Elsevier

Tetrahedron

Volume 66, Issue 47, 20 November 2010, Pages 9252-9262
Tetrahedron

A Pd[0]-catalyzed Ullmann cross-coupling/reductive cyclization approach to C-3 mono-alkylated oxindoles and related compounds

https://doi.org/10.1016/j.tet.2010.09.042Get rights and content

Abstract

The Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes 1ae with the brominated heterocycles 2af delivers the expected products 3aj in good to excellent yields. The reductive cyclization of such products, as well as N-acyl derivatives 3k, l, and m, has been investigated and provided the C-3 mono-substituted oxindoles 5ad, f, g, k, and m, the direct reduction products 4i and j or indole 5l.

Introduction

The oxindole or indolone motif represents a privileged structure in medicinal chemistry.1 Thus, for example, this heterocycle is encountered in antiproliferative agents,2 in serotonergic agents,3, 3(a), 3(b) in growth hormone secretagogues,4 in the anti-Parkinsonian drug ropinirole,5 in P-glycoprotein-mediated MDR inhibitors,6 in non-opioid nociceptin receptor ligands,7 and in anti-inflammatory agents.8 In addition, a number of prominent natural products embody oxindole substructures including welwitindolinone A isonitrile,9, 10, 10(a), 10(b), 10(c) rhynchophylline,10 horsfiline,11 coerulescine,12 elacomine,13 gelsemine,14 the gelsenicine-related oxindole alkaloids,15 and the spirotryprostatins.10, 10(a), 10(b), 10(c), 16 Most of these display intriguing biological properties. Oxindoles also serve as precursors to a range of other heterocyclic compounds including indoles proper.17, 17(a), 17(b), 17(c), 17(d) Accordingly, numerous routes to the title heterocyclic system have been developed and various of these have been summarized in recent reviews.10, 10(a), 10(b), 10(c), 18, 18(a), 18(b), 18(c) Notwithstanding the impressive repertoire of methodologies available, the controlled assembly of C3-mono-alkylated oxindoles remains a challenging matter.19, 19(a), 19(b), 19(c) Herein, therefore, we describe a new approach to such systems that arises from our earlier studies20, 20(a), 20(b), 20(c) on the Pd[0]-catalyzed Ullmann cross-coupling reaction.

Section snippets

Synthetic plan

On the basis of our earlier work20 we proposed (Scheme 1) a two-step method for preparing oxindoles. This involved an initial Pd[0]-catalyzed Ullmann cross-coupling21 of o-nitrohaloarenes 1 with an α-brominated α,β-unsaturated cycloimide, lactam or lactone of the general form 2 to give the corresponding o-nitroarylated heterocycle 3. In the second step of the proposed sequence, the cross-coupled compound 3 would be treated with dihydrogen in the presence of palladium on carbon so as to effect a

Conclusions

A new method for the synthesis of C-3 mono-alkylated oxindoles has been developed. This involves the Pd[0]-catalyzed Ullmann cross-coupling of o-nitrohaloarenes with various α-brominated α,β-unsaturated cycloimides, lactams or lactones followed by reductive cyclization of the coupling products. The cross-coupling process can be carried out effectively in the presence of a useful range of functionalities and the reductive cyclization process proceeds smoothly provided the trans-acylation step 45

General experimental procedures

Proton (1H) and carbon (13C) NMR spectra were recorded on either a Varian Gemini or a Bruker AV800 machine operating at 300 and 800 MHz, respectively. Unless otherwise specified, spectra were acquired at 20 °C in deuterochloroform (CDCl3) that had been filtered through basic alumina immediately prior to use. Chemical shifts are recorded as δ values in parts per million (ppm). Infrared spectra (νmax) were normally recorded on a Perkin–Elmer 1800 Series FTIR Spectrometer and samples were analyzed

Acknowledgements

We thank the Institute of Advanced Studies for financial support including the provision of a travel grant to J.K.R. that allowed him to spend a period of leave at The Australian National University.

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