Rearrangement of 3,5-dicyano-1,4-dihydropyridines to densely functionalized cyclopentadienes Stefania Fusi a, * , Fabio Ponticelli a , Antonio Ventura a , Mauro F. A. Adamo b, * a Dipartimento di Chimica, Università di Siena, Via Aldo Moro, Siena 53100, Italy b Centre for Synthesis and Chemical Biology (CSCB), Department of Pharmaceutical and Medicinal Chemistry, The Royal College of Surgeons in Ireland, 123 St. Stephen’s Green, Dublin 2, Dublin, Ireland article info Article history: Received 12 June 2008 Revised 15 July 2008 Accepted 24 July 2008 Available online 29 July 2008 Keywords: 1,4-Dihydropyridine Rearrangement Ring contraction abstract 3,5-Dicyano-1,4-dihydropyridines underwent ring contraction to give functionalized cyclopentadienes upon treatment with trifluoroacetic anhydride. Ó 2008 Elsevier Ltd. All rights reserved. Dihydropyridines (DHPs) have a rich medicinal chemistry. 1 In particular, 4-aryl-substituted 1,4-dihydropyridines are an impor- tant class of organic calcium-channel modulators used for the treatment of cardiovascular diseases. 2 More recently, DHPs were recognized as inhibitors of the per- meability-glycoprotein (P-gp). 3 This finding revitalized the interest of the synthetic community in the 1,4-dihydropyridine core. 4 As a part of our ongoing studies on the synthesis of bioactive compounds, 5 we became interested in preparing 1,4-dihydropyr- idines 1 bearing two symmetrical ketone functionalities at C-3 and C-5 (Scheme 1). A retrosynthetic analysis of target 1 identified 3,5-dicyanodihydropyridine 4 as a suitable starting material. In our plan, protection of 4 as its N-trifluoroacetate 3 and subsequent treatment with a Grignard reagent would furnish the protected target 2. Then hydrolysis of the trifluoroacetamide in 2 would give the desired compound 1. Reaction of 3 with various Grignard reagents was identified as a simple and effective means to expand the diversity of scaffold 4, while the trifluoroacetate group in 3 would activate the two nitrile groups towards nucleophiles. Compound 4 was prepared using a literature procedure, 6 and then was treated with trifluoroacetic anhydride (TFA) and triethyl- amine (TEA). Surprisingly, this reaction furnished compound 5 in 43% isolated yield as the exclusive product (Scheme 2). The struc- ture of 5 was determined by X-ray analysis (Fig. 1). 7 Intrigued by this result, we have studied the reaction of com- pound 4 with TFA and TEA by 1 H NMR. This study revealed that reaction of 4 with TFA generated the desired target 3 in quantita- tive amounts and in a very short reaction time (Table 1). Typically 0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2008.07.129 * Corresponding authors. Tel.: +39 0577 234273; fax: +39 0577 234278 (S.F.). E-mail address: fusiste@unisi.it (S. Fusi). N H O O R R N CN NC COCF 3 N O O R R COCF 3 N H CN NC 1 2 3 4 Grignard Addition Protection Hydrolysis Scheme 1. Tetrahedron Letters 49 (2008) 5820–5822 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet