# A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry

Carlo Sambiagio, David Schönbauer, Rémi Blieck, Toan Dao-Huy, Gerit Pototschnig, Patricia Schaaf, Thomas Wiesinger, Muhammad Farooq Zia,

Joanna Wencel-Delord, Tatiana Besset, et al.

► To cite this version:

Carlo Sambiagio, David Schönbauer, Rémi Blieck, Toan Dao-Huy, Gerit Pototschnig, et al. A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry. Chemical Society Reviews, 2018, 47 (17), pp.6603-6743. 10.1039/c8cs00201k. hal-02024530

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Featuring work from the research groups of Dr Tatiana Besset, CNRS Rouen, France, Prof. Bert U. W. Maes, University of Antwerp, Belgium, Dr Joanna Wencel-Delord, Université de Strasbourg, France, and Assoc. Prof. Michael Schnürch, TU Wien, Austria.

A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation. Additionally, directions for future research are proposed by identifying areas in which more research could lead to more generally applicable, more environmentally benign, and also more industry friendly transformations. Such investigations are ongoing in the groups of all PIs co-authoring this manuscript.

As featured in:

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See Michael Schnürch et al., *Chem. Soc. Rev.*, 2018, **47**, 6603.
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Cite this: *Chem. Soc. Rev.*, 2018, 47, 6603

# A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry†‡

Carlo Sambiagio,InDª David Schönbauer,ᵇ Remi Blieck,ᶜ Toan Dao-Huy,ᵇ Gerit Pototschnig,ᵇ Patricia Schaaf,InDᵇ Thomas Wiesinger,ᵇ Muhammad Farooq Zia,ᵇ Joanna Wencel-Delord,ᵈ Tatiana Besset,ᶜ Bert U. W. MaesInDª and Michael SchnürchInDª*ᵇ

The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C–H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C–H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C–H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C–H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.

Received 14th March 2018

DOI: 10.1039/c8cs00201k

rsc.li/chem-soc-rev

## 1. Introduction

Metal catalysed C–H functionalisation chemistry is a rapidly expanding field with research going into many different directions.¹⁻²¹ Due to the ubiquity of C–H bonds in organic molecules, selective functionalisation of a specific C–H bond is highly challenging. In aromatic heterocycles, the heteroatoms usually guide the regioselectivity of C–H functionalisation

reactions due to their influence on the electron density of the different C–H positions.²²⁻²⁶ On arenes or aliphatic compounds, such intrinsic reactivity differences are significantly less pronounced, and selective cleavage of a specific C–H bond is more difficult, even though substituents in arenes can obviously have a significant effect. One way to overcome this problem is the assistance of directing groups (DGs), consisting of a coordinating moiety (an “internal ligand”), which directs a metal catalyst into the proximity of a certain C–H bond in the molecule, leading to its selective cleavage and subsequent functionalisation.¹⁷,²⁷⁻³³ This strategy allows to overrule innate reactivity in (hetero)arenes. A schematic example of this is shown in Fig. 1 for a number of common unsaturated heterocycles, where a comparison with classical electrophilic substitution is given.³⁴

DG-assisted C–H functionalisation started to gain momentum in the mid-1990s after a landmark contribution by the group of Murai.³⁵ In this paper, a ketone DG enabled the Ru(II)-catalysed *ortho*-alkylation of arenes with alkenes, clearly illustrating that

<footnote>ª Organic Synthesis (ORSY), Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium</footnote>

<footnote>ᵇ Institute of Applied Synthetic Chemistry, TU Wien, Getreidemarkt 9/163, A-1060 Vienna, Austria. E-mail: michael.schnuerch@tuwien.ac.at</footnote>

<footnote>ᶜ Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France</footnote>

<footnote>ᵈ Laboratoire de Chimie Moléculaire (UMR CNRS 7509), Université de Strasbourg, ECPM 25 Rue Becquerel, 67087 Strasbourg, France</footnote>

<footnote>† Dedicated to the memory of Prof. Walther Schmidt.</footnote>

<footnote>‡ Electronic supplementary information (ESI) available. See DOI: 10.1039/c8cs00201k</footnote>
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Review Article

the regioselectivity issued might be selectively tackled if
formation of a metallacyclic intermediate occurs. Since then,
a huge number of papers on the topic have been published,
expanding the scope of potential DGs and of chemical trans-
formations which can be carried out.

1.1. Limitations to the use of C-H functionalisation in molecules for R&D or in total synthesis

Most of the published contributions can be classified as method-
ological papers. Typically, substrates are designed which align
themselves nicely in order to allow a selective C–H cleavage. The
complexity of these substrates is typically limited, since they are
usually from the pool of readily available small molecules
featuring a standard functional group (FG) compatibility.
Applications in the field of R&D³⁶⁻³⁸ and total synthesis of
complex molecules³⁹⁻⁴⁵ have been reported, however those

remain the exception. For the former it is of course difficult
to get an objective view on the situation as most results
obtained in fine chemicals industry are never published. However,
when comparing the number of cross coupling reactions and
direct C–H functionalisations disclosed in the scientific litera-
ture by industry, one can safely conclude that the area is still
in its infancy. This is somewhat surprising, considering
the amount of transformations, which have been reported so
far from academia and the wide variety of DGs which can
potentially promote them. You might think that in a retro-
synthesis, you frequently run into situations, in which transi-
tion metal-catalysed C–H functionalisation would be a potential
and even the preferred option. So what are the reasons why
C–H functionalisation has not yet reached the level of general
applicability which related transformations, e.g. cross-coupling
reactions, have achieved already quite some time ago?

<figure><img src="image_6.png" /><figcaption>Carlo Sambiagio</figcaption></figure>

Carlo Sambiagio studied chemistry at the University of Cagliari (IT), acquiring his Master's degree in 2011. He then moved to the University of Leeds (UK), completing his PhD on Cu-catalysed cross-couplings in 2015, under the supervision of Prof. Patrick McGowan. After that he spent two year as a postdoc in the Maes group in Antwerp (BE), mostly exploring aerobic oxidation chemistry. Carlo has recently moved to the Eindhoven University of Technology (NL) as a EU Marie

Curie fellow to work on flow chemistry with Prof. Timothy Noël. His interests generally include metal-catalysed transformations and the development of new methodologies for organic synthesis.

<figure><img src="image_7.png" /><figcaption>David Schönbauer</figcaption></figure>

David Schönbauer was born 1989 and is currently working towards his PhD at Technische Universität Vienna in the Institute of Applied Synthetic Chemistry, where he also finished his Master studies 2017. His current research in the field of C–H functionalisation is supervised by Professor Michael Schnürch and focuses on the activation of C(sp³)–H bonds.

<figure><img src="image_8.png" /><figcaption>Joanna Wencel-Delord</figcaption></figure>

Joanna Wencel-Delord was educated in chemistry at the Ecole Nationale Supérieure de Chimie de Rennes, France and she received her PhD in 2010 from the University of Rennes 1, France (Dr C. Crévisy and Dr M. Mauduit). After postdoctoral studies with Prof. F. Glorius at the Westfälische Wilhelms-Universität Münster (Germany) and temporary assistant professor position (ATER) at the University of Strasbourg (Prof. P. Compain), she joined CNRS in 2013 as an associate

researcher in the group of Prof. F. Colobert (University of Strasbourg, France). Her research focuses on the transition metal-catalysed asymmetric C–H activation.

<figure><img src="image_9.png" /><figcaption>Tatiana Besset</figcaption></figure>

Dr Tatiana Besset obtained her doctoral degree in organic chemistry (2009) at Grenoble University (Dr Greene's group, France). She then moved to Münster WWU (Germany) as a postdoctoral fellow in the group of Prof. Glorius. In 2011, she joined the group of Prof. Reek (Amsterdam University, Netherlands), as a postdoctoral fellow in collaboration with Eastman company. Since 2012, she is working as a CNRS Associate Researcher in the team

headed by Prof. Pannecoucke, UMR 6014-CNRS, Rouen University, INSA (France). Her research program is focused on transition metal-catalysed C–H activation and the development of new strategies to access fluorinated molecules.
<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /><figcaption>Fig. 1 Examples of classical reactivity versus DG approach.</figcaption></figure>

Considering cross-coupling reactions, it can be noticed that the majority of coupling partners organometals and (pseudo)halides (Suzuki–Miyaura, Stille, Negishi, Hiyama), or (pseudo)halides and olefins (Heck) or alkynes (Sonogashira) in order to create new C–C bonds without regioselectivity issues. Hence, in retro-synthetic analysis, cross-coupling reactions are quickly identified

and nowadays these are standard transformations frequently applied in all contexts of synthesis, also including the most complex area of total synthesis of natural products. Additionally, the metals applied are also only a few with Pd being the single most important one dominating the field, followed by Cu and Ni (recently). All other metals play only relative minor roles at the moment, although research in this field is also increasing.

In case of C–H functionalisation, the situation is much more complex due to the higher diversity in coupling partners which often react *via* distinctively different reaction mechanisms, and a large variety of specific additives which these reactions require (often complex mixtures of reagents and additives are required for each transformation). To facilitate the understanding and the choice of a specific procedure, below are listed the different types of additives and their roles in C–H functionalisation reactions. It is important to stress that, although the main classes of additives and roles are relatively clear, many compounds can have more than one distinct role in the reaction, therefore their choice and combinations is not straightforward.

* Oxidants: most often Cu salts (commonly Cu(OAc)₂), and Ag salts (sometimes Mn salts) are used in stoichiometric or superstoichiometric amounts in oxidative reactions. Other oxidants, used alone or in combination with Cu or Ag are benzoquinones, peroxides, O₂/air, K₂S₂O₈ or hypervalent iodine compounds.

* Catalytic Ag salts: catalytic amounts of Ag salts are often used in combination with groups 8 or 9 metal halide dimers, commonly used as catalysts (e.g. [RhCp*Cl₂]₂). In these cases the Ag acts as a halide scavenger, and the counteranion (usually OTf, NTf₂, or SbF₆) promotes the *in situ* formation of cationic metal catalysts in solution. When a suitable preformed cationic metal catalyst is used, the addition of such additives is generally not required.

* Carboxylates: carboxylates (acetates, benzoates, pivalates, adamantanecarboxylates, trifluoroacetates and others) are very

<figure><img src="image_12.png" /><figcaption>Bert U. W. Maes</figcaption></figure>

Bert Maes obtained his PhD from UAntwerpen and subsequently received a prestigious post doc position of the National Science Foundation in Belgium (FWO-Flanders). He performed post-doctoral work in France at the École Normale Supérieure in Paris with Prof. Anny Jutand, studying fundamental mechanisms in catalysis. In 2003 he was appointed assistant professor (docent) in the Department of Chemistry at UAntwerpen. He

currently is a full professor of Organic Chemistry and spokesman of the Organic Synthesis division (ORSY). His research interests include heterocyclic chemistry, organometallic chemistry, homogeneous catalysis and sustainable chemistry.

<figure><img src="image_13.png" /><figcaption>Michael Schnürch</figcaption></figure>

MS received his PhD in 2005 from TU Wien (supervisor Prof. Peter Stanetty). During his PhD-studies, he was on a 4 month sabbatical in the group of Prof. Victor Snieckus at Queens University (Kingston, Ontario). He was then post doc with Prof. Dalibor Sames at Columbia University as Erwin Schrödinger fellow. Then, he became Assistant Professor at TU Wien and completed his habilitation in 2013. Subsequently, he was

promoted to Associate Professor for Organometallic Chemistry in 2016, a position he still holds. Additionally, he is currently the Chair of the COST Action CHAOS (C–H Activation in Organic Synthesis).
<figure><img src="image_14.png" /></figure>

common additives in many C–H functionalisation protocols. Their role is mostly related to their ability to deprotonate the desired C–H bond, often *via* a concerted metallation–deprotonation (CMD) pathway (also termed ambiphilic metal ligand activation (AMLA)).²,⁴⁶,⁴⁷ These additives are generally added as acids in stoichiometric or catalytic amounts, often in combination with bases, or can be added as their Cu, Ag, Zn, Na salts.

* Ligands: although typically no external ligands are required in C–H functionalisation reactions (the DG acts as an “internal ligand”), in some cases an external auxiliary (catalytic amounts) is required to facilitate the reaction. These can be phosphines, carbenes, mono-protected aminoacids (MPAA) or other bidentate ligands. Noteworthy, the choice of the ligand will strongly depend on the mechanism of a targeted transformation (for instance Pd(II)/Pd(0) catalysis vs. Pd(II)/Pd(IV) catalytic cycle).

* Lewis acids: in this category many compounds can fall, including some of the above. Although most often simple compounds are used, such as Zn salts, the applied Lewis acids span over a wide range of reagents also including more exotic In/Gd salts or BPh₃, as can be seen in the examples in this review. These can display different roles, including the activation of coupling partners (e.g. activation of ketones/aldehydes in alkylation reactions), and can be added in stoichiometric or catalytic amounts.

* Bases: a number of different bases, usually inorganic ones, e.g. carbonates are used to neutralize acids formed during the reaction, or to facilitate deprotonation of the starting materials/reactants/additives used. It is worth noting that common bases used for cross coupling reactions, such as Cs₂CO₃, are instead not often encountered in C–H functionalisation, while Na, K, or Li counterparts are generally more effective (Ag₂CO₃ is often used as both oxidant and base).

The variety of additives and reaction conditions encountered in this field is also reflected by the range of metals which are applied as catalysts. There is no such thing as a single dominant metal species, but Pd,⁴⁸,⁴⁹ Rh,⁵⁰,⁵¹ and Ru⁵²⁻⁵⁴ share together the top spot. Moreover, increasing examples using Ni,⁵⁵⁻⁵⁸ Co,⁵⁵,⁵⁹⁻⁶⁴ Ir,⁶⁴⁻⁶⁶ Cu,⁶⁷⁻⁶⁹ Fe,³,⁵⁵,⁶³,⁷⁰,⁷¹ and Mn⁷²⁻⁷⁴ are appearing in the literature.

Naturally, such a manifold of metals with often distinctively different properties adds a lot of complexity to the field. This is of course an advantage for method development, since it is only logical that a larger pool of catalyst candidates allows also for a larger variety of possible transformations. On the other hand, the complexity has reached a level where it is very difficult to keep track of the developments and to get an overview of what is actually possible in C–H functionalisations.

What does this mean for a synthetic chemist planning a multistep synthesis of a molecule? The retrosynthetic disconnections might frequently lead to situations in which C–H functionalisation chemistry could be applied. However, because of the diversity of the field and the lack of a general and easy to consult overview, its application is unfortunately not even considered in many cases. This is the shortcoming which the authors attempted to address by this review. So overall, this review aims at giving a comprehensive overview on the types of

FGs available for transition metal-catalysed C–H cleavage reactions and the types of transformation they allow, and the associated required “reaction cocktail”. This should be very useful for taking this research field to the next step, the more frequent application in syntheses, also at late stages of prolonged synthetic sequences.

## 1.2. Structure and scope of the review

Our aim in this review was to present the DGs and possible transformations in a concise way so that all readers can easily find the specific transformation looked for. Hence, the review is divided in sections dedicated to specific types of DGs: (i) monodentate carbonyl-containing DGs, (ii) bidentate DGs, (iii) heterocyclic DGs, and (iv) heteroatom-based DGs (N, S, P, Si...). These main sections are further subdivided into specific functional groups (e.g. ketones, amides, etc.), and then into alkylations, alkenylations, arylations, etc. In turns, for each of these subsections, the different procedures reported in the literature have been summarised in schemes, making it easier to compare them with each other. To facilitate this task, a list of advantages/disadvantages has been added for each procedure, concerning issues such as selectivity, substrate scope, reaction conditions, DG removal, and overall greenness. We realise that said advantages/disadvantages can be somewhat subjective, and what is good for one purpose may not be so good for another. For example, the use of halogenated solvents has been considered as a drawback in this review. This has not the aim of criticising the research methodology, neither reducing the value of the results reported, but the use of such solvents is a no-go in chemical manufacturing, and therefore is something that necessarily has disadvantages in terms of that procedure being used for such a purpose. The same reasoning applies to the other advantages/disadvantages considered in the review. In particular, among the drawbacks, the following have been specifically listed: toxic solvents; reaction temperatures > 120 °C; reaction time > 24 h; (most) yields < 70%; superstoichiometric amounts of (metal) oxidants in oxidative couplings; regio- or stereoisomeric mixtures; specific limitations in scope or FG tolerance (e.g. sensitivity to steric hindrance); use of additional ligands, unless in stereoselective reactions (the DG is already a ligand, and most non-stereoselective procedures do not require additional ligands). As positive aspects, the following are instead considered: green(er) solvents; reaction temperature < 50 °C; reaction times < 10 h; (most) yields > 80-90%; particularly good FG tolerance (halide, methoxy, alkyl, ester and cyanide are considered generally standard substituents, if something more advanced, such as alkene, alkyne, boryl, silyl, or free NH/OH groups are also tolerated, this has been mentioned as an advantage); other substrates and other DGs available for the reaction; DG removal (when specifically mentioned); *in situ*, one-pot, or cascade processes; scalability. Other aspects have not been mentioned as specific advantages/disadvantages, mostly because of the lack of a real distinction between the two; a catalyst loading up to 10 mol% metal has been considered standard, as most protocols use these amounts, though it does not mean this is what is acceptable for chemical development purposes (higher than 10 mol% metal for expensive catalyst has
<figure><img src="image_15.png" /></figure>

been considered specifically as a disadvantage); characteristic of reactants have also not been generally considered (e.g. availability or cost), as a large variety exist and price is heavily depending on the scale required.

Another important aspect of the review is the stress that has been placed on the DG removal. The removal of DGs is an important drawback in C–H functionalisation chemistry, as the DG might not be required after the directed step, and its removal is therefore necessary (which is an extra synthetic step). Several DGs are actually not removable (depending on the substrate as well) which is no problem when they anyway constitute a (precursor) part of the target molecule, while others are easily removed or modified. We tried to incorporate all the possible protocols for the removal or modification of the DGs in each section, so that the reader will be immediately aware of what can currently be done with the DG in use. This information is often not reported in reviews dealing with C–H functionalisation. The removal of the DG has also been listed as a specific advantage in each procedure, in case this is specifically investigated by the authors. So not being mentioned does not mean it could not be done, it is just not reported in the original publication.

It has to be mentioned that sometimes different publications use different terms for the very same transformation. For the sake of simplicity, in this review each transformation has the same name in all entries. For example, the coupling of olefins with arenes to give alkylated arenes is either classified as alkylation or hydroarylation in literature. It was decided for this review to look at the reaction product and see what happened to the part of the molecule which carried the DG. Hence, in case the arene carried the DG, the reaction is always classified as an alkylation reaction.

This review aims at being comprehensive in the regard that all DGs and potential transformations with the DG are listed, however, reporting every single variant of a given transformation would just be beyond the scope of this review. In such cases a selection had to be made by critically looking at the reported protocols and choosing representative examples to give a clear flavour on chemical diversity searched for by the synthetic chemist. It is clear that such a selection will always be biased and readers might find that one or the other example should have been selected differently.

The speed in which new contributions are brought forward in the field is amazing. This shows the high relevance of this area of research and the potential of the field. For writers of a review it brings certain problems as well, most importantly which time frame to cover and which examples to include? As a starting point, we used the very comprehensive review by Zhanxiang Liu and Yuhong Zhang published in early 2015, which covers literature until the end of 2014.¹⁷ Hence, our review starts at the beginning of 2015 until the end of 2017.

## 2. Ketone DGs

The carbonyl group in ketones was historically amongst the first DGs to be used in C–H functionalisation chemistry.

<figure><img src="image_16.png" /><figcaption>Fig. 2 Murai's ketone-directed alkylation.</figcaption></figure>

Already in 1993, a pioneering work for ketone-directed alkylations was published by Murai *et al.*³⁵ In this landmark contribution, the first highly efficient and selective C–H cleavage with a simultaneous C–C bond formation mediated by a Ru complex on different aromatic ketones (e.g. naphtyl, furan, thiophene) with mono- and di-substituted olefins was shown. The mechanism proposed in this paper served as blueprint for many more contributions to come, and can be considered as one of the most important starting points for the field of C–H functionalisation chemistry, as we experience it today. It was proposed that the carbonyl function first pre-coordinates the metal catalyst, which brings it into a position in close proximity to the C–H bond *ortho* to the ketone function (Fig. 2). This allows C–H insertion of Ru into the C–H bond. Then, one PPh₃ ligand is replaced by the olefin, first *via* π- then *via* σ-bonding. Finally, reductive elimination forms the new C–C bond and the catalyst dissociates again.

25 years later, the field is still very active and new contributions are brought forward continuously and even though the field has been recently reviewed,⁷⁵ a significant number of new contributions has been published, which will be treated in this section. This is certainly due to the manifold of opportunities of further manipulation a ketone allows, and also the ease of introduction *via* various methods, e.g. Friedel-Crafts acylation. From the very beginning, Ru proved to be especially well suited for ketone-directed C–H activation reactions followed by Rh, with other metals playing only a minor role.

### 2.1. Arylation

Kakiuchi and co-workers tackled the problem of arylating sterically demanding diaryl and aryl-alkyl ketones by designing Ru catalysts of the general structures [RuHCl(CO)(PAr₃)₃] and [RuH₂(CO)(PAr₃)₃].⁷⁶ 3,3',5,5'-Tetramethylbenzophenone served as model substrate and a boronic acid ester as the aryl source.
<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /><figcaption>Scheme 1 Ketone-directed arylations.</figcaption></figure>

For this substrate, [RuHCl(CO)(P(4-MeO-3,5-Me₂C₆H₂)₃)] turned out to be the best performing catalyst, whereas for the pivalophenone derivative 1-(3,5-dimethylphenyl)-2,2-dimethylpropan-1-one [RuH₂(CO)(P(3-MeC₆H₄)₃)] performed best (Scheme 1A).

Again using boronic esters as aryl sources, Lu and Sun developed a Rh catalysed protocol for arylating alkyl-aryl ketones exclusively at the C(sp²)-H bond.⁷⁷ Di-arylated products were not observed, even in the absence of steric bulk. Additionally, yields were generally excellent and frequently >90% (Scheme 1B).

Rao reported on a dimerization of aromatic ketones leading to 2,2'-dicarbonylated biaryls *via* a Pd(II)-Pd(IV) catalytic cycle (Scheme 1C).⁷⁸ Substituted benzophenone derivatives and also alkyl-aryl ketones worked well towards the homodimers. More importantly, the authors showed that also two different ketone substrates can be applied leading to heterocoupling products in yields between 61–82%. In these cases, the more electron-rich ketone had to be used in excess. This is a significant improvement to traditional routes towards the same type of products.⁷⁹,⁸⁰ Furthermore, the method was not limited to ketones as DG but also esters and carbamates were applied.

