<figure><img src="image_139.png" /></figure>

<figure><img src="image_140.png" /><figcaption>Scheme 69 Alkenylation, alkynylation and annulation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

A Pd-based catalytic system was used by Wu and Ye to achieve the functionalisation of arenecarboxamides with 1-iodoglycals.⁴²³ An additional ligand derived from L-proline was required to obtain good to high yields (51–91%) and mono-selectivity (Scheme 69D), even if traces of diglycosylated compounds were generally detected. Various substituents on the amide partner were tolerated, such as a bromine atom particularly useful for further post-modifications.

In 2017, alkynes were also used by Chatani to perform alkenylation of *ortho*-substituted arenecarboxamides with alkynes relying on a Rh catalyst (Scheme 69E).⁴²⁴ This alkenylation reaction tolerated a broad array of substituents on the aromatic ring (Me, OMe, Cl, F, Br, Ac, NO₂, aryl).

Zhang performed a Pd-catalysed alkenylation of aryldifluoro-acetic acid derivatives bearing the 8-aminoquinoline scaffold, *via* a six membered palladacycle.⁴²⁵ The reaction showed excellent selectivity with only mono-substituted compounds detected with a large scope of styrenes and allylated reagents (Scheme 69F) with moderate to excellent yields (27–99%). However, small amounts of di-alkenylated compounds were observed with *para*-substituted arenecarboxamides, especially with F, COMe and SO₂Me as substituents.

The alkynylation of C(sp²)-H bond was reported multiple times using a Ni-based catalytic system. In 2015, the groups of

Li and Balaraman used (triisopropylsilyl)ethynyl bromide as coupling partner for the functionalisation of benzamides.⁴²⁶,⁴²⁷

In the former case, the reaction was also applied to acrylamide derivatives, but the use of a flexible bis(2-dimethylaminoethyl)-ether (BDMAE) as ligand was required (Scheme 69G). The system developed by Balaraman required additional benzoic acid (Scheme 69H). In this case, important amounts of di-alkynylated products were observed with *para*-substituted arenecarboxamides.

In 2016, Balaraman published a Co-catalysed di-alkynylation of arenecarboxamides with an 8-aminoquinoline pattern as DG (Scheme 69I).⁴²⁸ Di-Alkynylated compounds were generally obtained except in few cases, and several common FGs were tolerated (Br, Cl, F, Me, OMe, CF₃, NMe₂).

Chatani and co-workers published an annulation reaction after a twofold C–H bond activation (Scheme 69J).⁴²⁹ The annulation reaction could be inhibited by addition of a proton source, such as pivalic acid, resulting in alkenylation of the aromatic ring in *ortho* position, and various FGs on the amide coupling partner were tolerated (alkyl, OR, SMe, CF₃). A similar annulation reaction with alkynes was developed by Huang using Ni(cod)₂ as catalyst without any additive (Scheme 69K). Otherwise, the use of an electron-rich phosphine ligand favoured a [4+2] annulation yielding isoquinolones.⁴³⁰
Other metals were also studied in the last three years.

In 2017, Nicholls disclosed a Co-catalysed alkenylation of arenecarboxamides with various 1,3-diynes to form alkynylated isoquinolone derivatives (Scheme 69L).431 Note that the remaining alkyne was able to undergo another C–H activation process to synthesize bis-heterocycles.

Similarly, Ilies and Nakamura reported an oxidative annulation of acrylamide derivatives with alkynes catalysed by Fe, leading to the formation of pyridones (Scheme 69M) in typically excellent yields (up to 99%).432 When arenecarboxamides were used, the corresponding isoquinolones were obtained albeit with a narrow scope. Due to the key role of the *in situ* formed silylmethylzinc reagent, slight modifications in the reaction conditions led to the formation of mono-alkenylated products.

#### 14.1.1.1.5. Isocyanide insertion and reaction with nitroalkanes.

The synthesis of 3-iminoisoindolinones was realized with various catalytic systems using amides derived from 8-aminoquinoline as DG. A Cu-catalysed formal [4+1] cycloaddition of benzamides with isonitriles was reported by Hirano and Miura in 2015 (Scheme 70A) giving moderate to good yields (21–85%).433 In 2016, Lei and Hao published a Ni(acac)₂ catalysed reaction giving access to the same products (Scheme 70B) with typically good yields (> 70%).434

In 2016 and 2017, three protocols using a Co catalyst were studied by the groups of Hao,435 Ji437 and Sundararaju.436 In the former case (Scheme 70C), synthetically useful yields were obtained (30–85%) and a mixture of regioisomers was only observed for the arenecarboxamide bearing a fluorine as substituent at the *meta* position.

The protocol reported by Sundararaju provided the same selectivity (Scheme 70D), good yields (35–96% yield), and a mixture of regioisomers was only observed with *meta*-trifluoromethylated arenecarboxamides.436 An extension to acrylamide

derivatives was possible, albeit the corresponding products were obtained only with poor to moderate yields (27–63%).

The system developed by Ji showed good tolerance to steric hindrance, for instance tolerating a mesitylene group attached to the isocyanide partner (Scheme 70E).437 Generally, aromatic isocyanides are known to be difficult coupling partners. The transformation was efficient with arenecarboxamides (typically > 70% yield) and compatible with acrylamide derivatives giving moderate yields in the latter case (45–74%).

The use of nitromethane as a coupling partner was studied by the group of Tan.438 This reaction gave direct access to 3-hydroxyimino-1-isoindolinones (Scheme 70F). Note that 3-methylene-1-isoindolinones were obtained when other nitroalkanes were used.

#### 14.1.1.1.6. Carbonylation.
In the period 2015–2017, four protocols for carbonylation of C(sp²) centres avoiding the use of toxic CO gas were disclosed. The first, reported by Ge, employed DMF as a carbonyl surrogate and was applied to a wide range of amides, including arenecarboxamides (Scheme 71A) and aliphatic amides for the direct carbonylation of C(sp³) centres.439 A synergistic Ni/Cu system under oxygen was adopted, the Ni being coordinated to the DG and the Cu generating the electrophilic species from DMF.

A second Cu-catalysed carbonylation using 2,2'-azobisisobutyronitrile (AIBN) was reported in 2016 by Koley.440 With arenecarboxamides, only carbonylated compounds were observed with good yields (49–96%), but attempts to generalise this method to heteroarenecarboxamides gave only cyanated compounds (Scheme 71B), typically with excellent yields (mostly > 90%).

Another carbonylation was reported in 2016 by Zhang, using diisopropyl azodicarboxylate (DIAD) as carbon monoxide surrogate.441 Various arenecarboxamides were used, including compounds substituted with F, Cl, Br, CN, NO₂, CF₃ or OMe

<figure><img src="image_141.png" /><figcaption>**Scheme 70** Reactions with isocyanide and nitromethane using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

<figure><img src="image_142.png" /><figcaption>**Scheme 71** Carbonylation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

<figure><img src="image_143.png" /></figure>
<figure><img src="image_144.png" /></figure>

<figure><img src="image_145.png" /><figcaption>Scheme 72 Trifluoromethylation and halogenation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

and yields were typically around 70%. Several azodicarboxylates were also efficient for this reaction and three acrylamide derivatives were functionalised (Scheme 71C).

The last example was published by Daugulis in 2017, also using DIAD and a Co-based catalytic system, for the carbonylation of sulfonamide derivatives (Scheme 71D).<sup>442</sup> This reaction gave easy access to 2-sulfobenzoic acid imides in moderate to good yields (47–73%).

**14.1.1.1.7. Trifluoromethylation.** Tan published in 2016 a Cu-mediated protocol for the trifluoromethylation of arencarboxamides using the Togni reagent II under mild conditions (Scheme 72A). This selective method was robust (water as additive, air tolerant), efficient (36–80% yield) and tolerant to a large scope of substituents (alkyl, F, Cl, CF₃, OR, CO₂R, aryl).<sup>381</sup>

**14.1.1.1.8. Halogenation.** In 2016, Koley reported a Ni catalysed iodination of amides derived from 8-aminoquinoline.<sup>443</sup> This process used molecular iodine and gave selectively monoiodonated compounds (Scheme 72B) in good yield (typically >70%), with a good FG tolerance (alkyl, OR, CF₃, Cl, Br, NO₂, CN, aryl). Note that one non-aromatic amide was also reactive and was obtained in good yield.

**14.1.1.1.9. C-N bond formation.** Direct amination of arenecarboxamides was reported by Liu and Zhang using a Ni catalyst.<sup>444</sup> Being efficient (48–81% yield) with several secondary amines (Scheme 73A), this reaction provided mono-functionalised products and mechanistic studies suggested the involvement of a Ni¹/Ni³¹ catalytic cycle.

A Cu-catalysed protocol was reported by Daugulis in 2016.<sup>445</sup> The transformation was efficient with secondary amines, but the use of 1 equivalent of Cu was required in case of primary amines and aniline derivatives leading to the corresponding products in moderate to good yields (Scheme 73B). Note that slightly modified conditions were used for the amination of electron-poorer derivatives such as sulfonamides, which was also described in this study.

Another Cu-based system was developed by Jana for the amination of arenecarboxamides, using anilines and an excess of hydrated Cu(OAc)₂ (Scheme 73C). A broad range of substrates with different substitution patterns was functionalised and the synthetic utility of this transformation was further demonstrated by the gram scale synthesis of a bioactive compound, namely mefenamic acid.<sup>446</sup> Worth to mention that an

<figure><img src="image_146.png" /><figcaption>Scheme 73 Amination and nitration of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

extension to heteroaryls as coupling partners was reported by Punniyamurthy also relying on a Cu-mediated transformation.<sup>447</sup>

The synthesis of valuable triarylamines was performed in 2017 by Niu and Song by means of a Co-catalysed C–H bond activation strategy in the presence of an excess of aniline (Scheme 73D).<sup>448</sup>

Studying the properties of sulfoximines, Bolm used dibenzothiophene sulfoximine as an interesting ammonia surrogate in order to access valuable primary amines.<sup>449</sup> The surrogate was recycled and mono-amination was observed in all cases (Scheme 73E), but unfortunately only few examples were high yielding (20–86% yield, mostly <60%)

In addition to amination, the nitration reaction was also investigated, and *ortho*-nitration of (hetero)arencarboxamides was performed by a Cu mediated C–H bond activation, and tolerated common FGs (aryl, alkyl, F, Cl, Br, CF₃, CO₂R, OMe).<sup>450</sup> By changing the solvent and the base and under higher reaction temperature, the selectivity of the reaction was switched from mono- to di-nitration (Scheme 73F).

**14.1.1.1.10. Hydroxylation.** A Cu-mediated *ortho*-hydroxyl-ation of arenecarboxamides was reported by Jana and the chemoselectivity was controlled using pyridine as suggested by the author, probably by stabilizing a monomeric species and facilitating the reductive elimination (Scheme 74A). Indeed, in its absence, a dimerization process took place with some substrates.<sup>377</sup> Note that, in comparison with the PIP DG, the
<figure><img src="image_147.png" /></figure>

<figure><img src="image_148.png" /><figcaption>Scheme 74 Hydroxylation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

amide derived from 8-aminoquinoline was less efficient to promote the related alkoxylation reaction.⁴⁵¹

**14.1.1.1.11. Thiolation and trifluoromethylthiolation.** In 2015, a direct Ni catalysed *ortho*-thiolation was reported by Zhang with diaryl disulfides.⁴⁵² Both, arenecarboxamides and acrylamide derivatives were suitable substrates, giving desired products in good yields (mostly around 80%) and the presence of TBAI and *o*-nitrobenzoic acid as additives was required (Scheme 75A).

Kambe also studied Ni-catalysed thiolation and sulfonylation reactions with disulfides.⁴⁵³ Although the transformation was efficient (36–96% yield), a mixture of mono- and di-thiolated compounds was obtained with unsubstituted or *meta*- and *para*-substituted arenecarboxamides (Scheme 75B). Regarding the sulfonylation reaction, mono-sulfonylation of arenecarboxamides occurred (33–55% yield) along with traces of sulfonylation of the 8-aminoquinoline auxiliary with sulfonyl chloride under Ni-catalysis (Scheme 75C).

<figure><img src="image_149.png" /><figcaption>Scheme 75 Thiolation and trifluoromethylthiolation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>

Another sulfonylation reaction was reported by Tan in 2015 using a Cu-mediated system and sodium sulfinates, prepared from sulfonyl chlorides.⁴⁵⁴ The reaction showed good tolerance to steric hindrance, moderate to good efficiency (46–80% yield) and a large variety of sulfinates proved to be good coupling partners (Scheme 75D).

An original reagent for C–S bond formation was used by Messaoudi in 2016, performing the thioglycosylation of arene-carboxamides.³⁸⁴ Such thioglycosides (Scheme 75E) obtained with moderate to good yields (25–88%) could mimic their *O*-glycosides equivalents, with enhanced stability. However, in case of arenecarboxamides unsubstituted at the *ortho*-position, mixtures of mono- and di-functionalised compounds were obtained.

In 2017, a diastereoselective trifluoromethylthiolation of acrylamide derivatives was reported by Bouillon and Besset, using PdCl₂ as catalyst.⁴⁵⁵ Z-SCF₃-containing olefins were selectively synthesised in good yields (typically >70%), using the Munavalli reagent as both the SCF₃ source and the oxidant (Scheme 75F). Mechanistic studies suggested that the C–H bond activation event was the rate-determining step.

Finally to avoid the installation of the DG, a one-pot procedure was reported in 2017 by Liu and Wei for the C–S bond formation *via* C–H bond activation.⁴⁵⁶ The initial conditions gave access to di-thiolated compounds, and mono-thiolated products were selectively prepared in moderate to good yields (53–81%) by changing the base and using a lower amount of thiol derivatives (Scheme 75G).

**14.1.1.1.12. Selenylation.** Two protocols for C–Se bond formation by C–H activation were reported in the 2015–2017 period. The first one, published by Baidya in 2016, reported the arylselenylation of arenecarboxamides catalysed by Cu.⁴⁵⁷ Selective di-functionalisation was observed and a wide range of FGs was tolerated on both the arenecarboxamides or the selenated coupling partners (Scheme 76A). Substitution of the 8-aminoquinoline auxiliary was also well tolerated.

The second example was the Ni-catalysed synthesis of benzo-isoselenazolone derivatives under air atmosphere, reported by Nishihara in 2017.⁴⁵⁸ Mechanistic studies suggested that

<figure><img src="image_150.png" /><figcaption>Scheme 76 Selenylation and silylation of C(sp²) centres using 8-aminoquinoline-derived amides as DG.</figcaption></figure>
<figure><img src="image_151.png" /></figure>

the C–H bond cleavage is the rate-determining step of the reaction (Scheme 76B).

#### 14.1.1.1.13. Silylation.
A regio- and stereo-selective silylation of acrylamide derivatives was reported by Zhang in 2017.⁴⁵⁹ The reaction had a good FGs tolerance (Scheme 76C) and was efficient with α-substituted acrylamides. In contrast, only moderate yields were obtained with β-substituted derivatives. A stable palladacycle was characterized and explained the observed Z-selectivity.

#### 14.1.1.2. C(sp³)-H functionalisation.
The 8-aminoquinoline derived amides have been widely investigated in transition metal catalysed directed functionalisation of C(sp³)-H bonds and represent without any doubt a privileged bidentate DG for series of transformations.

##### 14.1.1.2.1. Arylation.
Pd-Catalysed arylation of unactivated aliphatic amides at the β-position constituted the most exemplified transformations with this DG. Since 2015, different coupling partners were used such as (diacetoxyiodo)arenes, the commonly used aryl halides (mainly iodide) and more scarcely polyfluoroarenes.⁴⁶⁰

Qin reported on Pd(II)-catalysed arylation of unactivated aliphatic amides using (diacetoxyiodo)arenes as arylation reagents via a Ag salt-free process, a real asset compared to other approaches (Scheme 77A).⁴⁶¹ Note that in this transformation the presence of Cs₂CO₃ was crucial. The selective mono-functionalisation of secondary C(sp³)-H bonds was achieved, albeit in case of a primary C(sp³)-H, a mixture of mono- and di-functionalised products was obtained.

Using aryl iodides as coupling partners, the Pd(II)-catalysed arylation of O-methyl lactic acids provided an efficient access to chiral β-aryl-α-methoxy acids under mild conditions (Scheme 77B).⁴⁶² In this approach disclosed by Shi, no

diarylation was observed. Note that the reaction was restricted to the functionalisation of primary C(sp³)-H bonds. One of the main limitations was the necessity to install the DG on the substrate. Consequently, as an improved protocol, the *in situ* generation of the bidentate DG and its use in a Pd-catalysed arylation reaction of unactivated aliphatic amides were independently studied by the groups of Babu⁴⁶³ and Liu.⁴⁶⁴ They developed a multicomponent reaction of acid chloride, aryl iodide and 8-aminoquinoline with a similar Pd-based catalytic system. In the former study, the monoarylation of linear aliphatic amides (22 examples, 50–97% yield) was reported. Note that in case of cycloalkanes, products resulting from a diarylation reaction (14 examples, 25–83% yield) was obtained (Scheme 77C). It is worth to mention that the Ag salt-free protocol reported by Liu was tolerant to various alkyl chains (Scheme 77D).

Moreover, the Pd-catalysed arylation of α-cyano aliphatic amides was also investigated, offering an access to useful and privileged more complex molecules.⁴⁶⁵ Extension of these reactions to the use of heteroaryl iodides as coupling partners was possible. Indeed, transition metal-catalysed heteroarylation of aliphatic amides were reported using iodopyridines as studied by Bach (Scheme 77E).⁴⁶⁶ Thiophene derivatives were also used by Xu and Qiu (Scheme 77F)⁴⁶⁷ as well as by Xia and Yin (Scheme 77G).⁴⁶⁸ In the last cases, the heteroarylation did tolerate several FGs on the heteroaromatic ring (Cl, Br, I, OR, C(O)R, CO₂R, aryl) and was carried out under Ni catalysis.⁴⁶⁹,⁴⁷⁰

This bidentate DG was not restricted to β-functionalisation as the arylation at the γ position was also successfully achieved via Pd-catalysis by Maiti (Scheme 77H)⁴⁷¹ and Babu (Scheme 77I),⁴⁷² although so far restricted to specific substrates with blocked β-position.

