DOI: 10.1002/adsc.201400072 Synthesis of Thieno-Fused Heterocycles through Reiterative Iodocyclization Luigi Aurelio, a Rohan Volpe, a Rosliana Halim, a Peter J. Scammells, a and Bernard L. Flynn a, * a Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia E-mail : bernard.flynn@monash.edu Received: January 20, 2014; Published online: May 6, 2014 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400072. Abstract: Iodocyclization of ethynyl methyl sulfides gives 3-iodo-2-thiomethyl heterocycles, setting up the synthesis of thieno-fused systems through a sub- sequent iteration of alkyne coupling and iodocyliza- tion. This approach can also be exploited in the syn- thesis of polyfused thiophenes. In developing this protocol it was necessary to address issues associat- ed with unfavourable electronic bias and redox sen- sitivity in some substrates. The manner in which these have been addressed should prove useful else- where in iodocyclization chemisty. Keywords: cyclization; iodocyclization; sulfur het- erocycles; synthetic methods Thieno-fused thiophenes, pyrroles, furans and their benzo-fused equivalents are valued for their photonic and electronic properties as well as their biological ac- tivity (Figure 1). [1,2] While such thiophene ring struc- tures are rare in nature the natural product thienoin- doline has been isolated from Streptomyces albogri- seolus, exhibiting potent plant-growth regulatory properties and inhibition of nitric oxide synthase. [2d,e] While iodocyclization has emerged as one of the most effective methods for the synthesis of a signifi- cant number of heterocycles, its application to poly- fused systems has hardly been explored. [3,4] An impor- tant subset of these iodocyclization methods, useful in the construction of 5-membered heterocycles, involves reaction of 1 with iodine (Scheme 1). In these cases, iodocyclization is accompanied by concomitant expul- sion of an electrofugal methyl group from the hetero- ACHTUNGTRENNUNGatom X as MeI, giving a 3-iodoheterocycle 2. [3,5] An attractive possibility for the application of this method to polyfused heterocycles is to employ 2 (R = X’Me) in a further alkyne coupling and iodocycliza- tion to give 3 which, in turn, can be subjected to fur- ther iterations of alkyne coupling and iodocyclization. Herein, we describe the successful development of such a strategy for the synthesis of thienofused het- erocycles 3 (X’ = S). [6] A particular focus of this study has been overcoming some of the inherent limitations that have emerged in the application of iodocycliza- tion to these targets (see below). Our investigations into a reiterative coupling–iodo- cyclization strategy centered on ready access to alkyn- yl methyl sulfides 5 from aryl iodides 4 (Scheme 2). Initial attempts to prepare the benzyl equivalent of 5, 5’, by direct coupling of ethynyl benzyl sulfide with 4b using different Pd-mediated coupling techniques [So- nogashira (M = H), Kumada (M = Mg), Negishi (M = ZnCl) and Stille (M = SnBu 3 )] were all unsuccessful Figure 1. Polyfused 5-membered heterocycles. Scheme 1. Reiterative approach to fused heterocycles. 1974  2014 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim Adv. Synth. Catal. 2014, 356, 1974 – 1978 COMMUNICATIONS