Richard P. Hsung

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.

Ynamides in ring forming transformations.

The ynamide functional group activates carbon-carbontriple bonds through an attached nitrogen atom that bears an electron-withdrawing group. As a result, the alkyne has both electrophilic and nucleophilic properties. Through the selection of the electron-withdrawing group attached to nitrogen, chemists can modulate the electronic properties and reactivity of ynamides, making these groups versatile synthetic building blocks. The reactions of ynamides also lead directly to nitrogen-containing products, which provides access to important structural motifs found in natural products and molecules of medicinal interest. Therefore, researchers have invested increasing time and research in the chemistry of ynamides in recent years. This Account surveys and assesses new organic transforma-tions involving ynamides developed in our laboratory and in others around the world. We showcase the synthetic power of ynamides for rapid assembly of complex molecular structures. Among the recent reports of ynamide transformations, ring-forming reactions provide a powerful tool for generating molecular complexity quickly. In addition to their synthetic utility, such reactions are mechanistically interesting. Therefore, we focus primarily on the cyclization chemistry of ynamides. This Account highlights ynamide reactions that are useful in the rapid synthesis of cyclic and polycyclic structural manifolds. We discuss the mechanisms active in the ring formations and describe representative examples that demonstrate the scope of these reactions and provide mechanistic insights. In this discussion, we feature examples of ynamide reactions involving radical cyclizations, ring-closing metathesis, transition metal and non-transition metal mediated cyclizations, cycloaddition reactions, and rearrangements. The transformations presented rapidly introduce structural complexity and include nitrogen within or in close proximity to a newly formed ring (or rings). Thus, ynamides have emerged as powerful synthons for nitrogen-containing heterocycles and nitrogen-substituted rings, and we hope this Account will promote continued interest in the chemistry of ynamides.