An example which can be counted to arylation reactions as well is the synthesis of [60]fullerene-fused tetralones *via* a Pd catalysed protocol.⁸¹ [60]Fullerene reacted with a series of alkyl-aryl ketones. Even though the yields were low (10–31%), this is an interesting example showing the diversity of possible coupling partners (Scheme 1D).

Ramana investigated the C3-arylation of 2-arylbenzofurans using either arylboronic acids or the corresponding potassium trifluoroborates as the aryl source.⁸² Almost the same conditions as for their alkylation protocol could be used (see Section 2.2) but interestingly AgOAc had a detrimental effect and only in its absence, high yields were obtained and also excellent FG tolerance was observed (Scheme 1E).

## 2.2. Alkylation

In 2015, the group of Prabhu reported on the addition of maleimides mainly to acetophenones, which is formally an alkylation reaction (Scheme 2A).⁸³ Also 2-acetylthiophene was a suitable starting material, however with a decreased yield of 54%, whereas two benzophenone derivatives were as efficient as the acetophenones. Noteworthy are the DFT studies in this contribution, which strongly favour a CMD mechanism over an electrophilic aromatic substitution or a mechanism involving an oxidative addition. One year later, Kim and Kim reported a similar protocol applied to chromones and xanthones.⁸⁴ By switching to a Rh catalyst, they could reduce the catalyst loading significantly (Scheme 2B). Acetyl-directed alkylation (as well as amidation and alkenylation) was also reported by Zhang (Scheme 2C).⁸⁵ Relatively high catalyst and ligand loadings were required but on the upside, an uncommon substrate, tetraphenylene, was used in this transformation.

Recently, an Fe catalysed alkylation protocol was published by Kakiuchi and co-workers (Scheme 2D).⁸⁶ Using simple Fe(PMe₃)₄ as catalyst without any additional ligand or other additives, alkyl-aryl ketones were alkylated with substituted olefins (mainly alkenyl silanes) in excellent yields under neat conditions. Also cyclic alkyl-aryl ketones (e.g. 2,2-dimethyltetralone) could be used as substrates. Diaryl ketones did not react as efficiently and required higher catalyst loading and trialkylation was observed as the major product. The proposed mechanism followed the initial suggestion by Murai.³⁵

One rare example of *ortho* methylation was recently disclosed by Iliés and Nakamura (Scheme 2E).⁸⁷ AlMe₃ served as alkyl source and simple Fe(acac)₃ as catalyst. However, the addition of a less common ligand, Me₂N-TP (see Scheme 2E) was necessary. As usual in most of such alkylation reactions, mixtures of mono- and di-alkylated products were obtained if permitted by the

<figure><img src="image_19.png" /><figcaption>Scheme 2 Ketone-directed alkylations.</figcaption></figure>
<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /><figcaption>Scheme 3 Ketone-directed alkylation on carbo- and heterocycles.</figcaption></figure>

substrate structure. In the same paper also carboxylic acids were used as DGs (see Section 4).

All examples so far gave exclusively the synthesis of linear products. However, Ramana and co-workers showed that tuning the catalytic system allowed to switch between linear and branched products in the C3-alkylation of 2-arylobenzofurans with acrylates (Scheme 3A).⁸⁸ Whereas the selectivity for branched products was generally in the 9/1 (branched/linear) range, for linear products it was often significantly lower. Recently, the group published a follow-up paper trying to elucidate *via* DFT calculations how the linear/branched selectivity was controlled.⁸⁹ They calculated transition states leading either to the linear or to the branched products, which are both feasible pathways. The transition state towards the branched product turned out to be significantly lower in energy, which goes in line with the experimental observations. Furthermore, the method was extended to the C2-alkylation of 3-aryloxybenzofurans.⁸⁹ On this second type of substrates, the linear product was preferred with high selectivity (20/1) and no protocol for the branched products was disclosed (Scheme 3B).

The very same reagent was also used for another functionalisation/cyclisation sequence using 3-ketoindoles as substrates (Scheme 3C and D).⁹⁰ Initially, the authors found two products, the one alkylated in C4, and one derived from

alkylation and subsequent cyclisation in C2. At the beginning, they could successfully optimise the reaction towards selective formation of the C4 alkylated products with good to excellent yields (36–98%). Subsequently, also the second type of products could be obtained selectively, however, generally in lower yields (~10% lower) for similar examples. In both cases, [RhCp\*Cl₂]₂ was used as the catalyst, but the additives differed, as can be seen in Scheme 3C and D.

An interesting example has been reported by Wan and Li.⁹¹ Using phenylacyl ammonium salts as substrates (which can also be produced *in situ*) in combination with α-diazo esters led to benzocyclanone products (Scheme 3E). Key was the unprecedented presence of an oxidizing C-N bond in the substrates which allowed this overall redox-neutral process. Detailed mechanistic studies were carried out, including DFT calculations.

The group of Zhu used enaminone starting materials for the synthesis of naphthalene derivatives using either α-diazo-β-ketoesters (Scheme 3F) or alkynes (Scheme 4H) as coupling partners.⁹² In case of α-diazo-β-ketoesters as coupling partners the initial step is an alkylation and good FG tolerance on the substrate was observed. Synthetically useful yields between 50–85% were reported and various alkyl residues including cyclopropyl can be in position R².

## 2.3. Alkenylation

Yu explored the application of distal weakly coordinating DGs, including ketones (Scheme 4A).⁹³ In this report, the ketone functionality is not directly attached to the aromatic ring but separated by a -CH₂-, or in one case a -CH₂CH₂- spacer. Yields for the reaction with acrylates are moderate and selectivity between mono- and di-alkenylation is an issue.

Bakthadoss et al. showed that basically the same reaction conditions could be applied for the alkenylation of chromanones as well, in this case in dioxane as solvent (Scheme 4B).⁹⁴ Yields were commonly good (60–81%) and the typical range of FGs was tolerated.

Again on tetraphenylenes, Zhang also reported alkenylation reactions (Scheme 4C).⁸⁵ In this case, the catalyst loading could be significantly reduced and no ligand was required, although 2 equiv. of Cu had to be used. Besides acrylates, also alkenyl sulfoxides and -phosphates as well as styrene derivatives could be used.

Szostak's group showed the ketone-directed hydroarylation of internal alkynes leading to alkenylated arenes (Scheme 4D).⁹⁵ A low Ru loading could be applied; however the *E/Z* ratio left room for improvement. In this contribution, the DG showed significant variation as opposed to many contributions which relied primarily on the acetyl group. Further elaboration of the obtained alkenylated products to a series of useful compounds was also demonstrated.

Prabhu and co-workers showed that a ketone DG in position 3 of indoles leads to alkenylated products either at the C2- or C4-position.⁹⁶ The source of this regioselectivity is primarily the electronic nature of the DG. For R = Me/Et, alkenylation took place in C2-position under Ru catalysis (Scheme 4E).⁹⁶
<figure><img src="image_22.png" /></figure>

<figure><img src="image_23.png" /><figcaption>Scheme 4 Ketone-directed olefinations on various substrates.</figcaption></figure>

Also an amide DG gave the same regioselectivity. In case of R = t-butyl, di-alkenylation in C2- and C4-position was observed and for R = phenyl di-alkenylation in C2-position and on the DG occurred. For R = CF₃ and using a Rh catalyst, exclusive C4 alkenylation was observed (Scheme 4F).⁹⁶ Trying to elucidate the origin of this regioselectivity, the authors have reason to believe that COCF₃ is the weaker coordinating DG, which eventually does not direct C–H activation by precoordination but rather stabilizes a metal–arene σ complex that forms due to electrophilic metallation. An ester or an aldehyde as DG also gave C4 alkenylation. Such examples, giving guidelines for achieving different regioselectivity, are of significant importance for further promoting the application of C–H functionalisation in complex syntheses.

Another peculiar ketone DG was developed by Lan and Li, namely phenylacyl ammonium salts (Scheme 4G).⁹¹ Using a Rh catalyst, *ortho* alkenylation was obtained in good yields with styrene derivatives. However, also alkyl substituted olefins could be applied with the drawback that sometimes, mixtures of *E* and *Z* isomers were obtained. It is noteworthy that the ammonium group was cleaved during the reaction, overall leading to *ortho* alkenylated acetophenone derivatives. Noteworthy, the reaction does not require an external oxidant since the ammonium salt of the DG takes over this role.

The group of Zhu used enaminone starting materials for the synthesis of naphthalene derivatives using either alkynes (Scheme 4H) or α-diazo-β-ketoesters (Scheme 3F) as coupling partners.⁹² In the case of alkynes, only 1,2-diphenylacetylene was used as reaction partner but good FG tolerance on the substrate was observed and synthetically useful yields between 50–85% were reported. According to the proposed mechanism, the initial step is a Rh-catalysed alkenylation.

## 2.4. Alkynylation and acylation

One example of an alkynylation reaction was reported by Jiang and Huo (Scheme 5A).⁹⁷ TIPS protected bromo acetylene was used as alkyne source under Ir(III) catalysis. Aromatic and

<figure><img src="image_24.png" /><figcaption>Scheme 5 Ketone-directed alkynylation, acylation and C–N bond formation.</figcaption></figure>

heteroaromatic ketones worked equally well and a range of substituents were tolerated with good yields (generally ~70%). On the downside was the large amount of a mixture of three different Ag salts and the requirement for halogenated solvents. Esters can be used as alternative DGs, although the ketone showed a better directing effect, whereas an amide or pyrazole DG were superior to the ketone. Such studies, allowing the ranking of directing ability of different DGs, are unfortunately rare but extremely important for the application of C–H functionalisation to the synthesis/modification of complex molecules, carrying many FGs.

Decarboxylative acylation was reported by Yu and co-workers (Scheme 5B).⁹⁸ As acyl source, α-oxocarboxylic acids were used
<figure><img src="image_25.png" /></figure>

under Pd catalysis. The authors suggested an acyl radical as important intermediate, which was supported by a radical trapping experiment with TEMPO.

## 2.5. C-N bond formation

Ackermann disclosed Ru catalysed imidation of aryl-t-butyl ketones using N-tosyloxyphthalimides (Scheme 5C).⁹⁹ The obtained products were easily transformed to the corresponding amines using standard conditions (N₂H₄), which gave valuable 2-amino-phenones. Those can be converted to a series of nitrogen containing heterocycles.

Using aromatic or aliphatic sulfonyl azides, it was again Zhang who showed amidation of terpenylenes with high FG tolerance (Scheme 5D).⁸⁵

Dioxazolones became popular amidating agents in recent years in the field of C-H activation. Interestingly, two groups almost simultaneously exploited this reagent on enaminones. Zhu and co-workers developed a Co(III)-catalysed protocol,¹⁰⁰ whereas Li developed Co(III)-and Rh(III)-catalysed reactions.¹⁰¹ The two Co(III)-catalysed protocols used both [Cp\*Co(CO)I₂] as catalyst (Scheme 5E). The substrate scope and yield (typically >80%) were comparable and all common FGs seemed to be tolerated. The amidated product was then transformed to 4-quinolones under acidic conditions (not shown).

# 3. Aldehydes as DGs

Aldehydes are frequently applied in C-H functionalisation chemistry in case of the formation of so-called “transient” DGs, where a DG is formed and cleaved *in situ*. A prominent example is the formation of imines from aldehydes (or ketones) and amines. Since this subject has been reviewed very recently,¹⁰²,¹⁰³ this type of chemistry is not included in this chapter and only examples where the aldehyde function is the actual DG are discussed. Hence, in the timeframe covered by this review, only three examples have been reported and only in one example the aldehyde function remains in the final products, whereas in the other two examples it acts as traceless DG.

The first example used the aldehyde function as a traceless DG in a Rh catalysed reaction with alkynes (Scheme 6A).¹⁰⁴ 2-Aryl-3-formylindoles were used as starting materials. In the first step (according to the proposed mechanism), the

aldehyde-directed an alkenylation at C2-position of the indole core. Rh was then suggested to be involved in the decarbonylation process and further activation of a C-H bond of the N-aryl group as well leading overall to indolo[1,2-a]quinolones in high yields (up to 94%, frequently >80%), which is overall an elegant access to this system.

Also in the second example, the aldehyde DG was removed under the applied reaction conditions, this time in an arylation protocol (Scheme 6B).¹⁰⁵ Initially, salicylaldehyde was used as the starting material and aryl iodides as coupling partner. Arylation took place *ortho* to the formyl group, which was cleaved under the applied reaction conditions leading overall to *meta* substituted phenols in yields around 50%. Regarding the mechanism, experiments actually pointed towards a reaction sequence in which the first step is the oxidation of the salicylaldehyde to salicyclic acid (which would mean that the actual DG is the acid function), which is then removed *via* decarboxylation. The advantage of starting from the aldehyde function is that salicylic aldehyde derivatives could be prepared much more easily from the corresponding phenols than salicylic acids.

The one example keeping the aldehyde function reported sulfamidation of indoles in position 4 (Scheme 6C).¹⁰⁶ This Ir catalysed method could be run at room temperature and delivered typically high yields of the desired products. Noteworthy, the application of the method to a gram scale synthesis was reported showing the scalability of this transformation.

# 4. Carboxylic acids as DG

Even though carboxylic acids are a frequently occurring FG, it has been added rather late to the repertoire of DGs. The majority of contributions regarding carboxylic acid-directed *ortho* C-H functionalisation were only made since the late 2000s and the field has been recently reviewed.¹⁰⁷,¹⁰⁸

The benefits of carboxylic acids as DGs are quite striking as they are naturally abundant and relatively easy to introduce. They can either be cleaved or further transformed *via* decarboxylative coupling reactions, often possible to perform *in situ* or in one-pot fashion.¹⁰⁹,¹¹⁰ Furthermore, the possibility to remove the group catalytically led to the development of its use as a traceless DG.¹¹¹ However, carboxylates are usually weakly coordinating to the catalyst and are often disfavoured in comparison to stronger DGs (*e.g.* pyridines, bidentate amides). They can also undergo undesired side reactions such as hydrodecarboxylation as these are also catalysed by transition metals,¹¹² which is an additional difficulty in developing carboxylic acid-directed C-H functionalisation processes.

## 4.1. C(sp²)-H activation

4.1.1. **Arylation.** Within this section, the recent advances in directed *ortho* arylation reactions are divided into: (i) arylations keeping the carboxylic acid moiety intact, (ii) arylations with carboxylates as traceless DGs, and (iii) methods in which the arylated product undergoes a consecutive ring-closing reaction with the carboxylate DG. Before 2015 arylations were widely

<figure><img src="image_26.png" /><figcaption>Scheme 6 Aldehyde-directed C-H functionalisation.</figcaption></figure>
<figure><img src="image_27.png" /><figcaption>A</figcaption></figure>

<caption>B</caption>

<caption>C</caption>

<caption>D</caption>

<figure><img src="image_28.png" /><figcaption>E</figcaption></figure>

<figure><img src="image_29.png" /><figcaption>F</figcaption></figure>

<figure><img src="image_30.png" /><figcaption>G</figcaption></figure>

<figure><img src="image_31.png" /><figcaption>H</figcaption></figure>

<figure><img src="image_32.png" /><figcaption>I</figcaption></figure>

<figure><img src="image_33.png" /><figcaption>J</figcaption></figure>

<caption>Scheme 7 Arylation with carboxylic acids as DG.</caption>

catalysed by Pd, with other metals applied only scarcely.¹⁷ Recent years showed more and more other transition metals such as Rh, Ir or Ru becoming of greater importance.

For example, the group of Gooßen developed a protocol using aryldiazonium salts as aryl sources, which was catalysed by Ir and proceeded at a mild temperature of 60 °C (Scheme 7A).¹¹³ Additionally, only a sub-stoichiometric amount of base and Ag salt was needed and acetone was used as solvent. Notably the weakly coordinating carboxylic acid controlled the regio-selectivity even if “stronger” DGs are present (e.g. *o*-acetamide). The regioselectivity was greatly influenced by steric factors. If *meta* substituted acids were the substrates, the easier accessible position was arylated exclusively and if both *meta* positions were occupied, no conversion took place. The parent benzoic acid gave a 1:1 mixture of mono- and di-arylated product. The transformation converted a wide range of different diazonium salts. However, heterocyclic salts did not react.¹¹³

Coupling with aryl halides was achieved with both Pd (Scheme 7B and C) and Ru (Scheme 7D–G). Ren (Scheme 7B) reported a selective mono-arylation with aryl iodides in water (with the use of TWEEN 20 as a surfactant).¹¹⁴ The yields were generally good to excellent. However, some sensitivity to steric hindrance in *ortho* substituted benzoic acids was observed. For instance, in comparison to 4-chlorobenzoic acid (88% yield), the 2-chloro acid reacted more slowly, and only 73% yield was reported.

Weiping Su reported another Pd catalysed arylation¹¹⁵ (Scheme 7C). The reaction used a mono-protected amino acid (MPAA) as a ligand, proceeded at room temperature and tolerated a broad range of substrates. However, this reaction was more sensitive to substitution in the *ortho* position to the acid moiety.

Even the relative small methyl group reduced the yield by 20% compared to its *para* and *meta* regioisomers. The authors stated that the formation of the palladacycle might be prevented due to steric reasons, which also explains the exclusive monoarylation of this transformation.

Ru-Catalysed approaches were investigated by several groups (Scheme 7D–F). For example, Larrosa reported an arylation using aryl iodides in *t*-BuCN as a solvent (Scheme 7D).¹¹⁶ Several different aryl iodides were used as reactants in this protocol. Generally, *para* and *meta* substituted iodides gave better yields and electronic properties seemed to have a minor influence on the reactivity. Acids substituted in *ortho* position gave usually excellent yields. Remarkably, 3,6-disubstituted benzoic acids provided the arylated products as well, despite the considerable steric hindrance. However, if *meta* substituted acids were used 3.0 equiv. of water had to be added and di-arylation became an issue. Its extent depended mainly on steric congestion of the substituents. *para* substituted acids gave the di-arylated products exclusively. The protocol was also applicable to indole carboxylic acids in various positions and even in certain cases without any protection of the indole nitrogen.

With the help of Ru catalysis, significant improvement was made in making aryl bromides and chlorides applicable for this kind of reaction. Gooßen developed a catalytic system with [Ru(*p*-cymene)Cl₂]₂ and PEt₃·HBF₄, which gave good yields with aryl bromides as substrates (Scheme 7E).¹¹⁷ The corresponding chlorides could be transformed as well, when pipecolinic acid was used as ligand instead of triethyl phosphine. Both protocols converted a broad range of different substrates. Synthetically useful was as well the possibility to protodecarboxylate the product *in situ* using a Cu catalyst. A very similar system

<figure><img src="image_34.png" /></figure>
<figure><img src="image_35.png" /></figure>

by Weix (Scheme 7F) used aryl iodides (and bromides) as substrates.¹¹⁸ Even a broad scope of heteroaryl halides was reported for this transformation. Furthermore, when 2-iodophenols were used as substrates, an additional lactone formation offered an access to benzochromenones (see also Scheme 8A). Interestingly in both protocols, ketones or amides did not act as competing DGs, which opened possibilities for consecutive C-H functionalisation.

Ackermann reported a protocol with PCy₃ as ligand and [(Ru(MesCO₂)₂(p-cymene))] as precatalyst (Scheme 7G).¹¹⁹ Arylation with the corresponding aryl bromides proceeded smoothly. Additionally, alkenes and alkynes were suitable substrates to achieve alkenylations/alkynylations similar to the transformations shown in the previous section. Both methods used NMP as solvent and K₂CO₃ as base.

All mentioned Ru catalysed protocols did not need any halogen scavenger (e.g. Ag salt) to facilitate the reaction (Scheme 7D–G). However, di-arylation could not be suppressed by neither of the protocols, which made the use of *ortho* substituted acids mandatory. This is in contrast to the Pd catalysed reactions (Scheme 7B and C). In such cases if a *meta* substituent at the carboxylic acid was used, the reactions proceeded regioselectively due to steric reasons.

In the field of oxidative C-H activations, transformations with the retention of the DG and also annulations were reported (Schemes 7H, I and 8A–C). Chao-Jun Li reported an cross-dehydrogenative Rh catalysed homocoupling of benzoic

acid derivatives.¹²⁰ The protocol was later improved to achieve heterocoupling between electron-rich and electron-poor acids (Scheme 7H).¹²¹ Another cross-dehydrogenative C-H activation developed by You¹²² used thiophene and furan derivatives as coupling partners (see Scheme 7I). The reaction was again catalysed by a Rh species and showed good FG tolerance. Notably, a subsequent intramolecular Pd catalysed oxidative coupling between the acid and the C3 position of the heterocycle gave the corresponding lactones.

Arylation could also be achieved using phenylacetic acid derivatives under Pd catalysis *via* 6-membered metallacycles. One contribution used –OH protected mandelic acid to functionalise in *ortho* position to the residue (Scheme 7J).¹²³ As expected under Pd catalysis, mono-arylation was observed and substrates with *ortho* substituents to the DG failed to react. It is noteworthy that the stereochemistry in case of a chiral substrate is completely retained.

Regarding arylations that are followed by a ring closing reaction, the already mentioned protocol developed in the group of Weix (see Scheme 7F) yielded chromenones if a hydroxy group was present *ortho* to the halide (Scheme 8A).¹²⁴ In the group of Jingsong You an oxidative Pd catalysed arylation, followed by *in situ* ring closure *via* acylation (Scheme 8B) was developed.¹²⁵

A rather unusual double C-H activation reaction also formed polycycles upon lactonization (Scheme 8C).¹²⁶ Quite interestingly, the first C-H activation is actually directed by the sulfur atom of a thioether and only at a later stage of the catalytic cycle coordination to the carboxylic acid occurred.

As previously mentioned, carboxylic acids could also be applied as traceless DGs. The first (although in a separate reaction after workup) protocol using this idea was developed by Daugulis in 2007.¹²⁷ The development towards a one-pot protocol in 2011 could be seen as the start of the quest towards the application of carboxylic acids as traceless DGs.¹²⁸ This approach is very convenient and enhances the utility of directed C-H functionalisation, since the removal of DGs can be difficult. Recent progress in the traceless carboxylic acid-directed arylations over the last years are summarized in Scheme 9A–D.

