Xacobe C. Cambeiro

Au-Catalyzed Cross-Coupling of Arenes via Double C–H Activation

The first methodology for Au(I/III)-catalyzed oxidative cross-coupling of arenes via double C-H activation has been developed. The reaction is fully selective for the cross-coupling between electron-rich hetero-/carbocyclic arenes and electron-poor arenes bearing relatively acidic C-H bonds. The inherently high cross-selectivity of the system obviates the need for directing groups or a large excess of one of the coupling partners.

Redox-controlled selectivity of C-H activation in the oxidative cross-coupling of arenes

The ultimate application of C H activation to the synthesis of biaryl compounds is a reaction in which two non-prefunctionalized arenes are cross-coupled. Such an oxidative crosscoupling would substantially streamline synthetic strategies, resulting in greener methods. To date, these oxidative couplings have been catalyzed almost exclusively by Pd, with some recent examples using Cu. 4] However, several drawbacks remain to be addressed before these methods can be widely applied. First, harsh reaction conditions are commonly needed, with strong acids required as solvents and/or temperatures typically exceeding 110 8C. Second, poor regioselectivities are generally obtained with substituted arenes. Finally, in most oxidative couplings, both coupling partners are activated by Pd or Pd species that have very similar selectivities, which results in the need for using 30– 300 equiv of one of the two arenes to ensure that crosscoupling, rather than homo-coupling, is achieved. We hypothesized that a transition metal capable of presenting orthogonal C H activation selectivities depending on its oxidation state would allow a new approach towards the rational design of oxidative cross-coupling methods with high selectivities. Herein, we demonstrate that Au species present this unique redox-controlled selectivity and highlight their potential use for the design of novel cross-couplings involving oxidative double C H activation. These Au-mediated transformations proceed at lower temperatures than current Pd systems, and display excellent regioselectivities, high crossversus homo-coupling selectivities (thus avoiding the need for vast excesses of the arenes), and are compatible with Pdsensitive groups, such as I and Br. We have recently reported that Au salts are able to mediate the C H activation of electron-poor arenes at just 50 8C (Scheme 1a). This contrasts with the well-known ability of Au salts to perform C H activation of electronrich arenes, even at room temperature (Scheme 1b). 9] We thus hypothesized that, if Au and (III) salts are completely selective for electron-poor and -rich arenes, respectively, this interesting property of Au could be exploited to provide a completely selective double C H activation-based crosscoupling method (Scheme 2). In our hypothetical process, a mixture of an electron-poor (1) and an electron-rich (3) arene would initially react with a Au salt, leading to selective C H activation of 1. Upon addition of an oxidant, aryl–Au species I would be oxidized to Au complex II, which in turn would perform selective C H activation on the electron-rich arene, forming biaryl 4 upon reductive elimination. The development of such a process presents a number of challenges: 1) Despite the few recent methods suggested to proceed by a Au redox cycle, to date none involve the oxidation of aryl–Au species I. 2) C H activation by aryl– Au species II has never been demonstrated, although it may be a step in the homocoupling of electron-rich arenes. 3) Aryl–Au species have been suggested to undergo ligand scrambling by transmetalation, giving rise to homocoupling products. 10] Initially, we explored the coupling of o-iodoanisole with aryl–Au 2a (Table 1), which was prepared under our standard C H activation conditions (Scheme 1 a) in 99% yield. Oxidant optimization revealed that, whereas in the absence of oxidant no product was obtained, the desired cross-coupling product could be observed, albeit in low yields, Scheme 1. Au versus Au C H activation. EDG= electron-donating group, EWG = electron-withdrawing group.

Arene–Metal π-Complexation as a Traceless Reactivity Enhancer for C–H Arylation

Current approaches to facilitate C-H arylation of arenes involve the use of either strongly electron-withdrawing substituents or directing groups. Both approaches require structural modification of the arene, limiting their generality. We present a new approach where C-H arylation is made possible without altering the connectivity of the arene via π-complexation of a Cr(CO)3 unit, greatly enhancing the reactivity of the aromatic C-H bonds. We apply this approach to monofluorobenzenes, highly unreactive arenes, which upon complexation become nearly as reactive as pentafluorobenzene itself in their couplings with iodoarenes. DFT calculations indicate that C-H activation via a concerted metalation-deprotonation transition state is facilitated by the predisposition of C-H bonds in (Ar-H)Cr(CO)3 to bend out of the aromatic plane.

