A Silver(I)-Catalyzed Intramolecular Ficini's [2 + 2] Cycloaddition Employing Ynamides.

We reported the first examples of Ficini’s [2 + 2] cycloaddition, or the Ficini reaction, employing ynamides in 2010 after a 13-year long attempt.1 This final success came more than 40 years after Ficini2–5 had disclosed perhaps the most useful carbon-carbon bond forming reaction involving ynamines.2,6 The Ficini reaction3 entails a stepwise and thermally driven [2 + 2] cycloaddition7 of ynamines with α,β-unsaturated ketones, while our reaction1 with ynamides 1 were promoted with Cu(II)/Ag(I) salts, leading to the formation of cyclobutenamides 3 via the proposed zwitter ionic intermediate 2 [Scheme 1]. Mezzetti8 subsequently reported a beautiful account of asymmetric Ficini [2 + 2] cycloadditions using a chiral dicationic Ru(II) complex. However, an intramolecular variant of the Ficini reaction has remained untapped using ynamides.9 Given that ynamides have become a powerful and versatile functional group in organic synthesis in the last 20 years,10,11 a successful intramolecular Ficini reaction using ynamides tethered with an enone motif as shown in 4 could prove to be a tantalizing possibility for constructing complex polycycles. We wish to communicate here our success in establishing the concept of an intramolecular [2 + 2] cycloaddition employing ynamides and its current limitations. Scheme 1 Ficini’s [2 + 2] Cycloaddition Using Ynamides. Our work commenced first with a new finding experimentally for the intermolecular [2 + 2] cycloaddition. We observed that it is not necessary to use both Cu(II) and Ag(I) catalysts to promote the intermolecular reaction. As shown in Table 1, the initial keys to render the [2 + 2] cycloaddition successful are that ynamides cannot be terminally unsubstituted as in 7 [entries 1 and 2], and that 20 mol% CuCl2 and 60 mol% AbSbF6 were found to be the most suitable catalytic system1 to afford the desired cycloadduct 10 in high yield from ynamide 9 [entry 3]. However, our efforts post publication reveal that either Cu(II) or Ag(I) salt alone could catalyze this cycloaddition, and that silver is actually more superior. More specifically, AgNTf2 in 10 mol% appears to be the best catalyst overall [entries 9 and 10]12 in providing comparable outcome as those promoted by both CuCl2 and AbSbF6. While AgBF4 also worked quite effectively [entry 6], the reaction took a much longer time [entries 6–8]. Table 1 The Effectiveness of Silver Salts. The discovery of Ag(I) catalyst proves out to be essential, as it turned out that the presence of 20 mol% CuCl2 and 60 mol% AbSbF6 were completely ineffective for the intramolecular [2 + 2] cycloaddition of ynamides 11a–d.13–15 Consequently, we focused on the silver catalyst and quickly found that AgNTf2 again was the best silver salt [entries 1–3 versus entry 4 in Table 2]. In addition, yields were better when the reaction was carried out in CH2Cl2 [entry 4 versus entries 6–9] and at higher concentrations [entries 4 and 12 versus entries 10 and 11].16 Lastly, the nature of the electron withdrawing group on the nitrogen atom did not appear to have a significant impact on the reaction [entry 4 versus entries 13–15]. Table 2 A Ag(I)-Catalyzed Intramolecular Cycloaddition. Relative stereochemistry was assigned using nOe experiments performed using cycloadduct 12a [Figure 1], and the scope of this cycloaddition is showcased in Figure 2. It is noteworthy that when the nitrogen atom is substituted with an alkene, yields of the cycloaddition are lower [see 13–16]. This is likely due to competing complexation of the olefin with the silver catalyst followed by decomposition pathways. Only when there is sufficient distance between the olefin and the nitrogen atom, the cycloaddition could be improved [see 16]. Figure 1 Stereochemical Assignment of 12a via nOe Experiment. Figure 2 Scope of the Intramolecular Cycloaddition. Unfortunately, when we turned to ynamide 20 in hope of obtaining cycloadduct 21, we found instead only the half-cycloaddition product 22 after numerous attempts [Scheme 2]. While the relative stereochemistry is unassigned, isolation of 22 is most likely a result of direct hydrolysis of the zwitter ionic intermediate 23 after the first bond formation, although the desired cycloaddition could have taken place, and that a subsequent hydrolytic ring-opening of the desired cycloadduct 21 could lead to 22. On the other hand, only when utilizing AgOTf as the catalyst, did we find the corresponding half-cycloaddition product 24 from ynamide 11a. In all other cases, cycloadducts in which the cyclobutenamide is fused to a 6-membered ring could be prepared without problem. This distinct contrast suggests that the ring strain in the anticipated cycloadduct 21, where the cyclobutenamide is fused to a 5-membered ring, could be responsible in deterring the cycloaddition pathway.17 Scheme 2 Observations of the Half-Cycloaddition Products. We then examined electrocyclic ring-opening of these [2 + 2] cycloadducts.18 As shown in Scheme 3, a highly torquoselective conrotatory ring-opening of cyclobutenamides 12a and 12d could take place effectively at 100 °C to afford 2-amidodienes 25a and 25d, respectively. Likewise, 2-amidodienes 26 and 27 could also be obtained in high yields from their respective starting cyclobutenamides 15 and 16. The high level of torquoselectivity is predictably a result of the ring-junction hydrogen [in blue] rotating inwardly with respect to the cyclobutene ring to avoid the formation a trans-cyclohexene ring. This rotational preference trumps the inward rotation favored from the electron withdrawing carbonyl group based on Houk’s prediction,19 and leads to the exclusive formation of Z-vinylogous amide, which was assigned using nOe experiments. Scheme 3 Pericyclic Ring-Opening of the [2 + 2] Cycloadducts. In addition, it is noteworthy that these 2-amidodienes favor the S-trans conformation with ∆E being 4.03 kcal mol−1 for 25a from B3LYP/6-31G* [Spartan™] calculations. Such conformational preference for S-trans is likely to avoid allylic strain. Consequently, our preliminary attempts to carry out an obvious application in the form of [4 + 2] cycloadditions were not successful using 2-amidodienes 26 and 27, with the latter as an attempt for a possible intramolecular [4 + 2] cycloaddition.20 We are currently exploring other possible applications that can distinctly showcase synthetic potential of these highly functionalized unique dienes. We have described here an intramolecular [2 + 2] cycloaddition using N-sulfonyl substituted ynamides tethered to an enone motif. This intramolecular Ficini reaction could be effectively catalyzed using AgNTf2. Our work represents the first examples of an intramolecular variant of Ficini’s original ynamine–[2 + 2] cycloaddition. Efforts are underway in further development of this new cycloaddition and its applications.