Furthermore, cyclic saturated compounds were also functionalised. Pd-Catalysed arylation of symmetric cycloalkanecarboxamides

<figure><img src="image_152.png" /><figcaption>Scheme 77 Arylation of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>
<figure><img src="image_153.png" /></figure>

<figure><img src="image_154.png" /><figcaption>Scheme 78 Diastereoselective or enantioselective arylation of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

at the β-methylene position was investigated by Chen (Scheme 78A).473 Derivatives of various ring sizes were studied giving efficient access to the corresponding mono-arylated products with high cis diastereoselectivity. Note that the efficiency of the reaction was dependent on the ring size of the substrate; 5-membered rings (24–68% of mono-arylated products and 2–5% of di-arylated products), 4 membered ring (25–32% mono- and 46–64% di-), 6 membered ring (33–54% mono- and 15–17% di-) and 7 membered ring (43% mono- and 5% di-). Surprisingly, the commonly used amide derived from pivalic acid was unreactive.

Hoshiya and Shuto disclosed a new protocol for the synthesis of 1,1,2,3-type chiral tetra-substituted arylcyclopropanes by means of a diastereoselective Pd(II)-catalysed C–H bond functionalisation (Scheme 78B).474 The nature of the alcohol protecting group turned out to be crucial for the efficiency of this difficult reaction by influencing steric and electronic features of the cyclopropane. Noteworthy, the tri-substituted chiral cyclopropane used as starting material was prepared in 5 steps from (R)-epichlorohydrin.

In addition, functionalisation of cyclobutanes was also described in a process involving a Pd(II)-catalysed cascade reaction: (1) synthesis of cyclobutanes from 6-bromohexanamides via a Pd(II)-catalysed intramolecular methylene C–H alkylation followed by a subsequent (2) intermolecular C–H bond functionalisation (i.e. arylation, alkenylation, alkylation, alkynylation, allylation, benzylation and alkoxylation) with various RX coupling partners offering an access to quaternary carbon centered cyclobutanes (not shown).475

Only rare protocols investigated diastereoselective or enantio-selective arylation of aliphatic amides. In 2015, Babu reported a Pd-catalysed diastereoselective arylation of aliphatic chains of a prochiral methylene group in β-position, with different substitutions patterns such as derivatives bearing a substituent at the α- or the γ-position and α- and β-disubstituted ones as well as (S)-2-phenylbutanamide for instance (Scheme 78C).371

The enantioselective arylation of secondary C(sp³) centers at the β-position of aliphatic amides was studied by Duan (Scheme 78D).476

<figure><img src="image_155.png" /><figcaption>Scheme 79 Arylation of C(sp³) centres of saturated heterocycles with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

The presence of chiral phosphoric acids and amides enabled controlling the enantioselectivity and was beneficial to the reaction rate.

Several groups investigated the arylation of unactivated secondary C(sp³)–H bonds of saturated heterocycles such as tetrahydrofuran- and 1,4-benzodioxanecarboxylic acid (Babu, Scheme 79A),370 proline (Liu and Zhang, Scheme 79B),477 furan-, N-protected piperidine- and THP carboxylic acid derivatives (Bull, Scheme 79C)378 as well as L-pipecolinic acid derivatives (Cao and Wu, Scheme 79D).478 In the last case, the method appeared to be robust with all excellent yields, typically around 80%, and tolerated a variety of FG such as free alcohol, nitrile and halogens. Moreover, using a similar catalytic system (Pd(OAc)₂ (5 mol%), AgOAc (2 equiv.), toluene, 110 °C), the β-arylation of dipeptides was achieved offering the possibility to functionalise protected amino acids as well as at the C-terminus of peptides (not shown).479

14.1.1.2.2. Alkylation. The Shi group reported a protocol based on a Co-catalysed intramolecular process leading to bicyclo[n.1.0]-alkanes in decent to good yields (32–77%) (Scheme 80A).480 The main drawbacks were a rather high catalyst loading and a relatively narrow FG tolerance (alkyl, Br, F). The same group developed an intermolecular process based on the Pd-catalysed functionalisation of O-alkylated lactic acid derivatives with alkyl iodides (linear or branched ones) to access chiral α-alkoxy acids in average (50–60%) yields (Scheme 80B).481 Only the mono-alkylated products were synthesised and the synthetic potential of this approach was demonstrated by a good tolerance to several FGs (halogene, amides, ester, protected alcohol and amine among others).

Alkylation of more rigid skeletons was possible as reported by Uenishi, who successfully developed a Pd-catalysed C–H bond functionalisation of a tertiary carbon of chiral cyclopropane derivatives with alkyl iodides and bromides (Scheme 80C) obtaining low to excellent yields (22–93%).482
Review Article

<figure><img src="image_156.png" /><figcaption>Scheme 80 Alkylation, cyanomethylation and alkoxycarbonylation of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

In an interesting example, acetonitrile was used for Pd-catalysed cyanomethylation of unactivated aliphatic amides, by primary and secondary C(sp³)-H bond activation. The transformation displayed good β-selectivity, tolerated a broad scope of bulky aliphatic groups, and the methyl C-H bonds were preferentially functionalised in the presence of methylene C-H bonds (Scheme 80D).³⁸⁵

Phosphonoalkyl iodides were also suitable coupling partners as demonstrated by the Pd-catalysed alkylation of aliphatic chains from Yang, which offered access to valuable chiral γ-phosphono-α-amino acids using (iodomethyl)phosphonate (Scheme 80E) with yield typically around 70% and up to 97%.⁴⁸³

14.1.1.2.3. **Alkoxycarbonylation.** Shi investigated the alkoxycarbonylation reaction of both primary and secondary C(sp³)-H bonds via a Pd(II)/Pd(IV) catalytic cycle (Scheme 80F).⁴⁸⁴ The use of alkyl chloroformates as carbonyl sources constituted a real asset for this transformation. The quantity of Ag salt was important to prevent the intramolecular C-N bond reductive elimination as alternative reaction pathway, even though its exact role was not elucidated. Functionalisation at the β- and even γ-position was possible, albeit in lower yields in the last case.

14.1.1.2.4. **Alkenylation.** Transition metal catalysed alkenylation of aliphatic amides were investigated using different

coupling partners. Rao reported a procedure based on a Pd-catalysed alkenylation with vinyl iodides. Access to linear E-olefins from E-iodo alkenes and Z-isomers from Z-olefins was obtained, albeit with moderate E/Z ratios in the latter case (Scheme 81A).⁴⁸⁵

Internal alkynes turned out to be suitable coupling partners in the alkenylation of aliphatic chains under Ni-catalysis as demonstrated by the methodologies developed by You (Scheme 81B)⁴⁸⁶ and Maiti (Scheme 81C).⁴⁸⁷ Zhang used terminal alkynes (Scheme 81D).³⁰⁸ The system developed by Maiti was efficient with a broad scope of diaryl alkynes, and tolerant to common FGs (OR, CO₂R, NO₂, CF₃). Alternatively, organoborate reagents were employed in an Fe-catalysed transformation, albeit restricted to few examples of alkenylated products (3 cases).⁴⁸⁸

A Co-catalysed reaction of aliphatic amides with terminal alkynes leading to the corresponding pyrrolidinones was reported by Zhang (Scheme 81E).⁴⁸⁹ Alkenylation of unactivated aliphatic C(sp³)-H bonds was also investigated by the same group, who developed a Cu(II)-catalysed and Ag(I)-mediated sequential alkynylation with alkynyl carboxylic acids and annulation via a decarboxylative process, offering access to pyrrolidinone derivatives (Scheme 81F).⁴⁹⁰

Shi also demonstrated that a Ni/Cu co-catalyst system might be used for the oxidative coupling of unactivated aliphatic amides with ethynyltriisopropylsilane as the terminal alkyne (not shown).⁴⁹¹

14.1.1.2.5. **Carbonylation.** Carbonylation of aliphatic chains has attracted a lot of attention as demonstrated by recent contributions. In course of their investigations towards the carbonylation of aromatic amides by means of Ni/Cu catalysis, Ge extended this approach to the functionalisation of aliphatic amides using DMF as carbon source in an oxygen atmosphere (Scheme 81G) giving good yields in the 60–80% range.⁴³⁹ Transformations involving Co catalysts with carbon monoxide reagent were also efficient as depicted by the group of Gaunt (Scheme 81H) with moderate to good yields (49–89%) and a good FG tolerance with for instance presence of a phthalimide group.⁴⁹² Similar systems were also reported by Sundararaju (Scheme 81I) with decent to good yields (15–87%)⁴⁹³ and by Lei (Scheme 81J) typically with yields around 70%.⁴⁹⁴

14.1.1.2.6. **Halogenation.** Only one report using the amide derived from 8-aminoquinoline was depicted for a chlorination reaction between 2015–2017. Besset studied the Pd-catalysed chlorination of unactivated aliphatic chains at room temperature in presence of NCS (Scheme 82A).⁴⁹⁵ The transformation was regioselective and even though both mono- and di-chlorinated products were obtained, they were easily separable by column chromatography. The reaction also tolerated the presence of common FGs such as halides, and gave typically a total yield between 60 and 70%. Worth to mention is that no chlorinated product at the C5 position of the 8-aminoquinoline was detected.

In addition, to the reports from Yu⁴⁹⁶ and Shi⁴⁹⁷ who investigated the Pd-catalysed fluorination of amino acid derivatives
<figure><img src="image_157.png" /></figure>

<figure><img src="image_158.png" /><figcaption>Scheme 81 Alkenylation and carbonylation of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

<figure><img src="image_159.png" /></figure>

at the β-position with other DGs, the Pd-catalysed directed fluorination of unactivated aliphatic chains with this bidentate DG was studied by the groups of Xu (Scheme 82B)⁴⁹⁸ as well as Wu, Zhang and Huang (Scheme 82C).⁴⁹⁹ In both cases, an electrophilic fluorinated reagent was used and a Pd(II)/Pd(IV) process was proposed to promote the reductive elimination step in this challenging transformation.

14.1.1.2.7. C–O bond formation. The Pd-catalysed C–O bond formation by C(sp³)–H activation was investigated by several groups. A protocol was proposed by Chen and Rao for the β-hydroxylation of aliphatic amides (Scheme 82D) with moderate to good yields (24–72%).⁵⁰⁰ In this catalytic system, water was used as the hydroxyl group source and the 1-hydroxy-1,2-benziodiolol-3-(1H)-one as oxidant. The reaction is moisture tolerant and in most cases, mono-hydroxylation occurred except for substrates bearing two methyl groups.

Acetoxylation reactions of methylene groups on aliphatic chains and benzylic positions were studied by Shi (Scheme 82E)⁵⁰¹ under oxidative conditions (use of oxone/Ac₂O) and gave the corresponding *anti*-β-hydroxy-α-amino acid amides in typically a yield around 60%, and up to 86%. Interestingly, these compounds were prepared in moderate to high diastereoselectivity *via* a sequential C–H functionalisation (mono-arylation or alkylation followed by an acetoxylation reaction). Note that to get a better understanding on the diastereoselectivity in Pd-catalysed alkoxylation of cyclic alkanecarboxamides, a study was reported by Rao (not shown).⁵⁰²

Stable nitroxyl radicals were used by the group of You to perform aminoxylation of C(sp³)–H bonds (Scheme 82F).⁵⁰³ This Ni-catalysed system gave fair to good yields (35–91%) and was tolerant to various FGs (halides, allyl, OMe, alkyl, aryl). Organosilanes were also suitable coupling partners allowing the aryloxylation/vinyloxylation of unactivated aliphatic chains as described by Zhang (Scheme 82G).¹⁴⁹

14.1.1.2.8. C–N bond formation. The transition metal catalysed C–N bond formation was investigated by several research groups over the 2015–2017 period. The access to β-lactams was achieved by intramolecular processes by Yang and You (Scheme 83A)⁵⁰⁴ and by Cao and Wu (Scheme 83B).⁵⁰⁵ In the first case, the use of Cu as catalyst was effective. In the second one, Pd was required. A large array of FGs was tolerated (alkyl, OR, F, Cl, Br, NO₂, aryl) and excellent yields were typically obtained, mostly around 80–90%. Isoindolinones were also accessible thought a benzylic C(sp³)–H bond activation, as described by Hirano and Miura (Scheme 83C).⁵⁰⁶ Intermolecular processes were also disclosed, using simples alkylamines (Scheme 83D and E).⁵⁰⁷,⁵⁰⁸ Both systems are Cu-mediated, but in the first case the scope was limited to secondary cyclic alkylamines. However, a broad variety of substituent was tolerated on the amide partner (aryl or bulky aliphatic groups). In the latter case, both cyclic and acyclic dialkylamines were efficient.

14.1.1.2.9. Sulfenylation, sulfonylation and trifluoromethyl-sulfenylation. Since 2015 several groups (Shi,⁵⁰⁹ Zhang,⁵¹⁰ Shi⁵¹¹ as well as Qiu, Xu and Yin⁵¹²) investigated the Ni-catalysed
<figure><img src="image_160.png" /></figure>

<figure><img src="image_161.png" /><figcaption>Scheme 82 Halogenation and C–O bond formation on C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

<figure><img src="image_162.png" /><figcaption>Scheme 83 Amination of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

sulfonylation of aliphatic chains using generally disulfides or thiol derivatives (Scheme 84A–D). These protocols were

<figure><img src="image_163.png" /><figcaption>Scheme 84 Sulfenylation, sulfonylation, trifluoromethylthiolation and silylation of C(sp³) centres with 8-aminoquinoline-derived amides as DG.</figcaption></figure>

complementary using either aromatic disulfides and even thiols (Scheme 84A and B) or both aromatic and aliphatic ones (Scheme 84C and D). Note that depending on the reaction conditions and the substrate skeleton, mono- and/or di-functionalised products were obtained. This approach was not restricted to the C–S bond formation, since an extension to a C–Se bond construction was also reported (Scheme 84B).

A first example of a Pd-catalysed sulfonylation using sodium sulfinates was studied by Shi (Scheme 84E).⁵¹³ Efficient with a large scope of sodium sulfinates, this reaction also tolerated the presence of common FGs on the amide partner (alkyl, aryl, F, Cl, CF₃, Br). In addition, the Pd-catalysed direct introduction of a SCF₃ group by C–H bond activation was developed by Besset, the sole report of the trifluoromethylthiolation of a primary C(sp³)–H bond reported so far (Scheme 84F).³⁷³ Decent yields were obtained (up to 53%) and this reaction was compatible with the presence of various common FGs. Besides, a large variety of aliphatic carboxamides were functionalised such as
those derived from pivalic acid, α,α-dimethyl hydrocinnamic acid, phenylacetic acid and even more challenging substrates bearing a C–H bond at the α position of the carbonyl group. The synthetic utility of this transformation was further illustrated by the synthesis of analogues of bioactive molecules (ibuprofen and naproxen).

14.1.1.2.10. **Silylation.** Silylation of unactivated aliphatic chains, α-amino acid derivatives by means of Pd-catalysis at the β-position and even at the γ-one were studied by Zhang (Scheme 84G),⁵¹⁴ Shi (Scheme 84H)⁵¹⁵ and Maiti (Scheme 84I),⁵¹⁶ respectively. Albeit an excess of the coupling partners was generally necessary, with these three protocols functionalisation at the β- and even at the γ-position when the β-position was di-substituted was possible and extension to germanylation was even possible as depicted by Maiti.

### 14.1.2. Amides derived from 5-chloro-8-aminoquinoline and from 5-methoxy-8-amino-quinoline.
As the C5 position of the 8-aminoquinoline part of the bidentate DG might also be reactive, competitive pathways might be observed and in some reports, the selective functionalisation at the C5 position was achieved.³⁶⁰⁻³⁶⁹ To tackle this issue, the design of new bidentate DG was realized and the amides derived from either 5-chloro-8-aminoquinoline (Q'NH₂) or 5-methoxy-8-amino-quinoline (MQNH₂) were investigated instead.

#### 14.1.2.1. C(sp²)–H functionalisation.
The amide derived from 5-chloro-8-aminoquinoline was employed as bidentate DG in the Ni(II)-catalysed sulfonylation of carboxamides as reported by Chatani (Scheme 85A).⁵¹⁷ A mechanism involving a Ni(II)/Ni(IV) catalytic cycle was proposed, albeit the authors cannot rule out a radical pathway. Note that the 5-methoxy-8-quinolinyl derived amides led to the decomposition of the starting materials.

In the course of their studies regarding the synthesis of isoindolinones *via* Pd catalysis, Wei showcased that the amides derived from 5-chloro-8-aminoquinoline and from 5-methoxy-8-aminoquinoline were efficient DGs in Pd-catalysed C–H bond functionalisation of benzamides with anhydrides and carboxylic acids (Scheme 85B).⁴²⁰ Note that only four examples were reported.

#### 14.1.2.2. C(sp³)–H functionalisation.
It was reported that for arylation of C(sp³) centres, aryldiazonium salts were suitable

<figure><img src="image_164.png" /><figcaption>**Scheme 85** Functionalisation of C(sp²) centres using amides derived from 5-chloro-8-aminoquinoline (Q'NH₂) and from 5-methoxy-8-amino-quinoline (MQNH₂) as DGs.</figcaption></figure>

<figure><img src="image_165.png" /><figcaption>**Scheme 86** Functionalisation of C(sp³) centres using amides derived from 5-chloro-8-aminoquinoline (Q'NH₂) and from 5-methoxy-8-amino-quinoline (MQNH₂) as DGs.</figcaption></figure>

coupling partners. Indeed, by combining Pd catalysis and photoredox, Polyzos achieved the arylation of aliphatic amides derived from Q'NH₂ with α-quaternary centers in moderate to good yields (21–78%, Scheme 86A).⁵¹⁸ The transformation was selective towards primary C(sp³) centres and even a benzylic methylene group remained unaffected.

