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A stereoselective intramolecular normal demand [4 + 2] cycloaddition of allenamides under thermal conditions without metal assistance is described. This work led to the development of a stereoselective tandem propargyl amide-isomerization–[4 + 2] cycloaddition sequence amenable for rapid assembly of complex nitrogen heterocycles.
We have been embarking on the chemistry of allenamides in the last ten years.1,2 In particular, allenamides have proven to be an excellent source of nitrogen-stabilized oxyallyl cations3,4 through DMDO-epoxidation, thereby allowing us to develop highly stereoselective [4 + 3] cycloaddition manifolds5–7 including intramolecular8,9 cycloadditions such as using N-tethered allenamide 19 en route to synthetically useful nitrogen heterocycle 3 [Scheme 1]. However, the dependence on DMDO as the key oxidant for the transformation can pose a challenge in terms of scale and operational convenience. Mascareñas’s report10 intrigued us because of their usage of PtCl2/CO in catalyzing a [4 + 3] cycloaddition of allenes. More significantly, they also documented that a different catalyst [AuCl] could effectively direct the reactivity toward the competing [4 + 2] cycloaddition instead of the [4 + 3] cycloaddition. Recently, Toste11 revealed a similar divergence in [4 + 2] versus [4 + 3] cycloaddition when using different ligands along with a Au(I) catalyst. Our own efforts in exploring Mascareñas’s PtCl2 versus AuCl protocol10,12,13 while adopting allenamides led us to an interesting and different direction than the initially anticipated issues regarding competing [4 + 3] and [4 + 2] cycloadditions [see 4-TS4+3→6 vs. 4-TS4+2→7, respectively, in Scheme 1]. We report here a rare normal electron-demand1,14–17 [4 + 2] cycloaddition involving electron-rich heteroatom-substituted allenes under thermal conditions and a stereoselective tandem propargyl amide isomerization–intramolecular [4 + 2] cycloaddition sequence.
To commence our studies, we initially examined an N-Boc- substituted allenamide, but it was not useful for platinum and gold protocols [see footnote 18 for results]. Consequently, N-sulfonyl-allenamide 919 was prepared from propargyl amide 8 via our base-promoted isomerization protocol using cat t-BuOK.20 We quickly found that with the exception of AuCl [entries 5–7 in Table 1], platinum catalysts [entries 1–4] and Au(III) catalyst [entry 9] were not useful in generating any cycloaddition types of products. Concentrations did not appear to have any impact, as reactions run at 0.04 M led to the same outcome.
Most intriguingly, the illustration of the corresponding [4 + 2] cycloadduct 10 shown in Table 1 of hindsight after a series of subsequent studies. As shown in Figure 1, although 10 and its regioisomer 11 are readily distinguishable, it is not obvious how to unambiguously distinguish 10 from potential [4 + 3] cycloadduct 12 solely based on the key 1H NMR resonances. However, as we continued our explorations and began to achieve high yielding reactions with silver salts [entries 10–13], Brønsted acids [entries 14 and 15, and then, ultimately simple thermal conditions with [entry 16] or without 4Å MS [entry 17], we recognized that this did not appear to be a simple [4 + 3] cycloaddition process. Instead, it turned out to be exclusively a [4 + 2] cycloaddition pathway under all conditions after attaining an X-ray crystal structure [vide infra].
The ability to pursue this cycloaddition thermally represents a unique opportunity for two major reasons. Firstly, as shown in Table 2, this thermally driven allenic-[4 + 2] cycloaddition manifold possesses a much broader synthetic potential than previous work.10,11
The substrate scope is comprised of: (1) Different N-substituents [entries 1–3] including carbamates; (2) substitutions at the allenic γ-position [(±)-15a and (±)-15b in entries 4 and 5, respectively] that gave the respective cycloadducts 16a and 16b with the major isomers shown as assigned via nOe experiments [Figure 2]; (3) various furan substitutions [entries 6 and 7]; (4) a longer tethering that led to the regiochemical outcome in favor of the internal olefin of the allenic motif [22 in entry 8], which is found as a single diastereomer;21 and also notably in this case, when using 10 mol% of AgBF4 and 4Å MS, 22 was isolated in 58% yield as the only regioisomer after heating in toluene at 110 °C for 36 h;21 and lastly, (5) a simple butadiene [entry 9].
The X-ray structure of cycloadduct 14a unambiguously confirms the [4 + 2] cycloaddition pathway [Figure 2], and it provides a general mechanistic picture for this allenic cycloaddition. Based on the nOe assignments of the respective major isomers for 16a and 16b [dr 3:1], the current mechanistic picture also implies that the furan approaches from the more hindered side with R ≠ H. We are not certain of reasons behind this contra-steric approach.
Secondly and more importantly, we recognized the possibility of developing a tandem sequence consisting of propargyl amide isomerization followed by cycloaddition. As shown in Scheme 2, In the presence of 20 mol% t-BuOK at 65 °C, isomerization of propargyl amide 8 and the ensuing cycloaddition led to 10 in 86% yield over three steps furan [or two steps from commercially available 2-(furan-2-yl)ethanol 26]. Likewise, cycloadduct 29 could be obtained in 68% yield in two steps from furfuryl alcohol. We note here that without t-BuOK, this tandem process does not take place even after heating in toluene at 110 °C for 24 h, thereby suggesting that the tandem sequence proceeds through exclusively the respective allenamide intermediate.
In addition, with platinum or gold catalysts, the reaction proceeded through a very different pathway.22,23 Moreover, in a related example from Kanemastu’s account,15 5.0 equiv of t-BuOK was used and the reaction afforded ring-opened and aromatized products instead of furan-cycloadduct 29. The use of catalytic amount of t-BuOK proves to be the key in accessing these structurally more useful cycloadducts.
Finally, this tandem process is general for a range of propargyl amides [Table 3] including those that are terminally substituted [entries 2–4], thereby also representing first examples of successful based-promoted isomerizations of terminally substituted propargyl amides to allenamides.20,24 It is noteworthy that all propargyl amides employed here were prepared from respective furyl alcohols featuring a Mitsunobu reaction using N-sulfonylated propargyl amine [see 27 in Scheme 2], allowing this tandem process amenable for facile constructions of complex nitrogen heterocycles from very simple commercially available material.
We have described here a rare normal electron-demand [4 + 2] cycloaddition of N-tethered allenamides under thermal conditions without assistance of any metals. Our efforts also led to the development of an efficient and highly stereoselective tandem propargyl amide-isomerization–[4 + 2] cycloaddition sequence amenable for rapid assembly of highly functionalized nitrogen heterocycles from very simple commercial furyl alcohols. Applications of this method toward constructing isoquinoline, quinoline, or isoindole containing natural products are underway.
Authors thank NIH-NIGMS [GM066055]. Authors also thank Dr. Vic Young [University of Minnesota] for providing X-ray structural analysis.