A detailed study of amidine synthesis from N-allyl-N-sulfonyl ynamides is described here. Mechanistically, this is a fascinating reaction consisting of diverging pathways that could lead to deallylation or allyl transfer depending upon the oxidation state of palladium catalysts, the nucleophilicity of amines, and the nature of the ligands. It essentially constitutes a Pd(0)-catalyzed aza-Claisen rearrangement of N-allyl ynamides, which can also be accomplished thermally. An observation of N-to-C 1,3-sulfonyl shift was made when examining these aza-Claisen rearrangements thermally. This represents a useful approach to nitrile synthesis. While attempts to render this 1,3-sulfonyl shift stereoselective failed, we uncovered another set of tandem sigmatropic rearrangements, leading to vinyl imidate formation. Collectively, this work showcases the rich array of chemistry one can discover using these ynamides.
The use of heteroatom-substituted oxyallyl cations in (4 + 3) cycloadditions has had a tremendous impact on the development of cycloaddition chemistry. Extensive efforts have been exerted toward investigating the effect of oxygen-, sulfur-, and halogen-substituents on the reactivity of oxyallyl cations. Most recently, the use of nitrogen-stabilized oxyallyl cations has gained prominence in the area of (4 + 3) cycloadditions. The following article will provide an overview of this concept utilizing nitrogen-stabilized oxyallyl cations.
Chiral oxazolidinones were previously thought to control cycloaddition stereoselectivity by steric crowding of one face of the substrate. We have discovered that in 4+3 cycloaddition reactions of oxallyls, the stereoinduction is caused instead by stabilising CH–π interactions that lead to reaction at the more crowded face of the oxazolidinone. Density functional theory calculations on the 4+3 cycloadditions of oxazolidinone-substituted oxyallyls with furans establish unexpected transition state conformations and a new explanation of selectivity.
A de novo transformation of N-allyl-N-sulfonyl ynamides to amidines is described featuring a palladium-catalyzed N-to-C allyl transfer via ynamido-palladium-π-allyl complexes.Our involvement in the studies of Huisgen's azide-[3 + 2] 1-3 cycloadditions employing ynamides 4-7 led us to an exciting possibility. As shown in Scheme 1, under copper(I)-catalyzed conditions, 8 while triazolyl copper intermediates 1 could be trapped with electrophiles other than proton to afford more substituted triazoles 2 ,9,10 when R 2 = Ts, it could also readily lose N 2 in a retro-[3 + 2] manner to give ynamido-copper complexes 3a in equilibrium with ketenimine-copper complexes 3b. A series of elegant studies have since appeared reporting nucleophilic trappings of 3 in both inter-and intramolecular fashion, leading to amidines and amidates. 11-14 The potential of harvesting new reactivities from ynamido-metal complexes captured our attention. Consequently, we examined a different pathway that can provide general access to ynamido-metal π-allyl complexes 5a and 5b from N-allyl-N-sulfonyl ynamides 4. We report here a de novo synthesis of pharmacologically useful amidines 15-18 from ynamides featuring a palladium-catalyzed N-to-C allyl transfer through ynamido-π-allyl complexes.While identifying a suitable palladium catalyst for our intended reaction pathway was not difficult, we found two amidine products. As shown in Table 1, when treating N-allyl-Nsulfonyl ynamide 6 with 5 mol% of Pd(PPh 3 ) 2 Cl 2 in the presence of c-hex-NH 2 in THF at 65°C , both amidines 7 and 8 were observed. 19 Intriguingly, the ratio of 7 and 8 depended upon the amount of c-hex-NH 2 that was used. A greater amount of c-hex-NH 2 [3-5 equiv] predominantly led to the formation of 7 in which the allyl group is lost [entries 1 and 2], while 1.0 equiv of c-hex-NH 2 and/or addition with the use of syringe pump began to favor the formation of 8 in which the allyl group had undergone an N-to-C transfer [entries 3 and 4]. E-mail: rhsung@wisc.edu. Thirdly, we explored ynamides 29a-e with variations on the acetylenic substituent [ Table 3]. It is noteworthy that while Pd(PPh 3 ) 4 was effective in promoting allyl transfer when using primary amines, it was not useful for secondary amines [with the exception of 22] and only the usage of Pd 2 (dba) 3 and xantphos led to allyl transferred amidines.
NIH Public AccessA proposed model consistent with our observations is shown in Scheme 2. While all evidence points toward the presence of ynamido-P d-π-allyl complexes 5a in equilibrium with the ketenimine complex 5b through an oxidative addition, 22,23 the pathway clearly diverged thereafter depending upon the concentration of the amine HNR 2 and the nature of the ligand. We believe the first equivalent of HNR 2 effectively gave the amidinyl Pd-π-allyl complexes 31a and 31b via nucleophilic addition to 5b. An ensuing reductive elimination of 31a and/or 31b would lead to respective allyl transferred amidines 32a and 32b, and 32a appears to tautomerize favorably to 32b.Howe...
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