Synthesis of Amidines Using N-Allyl Ynamides. A Palladium-Catalyzed Allyl Transfer through an Ynamido−π-Allyl Complex

Abstract

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...

Ynamides: A Modern Functional Group for the New Millennium

“…Hsung142 recently disclosed a thermal aza -Claisen rearrangement of silylated ynamides 555 to isolable ketenimines 556 , which can be trapped in situ with nucleophilic amines (Scheme 147). In refluxing toluene, the reaction proceeded efficiently to give allylated amidines 557 in high yields as a complementary method to the palladium-catalyzed reaction (Section 3.7).…”

“…Hsung and Zhang142 recently reported a possible metallo-ynamido complex in their work on the synthesis of amidines 668 from N -allyl ynamides 665 (Scheme 167). Pd(0) was found to catalyze an N -to- C allyl transfer presumably through oxidative addition into the C — N bond to form an ynamido-Pd-π-allyl complex in equilibrium with the ketenimine-Pd complex 666 .…”

Lithium Hexamethyldisilazane Transformation of Transiently Protected 4-Aza/Benzimidazole Nitriles to Amidines and their Dimethyl Sulfoxide Mediated Imidazole Ring Formation

“…It was also adapted to prepare N -substituted amidines 25 related to earlier derivatives. 26 However, for BI and azaBI systems, LHMDS deprotonates the ring NH, preventing the desired reaction due to a delocalized negative charge on the nitrile. Thus, amidines of such systems are usually prepared by one of the other two methods.…”

Carbocyclization Cascades of Allyl Ketenimines viaAza-Claisen Rearrangements ofN-Phosphoryl-N-allyl-ynamides

“…4 Most notably, it was demonstrated that N -phosphoryl- N -allyl ynamides 1 [for EWG = PO(OR) 2 ] could undergo a thermal 3- aza -Claisen rearrangement 5,6 to generate allyl ketenimine 7 intermediates 2 in situ without suffering a subsequent facile 1,3-shift observed in related N -sulfonyl systems [ 1 ➡ 4 when EWG = ArSO 2 ], leading to an effective formation of structurally unique quaternary nitriles 5 8,9 (Scheme 1). While such a 1,3-sulfonyl shift can be of immense interest, 10 it precluded us from developing a useful carbocyclization of allyl ketenimines 4 .…”