Chapter 1
Functionalization of Heteroaromatic Substrates using Groups 9 and 10 Catalysts

Pedro Villuendas, Sara Ruiz and Esteban P. Urriolabeitia

CSIC-Universidad de Zaragoza, Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), Department of Activation of Bonds by Metallic Complexes, Pedro Cerbuna 12, E-50009, Zaragoza, Spain

1.1 Introduction

A hydroarylation reaction is the formal addition of aromatic or heteroaromatic CH bonds across an olefin CC or an alkyne CC bond, as represented in Figure 1.1b,d, respectively. This CC bond forming reaction, catalyzed by transition metals, is one of the most popular synthetic tools in metal-mediated organic synthesis to introduce alkyl or alkenyl groups at given positions of aromatic or heteroaromatic compounds. It combines a perfect atom economy, the use of simple, non-prefunctionalized reagents, and an environmentally benign design. From the point of view of the synthesis shown in Figure 1.1, it is evident that hydroarylation of olefins is an alternative route to the Friedel-Crafts alkylation (Figure 1.1a), while hydroarylation of alkynes can be considered complementary to the alkenylation of (hetero)aromatic rings (i.e., Heck and Fujiwara-Moritani reactions, Figure 1.1c). A quick comparison shows that Friedel-Crafts alkylation needs halogenated precursors, strongly acidic reagents, usually high temperatures and long reaction times, shows moderate to poor selectivity, and generates stoichiometric amounts of waste products, while Heck (or Suzuki, Sonogashira, and other couplings) also needs halogenated substrates and produces large amounts of residue. It is clear that hydroarylation provides additional simple and advantageous pathways to landmark CC bond forming reactions.

Figure 1.1 General intermolecular hydroarylation of CC multiple bonds with (hetero)aromatic substrates and comparison to Friedel-Crafts alkylation.

The processes shown in Figure 1.1 are general examples of intermolecular couplings. The corresponding intramolecular versions, where the heteroaromatic ring and the olefin or the alkyne are linked by a tether, are also well known. Both processes, intra- and intermolecular, involving alkenes and alkynes, have been used as main synthetic tools for the synthesis and functionalization of a myriad of heterocycles, whose industrial and academic importance resides in the fact that they are basic scaffolds of products with biological and pharmacological activity, new optical materials, or important synthetic precursors and intermediates [1-3]. Due to the importance and the widespread use of these reactions, several reviews covering this area have been published along the years [4-28].

An additional important aspect of the hydroarylation reaction is the selectivity of the reaction, which is closely related to the mechanism through which it takes place. Figure 1.2 exemplifies the most representative cases found for heteroarene-alkyne coupling, and a very similar mechanism scheme can be drawn for reactions involving olefins.

Figure 1.2 Hydroarylation of alkynes: mechanisms and selectivity of the resulting compounds.

The reaction can take place either through alkyne activation or heteroarene activation. In the former case, vinylidene or p-complexes are formed as intermediates, and subsequent reaction with electron-rich arenes results in the formation of the vinylated derivatives, usually as a mixture of cis and trans stereoisomers. The reaction can also occur through metalation of the arene through CH bond activation, either by oxidative addition or by concerted-metallation deprotonation. The resulting intermediates undergo migratory insertion of the alkyne into the MC bond or the MH bond, respectively. Protodemetalation or reductive elimination by CC coupling afford selectively the cis-adducts.