The Pd(II)-catalysed benzylation of aliphatic amides *via* a cross dehydrogenative coupling was disclosed by the group of Chatani (Scheme 86B).⁵¹⁹ The transformation was selective for the β-position leading to the corresponding products in 40–75% yields and a real asset of this reaction was the use of toluene derivatives as reagent (10 equiv.) and not as a solvent. The use of this bidentate DG was not restricted to the C–C bond formation as the β-halogenation of unactivated aliphatic chains was also reported by Rao⁵²⁰ and Chatani.⁵²¹ Rao developed a protocol enabling the halogenation of C(sp³) centres at room temperature *via* Pd catalysis (Scheme 86C). This bidentate DG was crucial for the success of the transformation since when the amide derived from 8-aminoquinoline was used, introduction of the chlorine atom at the C5 position was observed. Key features need to be highlighted such as (1) good FG tolerance (NO₂, Br, F, acetyl, CF₃), (2) the functionalisation of substrates bearing secondary, tertiary and quaternary centers at the α-position of the carbonyl groups (28–85% yields) and (3) the possibility to convert the C–X bond into various C–FG bonds.⁵²⁰ Note that depending on the skeleton of the amides, mono- or poly-halogenation occurred. Importantly, the amide derived from Q'NH₂ was easily cleavable under acidic conditions (BF₃·Et₂O or concentrated H₂SO₄, 100 °C).⁵²⁰

Chatani showed that a Ni catalyst was suitable for the iodination reaction of aromatic and aliphatic amides derived

<figure><img src="image_166.png" /></figure>
<figure><img src="image_167.png" /></figure>

from Q'NH₂ with simple molecular iodine (I₂), leading to the corresponding iodoarenes (44–83%) (not shown) or β-lactams (27–91%), respectively (Scheme 86D).⁵²¹ When aromatic amides were used as substrates, mono- and di-iodinated products were obtained depending on the substitution patterns of the starting material (not shown), albeit in case of aliphatic chains, the corresponding iodinated products were not isolated affording a direct access to β-lactams.

Amides derived from 5-methoxy-8-aminoquinoline (MQNH₂) were used in few reports involving Pd⁵⁰⁵ or Cu⁵⁰⁴,⁵⁰⁶ catalysed C–N bond formation and Pd-catalysed C–Cl bond formation.⁴⁹⁵ Indeed, although the methodologies were mainly developed for the amide derived from 8-aminoquinoline (QNH₂) as DG, the good reactivity and the easy cleavage of the MQ-based DG in the presence of CAN⁴⁹⁵,⁵⁰⁴,⁵⁰⁵,⁵²¹–⁵²³ or a demethylation/oxidation sequence⁵⁰⁶ towards the corresponding amides make this DG particularly attractive. Worth is to mention that only a small number of examples with MQ-based DG was depicted in these reports (1 to 3 max), hence only showcasing the potential of this DG. In addition, it was successfully applied in the C–C bond formation. Indeed, recently, Shi reported the Pd-catalysed β-arylation of alanine derivative (15 examples, 68–93% yields, Scheme 86E) and the subsequent amidation *via* an intra-molecular process leading to the corresponding highly valuable α-amino-β-lactams.⁵²² It is important to highlight that the cleavage of the DG was achieved for several products (6) in moderate to high yields (23–83%).

### 14.1.3. Sulfonamides featuring 8-aminoquinoline and amides featuring phenylenediamine as DGs.
In 2015, White-oak, Ribas and co-workers investigated sulfonamides featuring 8-aminoquinoline as an analogue of the corresponding amide with first row transition metals (Scheme 87A).⁵²⁴ Indeed, a Co-catalysed reaction between arenesulfonamides with terminal and internal (symmetrical or not) alkynes yielding sultams was developed in the presence of Mn(OAc)₃. This approach turned out to be highly regioselective and with good functional group tolerance. Lots of efforts were made to cleave the DG although without success.

<figure><img src="image_168.png" /><figcaption>Scheme 87 Functionalisation of C(sp²) centres using sulfonamides featuring 8-aminoquinoline and amides derived from phenylenediamine as DGs.</figcaption></figure>

Then, Sundararaju reported a similar study involving Co-catalysis (45–90% yield) (Scheme 87B).⁵²⁵ Finally, a slightly different catalytic process was developed by the group of Yang (Scheme 87C).⁵²⁶ In that case, no Mn salt was required as NaClO₃ was used as an alternative oxidant and PivOH played a key role. Aromatic and aliphatic terminal alkynes were suitable coupling partners as well as internal alkynes. When unsymmetrical aryl alkyl alkynes were used a mixture of regioisomers was obtained, the aryl group being at close proximity of the nitrogen atom as major isomer.

Very recently, a new N,N-bidentate DG based on a 2-amino-phenyl moiety was designed by Watkins (Scheme 87D).⁵²⁷ It was successfully employed in a Pd-catalysed arylation of benzamide derivatives (>30 examples, up to 84% yield). Mono-arylated compounds were obtained and (hetero)aromatic iodides such as benzophenone, pyrimidines, and pyridine were suitable coupling partners. With this bidentate DG, the typical use of a Ag salt was no longer necessary as it could be replaced with Mn(OAc)₂. The DG was efficiently removed under basic conditions (NaOH/EtOH under reflux).

#### 14.1.4. Amide derived from 2-(2-pyridyl)-2-isopropylamine.

The PIP based DG derived from 2-(2-pyridyl)-2-isopropylamine (PIPNH₂) has been extensively studied since its design in 2013.⁵²⁸,⁵²⁹ This removable DG has shown great potential in direct C–H bond functionalisation with various transition metals, the most commonly used being Ni, Co, Cu and Pd catalysts. Its removal might be achieved *via* a nitrosylation/hydrolysis sequence,⁴⁵¹,⁵³⁰–⁵³⁵ a two step process *via* the *in situ* esterification of an electrophilic pyridinium triflate intermediate⁴⁹⁷ or under acidic conditions.⁵³⁶–⁵³⁸

##### 14.1.4.1. C(sp²)-H functionalisation

14.1.4.1.1. Arylation. Since 2015, several groups were interested in arylation and heteroarylation of carboxamides. Two reports from Shi focused on Ni catalysed arylation of (hetero)arene carboxamides using aryl boron reagents⁵³⁹ or arylsilanes⁵³⁰ as alternatives to the more classically used Ar₂I⁺X⁻ and ArX coupling partners. In the former case, a Ni(II)/Ni(III) catalytic pathway was proposed and the reaction proved to be efficient (40–85%), tolerant against several FGs (Cl, CF₃, OMe, F) and steric hindrance (Scheme 88A).⁵³⁹ In the latter case, the use of non-toxic and safe to handle arylsilanes are key advantages and the transformation proceeded *via* a fluoride-promoted transmetallation in moderate to good yields (26–92% yields, Scheme 88B). The PIP based DG was removed after a nitrosylation/hydrolysis sequence affording the corresponding acid.⁵³⁰

A complementary approach relied on a Cu/Ag-mediated arylation of (hetero)arenecarboxamides using 2-thiophenecarboxylic acids as coupling partners (Scheme 88C).⁵³¹ In this reaction, a protodecarboxylation/dehydrogenative coupling process was involved. The same authors reported that thiophenes were also suitable coupling partners. Indeed, they developed a Cu-catalysed oxidative dehydrogenative arylation of a panel of thiophene compounds and the reaction turned out to be tolerant to halogen and carbonyl groups for instance (Scheme 88D).⁵⁴⁰ To further demonstrate the synthetic utility of this bidentate
<figure><img src="image_169.png" /></figure>

<figure><img src="image_170.png" /><figcaption>Scheme 88 Transition metal catalysed functionalisation of C(sp²) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.</figcaption></figure>

DG, a Pd-catalysed PIP-directed arylation of C(sp³)-H bonds was successfully developed by Baudoin, offering an access to the aeruginosin family of marine natural products (not shown).⁵⁴¹

Arylation reactions with this DG were not restricted to het(arenes) as ferrocenecarboxamides were functionalised with aryl iodides *via* Pd catalysis (30–81% yield) as developed by Yang, Wu and Wu (Scheme 88E).³⁹⁴ Note that the amide derived from 8-aminoquinoline was also a suitable DG in this transformation (see Section 14.1.1).

#### 14.1.4.1.2. Alkylation.
The alkylation of aromatic carboxamides bearing PIP as DG were reported by Lu and Li (Scheme 88F and G). Indeed, they developed two Co catalysed protocols. In one case, the dicumyl peroxide (DCP) was employed playing the role of both source of the methyl group and hydrogen acceptor *via* a radical process.⁵⁴² In the second case, an oxidative cross dehydrogenative coupling with various alkylated derivatives (alkanes, (thio)ethers and toluene derivatives) was reported (47 examples, up to 85% yield).⁵⁴³

#### 14.1.4.1.3. Alkynylation.
The group of Shi investigated the alkynylation of aromatic and heteroaromatic amides. At first, a protocol using a Cu catalyst and terminal alkynes was developed, a clear advantage compared to the existing approaches (Scheme 89A).⁵³² Then, they studied a modified process involving a low Ni catalyst loading with bromoalkynes as coupling partners (Scheme 89B).⁵³³ The efficient reaction turned out to

<figure><img src="image_171.png" /><figcaption>Scheme 89 Alkynylation of C(sp²) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.</figcaption></figure>

be chemoselective towards the synthesis of mono- or di-alkynylated products depending on the amount of alkynes used, in 62–98% yield and 52–99% yield, respectively.

Additionally, a Ni(II)-catalysed dehydrogenative alkynylation using O₂ as the sole oxidant was developed,⁵⁴⁴ a clear advantage compared to their previous report,⁵³² in which a superstoichio-metric amount of a Ag salt was necessary (55–95%, 28 examples, Scheme 89C). It is worth to note the key role of PIP as DG since all other bidentate DGs failed except the one derived from 8-amino-quinoline providing the expected product only in poor yield (37%).

#### 14.1.4.1.4. Halogenation.
Shi developed in 2016 the first Ni-catalysed halogenation of aromatic and heteroaromatic amides using inexpensive and readily available LiX salts as halide source (Scheme 90A).⁵³⁶ Note that a slight change of the catalytic system (NiCl₂(PPh₃)₂ 10%, LiCl 3 equiv., KMnO₄ 2.2 equiv., tBuCN, O₂, 140 °C, 24 h), compared to the one used for the bromination and iodination reaction, allowed the formation of a C-Cl bond (not shown). Aromatic derivatives bearing various FGs (halogen, Ac, CF₃) were functionalised in about 41–92% yield (20 examples) as well as heteroaromatic amides, albeit in somehow lower yields (30–76%, 9 examples). For unsubstituted and some para-substituted arenecarboxamides, mixtures of mono- and di-halogenated products were observed.

#### 14.1.4.1.5. Alkoxylation.
C–O bond formation was also studied in recent years and two protocols for methoxylation (Scheme 90B)⁴⁵¹ and acyloxylation (Scheme 90C)⁵⁴⁵ *via* Cu catalysis were developed by Shi. In the first case, aromatic and heteroaromatic derivatives bearing various FGs (e.g. CF₃, NO₂, halogen) were methoxylated in moderate to good yields (25–96%). In the latter case, sterically hindered benzoic acids were crucial, as no expected product was obtained in presence of benzoic acid. The scope is pretty narrow (11 examples, 29–70%) and in several cases, mixture of products (mono- and di- as well regioisomers (one case) were obtained). The authors proposed a Cu(II)/Cu(III) catalytic cycle.

#### 14.1.4.1.6. Sulfenylation and sulfonylation.
The PIP bidentate based DG was particularly efficient for sulfenylation and sulfonylation reactions *via* Ni catalysis.
<figure><img src="image_172.png" /><figcaption>Scheme 90 C(sp³)-heteroatom bond formation using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.</figcaption></figure>

In 2014, seminal works on transition metal catalysed C-S bond formation were developed using Pd⁵⁴⁶ or Rh⁵⁴⁷ catalysts. One year later, key contributions in that field were reported by Lu and Shi using low cost metals, especially Ni catalysts. Indeed, using aryl disulfides as electrophilic sulphur sources, Lu developed a Ni-catalysed sulfenylation reaction; the use of a catalytic amount of benzoic acid was essential to promote the reaction in typically about 80-90% yields, except for three derivatives (Scheme 90D).⁵³⁷ Afterwards, Shi disclosed another Ni-catalysed protocol which did not require an additional oxidant, although in that case an extra ligand was required (up to 93% yield, Scheme 90E).⁵⁴⁸ For this transformation a Ni(II)/Ni(IV) catalytic cycle was proposed. Note that a complementary study was reported by Shi dealing with the Cu-mediated sulfenylation of heteroaromatic amides (37 examples, 83-99% yield, Scheme 90F).⁵⁴⁹

The sulfonylation reaction using sodium sulfinates was also studied by Shi⁵³⁴ (26 examples, up to 80% yield) as well as Gong and Song (33 examples, up to 90% yield),⁵⁵⁰ using a Cu- or Ni-catalyst, respectively (Scheme 90G and H).

### 14.1.4.2. C(sp³)-H functionalisation.
The PIP-based bidentate DG was also successfully employed in transition metal catalysed

<figure><img src="image_173.png" /><figcaption>Scheme 91 Pd-Catalysed functionalisation of C(sp³) centres using the amide derived from 2-(2-pyridyl)-2-isopropylamine as DG.</figcaption></figure>

C-O, C-N and C-F bond formation by activation of C(sp³)-H bonds. Regarding C-O bond formation, this DG was mainly employed in intramolecular processes for the functionalisation of secondary C(sp³) centers leading to the corresponding lactones and cyclic ethers as concomitantly studied by the groups of Shi⁵⁵¹ and Ye,⁵³⁵ using a similar catalytic system (Scheme 91A and B).

#### 14.1.4.2.1. Amination.
Zhang studied Pd-catalysed direct amination of unactivated methylene C(sp³)-H bonds using azodiformates as the amino source, especially the diethyl azodicarboxylate, offering access to β-amino acid analogues (Scheme 91C).⁵³⁸ The transformation was achieved on primary and secondary C(sp³) centers and turned out to be sensitive to steric hindrance. Note that the amide derived from 8-aminoquinoline was also a suitable substrate even though providing the expected derivatives in lower yields.

#### 14.1.4.2.2. Fluorination.
The Pd-catalysed fluorination of amino acids at the β-position was independently reported by the groups of Shi⁴⁹⁷ and Ge⁵⁵² using SelectFluor as the fluorine source. Shi reported the first example of the fluorination of aliphatic and benzylic methylene C(sp³)-H bonds via an inner sphere mechanism and the PIP amide group was cleaved leading to the corresponding esters (Scheme 91D).⁴⁹⁷ In the latter case, the functionalisation was extended to the fluorination of aliphatic amides and good yields were obtained on unactivated aliphatic amides with various skeletons (Scheme 91E).⁵⁵²

### 14.1.5. Amides derived from 2-(2-pyridyl)ethylamine and 2-(aminomethyl)pyridine.
In contrast, only a handful of reactions used amides derived from 2-(2-pyridyl)ethylamine (PE) and
<figure><img src="image_174.png" /></figure>

<figure><img src="image_175.png" /><figcaption>**Scheme 92** Functionalisation of C(sp³) centres using the amides derived from 2-(2-pyridyl)ethylamine (PE) and 2-(aminomethyl)pyridine (PM) as DGs.</figcaption></figure>

2-(aminomethyl)pyridine (PM), probably due to a less favourable geometry of the intermediate, have been reported.

In 2016, He and Chen reported a Pd-catalysed arylation of phthaloyl alanines at the β-position using amides derived from PE as bidentate DG (Scheme 92A).⁵⁵³ With two sets of reaction conditions (conditions A, 16–90%; conditions B, 15–72%), they successfully employed sterically hindered *ortho*-substituted aryl iodides (e.g. OMe, NO₂, Me, OAc, COMe, F), a significant synthetic challenge. The transformation was really selective as no product resulting from di-arylation or β-lactam byproducts were observed. However, when the arylation at the β-methylene position was concerned, mono-arylated products were obtained in rather lower yields (<48%). Note that PE-directed arylation of isoleucine derivatives at the γ-position was previously reported by the authors.⁵⁵⁴ In comparison, when PM was used as DG (Scheme 92B), the reaction was really sensitive to steric hindrance leading to poor yields (15–26%) with 2-substituted aryl iodides but the transformation was still efficient with *para*-substituted aryl iodides (62–86% yields).⁵⁵³

The PM DG was also employed in the Pd-catalysed arylation of diamondoids with aryl iodides (36–87%), a synthetic challenge due to the large number of possible C–H bonds to be functionallyised (Scheme 92C).⁵⁵⁵

### 14.1.6. Picolinamides.
Since the pioneering work of Daugulis,³⁴⁴ the use of this N,N-bidentate DG has been extensively investigated in various transformations.⁵⁵⁶⁻⁵⁵⁸ The cleavage of this DG was conducted under acidic,⁵⁵⁹,⁵⁶⁰ basic⁵⁶¹⁻⁵⁶⁶ and reductive acidic⁵⁶² conditions as well as after a treatment with PCl₅/2,4-lutidine then MeOH and an aqueous work-up.⁵⁶⁷

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

##### 14.1.6.1.1. Arylation and alkylation.
Pd-Catalysed arylations of thiophene derivatives and allylamines were reported. In 2016, Babu and co-workers disclosed picolinamide-directed arylation of the C3-position of 2-(aminoethyl)thiophenes with aryl iodides and heteroaryl iodides in low to good yields and in a regioselective manner (Scheme 93A).⁵⁶⁸ The same group used a similar catalytic system for arylation of allylamines at the γ-position leading to the corresponding cinnamylamines with good to high E/Z ratios (up to 2:98) in the favour of the challenging Z isomers (Scheme 93B).⁵⁶⁹ Note that substrates

<figure><img src="image_176.png" /><figcaption>**Scheme 93** Picolinamide-directed arylation and alkylation of C(sp²) centres.</figcaption></figure>

bearing a primary γ-C(sp³) center and a γ-C(sp²) center led to di-arylated products. Furthermore, Shao and He reported the Pd-catalysed cyclisation of alkenyl anilines *via* oxidative arylation (not shown).⁵⁷⁰

For the methylation of arenes, two reports were published using either AlMe₃ or MeI as the methyl source. In 2015, Ilies and Nakamura developed a protocol allowing methylation of arenes *via* Fe catalysis, involving a plausible Fe(III)–Me intermediate (Scheme 93C).⁴⁰³ Although efficient, only a couple of examples were reported and the selectivity for monomethylation *vs*. di-methylation depended on the substrate substitution pattern.