Ru-Catalyzed C–H Arylation of Fluoroarenes with Aryl Halides

Although the ruthenium-catalyzed C–H arylation of arenes bearing directing groups with haloarenes is well-known, this process has never been achieved in the absence of directing groups. We report the first example of such a process and show that unexpectedly the reaction only takes place in the presence of catalytic amounts of a benzoic acid. Furthermore, contrary to other transition metals, the arylation site selectivity is governed by both electronic and steric factors. Stoichiometric and NMR mechanistic studies support a catalytic cycle that involves a well-defined η6-arene-ligand-free Ru(II) catalyst. Indeed, upon initial pivalate-assisted C–H activation, the aryl-Ru(II) intermediate generated is able to react with an aryl bromide coupling partner only in the presence of a benzoate additive. In contrast, directing-group-containing substrates (such as 2-phenylpyridine) do not require a benzoate additive. Deuterium labeling and kinetic isotope effect experiments indicate that C–H activation is both reversible and kinetically significant. Computational studies support a concerted metalation–deprotonation (CMD)-type ruthenation mode and shed light on the unusual arylation regioselectivity.

A multipurpose gold(I) precatalyst

[Au(tmbn)(2)](SbF(6)) is the first gold(I) complex supported by two nitrile ligands that is indefinitely stable at room temperature. This is a highly versatile precatalyst that can be used for the preparation of active and robust solid-supported gold(I) catalysts.

Continuous-flow enantioselective α-aminoxylation of aldehydes catalyzed by a polystyrene-immobilized hydroxyproline

Summary The application of polystyrene-immobilized proline-based catalysts in packed-bed reactors for the continuous-flow, direct, enantioselective α-aminoxylation of aldehydes is described. The system allows the easy preparation of a series of β-aminoxy alcohols (after a reductive workup) with excellent optical purity and with an effective catalyst loading of ca. 2.5% (four-fold reduction compared to the batch process) working at residence times of ca. 5 min.

Continuous flow enantioselective arylation of aldehydes with ArZnEt using triarylboroxins as the ultimate source of aryl groups

Summary A continuous flow system for the synthesis of enantioenriched diarylmethanols from aldehydes is described. The system uses an amino alcohol-functionalized polystyrene resin as the catalyst, and the arylating agent is conveniently prepared by transmetallation of triarylboroxins with diethylzinc.

Reaction of Alkynes and Azides: Not Triazoles Through Copper–Acetylides but Oxazoles Through Copper–Nitrene Intermediates

Well-defined copper(I) complexes of composition [Tpm*(,Br) Cu(NCMe)]BF4 (Tpm*(,Br) =tris(3,5-dimethyl-4-bromo-pyrazolyl)methane) or [Tpa(*) Cu]PF6 (Tpa(*) =tris(3,5-dimethyl-pyrazolylmethyl)amine) catalyze the formation of 2,5-disubstituted oxazoles from carbonyl azides and terminal alkynes in a direct manner. This process represents a novel procedure for the synthesis of this valuable heterocycle from readily available starting materials, leading exclusively to the 2,5-isomer, attesting to a completely regioselective transformation. Experimental evidence and computational studies have allowed the proposal of a reaction mechanism based on the initial formation of a copper-acyl nitrene species, in contrast to the well-known mechanism for the copper-catalyzed alkyne and azide cycloaddition reactions (CuAAC) that is triggered by the formation of a copper-acetylide complex.

A silver-free system for the direct C–H auration of arenes and heteroarenes from gold chloride complexes

A new methodology for the direct C–H auration of electron-deficient arenes and heteroarenes with simple bases and readily available [Au(PR3)Cl] complexes is described. This system allows the preparation of a wide scope of aryl–Au(I) compounds without the need for using Ag(I) additives or preparing and isolating basic Au(I) hydroxide complexes.

C–H Functionalisation of Heteroaromatic Compounds via Gold Catalysis

In this chapter, examples of the C–H functionalisation of heteroarenes using Au catalysis are presented. The majority of examples to date describe the hydroheteroarylation of multiple bonds or Friedel–Crafts-type substitution reactions with heteroaromatic nucleophiles. These reactions are redox neutral and take advantage of the Lewis acidity of Au complexes. The reactivity of [Au(I)] and [Au(III)] in C–H activation of heteroaromatics is also discussed, and examples where this mode of reactivity has been used in oxidative couplings as well as redox-neutral reactions for the functionalisation of heteroarene C–H bonds are presented.