Combined directed ortho-metalation, remote metalation, and Stille cross-coupling strategies. Concise stereoselective synthesis of polysubstituted 9H-fluoren-9-ones Anne-Sophie Castanet a , David Tilly a , Jean-Baptiste Ve ´ron a , Subhendu S. Samanta a,b,y , Asish De b , Tapan Ganguly b , Jacques Mortier a, * a Universite ´ du Maine and CNRS, Unite ´ de Chimie Organique Mole ´culaire and Macromole ´culaire (UMR 6011), Faculte ´ des Sciences, Avenue Olivier Messiaen, 72085 Le Mans Cedex 9, France b Indian Association for the Cultivation of Science, 700 032 Jadavpur, Kolkata, India Received 10 January 2008; received in revised form 25 January 2008; accepted 31 January 2008 Available online 3 February 2008 Abstract The new sequential stereoselective synthesis of diversely substituted 9H-fluoren-9-ones by ortho-lithiation/Bu 3 SnCl quench of unprotected benzoic acids followed by Stille cross-coupling reaction and remote metalation is reported. Ó 2008 Elsevier Ltd. All rights reserved. Keywords: ortho and Remote metalations; Stille reaction; Benzoic acids 1. Introduction Substituted fluorenones and fluorenes are interesting target molecules in organic synthesis. The 9H-fluoren-9-one skeleton occurs inter alia in a wide range of substrates, including marine sediments, 1 kerogen pyrolyzates, 2 weathered surface retorted oil shales, and Wilmington petroleum. 3 9H-Fluoren- 9-ones are also known to function as photoinitiators in various photochemical reactions. 4 Both 9H-fluoren-9-ones and 2- nitrofluorene behave as acceptors in photoinduced electron transfer. 4a On the other hand, non-peptidic compounds that contain a biphenylcarboxylic acid group have shown to inhibit HIV-1 protease. 5 Biphenylcarboxylic acids are potential objects of interesting photophysical studies in view of our recent findings 6 on photoinduced electron transfer in carbo- xylic acids. We recently reported on a general method for the construc- tion of fluorenones by thematic variation of inter-connecting synthetic methodologies. 2-Biphenylcarboxylic acid (1) read- ily undergoes metalation ortho to the carboxylate substituent (C 3 ) 7 when treated with s-butyllithium (s-BuLi) in THF at 78  C (reaction A). 8 Trapping with a variety of electrophiles gives diversely 3-substituted 2-biphenylcarboxylic acids 2 with good yields. Treatment of 2 with the Lochmanne Schlosser superbase (n-butyllithium/t-BuOK) (LICKOR) 9 af- fords the fluorenone skeleton 3 arising from the metalation of the remote C 2 0 site (reaction B). 10 On the other hand, 2-biphenylcarboxylic acid (1), when treated successively with (1) LICKOR (3.5 equiv) in THF or benzene at 20e60  C, (2) n-BuLi (2 equiv, rt to 60  C), and (3) an electrophile (EX), gives the fluorenone skeleton 3 that arises from the metalation of the remote C 2 0 site (reaction C). We have shown 11 that the doubly charged dimetallo dialkoxide group C(OM) 2 (M¼Li, K) of 4 acts as a new director of ortho- metalation and presumably directs a second metalation in the adjacent position (C 1 ) affording the stable 1-metallo-9H- fluoren-9,9-dimetallo dialkoxide 5 that can be trapped by electrophiles. * Corresponding author. Tel.: þ33 243 833 336; fax: þ33 243 833 902. E-mail address: jacques.mortier@univ-lemans.fr (J. Mortier). y Deceased. 0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tet.2008.01.122 Available online at www.sciencedirect.com Tetrahedron 64 (2008) 3331e3336 www.elsevier.com/locate/tet