The potential of this reaction was very clear from the first examples of hydroarylation of alkenes and alkynes, which were reported during 1978-1980 by Hong and Yamazaki [29-34]. In these works, the reaction of benzene (and other arenes) as solvents with Ph2CCO [29], ethylene [30, 34], or alkynes [31] under Rh catalysis and CO atmosphere afforded Ph2CHC(O)Ar (Ar = C6H5 in 68% yield based on ketene; other aryl groups in 53-57% yield), styrene (yields up to 9170% based on Rh atom), and stilbenes (around 45% yield based on alkyne), respectively, among other byproducts [33]. The processes are shown in Figure 1.3a-c. While the formation of the substituted acetophenone and stilbenes are true hydroarylations, the production of styrene is formally a Fujiwara-Moritani oxidative coupling. The coupling with alkynes was extended to heteroarenes such as furan (80% yield; 41-86% for substituted furanes), thiophene (48%) and N-methylpyrrole (31%), as shown in Figure 1.3d [32]. In 1993, Murai and coworkers described the regioselective ortho-alkylation of acetophenones with different alkenes (Figure 1.3e), catalyzed by Ru-complexes, a milestone reaction considered a paradigm of atom- and step-economy [35]. This work was also one of the former examples of chelation-assisted functionalization, and paved the way for future research in the area. It is also worth mentioning the work of Fujiwara and coworkers, who in 2000 reported a very efficient addition of simple arenes to alkynes catalyzed by Pd(II), Pt(II), or other electrophilic metals. The reaction takes place in a mixture of CF3CO2H (which increases the electrophilicity of the catalyst) and other solvents, and affords unusual trans-hydroarylated compounds under kinetic control (Figure 1.3f) [36].

Figure 1.3 Examples of seminal hydroarylation reactions.

This chapter aims to cover the most relevant literature on hydroarylation reactions, catalyzed by transition metals from groups 9 and 10, involving heteroaromatic substrates. In particular, only hydroarylation reactions involving challenging cleavage of heteroaryl CH bonds will be considered, excluding most of those dealing with aryl halides and/or arylboronic acids. The chapter has been organized taking into account the nature of the heterocycle to be functionalized, since this type of classification gives to the reader an overview of how many different structural motifs are accesible starting from each individual ring; that is, the versatility of each substrate. Therefore, furans, thiophenes, indoles, pyrroles, pyridines, and other miscellaneous heterocycles will be described separately.

1.2 Thiophenes, furans, and Related Heterocycles

Hong et al. [32] reported in 1980 that under an atmosphere of CO the catalyst Rh4(CO)12 is able to achieve the activation of aromatic CH bonds in five-membered heteroarenes and, in this way, promote the hydroarylation of alkynes. Both unsubstituted and 2-substituted furans react at the a-position (Figure 1.4a). When the reaction is performed with an unsymmetrical alkyne (1-phenylpropyne), the process is regioselective, obtaining the isomer with the phenyl group attached to the same C of the alkene as the furyl ring. The CO pressure must be higher than 10 kg/cm2 in order to avoid cyclotrimerization of the alkynes, and furan is added in great excess (acting as the solvent). If both a-positions are occupied by substituents (2,5-dimethylfuran), then the functionalization takes place at the ß-position, although the yield (40%) is lower than that of mono-a-substituted furans. All these reactions yield vinyl derivatives as a mixture of Z and E isomers, enriched in the Z isomer in all cases. The authors propose that the E isomer is first formed, but after some time the Z isomer becomes predominant in the mixture since it is thermodynamically more stable. The same catalytic system was applied to thiophene to obtain the corresponding 2-vinylated heterocycle (Figure 1.4b). Competitive experiments were carried out in order to determine the relative reactivity of various heterocycles. Furan was found to be more reactive than thiophene, which in turn is more reactive than N-methylpyrrole. All of these heteroaromatic substrates are more reactive than benzene toward acetylenes [32].

Figure 1.4 Hydroarylation of alkynes under Rh catalysis (yields are based on alkyne).

As previously mentioned, the group of Fujiwara was pioneer in developing hydroarylation reactions using alkynes [36]. The year 2000 saw the publication of several seminal papers dealing with this topic, which describe the efficient hydroarylation of alkynes and alkenes with electron-rich aromatic substrates using catalytic amounts of Pd(II) or Pt(II) compounds, in solvent mixtures containing trifluoroacetic acid (HTFA), and both inter- and intramolecular transformations were reported [36, 37]. These reactions are proposed to proceed through alkyne-activation pathways by coordination to cationic and electrophilic complexes of the metals. In the same year the Fujiwara group dedicated another work to heterocycles, making use of the same catalytic process [38]. From a number of reports of detailed exploration of the reactivity of pyrrole and indole derivatives, a single example of the functionalization of a furan derivative is presented (Figure 1.5a): 2-methylfuran adds to an alkynoate at room temperature in the presence of catalytic Pd(OAc)2 (5%) in acetic acid, affording exclusively the Z-heteroarylalkene. The addition of...