![]() In this case, oxygen insertion had occurred, as anticipated, at the more substituted C–C bond. C: O-Mesitylenesulfonyl-hydroxylamine, CH 2Cl 2, 0☌, then Al 2O 3, PhH/MeOH(3:1).Ĭorrespondingly, 3f was converted to lactone 5 in 70% yield (entry 2). A: Trimethylsulfoxonium iodide, NaH, DMF, then LiI, THF B: CF 3CH 2OH, H 2O 2. 11 It is appropriate to note that 4 corresponds to the cycloadduct of a hypothetical Diels-Alder reaction of 2f and the non-functional dienophile, 3-cyclopentenone ( 10).ĪKey. Thus, methylene insertion had occurred exclusively at the more substituted C–C bond, as consistent with the findings of Markó and co-workers. For instance, treatment of cycloadduct 3f with trimethylsulfoxonium iodide and NaH in DMF (A) afforded the spiroepoxide 11 which, upon exposure to lithium iodide, underwent rearrangement to produce cyclopentanone 4, apparently as a single regioisomer (entry 1). Given the now enhanced availability of 1 and its powerful dienophilicity, we explored some aspects of the chemistry of adducts 3 with a view to reaching otherwise inaccessible target structures via Diels-Alder logic ( Table 2). The results provided in Table 1 clearly demonstrate that cyclobutenone 1 is a far more reactive dienophile than are the analogous unsubstituted 5- and 6-membered cycloalkenones. 10 In fact, in our hands, the uncatalyzed reaction of cyclopentadiene with cyclopentenone was only 40% complete after 36h at 150 ☌. 9 By contrast, non-catalyzed Diels-Alder reactions of cyclopentenone or cyclohexenone as dienophiles typically require much higher temperatures (180–250 ☌). While the magnitude of the effect could not have been predicted in advance, the rate enhancement with 1 must reflect the favorable effects of re-hybridization of two particularly strained sp 2 carbons in the cycloaddition transition state. This is remarkable in that vicinal di-activation is a common rate enhancing feature in Diels-Alder cycloadditions. In our estimation, 1 is quite similar in its Diels-Alder reactivity profile to maleic anhydride. 7c Reactions of cyclobutenone with less reactive dienes 2g– j were conducted with Lewis acid activation (ZnCl 2) 8 to produce cycloadducts in moderate to good yields (entries 7–10). The structure of 3e was confirmed by X-ray crystallographic analysis. Not surprisingly, dienes 2c, 2e, and 2f require higher temperatures (45 ☌) and longer reaction times to produce cycloadducts (entries 3, 5–6). Dienes 2a, b, and d gave rise, predominantly, to endo products (entries 1, 2, 4). Accordingly, it was stored as a solution in chloroform.Īctivated acyclic dienes 2a- c were explored and found to be quite reactive in Diels-Alder reactions with 1 ( Table 1). 7a,b Cyclobutenone ( 1) was found to be prone to polymerization when stored in the neat state, even at very low temperatures. We developed a modified version of the Sieja protocol in which a much milder Hunsdiecker-type decarboxylation-bromination was utilized, leading to gram-scale quantities of 1. Sieja 5 had actually described a preparation of cyclobutenone 1, following a very harsh Hunsdiecker-type decarboxylation-bromination of 3-oxo-cyclobutanecarboxylic acid 6 and subsequent elimination. 3) could well represent particularly useful platforms for further elaborations (vide infra).ĭCycloadduct 3h was isolated in 40% yield in the absence of ZnCl 2. Moreover, we could foresee that the products of such Diels-Alder reactions (cf. We anticipated that perhaps the ring strain of 1 might well serve to enhance its dienophilicity relative to corresponding cyclopentenones or cyclohexenones. ![]() ![]() Remarkably, although cycloadditions of substituted cyclobutenones have been reported, 4 we were unable to find a report of a Diels-Alder reaction of the parent cyclobutenone ( 1, Table 1). 3 While both of these dienophiles are known to undergo Lewis acid catalyzed Diels-Alder cycloaddition with less activated dienes, such applications require substrates which are stable to Lewis acids. However, under strictly thermal conditions, parent cyclenones such as cyclohexenone and cyclopentenone are relatively unreactive unless the diene contains strategically placed activating groups. 2Īccess to higher levels of complexity might well be facilitated if the dienophilic double bond in a Diels-Alder reaction is already housed in an existing ring. ![]() Indeed, the Diels-Alder reaction has proven to be a valuable resource in reaching many natural products of novel architecture. 1 The 6-membered rings created through Diels-Alder technology can be substructures of relatively simple targets or may be of value in building molecules of considerable complexity. The power of the Diels-Alder cycloaddition reaction in organic synthesis is widely appreciated. ![]()
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