Another protocol from Zhang and Ma described the Pd-catalysed methylation of the amide derived from (S)-tyrosine analogues (Scheme 93D).⁵⁵⁹ It is worth to mention that only this DG was efficient for this di-methylation reaction and a scale up on *ca*. 20 g was successfully achieved with the complete retention of the chiral information.

##### 14.1.6.1.2. Alkenylation.
Two examples of alkenylation/annulation reactions have appeared since 2015. Rodriguez, Arrayás and Carretero reported a Rh(I)/Rh(III) catalysed functionalisation of aromatic picolinamide derivatives with internal alkynes (Scheme 94A and B).⁵⁶¹ Depending on the choice of Rh catalyst (Rh(I) vs. Rh(III)), a nice divergent site-selectivity control was achieved *via* selective functionalisation of either the aromatic or the heteroaromatic part (the DG itself) of N-substituted picolinamide compounds. Depending on the reaction conditions, the synthesis of isoquinoline derivatives or the olefination of benzylamine and phenethylamine derivatives was achieved. Note that in the latter case, the di-olefinated products were obtained except on specific substrates. Symmetrical and unsymmetrical alkynes were used as coupling partners; the observed regioselectivity depended on the alkyne substitution. This study was strongly supported with several mechanistic studies and DFT calculations.

Two years later, the same group reported a protocol for the synthesis of 1,4-dihydroisoquinoline compounds (56–96% yield)
<figure><img src="image_177.png" /></figure>

<figure><img src="image_178.png" /><figcaption>Scheme 94 Picolinamide-directed alkenylation and alkynylation of C(sp²) centres.</figcaption></figure>

from benzylamines taking advantage of Co catalysis and using molecular O₂ as oxidant (Scheme 94C).⁵⁶² An interesting feature is that, in contrast to Rh catalysis, dialkyl alkynes were more efficient in that case as compared to diaryl ones. Additionally, terminal alkynes were suitable coupling partners as well. When unsymmetrical alkynes were used, the regioselectivity seemed to be controlled by electronic factors: 1-aryl-1-alkynes provided only one single diastereoisomer albeit no regiocontrol was observed with dialkylated alkynes.

The Co-catalysed alkynylation of benzylamine derivatives was studied by Balaraman and co-workers (Scheme 94D).⁵⁷¹ The transformation was FG tolerant (NO₂, Br, OMe) and importantly, primary, secondary, tertiary and even enantiopure benzylamines were suitable substrates. Depending on the substrate, mono-, di-alkynylated products or even a mixture was obtained.

#### 14.1.6.1.3. Cyanation.
Recently, the use of picolinamide as DG allowed the cyanation of naphthalene derivatives via Cu catalysis. Using this cost-attractive transition metal, the functionalisation of a panel of naphthalenes was possible using benzoyl cyanide as the cyano source (Scheme 95A).⁵⁶⁰ Although efficient, the transformation turned out to be sensitive to the substitution pattern of the substrate.

#### 14.1.6.1.4. Trifluoromethylation.
Using an inexpensive Ni catalyst and the Langlois' reagent, Zhang reported the trifluoromethylation of arylamines under mild conditions (50 °C, air atmosphere) with cheap oxidant leading to the corresponding trifluoromethylated products in moderate to good yields (Scheme 95B). It is worth mentioning that this transformation was carried out in water and the catalytic system was recycled and reused about eight times.⁵⁷²

<figure><img src="image_179.png" /><figcaption>Scheme 95 Picolinamide-directed functionalisation of C(sp²) centres.</figcaption></figure>

#### 14.1.6.1.5. Acetoxylation.
In 2017, Zeng reported a Co-catalysed cross dehydrogenative coupling (CDC) between picolinamide derivatives with aliphatic and aromatic carboxylic acids (Scheme 95C).⁵⁷³ It is worth mentioning that this transformation was mainly restricted to naphthalene compounds and only two N-benzyl substituted 2-pyridinecarboxamides were functionalised as well, although in low yields (25 and 37%). Acetoxylation at the remote e-C(sp²)-H bond was studied by Babu using this bidentate DG (not shown).⁵⁷⁴

#### 14.1.6.1.6. Amination.
The regioselective amination of 1-naphthylamine derivatives at the C8-position was independently reported by Yang, Wu and Wu⁵⁶³ as well as Punniyamurthy⁵⁶⁴ using a Pd or Cu catalyst, respectively (Scheme 95E and F). The Pd-catalysed mono-amination of naphthalene derivatives was achieved (up to 89% yield). Although the diversity in term of naphthalene derivatives was rather limited (4 different skeletons), several cyclic secondary aliphatic amines were suitable.⁴⁷¹ Under Cu catalysis the introduction of indoles was possible in moderate to good yields (39–74%) and a large variety of FGs was tolerated on the indole skeleton (e.g. halogen, ester, vinyl, allyl) and even 7-azaindole.⁵⁶⁴ The approach was also applied to the introduction of azoles, albeit only 3 examples were reported (51–69%). Note that the arylation of the NH of the picolinamide part was also reported with boronic acids (not shown).⁵⁷⁵

Hirano, Miura and co-workers also investigated the Cu-promoted intramolecular amination reaction on phenethylamine
<figure><img src="image_180.png" /></figure>

derivatives. Indeed, in 2015, two sets of reaction conditions were established for the synthesis of indolines under microwave irradiation *via* a Cu-mediated or catalysed process using MnO₂ as a terminal oxidant in the last case (Scheme 95F).⁵⁷⁶ In 2017, the same authors reported a DG controlled divergent process which allowed, in case of NHPA as DG, the selective access to indole derivatives starting from enamides *via* a Cu-catalysed intramolecular C–H bond amination reaction (Scheme 95G).⁵⁷⁷

14.1.6.2. *C(sp³)–H functionalisation.* The picolinamide DG has played an interesting role in the Pd-catalysed alkenylation of aliphatic amines at the δ-position with alkynes in a highly selective manner.⁵⁶⁷ Indeed, to date δ-C(sp³)–H bond functionalisation remains scarce and often occurred on substrates on which the γ-position was less accessible or sterically hindrance favoured a six-membered intermediate rather than the kinetically favoured five-membered metallacycle. Impressively, the functionalisation was completely site-selective even in presence of accessible γ-C(sp³)–H bonds. The reaction provided the corresponding products in moderate to good yields, and the role of 2,6-dimethylbenzoquinone (2,6-DMBQ) was crucial as both ligand and co-oxidant (Scheme 96A). Note that when unsymmetrical alkynes were used, mixtures of isomers were obtained, with moderate to good selectivity depending on the specific examples. Remote functionalisation was also successfully achieved by the Maes group, who developed a protocol for the remote C5-(hetero)arylation of 3-aminopiperidine *via* a Pd-catalysis (Scheme 96B).⁵⁶⁵ Indeed, starting from commercially available 1-Boc-3-aminopiperidine, they offered an access to cis-3,5-disubstituted piperidines in typically 60–70% yields (up to 82%). The mono-arylation only occurred in a regio- and stereo-selective manner. The nature of the nitrogen protecting group had a strong impact on the outcome of the reaction: a shutdown of the reactivity was observed with benzyl and carbamoyl protecting groups, while lower to good yields were obtained with pivaloyl, tosyl and alkoxycarbonyl groups. Albeit a large excess of (het)ArI

<figure><img src="image_181.png" /><figcaption>Scheme 96 Picolinamide-directed alkenylation, arylation, carbonylation and esterification of C(sp³) centres.</figcaption></figure>

was used, the unreacted reagent was easily recovery. Finally, very high yields were obtained with heteroaromatic compounds as coupling partners (two examples, 84 and 95% yields). In addition, the Pd-catalysed carbonylation of N-alkyl picolinamides was possible using this bidentate DG (Scheme 96C).⁵⁶⁶ With the methodology developed by Wang, not only γ-lactams and γ-amino acids were synthesized in high yields (60–90% yield) but this approach allowed the total synthesis of bioactive rac-pregabalin. Note that TEMPO was used as oxidant in the transformation.

Finally, the regioselective Pd-catalysed esterification between two different alkylbenzenes was developed by Liu and Zhang (Scheme 96D) and products were obtained in a typical 50–70%.⁵⁷⁸ In this transformation, the role of picolinamide as DG was crucial to ensure the esterification reaction since the tested benzamide and acetanilide were completely inefficient; the oxygen from the benzyl esters comes from the O₂ in the air.

14.1.7. **Triazolyldimethyl (TAM) based amides.** Since the first design of a triazole-based bidentate auxiliary by the group of Ackermann in 2014,⁵⁷⁹ the triazolyldimethyl (TAM) based amides proved to be an efficient bidentate DG in C–H bond activation involving Pd, Fe, Mn and Co catalysis. In addition, the DG was easily cleavable under acidic conditions⁵⁸⁰⁻⁵⁸⁴ or using nitrosonium tetrafluoroborate under mild conditions.⁵⁸⁵

14.1.7.1. *C(sp²)–H functionalisation*

14.1.7.1.1. **Alkylation.** In 2015, the combination of Fe catalysis and TAM as bidentate DG allowed the methylation and ethylation of anilides (Scheme 97A).⁵⁸⁰ Using cheap FeCl₃ as catalyst in presence of ZnCl₂·TMEDA as additive, most likely involved in the transmetallation step, the methylation of arenes (71–96%) and heteroaromatic derivatives such as pyrrole, furan and thiophene was achieved (49–60% yield). The approach was

<figure><img src="image_182.png" /><figcaption>Scheme 97 Alkylation, allylation, alkenylation and alkynylation of C(sp²) centres using triazolyldimethyl amide as DG.</figcaption></figure>
<figure><img src="image_183.png" /></figure>

also successfully extended to the functionalisation of the challenging olefinic C–H bonds leading to the selective formation of the Z isomers (57 and 90% yields).

The same group further investigated the potential of the bidentate DG in Fe-catalysed C–H allylation and alkylation of amides (Scheme 97B).⁵⁸⁵ Using allyl chloride, the functionalisation of a broad range of substrates was possible including arenes, ferrocenes,⁴⁰⁸ heteroarenes and alkenes (47–92% yield). When substituted allyl chlorides were reacted, allylated benzamides were obtained with moderate to good regioselectivity (from 2:1 to 5.7:1) in favour of the branched products. Moreover, primary and secondary alkyl bromides were also suitable coupling partners. Note that such transformations were not restricted to Fe catalysis, since very recently Ackermann and co-workers reported a MnCl₂-catalysed alkylation of amides with alkyl halides (up to 90% yield) (Scheme 97C).⁵⁸² They developed a process involving a low-valent Mn catalyst, for which the presence of zinc additives and phosphine ligands were no longer required.

#### 14.1.7.1.2. Alkynylation and alkenylation.
In 2017, Ackermann and co-workers reported the Fe-catalysed alkynylation of aromatic amides using several silylated alkynyl halides (Scheme 97D).⁵⁸⁶ This is an efficient process, which allowed the synthesis of mono-alkynylated products in 44–71% yields under mild reaction conditions. This reaction was also successfully applied to heteroaromatic and olefinic compounds (54–59%, 4 examples). Note that the methodology was further applied to the synthesis of the corresponding isoquinolones *via* a two-step sequence (alkynylation/desilylation-cyclisation).

A TAM-DG promoted olefination of aromatic systems using activated olefins such as acrylates, vinyl phosphonate, or vinyl sulfones was reported by Shi and co-workers (Scheme 97E).⁵⁸⁷ Interestingly, O₂ was suitable as oxidant. Although efficient (typically 80–90% yield), mixture of mono- and di-olefinated compounds were observed in case of *meta*- and *para*-substituted derivatives. In 2016, Chen and Shi, published a Pd-catalysed alkynylation reaction under mild reaction conditions (Scheme 97F).⁵⁸³ This reaction was tolerant to various FGs (e.g. NO₂, CF₃, F), provided the corresponding products in high yields (76–93%) and no Ag was required, a real asset.

#### 14.1.7.2. C(sp³)-H functionalisation: alkylation and Alkynylation.
In the course of their investigation of Fe-catalysed methylation of anilides,⁵⁸⁰ the group of Ackermann showcased the generality of their approach by an extension to the methylation of unactivated aliphatic amides (3 examples) in moderate to good yields (Scheme 98A). This bidentate DG also demonstrated its efficiency in the alkynylation of primary and secondary C(sp³)-H bonds (Scheme 98B). Various aliphatic derivatives (16 examples) including *N*-protected amino acids were functionalised in moderate to high yields (45–86%), moderate to good diastereoselectivity and di-functionalisation reactions were observed in some cases.⁵⁸³

### 14.1.8. Other bidentate DGs based on heterocycles.
Other *N*,*N*-bidentate DGs based on heterocycles were reported including those combining an amide part and a heterocyclic unit such as

an oxazoline, pyrazole, benzothiadiazole and alkylbenzimidazole. Those DGs were mainly used in the formation of C–O and C–S bonds either on aromatic or aliphatic derivatives.

#### 14.1.8.1. Amide-oxazoline

##### 14.1.8.1.1. Alkylation.
Using the 2-(2-oxazolinyl)phenyl moiety on the amide nitrogen, the group of Yu developed a Cu-catalysed oxidative coupling of aromatic amides with malonate derivatives, offering a straightforward access to isoindolinone compounds in 40–75% yields (Scheme 99A).⁵⁸⁸

##### 14.1.8.1.2. Acetoxylation.
In 2015, Ge and Li reported the Pd-catalysed acetoxylation of amide-tethered oxazoline. Indeed, *via* a six-membered bidentate complex with Pd(II), the di-acetoxylation of various aromatic and heteroaromatic amides was achieved in the presence of PhI(OAc)₂ playing the role of both oxidant and OAc source in 32–73% yields (Scheme 99B).⁵⁸⁹ It turned out that depending on the substitution pattern of the substrate, mono-acetoxylation was achieved. Note that using very simple conditions, Yu also developed Cu-mediated hydroxylation of aromatic amides (Scheme 99C).⁵⁹⁰ The transformation was tolerant to various FGs (alkyl, CF₃, F, I, Cl, vinyl moiety) and provided the products in 37–86% yields.

##### 14.1.8.1.3. Sulfenylation.
The formation of a C–S bond by making us of *N*-[2-(2-oxazolinyl)phenyl] amides was also studied by Manolikakes (Scheme 99D)⁵⁹¹ as well as Liu and Chen (Scheme 99E)⁵⁹² *via* Cu mediated transformations using

<figure><img src="image_184.png" /><figcaption>**Scheme 99** Functionalisation of C(sp²) centres using 2-(2-oxazolinyl)-phenyl amide as DG.</figcaption></figure>
<figure><img src="image_185.png" /><figcaption>Scheme 100 Functionalisation using amides derived from other heterocyclic amines as bidentate DGs.</figcaption></figure>

either sodium sulfinates (22–82% yield) or 2-mercaptobenzimidazoles as coupling partners (up to 84%). In both transformations, a good FG tolerance was noted (e.g. Cl, CF₃, acetyl).

**14.1.9. Other N,N-bidentate DGs.** The amide derived from (2-aminophenyl)pyrazole (PPNH₂) was employed for the Cu-mediated etherification of (hetero)arenes and alkene derivatives using PhSi(OR)₃, Si(OR)₄ or ROH/Si₂Me₆ as coupling partners leading to the corresponding products with yields up to 87% (Scheme 100A). The DG was easily removed under Lewis acid mediated methanolysis (BF₃·Et₂O/MeOH, 100 °C) leading to the corresponding ester.⁵⁹³

Amide derived from 4-amino-2,1,3-benzothiadiazole (BTDNH₂) was studied by Babu in Pd-catalysed arylation and acetoxylation (2 examples) of linear aliphatic carboxamides in yields 52–97% yields (Scheme 100B).⁵⁹⁴ In case of cyclic carboxamides, di-functionalisation generally occurred although in some cases, mixtures of mono- and di-functionalised products were obtained. Its cleavage was achieved under basic conditions (NaOH, ethanol, 85 °C) to access the corresponding carboxylic acid.

