Ynamides in Ring Forming Transformations

Abstract

Conspectus The ynamide functional group activates carbon-carbon triple 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 transformations 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.

Synthesis of aminopyrazoles from sydnones and ynamides

“…34 Alternative popular synthetic routes to ynamides include copper-catalysed amidative cross-coupling processes. [35][36][37][38][39][40][41][42][43] The sydnones could be accessed via a two-step procedure consisting of the nitrosation and cyclodehydration of Narylglycines, as extensively reported in the literature. 1 Further functionalisation of the C4 position of the sydnone scaffold was achieved by Pd-catalysed direct arylation 44 or lithiation followed by quenching with electrophiles, affording a range of 4-substituted sydnones with different properties.…”

Novel ynamide structural analogues and their synthetic transformations

“…[15][16][17] Particularly, in the past 15 years, interests in this versatile building block have raised dramatically. [18][19][20][21] This boom is closely related to the fact that rapid development of efficient synthesis methods [22][23][24][25][26] has rendered ynamides highly accessible.…”

Basenfreie katalytische asymmetrische C‐C‐Kupplung mit terminalen Inamiden als effizienter Zugang zu multifunktionellen Trifluormethylalkoholen

“…Wirv ermuteten, dass eine katalytische asymmetrische Methode für die Addition von terminalen Inamiden an Tr ifluoracetophenon und seine Derivate die verbleibenden Nachteile der Reaktion mit Alkinen, insbesondere die Verwendung eines Überschusses an pyrophorem Dimethylzink, ausräumen kçnnte.D ie enantioselektive Synthese von Inamidderivatisierten, CF 3 -substituierten Propargylalkoholen würde gleichzeitig einen neuen Zugang zu einer Vielfalt an hoch funktionalisierten chiralen chemischen Bausteinen çffnen, wenn man die einzigartige Reaktivität der polarisierten Nsubstituierten Dreifachbindung nutzen kçnnte (Schema 1). [13] Die jüngste Einführung einer praktischen zweistufigen Synthese für terminale Inamide aus Tosylamiden und Tr ichlorethylen durch Anderson et al war ein exzellenter Ausgangspunkt für unsere Studie. [14] Zu Beginn dieser Untersuchung verwendeten wir NEthinyl-N-butylbenzolsulfonamid (1) Obwohl erfolgversprechende Ergebnisse mit Chinin erhalten wurden, [16] wendeten wir uns Tr osts Bis-ProPhenolen zu, da diese im Sinne einer Ligandenoptimierung einfacher zu modifizieren sind.…”