Alkali-metal mediated zincation of N-heterocyclic substrates using the lithium zincate complex, (THF)Li(TMP)Zn(tBu) 2 and applications in in situ cross coupling reactions Victoria L. Blair a,⇑ , David C. Blakemore b , Duncan Hay b , Eva Hevia a,⇑ , David C. Pryde b a WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Glasgow G1 1XL, UK b Worldwide Medicinal Chemistry, Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK article info Article history: Received 22 April 2011 Revised 3 June 2011 Accepted 24 June 2011 Available online 1 July 2011 Keywords: Metallation Zincation N-Heterocycles Lithium Mixed-metal reagents abstract This study investigates the ability of the mixed-metal reagent [Li(TMP)Zn(tBu) 2 ] 1 to promote direct Zn– H exchange reactions (zincations) of a wide range of N-heterocyclic molecules. The generated metallated intermediates from these reactions are intercepted with I 2 and some of them are also employed as pre- cursors in Pd-catalysed Negishi cross-coupling applications. A comparison with recent precedents in met- allation chemistry reveals that for some of these heterocycles, 1 allows improved conversions, under milder conditions and in certain cases, even gives unique regioselectivities. Ó 2011 Elsevier Ltd. All rights reserved. Nitrogen-containing heteroaromatic ring systems are key struc- tural units present in a multitude of pharmaceuticals, natural prod- ucts, agrochemicals and other biologically active molecules, making methods to enable their selective functionalization of great value in synthesis. 1–3 One of the most important methodologies which allows the incorporation of these important molecules into more complex molecular scaffolds is deprotonative metallation, traditionally using strong bases, such as alkyl lithiums and lithium diamides. 4,5 However, despite their extensive applications, the use of these reagents (which generate in situ highly reactive (het- ero)aryllithiums) imposes severe limitations including the need for cryogenic temperatures, limited functional group tolerance, restricted regioselectivity and incompatibility with Pd cross-cou- pling methods. Searching for more efficient reagents which can overcome these important drawbacks, a new generation of multimetallic reagents have been developed that allows the regioselective metallation of various functionalised aromatic and heteroaromatic substrates offering a wider functional group tolerance, and often requiring milder reaction conditions. 6–8 Pioneering work in this area includes Kondo and Uchiyama’s TMP–zincate complex [Li(TMP)Zn(tBu) 2 ], 9–11 (TMP = 2,2,6,6-tetramethylpiperidide), Mulvey’s sodium re- lated analogue [(TMEDA)Na(TMP)Zn(tBu) 2 ] 6,12 (TMEDA = N,N,N 0 ,N 0 - tetramethylethylenediamine), and Knochel’s Turbo-Grignard TMPMgClÁLiCl 13,14 and related salt-supported reagents such as lith- ium magnesiate Mg(TMP) 2 Á2LiCl when paired with the halide ZnCl 2 . 15 Within the context of TMP-dialkyl zincates, the isolation and structural characterization of key metallation intermediates (prior to any electrophilic interception) have demonstrated that these deprotonations are in fact direct zincations (alkali-metal mediated zincation, AMMZn) as exemplified in Scheme 1 which feature the structural outcome of the AMMZn of anisole by lithium-zincate [Li(TMP)Zn(tBu) 2 ] 1. 16 Herein we report a reactivity study using the lithium-zincate base [Li(TMP)Zn(tBu) 2 ] 1 (Scheme 1) with a range of N-containing heteroaromatic substrates. The intermediate zincated heterocycles were quenched with I 2 to determine the regioselectivity of the metallation, or cross-coupled with various electrophiles under Pd-catalysis. Our results are compared and contrasted to related reactions within the literature. Zincate 1 was prepared in situ according to the reported litera- ture procedure (by mixing LiTMP with tBu 2 Zn using THF as a sol- vent) 9 and reacted with several heteroarenes such as substituted pyridines, diazines and their benzo derivatives (Table 1). Thus, 2-methoxypyridine (2) was zincated selectively at the 3- position with 1 (1 equiv, 25 °C, 2 h), and after I 2 addition gave the 3-iodo product 2a in a 92% yield (entry 1). This metallation reg- ioselectivity of 2 has been previously reported using the aluminate base [iBu 3 Al(TMP)Li] 18 however, low temperatures (À78 °C) and an excess of base (2.2 equiv) were required to achieve 82% yield of 2a. 0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2011.06.090 ⇑ Corresponding authors. E-mail address: eva.hevia@strath.ac.uk (E. Hevia). Tetrahedron Letters 52 (2011) 4590–4594 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet