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.






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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






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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.






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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 Dickinson's first preparation and concise characterizations of 1,2-propadienyl-2-pyrrolidinone in 1967 (Scheme 5).11






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Scheme 4








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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.






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Scheme 6








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Scheme 24








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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.

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Allenamides: A Powerful and Versatile Building Block in Organic Synthesis

Contemporary Carbocation Chemistry: Applications in Organic Synthesis

Propargylic alcohols and their derivatives are important classes of organic compounds that can be easily accessible from terminal alkynes and aldehydes or ketones. They are attractive and have been extensively applied as synthetic intermediates in modern organic synthesis. Recent investigations on the chemistry of propargylic alcohols and their derivatives disclosed a variety of highly efficient Lewis acid-catalyzed cascade reactions based on Meyer–Schuster rearrangement of propargylic alcohols and [3,3] rearrangement of propargylic esters and propargyl vinyl ethers. A tremendous number of structurally versatile enones, carbocycles, and heterocycles have been constructed through these methodologies. These advances, including our recent researches in this field, are summarized in this review.

Recent Advances on the Lewis Acid-Catalyzed Cascade Rearrangements of Propargylic Alcohols and Their Derivatives

2-Propargyl Alcohols in Organic Synthesis

Gold catalyzed [3+2] cycloaddition of N-allenyl amides with azomethine imines.

Tandem Reaction of Propargyl Alcohol and N-Sulfonylhydrazone: Synthesis of Dihydropyrazole and Its Utility in the Preparation of 3,3-Diarylacrylonitrile

Copper-catalyzed cascade approach to 1,3-diazabicyclo[3.1.0]hex-3-enes from aziridines and ethyl diazoacetate

The reaction is catalyzed by BF3·Et2O as a Lewis acid and is effective for terminal and internal propargyl alcohols and aromatic and aliphatic N-sulfonylhydrazones

Tandem Reaction of Propargyl Alcohol and N-Sulfonylhydrazone: Synthesis of Dihydropyrazole and Its Utility in the Preparation of 3,3-Diarylacrylonitrile.

An efficient and general synthesis of 1,3-diazabicyclo[3.1.0]hex-3-enes via the copper-catalyzed cascade reaction of aziridines with ethyl diazoacetate is described.

Shan Wen

Papers

Tandem Reaction of Propargyl Alcohol and N-Sulfonylhydrazone: Synthesis of Dihydropyrazole and Its Utility in the Preparation of 3,3-Diarylacrylonitrile

Copper-catalyzed cascade approach to 1,3-diazabicyclo[3.1.0]hex-3-enes from aziridines and ethyl diazoacetate

Tandem Reaction of Propargyl Alcohol and N-Sulfonylhydrazone: Synthesis of Dihydropyrazole and Its Utility in the Preparation of 3,3-Diarylacrylonitrile.

Copper-Catalyzed Cascade Approach to 1,3-Diazabicyclo[3.1.0]hex-3-enes from Aziridines and Ethyl Diazoacetate.