PAPER 451 Iodoxybenzoic Acid (IBX): An Efficient and Novel Oxidizing Agent for the Aromatization of 1,4-Dihydropyridines 1 Iodoxybenzoic Acid J. S.Yadav,* B. V. S. Reddy, A. K. Basak, G. Baishya, A. Venkat Narsaiah Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India Fax yadavpub@iict.res.in; E-mail: +91(40)27160512 Received 7 July 2005; revised 17 August 2005 SYNTHESIS 2006, No. 3, pp 0451–0454xx.xx.2005 Advanced online publication: 21.12.2005 DOI: 10.1055/s-2005-918519; Art ID: Z13405SS © Georg Thieme Verlag Stuttgart · New York Abstract: Hantzsch 1,4-dihydropyridines undergo smooth aromati- zation catalyzed by iodoxybenzoic acid (IBX) to afford the corre- sponding pyridine derivatives in high yields. All the reactions were carried out in DMSO solvent at 80–85 °C for a period of two to four hours to complete conversion of the substrates. Keywords: hypervalent iodine reagents, dihydropyridines, aroma- tization, DMSO, pyridine derivatives Hypervalent iodine reagents have recently attracted much attention as powerful oxidants in organic synthesis be- cause of their selective and mild oxidizing properties. 2 Among the various hypervalent iodine reagents, o-iodoxy- benzoic acid (IBX) is a versatile oxidizing agent due to its high efficiency, ease of preparation, mild reaction condi- tions and its stability against moisture and air. A wide range of functional group tolerance and high-yielding re- actions without over oxidation have made IBX very famil- iar for the oxidation of various alcohols. Recently, the use of IBX as a mild oxidant has been extended to many other elegant oxidative transformations by Nicolaou et al. 3 Hantzsch 1,4-dihydropyridines are often regarded as the models of the naturally reduced nicotinamine adenine di- nucleotide [NADH] co-enzyme which functions as redox reagent for biological reactions. 1,4-Dihydropyridines are rapidly emerging as the most important class of drugs for the treatment of cardiovascular disease. 4 These com- pounds generally undergo oxidative metabolism in the liver by the action of cytochrome p-450 to form the corre- sponding pyridine derivatives, which exhibit anti-hypoxic and anti-ischemic activities. Further, metabolism involves the cleavage of the ester groups. Some of the representa- tives of this class show acaricidal, insecticidal, bactericid- al and herbicidal activities. On the other hand, these compounds are starting materials for the synthesis of anti- bacterial 1,6-naphthyridines and 1,2-benzisoazalenes. 5 The oxidation of Hantzsch 1,4-dihydropyridines is one of the ubiquitous issues in organic chemistry. Generally, strong oxidants such as CrO 3 , HNO 3 , KMnO 4 , cupric ni- trate, ferric nitrate and CAN, and pyridinium chromate have been used to accomplish this oxidation. 6 However, many of these methods suffer from the use of strong acidic conditions and require extended reaction times or the need of excess oxidant and also the yields reported are far from satisfactory. Thus, there is a need for the development of novel reagents that provide beneficial levels of mildness and efficiency. Scheme 1 In continuation of our interest in developing new synthetic methodologies 7 herein, we wish to report an efficient pro- tocol for the aromatization of Hantzsch 1,4-dihydropy- ridines using the inexpensive and readily available iodoxybenzoic acid (IBX) as the novel oxidant (Scheme 1). For instance the treatment of diethyl 2,6-di- methyl-4-(p-methoxyphenyl)pyridine-3,5-dicarboxylate with IBX (1.5 equiv) in DMSO at 80–85 °C for 2.5 hours afforded the corresponding pyridine derivative 2a in 86% yield. In a similar manner, various Hantzsch 1,4-dihydro- pyridines were aromatized without any problem. To es- tablish the generality of this method, various alkyl, aryl and heterocyclic substituents present on Hantzsch 1,4-di- hydropyridines were oxidized under these reaction condi- tions. In all cases, the reactions proceeded readily with high efficiency. The influence of various solvents on the yield of the reaction was investigated using EtOAc, MeCN, CH 2 Cl 2 , CHCl 3 , THF and MeOH. The oxidation reaction takes place smoothly in DMSO solvent and the products were obtained in very good yields. This can be attributed to the enhanced solubilizing power of the sol- vent for the oxidation as well as the substrate. In general, the reactions are very clean, high yielding and complete within two to four hours reaction time. The possible mechanism for the oxidation reaction using IBX, proceed via an ionic, concerted pathway or by an en- suing single electron transfer (SET) from 1,4-dihydropy- ridine to the iodoxybenzoic acid to afford a nitrogen radical cation, followed by fragmentation (Scheme 2). Both of these processes consequently supply the desired pyridine derivatives along with o-iodosobenzoic acid (IBA). This method is very mild and tolerates several sub- stituents present on alkyl, alkoxy, benzyl, cinnamyl and heterocyclic groups, which were in the 4-position of dihy- dropyridines. No debenzylation or dealkylation was ob- N H OEt O EtO O Me Me R N OEt O EtO O Me Me R IBX DMSO, 80–85 °C 1 2