The coupling of aryl iodides with salicylic acid derivatives was achieved by the use of PdPEPPSI-IPr as catalyst (Scheme 9A).¹²⁹ Both electron-poor and -rich aryl iodides were good coupling partners in this regioselective protocol, although *meta* substituted iodides were not well tolerated, possibly due to steric reasons. Different salicylic acid derivatives could be converted with good yields. However, very electron-rich substrates gave lower yield, due to protodecarboxylation. Industrially appealing is the option to substitute the sub-stoichiometric amount of Ag salt with environmentally more benign tetramethylammonium chloride. In a previous study the same group showed that the typically required Ag salts, which are regenerating the catalyst after the catalytic cycle, can be replaced with a quaternary ammonium salt.¹³⁰

Notably, pyridine carboxylic acids could also be functionalised (Scheme 9B), which is remarkable since C-H functionalisation on electron-poor heterocycles is rarely reported.¹³¹

<figure><img src="image_36.png" /><figcaption>■ Mechanism for the coupling with thioethers</figcaption></figure>

<figure><img src="image_37.png" /><figcaption>Scheme 8 Annulation reactions.</figcaption></figure>
<figure><img src="image_38.png" /><figcaption>Scheme 9 Arylation with carboxylic acids as traceless DG.</figcaption></figure>

The protocol was applicable with retention of the carboxylic acid. However, a decarboxylative protocol (Cu catalysis) was also reported in the same contribution. A competing experiment with 6-phenylpyridine-3-carboxylic acid showed that the carboxylic acid overrules the DG ability of pyridine. The compound is arylated in 4-position (43%) and only small amounts (4%) of arylation at the phenyl moiety were observed.

Oxidative heteroarylation (mainly with thiophenes) was established with [RhCp\*Cl₂]₂ as catalyst and Ag₂CO₃ as oxidant (Scheme 9C and D).¹³²,¹³³ Both methods showed a good substrate scope, including nitriles, acetamides or halides, but differed in their use of additives and solvent.

**4.1.2. Alkylation and allylation.** The addition to maleimides with the carboxylate as traceless DG has been reported rather recently. Ackermann and co-workers used a Ru carboxylate catalyst for this transformation (Scheme 10A).¹³⁴ The reaction conditions were optimised with the support of DFT calculations. They commenced their theoretical studies with the Ru catalysed alkenylation with alkynes (Scheme 13B–D). In contrast to the already mentioned computational study by the group of Hong¹³⁵,¹³⁶ their calculations showed no significant solvent effect of this reaction. They continued the study towards the alkylation with maleimides for which they calculated also a negligible solvent effect. The reaction tolerated several FGs (CN, F, Br, I, NO₂) and also heteroaromatic acids were converted. The scope included several *ortho-* and *para*-substituted acids, which gave only one product. Additionally, one example with a phenyl residue *meta* to the acid was given. In this case, functionalisation in C6-position occurred exclusively. Additionally, also cyclohexenecarboxylic acid and different acrylic acids were convertible by this transformation (61–81% yield, Scheme 10A).¹³⁴ Baidya also used a Ru catalyst for the same transformation, obtaining very similar results regarding yields, scope and regioselectivity (Scheme 10B).¹³⁷ Interestingly with [Ru(*p*-cymene)Cl₂]₂ as precatalyst, the addition of

<figure><img src="image_39.png" /><figcaption>Scheme 10 Alkylation and allylation reactions directed by carboxylic acids.</figcaption></figure>

base is necessary. A Rh catalysed protocol was also reported (Scheme 10C).¹³⁸ This rather fast reaction also worked on substituted acrylic and heteroaromatic acids as substrates. However, no electron-deficient acids were reported. This time the addition of acetic acid to the reaction mixture was necessary. Interestingly, the three mentioned protocols differed in their need of acid or bases. Whereas in the first transformation (Scheme 10A) neither acid nor base was needed. The other two needed either base (Scheme 10B) or acid (Scheme 10C) in the reaction mixtures.

Quite interesting was an intramolecular allylation (Fujiwara–Moritani reaction) catalysed by an electron poor Rh complex (Scheme 10D).¹³⁹ Presumably, the carboxylate-directed the *ortho* C–H functionalisation.

The ketone-directed methylation reported in Scheme 2 was also effective using carboxylic acids (Scheme 10E).¹⁴⁰ This rare example of Fe catalysis proceeded under mild conditions with good FG tolerance. Furthermore, this transformation was also applicable with esters and amides.

**4.1.3. Alkenylation.** In the area of alkenylation reactions, two main reaction types can be distinguished: (i) oxidative reactions with olefins or alkynes followed by annulation to yield the corresponding lactones, typically employing Ag or Cu as oxidants (Scheme 11)¹⁴¹ (ii) secondly, oxidative couplings with olefins without annulation (Scheme 13A and E–G), and (iii) hydroarylation reactions with alkynes under redox-neutral conditions (Scheme 13B–D).¹⁴²

Major advances were made in the use of Ru catalysis and also a reaction with Co was published. Ackermann and co-workers reported a quite interesting example of a mild reaction, that used only oxygen as oxidant (Scheme 11A).¹⁴³ The transformation gave good to excellent yields with good FG tolerance at 45 °C in methanol. Importantly, unsymmetrical alkyl–aryl alkynes gave a single regioisomer placing the alkyl group in the C4 position of the final product.

<figure><img src="image_40.png" /></figure>
<figure><img src="image_41.png" /></figure>

<figure><img src="image_42.png" /><figcaption>Scheme 11 Alkenylations directed by carboxylic acids to access lactones.</figcaption></figure>

<caption>■ Mechanism for the decarboxylative cyclisation with alkynes</caption>

A Rh catalysed annulation developed by Tanaka also proceeded under very mild conditions (Scheme 11B).¹⁴⁴ However, the use of DCM made this protocol environmentally less attractive. The authors classified the used alkynes into three groups depending on their coordination ability to the catalyst and developed three different protocols accordingly. They differ in the amount of Cu salt and the use of different additives and solvent. These variations enlarge the scope of applicable alkynes and might make the protocol applicable in the synthesis of more complex molecules and can be used as a guideline for a development of specific reaction conditions. Despite the low temperature, the reaction showed limited FG tolerance on the substrates and gave regioisomeric mixtures if unsymmetrical alkynes were used. Notably, though, the reaction also worked with heteroaromatic acids and methacrylic acids as substrates.¹⁴⁴

The first carboxylic acid-directed C–H functionalisation with (mainly) diaryl alkynes catalysed by Co was reported by Sundararaju (Scheme 11C).¹⁴⁵ Different acids could be converted with good to excellent yields (61–92%). Unsymmetrical alkyl–aryl alkynes gave regioisomeric mixtures with a preference for the isomer with the alkyl residue in C4-position and the aryl moiety in C3-position of the products. Quite interestingly, if a strong chelating group such as an azaindoyl moiety was installed at the *para* position to the carboxylic acid, the directing effect was still ensured by the acid. Similar to the Rh catalysed annulation by Tanaka (Scheme 11B), the protocol also converted methacrylic acids with good yields. Notably, unsubstituted acrylic acid could also be converted, albeit with low yield (33%).

One example for the formation of isocoumarines without the use of alkynes, was reported by Ting-Bin Wen 2016 (Scheme 11D).¹⁴⁶

This protocol utilises vinyl acetates and is a rare example of a C–H functionalisation with electron-rich olefins. Both electron-rich and -poor carboxylic acids were tolerated and no di-alkenylated product was observed. The reaction proceeded smoothly with arylvinyl acetates as reactants. However, if alkylvinyl acetates were used, a five membered lactone with an exocyclic double bond (Z selective) was observed as a side product in considerable amounts (not shown).

The same Rh species gave the aforementioned 5-membered lactones as the main products, if electron-deficient olefins were used instead. Acrylic esters were transformed regioselectively with moderate to good yields into 5 membered lactones with exocyclic olefins with *E* selectivity (Scheme 11E).¹⁴⁷ Although dialkenylation did not occur, *ortho* unsubstituted acids gave usually lower conversions.

Both mentioned protocols used stoichiometric amounts of Cu or Ag salts as oxidants, which is clearly a disadvantage regarding environmental sustainability. An interesting alternative to several transformations regarding the oxidant was reported by the group of Wang.¹⁴⁸ N–O containing molecules were used as an external oxidant and might be an alternative approach to certain transformations.

A special decarboxylative annulation to six-membered lactones of α-ketoacids with Cu(OAc)₂ as oxidant was also reported under Ru catalysis (Scheme 11F).¹⁴⁹ The reported substrate scope included chloro and free hydroxy substituents on the acid moiety. However, only internal symmetric alkynes were reported (alkyl as well as aryl residues).

This reaction proceeds *via* the formation of an initial eight-membered ruthenacycle. After uptake of oxygen, incorporated
<figure><img src="image_43.png" /></figure>

in the carbonyl group of the product, carbon dioxide is released, and the catalytic Rh(II) species is reformed by oxidation (Scheme 11, bottom right).

As an example of an activation at a non-aromatic C(sp²)–H bond, the formation of α-pyranones was reported by Gogoi and co-workers (Scheme 11G).¹⁵⁰ The reaction proceeded under Ru catalysis and the β carbon of a cinnamic acid derivative was activated. Subsequent insertion of an alkyne and reductive elimination furnished the six-membered ring. This transformation converted heteroaromatic cinnamic acids as well with good yields and accepted both diaryl as well as dialkyl alkynes. However, the use of unsymmetrical alkynes gave mixtures.

Under different reaction conditions, saturated lactones can be formed instead of unsaturated ones, depending on the use of oxidant and/or the used coupling partners (alkynes, olefins) of the protocols. As can be seen in Scheme 12, *ortho*-directed alkenylations and subsequent nucleophilic attack of the carboxylate group, followed by protonation, resulted in saturated 5-membered lactones. Shishido reported a transformation with unsymmetrical internal alkynes under ZrO₂ supported Ru catalysis (Scheme 12A).¹⁵¹ Notably, the catalyst could be recycled for at least five runs and the reaction required only a catalytic amount of base. The regioselectivity was generally good. However, not a broad FG tolerance was reported.

Substantially milder reaction conditions were sufficient for the oxidative coupling with acrylates (Scheme 12B).¹⁵² Under O₂ atmosphere and a reaction temperature of 60–80 °C, bromo and iodo substituents were tolerated and no di-alkenylated product was observed. A similar cyclisation was also reported by Zhu for cyclic acrylic acids (Scheme 12C).¹⁵³ The reaction was catalysed by a Rh complex and Cu(OAc)₂ was used as oxidant. Quite interestingly, under the reaction conditions (acidic, metal salts and 120 °C) N-Boc protected substrates were converted with moderate yields without any cleavage of the carbamate.

Alkenylation without annulation and subsequent decarboxylation could be achieved with alkenes under oxidative conditions or with alkynes under redox-neutral conditions. These transformations make *meta* substituted aryls more easily accessible if an *ortho* substituted acid is used as substrate and *in situ* protodecarboxylated. In recent literature, alkenylation protocols by the Ackermann¹⁵⁴ (Scheme 13B), Hartwig/Zhao¹⁵⁵ (Scheme 13C) and Gooßen¹⁵⁶,¹⁵⁷ groups (Scheme 13D) have appeared.

<figure><img src="image_44.png" /><figcaption>Scheme 12 Alkenylation directed by carboxylic acids and subsequent annulation to alkylated lactones.</figcaption></figure>

<figure><img src="image_45.png" /><figcaption>Scheme 13 Alkenylation directed by carboxylic acids.</figcaption></figure>

All three protocols used Ru complexes that catalysed the alkenylation as well as the *in situ* decarboxylation. Ackermann also included a report of an oxidative coupling between salicylic acids and electron-poor olefins, using V₂O₅ as oxidant (Scheme 13A).¹⁵⁴ For this transformation, the FG tolerance regarding the olefin was quite good. However, the alkenylation with internal alkynes (Scheme 13B) converted also benzoic acid derivatives and was not restricted to salicylic acids.¹⁵⁴ Furthermore, examples with aryl and alkyl (also unsymmetrical) alkynes were provided. Interestingly, nitro-, fluoro- and bromo groups *ortho* to the acid were tolerated and gave moderate to good yields. Both *para* and *ortho* residues to the acid naturally gave the corresponding *meta* products. However no example of *meta* substituted acids (to potentially generate the *para* alkenylated product) was reported.

A very similar protocol by Hartwig and Zhao (Scheme 13C) demonstrated a broad substrate scope.¹⁵⁵ The same substitution pattern regarding the acid was reported with comparable yields (*ortho* and *para* substituents to COOH). As expected, *meta* substituted substrates delivered mixtures of regioisomers. However, if sterically more demanding substituents (*e.g.* –NMe₂, –iPr, –tBu)
<figure><img src="image_46.png" /></figure>

were used, the *para* substituted product (after decarboxylation) was formed regioselectively.

Interestingly, in comparison to Ackermann's protocol, nitro groups on the acid were not tolerated, but the unsubstituted benzoic acid gave a much higher yield (80% vs. 43% in Ackermann's protocol). Upon the addition of 20 mol% Cu(OAc)₂, good regioselectivity of aryl-alkyl alkynes was achieved (placing the aryl residue on the sterically less demanding position of the olefin product).

Goosën developed a similar protocol for methyl aryl alkynes (not shown)¹⁵⁷ that was tailored towards a larger substrate scope (see Scheme 13D).¹⁵⁶ Additionally, a considerably faster version under microwave irradiation was also reported. The scope for both protocols was broad and no additional additives were necessary to convert asymmetric alkynes.

Regarding the mechanism of the reported Ru catalysed alkenylation reactions, a computational study by Hong gave possible insights to the selectivity of these transformations.¹³⁵ It was shown, that the chemoselectivity (*i.e.* consecutive annulation *versus* decarboxylation) was strongly depending on the size of the ruthenacylce prior to the decarboxylation and the polarity of the solvent used.

The alkenylation of indoles was achieved *via* Rh catalysis under relatively harsh conditions, since DCM had to be heated to 100 °C (Scheme 13E).¹⁵⁸ This transformation made fluorescence-active indoles easily accessible as it gave the di-alkenylated compounds exclusively.

One example of a decarboxylative annulation was the formation of polyarenes by C–H functionalisation of diphenyl acetic acids (Scheme 13F).¹⁵⁹ The transformation was catalysed by Pd(OAc)₂ with a MPAA as ligand. First the substrate was alkenylated *via* typical carboxyl-directed C–H activation. Subsequently, the *ortho* C–H bond of the second ring was activated and an intramolecular annulation occurred. The oxidation was mediated by benzoquinone under O₂ atmosphere. Notably, this method constructed different (hetero)anthracene derivatives in a direct way.

The previously described mono-arylation of OH protected mandelic acids (see Scheme 7J) was not only accepting aryl halides but also electron poor olefins as substrates (among them one example with phosphonates) (see Scheme 13G).¹²³ More importantly, the reaction proceeded also with *N*-protected α-phenylglycine instead of mandelic acid, which enabled a fast route to unnatural amino acids. The yield of the corresponding alkenylated amino acids was generally good to excellent (62–88%).

#### 4.1.4. Alkynylation.
Alkynylation directed by carboxylates has not been extensively studied and is mostly realized with (bromoethynyl)triisopropylsilane. Zen reported two protocols (Scheme 14A and B). Protocol A involved Ir catalysis¹⁶⁰ and tolerated FGs such as OH, NMe₂ or halides. Generally, the conversion of electron-rich acids was high (76–93%). For electron-poor substrates, the yield was significantly lower (35–50%). Additionally, if both *ortho* positions to the acid were unsubstituted, di-alkynylated products were observed. The ratio of this twofold C–H functionalisation depended on the sterical demand of the remaining substituents and on the general reactivity of

the acid. Notably, phenylacetic acids were also tolerated under slightly different conditions. The reaction was also performed with unprotected indolyl- and thiophenyl-3-carboxylic acids yielding 2-alkynylated products in moderate yields (49–67%).

Protocol B, the alkynylation catalysed by [RuCl₂(*p*-cymene)]₂ showed a similar substrate scope (see Scheme 14B).¹⁶¹ The conversion for electron-poor substrates was also lower than for more activated compounds.

A similar procedure was reported by Dorel (Scheme 14C).¹⁶² This time DCE instead of an alcohol was used as solvent, a disadvantage regarding green chemistry efforts. As the protocol was also applied in a phenol-directed *peri* alkynylation, free phenols were also accepted as substrates for this protocol. Additionally, also nitro groups and unprotected aldehydes were tolerated FGs for this transformation.

Ackermann reported a transformation with a Ru carboxylate as the catalytic species (Scheme 14D).¹⁶³ In comparison to the transformations above, this protocol showed slightly better yields for electron-poor substrates. However, the reaction conditions were not as mild and di-alkynylation still remained a problem. A decarboxylative protocol was also reported. Under elevated temperatures and addition of acetic acid after the product formation, the carboxyl group was removed without the typically employed Ag or Cu salts.

One example of alkynylation/lactonisation was reported making use of terminal alkynes and Ag₂O as oxidant (Scheme 14E).¹⁶⁴ This very fast reaction gave moderate to good yields with a relatively broad substrate scope. Notably, only stoichiometric amounts of alkyne were used and the reaction gave the *Z* isomer exclusively. However, both positions *ortho* to the acid were alkenylated and the alkylated lactone was formed as a side product.

#### 4.1.5. Aminocarbonylation.
The synthesis of *meta*-substituted aromatic amides can be achieved by an *ortho* amidation and subsequent decarboxylation of benzoic acid derivatives (Scheme 15A).¹⁶⁵ This Rh catalysed transformation used

<figure><img src="image_47.png" /><figcaption>Scheme 14 Alkynylation directed by carboxylic acids.</figcaption></figure>
<figure><img src="image_48.png" /></figure>

<figure><img src="image_49.png" /><figcaption>Scheme 15 Aminocarbonylation directed by carboxylic acids.</figcaption></figure>

<figure><img src="image_50.png" /><figcaption>Scheme 16 C-Heteroatom bond formation directed by carboxylic acids.</figcaption></figure>

isocyanates to install the amide group and the carboxylate was subsequently removed using CuO. The methodology was applicable to *ortho* and *para* substituted acids, which gave the same *meta* amidated product.

Arylisocyanates could also be applied in a synthesis of cyclic *N*-aryl imides (Scheme 15B).¹⁶⁶ In this case, *α* substituted acrylic acids reacted with the isocyanates under Rh catalysis *via* a *β* vinyl C–H activation.

4.1.6. **C-Heteroatom bond formation.** *ortho*-Directed C–H functionalisation of benzoic acid derivatives with sulfonyl azides under Ir catalysis yielded *N*-sulfonyl substituted anthranilic acids (see Scheme 16A).¹⁶⁷ A one-pot procedure for protodecarboxylation (either with Pd or Cu), giving access to *N*-sulfonyl substituted anilines was also disclosed. Furthermore, also cyclic olefins were transformed under these reaction conditions.

Selenation and thiolation could be achieved by reaction with diselenides or disulfides under Ru catalysis (Scheme 16B).¹⁶⁸ The process proceeded generally to mono-chalcogenation for *meta* substituted arenes. However, apart from MOM-protected 4-hydroxybenzoic acid, *para* substituted acids were functionallyised in both *ortho* positions to the acid. Different substituted diselenides could be transformed with good yields and the protocol also tolerated diphenyl disulfides. More importantly, this method provides the possibility to synthesise chalconyxanthones *via* an intramolecular Friedel-Craft acylation by addition of triflic acid to the crude mixture after the reaction. For this annulation benzoic acids carrying halides, ethers, alkyl, and aryl groups were tolerated and also thiophene carboxylic acid was used as substrate giving good yields (58–86%) over two steps.

## 4.2. C(sp³)-H activation

Advances have been made in the *β*-C(sp³)-H activation and arylation of propionic (also *α*-amino) acids. Zhao,¹⁶⁹ Yu¹⁷⁰ and van Gemmeren¹⁷¹ all reported Pd catalysed protocols for this transformation (Scheme 17A–C).

<figure><img src="image_51.png" /><figcaption>Scheme 17 Functionalisation of C(sp³)-H bonds directed by carboxylic acids.</figcaption></figure>

Zhao (Scheme 17A) focused on the arylation of *N*-phtaloyl alanines to synthesise non natural amino acids in a one-step procedure.¹⁶⁹ Generally, the scope of the transformation regarding aryl iodides was good, and the yields reported are in the 62–90% range. The reactions covered a wide range of *para*- and *meta*-substituted aryl iodides, one example of *ortho* substitution was also reported (1-fluoro-2-iodobenzene). Notably, different substituents in the *α* position of the acids were also accepted, and gave good yields if the aryl iodide was the limiting substrate (45–75%). Interestingly, it was even possible to arylate substrates with a quaternary *α* carbon. Limitations were shown with acids substituted in *β* position as they gave only traces of the product.¹⁶⁹

The protocol developed by Yu (Scheme 17B) focused again on *N*-phtaloyl alanine as substrate.¹⁷⁰ Here instead of a MPAA a fused pyridine ligand was used. This protocol also accepted acids with a quaternary carbon adjacent to the site of activation.

An improvement regarding the generality of the method of Zhoa has been achieved with the use of another MPAA as ligand and by using a different base and Ag salt (Scheme 17C).¹⁷¹ This protocol showed a broad substrate scope regarding the propionic acid derivatives and also tolerated a quaternary centre at the *α* position to the acid. In contrast to the above method, the acid derivatives were used as limiting substrate here.

## 5. Esters as DGs

The ester group is omnipresent in natural as well as synthetic organic molecules. Furthermore, esters can be introduced or interconverted by a variety of methods and the need for the development of reliable ester-directed C–H functionalisation procedures is therefore obvious. Pioneering work was performed in the 90s by Trost¹⁷² and Murai.¹⁷³ However, esters coordinate weakly to metal catalysts, which make the development of successful protocols difficult. Therefore, not many contributions have yet been reported in the field. Compared to the free acids much fewer examples have been disclosed in the last three years, which will be discussed in the following section.
<figure><img src="image_52.png" /></figure>

## 5.1. C(sp²)–H activation

**5.1.1. Alkylation.** Mn could be successfully applied as catalyst for an alkylation reaction (Scheme 18A).¹⁷⁴ This borane promoted transformation used epoxides and methyl benzoates to furnish five-membered lactones. Different aromatic esters could be converted. Notably, the authors also showed that the protocol was applicable on more complex molecules. One example of a sugar and steroid derivative were provided. With regard to the reagent, the oxiran and arylated derivatives were also reported as effective coupling partners.

