shown to be higher in energy in the cases studied. The original Himbert cycloaddition chemistry is also extended from heterocyclic to carbocyclic systems, with computational guidance used to predict thermodynamically favorable cases. Complex polycyclic scaffolds result from the combination of the cycloaddition and subsequent ring-rearrangement metathesis reactions.

Nitrone Cycloadditions of 1,2-Cyclohexadiene

“…From diradical 27 , cyclization furnishes 14a or 14b (via TS3a or TS3b ); the formation of 14a is favored by 1.2 kcal/mol, which correlates to the observed 10:1 ratio of products. Therefore, we propose that both stepwise and concerted mechanisms for cycloaddition are in competition, a phenomenon we have previously observed in our studies on Diels–Alder reactions with allenes, 17,18 which are known to be very reactive and form relatively stable allylic radical intermediates.…”

Computation and Experiment Reveal That the Ring-Rearrangement Metathesis of Himbert Cycloadducts Can Be Subject to Kinetic or Thermodynamic Control

“…When faced with situations in which the collection of more experimental data is not likely to increase our understanding of reaction mechanisms or outcomes, our UCI and UCLA groups have engaged in fruitful collaborations, with the latter group providing expertise in DFT calculations of ground-state energies and transition states. 1b,10 In this section, we will demonstrate how the collection of aberrant/unexpected results described above can in fact be reconciled via careful consideration of both kinetic and thermodynamic reaction parameters; the key data required to shed light on the unusual experimental outcomes could only be obtained by calculation.…”

“…We have recently reported 1 the use of the Himbert arene/allene intramolecular Diels–Alder (IMDA) reaction 2 to generate strained bridged polycyclic lactams that are, in many cases, excellent substrates for ring-rearrangement metathesis to afford the corresponding fused isomeric polycycles (Scheme 1). However, upon delving deeper into this chemistry, we have found several substrates that unpredictably did not undergo metathesis rearrangement, some examples of unexpectedly diastereoselective rearrangements, and some interesting qualitative differences in metathesis reaction rates among quite similar substrates.…”

Direct Dearomatization of Pyridines via an Energy-Transfer-Catalyzed Intramolecular [4+2] Cycloaddition

“…To rationalize the observed regio-and diastereoselectivity, DFT calculations were conducted and the result is partially outlined in Figure 6 (see Supplemental Information for details). 40 Accordingly, the triplet energy transfer from photoexcited [Ir-F]@polymer (E T = $60.8 kcal/mol) to substrate E-4ad (calculated as E T = 45.8 kcal/ mol), as well as its rotamer E-4ad 0 (calculated as E T = 46.5 kcal/mol), is thermodynamically feasible. From the resulting excited state, relaxation to the ground state would lead to a statistical mixture of Zand E-configured starting material 4ad or 4ad 0 , which is in excellent agreement with the observed E4Z isomerization under the photosensitized conditions (Figure 5A).…”