LETTER 2154 Synthesis of Functionalized 2¢,4-Diarylbenzophenones Based on Site-Selective Suzuki Cross-Coupling Reactions Synthesis of Functionalized 2¢,4-Diarylbenzophenones Muhammad Nawaz, a Muhammad Adeel, a Muhammad Farooq Ibad, a Peter Langer* a,b a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de Received 6 April 2009 SYNLETT 2009, No. 13, pp 2154–2156xx.xx.2009 Advanced online publication: 10.07.2009 DOI: 10.1055/s-0029-1217544; Art ID: G11809ST © Georg Thieme Verlag Stuttgart · New York Abstract: The palladium(0)-catalyzed Suzuki cross-coupling reac- tion of the bis(triflates) of 2¢,4-dihydroxybenzophenones afforded 2¢,4-diarylbenzophenones. The reactions proceeded with very good site selectivity. The first attack occurred at carbon atom C-4. Key Words: benzophenones, cross coupling, palladium, site selec- tivity, Suzuki reaction 4-Arylbenzophenones possess a wide range of pharmaco- logical properties. This includes, for example, cytotoxic 1 and antibacterial activity, 2 inhibition of 3 H-progesterone binding, 3 inhibition of the interleukin (IL-1) biosynthe- sis, 4 inhibition of the human type-2 steroid 5a-reductase, 5 inhibition of COX-1, 6 and inhibition of human liver mi- crosomes. 7 2-Benzoylfluorenones and 2-benzoylfluo- renes, which are structurally related to 4-aryl- benzophenones, also represent pharmacologically rele- vant entities. 8 The 4-arylbenzophenone core structure is present, albeit hidden in a polycyclic framework, in vari- ous naturally occurring anthraquinones and tetracyclins. 9 Microtubules represent an important target for anticancer therapy. The benzophenone phenstatin, 2-hydroxy- and 2- aminobenzophenones act as antitubulin agents. 10,11 We have reported that 4-(2-hydroxybenzoyl)salicylic acids show a good in vitro activity in a selectin bioassay. 12 Functionalized benzophenones are also widely used as photosensitizers 13 and UV filters. 14 Classic syntheses of benzophenones rely on reactions of aryllithium or magnesium reagents with aldehydes and subsequent oxidation and on Friedel–Crafts acyla- tions. 11a,15 For the synthesis of functionalized benzophe- nones (e.g. containing a hydroxy, halide or ester group), these methods often give unsatisfactory results, due to competing side reactions. Therefore, the development of alternative methods is of considerable interest. 16 Recently, we have reported 12 a new approach to 4-(2-hydroxyben- zoyl)salicylates by domino ‘Michael–retro-Michael– Mukaiyama–aldol’ reactions of 3-formylchromones with 1,3-bis(silyloxy)-1,3-butadienes. Herein, we report the synthesis of 2¢,4-diarylbenzophenones based on what are, to the best of our knowledge, the first palladium(0)-cata- lyzed Suzuki cross-coupling reactions of bis(triflates) of 2¢,4-dihydroxybenzophenones. These reactions proceed with very good site-selectivity. 17 The products, function- alized 4-arylbenzophenones and 2¢,4-diarylbenzophe- nones, are not readily available and have only scarcely been reported in the literature so far. The TMSOTf-mediated reaction of 3-formylchromone (2) with 1,3-bis(trimethylsilyloxy)buta-1,3-diene (1) af- forded the 2¢,4-dihydroxybenzophenone 3. 12 Its formation can be explained by a domino ‘addition–retro-Michael– Mukaiyama–aldol’ reaction (Scheme 1). Scheme 1 Synthesis of 3. Reagents and conditions: (i) 1. 2 (1.0 equiv), Me 3 SiOTf (0.3 equiv), CH 2 Cl 2 , 0 °C; 2. 1 (1.1 equiv), 0 °C → 20 °C, 12 h; 3. HCl (10%). 2¢,4-Dihydroxybenzophenone 3 was transformed into the bis(triflate) 4 in 84% yield (Scheme 2). The Suzuki reac- tion of 4 with boronic acids 5a–j afforded the novel 2¢,4- diarylbenzophenones 6a–j in good yields (Scheme 2, Me 3 SiO O O O O O OH OH O Me 3 SiO O OSiMe 3 O OMe O O OH O OMe O + H 2 O O Me 3 SiO O + 2 3 (60%) OMe SiMe 3 – (Me 3 Si) 2 O A B D SiMe 3 Me 3 SiOTf i OSiMe 3 OMe 1 Me 3 SiOTf O O O OSiMe 3 O OMe + SiMe 3 C SiMe 3 Me 3 SiOTf – OTf – OTf Downloaded by: Universität Rostock. Copyrighted material.