Also 2,2-diphenyloxiran was converted, albeit with low yield (23%). If the aryl residue was replaced with a *t*-butyl group the unsubstituted furanone was formed. Presumably a Meinwald rearrangement leads to the formation of formaldehyde that is incorporated into the five membered ring.

**5.1.2. Alkenylation.** Oxidative alkenylations with α,β-unsaturated olefins to alkyl phenylacetates could be achieved under Pd catalysis with MPAAs as ligands (Scheme 19A).¹⁷⁵ The protocol could also be applied to amides, Weinreb amides and ketones as DGs (see Sections 2, 6 and 7). If electron rich esters were used, the reported yields were good (52–87%). Compared to Weinreb amides, the reaction proceeded with better mono-selectivity (6:1 for ester DG in comparison to 1:2 for Weinreb amide DG on phenylacetate). The authors argued that the products were easier released by the metal species and hence di-alkenylation did not preferentially occur.

Also under Pd catalysis, Zhao and co-workers reported a similar transformation, with quite an broad substrate scope (Scheme 19B).¹⁷⁶ Ac-Gly-OH was replaced with 1,10-phenantroline as bidentate ligand, and instead of alkyl esters, they employed a 2-(1,3-dimethoxy)propyloxy handle. The authors speculated that this residue enhanced the coordination ability of the substrate (compared to methyl, ethyl or 2-methoxyethyl residues) to prevent an unselective Fujiwara–Moritani reaction and mono selectivity of the reaction (33:1) was achieved.

<figure><img src="image_53.png" /><figcaption>Scheme 19 Ester-directed oxidative alkenylation reactions.</figcaption></figure>

Notably, with this method also synthetically useful yields were reported for starting materials carrying electron withdrawing groups (60–82%). Heterocyclic esters also proved to be good substrates. Additionally different esters were converted with good yields: instead of phenyl acetates, also phenylpropionic acid esters and α substituted phenylacetates were possible substrates. Additionally, the method was not limited to acrylates but also α,β unsaturated nitriles, amides, and ketones were applicable as reaction partners.

Loh reported alkenylations of α-substituted acrylates with olefins (mostly acrylates) (Scheme 19C).¹⁷⁷ The vinylic C–H activation was catalysed by Ru and used Cu(OAc)₂ as oxidant. Different alkyl and aryl substituents were reported as possible substrates for the transformation. To achieve full conversion of the α-substituted acrylate, 2 equiv. of the coupling partner were necessary, as homodimerization of the unsubstituted acrylate was also observed. The stereoselectivity (Z/E) was usually about 9:1 and increased if a bulkier α substituent (R¹) was used as coupling partner. Regarding olefin coupling partners, α,β-unsaturated sulfones (56%) and phosphonates (22%) could be also converted.

Alkenylation reactions with consecutive annulation were also reported with ester DGs as depicted in Scheme 20.

The synthesis of indenones under Co catalysis was reported by Li (Scheme 20A)¹⁷⁸ and Zhang (Scheme 20B).¹⁷⁹ Both protocols employ [CoCp\*(CO)₂] as precatalyst and a Ag salt as additive. The method developed by Li *et al.* used additionally Zn(OAc)₂ to enhance reactivity by coordination of the metal to the ester. If the substrate carried a *meta* substituent, the regioselectivity depended on the size and ligating ability of the residue. A *meta*-methoxy ester gave a regioisomeric mixture of 1.2/1, whereas the smaller fluorine atom also coordinated to the catalyst, directing the alkyne into the more hindered position (15/1 regioisomeric ratio).¹⁷⁹

The second Co catalysed annulation (Scheme 20B) seemed to be more sensitive to the electronic effects of the aryl substituents. Activating (OMe, Me) residues led to good yields, whereas low yields were observed if esters, –CF₃ or other

<figure><img src="image_54.png" /><figcaption>Scheme 20 Ester-directed alkenylation and consecutive annulation.</figcaption></figure>
<figure><img src="image_55.png" /></figure>

electron-withdrawing substituents were present in the substrate. Different symmetrical aryl alkynes were converted in moderate to good yields (44–72%). Additionally, the authors provided one example of an unsymmetrical alkyne (methyl, phenyl). In this case the regioisomer with the phenyl group α to the carbonyl was preferred (2 : 1).

Lactones can also be used as DGs. Patel *et al.* reported on an oxidative annulation of alkynes to 2-arylbenzoxazinones (Scheme 20C).<sup>180</sup> The authors suggest the opening of the oxazinone to *N*-benzoylanthranilic acid under AgOAc/AcOH mediation. The free acid is then coordinating to the Rh catalyst to give a five membered ruthenacycle, which directs the alkyne to be incorporated into the desired position. The coordinating ability of the nitrogen in the substrates did not hinder the transformation in any way and the use of different internal alkynes (alkyl, aryl and alkoxy substituted) were demonstrated. Furthermore, it was also shown in one example that an unsymmetrical alkyne gives only one regioisomer. In this case the smaller residue was situated *para* to the carbonyl group. Different FGs on the lactone were tolerated such as halides and SMe. Annulation with 2-phenylquinolin-4-(1H)-one as substrate was also demonstrated.

Cui reported a Rh catalysed alkenylation/cyclisation directed by peroxyesters, serving as internal oxidant (Scheme 20D).<sup>181</sup> Several different peroxyesters were used in the reaction. However, only limited FG tolerance was observed. Different internal alkynes (alkyl and aryl) were also used as substrates. Additionally, also unsymmetrical alkynes were converted with very good regioselectivity (again the smaller residue is situated adjacent to the aromatic ring).

**5.1.3. Borylation.** The C–B bond is of great importance in organic chemistry, mainly due to cross-coupling chemistry. However, methods for DG assisted C–H borylations are relatively rare.<sup>31</sup>

Li reported on a N,B ligand that enables *ortho*-directed C–H borylations with esters as DGs (Scheme 21A).<sup>182</sup> In combination with [IrCl(cod)]<sub>2</sub> as precatalyst, the authors reported high yields for the C–H borylation with B<sub>2</sub>pin<sub>2</sub>. Di-borylation could be excluded if large alkoxy groups (*tBu*) were used at the ester.

Although not strictly a group-directed reaction (the ester moiety does not coordinate to the catalyst itself but to its ligand), *para* selective borylation was achieved by the group

of Chattopadhyay (Scheme 21B).<sup>183</sup> This reaction was also catalysed by Ir. The excellent *para* selectivity was achieved by non-covalent interaction between the ester moiety of the substrate and the ligand (see TS in Scheme 29B). Different aryl esters were borylated with good to excellent yields. The transformation was also applicable to electron poor and rich heteroaryls. The authors showed, that esters were necessary to direct the C–H activation, since ketones, aldehydes, and carboxylic acids were all reduced under the reaction conditions, and did not yield the desired product.

**6. Monodentate amides as DGs in C–H
functionalisation reactions**

Substituted as well as unsubstituted amides proved to be extremely valuable as DGs in C–H activation. The first example utilizing a primary amide (CONH<sub>2</sub>) in C–H activation was presented by Li *et al.* in 2012.<sup>184</sup> By now, amides are amongst the most frequently applied DGs in C–H functionalisation chemistry. The largest part of these contributions takes advantage of bidentate DGs including an amide moiety. However, these groups are treated in a separate chapter (see Section 14). Within this chapter, solely amide DGs are treated which use a mono-dentate binding mode.

Due to the plethora of examples reported since 2015 con-
tributions with great variations regarding the introduced residue
have been disclosed, and also the substrate variety is significant
including the activation of C(sp<sup>2</sup>)-H and C(sp<sup>3</sup>)-H bonds alike.
Most contributions still take advantage of precious metals, but it
can be seen that base metal catalysis is moving forward and
becomes more and more important.

**6.1. C(sp²)-H functionalisation**

6.1.1. **Arylation.** Arylation reactions are the most frequently reported transformation in C–H activation chemistry. A variety of different aryl sources can be used as coupling partner, which is also reflected in the examples for amide-directed arylation reactions displayed in Scheme 22. In contrast to alkylation reactions, the reports on arylation reactions mainly relied on a Pd species as catalyst. One exception was the Ir catalysed arylation with diaryliodonium salts published by Shi and Yuan (Scheme 22A).<sup>185</sup> In this contribution, they applied a protocol previously reported for *ortho* arylation of *O*-methyl ketoximes<sup>186</sup> to *N*-aryl-2-pyrrolidinone as substrate. FG tolerance was excellent, but electron withdrawing residues reduced the yields to the 50% range, whereas electron donating ones gave yields also &gt; 90%. On the Mes-I-Ar<sup>+</sup>OTf<sup>-</sup> species, which was used as coupling partner, also bromo and iodo were tolerated and Ar could also be thiophene or naphthalene.

The group of Kianmehr introduced arylsulfonyl chlorides as
aryl source in amide-directed *ortho* arylation (Scheme 22B).<sup>187</sup> The
reaction system was rather simple comprising of PdCl<sub>2</sub> and
Li<sub>2</sub>CO<sub>3</sub> but required 10 mol% catalyst loading. Still, yields were
high (71–96%) and the reaction gave only mono-arylated products.

<figure><img src="image_56.png" /><figcaption>Scheme 21 Ligand-assisted *ortho* and *para* borylation.</figcaption></figure>
<figure><img src="image_57.png" /></figure>

<figure><img src="image_58.png" /><figcaption>Scheme 22 Amide-directed arylation reactions.</figcaption></figure>

In fact, the presence of an *ortho* methyl group shut down the reaction completely.

A quite peculiar transformation was reported by Park and Hong. They developed an efficient strategy to build up triphenylene frameworks by using a cyclic diaryliodonium salt as aryl source, which basically resulted in *ortho* and *meta* arylation of mainly *N*-phenyl pivalamide substrates (Scheme 22C).¹⁸⁸ The reaction required the presence of a substituent in one of the *ortho* position for obtaining high yields (71–95%), since otherwise only a maximum of 30% was obtained. Switching to *N*-aryl-2-pyrrolidinone as substrate allowed a two-fold reaction with the iodonium salt species leading to heptacyclic products in moderate yields.

Dimerisation of benzamides towards 5*H*-dibenzo[c,e]azepine-5,7(*6*H)-diones was reported by the group of Bao (Scheme 22D).¹⁸⁹ Since the reaction required a relatively strong oxidant to proceed, the authors favoured a Pd(II)/Pd(IV) catalytic cycle, however, they did not carry out mechanistic investigations. Regarding the benzamide substrate, *meta* and *para* substitutents were tolerated (Me, OMe, tBu, F, Br, Cl) but *ortho* substitution shut down the reaction.

Kumar and co-workers used primary phenylacetamides as substrates, which suggested that in this case not a 5-membered, but a 6-membered palladacycle was involved in the catalytic cycle.¹⁹⁰ In this case, aryl iodides were the coupling partners, which allowed the presence of bromide in the substrate (Scheme 22E). Otherwise, mainly “inert” FGs were used such as Me, OMe, Cl, F and NO₂. Noteworthy was the good selectivity for mono-arylation and a gram scale experiment which showed the potential for scale up.

Tan and co-workers focused on the arylation of 3-carboxamido thiophene and aryl bromides (Scheme 22F).¹⁹¹ The amide nitrogen contains a pentafluorphenyl. Arylation took initially part in position two and in some cases 2,4-diarylated compounds were

<figure><img src="image_59.png" /><figcaption>Scheme 23 Tandem amide-directed arylation-oxidative coupling.</figcaption></figure>

observed (maximum 15%). Also heterocyclic bromides could be used as coupling partner and it has to be mentioned that 2 equiv. of halide were applied in order to get good yields (51–87%, 15 examples). Besides the thiophene substrate, in one case also a 3-furancarboxamide was arylated using phenyl iodide (59% mono, 17% diarylation). Additionally, gram scale experiments were carried out as well and starting from 2-aryl-3-thiophencarboxamide, bromination conditions for selectively brominating either in position 4 or 5 were disclosed.

A cascade of C(sp³)-H and C(sp²)-H activation has been reported by Stamos and Yu (Scheme 23 see also Section 15.5).¹⁹² According to the proposed catalytic cycle, the first step was a pyrazole-directed arylation of a *t*-butyl group (Scheme 23, blue bond formed), whereas the second step was an oxidative coupling between position 4 of that same pyrazole and the introduced aryl ring (Scheme 23, red bond formed). This C–H activation step of the pyrazole was indeed amide-directed. Both steps were Pd catalysed and could be run under air, not uncommon for an oxidative coupling step. The range of FGs on the aryl iodide was remarkable and yields between 45–78% were obtained. The *t*-butyl group could be substituted for other quaternary centres, whereas the arylation always took place at a methyl group.

**6.1.2. Alkylation and allylation.** Alkylation reactions are generally less frequently reported as arylation reactions. Still, a series of interesting alkylation reactions has been reported using quite a variety of alkyl sources.

The group of Glorius reported Co catalysed allylation using methyl allyl carbonate as the allyl source (Scheme 24A).¹⁹³ Besides using pyrimidine as DG, *N*-alkylated amides were applied as well and it was shown that mono- and di-alkylated amides worked as well and that steric bulk on the amide was well tolerated, including a *t*-butyl group. Besides substituted benzamides, also acrylamides and 3-furan- and 3-thiophencarboxamides could be allylated as well. In most cases yields were in the 60–80% range.

Another allylation procedure was reported by Yan, this time using allyl bromides and a Rh catalyst (Scheme 24B), which made the procedure less attractive but the advantage was the commercial availability of the Rh catalyst, which is unfortunately not yet the case for many Co species.¹⁹⁴ Additionally, the reaction was carried out at room temperature. Yields were in a preparatively useful range (34–93%) but in this case also di-allylated products were formed. Further cyclisation of the allylated products to tetrahydroisoquinolin-1-ones was reported as well.

A significant challenge are typically methylation reactions since the often applied alkyl sources, namely olefines, are not an option and alternative methyl sources need to be found. Ilies and Nakamura have published a Mn catalysed protocol using
<figure><img src="image_60.png" /></figure>

<figure><img src="image_61.png" /><figcaption>Scheme 24 Amide-directed alkylation and allylation reactions.</figcaption></figure>

MeMgBr as alkyl source, which worked with remarkable low catalyst loading (0.01–1 mol%) (Scheme 24C).¹⁹⁵ Amongst the advantages of this protocol was the simplicity of the catalyst, $MnCl_2·LiCl$ without any ligand, the mild conditions, and high TONs. The use of Grignard species as methyl source naturally raised the question of FG tolerance. Remarkably, even bromide was tolerated. A disadvantage was again the formation of mono- and di-methylated products in case the substrate allowed a second methylation.

The group of Ackermann reported alkylation using methyl vinyl ketone as alkyl source, introducing a butanone side chain on an aryl ring (Scheme 24D).¹⁹⁶ The reaction was Ru catalysed and required MesCOOH (1 equiv.) and MesCOOK (0.3 equiv.) as additives but water could be used as solvent. Yields were preparatively useful (45–81%) and electron donating and electron withdrawing substituents on the aryl ring are tolerated as well as bromine. Further cyclisation of the initial products to 2-methylquinolines was reported as well.

An Ir-catalysed reaction of aromatic amides with diazonalonates has been reported by the group of Wang (Scheme 24E).¹⁹⁷ Using dimethyl diazonalonate led to the formation of products with both ester moieties still in place. Switching to methyl t-butyl malonates led to methyl esters of arylacetic acids, since the t-butyl group was cleaved under the reaction conditions with subsequent decarboxylation. The reaction worked also on electron rich heterocycles and tolerated the presence of halides (F, Cl, Br, I) and series of other FGs without significant influence on the yields (typically > 80%!).

Very recently, they expanded this method, most importantly to methylation reactions as well.¹⁹⁸ In this case the alkyl source was a sulfonium salt and stoichiometric amounts of $Cu(OAc)_2$ were required. Yields were mediocre in most cases, but still it was one rare example for a methylation reaction (not shown).

N-Substituted succinimides have been used as alkylation source in the broader sense as well. Naturally, this allowed only the introduction of a very specific group. Prabhu and co-workers showed that this transformation works under Ru catalysis and several additives (Scheme 24F).¹⁹⁹ The FG tolerance

was not that broadly investigated, but iodine was tolerated which was important for further elaboration of the scaffold. In competition experiments it was shown that in presence of other potential DGs (ketone, aldehyde, acid, ester) it was still the amide which exhibited the directing effect.

The group of Novak disclosed a Pd catalysed protocol for the trifluoroethylation of N-aryl-anilides with an iodonium salt (Scheme 24G).²⁰⁰ The introduction of fluorine moieties onto molecules is of course highly interesting in context of medicinal chemistry projects and drug development. The protocol showed high yields (typically > 70% and up to 95%) and remarkable FG tolerance. Most remarkable, esters, boronic acid esters and $NO_2$ were tolerated. In the presence of an acetyl group it was still the amide which directed the trifluoroethylation.

A special case was the enamide directed α-alkylation with unactivated alkenes reported by Dong (Scheme 25A).²⁰¹ As mentioned, the starting material was a cyclic enamide, which was first alkenylated. Adding afterwards hydrochloric acid to the reaction mixture cleaved the DG *in situ* and delivered α-alkylated ketones as products. With unactivated olefins, the new C–C bond is formed towards the C2 position of the olefin substrate, and not to C1 as it is the case with often applied acrylate species. Only few FGs were present in the starting materials and yields ranged from 20–73%.

<figure><img src="image_62.png" /><figcaption>Scheme 25 Amide-directed enamide and aldehyde alkylation.</figcaption></figure>
<figure><img src="image_63.png" /></figure>

The group of Willis reported that also a formyl C–H bond can be alkylated and alkenylated.²⁰² The carbonyl oxygen of the amide was in this case involved in the formation of an intermediate rhodacycle using β-amido aldehydes as substrates (Scheme 25B). However, the amide DG can be replaced by a keto- or ester group as well. FG tolerance on the alkene was quite good (Br, OH, acetal, ester, carbamate, aryl) and frequently yields >90% were observed.

A special case are alkylation reactions in which the alkylated product immediately cyclised under the applied reaction conditions to heterocyclic ring systems. Several such examples have been reported in the last three years. Patel and Borah reported the synthesis of oxindoles from acetanilides and Ir(III) catalysis.²⁰³ The diazo derivative of Meldrum's acid was the required reaction partner (Scheme 26A). Initially, the acid was attached with its C2 carbon to the *ortho* position of the amide function. Subsequent proton induced (formed from NaOAc) intramolecular cyclisation with the amide group delivered the target compounds.

Huang and co-workers reported an allylation-cyclisation sequence to tetrahydroquinoline derivatives.²⁰⁴ Overall, they carried out a complex four component reaction using aniline derivatives, an anhydride (in most cases acetic anhydride), allylic alcohol, and 2,2,2-trifluoroethanol (Scheme 26B). The anhydride and the aniline derivative form *in situ* the corresponding amide, which directed the allylation with the allylic alcohol leading to a 3-arylpropanal derivative. Next, this intermediate cyclised to a 2-hydroxy-N-acetyl tetrahydroquinoline derivative and after a final etherification with trifluoroethanol (or other alcohols) the desired products were obtained. Due to this complex sequence there was a larger variation in yields (41–91%) but excellent functional group tolerance was observed.

Kapur and co-workers reported a similar sequence, but in absence of a second alcohol.²⁰⁵ Hence, the etherification did not occur but elimination of water and further aromatisation to quinoline derivatives (Scheme 26C). More than 30 examples have been reported in this contribution.

<figure><img src="image_64.png" /><figcaption>Scheme 26 Amide-directed alkylation/allylation-cyclisation sequences.</figcaption></figure>

The group of Wei Zeng reported an alkylation/annulation sequence towards pyrimido[1,6-a]indole-1(2H)-ones under [Cp*RhCl₂]₂ catalysis with α-diazocarbonyl reagents (Scheme 26D).²⁰⁶ The method gave good access to this scaffold with the majority of examples in yields >70%. In the indole substrate Br and COOMe was tolerated amongst other less reactive FGs. The scope in R¹ was mainly limited to carboxylic acid esters whereas R² seemed to tolerate a wide range of alkyls and aryls.

### 6.1.3. Alkenylation.
Alkenylation reactions are of significant importance since the introduced double bond can be used as handle for subsequent elaboration of a scaffold. Often, the alkenylated product is not the final target, but *in situ* further transformed *via* cyclisation reactions to different heterocyclic products. Such examples will be treated in the following section. Here, only procedures will be discussed in which no further reactions took place and the alkenylated product was isolated.

Alkenylation using vinyl acetate was reported by Zhang and Wen under Rh catalysis.²⁰⁷ This Fujiwara–Moritani reaction required only 2.5 mol% [Cp*RhCl₂]₂ as catalyst and was carried out under air (Scheme 27A). Hence, 0.3 equiv. of Cu(OAc)₂ were sufficient to get to good yields. Many FGs were tolerated including bromine. *ortho* and *meta* substituted N-arylacetanilides gave only mono-alkenylated products, however, the unsubstituted or *para*-substituted derivatives gave mixtures of mono- and di-alkenylated products. The reaction was also carried out on a 7 mmol scale and it was shown that the products can be further cyclised to N-acetylindoles by adding 6 M HCl.

Huang and Zhao showed that acrylates could be used to alkenylate N-acylindolines and tetrahydroquinolines in positions 7 and 8, respectively, under Ru catalysis (Scheme 27B).²⁰⁸ *ortho* alkenylation of N-arylpivalamides was also demonstrated under the same conditions. Besides acrylates, many other olefinic substrates carrying an electron withdrawing group could be

<figure><img src="image_65.png" /><figcaption>Scheme 27 Amide-directed alkenylation reactions.</figcaption></figure>
<figure><img src="image_66.png" /></figure>

used as olefin source as well. Generally, good to excellent yields (typically 70–95%) were obtained.

Shortly thereafter, Xu and Pan showed another remote alkenylation, this time of indazoles and under Rh catalysis in which they also demonstrated the cleavage of the DG (Scheme 27C).²⁰⁹

An interesting example was reported by Yoshino and Matsunaga. In this example, the DG actually migrated from the indole nitrogen to the C2 carbon of the introduced olefin group (Scheme 27D).²¹⁰ Usually, proto demetallation would deliver the *N*-acylated 2-alkenylated indoles using alkynes as olefin source. Slowing down this proto demetallation step was key in order to allow DG migration. [Cp\*Co\textsuperscript{III}(CH₃CN)₃](SbF₆)₂ was identified as best performing catalyst and regarding the DG, morpholine amide performed significantly better as compared to other *N*-disubstituted amides. Good FG tolerance was observed and yields were frequently above 70% (up to 99%).