Furthermore, the amide derived from [2-(1-alkylbenzimidazolyl)]-2-isopropylamine offered a good alternative, in Cu-catalysed sulfenylation of aromatic and olefinic amides (47 examples, Scheme 100C).⁵⁹⁵ Note that the Pd-catalysed arylation of thiophene derivatives using pyrazine-2-carboxamide as DG was also reported (not shown). A two steps sequence (N-Boc) protection/hydrazinolysis (NH₄I, NH₂NH₂·H₂O) under microwave irradiation afforded the Boc-protected MBIPNH₂ and the corresponding N-acylhydrazide in good yield.⁵⁶⁸

## 14.2. N,S-Bidentate DGs

An interesting alternative to N,N-bidentate DGs relies on the use of N,S-bidentate DGs, easily cleavable under acidic (HCl, MeOH, 100 °C)⁵⁹⁶ or basic⁵⁹⁷,⁵⁹⁸ (KOH, 80–85 °C) conditions. Although restricted to a handful of examples, these N,S-bidentate DGs were successfully applied in the arylation of alkanecarboxamides, especially on challenging cyclopropane derivatives.

<figure><img src="image_186.png" /><figcaption>Scheme 101 Arylation using N,S-bidentate DGs.</figcaption></figure>

In 2015, Babu studied the arylation of thiophene- and furan-2-carboxamides by directed C–H bond activation using either the amide derived from 8-aminoquinoline or the 2-(methylthio)-aniline.³⁹¹ Using the bidentate N,S-DG, a selective Pd-catalysed C–C bond formation of thiophen- and furan-2-carboxamides at the C3 position was achieved using (hetero)aryl iodides as coupling partners in 25–81% yields (Scheme 101A). Then, the same group investigated the use of this N,S-DG in the functionalisation of C(sp³)–H bonds. Hence, they described the Pd-catalysed arylation of cyclopropanecarboxamides followed by ring opening of the cyclopropanes using the amide derived from 2-(methylthio)aniline as DG (not shown).⁴⁷² Interestingly, di- or tri-arylation and the formation of a C–O bond was reported within a one pot process, leading to anti β-acyloxy amides in 10–86% yields, although an excess of Ag salt was necessary (Scheme 101B).⁵⁹⁹

Then, Wencel-Delord and Colobert employed amides derived from enantiopure sulfinyl anilines in the diastereo-selective arylation of cycloalkanes (cyclopropanes and cyclobutanes) leading to the corresponding compounds in moderate diastereoselectivities (60/40 to 80/20), in 26–92% total yield of both diastereoisomers. It is worth to mention that both diastereomers were easily separated by column chromatography offering access to enantiopure compounds after cleavage of the DG (Scheme 101C).⁶⁰⁰

In 2017, Chen and He published a Pd-catalysed β-methyl and even more challenging β-methylene C–H arylation with sterically hindered aryl iodides by playing with the nature of the *ortho*-sulfinyl aniline auxiliaries (R³ = Me, C₆H₄Me) (Scheme 101D).⁶⁰¹ The reaction showed a good FG tolerance (NO₂, F, OMe, CO₂Me) for *ortho* substituted aryl iodides and

<figure><img src="image_187.png" /></figure>
<figure><img src="image_188.png" /></figure>

about 60–70% as typical yields. The same year, a diastereo-
selective transformation was developed by Wencel-Delord and
Colobert (Scheme 101E), offering an access to arylated aliphatic
amides at the β-methylene position (up to 9/1 dr), which was
extended to one example of acetoxylation (91% yield, 7/3 dr).⁵⁹⁸

Miura and Shishido reported Ru-catalysed alkenylation of N-tosyl aromatic amides with internal alkynes followed by a cyclisation process affording the corresponding isoindolinones in 27–71% yields (not shown).⁶⁰²

14.3. N,O-Bidentate DGs

In this section the recent progresses involving N,O-bidentate DGs
will be discussed. Indeed, a couple of them were investigated
such as the bidentate amide derived from 2-pyridinamine-N-
oxide, 1-aminoanthraquinone and the oxalyl amides.

**14.3.1. Amide derived from 2-aminopyridine-N-oxide.** The bidentate amide derived from 2-aminopyridine-N-oxide (PyO) demonstrated remarkable features in several C–H bond activation transformations. Both, the NO and NH part of the amide are generally crucial to ensure the reaction.

**14.3.1.1. C(sp²)–H functionalisation.** The pyridine-N-oxide moiety was used with first row eco-friendly transition metals such as Co and Ni catalysts. Besides its efficiency, a key advantage of this bidentate DG is its removal, which could be easily realized under basic conditions.<sup>603–608</sup>

**14.3.1.1.1. Alkenylation.** Such DGs were successfully applied in Co- and Ni-catalysed C(sp²)-H alkynylation/annulation reactions.

An interesting approach towards heterocycles was developed
by the groups of Macgregor and Ackermann (Scheme 102A).⁶⁰⁹
Under mild conditions and using oxygen as the sole oxidant,
the synthesis of 6-membered isoquinolone derivatives from

aromatic derivatives was achieved using Co(II)-catalysis. The
transformation turned out to be particularly efficient and
highly regioselective and terminal as well as internal alkynes
were suitable coupling partners. The regioselectivity of
the reaction steered from electronic reasons as suggested by
computational DFT investigations.

Niu and Song also investigated the synthesis of isoquinolone and isoindolinone derivatives by slightly changing the catalytic system *via* a Co-catalysed decarboxylative C–H activation using alkynylcarboxylic acids (Scheme 102B).<sup>610</sup> The use of a catalytic amount of a Ag salt in the catalytic system to access isoquinoline compounds was a real asset of this approach, O<sub>2</sub> playing the role of terminal oxidant.

Furthermore, Niu and Song reported the Ni-catalysed func-
tionalisation of a panel of amides with terminal alkynes *via*
a twofold C–H activation process leading to substituted
3-methyleneisoindolin-1-ones (Scheme 102C).<sup>611</sup> The reaction
demonstrated a good FG tolerance including halides and
thiophene derivatives, and the stereoselectivity of the reaction
was moderate to excellent (Z/E ratio from 52/48 to 100/0).

The same authors also developed a Co-catalysed alkynylat-
tion/annulation reaction of amides with terminal alkynes as
coupling partners in presence of AgOAc as the terminal oxidant
(Scheme 102D).<sup>612</sup> The nature of the bidentate DG turned out to
be crucial as other DGs were inefficient in that transformation.
Both Co(II) and Co(III) might be used, CoC<sub>2</sub>O<sub>4</sub>·4H<sub>2</sub>O being the
most efficient. The reaction was applied to a wide range
of compounds (36 examples), although internal alkynes and
aliphatic ones were not suitable coupling partners.

**14.3.1.1.2. Alkoxylation, amination.** Another example
showcasing the unique properties of this bidentate DG was
reported again by Niu and Song, who published Co-catalysed
alkoxylation of aromatic and olefinic carboxamides under mild
reaction conditions (Scheme 103A).<sup>604</sup> Later on, the same group
extended this approach to the amination of arenecarboxamides
with alkylamines (Scheme 103B).<sup>605</sup>

**14.3.1.2. C(sp³)–H functionalisation.** This DG was also successfully applied in C(sp³)–H bond functionalisation. In 2015, Zeng and Lu reported a Pd catalysed pyridine-N-oxide-directed arylation of alkane carboxamides with aryl iodides (Scheme 104A).<sup>606</sup> The functionalisation of both primary and secondary C(sp³) centres was achieved at the β- and even the γ-position on suitable substrates. Substitution on the pyridine

<figure><img src="image_189.png" /><figcaption>**Scheme 102** Alkenylation of C-(sp²) centres using 2-pyridine-N-oxide amide as DG.</figcaption></figure>

<figure><img src="image_190.png" /><figcaption>**Scheme 103** Alkoxylation and amination of C(sp²) centres using 2-pyridine-N-oxide amide as DG.</figcaption></figure>
part of the DG with halides, CF₃ and NO₂ groups was tolerated. Note that mono- and di-arylated products were obtained and the overall efficiency of the transformation was substrate-dependent.

A similar transformation was then further studied by the same authors, and aliphatic amides were functionalised with a large number of aryl iodides leading to mono- or di-functionalised products depending on the substrate (Scheme 104B).⁶⁰⁷

This DG was not restricted to the formation of C–C bonds, since very recently, the group of You demonstrated that this bidentate DG was successfully used in the oxidative amination of unactivated C(sp³)–H bonds with azoles *via* a Cu mediated process (Scheme 104C).⁶⁰⁸ Note that an extension of this transformation *via* Ni catalysis was also reported using in that case the amide derived from 8-aminoquinoline as DG.

**14.3.2. Oxalyl amide group.** In 2014, Yao and Zhao designed a new auxiliary, the N,O-bidentate oxalyl amide group (NHOA or NHCODIPA).⁶¹³ Since this initial study, the system was applied for several transformations. This DG was mainly cleaved under basic conditions (KOH/EtOH, 80 °C;⁵⁹⁰ NaOH, THF/MeOH, 50–100 °C⁶¹⁴–⁶¹⁷ or NaOMe, MeOH, rt⁶¹⁸) or *via* a N-Boc protection and then cleavage under basic conditions (KOH, EtOH/Et₂O, rt).⁵⁹¹

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

**14.3.2.1.1. Arylation and alkenylation.** Shi and Zhao reported the Pd-catalysed *meta* arylation of β-arylethylamine *via* a Catellani reaction using NHOA as a bidentate DG (Scheme 105A).⁶¹⁹ Using norbornene as the transient mediator, the transformation was tolerant to various FGs, leading to the expected compounds in good yields and various aryl iodides bearing *para*, *meta* or *ortho* substituents were suitable. It is worth to mention that the *mono* *meta* arylation was possible on substrates bearing substituents at the *ortho* and *meta* positions. In contrast, when unsubstituted arenes were reacted, only *meta* di-arylated products were obtained. To further showcase the synthetic utility of their approach towards the synthesis of polyfunctionalised β-arylethylamines, the authors investigated the Pd-catalysed oxalyl-amide-directed functionalisation of *meta* arylated β-arylethylamines. This protocol turned out to be general and alkynylation, iodination, acetoxylation and amination reactions were achieved in moderate to good

<figure><img src="image_191.png" /><figcaption>**Scheme 105** Functionalisation of C(sp²) centres using oxalyl amide as DG.</figcaption></figure>

yields (42–82%), although some di-alkynylated products were produced in 17–30% yields (not shown).⁶²⁰

The same group also investigated Rh(III)-catalysed oxidative C–H/C–H cross-couplings of benzylamines and heteroarenes (Scheme 105B).⁶¹⁴ When the *ortho* position was unsubstituted, mixtures of mono- and di-heteroarylated products were obtained, the ratio mono-/di-being dependent on the substitution pattern of the aromatic system.

In the course of their investigation for the Pd-catalysed arylation of 3-(aminoethyl)thiophene derivatives, the group of Babu showed that among the possible DGs for this transformation, the NHOA DG turned out to be efficient affording the products in 57 to 75% yields and the reaction was also performed on a gram scale (Scheme 105C).⁶⁵⁸

The NHOA DG was also used in Pd-catalysed olefination of β-arylethylamines (Scheme 105D).⁶²¹ The reaction works with a broad array of functionalised olefins and a good selectivity for mono-olefination was observed in case of electron rich olefins such as allyl acetate, 3,3-dimethyl-1-butene and styrene derivatives. In contrast for more reactive olefins such as acrylamide, acrylonitrile, acrylaldehyde and vinyl sulfone, a mixture of mono- and di-olefinated products was obtained.

**14.3.2.1.2. Carbonylation.** Carbonylation of β-arylethyl- and benzylamines were achieved using different reagents. Indeed, in 2016, a first report from Huang and Zhao on the Pd-catalysed carbonylation using carbon monoxide as the CO source was reported (E).⁶¹⁵ Then, Zhao and Shi developed an improved protocol based on a Ru-catalysed carbonylation reaction, which demonstrated interesting features such as the use of isocyanate as CO source and the absence of oxidants (F).⁶¹⁸ 21 derivatives were functionalised with up to 96% yields.

<figure><img src="image_192.png" /><figcaption>**Scheme 104** Arylation and amination of unactivated C(sp³)–H bonds using 2-pyridine-N-oxide amide as DG.</figcaption></figure>
<figure><img src="image_193.png" /><figcaption>**Scheme 106** Silylation and germanylation of C(sp²) centres using oxalyl amide as DG.</figcaption></figure>

**14.3.2.1.3. Silylation and germanylation.** This bidentate DG was also employed for the regioselective and monoselective silylation of benzylamine and phenylethylamine compounds *via* Pd catalysis at the γ- and δ-positions, respectively (Schemes 106, 26 examples, 43–90%).⁶¹⁶ This reaction was not restricted to aromatic derivatives since, using slightly modified reaction conditions, the silylation of 2-methylaniline derivatives was possible, albeit restricted to four examples in low to moderate yields (21–49%). It is worth to mention that the germanylation of benzylamines was also achieved by replacement of the hexamethyldisilane with Ge₂Me₆ (4 examples, 37–82%).

**14.3.2.2. C(sp³)-H functionalisation.** In 2015, the γ-arylation of aliphatic amines with aryl and heteroaryl iodides was investigated by Zheng, Huang and Zhao (Scheme 107A).⁶²² Upon Pd-catalysis, mono- or di-arylated products were obtained (47–83%) depending on the substitution pattern of the substrates. When heteroaryl iodides were used as coupling partners, low to high yields (23 to 78%) were obtained. Later, the same group used a similar catalytic system for the functionalisation of amino acids (Scheme 107B).⁶²³ ArI and heteroaryliodides were suitable coupling partners leading to the corresponding products in 45–86% and 36–83% yields, respectively. The carbonylation of aliphatic amines *via* a Pd-catalysed C–H bond functionalisation under carbon monoxide atmosphere was reported by Yao and Zhao (Scheme 107C).⁶¹⁷ Primary and secondary C(sp³) centers were functionalised in low to high yields (12–87%) and extended to the functionalisation of benzylamines (8 examples, 71–98%) (not shown).

<figure><img src="image_194.png" /><figcaption>**Scheme 107** Functionalisation of C(sp³) centres using oxalyl amide as DG.</figcaption></figure>

<figure><img src="image_195.png" /><figcaption>**Scheme 108** Acetoxylation of C(sp³) centres using amide derived from 1-aminoanthraquinone as DG.</figcaption></figure>

The reaction was even conducted on a gram scale. The authors suggested that 3-(trifluoromethyl)benzoic acid was important to stabilize the Pd intermediate.

**14.3.3. Amide derived from 1-aminoanthraquinone.** A unique example of Pd-catalysed directed acetoxylation using the amide derived from 1-aminoanthraquinone as bidentate DG was reported. In 2015, Cheng, Zhu and Zhang disclosed the Pd-catalysed acetoxylation of aliphatic amides at the α-position *via* a four-six-membered bicyclic metallacycle (Scheme 108A). Amides containing primary α-C(sp³)-H and α-methylene C(sp³)-H bond were smoothly functionalised in a selective manner (32–92% yields) and only the mono-acetoxylated products were observed. The bidentate DG was cleaved under basic conditions (NaOH, MeOH, reflux) and recycled.⁶²⁴

## 15. Heterocyclic DGs in C–H functionalisation

As for carbonyl-based and bidentate moieties, heterocycles are also a very common class of DGs for the functionalisation of C(sp²) and C(sp³) centres. The heterocycles that can be used as DGs are those featuring a C(sp²)-hybridised nitrogen atom, which act as the coordinating moiety for the formation of the metallacyclic intermediate essential to the C–H functionalisation. These DGs have attracted a lot of interest in the field for a number of reasons: (1) heterocycles are commonly found in bio-active and drug-like molecules, which allows late-stage modifications without requiring DG installation/removal; (2) if needed can be installed on the substrate in a number of ways; (3) despite being generally considered strong-coordinating DGs, their coordinating properties can be somewhat altered by substitution or by changing the heterocycle used for a specific transformation.

Although DG cleavage can be sometimes tricky with mono-heterocycles (i.e. pyridine), several methods have been developed during the years, thus increasing their synthetic utility. In the case of diheterocycles, cleavage (e.g. for pyrimidine) or modification of the DG (for example by ring opening) is intrinsically easier, although not often reported in publications involving less common heterocycles. The available cleavage/modification methods for heterocyclic DGs are discussed in each specific subsection. In this section, yields have been specifically reported in case of particularly high yields (most examples >80–90%) or lower than average (most <70% or lower) results, and in case of strong substrate-dependence. If not reported, average yields of 70–80% for most examples is to be assumed (see discussion in the Introduction section).

<figure><img src="image_196.png" /></figure>
<figure><img src="image_197.png" /></figure>

## 15.1. Pyridine as DG

The use of pyridine (as well as other heterocycles such as pyrazole and pyrimidine) as a DG in C–H functionalisation chemistry dates back to the late 1990s–early 2000s, when it was pioneered by Murai/Chatani first, who reported Ru-catalysed alkylations and carbonylations on C(sp²) and C(sp³) centres,⁶²⁵⁻⁶²⁷ and then by Sanford⁶²⁸,⁶²⁹ and Daugulis,⁶³⁰ who extended its use to Pd-catalysed acetoxylations and arylations. Since then, pyridine is one of the most frequently applied DGs in C–H functionalisation chemistry. This is possibly due to its simplicity and the easy installation into aromatic rings or aliphatic chains *via* cross coupling⁶³¹⁻⁶³³ or other methods.⁶³⁴ A great number of reactions have been reported with this DG, with a variety of protocols, reagents and reaction conditions. Recently this DG has also been commonly used for *meta*-selective C(sp²)–H functionalisation using Ru catalysts,⁶³⁵,⁶³⁶ which will not be treated in this review. Moreover, pyridine is the DG of choice for specific substrates, such as 2-pyridones, for which other DGs have proved ineffective.

Although this DG is typically not removable when attached to the substrate *via* a C–C bond, the ubiquity of pyridine rings

in many complex molecules (*e.g.* bioactive compounds), partially compensates this disadvantage, as its removal might not be required in all cases. The removal of this DG can nonetheless be achieved when attached to the substrate *via* a C-heteroatom bond (as is the case for N-(2-pyridyl)indoles, N-(2-pyridyl)anilines, or O-(2-pyridyl)phenols). These cleavage methods are discussed in Section 15.3.