Allenamides: A Powerful and Versatile Building Block in Organic Synthesis

In the past four decades, allenes have progressively risen from an unenviable status of being a structural curiosity to becoming one of the most powerful and versatile synthetic building blocks in organic synthesis.1–3 Although the focal theme of this review is centered on chemistry of allenamides, a proper introduction would need to commence with allenamines. Allenamides are functionally derived from allenamines,4 which along with structurally related systems such as allenol ethers5 and allenyl sulfides,6 can be classified as heteroatom-substituted allenes. Allenamines have been known for more than forty years since the first documentation of their preparations and characterizations in 1968 by Viehe.7 It is noteworthy that Viehe was at the time developing a based-catalyzed isomerization of propargyl amines as a useful protocol for synthesizing ynamines (Scheme 1), which had just come onto the scene as a useful synthetic building block.8–10 Allenamines were postulated as an intermediate en route to ynamines in this prototropic isomerization that follows essentially the zipper-type mechanism. Open in a separate window Scheme 1 The π-donating ability of nitrogen atom renders allenamines more electron-rich than simple allenes, thereby predisposing them to electrophilic activations. An electronic bias can be exerted through delocalization of the nitrogen lone pair toward the allenic moiety as demonstrated in the resonance form of allenamines. Accordingly, highly regioselective transformations can be achieved with consecutive addition of electrophiles and nucleophiles (Scheme 2). In addition to aforementioned regiochemical control, allenamines also offer a number of other advantages over simple allenes. The trivalent nature of the nitrogen atom allows: (1) Tethering of a chirality-inducing unit for providing stereochemical induction; concomitantly with the inclusion of a coordinating unit to provide conformational rigidity; (2) a much greater flexibility in designing intramolecular reactions or tandem processes than with oxygen- or sulfur-substituted allenes; and last but not the least, (3) a novel entry to alkaloids if the nitrogen atom can be preserved throughout the entire transformative sequence. Moreover, intramolecular reaction manifolds as shown with a possible diastereoselective cyclopropanation reaction (Scheme 2) can greatly manifest these remarkable features, particularly the latter two. Therefore, while the chemistry of other heteroatom-substituted allenes is of high impact and value to organic synthesis, allenamines should prove to be more attractive for developing stereoselective methodologies as well as rapid assembly of structural complexity.1,2 Open in a separate window Scheme 2 Without illustrating any specifics here on allenamine chemistry given all the comprehensive reviews,1,2 elegant precedents adopting allenamines in a range of transformations have indeed been documented to further support their synthetic potential and provoke interest from the synthetic community. Unfortunately, further developments had been severely thwarted because allenamines are also highly sensitive toward hydrolysis with a tendency to polymerize even at low temperatures (Scheme 3), thereby creating serious difficulties in their preparation and experimental handling.1,2 Consequently, the great potential of chemistry of nitrogen-substituted allenes could only be partially realized. Therefore, efforts to identify an allenamine-equivalent should be of high significance if it can strike the right balance between stability and reactivity. Open in a separate window Scheme 3 Toward this end, allenamides should represent ideal candidates as a stable allenamine-equivalent. Delocalization of the nitrogen lone-pair into the electron-withdrawing amido group should diminish its donating ability toward the allenic moiety, thereby leading to improved stability (Scheme 4). In short, the very simple fact that allenamides can champion an extra resonance form speaks volume of its superior stability over allenamines. It could be a great story if allenamides were a result of some clever design in search for a stable allenamine-equivalent. However, this is not true and the story is much less dramatic. Allenamides have co-existed along side of allenamines for all of the last four plus decades after Dickinsons first preparation and concise characterizations of 1,2-propadienyl-2-pyrrolidinone in 1967 (Scheme 5).11 Open in a separate window Scheme 4 Open in a separate window Scheme 5 In fact, Dickinson coined the term “allenamide” to describe 1,2-propadienyl-2-pyrrolidinone based the analogy of using enamides17 for Stork’s N-acylated enamines. To clarify reports by Cho12 and others,13 Dickinson concisely demonstrated that treatment of 2-pyrrolidinone with NaH and propargyl bromide had indeed led to the allenamide as the major and stable product also via the same prototropic isomerization pathway. Intriguingly, unlike Viehe’s work, allenamide did not undergo further isomerization to the respective ynamide, although with further treatment of NaOMe and pyrrolidine, ynamide was postulated as an intermediate en route to the N-acyl-pyrrolidine product. Nevertheless, this documentation of ynamide actually predated Viehe’s 1972 account,14 and chemistry of ynamides has indeed generated an immense amount of interest from the synthetic community in the last 15 years.15,16 To align with the history, our foray into this field coincides with both of Viehe and Dickinson’s work. In search of a useful synthetic method to construct chiral ynamides 16 years ago,10 we found that based-catalyzed prototropic isomerization of propargyl amides reliably arrested at the allenic stage and gave none of the desired ynamides10 (Scheme 6) regardless of nature of the base used, temperature, and solvents (also see Schemes 24 and ​and2525 vide infra). More importantly, to properly acknowledge a critical person in our entire endeavor in allenamide chemistry, I owe everything to the very first postdoctoral research fellow in my group, Dr. Lin-Li Wei [Ph.D. with Professor Teck-Peng Loh at National University of Singapore]. Dr. Wei, who was working on these isomerizations, pointed out that these allenamides that she had obtained could prove to be an excellent allenamine-equivalent, and evolve into highly versatile synthetic building blocks in organic synthesis. Open in a separate window Scheme 6 Open in a separate window Scheme 24 Open in a separate window Scheme 25 Given the precedent, the ease of preparation, and stability, the most critical question would be whether these allenamides could possess sufficient reactivity. A survey of the literature indicates that although it was far from a blank page, allenamides have been much less explored relative to allenamines.4,18–20 Precise reasons are not very clear, but there were very few citations on synthesis and applications of allenamides before 1989. While few more reports appeared from late 1980’s to mid-1990’s, the real outburst in chemistry of allenamides came 16 years ago, just as we also became deeply involved in the development of allenamide chemistry. Such sustained emergence strongly suggests that allenamides have set the gold standard for balancing reactivity and stability. They are becoming proven allenamine-equivalents that can be employed in a diverse array of stereoselective and intramolecular reactions that were not possible with traditional allenamines. They represent the ideal platform for pushing the limit of synthetic potential of nitrogen-substituted allenes. It is the purpose of this review to provide proper illustrations of the elegant chemistry involving allenamides that has come to pass, thereby eliciting a greater amount of interests from the synthetic community to create new allenamide chemistry. Lastly, this perspective that advancement of any field requires collective creativity and innovation from many people and not just a few individuals rings hollow here. On that note, although we are trying our very best to be comprehensive, it is likely that we have inadvertently missed some beautiful work for which we express our regret here in advance.