A second Co catalysed protocol was reported by Ellman (Scheme 27E).²¹¹ The first step was again an alkenylation reaction with a terminal alkyne. However, in the presence of NXS (mainly NIS), the olefine moiety was immediately halogenated. Mainly thiophene substrates were used (see Scheme 27E), but furan and pyrrole were also tested in single examples. The reaction performed at low temperature (40 °C) and the halide was incorporated on the C2 of the former alkyne with high regioselectivity.

If *N*-arylbenzamides were the substrates, the question arises whether the *N*-aryl or the *C*-aryl ring gets functionalised. Wang *et al*. found that in a [Cp\*RhCl₂]₂ catalysed alkenylation reaction, the key to control the alkenylation side was the presence of a non-coordinating anion, here introduced by AgOTf (Scheme 28).²¹² Initially, *N*-tolylferrocencarboxamide was used in a test reaction and in the absence of AgOTf the ferrocene moiety was alkenylated exclusively with methyl acrylate. When adding 20 mol% AgOTf the regioselectivity switched completely and only the tolyl ring was alkenylated. This arylation of the *N*-aryl ring was then further explored with *N*-aryl- *C*-ferrocenyl substrates as well as with *N*-aryl- *C*-aryl substrates.

<figure><img src="image_67.png" /><figcaption>Scheme 28 Amide-directed alkenylation with acrylates.</figcaption></figure>

<figure><img src="image_68.png" /><figcaption>Scheme 29 Amide-directed alkenylation of non-aromatic C(sp²) centres.</figcaption></figure>

C-Ring alkenylation with methyl acrylates led to isindolinones due to intramolecular cyclisation.

So far, only alkenylation of aromatic systems has been discussed. However, also olefinic systems have been alkenylated *via* amide-directed C–H activation. Zhang and Zhong reported two protocols for α,β-unsaturated amides, naturally in the β-position giving rise to products of 2Z configuration.²¹³,²¹⁴ In their first contribution (Scheme 29A), allyl acetate was the reaction partner, leading to (2Z,4E)-dienamide products. As could be expected, the allylated byproduct was formed as well but under the optimised conditions a selectivity of 95:5 or better for the desired product was reached. Also for the 2Z,4E configuration the reaction was not perfect, giving Z/E selectivities between 72:28 and 92:8 with typical yields in the 60–70% range. The second protocol used internal alkynes as alkenylation agent (Scheme 29B), which naturally eliminated the possibility for allylated byproducts giving 2Z,4Z configured products preferentially (frequently with >99:1 selectivity, depending on the nature of R³).

Also Bouillon and Poisson contributed to this field (Scheme 29C). In their case, 2-bromo-3,3,3-trifluoropropene was the coupling partner and gave the 2Z configuration.²¹⁵ This is a rare case in which a bromide is the leaving group since typically oxidative couplings (*e.g.* with acrylates) are predominant. Position 2 of the substrate was mainly substituted by aryl groups and substituents on the aryl moiety had only little impact on the yield (typically ~65%). Interestingly, when this position was not substituted, *i.e.* *N*,*N*-diisopropylacrylamide was used as the substrate, the configuration was *E* and not *Z*. The authors suggested that a Pd catalysed isomerisation might take place rapidly in this case.

The group of Willis disclosed an impressive amount of work on the C–H activation of aldehydes, mainly directed by amides but also examples for keto- and acid ester direction were reported.²⁰² They showed that switching between two Rh catalysts they could either get the linear (Scheme 30A) or the branched olefin (Scheme 30B) when terminal alkynes were the coupling partner. Linear products were obtained in excellent yields, frequently >90%. However, relatively few FGs were present. For the branched products, yields were a bit lower and the branched: linear ratio varied between 2:1 and 17:1. Using olefins as coupling partner alkylated products were obtained (not shown).
<figure><img src="image_69.png" /></figure>

<figure><img src="image_70.png" /><figcaption>Scheme 30 Amide-directed aldehyde olefination.</figcaption></figure>

**6.1.4. Alkenylations with further cyclisation.** This section focuses on examples where the alkenylated compound is immediately further transformed to a cyclised product. In such reactions, the amide DG is sometimes also involved in the cyclisation and one or more atoms end up in the cyclised products. The most common source for the olefin moiety in such alkenylation reactions are alkynes or acrylates, respectively derivatives thereof.

Several protocols have been reported in which the final product is a quinoline. In all these cases, the amide was attached *via* its nitrogen to the aryl moiety and the amide nitrogen ends up as the heterocyclic nitrogen. Within a few weeks, the groups of Li (Scheme 31A)²¹⁶ and Glorius (Scheme 31B)²¹⁷ reported Co catalysed protocols for this type of quinoline synthesis. The conditions are quite similar, Li used [Cp\*CoCl₂]₂ as catalyst whereas Glorius used [Cp\*CoI₂]₂ both in DCE as solvent and a Ag salt as additive. Li's protocol required 1 equiv. AgNTf₂ whereas Glorius used 20 mol% AgSbF₆ combined with 10 mol% Fe(OAc)₂ at slightly higher catalyst loadings. The yields and the substrate scope in both protocols were comparable as both reported that halides (amongst other FGs) were well tolerated. Typically, symmetrically substituted alkynes were used as coupling partners and in the few cases where unsymmetrically substituted alkynes were used, mixtures of regioisomers were obtained. In most examples acetamide was the DG, but also examples with other alkyls were reported to work, unless steric bulk was too large. In two examples, Glorius showed that addition of 1 equiv. Ag₂O gave N-acylated indole products (Scheme 31C) but better yields for this product class were obtained with urea derived DGs (see Section 9).

If the amide DG was attached to the aryl system the other way round, *i.e.* *via* the carbonyl carbon, reactions with alkynes led upon cyclisation to isoquinolones (or a related system, depending on the specific substrate). Chuang and Chen reported such a protocol under quiet environmentally benign conditions, since the reaction could be carried out in water under air with a Rh catalyst (Scheme 31D).²¹⁸ Again, symmetric aryl-aryl alkynes were the coupling partners in most cases but in three examples aryl-alkyl alkynes were used. The regioselectivity was actually quite good (87:13 up to 98:2) and the aryl ring always ended up in position 3 in the main product. One exception was the reaction of N-methyl-4-methoxybenzamide and N,N-dimethyl-3-phenyl-prop-2-yn-1-amine, where the regiochemistry was reversed and the aryl moiety was exclusively in position 4. A related transformation on thiophenecarboxamide substrates was reported by Miura and coworkers (not shown).²¹⁹

Similar, but Ru catalysed cyclisations have been disclosed by the groups of Swamy²²⁰ and Urriolabeitia (not shown).²²¹

<figure><img src="image_71.png" /><figcaption>■ Proposed mechanism for the deacylative coupling with alkynes</figcaption></figure>

<figure><img src="image_72.png" /><figcaption>Scheme 31 Amide-directed alkenylation-cyclisation sequences.</figcaption></figure>

The former one used chromene-3-carboxamides as substrates, the latter one various heterocyclic amides. Hence, in both cases a pyridinone ring was annulated to another heterocyclic ring, giving access to interesting scaffolds.

Tian and Van der Eycken published an intramolecular variant of this type of transformation (Scheme 31E).²²² This allowed them the synthesis of polycyclic systems which occurred in natural products as well. In their paper, they applied this method for building up a variety of polycycles in good to excellent yields, and also demonstrated the synthesis of two natural products, rosettacin and oxypalmatine.

When using acrylates instead of alkynes as the olefination reagent, isoindolin-1-ones are the resulting products as demonstrated by Lu and Yu (Scheme 31F).²²³ The olefinated product could be isolated only in a few cases (*e.g.* with N-C₆F₅-2-furancarboxamide as substrate or when styrenes were used as olefinic coupling partner instead of acrylates) and mainly spontaneous cyclisation to the isoindolin-1-ones *via* base mediated 1,4-conjugate addition was observed. Typical yields were in the range of 80–93%.
Review Article

Chem Soc Rev

<figure><img src="image_73.png" /><figcaption>Scheme 32 Miscellaneous amide-directed reactions.</figcaption></figure>

**6.1.5. Miscellaneous C–C bond forming reactions.** In this section, all C–C bond forming reactions which do not fit in any previous section are summarized.

*ortho* acylation of *N*-aryl acetamides with aldehydes was reported by Novak and co-workers (Scheme 32A).<sup>224</sup> They found that the presence of a catalytic amount of *B*(C<sub>6</sub>F<sub>5</sub>)<sub>3</sub> had a beneficial effect on catalysis and a series of aryl–aryl ketones were synthesized. Using aliphatic aldehydes, the yields were generally lower but overall there was a high variance of yields. Alternatively to aldehydes, *α*-oxocarboxylic acids can be used as acyl source in a decarboxylative reaction. Again *Pd(OAc)<sub>2</sub>* is used as catalyst in presence of an oxidant, in this case *K<sub>2</sub>S<sub>2</sub>O<sub>8</sub>* (not shown).<sup>225</sup>

Carboxamidation of enamides by isocyanides was reported by Liang and Luo (Scheme 32B).<sup>226</sup> So the amide-directed the introduction of another amide group at a terminal double bond. Fair to good yields were obtained and also good FG tolerance in this *Pd(OAc)<sub>2</sub>* catalysed protocol was observed.

The protocol reported by In Su Kim is according to the proposed mechanism a C–H alkylation in the first step.<sup>227</sup> However, this product was not isolated but a double bond migration occurred and hence this example was displayed in this special section (Scheme 32C). Acrylamides were the substrates and maleimides the coupling partners, which led to quite unusual but interesting product structures. With the optimized protocol ([Cp\*RhCl<sub>2</sub>]<sub>2</sub>, AgSbF<sub>6</sub>, PivOH) almost two dozen examples were reported in low to excellent yield range. The high yields (also >90%) were obtained with acrylamide derived substrates but other types of substrates performed significantly worse.

Finally, a peculiar cyclopentenylation reaction has been reported by Radhakrishnan and co-workers (Scheme 32D).<sup>228</sup> The reaction required a specific type of bicyclic diaza olefin and hence its utility was limited to very specific examples.

**6.1.6. Halogenation.** So far only C–C bond forming reactions were presented and these are also the majority of contributions. Starting from this section, also other transformations are discussed.

<figure><img src="image_74.png" /><figcaption>Scheme 33 Amide-directed halogenation reactions.</figcaption></figure>

Halogenation reactions *via* directed C–H-activation are of particular interest since they can be used to override the directing effects of substituents present in the substrate. Mück-Lichtenfeld and Glorius developed an *ortho* chlorination protocol of benzamides using a Rh catalyst (Scheme 33A).<sup>229</sup> Interestingly, often applied NCS did not work but trichloro-isocyanuric acid (TCC) or 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) in combination with 2-trifluoromethylpyridine as activator. The most interesting examples were of course in which the chlorination was directed at the *meta* position compared to a usually *ortho/para* DG (and of course *ortho* to the carboxamide group) such as methoxy or methyl.

Kapur and Das showed that under Pd catalysis, Weinreb amides and *N*-acylanilines could direct NXS promoted halogenation in their *ortho* positions (Scheme 33B).<sup>230</sup>

A similar transformation but with a Pd@MOF nanocomposite catalyst was reported by Martin-Matute and co-workers. The work was mainly dedicated to pyridine-directed halogenation, but also amides worked and recyclability of the catalyst was demonstrated (not shown).<sup>231</sup>

**6.1.7. C–O bond formations.** *N*-Sulfonylbenzamide-directed trifluoroethoxylation was reported by Ji and Li.<sup>232</sup> Since the sulfur was not involved in the directing effect, this example was still treated in the amide section (Scheme 34A). *Pd(OAc)<sub>2</sub>* was used as catalyst and PhI(OAc)<sub>2</sub> as oxidant. Amongst other FGs, bromine was tolerated and typically yields in the 60% range were obtained. Application of the method in the synthesis of the drug flecainide was demonstrated as well.

C8-Triflation of naphthalenes was developed by Xiao and Fu (Scheme 34B).<sup>233</sup> The optimised reaction conditions turned out to be quite complex since besides 10 mol% *Pd(OAc)<sub>2</sub>* also 0.5 equiv. benzophenone (BP), 1.2 equiv. TfOH, 0.8 equiv. TMSOTf and 2 equiv. *N*-fluoro-1,3,5-trimethylpyridinium triflate reagent were required giving moderate to good yields.

<figure><img src="image_75.png" /><figcaption>Scheme 34 Amide-directed C–O bond forming reactions.</figcaption></figure>

<figure><img src="image_76.png" /></figure>
<figure><img src="image_77.png" /><figcaption>Scheme 35 Amide-directed C-N bond forming reactions.</figcaption></figure>

Rh catalysed acyloxylation was reported by Xu and Li (Scheme 34C).²³⁴ The publication focused mainly on heterocyclic DGs but included also a table of amide-directed examples. Yields around 60% were typical.

Additionally, Chakraborti and co-workers developed a Pd catalysed hydroxylation protocol which they mainly applied to heterocyclic DGs (see Section 15.9).²³⁵ However, five examples of amide direction were reported but only three of them gave good yield (not shown).

**6.1.8. C-N bond formation.** Sukbok Chang and co-workers reported an unusual example of amide-directed C-H activation (Scheme 35A).²³⁶ The group they introduced was actually again an amide, which in turn could direct another amidation and so on and so forth. Overall iterative amidation was reported with dioxazolones as amidating reagent. Starting from *N*-phenyl pivalamide, the penta-amidated product could be obtained exclusively when 6 equiv. dioxazolone were used. The hexamidated product was never observed, most likely due to steric reasons.

The introduction of amine groups is a particular challenge in C-H activation chemistry. One example was disclosed by Sun and Yu using *N*-C₆F₅-benzamides and secondary dialkylamines as coupling partners (Scheme 35B).²³⁷ Hence, only tertiary amines were obtained. Switching to anilines as coupling partners, secondary *N*,*N*-diarylamines were the products. Yields are generally good in this [Cp\*RhCl₂]₂ catalysed method and FGs are tolerated to a relatively good extend.

## 6.2. C(sp³)-H activation

The activation of C(sp³)-H bonds is typically more challenging than activation of their C(sp²)-H counterparts. Not surprisingly, much less work has been published on this topic in recent years. In fact only three amide-directed examples (*i.e.* mono-dentate amides!) have been reported all coming from the lab of Jin-Quan Yu.

The first one dealt with arylation of methylene groups in β-position to the CONH(4-CF₃-C₆F₄) DG (Scheme 36A). In this case, even an enantioselective method was developed using a chiral *N*-acetyl protected 2-aminoethyl quinoline (APAQ) as ligand.²³⁸ They obtained e.r. of typically 95:5 using Pd(OAc)₂ as catalyst and aryl iodides as aryl source. Good FG tolerance and yields between 45-89% were reported. In a second contribution enantioselective alkenylation and alkynylation reactions were also reported (not shown).²³⁹

The second contribution reported a Pd catalysed borylation with B₂pin₂ as coupling partner (Scheme 36B).²⁴⁰ Methyl or

<figure><img src="image_78.png" /><figcaption>Scheme 36 Amide-directed C(sp³)-H functionalisations.</figcaption></figure>

methylene groups in β-position were borylated whereas the less sterically demanding was favoured (CH₃ over CH₂) in cases where there was competition. Noteworthy, also saturated carbocyclic systems (C3–C7) were successfully borylated.

# 7. N-Alkoxy- and Weinreb amides

Besides CONH₂, CONHR and CONR₂ amides, also *N*-alkoxy amides *i.e.* Weinreb amides have been used as DGs, however less frequently. Not surprisingly, relatively similar catalytic systems as compared to ordinary amides are applied also in this case and also the types of reactions reported show a large overlap with the examples in Section 6.

## 7.1. Arylation

Only two examples for arylation reactions of *N*-alkoxybenzamides have been reported in recent years. Bhanage and co-workers used anilines as aryl source, which were *in situ* converted to the corresponding diazonium salts (Scheme 37A).²⁴¹ After the initial C-H activation and arylation, the alkoxyamide actually directs a second C-H activation on the previously introduced aryl ring and delivers phenantridinones as the final products after reductive elimination. Mild reaction conditions and good to excellent yields (57–91%) are the main advantages of this protocol. Additionally, halogens (F, Cl, Br) are tolerated on the *N*-alkoxybenzamide substrate.

Land and You reported another arylation protocol, this time of *N*-aryloxyacetamides, under Rh catalysis. In this case, oxidative coupling between the position 2 of azoles and benzoazoles was realized with typical yields >70% (Scheme 37B).²⁴² Mainly oxazoles and benzoxazoles were applied but one example with benzothiazole and one with *N*-methylbenzimidazole was reported as well. Under the applied reaction conditions, the *N*-aryloxy amide was N-O cleaved and overall *ortho* arylated phenols were obtained as the products.

Jin-Quan Yu and co-workers reported a C(sp³)-H arylation catalysed by simple Pd(OAc)₂ and 2-picoline as ligand, which led to mono-arylation products (Scheme 37C).²⁴³ These monoarylated products could be subjected to a second arylation when a different ligand, namely 2,6-lutidine was used (Scheme 37D). The substrates applied were typically enantiopure and it was demonstrated that the stereocenter was not compromised by the reaction conditions. After the second arylation step, the

<figure><img src="image_79.png" /></figure>
Review Article

<figure><img src="image_80.png" /><figcaption>■ Mechanism of the C(sp²)-H arylation with anilines</figcaption></figure>

<figure><img src="image_81.png" /><figcaption>■ C(sp³)-H arylation</figcaption></figure>

<figure><img src="image_82.png" /><figcaption>Scheme 37 Arylation reactions directed by *N*-alkoxy and *N*-aryloxyamides.</figcaption></figure>

products were obtained in d.r. >20:1. Additionally, also the conversion of the *N*-methoxyalkanamide to a methyl ester was demonstrated and could be carried out in a single operation, again without compromising the stereocenter. Aryl- and hetero-aryl iodides were the applied coupling partners and the yield range was relatively large spanning from 32–91%. Excellent FG tolerance was reported.

## 7.2. Alkylation and allylation

The group of Huang reported on the alkylation of *N*-methoxybenzamides using alkyl iodides as coupling partners (Scheme 38A).²⁴⁴ The reaction was mono-selective for substrates carrying a substituent already in *ortho*- or *meta*-position. In case of *para* substituted compounds or the parent *N*-methoxybenzamide, mixtures of mono- and di-alkylated products were obtained. On average, the mono-alkylated product was favoured in a 6:1 ratio, which is remarkable considering the large excess of iodide (6 equiv.). A weakly coordinating ligand was important for achieving this degree of mono-selectivity. Amongst others, bromine as FG was well tolerated in this Pd(OAc)₂-catalysed protocol.

<figure><img src="image_83.png" /><figcaption>Scheme 38 *N*-Alkoxyamide-directed alkylation/allylation reactions.</figcaption></figure>

Notably, *N*-methylbenzamide gave the alkylated product only in 17% yield, whereas the *N*-methoxybenzamides gave products in the 60–90% range.

Huang, Li, and Wang disclosed a Rh(III)-catalysed allylation protocol using 2-vinylcyclopropane-1,1-dicarboxylate (or related compounds) as allyl source (Scheme 38B).²⁴⁵ The reaction showed excellent FG tolerance (including Br, I, NO₂, CN, COOMe) and yields around 80%. A large set of examples was reported and the products showed good *E/Z* selectivity (5:1 in the worst case, often ~20:1).

The group of Huang reported the synthesis of dihydroisoquinolinones *via* a Pd(OAc)₂ catalysed alkylation-cyclisation sequence (Scheme 38C).²⁴⁶ Initially, di-*t*-butyl peroxide was the alkyl source and the reaction proceeded smoothly in cyclohexane, unfortunately requiring 25 equiv. of TFA. Notably, if *N*-alkyl- or *N*-arylbenzamides were used, the reaction was inefficient, whereas most examples for *N*-alkoxybenzamides gave a yield ~80%. By adding 2 equiv. of K₂S₂O₈ to the reaction mixture, the peroxide could be replaced with a tertiary alcohol. The reaction with *t*-butanol gave essentially the same yield as with the corresponding peroxide. In cases were one methyl group was replaced by a longer alkyl chain, cyclisation occurred either to the methyl, or the other alkyl group leading to mixtures of products.

## 7.3. Alkenylation

Moving to alkenylation reactions, several more examples as compared to alkylation reactions were reported. They can be clustered into reactions in which the alkenylated product is isolated as the target molecule, and in examples in which the alkenylation is followed by a cyclisation step to an *N*-containing heterocycle, without isolation of the intermediate product.

Kapur reported pure alkenylation using cyclic aromatic Weinreb amides as substrates.²⁴⁷ The reaction was Ru-catalysed and acrylate or styrene derivatives were used as alkene sources (Scheme 39A). A wide range of electron withdrawing groups on the olefin were accepted, but yields were typically only in the 41–73% range. Cu(OAc)₂·H₂O was used as oxidant and AgSbF₆ as additive. In the end, the authors demonstrated typically further transformations of Weinreb amides and converted them into an aldehyde or ketone moiety.

<figure><img src="image_84.png" /></figure>
<figure><img src="image_85.png" /></figure>

<figure><img src="image_86.png" /><figcaption>Scheme 39 N-Alkoxy- and N-hydroxyamide-directed alkenylation reactions.</figcaption></figure>

A special case is the reaction with propargylic alcohols as coupling partners. Ma and co-workers showed that in this case an allene moiety was attached at the *ortho* position to the *N*-methoxybenzamide DG (Scheme 39B).⁶³ The most remarkable feature of this transformation was the fact that in case of chiral propargylic alcohols, the allene products are formed in ees between 94–98%. It has to be mentioned that the reaction required long reaction times, typically 72 hours but delivered typical yields ~70%. Furthermore, the intramolecular cyclisation of the products to several types of heterocycles was demonstrated as well, showing the synthetic potential of the disclosed method.

Alkenylation and also acetoxylation (not shown) of Weinreb amides was reported by Yu and co-workers (Scheme 39C).²⁴⁸ This protocol was also applied for other DGs such as ketones (see Section 2.3) and esters (see Section 5.1.2). In case of the Weinreb amides the substrate scope included only FGs which can be considered as innocent (F, Cl, CF₃, OMe), since they do not undergo any transformations under a wide range of C–H functionalisation conditions. Yields for the alkenylation were high (70–92%) for examples in which no di-alkenylation was possible. In the other cases, mixtures of mono- and di-alkenylated products were obtained. For acetoxylation, the yields were generally ~10% lower and the same issue with a two-fold functionalisation occurred.