### 15.1.1. C(sp²)–H bond functionalisation

15.1.1.1. Arylation. Many arylation procedures with pyridine as DG have been reported before 2014, and therefore are not included in this review. Nonetheless, several methods have been developed in the last few years. Szostak reported an unusual C–C cleavage/C–H functionalisation using activated benzamides as arylating agents (Scheme 109A),⁶³⁷ while boronic acids under Ru catalysis were utilised by Maheswaran (Scheme 109C).⁶³⁸ The hyper-valent iodine additive in this reaction was suggested to form a charge-transfer complex with the substrate, generating an aromatic radical cation⁶³⁹ which facilitates the formation of the ruthenacycle intermediate.

Punji and Wang reported the use of aryl iodides with Ni and Pd catalysis respectively (Scheme 109B and D).⁶⁴⁰,⁶⁴¹

<figure><img src="image_198.png" /><figcaption>Scheme 109 C(sp²)–H arylation using pyridine as DG.</figcaption></figure>
<figure><img src="image_199.png" /></figure>

While the first required preformed Ni(II) catalysts and the use of strong base, the latter employed O₂ as oxidant and green solvents, although a 10% Pd loading was required. Notably, both methods provide selective monoarylation, which is not always achieved. A coupling with aryl silanes was reported by Szostak (Scheme 109E).⁶⁴² Although this procedure avoids the use of stoichiometric Ag oxidants, still a superstoichiometric amount of CuF₂ was required, and a substrate-dependent selectivity (mono or diarylation) was observed. A recent paper by Kantchev demonstrated the use of the ionic liquid Bu₄NOAc as both base and solvent in the RuCl₃-catalysed coupling with aryl bromides (Scheme 109F).⁶⁴³ The reaction gave mostly mixtures of mono and diarylated products, but at the same time tolerates heteroaryls, free NH₂- and free OH-substituted aryl bromides. In 2015 Wang reported the Rh (monoarylation) or Ir (diarylation) catalysed reaction with diazoquinones leading to phenol-functionalised arenes (Scheme 109G).⁶⁴⁴ The next year a related transformation, using 3-diazoindolin-2-Imines as reactants was disclosed by Wang and Lu, giving 3-aryl-2-aminoindoles (Scheme 109H).⁶⁴⁵

Inspired by Szostak's arylation method using aromatic amides as arylation reagents (Scheme 109A), Zeng performed the arylation of indoles (and benzo[h]quinoline) using N-acyl saccarines as reagent under similar conditions (Scheme 109I).⁶⁴⁶ The use of boronic acids for indole arylation was instead reported by Kapur. This method provides good substrate scope and yields, although requiring stoichiometric amounts of both Cu and Ag (Scheme 109J).⁶⁴⁷ Ackermann recently reported the arylation of peptide-substituted indoles using aryl bromides. This procedure afforded good yields of arylated products, with no racemisation and good robustness. Importantly, peptides are tolerated on both coupling partners (Scheme 109K).⁶⁴⁸

The arylation of 2-pyridones with heteroaromatic compounds via cross dehydrogenative coupling was first reported by Miura and Hirano in 2014.⁶⁴⁹ Since then, further arylation procedures have been reported making use of diazoquinones and arylboron compounds (Scheme 109L-N).⁶⁵⁰⁻⁶⁵²

An example of stereoselective C–H arylation of olefins was reported by Ackermann in 2016 using a preformed phosphinous acid Ru(II) complex as catalyst (Scheme 109O).⁶⁵³ This method could also be applied to aromatic substrates using tetrazoles and oxazolines as DGs.

### 15.1.1.2. Alkylation.
Alkylation can occur *via* different mechanisms: (i) addition to unsaturated moieties, (ii) cross couplings, and (iii) carbene insertions. Due to the many protocols reported for such functionalisation with pyridine as DG, these strategies are treated separately. Cascade alkylation/cyclisation involving the pyridine DG will also be reported separately due to the different nature of the products obtained.

### 15.1.1.3. Addition to double bonds.
In 2015 Nishimura reported the Ir-catalysed regioselective (branched products) hydroarylation of vinyl, allyl and other alkenyl ethers, leading to alpha-arylated ethers.⁶⁵⁴,⁶⁵⁵ This reaction could be performed in a stereoselective manner using chiral biphosphine ligands (Scheme 110A).

The group-directed addition to aldehydes has been reported a number of times, and results in alpha-arylated alcohols. A Lewis or Brønsted acid additive in these reactions is necessary to activate the carbonyl group, and reduce the reversibility of the aldehyde insertion into the C–M bond. Zhou⁶⁵⁶ and Ding⁶⁵⁷ reported the Ru-catalysed addition to formaldehyde and electron-poor benzaldehydes (Scheme 110B and C). The scope in aldehydes was notably increased by Wang *et al.*, using a Mn catalyst and a combination of ZnBr₂ and Me₂Zn. This allowed the use of (hetero)aromatic, aliphatic, and even unsaturated aldehydes as reactants; moreover, heteroaromatic and olefinic substrates could also be easily functionalised (Scheme 110D).⁶⁵⁸ The synthesis of 2-oxoalkyarenes was achieved by Kakiuchi using cyclic alkenylcarbonates, synthetic equivalents of enolates (Scheme 110E).⁶⁵⁹ Despite the originality of the protocol, its use with pyridine as DG was only demonstrated on relatively few examples, and required a long reaction time (48 h).

An interesting protocol for a directed cascade C–H functionalisation/cyclisation was reported by Ellmann, giving diastereoselective formation of 3 contiguous stereocentres (Scheme 110F and G).⁶⁶⁰,⁶⁶¹ The benzylamine in the second protocol acts as an organocatalyst (enamine catalysis) to facilitate the intramolecular Michael addition, which is more difficult than in the first case.⁶⁶¹ These are two of the relatively rare examples where the cascade cyclisation does not involve the DG itself, which is often the case (e.g. Scheme 112).

Park and Chang reported the effect of different DGs on the chemoselectivity of the reaction of aromatic substrates with activated alkenes.⁶⁶² While with pyridine DGs, addition to the double bond was obtained selectively (Scheme 110H), the use of an amide DG in the same conditions resulted in selective olefination instead. This switch in selectivity was limited to the Ir catalyst used. The same reaction, catalysed by Re, was instead reported by Zhu and co-workers (Scheme 110H).¹⁷⁷ This protocol, occurring under CO atmosphere (CO acts as ligand for Re), is one of the few Re-catalysed C–H activation processes, and proved very efficient for a variety of substrates, including olefinic and heteroaromatic ones. In 2015 Bolm reported the hydroarylation of unactivated bicyclic alkenes with Ru catalysis using O₂ as oxidant (Scheme 110I).⁶⁶³

The functionalisation of indoles with activated ketones or aldehydes (alpha EWG-substituted) under Mn catalysis was reported by Ackermann (Scheme 110J).⁶⁶⁴ Although high loadings of Mn catalyst were used (up to 20% of the metal), the reaction gave good yields with a broad scope, and no additives were used (cf. Scheme 110B–D). It is worth noting that the C2 regioselectivity, despite the DG, was only observed with two very specific Mn catalysts ([Mn₂(CO)₁₀] and [MnBr(CO)₅]), while all the other catalysts tested resulted in C3 functionalisation (no DG effect).⁶⁶⁴

A similar procedure for the addition to maleimides was reported recently by Song and Gong (Scheme 110K).⁶⁶⁵ The reaction was air tolerant and worked effectively in EtOAc. Importantly, both these protocols were applied to the functionalisation of other heterocycles (e.g. pyrroles, selectively mono-functionalised).
<figure><img src="image_200.png" /><figcaption>Scheme 110 Pyridine-directed C(sp²)–H alkylations *via* addition to double bonds.</figcaption></figure>

Recently, the Glorius group developed two important methods for the C–H propargylation and 2-(indolyl)methylation of indoles using substituted bromoallenes and 4-ethynyl benzoxazinanones (Scheme 110L and M).⁶⁶⁶,⁶⁶⁷ Propargylation is a challenging transformation, as the corresponding alenylation might instead occur more easily. For this Mn-catalysed process, the use of BPh₃ as Lewis acid and a catalytic amount of H₂O proved crucial for obtaining good yields and selectivity (with respect to the allene product). The reaction works well with a variety of functionalised allenes, including 1,3,3-trialkyl, 3,3-dialkyl (giving terminal alkyne products), 1,3-dialkyl and 1-monoalkyl allenes, and with other heterocyclic substrates such as pyrroles and (benzo)thiophenes (Scheme 110L).⁶⁶⁶ A robustness screening was also performed for this reaction, showing compatibility with functionalities such as aniline, furan, ketones, amides and acetals. The use of 4-ethynyl benzoxazinanones, still under Mn catalysis, results in the C–H (2-indolyl)methylation of indoles and other heterocycles

*via* alkyne insertion into the intermediate manganacycle, release of CO₂, formation of an allene–Mn intermediate complex, and cyclisation with the nitrogen nucleophile (Scheme 110M).⁶⁶⁷ Even in this case a robustness screening showed compatibility with a variety of FGs.

Pyridine-directed, Ni-catalysed alkylation of 2-pyridones using a variety of aliphatic alkenes and dienes (including cyclooctadiene) was reported by Miura and Hirano in 2017.⁶⁶⁸ Despite being one of the few examples of alkylation on such substrates in recent times, the reaction proved fairly sensitive to the substitution pattern on the pyridone and the identity of the aliphatic alkenes/dienes used.

15.1.1.4. Cross coupling and carbene insertion. A number of alkylation reactions based on cross coupling type of reactions have been reported. A very recent example by Aissa's group demonstrated the use of sulfoxonium ylides as a replacement reactant for diazo compounds, leading to α-arylated aromatic or aliphatic ketones in good yields (Scheme 111A).⁶⁶⁹
<figure><img src="image_201.png" /></figure>

<figure><img src="image_202.png" /><figcaption>Scheme 111 Pyridine-directed C(sp²)–H alkylations via cross-coupling and carbene insertion.</figcaption></figure>

This was the first example of the use of such reactants, safer alternatives to diazonium compounds,⁶⁷⁰ in group-directed C–H functionalisation. Li and Liu reported very similar conditions for the alkylation of arenes and 2-pyridones respectively with alkyltrifluoroborates (Scheme 111B and C).⁶⁵¹,⁶⁷¹ The C6 alkylation of 2-pyridones was also performed *via* carbene insertion using diazo compounds (Scheme 111D).⁶⁷²

The Ni catalysed functionalisation of indoles using alkyl halides was achieved by Punji and co-workers (Scheme 111E).⁶⁷³ Although being a rare example of Ni-catalysed alkylation, this method required the use of a preformed Ni-catalyst, catalytic amounts of strong Li-amide bases, 2 equiv. of base and high temperatures to result in medium to good yields of functionalised indoles. The use of secondary alkyl halides was also possible, but 2 equiv. of KI as additive were required in this case.⁶⁷³

The functionalisation of non-aromatic C(sp²)–H bonds is considerably rarer, and much underdeveloped. Yoshikai reported the alkylation of cyclic alkenes with alkyl chlorides using Co catalysis (Scheme 111F).⁶⁷⁴ Despite having benefits such as being base metal-catalysed and allowing functionalisation at room temperature, the reaction requires the use of both a catalytic carbene and a superstoichiometric amine ligand (TMEDA), has a limited scope, and presents some regioselectivity issues for secondary alkyl chlorides, and therefore lacks generality.

15.1.1.5. **Alkylation/cyclisation.** The functionalisation of C–H bonds with unsaturated moieties can result in the subsequent

<figure><img src="image_203.png" /><figcaption>Scheme 112 Pyridine-directed alkylation/cyclisation.</figcaption></figure>

involvement of the DG in a cyclisation process between the newly installed functionality and the nucleophilic nitrogen atom of the pyridine. In 2015 Glorius investigated the use of diazomalonates in combination with Co catalysis. Instead of obtaining the expected alkylation product, the corresponding fused heterocycles, derived from nucleophilic attack of the pyridine to the ester moiety of the alkyl group, were obtained (Scheme 112A).⁶⁷⁵ Later the same group reported the use of pyridotriazoles as carbene precursors for a similar reaction. In this case, Rh catalysis had to be used, as Co pre-catalysts did not produce any cyclised or alkylated product (Scheme 112B).⁶⁷⁶

15.1.1.6. **Allylation.** A large variety of allylation procedures for the functionalisation of indoles have been reported in recent years, with a number of different reactants and leading to variedly functionalised side chains. Two main different classes of reactants have been utilised: alkenes with (1) a leaving group, or (2) a strained ring in alpha to the double bond. In both cases most mechanistic proposals involve a migratory insertion of the double bond into the metallacycle initially formed, followed by a general β-elimination of a suitable leaving group (β-oxygen, β-fluoro, β-bromo), or the release of ring strain *via* a β-carbon cleavage. For the latter, the β-carbon elimination is favoured over β-hydride elimination due to the release of the ring strain *via* ring opening. Alternative mechanisms occurring *via* oxidative additions have been suggested in some instances.⁶⁷⁷

In 2016 Kapur reported the allylation of indoles with allyl alcohols (unsubstituted, 1-monosubstituted, 1,1-disubstituted), which selectively resulted in non oxygenated products (Scheme 113A).⁶⁷⁸ The chemoselectivity arises from a selective β-hydroxide elimination rather than β-hydride elimination step in the mechanism. Advantages are regio-, chemo-, and diastereoselectivity, and the cleavage of the DG in a number of compounds.⁶⁷⁸ Many papers have appeared using Mn and Co catalysis, in combination for example with vinyldioxazolones⁶⁷⁹,⁶⁸⁰ (Scheme 113B), vinyl-cyclopropenes⁶⁷⁹,⁶⁸¹,⁶⁸² (Scheme 113C, Mn cat. shown), or diazabicyclic compounds⁶⁷⁹ (Scheme 113D). Among these, notable are the fluorinated side chains introduced with Ackermann's (Mn,⁶⁸³ Scheme 113E, and Co⁶⁸⁴) and Zhang's (Mn, Scheme 113F)⁶⁸⁵ procedures.

15.1.1.7. **Alkenylation.** Olefination reactions can occur *via* different mechanisms, mostly oxidative dehydrogenative coupling with olefins (Fujiwara–Moritani coupling, mostly with activated olefins),
<figure><img src="image_204.png" /></figure>

<figure><img src="image_205.png" /><figcaption>Scheme 113 Pyridine-directed allylations on C(sp²) centres.</figcaption></figure>

and hydrofunctionalisation of alkynes. Zhang reported the use of unactivated olefins for the functionalisation of arenes (Scheme 114A).⁶⁸⁶ The use of such alkenes as reactants is rare, as most C–H olefinations employ activated styrenes and acrylates. Li and Xu reported the use of acrylic acids as reactants, in combination with pivalic anhydride as additive (Scheme 114B).⁶⁸⁷ The formation of vinylic anhydride or mixed pivalic/vinylic anhydrides as intermediate results in a decarboxylative olefination process. The method shows good scope and generally excellent yields. Co catalysis was used for the hydro arylation of aromatic alkynes (Scheme 114C).⁶⁸⁸ The hydrofunctionalisation of alkynes bearing a leaving group in the propargylic position can proceed in two different ways. In case a Brønsted acid is added to the reaction, the olefination product is obtained, as recently reported for the olefination of indoles (Scheme 114D).⁶⁸⁹ In such a case the leaving group is maintained in the molecule and can be utilised successively. In the absence of acids the corresponding allene is obtained instead, as in Scheme 114E.⁶⁸⁹,⁶⁹⁰ Finally, noteworthy is the C7 functionalisation of indolines using styrenes, reported by Loh (Scheme 114F).⁶⁹¹

15.1.1.8. **Alkenylation/cyclisation.** The hydrofunctionalisation of dialkyl- or diarylalkynes in the presence of Rh(III), Ir(III), or Co(III) catalysts, a (super)stoichiometric oxidant and a non-coordinating anion source can result, instead of the

<figure><img src="image_206.png" /><figcaption>Scheme 114 Pyridine-directed C(sp²)–H olefination.</figcaption></figure>

olefinated product, in cyclisation products (extended π systems), interesting for their fluorescent properties and potential applications in material chemistry.⁶⁹² This process results in the formation of a C–C and a C–N bond in a cascade manner (Scheme 115A). Several examples have been reported recently, making use of diaryl- or dialkylalkynes,⁶⁹³–⁶⁹⁵ including the isolation of a 7-membered cobaltacycle intermediate (see general mechanism in Scheme 115, bottom).⁶⁹⁶ Interesting one-pot protocols have been reported by Cheng and Jun: in one case the formation of the olefinic substrate from an alkyl chain occurred *in situ* via oxidation, and in the other case the reaction of allylamine with two equivalents of the alkyne resulted in the formation of the 2-pyridinylarene substrate first, followed by olefination/cyclisation (Scheme 115B and C).⁶⁹⁷,⁶⁹⁸ Another cyclisation product can be obtained by using acrylates or similar as the olefination agent. As reported by Cheng, the Rh-catalysed reaction with 2 equivalents of acrylates in water and using O₂ as oxidant, results in the formation of pyridoisoindolium salts (Scheme 115D).⁶⁹⁹ The process was proposed to occur *via ortho* olefination, followed by intramolecular Michael addition of the pyridine to the activated olefin, deprotonation, and finally a second, intermolecular, nucleophilic attack to a second molecule of the acrylate.

