Cascade Reactions DOI: 10.1002/anie.201008160 Palladium-Catalyzed Cascade Reaction for the Synthesis of Substituted Isoindolines** Florence J. Williams and Elizabeth R. Jarvo* Isoindoline heterocycles have demonstrated potential in medicinal chemistry as they exhibit activity across diverse biological targets. They are present in molecules which act as bronchodilaters, N-methyl-d-aspartate agonists, multidrug resistance reversal agents, and fibrinogen receptor antago- nists. [1] While several approaches to the synthesis of unsub- stituted or monosubstituted isoindolines have been reported, [2] few methods exist to produce disubstituted isoindolines with high diastereoselectivity. [3] In addition, there are no diastereoselective methods for the synthesis of 1,3-disubstituted isoindolines that allow for incorporation of readily available boronic acids, which are practical building blocks in medicinal chemistry. Synthetic methods for isoindo- line synthesis that provide straightforward introduction of substitutents on the heterocycle would enable preparation of families of biologically significant compounds. We designed a cascade sequence for isoindoline synthesis that we anticipated could be catalyzed by a palladium(II) complex and would utilize boronic acids as a starting material (Scheme 1). The cascade reaction would initiate with aryla- tion of imine 1. [4] The resultant sulfonamide would engage the pendant allylic acetate by aminopalladation; b-acetoxy elim- ination would release the isoindoline product. [5, 6] A major challenge was identification of a catalyst with the appropriate electronic balance to facilitate all steps in the catalytic cycle. While nucleophilic arylation of imines requires electron-donating ligands, [4] migratory insertion is generally promoted by palladium(II) catalysts with electrophilic char- acter. [7] We selected phosphinite palladacycle 3, which is a catalyst with demonstrated activity for arylation of imines, [4b] with the thought that the p-accepting phosphonite would balance s donation from the aryl group. [8] In practice, we have found this complex to be an effective catalyst for our cascade sequence (see below). We began our investigation with reaction conditions similar to those employed for imine arylation. [4b] At room temperature, in the presence of catalyst 3, effective arylation of 1 with phenyl boronic acid occurs (Table 1, entry 1). Elevated reaction temperatures promote the cyclization reaction (Table 1, entry 2; Method A). Notably, isoindoline 2 is generated as a single diastereomer under these reaction conditions. Scheme 1. Proposed synthesis of isoindoline derivatives. L = ligand, Ts = 4-toluenesulfonyl. Table 1: Optimization of reaction conditions for cascade cyclizations. Entry ArBX 2 (equiv) T [8C] Method t [h] Yield [%] [a] 2 4 5 1 [b] PhB(OH) 2 (1) 23 – 48 < 5 85 < 5 2 PhB(OH) 2 (1) 80 A 24 93 < 5 7 3 (PhBO) 3 (0.5) 80 – 24 43 23 > 5 4 (PhBO) 3 (0.5) 110 B 10 90 < 5 < 5 5 2-naphthyl-B(OH) 2 (1) 80 A 19 35 10 30 6 2-naphthyl-B(OH) 2 (1) 80 A 7 57 12 22 7 (2-naphthyl-BO) 3 (0.5) 110 B 10 79 < 5 16 8 (m-BnOC 6 H 4 BO) 3 (0.5) 110 B 10 23 < 5 7 9 [c] (m-BnOC 6 H 4 BO) 3 (0.5) 110 C 2 67 < 5 5 [a] Determined by 1 H NMR spectroscopy of aliquots taken from the reaction mixture utilizing Ph 2 SiMe 2 as an internal standard. [b] Relative ratio of products to starting material reported. [c] 2 equiv of CsF added. Bn = benzyl. [*] F. J. Williams, Prof. E. R. Jarvo Department of Chemistry University of California, Irvine Irvine, CA 92697 (USA) Fax: (+ 1) 949-824-2210 E-mail: erjarvo@uci.edu Homepage: http://chem.ps.uci.edu/ ~ erjarvo/Jarvo_Group/ Home.html [**] This work was supported by an NSF CAREER Award (CHE-0847273). We thank Markus Dörr for preparation of isoindoline 2i. We thank Frontier Chemicals for donation of boronic acids and Heraeus Metal Processing for donation of palladium complexes. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/anie.201008160. 1 Angew. Chem. Int. Ed. 2011, 50,1–5  2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim These are not the final page numbers! Ü Ü