In one case also an *N*-hydroxyanilide has been used as substrate.²⁴⁹ Acrylates were used as coupling partners in this Rh catalysed protocol (Scheme 39D). The resulting products were almost exclusively of *E* configuration but in two examples isomerisation occurred giving then *E/Z* mixtures. These were the *t*-butyl and ethyl acrylates, however why exactly these two examples showed isomerisation was not explained. Also in this case the final products were amides since the *N*-hydroxy group was cleaved in course of the reaction (internal oxidant).

Zhang and Zhong reported an alkenylation protocol of *N*-methoxy amides, in which the methoxy group is cleaved under the applied Ru catalysed conditions (internal oxidant), leading to alkenylated amides as final products (Scheme 39E).²⁵⁰ In this case not aromatic but α,β-unsaturated *N*-methoxyalkan-carboxamides were used as substrate leading to the corresponding 2,4-diolefins with excellent *Z/E* selectivity often of 99/1. Yields however were low to good (22–70%).

### 7.4. Alkenylation with concomitant cyclisation

Several papers were published in which the alkenylation step is immediately followed by a cyclisation to a nitrogen containing heterocycle.

Li, Yang, and Zhou showed that indolines carrying an *N*-methoxycarbamoyl in position 1 can be alkenylated with alkynes in position 7 and then further cyclised to 6- or 7-membered rings, depending on the nature of the alkyne (Scheme 40A).²⁵¹ Dialkyl alkynes gave the 6-membered cyclisation product, whereas diaryl alkynes gave the 7-membered derivative. Otherwise, the reaction conditions in this Rh catalysed protocol were identical. Also alkylation with olefins and further cyclisation was reported. For this transformation the additive and solvent had to be changed (from NaOAc and MeOH to CsOAc and DMF) and acrylates were the reaction partners.

A Ru catalysed alkenylation-cyclisation reaction was reported by Bhanage and co-workers in PEG-400 as recyclable solvent (Scheme 40B).²⁵² *N*-Alkoxy or Weinreb amides were the best substrates and diphenylacetylene was the sole coupling partner and after cyclisation, in which the *N*-OMe bond is broken, isoquinolinones were the obtained products. Also carboxylic acids were applicable DGs for this reaction sequence

<figure><img src="image_87.png" /><figcaption>Scheme 40 Alkenylation-cyclisation sequences directed by *N*-alkoxyamide/ureas.</figcaption></figure>
<figure><img src="image_88.png" /></figure>

giving isocoumarins. If styrenes were the olefin source, no subsequent cyclisation occurred (not shown). For all transformations yields were typically > 80%.

Li and Wang investigated the reaction of 2,2-difluorovinyl tosylate with N-acyloxybenzamides under various Rh(II)-catalysed conditions, which gave access to different types of product.²⁵³ N-(Pivaloyloxy)benzamides led to 4,4-difluoro-3-alkoxy-3,4-dihydroisoquinolin-1(2H)-ones (Scheme 40C). If the pivaloyloxy group was exchanged for a methoxy group, no cyclisation took place but β-fluoride elimination delivered the alkenylated products (not shown). In addition, detailed DFT calculations were carried out in order to elucidate the reaction mechanism.

Finally, Meyer and Cossy reported an N-alkoxycarboxamide-directed macrocyclisation with an intramolecularly accessible alkyne (Scheme 40D).²⁵⁴ Macrocyclisation reactions are important transformations for natural product synthesis and new methods therefore highly welcome. The formation of 12-, 14, and even a 21-membered macrocyclic pyridinone were demonstrated. For such a challenging transformation, yields were actually quite good, getting as high as 82% in one example. The 21-membered ring was still formed in 32% yield.

### 7.5. Other transformations

The group of Chien-Hong Chen disclosed a Ru-catalysed alkynylation of aryls and heteroaryls using hypervalent iodine-alkyne reagents (Scheme 41A).²⁵⁵ FG tolerance was excellent (including bromine) and yields were typically around 70%.

Ketenimines were used for the annulation of N-methoxy-benzamides under Rh catalysis (Scheme 41B).²⁵⁶ Initially, 3-amino-1,1-diaryl methyl isoindolin-3-ones were isolated as products, which can be further converted to 3-(diarylmethylene)isoindolin-1-ones under Lewis acidic conditions via elimination of the amine. Using N-methoxy-1-naphthamides as substrates, this elimination occurred even spontaneously without any additional Lewis acid.

The halogenation of Weinreb amides (besides nitriles and amides, see Sections 10 and 6.1.6) was reported by

Kapur (Scheme 41C).²³⁰ NXS was used as halide source and 22 examples with yields between 49–81% were reported in this Pd(OAc)₂ catalysed protocol. The main focus was on bromination, but also iodination and chlorination was demonstrated. The presence of a nitro group shut down the reaction completely.

A quite peculiar transformation was reported by the group of Glorius (Scheme 41D).²⁵⁷ They used N-aryloxyacetamides as starting materials which were converted to N-(2-hydroxyaryl)-acetamides. So overall, an intramolecular amidation took place via migration of the amide group. The reaction required a bicyclic olefin as co-catalyst which enabled the amide migration. DFT-calculations and experimental mechanistic studies allowed them to propose a mechanism for this transformation. Electron withdrawing groups (CF₃, COOEt) directly on the aryl ring were not well tolerated, however, if they were separated by an aliphatic spacer yields were again high (typically 70–90%).

## 8. Carbamates

Only a few examples of carbamate-directed C–H activation reactions have been disclosed in the past three years. Hence, it is avoided to divide this part into further subsections. All reported examples deal with activation of C(sp²)–H bonds, either of aromatic or olefinic systems.

Kim and co-workers developed an allylation protocol for vinylic C(sp²)–H bonds using cyclic or acyclic allylic carbonates as the reaction partner (Scheme 42A).²⁵⁸ The reaction was catalysed by [RhCp\*Cl₂]₂ and performed at room temperature but consequently also took 36 h of reaction time. The yields in this transformation were low to good (28–82%) and in cases were Z or E products can be obtained, the selectivity is never better than 5:1. The same group also reported “alkylation” with maleimides under almost identical conditions.²⁵⁹

Boc-protected 2,3-dehydropiperidines can be arylated with arylboronic acids in position 2 using [RuCl₂(*p*-cymene)]₂.

<figure><img src="image_89.png" /><figcaption>Scheme 41 Various transformations directed by N-alkoxy- and N-aryloxy- and Weinreb amide.</figcaption></figure>

<figure><img src="image_90.png" /><figcaption>Scheme 42 Carbamate-directed transformations.</figcaption></figure>
<figure><img src="image_91.png" /></figure>

as catalyst (Scheme 42B).²⁶⁰ The method tolerated also heterocyclic boronic acids and delivered good yields, typically > 70%. Formyl protection of the dehydropiperidine worked as well.

Halogenation protocols using NXS under Pd catalysis have been reported with a number of different DGs. Also carbamates promote this chemistry as disclosed by Moghaddam and Jafari (Scheme 42C).²⁶¹ The halogenation is mono-selective and the second *ortho* position stayed untouched. In fact, if one *ortho* position carried a substituent already, no reaction occurred. Chlorine, bromine and iodine could be introduced equally well and yields were generally > 80%.

Finally, Satoh and Miura disclosed a carbamate directed alkenylation protocol *via* Rh catalysis. The transformation required 2 equiv. of Cu(OAc)₂ as oxidant, and could be carried out in an environmentally benign alcoholic solvent, namely tBuOH (Scheme 42D). It was shown, that after Boc-cleavage and imine formation, a thermal cyclisation to a pyridine ring could be carried out, leading to polyannelated ring systems.²⁶²

## 9. Urea derivatives as DGs

Urea derivatives have not been used as frequently as DGs as compared to amides or esters, but some progress has been made in the last three years. In several cases, urea derivatives are often tested concomitantly with related DGs such as amides or N-alkoxyamides, often in these contributions only for showing broader applicability of a method. In this section, examples will be presented in which urea based DGs make up for a large part of the corresponding contribution and are not only treated as a side note.

The group of Novak reported the alkylation of amides and urea derivatives using alkyl sulfonium salts as alkylating agents (Scheme 43A).¹⁹⁸ The most interesting application is in methylation reactions, since methods for introducing the CH₃ group *via* C–H activation are actually quite rare. The reaction conditions in this Pd(OAc)₂ catalysed reaction were quite mild (50 °C) but 5 equiv. of TFA were required. It has to be mentioned that FG tolerance was not really investigated in this report and yields were between 48–89%. The same group reported also an *ortho*-trifluoroethylation reaction of N-arylureas, where they basically applied a protocol they had previously used for the same transformation with amide substrates (Scheme 24G) and obtained excellent yields (Scheme 43B).²⁶³

<figure><img src="image_92.png" /><figcaption>Scheme 43 Urea-directed alkylation reactions.</figcaption></figure>

A third alkylation protocol was reported by Nishimura and co-workers.²⁶⁴ Mainly starting materials of the type N,N'-diaryl-N-methylurea were used. Alkylation took place at the N-methyl and not on the arene system (!), which was an unusual finding (Scheme 43C). Actually, the reaction worked with excellent yields, regularly > 90%. More than 30 examples were reported which showed excellent FG tolerance. This Ir-catalysed method used terminal olefins as the starting material and required one free NH group of the urea in order to allow coordination of the Ir species. Then, a 5-membered metallacycle was formed with the metal group before alkene insertion and reductive elimination delivered the final products.

The group of Lipshutz reported Pd catalysed arylation of N-aryl-N',N'-dimethylureas on the aryl systems.²⁶⁵ Depending on the choice of catalyst, they could use either aryl iodides (Scheme 44A, Pd(OAc)₂) or aryboronic acids (Scheme 44B, [Pd(MeCN)₄](BF₄)₂) as aryl source. Both arylation protocols gave good to excellent yields, whereas the boronic acid protocol gave higher yields in those examples where the same product was formed *via* both methods. Additionally, oxidative alkenylation, i.e. Fujiwara–Moritani reaction, was also reported, again with remarkably high yields in most cases. This transformation was particularly interesting since it could be run in water with low amounts of a surfactant (wt 2% PTS) at room temperature as well (Scheme 44C).

Later, a Rh catalysed variant was reported by Yi and co-workers (Scheme 44D).²⁶⁶ Also in this case N-aryl-N',N'-dimethylureas were the starting materials to be alkenylated on the aryl systems. However in this case, the alkenylated urea products were not isolated but further converted by ammonolysis and esterification (MeOH is the solvent in this reaction) to the corresponding O-methyl carbamates. Quite good yields (frequently > 90%) and substrate scope as well as good E-selectivity was observed.

The group of Jana reported reaction conditions, which gave two different products, just depending on the electronic nature of the applied olefine coupling partner.²⁶⁷ Again the same substrate class as in the previous examples was used in combination with styrene derivatives. In case of styrenes with electron

<figure><img src="image_93.png" /><figcaption>Scheme 44 Urea-directed arylation and olefination.</figcaption></figure>
<figure><img src="image_94.png" /></figure>

<figure><img src="image_95.png" /><figcaption>Scheme 45 Urea-directed alkenylation-cyclisation sequences.</figcaption></figure>

withdrawing or only slightly donating (e.g. CH₃) substituents, 2-arylated indoles were the product stemming from *ortho* alkenylation and subsequent aza-Wacker cyclisation as suggested by the authors (Scheme 45A). In case of 4-methoxystyrene or vinylnaphthalenes, the corresponding 2-arylindolines were the products (Scheme 45B). The authors proposed that a π-benzyl Pd species was formed which was better stabilised by methoxyarenes or naphthalenes, hence avoiding β-hydride elimination and allowed the immediate attack of this species with the free NH group.

A Pd catalysed alternative indoline synthesis was reported by the group of Han (Scheme 45C).²⁶⁸ In fact, the authors disclosed even an asymmetric variant of this transformation using Pd(OTs)₂(MeCN)₂ as precatalyst and a chiral sulfoxide-oxazoline (SOX) ligand. 1,3-Butadiene derivatives were the coupling partners of choice. Yields were mainly in the 50% range and the butadiene needed to carry an electron withdrawing group. However, e.r. of up to 95:5 were obtained.

A quite special case is the *meta* selective borylation of benzamides as reported by Kuninobu and Kanai.²⁶⁹ Of course the question arises why this example is presented in the urea section, and arguments could be found for both cases (and even for putting this example in the amine section). Actually, the amide group does not coordinate the metal, but the two NH groups of a urea derivative, and it is this urea derivative, which has included a bidentate pyridine group which coordinates the Ir catalyst (Scheme 46 bottom). So a secondary weak interaction *via* hydrogen bonding delivers the metal species *via* the ligand

<figure><img src="image_96.png" /><figcaption>Scheme 46 Ligand-assisted *meta* borylation.</figcaption></figure>

in proximity of the C-H bond to be broken. A wide variety of substituted benzamides and also carboxylic acid esters, and phosphoric acid esters (and derivatives thereof) have been used as starting materials demonstrating that the oxygen acting as hydrogen bond acceptor did not need to come from an amide. Interestingly, yields (only determined as NMR yields from *meta/para* mixtures) were either ~50% or >90% whereas electron withdrawing groups lead to the high yields. The *meta* selectivity showed quite some variation ranging from 3.3:1 up to >30:1.

## 10. Nitriles as DGs

In recent years, the application of nitriles as DGs has been dominated by directing functionalisation of an aromatic system *meta* to the DG.²⁷⁰⁻²⁷³

The nitrile function typically sits at the end of a spacer and points towards the C-H bond to be activated. Due to its linearity, the nitrile function is perfectly suited for this kind of activation mode. Only few *ortho* directing transformations have been reported. These will be treated here at the beginning of this chapter.

### 10.1. *ortho* directing

1,3-Dicyanobenzene has been arylated in position 2 under Pd(OAc)₂ catalysis using aryl bromides as the aryl source (Scheme 47A).²⁷⁴ Arylation occurred in position 2 in yields ranging from 45–81%. Interestingly, 2-bromo pyridine did not react whereas 3-bromo- and 4-bromopyridine did. One cyano group could be replaced by another electron withdrawing group such as Cl, F, or NO₂. 1,2-Dicyanobenzene reacted as well. Mechanistic studies of a similar arylation protocol were reported by the group of Ren.²⁷⁵

Finally, Kapur reported on *ortho* halogenation using several DGs, including benzyl nitriles (Scheme 47B).²³⁰ The reaction conditions were identical with those reported in previous sections (see Sections 6.1.6 and 7.5) and bromination and iodination with NBS and NIS were reported. As compared to the other DGs, namely Weinreb amides and anilides, yields were pretty much the same for comparable substrates.

### 10.2. *meta* and *para* directing

Further examples directed by the cyano function were mainly *meta* directing. As already mentioned, the cyano group has to be attached to a linker, in order to be able to bring the ligated metal in proximity to the C-H bond in *meta* position. What all examples have in common is the *ortho* substituted benzonitrile marked in blue in Fig. 3. The nature of the linker chain in

<figure><img src="image_97.png" /><figcaption>Scheme 47 Cyano-directed *ortho* functionalisation.</figcaption></figure>
<figure><img src="image_98.png" /><figcaption>Fig. 3 General strategy for designing *meta*-directing moieties.</figcaption></figure>

between can vary. Interestingly, the *ortho* position of the benzonitrile group does not get functionalised and the functionalisation of the more distant ring is favoured! It can be suspected that the metal catalyst gets coordinated by the nitrile nitrogen, which of course disfavours *ortho* functionalisation. The reported protocols differ in the length of the linker chain. However, most often a 3 or 4 atom linker was used whereas typically one or two of them are heteroatoms. Regarding the transformations reported in recent years, there was a strong focus on alkenylation reactions as can be seen in the subsequent section.

All examples in Scheme 48 used a four atom linker to connect the benzonitrile group, however, different solutions for this bridge were reported. Shangda Li and co-workers used N-nosylated amides (Scheme 48A),²⁷⁶ the group of Maiti relied on a sulphonic- or carboxylic acid ester (Scheme 48B and C),²⁷⁷ and Gang Li and co-workers applied a carbamate linker (Scheme 48D).²⁷⁸ All three protocols used Pd(OAc)₂ as precatalyst and a mono-protected amino acid (MPAA) mainly Ac-Gly-OH as ligand and olefins carrying electron withdrawing groups as coupling partners in HFIP as solvent. The unique features of this solvent have been highlighted recently.²⁷⁹,²⁸⁰ Differences can be found in the choice of oxidant. Also the yields of these three protocols were in a similar range. Li's work had the largest substrate scope regarding the aryl ring,²⁷⁶ whereas Maiti

showed that a wide range of electron withdrawing groups is tolerated in his protocol.²⁷⁷ However, the reaction was not exclusively *meta* selective and also other regioisomers are obtained in ratios between 6:1–20:1. Additionally, Shangda Li and Gang Li showed in their reports also a few examples of *meta* acetoxylation.²⁷⁶,²⁷⁸

Yu and Sun also used an amide linker, however his protocol is Rh catalysed and did not require Ac-Gly-OH or HFIP (Scheme 48E). In his catalytic system, [RhCp\*Cl₂]₂ was the catalyst and Cu(CO₂CF₃)₂ the oxidant with additional amounts of CF₃COOH in oxygen atmosphere and DCE as solvent. Also in this protocol, the reaction was not perfectly *meta* selective and ratios of *meta*: other isomers between 10:1–20:1 were observed. The yields are in the same range as for the previously discussed examples (49–85%).

The same group also showed that the number of linker atoms could be reduced to three as well and still the protocol using Pd(OAc)₂/MPAA in HFIP as solvent could be applied.²⁸¹ Instead of Ac-Gly-OH, formyl-Gly-OH was the ligand in this case. Again, *meta* selectivity was 20:1 at best, and no significant difference between the scope and yield of the above mentioned examples was observed (Scheme 49A).

The group of Maiti also used “shortened linker” DGs for *meta* functionalisation of arenes. In a first publication they

<figure><img src="image_99.png" /><figcaption>Scheme 48 Cyano-directed *meta*-alkenylation.</figcaption></figure>

<figure><img src="image_100.png" /><figcaption>Scheme 49 Cyano-directed *meta*-functionalisation.</figcaption></figure>

<figure><img src="image_101.png" /></figure>
demonstrated hydroxylation (Scheme 49D) and acetoxylation (Scheme 49E)²⁸² in a second one alkenylation (Scheme 49B and F)²⁸³ and finally also silylation (Scheme 49G) and germanylation reactions (Scheme 49C).²⁸⁴ For the hydroxylation, acetoxylation, silylation, and germanylation protocol the linker was sulphonic acid ester based. For the alkenylation, both sulphonic acid ester and carboxylic acid ester linkers were applied. The olefination reactions showed the same features as for the previously discussed 4-atom linker system. Hydroxylation reactions worked in yields between 50–77% and good to excellent *meta*-selectivity. Acetoxylations worked in the same yield range but with lower selectivity. In silylation and germanylation reactions only between 40–60% yield was obtained.

Again the group of Yu showed alkenylation reactions using a nitrile DG with a 5 atom linker (not shown). The method showed the same features discussed previously: Pd(OAc)₂, Ac-Gly-OH as ligand and HFIP as solvent. However, Ac-Gly-OH seemed not to be ideal for starting materials already carrying a substituent on the aromatic ring. Hence, Ac-Val-OH was identified as superior ligand in a second screening campaign. The results regarding *meta* selectivity were comparable to those in the examples discussed previously. The same was true for the yields and substrate scope. As an add-on in this publication, significant effort has been put into elucidation of the reaction mechanism *via* experimental and theoretical methods.

The group of Maiti investigated biphenyl-templates as para-DGs in olefination reactions (Scheme 50A and B).²⁸⁵,²⁸⁶ Therein, the directing nitrile moiety was attached to a biphenyl system, which was linked to the arene system to be alkenylated *via* a silyl ether. It was shown that it did not matter which of the aromatic systems was directly linked to the oxygen. Crucial for success was that the silyl moiety in the linker chain was bulky, since this forced the arene and biphenyl system to face into the same direction and hence enabled the nitrile to bring the metal catalyst in proximity of the *para* C–H bond. Yields for both types of substrate were in the synthetically useful range of >50%, in a good number of cases around 70%. Besides the *para*-alkenylated products also other regioisomers were formed

favouring the *para* product in ratios between 5:1 and 20:1. A few examples of acetoxylation were reported as well.²⁸⁵

By “inverting” the substrate, meaning that now the nitrile DG is placed on the arene part, *meta* alkenylation of biphenyls was achieved (Scheme 50C).²⁸⁷

## 11. Imines as DGs

Imines have been prominently used as DGs in recent years. One large application field was their use as so called “transient” DGs, in which the imine is formed *in situ*, enables a C–H activation reaction, and then gets cleaved again. Reactions such as hydroacylation, hydroarylation, hydroalkylation, arylation, alkenylation, amination, and halogenation have been realised with this approach. Since this field has been reviewed just now,¹⁰²,¹⁰³ these examples are excluded from this chapter and only examples are presented in which the imine is present from the beginning (and eventually cleaved after directing the metal catalyst), or *in situ* formed but then remains in the final product.

### 11.1. Arylation

Imine-directed arylations have not been the centre point of recent research in the field as can be seen by the small amount of examples. Szostak and co-workers reported a Ru(0)-catalysed protocol which works under neutral conditions (Scheme 51A),²⁸⁸ which have been applied previously for C(sp³)–H arylation of saturated heterocycles.²⁸⁹ Arylboronic acid esters were the aryl source. The protocol gave good to excellent yields (up to 96%) and tolerated the most common FGs. In one example it was shown that the imine could be formed *in situ* as well, which would then fall into the category of transient DGs.¹⁰²,¹⁰³

A second example was disclosed by Yoshikai using Co(acac)₃ as catalyst and aryl chlorides as aryl source (Scheme 51B).²⁹⁰ Both of these features make the protocol highly attractive, with the drawback of the requirement of 2.5 equiv. of a Grignard species and the resulting limited FG tolerance. Still, the protocol worked well on suitable examples with typical yields around 80% and the DG could be converted to a nitrile function.