Alternatively, the use of Rh might also result in the formation of two C–C bonds *via* a so-called “rollover cyclometallation” mechanism, where the nitrogen atom of the pyridine ring is not involved in the cyclisation, and can be used to promote a further C–H functionalisation (Scheme 115E). While the rollover mechanism is more common for doubly coordinating
<figure><img src="image_207.png" /></figure>

■ C-C / C-N bond formation

<figure><img src="image_208.png" /></figure>

GENERAL

+ diaryl- and dialkylalkynes tolerated (depending on conditions)

+ anions other than BF₄ possible

+ other heterocyclic DGs (pyrimidine, pyrazine, isothiazole, isoxazole, etc.)

+ other DGs (imines, diazenes)

- asymmetric alkynes results in mixtures

- no terminal alkynes

- high temperatures often needed

A

<figure><img src="image_209.png" /></figure>

B

<figure><img src="image_210.png" /></figure>

C

<figure><img src="image_211.png" /></figure>

D

■ Double C-C bond formation (rollover pathway)

<figure><img src="image_212.png" /></figure>

E

GENERAL

+ diaryl- and dialkylalkynes tolerated

- no terminal alkynes

- high temperatures often needed

<figure><img src="image_213.png" /><figcaption>Scheme 115 Pyridine-directed olefination/cyclisations via C-N bond formation or rollover pathways.</figcaption></figure>

ligands, such as bipyridines,⁷⁰⁰ or in the case of a pyridine-carbene moiety like the one in Scheme 115E,⁷⁰¹ its occurrence is far

less common in other substrates (e.g. indole substrate in Scheme 115E),⁷⁰² and is obviously facilitated by the absence of a non-coordinating anion in the reaction mixture.

**15.1.1.9. Alkynylation.** Generally speaking, alkynylation reactions in C–H functionalisation typically employ two main reactants: the hypervalent iodine compound TIPS-EBX [1-[(triisopropylsilyl)-ethynyl]-1,2-benziodoxol-3(1*H*)-one], and TIPS-bromoacetylene. Variations include other silyl protecting groups instead of TIPS or, more rarely, aryl(bromo)acetylenes or alkyl(bromo)acetylenes. Recent additions to the reagent pool for this transformation include propargylic alcohols (see below). Although the silyl protecting group can be easily cleaved, and the resulting acetylene subsequently functionalised, this is still an intrinsic limitation of this type of functionalisation. The use of terminal alkynes was shown to result in the formation of considerable amounts of Glaser–Hay coupling products.⁷⁰³,⁷⁰⁴

Relatively few examples of alkynylation with a pyridine DG have been reported recently. In 2015 Li reported the C6-alkynylation of pyridones with TIPS-EBX with a Rh catalyst,⁷⁰⁵ while Ni-catalysed reaction of indoles with TIPS-bromoacetylene was reported by Punji⁷⁰⁶ (Scheme 116A and B). Wen reported the use of 1,1-dimethylpropargyl alcohols as alternative reactants for alkynylation reactions. This reactant avoids the use of halogenated compounds and only results in the formation of acetone as side product. The intermediate metal–alkyne complex is obtained *via* β-carbon elimination from the alcohol-ligated catalyst, as previously reported.⁷⁰⁷ Application of such propargylic alcohols to the functionalisation of indoles and carbazoles,⁷⁰³ although resulting in relatively low and substrate-dependent yields, allows a larger variety of alkynes to be used (alkyl and aryl substituted, Scheme 116C and D) than the classical reactants. Noteworthy in this case are the mono-functionalisation of carbazoles (carbazoles get usually doubly functionalised) and the necessity of a 6-Me pyridine DG for the indoles (without the 6-Me another transformation occurs⁷⁰⁴).

Finally, alkynylation of indolines (C7) and ferrocenes have been reported by Loh and You using R-EBX (R = [Si], tBu) hypervalent iodine species (Scheme 116E and F).⁶⁹¹,⁷⁰⁸

Cascade alkynylation–cyclisation reactions are also possible. For instance, two methods for the synthesis of dipyridoimidazolium compounds were reported by Li (Scheme 116G).⁷⁰⁹,⁷¹⁰ Despite giving the same product, the two methods are mechanically very different. While Method A is technically a cascade directed alkynylation/cyclisation (Rh–alkyne complex is obtained *via* β-carbon elimination from the alcohol-ligated intermediate⁷⁰⁷), Method B was proposed to involve pyridine alkylation first, followed by enolisation and nucleophilic attack of the enol to the Co-activated pyridone ring, and Cu-mediated reduction.

**15.1.1.10. Cyanation.** Classical reactions for the cyanation of organic compounds are the Sandmeyer or the Rosenmund von Braun reaction, or cross coupling reactions between aryl halides and cyanide salts. All methods, in their classic version, require prefunctionalised substrates, and more importantly, the use of inorganic cyanides (very toxic) in the reaction.
<figure><img src="image_214.png" /></figure>

<figure><img src="image_215.png" /></figure>

A

+ some other substituents on alkylene

+ substituted pyridines possible

+ cleavable DG

- no real optimization

- DCE as solvent

<figure><img src="image_216.png" /></figure>

B

+ low cat loading

+ other heterocyclic substrates and DGs possible

+ external ligand added

+ only TIPS on alkylene

+ high temperature

<figure><img src="image_217.png" /></figure>

C

+ R = (hetero)aryl, alkyl (few examples)

+ reaction under air

+ cleavable DG

+ gram scale

- most yields <70%, and very substrate dependent

- 6-Me pyridine as DG necessary (different reaction with unsubstituted DG)

- high temperature and superstoich. Cu needed

<figure><img src="image_218.png" /></figure>

D

+ R = (hetero)aryl, alkyl (few examples)

+ reaction under air

- most yields <70%, and very substrate dependent

- high temperature and superstoich. Cu needed

<figure><img src="image_219.png" /></figure>

E

+ cleavable DG

+ low temperature

- DCE as solvent

<figure><img src="image_220.png" /></figure>

F

+ other DG: pyrimidine (1 ex.)

+ alcohols as solvent, room temp.

- almost no substrate substitution

- monofunct. only possible with 3-substituted pyridines or isoquinoline as DG

<figure><img src="image_221.png" /></figure>

G

**Method A:**

+ under air

+ Ar = (hetero)aromatic substrates

+ gram scale

- no aliphatic alkynes

- sensitive to hindrance in pyridone C5 and pyridine C3

**Method B:**

+ simple Co salts as cat.

+ under air

+ Ar = (hetero)aromatic substrates

+ gram scale

+ high temperature

- no aliphatic ketones

- sensitive to hindrance in pyridone C5

<figure><img src="image_222.png" /><figcaption>**Scheme 116** Alkynylation and alkynylation/cyclisation using pyridine-based DGs.</figcaption></figure>

Although a number of (safer) reactants have been recently utilised for the cyanation of C–H bonds, still a common feature is the atom uneconomic nature of these reactants, where more than 50% of the reactant mass is actually wasted.

Co-catalysed reactions were reported by Ackermann⁷¹¹a and Chang⁷¹¹b in 2015, employing respectively *N*-cyano-*N*-phenyl-tosylamide (NCTS) and *N*-cyanosuccinimide (Scheme 117A and B). While the first protocol required a lower amount of additives

<figure><img src="image_223.png" /></figure>

A

+ other heterocyclic DGs (no oxime or ester DGs)

+ cleavable DG in N-linked substrates

- DCE as solvent

+ good FG tolerance

+ other heterocyclic DGs (including purines)

+ easily prepared, stable reactant, easily removable byproduct

- several yields <70%

- DCE as solvent

B

+ O₂ as oxidant

+ other heterocyclic DGs and substrates

+ stoichiometric Cu required

+ high temperature

+ DMF as solvent

C

+ reaction under air

+ other iminonitriles and other DGs (pyrimidine, pyrazole) possible

- several yields <70%, substrate dependent

- other substrates: pyrrole (low yields, double func., furan and thiophene not reactive)

D

<figure><img src="image_224.png" /></figure>

E

+ cleavable DG

+ tolerates peptides (tryptophans)

+ cleavable DG

+ alcohols as solvents

+ low catalyst loading

+ other heterocyclic DGs

+ other substrates: pyrroles (yields <70%, cat. 3%)

- substrate-dependent

F

<figure><img src="image_225.png" /></figure>

G

+ alcohols as solvents

+ good substrate scope (cyclic and acyclic olefins)

+ substituted pyridines as DGs (no quinoline, amides, oximes)

- most yields <70%

<caption>**Scheme 117** Pyridine-directed *ortho* cyanation of C(sp²)–H bonds.</caption>

and catalyst, the use of a more stable reactant, and the good FG tolerance in the second protocol are noteworthy. A third protocol, reported by Jiang and co-workers, employed ethyl-(ethoxymethylene)cyanoacetate as a new reagent under aerobic oxidation conditions, but unfortunately stoichiometric Cu salts were required (Scheme 117C).⁷¹² Similar conditions (superstoichiometric Cu, air, 5% Pd cat.) were reported for the use of imininonitriles as cyanating agent (Scheme 117D).⁷¹³ The generation of cyanide ions from these two reactants has not been yet fully understood, but it appears to occur through oxidative processes. The cyanation of indoles with NCTS was reported by Ackermann⁷¹⁴ and Anbarasan⁷¹⁵ using Mn/Zn and Rh catalysis respectively (Scheme 117E and F). Notable features are the functionalisation of tryptophans in the first case and the substrate scope of substituted pyrroles (often only explored as secondary substrates) in the second. Anbarasan also reported the cyanation of non-aromatic C(sp²)–H bonds in both cyclic and acyclic olefins using a similar procedure (Scheme 117G).⁷¹⁶ This reaction was also applied to the formal synthesis of chlorpheniramine-based hystamine antagonists.

15.1.1.11. Acylation. This transformation is commonly achieved by using aldehydes or aldehyde precursors. An H-atom abstraction by an oxidant delivers the acyl radical, which then reacts with the cyclometallated Pd complex, giving a Pd(IV) intermediate (Scheme 118, bottom). A subsequent reductive elimination furnishes the acylated arene.

Aldehydes were generated *in situ* by aerobic oxidation of toluene to benzaldehyde in Jiao's protocol.⁷¹⁷ A heterogeneous
Review Article

Chem Soc Rev

<figure><img src="image_226.png" /><figcaption>Scheme 118 C(sp²)–H acylation using pyridine as DG.</figcaption></figure>

version of this reaction was reported by Zhaorigetu, using *tert*-butylperoxybenzoate (TBPB) as oxidant (Scheme 118A).⁷¹⁸ A decarboxylative procedure was instead developed by Liu, using mandelic acid derivatives as reactants (Scheme 118B).⁷¹⁹ The use of aldehydes themselves was reported by Deng in water, using sodium dodecylsulphate (SDS) as a phase-transfer catalyst/surfactant and *tert*-butylhydroperoxide (TBHP) as oxidant (Scheme 118C).⁷²⁰

Exceptions to the general mechanism were reported by Li and Wang, where the acylation product was obtained by formal addition to ketenes (also applied to C(sp³)–H bonds)⁷²¹ and nitriles (followed by hydrolysis)⁶⁵⁸ using Rh and Mn catalysis respectively (Scheme 118D and E).

Following the classical protocol with aldehydes, Dash demonstrated the functionalisation of carbazoles, resulting in double acylation (Scheme 118F).⁷²²

15.1.1.12. Alkoxy- and aminocarbonylation. Although other examples appeared with other DGs, only a few reports on pyridine-directed alkoxy- and aminocarbonylation were published recently. One example of the former was published by Wu in 2016, making use of Mo(CO)₆ as CO surrogate, and requiring the superstoichiometric addition of benzoquinone (BQ), NaOAc and Ag₂CO₃ (Scheme 119A).⁷²³ This protocol

<figure><img src="image_227.png" /><figcaption>Scheme 119 Pyridine-directed alkoxy- and aminocarbonylation.</figcaption></figure>

worked for a variety of aliphatic alcohols, but not for other nucleophiles. The aminocarbonylation of similar substrates was recently achieved by Driver using Mn(CO)₆ and nitroarenes (Scheme 119B).⁷²⁴ Nitrosoarenes, formed *in situ* by reduction by Mn, were identified in this case as the reactive species. In 2015 Ackermann reported a Mn-catalysed aminocarbonylation of indoles with isocyanates,⁷²⁵ one of the most commonly used reactants for this type of reactions.⁷²⁶ This reaction only required the catalyst and solvent, without the addition of any other additives or ligands (Scheme 119C).⁷²⁵

15.1.1.13. C–S bond formation. Very recently, Matsunaga⁷²⁷ and Wang⁷²⁸ reported the first protocols for Co-catalysed trifluoromethylthiolation of (hetero)aromatic substrates using (PhSO₂)₂NSCF₃ and AgSCF₃ as reactants (Scheme 120A and B). In both cases, halogenated solvents had to be used and relatively low yields (<70%) were obtained.

The use of DMSO as reactant for the methylthiolation of similar substrates was reported by Jain *via* a Cu-mediated reaction (Scheme 120C).⁷²⁹ Arylthiolation was reported by Zhang using N-(arylthio)benzamides,⁷³⁰ while sulphonylation can be performed *via* an Umpolung reaction with hypervalent iodine compounds, followed by reaction with sodium sulphinates⁷³¹ (Scheme 120D and E). Notably, the latter method is also suitable for the reaction with other nucleophiles.

The introduction of arylsulfonyl functionalities on indoles was recently reported with another method, using DABCO-(SO₂)₂ and aryldiazonium tetrafluoroborates in a multicomponent reaction catalysed by Pd(II) (Scheme 120F).⁷³² The reaction is initiated by the formation of an arylsulfonyl radical, which is then introduced at the indole C2 position.

Trifluoromethylthiolation of indoles and pyrroles was reported by Li using N-(trifluoromethylthio)saccharin under Rh/Lewis acid catalysis (Scheme 120G).⁷³³ Interestingly, the functionalisation of 3-substituted indoles also occurred in the absence of Rh and Ag additive, suggesting that Lewis acids alone could promote the reaction on such compounds.

Finally, Liu demonstrated the aryl- and alkylthiolation of 2-pyridones with disulfides under Cu/Brønsted acid catalysis (Scheme 120H).⁷³⁴ It is worth mentioning that, although some

<figure><img src="image_228.png" /></figure>
<figure><img src="image_229.png" /></figure>

<figure><img src="image_230.png" /><figcaption>Scheme 120 C(sp²)–S bond formation with pyridine DGs.</figcaption></figure>

of these reactions required an air atmosphere, an O₂ atmosphere proved deleterious for the reaction,⁷²⁸,⁷²⁹,⁷³⁴ presumably due to sulphur oxidation in the reactants/products.

15.1.1.14. C–B and C–Si bond formation. Organosilanes and organoboranes have important applications in organic chemistry, for example in cross coupling reactions, and C–H borylation and silylation have therefore been considerably investigated even before 2015.³¹,⁷³⁵ Pyridine-directed C(sp²)–H borylation and silylation have been reported by a number of research groups. The compounds obtained in this way, which often contain an internal Lewis acid–base interaction as shown in Scheme 121, also have applications in material science, due to their fluorescent properties.⁷³⁶⁻⁷³⁹ Due to these non-covalent interactions, the C–H functionalisation process itself has been suggested to occur with two main different mechanisms. In the first one, the reaction is initiated by the C–H cleavage/formation of a DG-coordinated metallacycle (metal = catalyst, as for most of group-directed functionalisations), followed by insertion of the boryl/silyl group.⁷⁴⁰⁻⁷⁴³ The other mechanism assumes the Lewis acid–base interaction as the initial step, followed by catalyst coordination/C–H cleavage, on the basis of non-successful metallacycle formation or to early stage Lewis acid–base interactions observed spectroscopically.⁷³⁹,⁷⁴⁴

<figure><img src="image_231.png" /><figcaption>Intramolecular Lewis Base–Acid interaction</figcaption></figure>

Scheme 121 Si–N and B–N non-covalent interactions during pyridine-directed functionalisations.

Borylation employs diboranes or boranes as reactants; in the latter case, the addition of a hydrogen acceptor (generally an olefinic compound) to promote the reaction (as commonly used for silylation with hydrosilanes, *vide infra*) might instead result in complete inhibition due to hydroboration of the unsaturated moiety.⁷³⁹ Several examples of borylation of 2-phenylpyridines and analogues have appeared in the recent literature. Murata and Ackermann reported the use of HBpin or B₂pin₂ in combination with Ru catalysts (Scheme 122A and B),⁷⁴⁰,⁷⁴² however only a few examples of C(sp²)–H borylation were shown (Ackermann’s protocol was nonetheless also applied for C(sp³)–H borylation, see Scheme 136).

Kuninobu reported an interesting Fe-catalysed protocol using 9-BBN (9-borabicyclo[3.3.1]nonane) as borylating agent (Scheme 122C),⁷³⁹ and Miura/Hirano disclosed a Rh-catalysed borylation of 2-pyridones (Scheme 122D).⁷⁴¹ The use of the reaction products as substrates in a Suzuki coupling nicely demonstrates the potential for applications in synthesis.

