Benzannulation via the Reaction of Ynamides and Vinylketenes. Application to the Synthesis of Highly Substituted Indoles

Abstract

A two-stage “tandem strategy” for the synthesis of indoles with a high level of substitution on the six-membered ring is described. Benzannulation based on the reaction of cyclobutenones with ynamides proceeds via a cascade of four pericyclic reactions to produce multiply substituted aniline derivatives in which the position ortho to the nitrogen can bear a wide range of functionalized substituents. In the second stage of the tandem strategy, highly substituted indoles are generated via acid-, base-, and palladium-catalyzed cyclization and annulation processes.

Batch and Flow Photochemical Benzannulations Based on the Reaction of Ynamides and Diazo Ketones. Application to the Synthesis of Polycyclic Aromatic and Heteroaromatic Compounds

“…8 A limitation of this tandem strategy, however, is that it cannot provide access to indoles with certain substitution patterns and to indoles fused to additional ring systems. As demonstrated below, the “second generation” variant of the benzannulation strategy addresses these limitations and extends the scope of this chemistry to include the construction of a number of highly substituted polycyclic indoles.…”

“…Further research in our laboratory has focused on the application of various heterocyclization processes in an extension of this “tandem strategy” to the synthesis of indoles bearing a high level of substitution on the six-membered ring. 8 …”

Cycloaddition and Electrocyclic Reactions of Vinylketenes, Allenylketenes, and Alkynylketenes

“…Amido-substituted vinylketenes generated by cyclobutenone ring opening react similarly, providing amido-substituted phenols that serve as precursors to quinolines, indoles, and other nitrogen-containing heterocycles. 18,19 An example of intermolecular vinylketene [4+2] cycloaddition is the reaction of 2-methyl(vinyl)ketene (generated in situ by a dehydrochlorination) with tetracyanoethylene (Scheme 2). 20 The presence of vinylketenes is not always proven, especially as amines are known to react with ketenes to form zwitterions.…”

“…59 It is also formed and observed in an argon matrix by dehydrochlorination 162 and by irradiation of diazoacetylallene. 163 When generated by gas-phase pyrolysis of 2-(benzoyloxymethyl)furan, the parent allenylketene (19) cyclizes to methylenecyclobutenone (124) (Scheme 146). 164 This conversion is the analog of the ring closure of vinylketene to cyclobutenone (Scheme 14), and is calculated to have a barrier of 33.7 kcal/mol for closure of the syn-conformer of allenylketene 19, which is found by computational studies to be less stable than methylenecyclobutenone (124) by 11.8 kcal/mol.…”

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.…”