Practical and high stereoselective synthesis of 3-(arylmethylene)isoindolin-1-ones from 2-formylbenzoic acid Miguel Angel Reyes-González, Angel Zamudio-Medina, Mario Ordóñez ⇑ Centro de Investigaciones Químicas - Universidad Autónoma del Estado de Morelos Av. Universidad 1001, 62209 Cuernavaca, Morelos, Mexico article info Article history: Received 25 July 2012 Accepted 9 August 2012 Available online 16 August 2012 Keywords: One-pot three-component reaction 3-Methyleneisoindolin-1-ones Horner reaction Aminophosphonates 2-Formylbenzoic acid abstract Practical and high stereoselective synthesis of 3-(arylmethylene)isoindolin-1-ones is reported. The syn- thetic method involves the preparation of dimethyl isoindolin-1-one-3-yl-phosphonates by a ‘one-pot’ three-component reaction of 2-formylbenzoic acid with 4-methoxybenzylamine or aminoacetaldehyde dimethyl acetal and dimethyl phosphite under solvent and catalyst free-conditions, followed by a Horner reaction with several aryl aldehydes. Ó 2012 Elsevier Ltd. All rights reserved. Introduction Substituted 3-methyleneisoindolin-1-ones type 1 are present in a great variety of natural products and are also known to possess a broad range of biological activities. For example, AKS 186 was found to inhibit vasoconstriction induced by thromboxane A2 analog, 1 whereas the derivative 2 has been claimed to exhibit local anesthetic activity superior to that of procaine, 2 and the compound 3 that pre- sented sedative activity. 3 Additionally, the 3-(arylmethylene)isoindo- lin-1-ones are useful intermediates in the synthesis of aristolactams, 4 lennoxamine, 5 narceine imide, 6 aristocularines, 7 fumaridine, 8 fuma- ramidine, 9 and in the synthesis of other heterocyclic compounds. 10 Due to the utility of substituted 3-methyleneisoindolin-1-ones as key synthetic intermediates in conjunction with their biological activity, several synthetic protocols for their synthesis have been developed in the last years, including the heteroannulation of o- (1-alkynyl)benzamides induced by treatment with a base 11 or a palladium(II) catalyst, Pd-catalyzed heteroannulations involving 2-iodobenzamides and terminal alkynes, 12 palladium(0)-catalyzed three-component reaction of 2-bromoacetophenone and a variety of primary amines under carbon monoxide pressure or titanium- isocyanate complex and carbon monoxide, 13 palladium-catalyzed carbonylation-hydroamination reaction of 1-halo-2-alkynylben- zene with amines, 14 ‘one-pot’ regioselective elimination cycliza- tion-Suzuki approach 15 or Sonogashira reaction of 2-(2,2- dihalovinyl)-benzamides, 16 reaction of phthalic anhydride with phenylacetic acid and sodium acetate and subsequent treatment with the appropriate amine, 17 CuI/L-proline catalyzed coupling of 2-bromobenzamides and terminal alkynes, 18 the Heck–Suzuki– Miyaura domino reactions involving ynamides, 19 iodocyclization of (E)-2-alk-1-enyl-N-benzylbenzamides, 20 reaction of isoindolin- 1-ones with aldehydes, 21 photodecarboxylative benzylations of phthalimide, 22 and the Horner condensation of 3-(diphenyl-phos- phinoyl)isoindolin-1-ones with aldehydes. 23 However, in spite of their potential utility, these procedures typically suffer from one or more disadvantages such as the use of expensive reagents or poor regioselectivity in the cases of unsymmetrical substrates, therefore is desirable to develop a more efficient, simple, and milder protocol. During our program aimed at the convenient synthesis of cyclic a-aminophosphonates, 24 herein, we report a new synthetic strat- egy for the high stereoselective synthesis of 3-(arylmethylene)-iso- indolin-1-ones N-substituted 7 and 8 by the Horner reaction of R'' N O R' R 1 N O AKS 186 N O NEt 2 2 AcO N O 3 F N O Me Me N Me OH 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.08.040 ⇑ Corresponding author. Tel./fax: +52 777 329 7997 E-mail address: palacios@uaem.mx (M. Ordóñez). Tetrahedron Letters 53 (2012) 5756–5758 Contents lists available at SciVerse ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet