A new approach to isoindolinone derivatives by sequential palladium iodide-catalyzed oxidative aminocarbonylation–heterocyclization of 2-ethynylbenzamides Bartolo Gabriele a,⇑ , Raffaella Mancuso b,⇑ , Ida Ziccarelli b , Giuseppe Salerno b a Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy b Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (CS), Italy article info Article history: Received 30 August 2012 Accepted 24 September 2012 Available online 29 September 2012 Keywords: Carbonylation Cyclization Heterocycles Isoindolinones Palladium abstract A novel approach to functionalized isoindolinone derivatives 3 is presented. It is based on a cascade pro- cess, consisting of PdI 2 /KI-catalyzed oxidative monoaminocarbonylation of secondary 2-ethynylbenza- mides 1 with nucleophilic secondary amines 2, followed by intramolecular conjugate addition of the arylamido group to the alkynylamido group of the intermediate alkynylamides. Products have been obtained in high to excellent yields starting from different N-alkyl 2-ethynylbenzamides and amines, under relatively mild conditions (100 °C under 40 atm of a 4:1 mixture of CO–air), working in a MeCN–amine mixture (2:1, v/v) for 5–15 h. Ó 2012 Elsevier Ltd. All rights reserved. PdI 2 /KI-catalyzed oxidative monoaminocarbonylation of 1-alkynes with nucleophilic secondary amines is a powerful meth- od for the direct synthesis of 2-ynamides starting from simple building blocks (Eq. 1). 1 When applied to suitably functionalized substrates, it can allow the direct synthesis of carbonylated hetero- cycles through a sequential process involving oxidative aminocarb- onylation of the terminal triple bond followed by intramolecular conjugate addition (Scheme 1). 2 PdI 2 cat RC CH + CO + R' 2 NH + (1/2) O 2 H 2 O O NR' 2 R ð1Þ In this Letter, we report a novel application of this kind of reactiv- ity to the direct synthesis of functionalized isoindolinone deriva- tives, 3 that are, 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3, starting from N-substituted 2-ethynylbenzamides 1 (available in four steps from 2-iodobenzoic acid) 4 and nucleophilic secondary amines 2, according to Scheme 2. To our knowledge, this is the first example of synthesis of this class of compounds by direct carbonylation of acyclic precursors. A non-carbonylative route to 3-[(carbamoyl)methylene]isoindolin-1-ones and 3-[(alkoxycarbon- yl)methylene]isoindolin-1-ones, involving an oxidative Pd- catalyzed reaction between N-methoxybenzamides and acrylamides or alkyl acrylate, has been recently developed. 5 3-[(Alkoxycarbonyl)methylene]isoindolin-1-one derivatives were also obtained in low to moderate yields (25–55%) by Pd-catalyzed oxidative alkoxycarbonylation of 2-alkynylbenzamides bearing an internal triple bond, through a completely different reaction course (nucleophilic attack by the amido group to the coordinated triple bond followed by alkoxycarbonylation). 6 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.09.109 ⇑ Corresponding authors. Tel.: +39 0984 49 2813; fax: +39 0984 49 2044 (B.G.); tel.: +39 0984 49 2816; fax: +39 0984 49 2044 (R.M.). E-mail addresses: b.gabriele@unical.it (B. Gabriele), raffaella.mancuso@unical.it (R. Mancuso). PdI 2 cat YH CO, R 2 NH, O 2 YH O NR 2 Y CHCNR 2 O (Y = O, NR') Scheme 1. Formation of carbonylated heterocycles through sequential PdI 2 -cata- lyzed oxidative monoaminocarbonylation of the triple bond—intramolecular con- jugate addition. PdI 2 cat CO, R' 2 NH, O 2 O NHR O NHR O NR' 2 N O CHCNR' 2 R O 1 2 3 Scheme 2. Synthesis of 3-[(dialkylcarbamoyl)methylene]isoindolin-1-ones 3 from secondary 2-ethynylbenzamides 1 and nucleophilic secondary amines 2 through sequential PdI 2 -catalyzed oxidative monoaminocarbonylation of the triple bond— intramolecular conjugate addition. Tetrahedron Letters 53 (2012) 6694–6696 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet