Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Highly Selective Pd-Catalyzed Direct C−F Bond Arylation of Polyfluoroarenes Zhi-Ji Luo, Hai-Yang Zhao, and Xingang Zhang* Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China S Supporting Information *
ABSTRACT: A directing-group-free palladium-catalyzed direct arylation of simple polyfluoroarenes with arylboronic acids through selective C−F bond activation is described. The combination of Pd(OAc)2 with BrettPhos was identified as an efficient catalytic system to promote the reaction with high regioselectivity and broad substrate scope. Preliminary mechanistic studies reveal that the oxidative addition of Pd to the C−F bond is involved in the catalytic cycle.
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To overcome these limitations, a suitable catalytic system that can selectively activate the C−F bond with broad substrate scope is the key. Considering that, usually, the activities of the C−F bonds of fluoroarenes depend on the electronic nature of the carbon that is fluorine attached,3d,5b,9 we envisioned that if a suitable transition-metal complex with significant nucleophilic character could facilitate the nucleophilic oxidative addition to the C−F bond10 it would be feasible to selectively activate the C−F bonds based on the electrophilicities of the carbon atoms. Herein, we describe a highly selective C−F bond activation through palladium-catalyzed cross-coupling of simple and readily available polyfluoroarenes with arylboronic acids. The employment of the Pd(OAc)2/BrettPhos catalytic system in this method features several advantages: (1) high efficiency and broad substrate scope, including inactive trifluoroarenes; (2) high regioselectivity without influence by N-containing heterocycle-based directing groups; (3) high functional group tolerance, even toward nucleophile sensitive ketone; and (4) synthetic simplicity and convenience without requirement of directing group and handling moisture-sensitive reagents. According to the hypothesis, we began our studies on the palladium-catalyzed cross coupling of pentafluorobenzene 1a with air-stable phenylboronic acid 2a (Scheme 1). After a survey of a series of reaction parameters, such as phosphane ligand, solvent, base, and palladium source, the combination of electron-rich and bulky ligand BrettPhos (5 mol %) with Pd(OAc)2 (2.5 mol %) in the presence of Cs2CO3 (2.0 equiv) in toluene at 120 °C achieved the arylated product 3a in 90% yield, along with small of amount of regioisomer 3a′ (4% yield; for details, see the Supporting Information, SI).
ver the past decades, substantial endeavors have been witnessed in developing efficient strategies and methods to access fluorinated compounds due to their prominent applications in life and materials sciences.1 However, in contrast to direct introduction of fluorine atom(s) into organic molecules,2 the transition-metal-catalyzed C−F bond activation to prepare fluorinated compounds has received less attention because of the robustness of the C−F bond and the lack of an efficient catalytic system to discriminate the reactivity of different C−F bonds.3 As an alternative to the conventional methods, the transitionmetal-catalyzed C−F bond activation not only can prepare some fluorinated compounds that other methods are hard to access, but also provides fundamental understandings of C−F bond activation. Although important progress has been achieved in the field recently, most of them focus on hydrodefluorination reactions.4 To date, the formation of C− C bond through transition-metal-catalyzed selective C−F bond activation remains a synthetic challenge.5 An effective approach to facilitate C−F bond activation with high ortho-selectivity is to employ a directing group.6 However, the intrinsic drawback of this approach by requirement of multiple steps to install the directing group into the substrates restricts its widespread synthetic applications. From the point of view of synthetic simplicity and efficiency, the use of simple and readily available fluorinated substrates for selective C−F bond activation would be more straightforward. In this regard, the regioselective nickel7 or palladium-catalyzed8 cross-couplings of simple polyfluoroarenes with arylmetals (Ar−M, M = B, Si, Mg, and Zn) have been developed. However, these methods either are limited to active substrates perfluoroarenes7c,e−g or suffer from low functional group compatibility and use of moisturesensitive arylmetals.7a,b,d,8b © XXXX American Chemical Society
Received: February 28, 2018
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DOI: 10.1021/acs.orglett.8b00692 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
In addition to demonstrating the generality of this catalytic system, perfluoroarenes and other polyfluoroarenes bearing 5− 3 fluorine atoms were also examined (Scheme 3). Mono-
Scheme 1. Palladium-Catalyzed Cross-Coupling of Pentafluorobenzene 1a with Phenylboronic Acid 2a
Scheme 3. Palladium-Catalyzed Cross-Coupling of Fluoroarenes 1 with Arylboronic Acids 2a To ascertain the substrate scope of this method, reactions of pentafluorobenzene with a series of arylboronic acids were examined (Scheme 2). Generally, moderate to good yields of 3 Scheme 2. Palladium-Catalyzed Cross-Coupling of Pentafluorobenzene 1a with Arylboronic Acids 2a
a
Reaction conditions (unless otherwise specified): 1 (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), 120 °C, 12 h. All reported yields are isolated yields. b1 (0.3 mmol, 1.0 equiv), 2 (1.2 mmol, 4.0 equiv).
arylation of perfluorobenzene and perfluorotoluene proceeded efficiently with observation of a small amount of diarylated products (4a and 4b). Other polyfluoroarenes were also competent coupling partners and exclusively furnished corresponding monoarylated products 4 with high regioselectivity. Importantly, many versatile functional groups, including nucleophile-sensitive moieties such as ketone, ester, and other groups such as cyano, nitro, and N-containing heteroaryl, were viable in the cross-coupling, in sharp contrast with previous approaches using arylmagnesiums as coupling partners, in which ketone and ester were incompatible with the reaction conditions (4c−e,i−k).7a,b Notably, for all of the tested polyfluoroarenes, the regioselectivity of arylation of the C−F bond is consistent with the SNAr-type reactions of polyfluoroarenes in which fluorine located at the ortho and meta positions to the site of nucleophilic attack benefits the substitution, but para fluorine shows a negative effect.9 For example, perfluoronitrobenzene provided the corresponding arylated product exclusively at the ortho position to the nitro group (4e).10 This finding was also observed by employing 1,2,3,5-tetrafluoro-4-nitrobenzene and 1,2,3-trifluoro-4-nitrobenzene as the model substrates 4i and 4j, where only ortho-monoarylated products were observed.10 Remarkably, the regioselectivity did not interfere with the Ncontaining heteroaryl-substituted polyfluoroarene previously demonstrated to be good substrates for highly ortho-selective C−F bond activation.6,14 The current palladium catalytic process exclusively provided para-arylated product without influence by the quinonlinyl group (4g), probably due to the steric effect of bulky ligand BrettPhos, which prevents the
a Reaction conditions (unless otherwise specified): 1a (0.3 mmol, 1.0 equiv), 2 (0.6 mmol, 2.0 equiv), 120 °C, 12 h. All reported yields are isolated yields. bReactions run at 140 °C.
with high para-selectivity (regioisomers 3′