### 11.2. Alkylations and allylations

Alkylation reactions represent a very special case in imine directed C–H functionalisation. Interestingly, non-precious

<figure><img src="image_102.png" /></figure>

<figure><img src="image_103.png" /></figure>

<figure><img src="image_104.png" /></figure>

<figure><img src="image_105.png" /><figcaption>Scheme 50 Cyano-directed para- (and meta-) alkenylation.</figcaption></figure>

<figure><img src="image_106.png" /></figure>

<figure><img src="image_107.png" /></figure>

<figure><img src="image_108.png" /><figcaption>Scheme 51 Imine-directed arylation reactions.</figcaption></figure>
<figure><img src="image_109.png" /></figure>

<figure><img src="image_110.png" /><figcaption>Scheme 52 Imine-directed alkylation/allylation reactions.</figcaption></figure>

metals play a dominant role in this field and examples for Fe, Co, and Mn catalysis have been reported.⁵⁵,⁶¹,⁷⁰,⁷²

Yoshikai, one of the pioneers in non-precious metal catalysed C–H activation reported on the C2 alkylation of indoles carrying an imine group in position three (Scheme 52A).²⁹¹ In the same contribution also alkenylation was disclosed, which will be discussed in the subsequent section. As catalyst simple Fe(acac)₃ could be applied, however an NHC ligand had to be added. One drawback in this type of chemistry was the necessity for a Grignard species, which naturally limited the FG tolerance. Still, in the presented examples good to excellent yields (up to 93%) were reported. Notably, the reaction worked well on indole but was inefficient on simple arene systems, however, a protocol for this type of substrates was reported previously.²⁹²

This aforementioned protocol also had the limitation of the requirement for Grignard reagents. In subsequent work, they tried to address this issue and it was found that addition of 50 mol% magnesium served the same purpose (Scheme 52B).²⁹³ However, still only examples with FGs not sensitive to Grignard species were included. Noteworthy, with styrenes as the alkyl source the branched products were obtained, whereas with vinyltrimethylsilane the linear products were formed, potentially due to the steric demand of the SiMe₃ group.

The two previous reports always used PMP protected imines as DG. However, the same group also demonstrated that unprotected imines can be used as well if ketimines are used (Scheme 52C).²⁹⁴ In fact, in competition experiments between PMP-protected imines and free imines, it was found that the latter reacted preferentially. In the present example vinyl silanes and terminal aliphatic olefins were the coupling partners always giving the linear products in good to excellent yields (up to 99%). In this contribution, the alkylated imines were also isolated in a number of cases. In case of pivalophenone imine, excellent selectivity for mono-alkylation products was observed

due to the steric bulk introduced by the *t*-butyl group. In a later contribution, the alkylated imines and their further photochemical transformation to nitriles was the focal point (Scheme 52D).²⁹⁰ This time, alkyl bromides were used as the alkyl source and it can be speculated that the alkyl bromides might eliminate to the corresponding olefins *in situ*.²⁹⁵ Again, the reactions worked typically with high yields, often in the 70–90% range. In both contributions the presence of a Grignard reagent was required again, leading to the same issues with FG tolerance.

Ackermann and co-workers showed N-PMP protected ketamine-directed introduction of a substituted allyl-group stemming from dioxolanone (Scheme 52E).²⁹⁶ The reaction was catalysed by MnBr(CO)₅ and gave the final products in decent yields with an E/Z selectivity of at least 7.3/1, often >20/1.

### 11.3. Alkenylation

C2-Alkenylation of indoles was reported by Yoshikai and co-workers under Fe catalysis (Scheme 53A).²⁹¹ Reaction conditions were similar to the ones for the alkylation disclosed in the same contribution. It has to be mentioned that E/Z selectivity was not good in 3 out of 8 examples and also yields varied between 18–84%, the lowest one being obtained by a dialkyl alkyne.

As we have seen in previous chapters, alkenylation reactions are often followed by a cyclisation reaction with a heteroatom nucleophile leading to heterocyclic systems. Imine DGs showed the same behaviour, since the lone pair of nitrogen could attack suitable groups which were introduced via the C–H activation step.

Several isoquinoline syntheses have been reported. Li and Wang developed a reaction between aromatic imines and alkynes using Cp\*Co(CO)I₂ as catalyst (Scheme 53B).²⁹⁷ In most cases the reaction was quite efficient giving yields >70%. Most examples used diaryl alkynes, but also dialkyl or terminal alkynes were applied successfully. Additionally, the transformation showed good FG tolerance. Later, a slight variation of that protocol was reported as well.¹⁴⁸

Another base metal catalysed isoquinoline synthesis was reported by Glorius and co-workers, this time using

<figure><img src="image_111.png" /><figcaption>Scheme 53 Imine-directed alkenylation and alkenylation-cyclisation reactions.</figcaption></figure>
MnBr(CO)₅ under redox neutral conditions (Scheme 53C).²⁹⁸ As coupling partners, tertiary propargylic carbonates were applied. The authors proposed that after C–H activation and olefination a carbonate elimination took place to deliver a reactive allene species, which was intramoleculary attacked by the imine to deliver the isoquinoline products. Yields were good to excellent, however not much FG tolerance was explored.

Using diazonalonates as reaction partners, isoquinolin-3-ones were the obtained products, again under Co catalysis (Scheme 53D).²⁹⁹ The reaction performed in TFE and unfortunately, transesterification of the product took place leading to mixtures of compounds in an otherwise high yielding protocol.

Almost simultaneously, Zhu³⁰⁰ and Jiao³⁰¹ reported two different protocols for the synthesis of quinazolines starting from carboximidates (Scheme 54A and B). Both groups relied on the same catalyst, namely [Cp*RhCl₂]₂ but used different sources for the nitrogen ending up in position 1 of the quinazoline. Zhu used dioxazolones whereas Jiao preferred benzylic azides in most cases. Comparing both protocols it can be seen that the use of dioxazolones gives a bit better yield, but also with azides >70% are achieved in almost every example. FG tolerance was basically identically good. Overall, Zhu's protocol was operationally simpler as could be seen by comparing the reaction conditions in Scheme 54A and B.

A rare case of rhenium catalysis was reported by Wang and colleagues (Scheme 54C).³⁰² In this contribution, an imine starting material was again reacted with an internal alkyne, as seen previously in isoquinoline syntheses. However, under ReBr(CO)₈ catalysis a [3+2] cycloaddition took place and the imine nitrogen did not end up in the ring but in position 1 of an indenamine product. The reaction worked well with a number of alkynes (diaryl, dialkyl, and aryl-alkyl). Good to

excellent yields were obtained (up to 98%) in this operationally simple protocol.

A second protocol in which the imine nitrogen ended up as amine function in an exocyclic position was disclosed by Zhang and co-workers.³⁰³ They reported that carboximidates could be alkenylated in *ortho* position using acrylates and [Cp*RhCl₂]₂ as catalyst (Scheme 54D). Until this point, this would be a quite standard transformation, however the consecutive sequence to the indenone products was quite interesting. It was proposed that an initial intramolecular cyclisation led to an *1H*-isoindole intermediate which was oxidised by Mn(OAc)₂ *via* a single electron transfer forming in presence of O₂ a peroxide intermediate (detected by LC-HRMS). This intermediate eventually ring opened and cyclised again, this time to the final product (Scheme 54, right). For a detailed discussion of this pathway we refer to the original paper.

The group of Jun reported a similar cyclisation, however without the subsequent oxidation-ring opening-cyclisation sequence and hence delivering *1H*-isoindoles as the products (not shown).³⁰⁴

Also iminoquinones have been used as DG, which have certainly different properties than ordinary imines, still this example is presented in this section (Scheme 54E and F).³⁰⁵ The reaction allowed fast access to a tricyclic system involving a number of olefins carrying different electron withdrawing groups. Depending on the catalytic system, different products were obtained. If only Pd(OAc)₂ was the catalyst, the saturated products of Scheme 54E were isolated, whereas if additionally 0.5 equiv. Cu(OAc)₂ oxidant was present, the products with an exocyclic double bond were formed (Scheme 54F), both in high yields.

In all previously discussed examples the imine group was already present in the starting material. There were also

<figure><img src="image_112.png" /><figcaption>Scheme 54 Imine-directed functionalisation–cyclisation sequences.</figcaption></figure>

■ Mechanism for the formation of indenone products

<figure><img src="image_113.png" /></figure>

<figure><img src="image_114.png" /></figure>
<figure><img src="image_115.png" /><figcaption>Scheme 55 *In situ* formed imine DGs and subsequent cyclisation.</figcaption></figure>

examples reported in which the imine was only formed *in situ* and then cyclisation took place to pyridium derived heterocycles. Besides the starting materials in Scheme 55, the imine intermediates are shown as well.

Both contributions in this field stem from the group of Cheng and run under Rh catalysis.³⁰⁶,³⁰⁷ In the first report, a three component reaction was carried out between a ketone or an aldehyde, an amine, and an internal alkyne. *Via* the imine intermediate, the desired pyridinium salts were formed quite efficiently with typical yields of > 80%.³⁰⁶ The second protocol was only a two component reaction, because the amine carried already an alkyne function for a subsequent intramolecular cyclisation.³⁰⁷ Also for this much more complex ring systems, good to excellent yields were reported surpassing 80% in almost every example. *Via* this route, facilitated access to protoberine alkaloids was granted.

## 12. Oximes and oxime derivatives

Oxime containing DGs are quite frequently applied and used in several variants, namely ketoximes, aldoximes and ethers and esters thereof. In 2016 the subject has been comprehensively reviewed,³⁰⁸ but since then again a good number of examples have been reported, which are now covered in this section. In several cases, besides the oximes also N-heterocyclic DGs have been tested in the same transformation. However, this chapter focuses solely on the oxime examples.

### 12.1. Arylation

Arylation reactions are usually amongst the most detailed studied transformation with any DG. For oximes, only a few examples have been reported in the last three years.

The group of Xu developed a site-selective biaryl synthesis *via* dehydrogenative C-H/C-H arylation under ball milling conditions (Scheme 56A).³⁰⁹ Mechanochemistry is an interesting, yet underrepresented method to introduce energy into a reaction system. In

<figure><img src="image_116.png" /><figcaption>Scheme 56 O-Methyl oxime-directed arylation reactions.</figcaption></figure>

a dehydrogenative approach, the question of regioselectivity is a major issue in cases where substituted arenes are the coupling partners. In this protocol, arenes bearing electron donating groups showed excellent *para* selectivity, whereas arenes with electron withdrawing groups such as acetophenone or methyl benzoate gave good *meta* selectivity, presumably because the *meta* position is more reactive towards $S_EAr$ reactions. Overall, the transformation showed excellent FG tolerance and gave yields in the 50–80% range.

Pd-Catalysed *ortho*-C-H arylation of acetophenone oxime ethers with aryl boronic acid esters was reported by Lee and co-workers (Scheme 56B).³¹⁰ The corresponding biaryl products were obtained in yields between 42–80%. Interestingly, besides the parent phenyl boronic acid ester, only derivatives carrying electron withdrawing substituents ($CF_3$, $NO_2$, COOEt) were applied. Noteworthy, the boronic acid ester can be used as crude material stemming from an Ir catalysed direct borylation.

The β-arylation of oxime ethers using diaryliodonium salts was developed for $C(sp^3)^-H$ bond activation by Chen and co-workers (Scheme 56C).³¹¹ The arylated oxime ethers were not isolated but immediately hydrolysed to the corresponding ketones. The reaction worked for a wide variety of ketoximes and generally gave yields around 80%. Most interestingly, the method was also applied to the arylation of complex natural product derived molecules (steroids).

### 12.2. Alkylation

Only few alkylation reactions have been reported in the last three years. Li and co-workers reported Rh(III)-catalysed direct alkylation of arenes using commercially available alkyl trifluoroborates (Scheme 57A).³¹² The method is especially interesting,

<figure><img src="image_117.png" /><figcaption>Scheme 57 O-Methyl oxime-directed alkylation reactions.</figcaption></figure>

<figure><img src="image_118.png" /></figure>
<figure><img src="image_119.png" /></figure>

since it allows simple methylation reactions. Yields were good, between 64–90% but only electron withdrawing FGs were reported amongst the examples (CN, NO₂, CF₃, COOEt).

*Via* ring opening of cyclopropanols β-aryl ketones were made accessible by the group of Li.³¹³ 16 examples were presented but not much FG tolerance was explored (Scheme 57B).

An alkylation in the broader sense was the synthesis of benzocyclobutenes *via* a Pd catalysed reaction with norbornenes (Scheme 57C).³¹⁴ Norbornene is a quite useful auxiliary in C–H activation chemistry, for example in the Catellani reaction.¹¹,³¹⁵ However, in the present transformation, the norbornene was not an auxiliary but a reaction partner and remained in the final products.

## 12.3. Alkenylation

*ortho*-Directed alkenylation reactions have been exploited extensively with a number of different DGs. As discussed in previous chapters, the alkenylation reaction was often immediately followed by a cyclisation towards a (hetero)cyclic ring system. Also with oxime derived DGs this behaviour was observed.

However, the first example to be discussed was dedicated to an alkenylation reaction in which no further cyclisation occurred. The group of Zhao reacted acrylates with benzylic alcohols masked by acetone oxime ethers under Pd catalysis (Scheme 58A).³¹⁶ The resulting alkenylated products were formed *via* a six- or seven-membered *exo*-acetone oxime ether palladacycle, in contrast to the often dominating 5-membered metallacycles. The reason why in this example no cyclisation occurred could be found in the architecture of the substrates. In this specific case, oxime benzyl ethers were the starting materials and olefination took place on the benzyl system. Hence, an intramolecular attack of the oxime nitrogen was disfavoured and the alkenylated products were stable.

<figure><img src="image_120.png" /><figcaption>**Scheme 58** Alkenylation reactions and alkenylation–cyclisation sequences directed by oximes and derivatives.</figcaption></figure>

Several isoquinoline syntheses have been reported in recent years. Basically simultaneously, the groups of Sundararaju³¹⁷ and Ackermann³¹⁸ disclosed [Cp\*Co(CO)I₂]-catalysed alkenylation/cyclisation sequences of oxime derivatives and diaryl alkynes. In the Sundararaju protocol, free OH ketoximes were used as substrates (Scheme 58B), whereas in Ackermann's transformation *O*-acetylated oximes were used (Scheme 58C). Both moieties act as internal oxidant in the respective transformations. The reaction conditions were almost identical, with the difference that the Ackermann protocol required AgSbF₆ as additive whereas in Sundararaju's procedure yields were better in its absence. Both transformations showed excellent FG tolerance and high yields.

An almost identical reaction was reported by Chen with the addition that besides oximes also *N*'-hydroxybenzimidamides were used as DG which then delivered 1-amino-isoquinolines as products (Scheme 58D).³¹⁹

Hua and co-workers developed an alkenylation–cyclisation sequence in which the oxime DG is formed *in situ* via reaction of a carbonyl group with hydroxylamine hydrochloride (Scheme 58E).³²⁰ Starting from chroman-4-ones, tricyclic fused pyridines were easily accessible, which allowed rapid access to the skeleton of cassiarins, a family of alkaloids with antimalarial activity. Yields were typically >80% and a hydroxyl and bromine function were tolerated without any loss in efficiency.

## 12.4. Acylation

Several examples for *O*-Me ketoxime-directed acylation of π-systems, aromatic and olefinic ones, have been reported.

The group of Jiao reported acylations of aryl systems using toluene under aerobic conditions as the acyl source, leading to benzophenone derivatives (Scheme 59A).³²¹ This Pd(OAc)₂ catalysed process is quite attractive since toluene is a simple, cheap, and stable starting material. The reaction required *N*-hydroxyphthalimide (NHPI) as additive which induced in presence of oxygen a radical process leading to the oxidation of toluene to a benzoyl radical, which could then be transferred to the *ortho* position of the oxime. Yields were in the 42–81% range and the most interesting FG tolerated was bromine, since that leaves a handle for further reactions.

The same group reported a similar approach, this time starting from benzylic alcohols or benzaldehydes, again with

<figure><img src="image_121.png" /><figcaption>**Scheme 59** *O*-Methyl oxime-directed acylation and acylation/cyclisation reactions.</figcaption></figure>
<figure><img src="image_122.png" /></figure>

NHPI under aerobic conditions (Scheme 59B).322 This modification showed broader FG tolerance with similar yields and also examples of aliphatic aldehydes were reported, allowing also the synthesis of aryl alkyl ketones.

The acylation of α,β-unsaturated *O*-methyl ketoximes with benzaldehydes resulted overall in an interesting new method for the synthesis of highly substituted furan derivatives (Scheme 59C).323 Highly functionalised furans were synthesised from α,β unsaturated *O*-methyl oximes by using Co catalysed aldehyde addition and cyclative capture. Twelve examples were prepared tolerating several important FGs (e.g. Br, COOR) with moderate to good yields (25–84%).

## 12.5. C–O bond formation

A good amount of oxime-directed C–O bond formations have been disclosed in recent years. Acetoxylation, hydroxylation and alkoxylations have been reported, all using Pd catalysis and various oxidants.

**12.5.1. Acetoxylation.** Dong and co-workers used 2,6-dimethoxy benzaldoxime as an efficient *exo*-type DG for arene C(sp²)–H acetoxylation (Scheme 60A).324 In this case, Pd(OAc)₂ was used as catalyst and PhI(OAc)₂ as the oxidant in a mixture of AcOH/Ac₂O as solvent. A low catalyst loading of 1 mol% was sufficient to obtain the desired products in good to excellent yields in cases where only mono-acetoxylation was possible. If there was no stericities induced preference for a single reaction, mixtures of mono- and diacetoxylation products were obtained.

Using substituted benzoic acids, Liao and Ji developed a mono-selective *ortho*-aryloxylation protocol of *O*-benzyl acetoximes, again catalysed by Pd(OAc)₂ (Scheme 60B).325 The benzoic acid as well as the benzyl part could carry common FGs and the transformation robustly gave 60–80% yield. As oxidant simple K₂S₂O₈ could be applied. In two examples also aliphatic acids were used, which worked as well as the benzoic acid derivatives.

<figure><img src="image_123.png" /><figcaption>Scheme 60 C–O bond forming reactions directed by oxime derivatives.</figcaption></figure>

An alternative to commonly used oxidants in organic chemistry was used by the group of Mei. In their acetoxylation of the β-position of an *O*-alkyl ketoximes, they relied on electrochemical oxidation (Scheme 60C).326 They described a large set of examples and compared the yields with an alternative oxidant, namely NaNO₃/O₂. In most examples, the electrochemical oxidation proved to be superior, giving yields >70% in many cases. Eventually this report inspires more research in this direction since replacing typical strong oxidants can be quite useful.

**12.5.2. Hydroxylation and alkoxylation.** Intramolecular alkoxylation towards saturated 5-, 6-, and 7-membered oxygen heterocycles has been reported by the group of Dong (Scheme 60D).327 As in their previously discussed acetoxylation protocol, they used Pd(OAc)₂ as catalyst and PhI(OAc)₂ as oxidant. The efficiency of this intramolecular cyclisation was dependent on the relative stereochemistry of the substrates. If anti diol derivatives were used, the yield was significantly higher as compared to the syn diastereoisomers. This was a nice extension to the repertoire of cyclisation reactions toward saturated O-heterocycles.

Pd-Catalysed *O*-methyl oxime-directed *ortho* C–H hydroxylation of arenes was reported by the group of Jiao under neutral conditions (Scheme 60E).328 Simple oxone was used as oxidant and also the catalyst system was simple (Pd(OAc)₂ + PPh₃). Overall, more than 40 examples were reported demonstrating the excellent FG tolerance and the high yields (typically 70–90%) in this protocol.

## 12.6. C–N bond formation

Another interesting transformation developed by Jiao is the amination of oxime ethers with anthranil (Scheme 61A).329 Anthranil is here a quite special reagent, since it gets ring opened and overall delivers a 2-formyl aniline moiety into the *ortho* position of the substrate. So basically two FGs are introduced at once. The reaction proved to be quite robust with yields between 62–86%. Regarding FGs, besides MeO and halides no further moieties were investigated, but the oxime DG can be replaced also by N-heterocycles.

In recent years, 3-substituted-1,4,2-dioxazol-5-one has established itself as a good source for the amide group in C–H activation chemistry. The group of Li also made use of this

<figure><img src="image_124.png" /><figcaption>Scheme 61 C–N and C–Se bond forming reactions directed by *O*-methyl oximes.</figcaption></figure>
<figure><img src="image_125.png" /></figure>

reagent in the amidation of CH₃ groups in carvone derived oxime methylether (Scheme 61B).³³⁰ The most interesting example was the late stage functionalisation of natural products, namely the oxime ether of (–)-santonin which worked with a number of 3-substituted-1,4,2-dioxazol-5-ones in 64–94% yield.

Besides acylations, the group of Jao disclosed also *ortho* nitration of aromatic oxime ethers using *t*-butyl nitrite as NO₂ source under radical conditions (not shown).³²¹ Acetophenone oximes (23 examples) bearing substituents such as Me, OMe, *t*-Bu, Br, and F were successfully converted into the corresponding *ortho*-nitrated products.

## 12.7. C-Se bond formation

Selenium-containing organic compounds are not very common and hence methods for introducing selenium are relatively rare. However, Wan and Li developed an aromatic oxime ether-directed Rh(III)-catalysed selenylation protocol of arenes (Scheme 61C). As selenylating reagents, electrophilic selenyl chlorides and diselenides were used. The catalytic system was highly efficient under mild conditions and delivered the corresponding products in typically > 80% yields.³³¹

# 13. Hydrazine and hydrazone derivatives as DGs

Hydrazines and hydrazones are not frequently applied as DGs in C–H activation chemistry. In most cases, it is not the parent FG which acts as DG, but substituted (or protected) variants thereof.

For hydrazines, few examples have been reported in which simple aryl hydrazines were the substrates. In the first one, the group of Cheng developed an alkenylation protocol in which the final products are *ortho* alkenylated anilines (Scheme 62A).³³² The actual DG is a hydrazone, since 1,2 equivalents of ketone, namely 3-pentanone, transform the hydrazine *in situ* to a hydrazone. Only then *ortho* C–H insertion by Rh took place and the olefination occurred with styrene derivatives or acrylates in quite good yields (> 70%). The catalyst was then also involved in the cleavage of the N–N bond and formation of the final aniline products.

A similar olefination reaction has been disclosed by Zhu and co-workers, however in this example there was no ketone added

and hence it is the hydrazine itself which exhibited the directing effect (Scheme 62B).³³³ With acrylates as coupling partners again *ortho* alkenylated aniline derivatives were the final products and also in this protocol yields were very good, typically > 80%. Additionally, the FG tolerance was also significant. Alternatively, alkyl–aryl alkynes could be reacted under the same reaction conditions. In these reactions indoles were obtained as products *via* a cyclisation after the olefination step. Interestingly, the aryl group always ended up in position 2 and the alkyl group in position 3 of the indole derivative.

