Ynamide carbopalladation: a flexible route to mono-, bi- and tricyclic azacycles.

Craig D Campbell,Amber L Thomson,Greg Carr,Oliver T Holton,P Ross Walker,Edward A Anderson,Helen A Chapman,C Adam Russell,Rebecca L Greenaway

doi:10.1002/chem.201501710

Craig D Campbell, Amber L Thomson + Show 7 more

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https://doi.org/10.1002/chem.201501710

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Abstract

Bromoenynamides represent precursors to a diversity of azacycles by a cascade sequence of carbopalladation followed by cross-coupling/electrocyclization, or reduction processes. Full details of our investigations into intramolecular ynamide carbopalladation are disclosed, which include the first examples of carbopalladation/cross-coupling reactions using potassium organotrifluoroborate salts; and an understanding of factors influencing the success of these processes, including ring size, and the nature of the coupling partner. Additional mechanistic observations are reported, such as the isolation of triene intermediates for electrocyclization. A variety of hetero-Diels–Alder reactions using the product heterocycles are also described, which provide insight into Diels–Alder regioselectivity.

Highlights

Nitrogen-containing ring systems are of fundamental importance in chemistry and biology, and the development of efficient and general methods for their preparation remains a key challenge for organic chemists.[1]
At the outset of our work, only a single study of ynamide carbopalladation had been disclosed,[4] which focused on the intramolecular carbopalladation of terminal ynamides by arylpalladium(II) complexes, terminating either through reduction of the inter mediate alkenylpalladium(II) species with ammonium formate, or Suzuki cross-coupling with an arylboronic acid, as employed in a total synthesis of the natural product lennoxamine
Among many methods for ynamide synthesis,[11] we were attracted to Hsung’s robust copper-catalyzed coupling of amides and bromoalkynes, which has been shown to tolerate a bromoalkene.[11f]. Our work began with the preparation of a range of bromoalkenyl amides (Scheme 2)

Summary

Introduction

Nitrogen-containing ring systems are of fundamental importance in chemistry and biology, and the development of efficient and general methods for their preparation remains a key challenge for organic chemists.[1]. To investigate the conditions that would be required to effect ynamide cyclization, we subjected bromoenynamide 3 a to coupling with stannane 19 a, with [PdCl2(PPh3)2] as the catalyst (10 mol %), using variable temperature 1H NMR spectroscopy (VT NMR) to monitor reaction progress (Figure 2).

Results

Conclusion