Kyle A. DeKorver

Ynamides: A Modern Functional Group For The New Millennium

An Overview on Ynamines Alkynes represent one of the most important and versatile building blocks in organic synthesis. Heteroatom-substituted alkynes, which can be considered as subgroups of alkynes, have also been vastly utilized in developing synthetic methods. In particular, ynamines [1-amino-alkynes or N-alkynyl amines] became the most valuable subgroup of alkynes after the establishment of their practical synthesis in the 1960s. The first attempt at preparation of an ynamine was reported by Bode1,2 in 1892. While well-characterized ynamines were reported in 19583 and 1960,4 a practical synthesis was not achieved until the effort led by Viehe5 in 1963 in addition to other subsequent works. In the ensuing twenty years, the synthetic significance of ynamines in organic and organometallic chemistry was firmly established by the work of many creative synthetic chemists. These elegant pioneer works have been informatively and carefully reviewed by Viehe in 19676 and 1969;7 Ficini in 1976;8 Pitacco and Valentin9 in 1979; Collard-Motte and Janousek10 in 1986; Himbert11 in 1993; and most recently by us12,13 and Katritzky14. Open in a separate window The synthetic eminence of ynamines is well merited because of the predicable regioselectivity in their transformations as shown by the generalization in Scheme i, and more importantly, because they are inherently highly reactive. However, this latter attribute is also the source of the limitation that has seriously hampered the development of ynamine chemistry, thereby shortening the period of its prominence in synthesis. Ynamines are very sensitive toward hydrolysis, as protonation of the electron-rich alkynyl motif affords reactive keteniminium intermediates, which upon trapping with water leads to simple amides in a rather expensive manner (Scheme i). This hydrolytic instability has caused much difficulty in the experimental preparation and general handling of ynamines, and more detrimentally, rendered ynamine chemistry inaccessible. Open in a separate window Scheme i Consequently, the synthetic utility of ynamines has suffered a dramatic decline during the last thirty years.15 The most glaring limitations have been in the development of intramolecular and stereoselective reactions.7–14 The only reported intramolecular reaction of ynamines was Genet and Kahns acid catalyzed addition of a hydroxyl group to an ynamine [i→ii in Scheme ii] in 1980,16 and although clever, it constitutes a hydrolytic process. Open in a separate window Scheme ii Besides Reinhoudts17 sole account in 1987 reporting hetero-[4 + 2] cycloadditions of chiral ynamine iii with nitroalkenes that led to cycloadducts iv in modest de, the only other notable studies were reported ten years later by Fischer18 showcasing [2 + 2] cycloadditions of chiral ynamides v and vi with vinylidene chromium carbene complexes, and another three years later by Pericas19 in their Pauson-Khand cycloadditions using chiral ynamines vii.

N-Allyl-N-sulfonyl Ynamides as Synthetic Precursors to Amidines and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift in Nitrile Synthesis

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.

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

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-pi-allyl complexes.

Copper-Catalyzed Ficini [2 + 2] Cycloaddition of Ynamides

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 successful example of ynamides participating in a thermal [2 + 2] cycloaddition with enones.

Introducing a New Class of N-Phosphoryl Ynamides via Cu(I)-Catalyzed Amidations of Alkynyl Bromides

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.

A Divergent Mechanistic Course of Pd(0)-Catalyzed Aza-Claisen Rearrangement and Aza-Rautenstrauch-Type Cyclization of N-Allyl-Ynamides

A fascinating mechanistic study of ynamido-palladium-pi-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.

An Intramolecular [2 + 2] Cycloaddition of Ketenimines via Palladium-Catalyzed Rearrangements of N-Allyl-Ynamides

A cascade of Pd-catalyzed N-to-C allyl transfer-intramolecular ketenimine-[2 + 2] cycloadditions of N-allyl ynamides is described. This tandem sequence is highly stereoselective and the [2 + 2] cycloaddition could be rendered in a crossed or fused manner depending on alkene substitutions, leading to bridged and fused bicycloimines.

Carbocyclization Cascades of Allyl Ketenimines via Aza-Claisen Rearrangements of N-Phosphoryl-N-allyl-ynamides

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.

Synthesis of Cyclopentenimines from N-Allyl Ynamides via a Tandem Aza-Claisen Rearrangement–Carbocyclization Sequence

We describe here details of our investigations into Pd-catalyzed and thermal aza-Claisen-carbocyclizations of N-allyl ynamides to prepare a variety of α,β-unsaturated cyclopentenimines. The nature of the ynamide electron-withdrawing group and β-substituent plays critical roles in the success of this tandem cascade. With N-sulfonyl ynamides, the use of palladium catalysis is required, as facile 1,3-sulfonyl shifts dominate under thermal conditions. However, since no analogous 1,3-phosphoryl shift is operational, N-phosphoryl ynamides could be used to prepare similar cyclopentenimines under thermal conditions through zwitter ionic intermediates that undergo N-promoted H-shifts. Alternatively, by employing ynamides bearing tethered carbon nucleophiles, the zwitter ionic intermediates could be intercepted, giving rise rapidly to more complex fused bi- and tricyclic scaffolds.

Synthesis of Amido-Spiro[2.2]Pentanes via Simmons-Smith Cyclopropanation of Allenamides.

A detailed account of 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 alpha-substituted allenamides, while the diastereoselectivity could be improved significantly based on a series of conformational analyses, both mono- and bis-cyclopropanation products were observed. Consequently, several structurally intriguing amido-methylene cyclopropanes could also be prepared.