The superiority of properly prepared lithium 1-N,N-dimethylaminonaphthalenide (LDMAN) over other aromatic radical-anions for the generation of organolithiums by reductive lithiation q Roman Ivanov a, * , Ilan Marek b , Theodore Cohen a, * a Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260, USA b The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and the Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel article info Article history: Received 10 October 2009 Accepted 23 October 2009 Available online 1 November 2009 abstract The use of lithium 1-N,N-dimethylaminonaphthalenide (LDMAN) is found to be considerably superior in yield, ease of operation, and cost to the far more widely used lithium p,p 0 -di-tert-butylbiphenylide (LDBB) in reductive lithiations by aromatic radical-anions to produce organolithium compounds, provided that careful temperature control is maintained during the generation of LDMAN. The main reason for the superiority is the great ease of separation of the aromatic byproduct dimethylaminonaphthalene by a dilute acid wash. Ó 2009 Elsevier Ltd. All rights reserved. Two 1978 papers reported the important finding that readily prepared alkyl phenyl thioethers could be converted into alkyllith- ium compounds by the aromatic radical-anion lithium naphthale- nide (LN). 1 Since that time, such reductive lithiation has developed into one of the most versatile methods known for generating syn- thetically useful organolithiums. 2 Other leaving groups have also been used, but they have proven considerably less versatile than the phenylthio group. 2 In 1980, two more useful aromatic lithium radical-anions, lithium 1-N,N-dimethylaminonaphthalenide 3 (LDMAN) 1, and lithium p,p 0 -di-tert-butylbiphenylide 4 (LDBB) 2, were introduced (Fig. 1). The former, 1, has the advantage over lith- ium naphthalenide that the byproduct of electron transfer, 1-dim- ethylaminonaphthalene, can be readily separated from the desired product in most cases by a dilute acid wash and of course it can be recycled; a subsidiary advantage is that LDMAN can be used in sol- vents other than THF, the solvent universally used in synthetic pro- cedures involving aromatic lithium radical-anions. 5 The latter, 2, has the advantage that it is a more powerful reducing agent than LN and presumably less subject to attack by the intermediate rad- ical generated in the process of reductive lithiation. A disadvantage of LDMAN is that above À45 °C it decomposes to 1-lithionaphthalene. This often appeared to be only a minor disad- vantage since most reductive lithiations are successful at À78 °C. Furthermore, for those reductive lithiations that require a higher temperature, a work-around was developed, referred to as the cat- alytic method, consisting of using, instead of preformed LDMAN, lithium metal and 25% 1-N,N-dimethylaminonaphthalene (DMAN). 3 The reasoning was that because the rate of reductive lithiation is greater than that of formation of the radical-anion, the concentration of radical-anion and especially of the dianion, suspected of being the precursor of 1-lithionaphthalene, would re- main extremely low and thus production of the latter would be inhibited. 2,6 Nevertheless, the use of the catalytic method is not a perfect solution to the problem of the decomposition of LDMAN at temperatures above À45 °C, because in many cases the use of preformed radical-anion gives superior results to the use of a cat- alytic amount of the aromatic species. 2 The use of LDMAN is rather widespread, 2,3,5,7,8 but considerably less so than the use of LDBB. 6b,9 In the past in our own laboratory, LDBB has generally been chosen unless the product of electrophile capture of the generated organolithium is non-polar in which case the use of LDMAN is virtually mandatory in order to ease the sep- aration of the aromatic byproduct from the desired product. The reason for the preference for LDBB is that except in cases in which there is a separation problem, LDBB generally gave somewhat superior yields than LDMAN. 10,7a 0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2009.10.121 q Taken in part from the Ph.D. thesis of Roman Ivanov, University of Pittsburgh, 2008. * Corresponding authors. Tel.: +1 412 624 8220; fax: +1 412 624 8611. E-mail address: cohen@pitt.edu (T. Cohen). N Li • + _ (CH 3 ) 3 C C(CH 3 ) 3 Li + • _ 1 2 Figure 1. Radical-anion reductive lithiation reagents. Tetrahedron Letters 51 (2010) 174–176 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet