Synthesis of estradiol backbone mimics via the Stille reaction using copper(II) oxide as co-reagent Erik Flöistrup a , Patrick Goede b , Roger Strömberg a , Johan Malm c,⇑ a Department of Bioscience and Nutrition, Karolinska Institutet, Novum, SE-141 83 Huddinge, Sweden b Department of Energetic Materials, Swedish Defence Research Agency FOI, Grindsjön Research Centre, SE-147 25 Tumba, Sweden c Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala University, BMC, Box-574, SE-751 23 Uppsala, Sweden article info Article history: Received 29 April 2010 Revised 10 August 2010 Accepted 27 October 2010 Available online 31 October 2010 abstract Sterically hindered biaryls and 2-phenylbenzo[b]thiophenes that can serve as templates for mimics of the estradiol backbone were prepared in modest to good yields by the Stille reaction using CuO as a co- reagent. Due to the neutral conditions applied in the Stille reaction, protection strategies were unneces- sary for hydroxy containing coupling partners. Ligandless coupling conditions were also evaluated. Ó 2010 Published by Elsevier Ltd. The synthesis of estrogenic mimetics is important due to the inherent side effects, low efficacy, and low oral bioavailability asso- ciated with the endogenous hormone estradiol (Fig. 1) in medicinal therapy. It is known that certain estrogen mimetics can be exploited as Selective Estrogen Receptor Modulators (SERMs), as exemplified by raloxifen (Fig. 1). 1 Furthermore, it has been shown that hindered 4 0 -hydroxy PCB’s can act as estradiol mimetics and exhibit estradiol-like properties. 2 The preparation of a number of different biphenyls using palla- dium-catalyzed cross-coupling of aryl boronic acids with aryl ha- lides and triflates, for the assembly of biaryls to mimic the steroidal backbone of estradiol, has been reported. 3 Yields were low, especially when the halogen cross-coupling partner was substituted at both ortho positions to give bis-ortho-substituted biphenyl derivatives (e.g. as in the estradiol mimetic, Fig. 1). An efficient method for palladium-catalyzed cross-coupling of organostannanes with aryl- and heteroarylbromides (Stille reac- tion) in the presence of metal oxides in stoichiometric quantities (co-reagent) has been developed by us. 4 This method is highly effi- cient when the standard cross-coupling tends to be sluggish and has for example been applied to the assembly of 5-heteroaryl nucleosides, 5 polythiophenes, 6 heteroaryl ferrocenes, 7 diphenylox- azoles, 8 and for the synthesis of a sterically-crowded atropisomeric 1,8-diacridylnaphthalenes, 9 as well as in microwave-promoted flu- orous phase conditions. 10 Even though organostannanes are known for their toxicity, and boronic acids and boronic acid esters (Suzuki-coupling) have emerged as the preferred coupling partners, 11,12 a number of key advantages of the use of stannanes can be identified. There is no need to apply protection strategies for base-sensitive groups since the Stille reaction conditions are usually non-aqueous and neutral. This advantage is especially appealing when considering the assembly of phenolic coupling partners. Organostannanes are usu- ally stable to a wide variety of reaction conditions, have long shelf lives, and are readily purified. It has also been shown that all remaining traces of organostannanes can be removed completely upon work-up in the presence of Et 3 Al or NaOH (aq). 13 The first objective of the present research was to prepare 2- phenylbenzo[b]thiophene derivatives, which could serve as a start- ing point for the preparation of raloxifen and derivatives thereof. The second objective was to carry out an investigation of whether the present method could be applied to the preparation of hindered biaryls that could serve as templates for mimics of steroidal back- bone of estradiol. Apart from cross-coupling conditions using Pd(0) with and without CuO (Method A), 14 ligandless conditions were employed. This technique 15,16 requires use of a palladium cat- alyst with more ‘loosely’ complexed ligands, in this case tris(diben- zylideneacetone)dipalladium (Pd 2 dba 3 ), and then exchanging those ligands in situ with another type of ligand. Our ligand of choice for the exchange was tri-furylphosphine (Method B). 17 S O OH Me OH H H H HO O N HO HO Me Me OH estradiol estradiol mimetic raloxifen Figure 1. Chemical structures of estradiol, raloxifen, and an estradiol mimetic. 0040-4039/$ - see front matter Ó 2010 Published by Elsevier Ltd. doi:10.1016/j.tetlet.2010.10.144 ⇑ Corresponding author. Tel.: +46 18 4714124; fax: +46 18 4714474. E-mail address: Johan.Malm@orgfarm.uu.se (J. Malm). Tetrahedron Letters 52 (2011) 209–211 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet