Chemical Society Reviews Functional Group Directed C –H Borylation Journal: Chemical Society Reviews Manuscript ID: CS-TRV-11-2013-060418.R1 Article Type: Tutorial Review Date Submitted by the Author: 30-Jan-2014 Complete List of Authors: Ros, Abel; Instituto de Investigaciones Químicas, Fernández, Rosario; University of Seville, Química Orgánica Lassaletta, Jose; Instituto de Investigaciones Qu �micas (CSIC), Page 1 of 18 Chemical Society Reviews Journal Name RSC Publishing ARTICLE Functional Group Directed C–H Borylation a b a Cite this: DOI: 10.1039/x0xx00000x A. Ros, R. Fernández and J. M. Lassaletta The direct borylation of hydrocarbons via C−H activation has reached an impressive level of sophistication and efficiency, emerging as a fundamental tool in synthesis for the versatility Received 00th January 2012, offered by organoboron compounds. As a remarkable particularity, the catalytic systems Accepted 00th January 2012 originally developed for these reactions are relatively insensitive to directing effects, and the DOI: 10.1039/x0xx00000x regioselectivity of the borylations is typically governed by steric factors. Likely stimulated by the great synthetic potential of the expected functionalised organoboranes, however, many www.rsc.org/ groups have recently focused on the development of complementary strategies for directed , site-selective borylation reactions where a directing group controls the course of the reaction. In this tutorial review, the different strategies and findings related to the development of these directed borylation reactions via C (sp 2)−H or C(sp 3)−H activation will be summarized and discussed. 1. Introduction oxidation, halogenation, amination and etherification (known as the Cham −Lam −Evans 4 reaction) etc. 5 In fact, the synthesis of Direct CH activation / functionalization of hydrocarbons has borylated products has been accomplished in an indirect way evolved as one of the most fundamental tools in modern via a directed metalation / borylation (transmetalation) synthetic chemistry, for it enables atom-economic, sequence. 6 straightforward routes to functionalized added–value products In consequence, the development of site −selective directed and intermediates. One of the most efficient reactions in this borylations (Scheme 2) provides a very attractive alternative to field is the direct borylation of hydrocarbons including arenes, alkenes and alkanes, which, in combination with cross– DG DG coupling methodologies, represents a powerful methodology 1 for the functionalization of raw materials (Scheme 1). C H C B Directed Borylation CH C B C E DG DG YB HY Borylation Coupling C H C B CH YB HY C B EX XB C E Scheme 2 Functionalization of hydrocarbons via direct borylation / cross −coupling strategies. Scheme 1 Functionalization of hydrocarbons via direct the directed ortho metalation (D oM) methodologies, not in borylation / cross −coupling strategies. terms of complementarity but for the distinct synthetic potential (much broader functional group compatibility, tolerance to Until recently, the regioselectivity in most of the catalytic oxygen and protic media, etc.) of organoboranes. An additional processes developed for the borylation of alkanes and arenes advantage of these methods is that cryogenic cooling can be was mainly governed by steric factors,2 and this circumstance avoided, eventually reducing energy costs in large scale has been exploited by using the direct borylation as a reactions. Consequently, the development of methods and complementary tool to the well established directed ortho strategies toward this goal has received considerable attention metalation (D oM) methodologies. 3 in the last few years. The aim of this review is to offer an It is clear, however, that much of the interest on the direct overview of the recent advances in this field. Indirect borylation of hydrocarbons rely on the advantages that approaches based in transmetalation to boron will not be organoboron compounds offer over more basic (or more toxic) discussed herein. aryl / alkylmetals, not only for their higher versatility in cross −coupling applications, but also for the specific 2. Directed borylations via C(sp 2)–H activation transformations developed for organoboranes, including This journal is © The Royal Society of Chemistry 2013 J. Name ., 2013, 00 , 1-3 | 1 Chemical Society Reviews Page 2 of 18 ARTICLE Journal Name As is the case in many other catalytic C −H functionalizations, developed a catalytic system based on the use of [Ir(µ- the directed borylation via C−H activation was first developed OMe)(cod)] 2 as the iridium source, and an electron-poor in arenes and heteroarenes. The different approaches have been phosphine such as P[3,5-(CF ) C H ] as the ligand, which was classified by the transition metal used. 3 2 6 3 3 able to catalyse the site-selective borylation of several substrates containing oxygen-based directing groups. This 2.1. Ir-catalysed borylations method was first applied to the ortho -regioselective borylation 9 It has been demonstrated that direct borylation catalysed by the of benzoates (Scheme 4). Using B 2pin 2 as the reagent, these 1:2 [Ir(µ-X)(cod)] 2/dtbpy (X = Cl, OMe) system takes place − through a [Ir(dtbpy)(BPin) 3] 16 e catalytically active species A.7,8 The lack of sensitivity of this process towards any directing effects by basic functionalities in the substrate can be arguably attributed to the lack of additional vacant coordination sites in the complex B formed upon coordination of directing functionalities. In this scenario, the reaction can only proceed via intermediate C, and steric factors represent the main contribution to regioselectivity (Scheme 3). Scheme 4 Oxygen-directed Ir-catalysed borylations. reactions take place in octane at 80 °C for 16 h, leading to the corresponding products in high yields and with complete regioselectivity, although a considerable excess of arene (5 eq.) is needed to avoid partial ortho,ortho ´-diborylations. The reactions tolerate the use of methyl, ethyl, isopropyl and tert - butyl esters as directing groups, while being suitable for substrates possessing electron-donating or electron- withdrawing functional groups. The methodology has been also Scheme 3 Analysis of regioselectivity in Ir-catalysed extended to the borylation of aryl ketones such as borylations. acetophenone, but a modest 56% yield of the ortho -borylated 10 product was attained in this case. The substitution of the In order to enable directing group effects in these reactions, phosphine ligand by AsPh 3, however, increases the catalyst different strategies based on catalyst or substrate modification activity so that yields higher than 100% based in the B 2Pin 2 have been recently developed, affording attractive site-selective reagent were observed.† The reactions take place at 120 °C for borylation methodologies for the synthesis of ortho -substituted 16 h, with a broad family of ketones containing different arylboronic esters and related borylated compounds. Three functional groups, to give the corresponding ortho -borylated types of approaches have been designed, with strategies products in high GC yields. A drop in the yield of ca 50% was comprising: observed after bulb-to-bulb distillation. The catalytic system 2:1 AsPh 3/[Ir( µ−OMe)(cod)] 2 also works for the borylation of 2.1.1. Chelate-directed borylations . C–H bonds of non-aromatic systems such as the vinylic β 11 A first strategy consists on the development of borylation position of α,β -unsaturated esters. Thus, 1- 2 procedures enabled by initial coordination of a basic cycloalkenecarboxylates can be borylated at the sp carbon with functionality (the more classical type of directing groups) to the total regioselectivity affording the corresponding borylated Ir catalyst. In this case, a modification of the ligand is the key products in moderate to excellent 20-96% yields. This to facilitate the generation of an additional vacant coordination borylation reaction is compatible with the presence of different site in the catalyst-substrate complex. Ishiyama, Miyaura et al . groups in the ester moiety. It is noteworthy that the phenyl 2 | J. Name ., 2012, 00 , 1-3 This journal is © The Royal Society of Chemistry 2012 Page 3 of 18 Chemical Society Reviews Journal Name ARTICLE group, which should be borylated under the Ir-catalysed cases the 2-methoxycarbonyl directing group. In the case of borylation conditions, remains unmodified after the reaction. thiophenes and furanes, however, minor amounts of A different approach toward directed, site-selective borylations regioisomers resulting from the borylation at position 5 were was recently reported by Sawamura et al. 12 In this case, solid- also observed. 14 supported monophosphine-Ir system, Silica-SMAP-Ir, was used as a suitable catalyst for the directed ortho -borylation of functionalized arenes in a very efficient manner. This reaction is successful with a range of functionalised arenes with different oxygenated directing groups, such as benzoates, benzamides, arylsulfonates, benzyl acetals, benzyl methoxymethylethers, leading to the corresponding borylated products with complete ortho -regioselectivity and good to excellent yields (based on B 2pin 2 using a 2:1 substrate-B2pin 2 ratio) in most cases (Scheme 5). Noteworthy, even the chlorine Cat. (0.5 mol%) DG DG B2pin 2 (0.5 eq) R R hexane, 25-50 °C H Bpin 50-108% DG = CO 2R, CONMe 2, SO 3Me, CH(OR)2, CH 2OMOM, Cl Ir OMe Scheme 6 Oxygen-directed borylations with Ir-supported P catalyst. Cat