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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.

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...

We describe here the first synthesis of N-phosphoryl ynamides featuring C- and P-chirality via copper(I)-catalyzed amidative cross-couplings between phosphoramidates and phosphordiamidates with alkynyl bromides. Also featured is a tandem aza-Claisen–hetero-[2+2] cycloaddition for the synthesis of N-phosphoryl azetidin-2-imines.

The Ficini [2 + 2] cycloaddition using N-sulfonyl substituted ynamides is described, featuring the utility of CuCl 2 and AgSbF 6 as catalysts. This work represents the first success example of ynamides participating in a thermal [2 + 2] cycloaddition with enones.More than 40 years ago, Ficini 1 disclosed perhaps the most useful carbon-carbon bond forming reaction involving ynamines 2 : a thermally driven stepwise [2 + 2] cycloaddition 3 of ynamine [1] with cyclic enones, leading to the formation of cyclobutenamine 3 [Scheme 1]. [4][5][6] In the last 15 years, ynamides have emerged as a superior synthetic equivalent of ynamines. 7,8 Beautiful chemistry in the area of [2 + 2] cycloadditions has followed by way of Tam's Rucatalyzed ynamide-[2 + 2] cycloaddition of norbornene, 9 Danhesier's thermal cycloaddition of ketenes, 10 and formal [2 + 2] processes through enyne cycloisomerizations using platinum or gold catalysts developed by Malacria 11 and Cossy. 12 However, a thermally driven stepwise [2 + 2] cycloaddition in a Ficini manner using ynamides remained elusive. 13 Our own efforts in trying to develop this cycloaddition reaction lasted for 13 years. We report here our first success in a Ficini [2 + 2] cycloaddition of ynamides.Over the last 15 years, we failed numerous attempts at succeeding Ficini [2 + 2] cycloaddition of ynamides using lactam or oxazolidinone substituted ynamides under thermal and/or Lewisacidic consitions. 14 In the current pursuit of this cycloaddition, we chose to employ N-sulfonyl substituted ynamides because the nitrogen pair of the sulfonamido group is more delocalized toward the alkyne. 15 Therefore, N-sulfonyl substituted ynamides possess enhanced nucleophilicity over simple amide or urethane substituted ynamides, and they are also less stable than amide or urethane substituted ynamides.However, to our disappointment, N-sulfonyl substituted ynamides such as 7 and 10 did not undergo any desired thermal cycloaddition [Scheme 2]. Even when we used quinone and adopt the more electron-rich para-methoxy benzensulfonyl group [Mbs] as shown in ynamide

A series of carbocyclization cascades of allyl ketenimines initiated through a thermal aza-Claisen rearrangement of N-phosphoryl-N-allyl ynamides is described. Interceptions of the cationic intermediate via Meerwein-Wagner rearrangements and polyene-type cyclizations en route to fused bi- and tricyclic frameworks are featured.

A fascinating mechanistic study of ynamido-palladium-π-allyl complexes is described that features isolation of a unique silyl-ketenimine via aza-Claisen rearrangement, which can be accompanied by an unusual thermal N-to-C 1,3-Ts shift in the formation of tertiary nitriles, and a novel cyclopentenimine formation via a palladium catalyzed aza-Rautenstrauch-type cyclization pathway.We recently reported an account on the synthesis of pharmacologically useful amidines [1][2][3][4] from ynamides 5,6 via a Pd(0)-catalyzed N-to-C allyl transfer. 7 As shown in Scheme 1, the formation of amidine 3 was proposed to proceed through ynamido-π-allyl complexes 2a or 2b after the initial oxidative addition [O.A.] of N-allyl-ynamides 1. Subsequently, after the addition of an amine, the reaction pathway would diverge from 4 or 5 depending upon the concentration of the amine HNR 2 and the nature of the palladium catalyst and ligands. Excess amount of amines or more nucleophilic secondary amines 8 tend to attack the ynamido-π-allyl complexes 4 [or 5], leading to deallylated-amidines 6, whereas Pd(0) catalysts such as Pd 2 (dba) 3 [instead of starting from Pd(II) species], and more bulky ligands such as X-phos 9 and/or bidentate ligands with unique bite angles such as xantphos 10,11 that presumably promote reductive elimination [R.E.] favored the formation of allyl transferred amidines 3. Given the novelty of these ynamido-metal complexes and the potential of harvesting new reactivities, we examined this reaction in greater details mechanistically and uncovered a unique ketenimine intermediate, a rare 1,3-Ts shift, and an unusual and formally a Nazarov-type pathway leading to cyclopentenimine formation. We report here these findings.Our initial experiments involved removing the amine nucleophile to suppress amidine formation in an attempt to isolate and/or observe key intermediates. As shown in Scheme 2, in the presence of 1 mol % of Pd 2 (dba) 3 NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript 7 at 70 °C afforded two interesting products: Cyclopentenimine 8 and silyl-ketenimine 9 in 5 % and 88% yield, respectively. 12 The yield of 9 was improved with the formation of 8 completely impeded when the reaction was run at lower temperatures. While characterizations of 9 were unambiguous given its stability, the formation of amidine 10 in 95% yield via treatment of 9 with c-hex-NH 2 solidifies the identification of this novel intermediate. 13 Despite the potential reactivity of N-sulfonyl-ketenimines, the surprising stability of ketenimine 9 is likely unique to the silyl substitution. 14,15 Under similar reaction conditions, ynamide 11 containing a Ph substituent led to a very different product, although in low yields. The product was initially assigned based on literature report 16 as cyclobutane bis-imine 13, presumably attained through a facile dimerization or [2 + 2] cycloaddition of the less stable ketenimine 12.The formation of ketenimines from N-allyl ynamides invokes an aza-Claisen rearrangement, ...

A detailed account on Simmons-Smith cyclopropanations of allenamides en route to amido-spiro[2.2]pentanes is described here. While the diastereoselectivity was low when using unsubstituted allenamides, the reaction is overall efficient and general, representing the most direct synthesis of both chemically and biologically interesting amido-spiro[2.2]pentane systems. With α-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analysis, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.