Allenyl Azide Cycloaddition Chemistry. Synthesis of Annelated Indoles from 2-(Allenyl)phenyl Azide Substrates

Abstract

Thermolysis of 2-(allenyl)phenylazides leads to a cascade cyclization sequence furnishing both C (2)-C(3) and N-C(2) cyclopentennelated indoles.Organic synthesis via diyl cyclization has had an episodic history, with surges in activity quickly following discovery of novel diradical generating reactions. 1 One of the more notable advances to emerge from this area of chemistry stemmed from the observation that N 2 extrusion from 4-methylene-1,2-diazenes led efficiently to triplet trimethylenemethane (TMM) diyls, species that have served a central role in numerous cyclization-and cycloaddition-based approaches to cyclopentanoid natural products. 2 One little studied modification of the TMM diyl, azatrimethylenemethane (ATMM), can be constructed, at least in principle, by simply exchanging one methylene fragment for a nitrogen (cf. 4 , Scheme 1). By analogy with TMM chemistry, the ATMM variant might provide ready access to polycyclic cyclopentanoid alkaloid frameworks. The development of ATMM chemistry has laged far behind its all-carbon cousin, but early studies that hinted at its existence 3 and more recent suggestions of its intermediacy in azide-allene cyclization cascades 4 (Scheme 1) may yet elevate this species to a position of prominence in lkaloid synthesis. C(2)-C(3) annelated indoles represent one potential target class for this chemistry, and given the success of the 1→5 conversion, wherein only cyclization through the imine species 4b was observed, it seemed plausible to expect that incorporation of an aryl residue in the allene-azide tether (cf. 6) would lead by analogy to the C(2)-C(3) cyclopentennelated indole products 7. As described in this report, this goal was achieved in practice. However, the unanticipated intervention of subtle electronic (?) effects, presumably as a consequence of the electronic connectivity supplied by the intervening aryl ring, served to divert some of the reactive intermediate(s) down alternative channels, leading to N-C(2) annelated products as well. A description of the scope of this process for cyclopentennelated indole synthesis with both alkenyl-and aryl-substituted 2-(allenyl)phenylazides is detailed below.The syntheses of suitable 2-(allenyl)phenylazides of the type 6 were accomplished by straightforward chemistry using Konno's procedure for palladium-mediated aryl(alkenyl)zinc ksf@chem.psu.edu. addition to propargylic acetates 9, 5 or the cuprate-based alternative procedure of Palenzuela, 6 Table 1. The azide function survived exposure to these organometallic reagents with no detectable decomposition, but attempts to add (Bu 3 Sn)CuSPh to 9a met with concomitant azide reduction to furnish an amide product following O-to-N acetyl transfer. The (alkenyl)allenyl azides 6a-6i were stable, isolable, and characterizable compounds, but the aryl-substituted analogues 6j-6m were sensitive to chromatography and could not be isolated in pure form. Therefore, these species were routinely carried on to the thermolysis procedure as crude materials. NIH Public AccessThe t...

Synthesis and Some Biological Properties of Pyrrolo[1,2‐a]indoles

“…9 Н ‐Pyrrolo[1,2‐ a ]indoles 269 were synthesized from substituted 2‐(allenyl)phenyl azides 270 . Thermolysis 270 led to a mixture of 1,4‐cyclopenta[ b ]indoles 271 and 3 Н ‐pyrrolo[1,2‐ a ]indoles 272 .…”

Cyclization Cascade of Allenyl Azides: Synergy Between Theory and Experiment

“…This degree of control is unexpected, taking into account the modest levels of diastereoselectivity typically reported for diradical collpase in other systems [15]. In a second series of experiments [14], o -azido phenylallene derivatives 8 also were tested and, surprisingly, their thermal transformations did not exhibit the complete regioselectivity of the former non-conjugated species. Mixtures of C—N and C—C bonded adducts were obtained in similar amounts (C—C/C—N ratios varying from 1:1.5 to 2.7:1).…”

“…Preliminary experimental work on the chemistry and the scope of this reaction provided promising results, but also left a number of questions unanswered (Fig. 3) [13, 14]. In the first exploratory campaign [13] the thermochemistry of 5-azidoallenes, exemplified by 1 and its aryl analogue 1 Ph provided indirect evidence for the intermediacy of an ATMM species in an apparent cycloaddition-extrusion-collapse reaction cascade (see Fig.…”

Addition Reactions: Cycloaddition

“…64 ee In the absence of organic solvents, Sc(OTf) 3 catalysed the cycloaddition of aziridines to nitriles to produce substituted imidazolines in good to excellent yields at room temperature and in an air atmosphere. The reaction is believed to progress through a highly reactive cationic intermediate in which the aziridine nitrogen is coordinated to Sc(OTf) 3 . 65 The phosphine-catalysed enantioselective 3 + 2-cycloaddition of buta-2,3-dienoates with arylimines yielded 2-aryl-3-pyrrolidines with 64% ee.…”