Furthermore, Cui and co-workers developed a synthesis of 1-aminoindoles *via* a Rh-catalysed intramolecular three component annulation (Scheme 62C).³³⁴ The aryl hydrazines were used as their HCl salts together with ethyl diazoacetoacetate and ketone using [Cp*RhCl₂]₂ as catalyst. According to the proposed mechanism, the hydrazine formed with the ketone the corresponding hydrazone and it was actually the sp² hybridized nitrogen of the hydrazone which directed the Rh to close proximity to the *ortho* C–H bond. This allowed the transfer of the ethyl acetoacetate to this position and cyclisation with the NH group delivered the final products. The transformation showed broad FG tolerance with typical yields between 50–80%.

Reddy and co-workers reported a direct arylation protocol of 1-arylhydrazine-1,2-dicarboxylates with aryl iodides and Pd(OAc)₂ as catalyst (Scheme 63A).³³⁵ The arylation worked quite well giving yields between 50–86% and some FG tolerance, most importantly a second iodine. The obtained products

<figure><img src="image_126.png" /><figcaption>Scheme 62 Hydrazine–HCl- and hydrazine-directed transformations.</figcaption></figure>

<figure><img src="image_127.png" /><figcaption>Scheme 63 Miscellaneous transformations directed by hydrazine/hydrazone/hydrazone derivatives.</figcaption></figure>
can be cyclised under oxidative conditions to the corresponding benzo[c]cinnoline derivatives.

Basically simultaneously to Cui's indole synthesis, the group of Zhu published another variant of this type of reaction. Starting from 1-aryl-2-Boc-hydrazines and diazodiesters or diazoketoesters 1-aminoindoles were obtained (Scheme 63B).336 The catalytic system was quite similar and a series of examples with high yields and good FG tolerance was reported. When they used N-Boc aromatic hydrazones as substrates, isoquinoline-3-ones were the products (Scheme 63C). Excellent yields were obtained using 0.5 equiv. AcOH as additive and slightly lower yields when LiOAc was used instead. More than 30 examples were reported with most yields in the 90% range.

Another indole synthesis starting from hydrazines, this time N-aryl, N'-Boc hydrazines, was reported by the group of Glorius under [Cp\*Co(CO)I₂] catalysis (Scheme 63D).337 Mainly symmetric diaryl alkynes were the coupling partners but in some cases also unsymmetrically substituted (e.g. aryl-alkyl) ones were used. The reaction showed good FG tolerance and also good to excellent yields, often > 85%.

Using [Cp\*RhCl₂]₂ benzoyl hydrazines have been transformed to isoquinolones *via* the reaction and subsequent cyclisation with diaryl alkynes (Scheme 63E). The resulting products have large conjugated π-systems and the authors also investigated their photophysical properties.338

The group of Zhu applied the starting material mentioned in Scheme 63C again, this time in a reaction with diaryl alkynes under [Cp\*Co(CO)I₂] catalysis (Scheme 63F).339 *Via* this method, 3,4-diarylated isoquinolines were obtained as products. Again, this is a well working reaction with good FG tolerance. The group of Sun disclosed a similar reaction under Rh catalysis (not shown).340

So far all examples dealt with C(sp²)–H activation. Dong and co-workers could also realise a C(sp³)–H activation, namely a Pd(OAc)₂ catalysed acetoxylation (Scheme 64A).341 As substrates served N2-protected hydrazones derived from 2,6-dimethoxybenzaldehyde and PhI(OAc)₂ was the acetyloxy source. As N-protecting group 5 different sulfones were used and

acetoxylation occurred in β-position. Quite a range of substrates were subjected to the reaction conditions and the typical yield was in the 50–70% range.

Dibenzylidenehydrazines can be considered as a hydrazone derivative as well. Two transformations on this type of substrate have been reported since 2015, all under Rh catalysis. Zhu reported the reaction with vinyloxirane leading to unsaturated alcohols (Scheme 64B).342 Interestingly, only mono-functionalisation occurred with 1.2 equiv. vinyloxirane.

The second procedure used diazodiesters as coupling partners and with 2 equivalents, difunctionalisation on both aromatic rings was obtained in good to excellent yields (Scheme 64C).343

## 14. Bidentate DGs

In this section, recent advances in the astute use of bidentate DGs in C–H bond functionalisation will be depicted. Indeed, from the seminal work of Daugulis on the use of the amide derived from 8-aminoquinoline as a bidentate chelating auxiliary,344 the scientific community put a lot of efforts in the design and use of a large panel of bidentate groups considerably enlarging the current tool-box of C–H bond functionalisation reactions. Consequently, over the years, a myriad of transformations was developed playing with the unique properties of various bidentate DGs and were already abundantly described in the literature.57,108,345–350 Indeed, such bidentate DGs appear today as key tools to achieve efficient transition metal catalysed directed C–H bond activation and were even successfully employed in strategies involving transient DGs, which will not be depicted in this review.103,351–359 In this section, an overview of the major contributions made in the 2015–2017 period will be provided. In particular, this part will focus on the recent advances made in transition metal-catalysed bidentate group-directed functionalisation of both aromatic and aliphatic compounds. At first, transition metal catalysed C–H bond functionalisation involving N,N-bidentate DGs will be discussed. Then, a focus on the promising, albeit still less studied, N,S- and N,O-bidentate DGs will be reported.

### 14.1. N,N-Bidentate DGs

Among all bidentate DGs, the N,N-bidentate ones represent the most commonly used auxiliaries for directed C–H bond activation.

14.1.1. Amides derived from 8-aminoquinoline. Amides derived from 8-aminoquinoline are by far the most common bidentate DGs and have received a lot of attention. Due to the large number of examples, a selection of the most relevant ones will be presented herein, providing to the reader a nice overview of the various possible transformations. It is worth mentioning that in contrast with most of the other bidentate DGs, amides derived from 8-aminoquinoline were successfully applied in transformations of both C(sp²) and C(sp³) centers. C(sp³)–H functionalisations are particularly challenging transformations as the functionalisation of less reactive aliphatic chains (with or without the help of the Thorpe–Ingold effect) in an

<figure><img src="image_128.png" /><figcaption>Scheme 64 Hydrazone and dibenzylidenehydrazine-directed transformations.</figcaption></figure>

<figure><img src="image_129.png" /></figure>
<figure><img src="image_130.png" /></figure>

efficient manner remains an intensive quest. In this regard, the combination of using high-valent transition metals with bidentate DGs turned out to be an efficient approach in various reactions.

Note that in some cases the transition metal-catalysed functionalisation of 8-aminoquinoline itself (rather than the substrate) at the remote C5 position was observed when using these amides as DGs. These cases will not be discussed in this review.<sup>360–369</sup> To overcome such an issue, though, a second generation of bidentate DGs was designed and the amides derived from 5-chloro-8-amino-quinoline and 5-methoxy-8-amino-quinoline were investigated (*vide infra*).

As the directing group often needs to be cleaved after the metal catalysed C–H bond functionalisation event, several strategies were developed leading to the corresponding carboxylic acid, amide or ester. Indeed, classical approaches relied on using basic or acid conditions to cleave the DG.<sup>370–378</sup>

If difficulties are met, additional steps such as N-methylation<sup>379–382</sup> or N-Boc<sup>383–387</sup> protection might be helpful in some cases for the deprotection of the DG under basic conditions. More recently, it has been demonstrated that oxidative cleavage<sup>388</sup> (ozonolysis followed by hydrolysis) as well as Ni<sup>-389,390</sup> and Co-catalysis<sup>387</sup> were also good alternatives for instance although so far less commonly used compared to classical acid and basic conditions.

### 14.1.1.1. C(sp²)–H functionalisation

**14.1.1.1.1. Arylation.** The arylation of C(sp²) centres has been extensively studied. In 2015, Babu reported a regiocontrolled arylation of C2-substituted thiophene or furan using aryl iodides as coupling partners.<sup>391</sup> Good chemo-selectivity was observed, with tolerance of a bromide substituent for further post-functionalisations (Scheme 65A) and yields typically around 60%.

Similar catalytic systems were applied for the arylation of acrylamides towards the synthesis of Z-cinnamamides by Babu<sup>372</sup> (Scheme 65B) and Xue/Jiang (Scheme 65C).<sup>374</sup> In the former case, a large scope of carboxamides was described with moderate to good yields, up to 88%. In the last case, attempts to extend the reaction towards the alkylation of acrylamides were performed, but with only low conversions.

The Pd-catalysed arylation of arenecarboxamides was reported in 2016 by Babu.<sup>392</sup> Di-arylated products were usually obtained (Scheme 65D) with moderate to good yields (25–85%), except when 5-iodoindole and 4'-iodoacetophenone were used, leading either to the exclusive formation of mono-arylated product or a mixture of compounds, respectively. Depending on the substitution patterns on the arenecarboxamides, mono-arylation or a mixture of mono- and di-arylated compounds were also observed (46–63%). The replacement of aryl iodides by a benzyl bromide derivative enabled the mono-benzylation reaction in decent yields.

The arylation reaction was extended in 2016 to N-(quinolin-8-yl)ferrocenecarboxamide by Kumar.<sup>393</sup> This Pd-based catalytic system gave access to di-arylated and mono- or di-alkylated ferrocenecarboxamides (Scheme 65E) and demonstrated a good

FG tolerance on the aryl iodide partners (alkyl, CF₃, OMe, NMe₂, Cl, I, acyl, NO₂). The efficiency of Ni(OTf)₂ was also evaluated, but lower yields were obtained.

A study performed by Yang, Wu an Wu also investigated the arylation of ferrocene derivatives (Scheme 65F).<sup>394</sup> The authors evaluated the potential of 8-aminoquinoline and 2-(2-pyridyl)-2-isopropylamine (PIPNH₂) derived carboxamide as DGs to promote the transformation. Good yields, around 70–85%, were usually obtained with the 8-aminoquinoline-derived amide.

Other metals than Pd were also investigated. For instance, mechanistic studies were undertaken by Lan on the Ru-catalysed arylation of benzamide.<sup>395</sup> Using Co(acac)₂ as catalyst, 8-aminoquinoline-derived amides were shown to dimerize.<sup>375</sup> An excellent regioselectivity was observed (Scheme 66A), but attempts to achieve the hetero-coupling of two different arene-carboxamides failed to get high selectivity. This reaction tolerated several common FGs (I, Br, NO₂, OMe, CF₃). Another example was reported in 2016, but required a stoichiometric amount of Co salt.<sup>396</sup>

A mixed DG strategy adopted by Niu and Song allowed the Co-catalysed arylation of benzamides and arylpyridines, offering an access to valuable biaryl systems.<sup>397</sup> This process required two parallel activations (SET and CMD pathways) for the formation of a high-valent Co intermediate coordinated to the coupling partners (Scheme 66B).

Three alternatives to the use of aryl halides were reported in the 2015–2017 period: cross coupling with arylboronic acids, a decarboxylative reaction with benzoic acids, and the use of an aryne precursor. Tan and coworkers published the arylation of arenecarboxamides with arylboronic acids mediated by Cu (Scheme 66C).<sup>379</sup> A stoichiometric amount of Cu(OAc)₂ is

<figure><img src="image_131.png" /><figcaption>Scheme 65 Pd-Catalysed arylation of C(sp²) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>
<figure><img src="image_132.png" /></figure>

<figure><img src="image_133.png" /><figcaption>Scheme 66 Arylation of 8-aminoquinoline-derived amides as DG.</figcaption></figure>

required, but a good selectivity as well as a good FG tolerance (F, Cl, Br, OMe, SMe, alkyl, aryl, CF₃, CN) were observed. The corresponding products were generally obtained in moderate to good yields (48–79%). A considerable kinetic isotope effect (KIE) was observed with deuterium-labelled compounds, suggesting that C–H bond cleavage was involved in the rate-determining step of the mechanism. A similar Co-based system proved to be efficient in the same transformation and was also suitable for the arylation of acrylamide derivatives.³⁸⁰

Concerning the decarboxylative process, Hirano and Miura reported a Cu-mediated arylation of benzamides using *ortho*-nitrobenzoic acids.³⁹⁸ This reaction allowed the synthesis of biaryl compounds bearing a nitro group (Scheme 66D) with low to excellent yields (14–85%). By slightly changing the reaction conditions (addition of a base), access to phenanthridinones was possible (not shown).

The use of arynes was reported in 2017 by Zhang, with a Cu-based catalytic system.³⁹⁹ *o*--(Trimethylsilyl)aryl triflates were employed as aryne precursors and the reaction offered access to phenanthridinones by means of an annulation process (Scheme 66E). The use of arynes is not common in C–H arylation processes, and this reaction is therefore a very interesting contribution to the field. A broad array of FGs was well tolerated on the amide partner (OMe, alkyl, CF₃, Br, I, F, CN, ester). In order to avoid the extra DG installation step, Wan published in 2015 a multicomponent protocol, where the amide formation and the Pd-catalysed arylation occurred as a cascade process with moderate to excellent yields (47–95%).⁴⁰⁰ This step-economic approach directly employed acyl chlorides, aryl iodides

and 8-aminoquinoline to obtain the 2,6-disubstituted products (Scheme 66F). The presence of a methyl group at the *ortho*- or *meta*-position of benzoyl chlorides led to the selective formation of mono-arylated products.

#### 14.1.1.1.2. Alkylation.
A selective Pd-catalysed monoalkylation of 8-aminoquinoline-functionalised benzamides was reported by Chen in 2015 (Scheme 67A).³⁷⁶ Notably, the control of the reaction time and the amount of NaHCO₃ added regulated the selectivity of the reaction, favouring either the mono- or the di-alkylated product with good yields with primary alkyl iodides (75–87%) and moderate to good yields with secondary alkyl iodides (31–88%).

A Ni-catalysed system was also reported in the same period by Chatani.⁴⁰¹ This protocol employed alkyl bromides with a wide range of substituted arenecarboxamides and acrylamide derivatives (Scheme 67B), resulting in good yields, typically >70%. An example with *para*-substituted arene carboxamide yielded the di-alkylated product. Benzylation and allylation reactions were also presented.

The Pd-based catalytic system described by Babu for arylation of thiophene and furan was also successfully applied with alkyl iodides (see Scheme 65A).³⁹¹ An Fe-catalysed alkylation of acrylamides and arenecarboxamides using a broad range of Grignard reagents was established by Ilies and Nakamura in 2015 (Scheme 67C).⁴⁰² A broad variety of substrates was used with excellent yields, mostly >90%. To avoid the homocoupling reaction of the alkyl partners and a possible β-H elimination, the stabilisation of an organoiron(III) species by the DG and an additional diphosphine ligand was crucial.

Other reagents were also suitable for the directed C–H alkylation. Indeed, the same group developed in 2015 a Fe(acac)₃ catalytic system using AlMe₃.⁴⁰³ Efficient with both 8-aminoquinoline- and picolinamide-derived DGs, this system was applied to a large scope of (hetero)arenecarboxamides (Scheme 67D) with moderate to excellent yields (48–99%), and was proven to be also active with AlEt₃.

The combination of organoaluminium reagents with 2,3-dichlorobutane as oxidant was reported by Xu and Zhang with a Co-based catalytic system.⁴⁰⁴,⁴⁰⁵ An excellent mono-selectivity was observed and AlMe₃ gave yields between 73–93%. Moderate to good yields (40–87%) were also obtained using AlEt₃ as alkyl source (Scheme 67E). Importantly, one example of C(sp³)–H bond methylation was reported with a moderate yield.

Another original reagent, dicumyl peroxide, was reported as a methyl precursor by Chatani in 2016 for the methylation of arenecarboxamides.⁴⁰⁶ This selective methylation occurred selectively on the less hindered *ortho*-position (Scheme 67F), and was totally inhibited by the addition of radical scavengers, demonstrating the radical character of the process. The following mechanism was proposed: coordination of the Ni catalyst with the bidentate DG followed by formation of the corresponding complex **A**. Then, the intermediate Ni(III) **B** was obtained from peroxide along with an alkoxy radical *via* a SET process. After decomposition of the alkoxy radical into a methyl radical and acetophenone, the Ni(IV) species (C) was
<figure><img src="image_134.png" /><figcaption>■ Methylation with dicumyl peroxide - mechanism</figcaption></figure>

<figure><img src="image_135.png" /><figcaption>■ Cyclisation with oxabenzonorbornadiene + amide cleavage - mechanism</figcaption></figure>

<figure><img src="image_136.png" /><figcaption>Scheme 67 Alkylation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

formed, which underwent reductive elimination/protonation steps to access the corresponding product and regenerated the Ni catalyst.

The *ortho*-alkylation of arenecarboxamides was also possible with butenolides and dihydrofurans using a Rh catalyst,⁴⁰⁹ generally providing mono-alkylated products (Scheme 67G) in synthetically useful yields (49–87%). Unfortunately, di-alkylation occurred with unsubstituted arenecarboxamides. In 2016, Cheng

performed the reaction between the 7-oxabenzonorbornadiene and derivatives with arenecarboxamides bearing an 8-aminoquinoline pattern, with typically excellent yields (>70%, up to 93%).⁴¹⁰ A [3+2] amide/alkene annulation took place, with cleavage of the 8-aminoquinoline group (Scheme 67H). A plausible mechanism was proposed: after coordination of the Co catalyst to the amide substrate, the formation of a metallacycle occurred, followed by the insertion of the bicyclic
alkene, an intramolecular nucleophilic addition, a protode-
metallation step and the elimination of the 8-aminoquinoline.

The Rh-catalysed directed alkylation with styrenes was reported by Chatani providing the corresponding linear products with excellent yields, mostly > 80% (Scheme 67I).<sup>411</sup> An electron-donating group on the arenecarboxamides accelerated the reaction, and a large panel of styrene derivatives were suitable.

The formation of isoindolin-1-ones by C–H bond alkylation/
cyclisation with Co catalysis and electron-deficient alkenes was
described by Ackermann in 2015.<sup>412</sup> This approach demon-
strated good FG tolerance and selectivity, except in the case of two
*meta*-substituted arenecarboxamides (Me or F as substituents),
for which a second isomer was obtained (Scheme 67J). A broad
range of substituents was tested, including Cl, Br, I, F, OMe or
NO<sub>2</sub>, and led to moderate to good yields (42–85%).

Another oxidative coupling, using maleimides as coupling partners and mediated by Cu(OAc)₂ was published by Hirano and Miura.⁴¹³ This method gave direct access to spirosuccinimide derivatives (Scheme 67K). A key role of Cy₂NMe was suggested to promote the C–H bond cleavage and to increase the rate of the reaction. This process required a large excess of Cu, but a similar reaction was reported by Jeganmohan using only a catalytic amount of Co(OAc)₂ in 2017.⁴¹⁴ Maleimides were also used by Chatani, without intramolecular cyclisation, giving access to the corresponding alkylated products.⁴¹⁵ This reaction was performed under Rh catalysis (Scheme 67L) and was also efficient under Ru-based conditions.

The alkylation of a C(sp²)–H bond of Cp rings was also examined in 2015. Methylation and ethylation of two palladacycles derived from ferrocene and a Co sandwich compound were realised (Scheme 67M) with moderate yields (31–66%).<sup>407</sup> The Pd-catalysed system developed by Kumar for (hetero)arylation of ferrocenecarboxamides<sup>393</sup> was equally efficient for the mono- and di-alkylation with alkyl iodides (Scheme 67N). The key to control the selectivity was the nature of the base: NaHCO<sub>3</sub> promoted mono-alkylation while Cs<sub>2</sub>CO<sub>3</sub> yielded di-alkylated products. A catalytic system using Co(acac)<sub>2</sub> for alkylation of ferrocene derivatives was also studied, but only one example using an 8-aminoquinoline-derived amide as DG was reported, with 28% yield.<sup>408</sup>

14.1.1.1.3. **Allylation.** The introduction of allyl groups was also studied in recent years. In course of their studies regarding the alkylation reaction of amides, Chatani demonstrated that the same catalytic system might be used for the allylation reaction of arenecarboxamides in presence of an allyl bromide.⁴⁰¹ For all examples, the presence of a substituent at the *ortho*- or *meta*-position allowed a steric control in order to give exclusively the mono-allylated products (Scheme 68A).

Sundararaju published in 2015 another Ni-based catalytic system using allyl bromide.⁴¹⁶ With *ortho*- and *meta*- substitution relative to the DG, mono-allylation occurred with moderated to good yields (40–87%) while di-allylation took place only with *para*-substituted or unsubstituted arene carboxamides (Scheme 68B). A Pd catalysed system was developed by Liu using 3-bromo-3,3-difluoropropene as coupling partner (Scheme 68C).³⁸³

<figure><img src="image_137.png" /><figcaption>Scheme 68 Allylation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

The reaction tolerated a wide range of substituents on the
arencarboxamides (OMe, Br, F, CF₃, alkyl, aryl).

Finally, three different groups (Maiti,⁴¹⁷ Jeganmohan⁴¹⁸ and Chatani⁴¹⁹) concomitantly reported a Co-catalysed allylation of arenecarboxamides using aliphatic olefins. In all cases, in order to avoid a mixture of mono- and di-functionalised compounds in this cross-dehydrogenative reaction, the aromatic carboxamide partners were *ortho*-substituted and only linear allylated products were observed (Scheme 68D).

14.1.1.1.4. *Alkenylation, alkynylation and annulation.* The formation of isoindolinones was reported by Wei using readily available reagents such as carboxylic acids or anhydrides as coupling partners (Scheme 69A).<sup>420</sup> In this process, the presence of an additional pivalic anhydride was required for the reaction with carboxylic acids.

Another original oxidative coupling using allenes was reported by Cheng in 2017.<sup>421</sup> The reaction took place specifically on the terminal carbon of mono-substituted allenes (Scheme 69B) and yields between 30 and 83% obtained. Note that when unsymmetrical or cyclic allenes were used, mixtures of products were obtained.

The Co-based catalytic system developed by Jeganmohan, mentioned in the allylation part,⁴¹⁸ was also efficient for alkenylation reactions. The addition was totally selective but only low to moderate yields (23–42%) were obtained. Surprisingly the acetate group was preserved during the process, and the reaction was applied to substituted allylic alcohols (Scheme 69C). It is worth to mention that a mechanistic study regarding the Pd-catalysed regioselective C–H olefination reaction with aliphatic alkenes was reported by Peng, Paton and Maiti.⁴²²

<figure><img src="image_138.png" /></figure>