Reaction Control in Synthetic Organic Photochemistry: Switching between [5+2] and [2+2] Modes of Cycloaddition

Abstract

Modern synthetic chemistry has evolved to such an extent that exquisite levels of chemo-, regio-, and stereocontrol can be readily achieved within complex, multifunctional molecules. Reaction control in synthetic photochemistry is a much more difficult prospect where the basic bond-forming step is generally controlled by the lifetime of a key excited state, the formation of which is often dominated by complex structural and photophysical issues. Different reaction pathways of a single chromophore (e.g. C=C bond) can be observed by populating either singlet or triplet states.[1] Further limited modes of selection can be achieved by irradiation at userselected wavelengths, [2] through higher exited states from multiphoton absorption, [3] and by feedback-based optical control using evolutionary algorithms and pulse shapers. [4] More recently our research group has demonstrated that photon flux can be a useful parameter in controlling reaction pathways, albeit within the scale limitations imposed by tunable dye lasers.[5]Herein we demonstrate how sensitized and nonsensitized reactions of N-alkenyl maleimides lead to a selective reaction from different bonds (CÀN vs. C=C) within the same molecule. This selection enables either a [5+2] or [2+2] cycloaddition pathway to be chosen, thus providing selective synthesis of complex 7,5-fused azepines or cyclobutanes, respectively.We previously described the intermolecular [2+2] photocycloaddition reactions of tetrahydrophthalimide anhydride 1 (Scheme 1) with alkenol and alkynol partners.[6] We found these reactions to be remarkably efficient, with the [2+2] cycloadducts (e.g. 2) being formed in high yields and with excellent stereoselectivity. In contrast, the attempted intramolecular [2+2] photocycloaddition of the pentenylsubstituted imide 3 yielded the tricyclic azepine 5 exclusively in excellent yield by a [5+2] pathway (attributed to cleavage of the C À N bond). [7] This observation has since proved to be a general trend with maleimide derivatives: [2+2] photocycloaddition is observed with intermolecular reactions and [5+2] photocycloaddition with intramolecular variants.More recently we have focused on exploring the scope of this [5+2] cycloaddition and its application in natural product synthesis.[8] During model studies towards the synthesis of the Stemona alkaloids we observed that an N-alkenyl maleimide displayed atypical [5+2] behavior (Scheme 2). Irradiation of the maleimide system 6 (containing an exocyclic alkene unit) led to a high yield of cycloaddition products, but for the first time the intramolecular [2+2] adduct dominated. Although chemically efficient, the low quantum yields (F [2+2] = 0.018 and F [5+2] = 0.009) illustrate photochemically inefficient bond-forming processes. This observation was initially disregarded as an anomaly; however, recent similar results have

Theoretical studies of spin state‐specific [2 + 2] and [5 + 2] photocycloaddition reactions of n‐(1‐penten‐5‐yl)maleimide

“…In other words, the S 1 state prefers [5 + 2] photocycloaddition and the T 1 state does [2 + 2] photocycloaddition. This spin state‐specific selectivity is consistent with experiments of Orr‐Ewing and coworkers . They have found that in most of N ‐alkenyl maleimides photoexcitation exclusively produces [5 + 2] photoproducts; photosensitized N ‐alkenyl maleimides merely generate [2 + 2] photoproducts.…”

“…In the T 1 state, [2 + 2] photocycloaddition reaction happens. Interestingly, on photosensitization, only [2 + 2] photoproducts are observed in all studied N ‐alkenyl maleimides; in contrast, on direct irradiation, only [5 + 2] photoproducts are observed in most N ‐alkenyl maleimides …”

“…Recently, Roscini et al experiment‐ally demonstrated that sensitized and non‐sensitized reactions of N ‐alkenyl maleimides have entirely different chemoselectivities and proposed a possible photocycloaddition reaction mechanism shown in Figure . Once N ‐alkenyl maleimides are excited on direct irradiation, the system first relaxes to the S 1 state; then, the CN bond of the maleimide moiety is broken, followed by [5 + 2] photocycloaddition reaction producing final photoproducts.…”

“…To date, photochemical reaction mechanisms of these N ‐alkenyl maleimides are still elusive . A few mechanistic details at atomistic level are unclear.…”

A general, enantioselective synthesis of 1-azabicyclo[m.n.0]alkane ring systems

“…1) are limited. 1–8 In general, the existing strategies for the construction of azabicyclic ring systems rely on Staudinger-aza-Wittig approaches, 9 7-exo- tet -cyclizations, 10,11 cycloadditions ([5+2], [4+2] and [2+2+2]), 12 ring-closing metathesis (RCM) strategies, 13 Mitsunobu approaches 14 and rearrangements (nitrone and intramolecular Schmidt rearrangements) 15,16 For the larger azabicyclic ring systems, routes are very rare, and those reported lack stereocontrol. 8,17 …”