Pyrrolo-dihydropteridines via a cascade reaction consisting of iminium cyclization and O–N Smiles rearrangement Jinbao Xiang, Lianyou Zheng, Hongxiang Xie, Xiaowei Hu, Qun Dang * , Xu Bai * The Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Haiwai Street, Changchun, Jilin 130012, PR China article info Article history: Received 11 April 2008 Received in revised form 27 June 2008 Accepted 1 July 2008 Available online 3 July 2008 Keywords: TiCl 4 Pteridine Iminium cyclization Smiles rearrangement Cascade reactions abstract The reactions of 5-pyrrolyl-pyrimidinyloxyacetaldehyde or methyl ketone with primary amines yielded hydroxymethylpyrrolopteridine derivatives via a cascade of iminium cyclization and O–N Smiles re- arrangement. The present cascade exhibited a different profile compared to the previously reported ones, which consisted of N–N Smiles rearrangement. Lewis acid (TiCl 4 ) under carefully controlled conditions was employed to suppress the competing formation of imine dimers to give the desired heterocycles. A plausible mechanism involving the iminium cyclization and Smiles rearrangement is proposed. This methodology has been used to generate a series of 6-hydroxymethylpyrrolo[1,2-f]pteridine derivatives with potential biological activities. Ó 2008 Elsevier Ltd. All rights reserved. 1. Introduction Pyrimidine moiety, as a structural component of several key bio- molecules, has been widely explored in designing privileged structures in medicinal chemistry and has attracted much great attention of organic and medicinal chemists. 1 Its fused bicyclic analogs, pteridines, have been reported to exhibit a variety of bio- logical activities and constitute the backbones of several marketed drugs. For example, methotrexate (MTX) is used as an anti-tumor agent and triamterene as diuretics. In addition, some pteridine derivatives are reported to have potent inhibitory activity against biological targets. 2 Despite interesting biological activities exhibi- ted by pteridines, few methodologies are available for the synthesis of pyrrolo[1,2-f]pteridines. 3 Therefore, efficient synthetic methods to access pyrrolo[1,2-f]pteridines are desired. Tandem reactions are often developed as efficient strategies in the synthesis of complex organic molecules, since they enable multiple transformations via a series of cascade reactions. 4 For example, tandem reactions have been applied to the synthesis of a number of important nitrogen-containing natural products. 4b,5 The success of tandem reactions provides the impetus to new synthetic strategies that combine existing reactions into new sin- gle-operation tandem reactions. Iminium cyclization reactions have been widely used for C–C bond formation to build various nitrogen ring systems. As an attractive strategy, both endo-cycli- zations and exo-cyclizations have been reported. 6 Another impor- tant reaction often reported in the synthesis of condensed heterocyclic systems is the Smiles rearrangement. 7 We have suc- cessfully combined the iminium cyclization reaction with a N–N Smiles rearrangement reaction and developed an unique cascade reaction to efficiently access pyrrolo[1,2-f]pteridines (Scheme 1). 3c As a result of our investigation on the scope of this new cascade reaction, we have demonstrated that this strategy can be extended to a similar pyridine system with an O–N Smiles rearrangement. 8 To further explore the scope of these types of cascade reactions, it is logical to investigate the potential of combining iminium cycliza- tion reactions with an O–N Smiles rearrangement within a pyrim- idine system as outlined in Scheme 2. Herein, the results from such investigations are reported. N N N Cl N R 1 O TFA/CH 2 Cl 2 N N Cl N N R 1 NH R 2 N N Cl N N R 2 NHR 1 A B C R 2 NH 2 Scheme 1. Tandem iminium cyclization and N–N Smiles rearrangement. * Corresponding authors. Tel.: þ86 431 85188955; fax: þ86 431 85188900. E-mail addresses: qdang@jlu.edu.cn (Q. Dang), xbai@jlu.edu.cn (X. Bai). Contents lists available at ScienceDirect Tetrahedron journal homepage: www.elsevier.com/locate/tet 0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.07.002 Tetrahedron 64 (2008) 9101–9107