DOI: 10.1002/adsc.200505261 Conversion of Amines to Imines Employing Polymer-Supported Sulfoxide (PSS) and Polymer-Supported Perruthenate (PSP): Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines Ahmed Kamal,* V. Devaiah, K. Laxma Reddy, N. Shankaraiah Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India Phone: ( þ 91)-40-2719-3157, fax: ( þ 91)-40-2719-3189, e-mail: ahmedkamal@iict.res.in, ahmedkamal@ins.iictnet.com Received: June 30, 2005; Accepted: October 24, 2005 Abstract: An efficient method for the oxidation of secondary amines to the corresponding imines has been developed by employing polymer-supported re- agents. This protocol has been extended for the gen- eration of a combinatorial library of substituted pyr- rolo[2,1-c][1,4]benzodiazepine derivatives and pro- vides a rapid and clean preparation avoiding conven- tional purification techniques. Keywords: combinatorial synthesis; (green) chemis- try; oxidation of secondary amines; polymer-sup- ported reagents; pyrrolo[2,1-c][1,4]benzodiazepines Introduction The use of combinatorial methods for the generation of chemical libraries [1] has recently increased at a tremen- dous pace. These methods are being adopted by the chemical industry to prepare novel materials par- ticularly in the area of pharmaceutical chemistry and catalysis. [2] Solid-phase organic synthesis is a powerful and rapid method for the generation of chemical libra- ries employing linear synthetic sequences on polymer- supported substrates. This technique has greatly simpli- fiedthepreparationofproducts,however,therearesev- eral associated problems and drawbacks that have not been completely addressed. Therefore, a somewhat modified strategy that allows the preparation of a large number of molecules in solution, in a linear or conver- gent manner, [3] through the sequential use of polymer- supported reagents in a multi-step process is increasing- ly becoming popular. [4] Theneedforsuchastrategyisof practical significance due to its ability to incorporate in- line purification protocols such as scavenging of the re- agent and by-products, [5] and catch-and-release [6] proce- dures. This enables the possibility for the direct high- throughput synthesis of molecules with higher purities that could be screened for biological activity without the need for further purification, i.e., avoiding chroma- tographic processes. The oxidation of an amine to the corresponding imine functionality is a very useful transformation, par- ticularly in the field of natural products. [7] Vederas and co-workers developed a polymer-supported sulfoxide (PSS) for the Swern oxidation process. [8] Similarly,poly- mer-supported perruthenate (PSP) has been prepared by Ley and co-workers [9] for the oxidation of alcohols to aldehydes and ketones. This reagent has been exten- sively utilized for various applications in organic trans- formations. [4a] The amine to imine oxidation process that has been reported [10] by the use of activated DMSO, has also been applied by us for the oxidation of cyclic secondary amines to the corresponding imines. [11] Also, TPAP is known for the oxidation of aminestoimines [12] andthisprocess,aswell,hasbeenex- tended for the preparation of imine-containing pyrro- lo[2,1-c][1,4]benzodiazepines. [13] Inrecentyears,therehasbeenconsiderableinterestin ring systems such as pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) that can recognize and bind to specific sequen- ces of DNA. [14] These compounds have been produced naturally from various Streptomyces species, that pos- sess antitumor antibiotic activity, e.g., anthramycin. [14c] These compounds bind selectively in the minor groove of the DNA while a covalent aminal bond is formed be- tweentheelectrophilicC11-positionofthePBDandthe nucleophilic attack of the C2-amino group of a guanine base [15] is generally responsible for the biological activi- ty. The DNA binding ability and anticancer activity de- pends on the type of substitution in the A and C rings as seen from the large number of compounds that have been synthesized based on this ring system (Figure 1). One of the PBD dimers (SJG-136), with an affinity for Pu-GATC-Py, is presently under clinical evaluation. [16] Previous studies on the PBD-based compounds have not only led to structurally modified PBDs [17] but also to the development of new synthetic strategies, [18] in- cluding solid-phase synthetic strategies. [19] In continua- UPDATES Adv. Synth. Catal. 2006, 348, 249–254 # 2006 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 249