Chem Soc Rev View Article Online TUTORIAL REVIEW View Journal | View Issue Arene C–H functionalisation using a removable/ modifiable or a traceless directing group strategy Cite this: Chem. Soc. Rev., 2014, 43, 6906 Fengzhi Zhang*ab and David R. Spring*b The use of coordinating moieties as directing groups for the functionalisation of aromatic carbon–hydrogen (C–H) bonds has become an efficient strategy for the selective construction of new carbon–carbon (C–C) and carbon–heteroatom (C–X) bonds in arenes. However many directing groups cannot be easily removed/ modified from the products after C–H functionalisation, thus limiting the structural diversity of the products. Received 25th April 2014 This limitation can be overcome by employing removable/modifiable or traceless directing groups which DOI: 10.1039/c4cs00137k can be easily attached to the starting materials and detached from the products. In this tutorial review, we give an overview of recent advances in this emerging field which have dramatically increased the synthetic www.rsc.org/csr applicability of C–H functionalisation processes. Key learning points (1) Traditionally inert C–H bonds can be functionalised. (2) Site-selective functionalisation of aromatic derivatives can be achieved with the assistance of directing groups. (3) Carefully designed directing groups can be readily removed or converted into other useful functional groups efficiently. (4) The functionalised aromatic compounds have use in natural product chemistry, medicinal chemistry and material chemistry. (5) The field is fast growing and has great potential to expedite the synthesis of complex molecules. 1. Introduction The direct cleavage of an unreactive C–H bond, followed by the formation of a new C–C or C–X bond at a specific site within a Scheme 1 Pd-mediated arene C–H olefination of chlorobenzene. molecule would constitute an ideal synthetic operation,1 avoiding the traditional requirement of preinstalled functional handles such as halide, triflate, boron or tin. One key limitation of this transformation is the poor regio- As early as 1968, the pioneering organometallic chemist Jack selectivity as there is little difference in reactivity between the Halpern stated that ‘‘the development of successful approaches various C–H bonds in substrates. A common strategy to address to the activation of C–H bonds remains to be achieved and this problem involves the use of substrates that contain metal- presently constitutes one of the most important and challenging coordinating functional groups, directing the metal to activate 2 problems in this whole field’’. Since then, the discovery of new proximal C–H bonds via cyclometallated intermediates. methods for C–H bond cleavage by transition-metal complexes In 1963, Kleiman and Dubeck reported the formation of an has been a long-standing goal of the synthetic community. azobenzenenickel complex 5 by treatment of azobenzene 4 with In 1967, Fujiwara reported the first olefination of benzene dicyclopentadienylnickel at 135 1C for 4 h (Scheme 2).4 The azo 3 with a styrene–palladium chloride complex. However, when functional group, working as a metal-coordinating directing mono-substituted arenes such as chlorobenzene 2 were exposed to the complex, a mixture of different isomers (3a, 3b and 3c)was obtained (Scheme 1). a College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, P. R. China 310014. E-mail: [email protected] b Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK. E-mail: [email protected] Scheme 2 First example of Ni-catalysed arene C–H bond activation. 6906 | Chem. Soc. Rev., 2014, 43, 6906--6919 This journal is © The Royal Society of Chemistry 2014 View Article Online Tutorial Review Chem Soc Rev group, brings the metal in close proximity to the ortho C–H bond An elegant report by Yu and co-workers in 2011 exemplifies to be activated, resulting in high levels of regioselectivity. After how directing group strategies can enable the diverse C–H func- reduction of the five-membered metallacycle 5 with lithium tionalisations of privileged molecular frameworks (Scheme 4).7 aluminium deuteride, the metal atom in the ortho-position of Sulfonamides are important pharmacophores found in nearly the azobenzene was replaced by deuterium to give product 6. 