(4+3) cycloaddition reactions of nitrogen-stabilized oxyallyl cations.

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.

Enamide-benzyne-[2 + 2] cycloaddition: stereoselective tandem [2 + 2]-pericyclic ring-opening-intramolecular N-tethered [4 + 2] cycloadditions.

Benzyne-[2 + 2] cycloadditions with enamides are described. This effort led to the development of a highly stereoselective tandem [2 + 2] cycloaddition-pericyclic ring-opening-intramolecular-N-tethered-[4 + 2] cycloaddition for rapid assembly of nitrogen heterocycles.

Efficient preparations of novel ynamides and allenamides

Abstract Practical syntheses of a series of novel ynamides and allenamides are described here. While a base-induced isomerization protocol of propargyl amides leads to an array of chiral and achiral allenamides, ynamides are prepared from enamides via bromination followed by base-induced elimination of the Z -bromoenamides. These ynamides and allenamides possess improved thermal stability compared to ynamines and allenamines. They can be isolated, purified, and handled with ease, and thus, should be synthetically more useful than traditional ynamines and allenamines.

Synthesis of α-Keto-Imides via Oxidation of Ynamides

A de novo preparation of alpha-keto-imides via ynamide oxidation is described. With a number of alkyne oxidation conditions screened, a highly efficient RuO2-NaIO4 mediated oxidation and a DMDO oxidation have been identified to tolerate a wide range of ynamide types. In addition to accessing a wide variety of alpha-keto-imides, the RuO2-NaIO4 protocol provides a novel entry to the vicinal tricarbonyl motif via oxidation of push-pull ynamides, and imido acylsilanes from silyl-substituted ynamides. Chemoselective oxidation of ynamides containing olefins can be achieved by using DMDO, while the RuO2-NaIO4 protocol is not effective. These studies provide further support for the synthetic utility of ynamides.

A Novel and Highly Stereoselective Intramolecular Formal [3+3] Cycloaddition Reaction of Vinylogous Amides Tethered withα,β-Unsaturated Aldehydes: A Formal Total Synthesis of (+)-Gephyrotoxin

Complex piperidinyl heterocycles (for example, 2) were accessed by using a novel intramolecular formal [3+3] cycloaddition reaction of vinylogous amides tethered with enals (for example, 1). This method has been applied to a formal total synthesis of (+)-gephyrotoxin (3).

α-Aryl-substituted allenamides in an imino-Nazarov cyclization cascade catalyzed by Au(I).

An imino-Nazarov cyclization using α-aryl-substituted allenamides is described. This gold(I)-catalyzed cascade is efficient and regioselective in constructing a diverse array of synthetically useful aromatic-ring fused cyclopentenamides. The success in this transformation represents a solution to the challenge in establishing an imino-Nazarov cyclization process.

A sequential metal-catalyzed C-N bond formation in the synthesis of 2-amido-indoles.

A sequential metal-catalyzed C-N bond formation employing ortho-haloaryl acetylenic bromides is described. The initial amidation is highly selective for C (sp)-N bond formation, leading to o-haloaryl-substituted ynamides that can be useful building blocks, while the overall sequence provides a facile construction of 2-amido-indoles.