200 drugs currently on the market, including the non-steroidal Cyclic platinum and palladium complexes and their corre- anti-inflammatory blockbuster drug Celecoxib 7b.Oneofthe sponding deuterium substituted products were also reported. potential bottlenecks in identifying promising drug candidates is This was the first example of using a metal-coordinating the rapid access to molecular diversity. Taking advantage of the functional group to control the regioselectivity of the transition- directing ability of the sulfonamide, Yu and co-workers applied metal insertion into a C–H bond. This early report demon- their newly developed Pd(II)-catalysed C–H functionalisation reac- strates the impressive reactivity of transition-metal catalysts in tion to a broad range of C–C and C–X bond-forming processes. activating C–H bonds with the assistance of metal-coordinating Six distinct analogues (8–13) of Celecoxib 7b were prepared using directing groups, and opened the door for aromatic C–H this approach, including carboxylation, carbonylation, olefination, functionalisation through this method. Since then many examples iodination, arylation or the alkylation process. Remarkably, the of stoichiometric C–H bond cleavage by various metals were coordinating ability of the sulfonamide group was able to override discovered,1 the development of a catalytic method as a key step that of the diazine, which is itself a commonly employed hetero- towards a synthetically useful process was not realised until the cyclic directing group, affording exclusive site-selectivity in the pioneering work of Murai in 1993 on ruthenium catalysed ortho- presence of multiple potentially reactive C–H bonds. The N-aryl alkylations of aromatic ketones with olefins.5 moiety of the sulfonamide can be kept as part of the pharma- Cyclopalladation of C–H bond containing aromatic compounds cophore or readily removed by hydrolysis with TFA in order to has been extensively investigated and has been found to proceed prepare other derivatives. Two years later, Yu and Baran success- along different pathways (Scheme 3).1,6 Astronglycoordinating fully applied the same strategy for the divergent functionalisation nitrogen-containing directing group was typically required to of the core of bioactive natural product (+)-hongoquercin through promote the facile cyclopalladation, which severely limits the the use of readily removable carboxylic acid and amide directing substrate scope. Nevertheless, these studies have served as a groups.7 These two examples demonstrate the power of the pivotal platform for further discovering and optimising this directing group assisted C–H functionalisation to the late-stage unprecedented mode of catalysis. Thus interest in directing group modifying a privileged molecular framework which would have strategies for catalytic C–H bond functionalisation processes has otherwise required many steps to make prior to the development increased dramatically. of these unprecedented transformations. Various directing groups, such as heterocycles, carbonyl- related functional groups, amines and alcohols, have been employed for catalytic arene C–H bond functionalisation and can be categorised into three different approaches (Scheme 5): Approach 1: after the C–H bond functionalisation of sub- strate 14, the directing group remains part of the product 15,or undergoes further cyclisation to form a heterocycle 16. These Scheme 3 Cyclopalladation models. directing groups cannot be conveniently removed or undergo Fengzhi Zhang received his PhD David Spring is currently a (2008) from the University of Professor at the University of Nottingham (UK) under Professor Cambridge within the Chemistry Nigel Simpkins. After post-doctoral Department. He received his work with Professors John Moses DPhil (1998) from Oxford (2008–2009, Nottingham) and University under Sir Jack Mike Greaney (2009–2011, Baldwin. He then worked as a Edinburgh), he joined the Univer- Wellcome Trust Postdoctoral sity of Cambridge working with Fellow at Harvard University Professors Matthew Gaunt (2011– with Stuart Schreiber (1999– 2013) and David Spring (2013– 2001), after which he joined the 2014). He then took up a faculty faculty at the University of Cam- Fengzhi Zhang position at Zhejiang University of David R. Spring bridge. His research programme Technology (China). His research is focused on synthetic chemistry interests include the discovery of novel catalytic reactions and their and chemical biology. synthetic applications. This journal is © The Royal Society of Chemistry 2014 Chem. Soc. Rev., 2014, 43, 6906--6919 | 6907 View Article Online Chem Soc Rev Tutorial Review Scheme 4 Selective arene C–H functionalisation directed by a sulfonamide group. (Scheme 5, approach 2). We will mainly focus on the C–C and C–X bond-forming reactions based on arene substrates using traceless directing groups (Scheme 5, approach 3). 2. C–C bond formation 2.1 Arylation The biaryl motif is ubiquitous in bioactive natural products, pharmaceuticals and functional materials. While Pd-catalysed cross-couplings such as Stille and Suzuki couplings have been successfully employed for biaryl synthesis, the requirement of prefunctionalisation of