Typical reactants for silylation are disilanes or hydrosilanes, the latter generally requiring the addition of a hydrogen acceptor to be efficient (norbornene is often used for this role, in super-stoichiometric amounts).⁷³⁵ Hydrosilanes/norbornene combinations have been used for the Ir-catalysed silylation of 2-arylpyridines by Oro/Iglesias and Kuninobu/Kanai (Scheme 123A and B).⁷⁴³,⁷⁴⁴ In the first case a preformed NHC–Ir(III) hydride complexes was used as catalyst for the silylation of 2-phenyl- and 2-thienyl-pyridines with a variety of silanes, ranging from triethyl to triphenyl and trialkoxy silanes. Interestingly, the catalyst also proved efficient for a variety of undirected C(sp²)–H silylations on (hetero)arenes.⁷⁴³ Kuninobu/Kanai’s protocol was developed instead for diarylfluorosilanes, and was not effective for non-fluorinated reactants.⁷⁴⁴

<figure><img src="image_232.png" /><figcaption>Scheme 122 Pyridine-directed borylation of C(sp²) centres.</figcaption></figure>
<figure><img src="image_233.png" /></figure>

A

B

<caption>Scheme 123 Pyridine-directed silylation of C(sp²) centres.</caption>

### 15.1.1.15. C-N bond formation

**15.1.1.15.1. Amidation.** While until 2014 a number of procedures were reported for C-H amidation using acyl azides as nitrene precursors, recently a number of different reactants have been employed for this transformation. Reactions with aminated hypervalent iodine reactants have been reported by Loh and DeBoef using catalytic Rh and stoichiometric Cu respectively, for the synthesis of N-aryl sulfonamides and phthalimides (Scheme 124A and B).⁷⁴⁵,⁷⁴⁶ A reaction with the electrophilic nitrogen source N-Boc-O-2,4-dinitrophenylhydroxylamine in water under Rh catalysis was developed by Lu (Scheme 124C).⁷⁴⁷ Notable features of this procedure are: the use of water as solvent, the good FG tolerance, and the possibility of functionalisation of purine-based nucleosides. Chang used a similar hydroxylamine reactant, N-Boc-O-acetylhydroxylamine, in the Co-catalysed amidation of arenes: in this case a variety of carbamates (other than N-Boc) could be employed in the reaction, and purines could be used as DG (Scheme 124D).⁷⁴⁸

The Cu-catalysed dehydrogenative C-H amidation with secondary amides has been reported by Chen using air as the sole oxidant (Scheme 124E).⁷⁴⁹ Here the formation of tertiary amides is remarkable, as most protocols result in the formation of secondary amides instead.

In 2015 Chang introduced dioxazolones as reactants for C-H amidation. Dioxazolones are safer and more reactive than the corresponding acyl azides, due to their relative stability and stronger coordination to the metal centre, which promotes faster reactions. Moreover, these reactants are simple to prepare and to handle. Chang⁷⁵⁰⁻⁷⁵² and Jiao⁷⁵³ reported their use in the directed amidation of arenes using Rh and Co catalysts, showing the reaction to be suitable for a number of different DGs (including purines, amides, and oximes, Scheme 124F). Notably, Chang reported the use of EtOAc as alternative solvent for a 200 mmol scale reaction.⁷⁵¹ Ackermann subsequently applied a similar procedure to the Co-catalysed amidation of indoles,⁷⁵⁴ while You employed Rh for the functionalisation of ferrocenes⁷⁵⁵ (Scheme 124G and H).

Very recently, the amidation of pyridones (C6) and isoquinolinones (C3) was reported with sulphonyl azides under Ir catalysis (Scheme 124I).⁷⁵⁶ Interestingly, C8-functionalisation of isoquinolinones could be performed in similar conditions in the absence of the heterocyclic DG.

**15.1.1.15.2. Amination.** C-H amination reactions also typically involved nitrenes obtained *in situ* from azides. For example,

<figure><img src="image_234.png" /></figure>

A

B

C

D

E

F

G

H

I

<caption>Scheme 124 Amidation reactions with pyridine DGs.</caption>

Lu demonstrated the reaction of 2-phenylpyridines with aryl azides in water, also allowing for a double *ortho*-functionalisation with two different azides (Scheme 125A).⁷⁵⁷ The use of anthranils (2,1-benzisoxazoles) as alternative, more stable nitrene precursors was independently reported by Wang and Li.⁷⁵⁸,⁷⁵⁹ The reaction of indoles with anthranils using polar protic solvents (H₂O or MeOH) and Rh catalysis resulted in a tandem amination-cyclisation process, leading to the formation of indoloquinolines (Scheme 125C).⁷⁵⁸,⁷⁵⁹ The same reaction was also shown to occur on 2-pyridones (Scheme 125D).⁷⁵⁹ Interestingly, the cyclisation did not occur when phenyl or thienyl substrates were investigated, and the reaction only resulted in the corresponding *o*-formylaniline-substituted product (Scheme 125B).⁷⁵⁸

**15.1.1.15.3. Azidation.** Narula reported in 2015 a protocol for the Cu-catalysed azidation of 2-phenylpyridines using benzotriazole sulfonyl azide (BtSO₂N₃) and K₂S₂O₈ as oxidant (Scheme 126).⁷⁶⁰

<figure><img src="image_235.png" /></figure>
<figure><img src="image_236.png" /></figure>

<figure><img src="image_237.png" /></figure>

<figure><img src="image_238.png" /></figure>

<figure><img src="image_239.png" /><figcaption>Scheme 125 Amination and related reactions with pyridine DGs.</figcaption></figure>

<figure><img src="image_240.png" /><figcaption>Scheme 126 Azidation of arenes using pyridine as DG.</figcaption></figure>

<figure><img src="image_241.png" /></figure>

<figure><img src="image_242.png" /></figure>

<figure><img src="image_243.png" /></figure>

<figure><img src="image_244.png" /></figure>

<figure><img src="image_245.png" /><figcaption>Scheme 127 Pyridine-directed C(sp²)–O bond formation.</figcaption></figure>

NaN₃ and 1-imidazole sulfonyl azide (ImSO₂N₃) also proved effective in these conditions.

15.1.1.16. C–O bond formation. Examples of C–O bond formation are somewhat limited in comparison to C–C and other C–heteroatom bond forming procedures, with yields often <70% or even <50%, possibly due to the strong coordinating ability of O, which might inhibit the catalysis by preventing reductive elimination or forming relatively stable complexes.⁷⁶¹,⁷⁶² Nonetheless, interesting advances are being made in terms of greener oxidants, cheaper base metal catalysts, and milder reaction conditions.

A number of papers on pyridine-directed C–O bond formation reactions on (hetero)arenes have been reported using Ru/PIDA,⁷⁶¹ solid-supported Pd/PIDA⁷⁶³,⁷⁶⁴ or simple Pd salts/peroxides⁷⁶⁵,⁷⁶⁶ combinations, leading to *ortho* acetoxylated, hydroxylated or alkoxylated compounds (in case of PIDA as oxidant, when H₂O or an alcohol are used as solvent, one-pot hydrolysis or alcoholysis of the acetoxylated product is obtained).

In the past few years, some reports appeared where O₂ was used as oxidant. Shen reported a direct alkoxylation with alcohols (only 3-methylpyridine could be used as DG, Scheme 127A),⁷⁶⁷ while Guis used aldehydes/O₂ as reagents in combination with Pd catalysis.⁷⁶⁸ In this case the reaction occurred *via* formation of an intermediate acyl peroxo-radical, followed by its reaction with the arene, ultimately resulting in hydroxylated compounds (Scheme 127B). Patel disclosed the benzoylation of arenes

using benzylethers and TBHP as oxidant under Cu catalysis (Scheme 127C).⁷⁶⁹ Although limited in yields and scope, this protocol is interesting as it shows different product selectivity from its Pd-catalysed counterpart (which gives acylated products).⁷⁷⁰ The formation of the ester product from the benzylic ether derives from Cu/TBHP mediated oxygenation to benzaldehyde and further to *t*-butyl arylperoxyester. The arylcarboxy radical generated by homolitic cleavage of this intermediate is finally introduced at the *ortho* position in the substrate.⁷⁶⁹ A very recent remarkable paper by Li and Xu demonstrated the acyloxylation of 2-phenylpyridines and analogues with carboxylic acids and Rh catalysis (Scheme 127D).²³⁴ Though using a superstoichiometric amount of Ag as oxidant, this protocol was applicable to a broad range of carboxylic acids: aliphatic (incl. saturated heterocyclic rings), (hetero)aromatic and vinylic reacted in good yields, often >80%. Moreover, a range of DGs proved effective in this protocol, and amides were used for the acylation of olefinic substrates, although in modest yields (<70%).²³⁴

Finally, the acetoxylation of indoles (2-substituted, C7 functionalisation) and carbazoles was reported by Miura using acetic acid, Ru catalysis, and Ag oxidant (Scheme 127E).⁷⁷¹ It is worth noting that the functionalisation of unsubstituted indoles was not observed, either in C7 or in C2.

15.1.1.17. C–Halogen bond formation. C–H halogenation, as for arylation reactions, also suffered from the formation of mixtures of mono and di-halogenated compounds. In recent years, a few synthetic methods showing good selectivity were
<figure><img src="image_246.png" /></figure>

<figure><img src="image_247.png" /><figcaption>Scheme 128 Pyridine-directed C(sp²)–H halogenation reactions.</figcaption></figure>

reported by a number of research groups and in different conditions. The use of simple and cheap NaX salts as reactants for the introduction of Cl, Br and I reported by Wang in 2015 is certainly a landmark (Scheme 128A).<sup>772</sup> This method is the most atom economic reaction available in the series, although a limited substrate scope was investigated. The use of *N*-halosuccinimides as halogenating reactants using Pd supported on Cr- or Fe-based MOFs as heterogeneous catalysts was investigated by Martin-Matute (Scheme 128B).<sup>773</sup> Although having a number of clear advantages, such as mild conditions and recyclability of the catalyst, the catalytic results are unfortunately considerably dependent on the substrate and DG employed, presumably due to the steric hindrance of the starting materials and the rigid structure of the MOFs. It is worth mentioning that, although the catalysts could be reused for several runs, some degradation of the solid structures was observed, as well as its halogenation as a side process. Similar reactions, using Pd@CNT (carbon nanotubes)<sup>763</sup> or other Pd@MOFs (Zr-based)<sup>774</sup> were reported by Ellis and Cohen.

Wu reported the use of benzyl chloride as halogenating agent under oxidising conditions (Scheme 128C).<sup>775</sup> While using PdCl<sub>2</sub>, as catalyst, and under O<sub>2</sub> atmosphere, selective C–Cl bond formation was obtained, switching the catalyst to a preformed palladacycle with a ferrocenylimine ligand and adding a base under air, resulted in the selective acylation of the C–H bond (not shown).<sup>775</sup> In the chlorination case, the intermediate tBuOCl is suggested as actual reactant, while in the second case the formation of an acyl radical is responsible for the reaction. In 2015 Li reported the synthesis of diaryliodonium salts starting from PIDA, PTSA (*p*-toluensulfonic acid) and a DG-equipped arene under Rh catalysis (Scheme 128D).<sup>776</sup> These compounds can be used as intermediates for the formation of C–C, C–O, C–N, C–S and C–P bonds using a variety of nucleophiles (see also Scheme 120E). It is worth noting, however, that many procedures have been reported for the direct

formation of such bonds with the same DGs, and the synthetic utility of this two-step procedure is therefore rather limited.

### 15.1.2. C(sp³)–H bond functionalisation.
The functionalisation of activated C(sp³)–H bonds, such as benzylic, allylic, or in *α* to a heteroatom, has been much investigated, even without the facilitating effect of a DG. The activation and functionalisation of unactivated C(sp³)–H bonds is instead considerably more difficult, due to the intrinsically stronger bonds, and selectivity is also challenging due to the presence of several similar bonds in a typical organic molecule. Group-directed C(sp³)–H bond functionalisation has been explored during the last two decades, and brought important improvement in the field. A plethora of effective transformations has been reported throughout the years. Although mostly bidentate DGs have been used for the functionalisation of C(sp³)–H bonds in the last few years,<sup>777,778</sup> several examples employing monodentate DGs, including heterocycles, have appeared, after the pioneering work of Sanford,<sup>629,779</sup> Chatani,<sup>780</sup> and Daugulis,<sup>630</sup> among others. For the azine-based DGs, the substrates investigated fall mainly in two classes: 8-methylquinoline and 2-ethylpyridine derivatives, which will be treated in this section.

8-Methylquinolines are the most common substrate investigated, and its functionalisation is generally easier than that of 2-ethylpyridines, due to its benzylic nature. Typically, substitution on the aromatic rings is tolerated, although in some instances strong EWG substituents and steric hindrance in C7 or C2 can inhibit the reaction to various degrees. In general, apart from a few cases, substitution at the benzylic position (e.g. 8-ethylquinoline) strongly suppresses C–H activation.

2-Ethylpyridines (and in general any other flexible substrate), on the other hand, present the intrinsic issue of the flexibility of the alkyl chain, which makes the coordinating ability of the azine less efficient (metallacycle formation). In such substrates, monofunctionalisation may also pose some challenges, due to the lack of steric hindrance in close proximity. These issues are generally tackled by using branched alkyl chains instead of linear ones, to reduce flexibility/rotation (Thorpe–Ingold effect) and increase the steric hindrance around the desired C–H bond.

As C–C bonds connect the azine to the functionalisable C–H bonds, the DG is not cleavable in such substrates. Quinoline substrates can, however, be easily reduced to tetrahydroquinoline with NiCl<sub>2</sub>/NaBH<sub>4</sub>,<sup>781–783</sup> H<sub>2</sub>/Pd@C,<sup>721</sup> H<sub>2</sub>/PtO<sub>2</sub>,<sup>784</sup> or NaBH(CN)<sub>3</sub>/BF<sub>3</sub>–Et<sub>2</sub>O,<sup>785</sup> hereby enlarging the application scope. The same reduction is in theory possible for 2-ethylpyridine derivatives, to produce piperidines, but it has not been used in the context of C–H functionalisation.

#### 15.1.2.1. Arylation.
A few arylation procedures have been reported by Glorius, Shi/Xia and You under Rh/Ir catalysis, for the functionalisation of both 8-methylquinolines and 2-ethylpyridines. In 2015 Glorius reported the Rh-catalysed arylation of both substrates with aryl boroxines (Scheme 129A).<sup>786</sup> Despite the use of up to 2 equiv. of boroxine (6 equiv. Ar) and superstoichiometric Ag as oxidant (due to boroxine homocoupling as a side reaction) the reaction gave good yields for both substrates. While only 8-benzylquinoline was functionalised for this class
<figure><img src="image_248.png" /></figure>

substituted quinolines as DGs, and the FG tolerance on the heteroarene partner, which includes esters, amides, aldehydes, halides and alkenes, furnishing yields in most cases >60%.⁷⁸⁹

### 15.1.2.2. Alkylation.
For alkylation, 8-methylquinoline is the substrate of choice and, to our knowledge, no alkylation on 2-ethylpyridine derivatives have appeared in the last 3 years. Investigations using typical reactants such as α,β-unsaturated carbonyls and diazocompounds have been undertaken. A notable exception is the use of cyclopropanols as alkylating agents, reported by Li.⁷⁹⁰ In this case only two examples of C(sp³)–H alkylation were reported, thus this method is not covered in Scheme 130. Another interesting exception is the use of allylic alcohols as alkylating agents, reported in 2017 by Kim (Scheme 130A).⁷⁸³ Apart from the new reactant used, this reaction occurs in water under air and a range of substituted quinolines could be functionalised in

<figure><img src="image_249.png" /><figcaption>Scheme 129 Arylation of 2-ethylpyridines and 8-methylquinoline derivatives.</figcaption></figure>

of substrates, both branched and linear 2-ethylpyridine analogues were tested in the reaction: branched substrates reacted to give selectively monoarylated products, while linear-chain substrates resulted in varying amounts of diarylated product.⁷⁸⁶

The arylation of 2-ethylpyridines with diaryliodonium salts was reported by Shi under Ir catalysis (Scheme 129B).⁷⁸⁷ This reaction, although requiring 3 equiv. of the substrate to avoid difunctionalisation, works well with a variety of azines (pyridines, pyrazines, quinolines, 73–95% yield) and azoles (pyrazole, isoxazole, 45–52%). The possibility to introduce aromatic rings other than *p*-tolyl was demonstrated using aliphatic oximes as substrates.⁷⁸⁷ In 2016 Glorius reported another protocol for the arylation of 8-benzylquinolines, this time with aryl bromides (Scheme 129C).⁷⁸⁸ The use of a chiral carbene ligand allowed the formation of enantio-enriched products (e.r. between 80/20 and 90/10). This reaction proved to be fairly substrate sensitive, with yields ranging between 42 and 86%, depending on the substituent on the benzylic ring of the substrate and the aryl bromide used.⁷⁸⁸

Finally, an interesting protocol from the You group specifically aimed at the heteroarylation of 2-ethylpyridines and 8-methylquinolines appeared in 2017 (Scheme 129D).⁷⁸⁹ Apart from the specific functionalisation with substituted thiophenes, benzothiophenes and furans, this is a challenging dehydrogenative coupling between a C(sp³)–H and a C(sp²)–H bond. Whereas the high temperature (140 °C), the 3 equiv. of oxidant (6 equiv. Ag overall) required, and the sensitivity to the Thorpe–Ingold effect can be seen as drawbacks, very notable features are: the use of alcohols as cosolvents for 2-ethylpyridines, the use of

<figure><img src="image_250.png" /><figcaption>■ Allylic alcohols vs α,β-unsaturated ketones</figcaption></figure>

<figure><img src="image_251.png" /><figcaption>Scheme 130 Alkylation of 8-methylquinoline derivatives.</figcaption></figure>
good yields. The use of alcohols other than 3-buten-2-ol required a mixture H₂O/PEG (polyethylene glycol) as solvent, and resulted in generally lower yields (<70%).⁷⁸³

Two very similar protocols for the alkylation with α,β-unsaturated ketones were reported by Li/Chang and Li (Scheme 130B).⁷⁸¹,⁷⁹¹ Both protocols, using Rh catalysis in halogenated solvents at low/mild temperatures gave generally high yields of the desired alkylated quinolines. Somewhat lower yields were obtained with function- alised substrates, in particular sensitivity to steric hindrance in C7 was noted in both cases. The reactions proceeded well with aliphatic and (hetero)aromatic vinyl ketones.⁷⁸¹,⁷⁹¹ The formation of the same product starting from both vinyl alcohols and α,β-unsaturated ketones is due to different mechanisms. For the latter, the formal 1,4-addition product is obtained by migratory insertion of the double bond into the initial rhodacycle, followed by hydrolysis (protodemetallation). In the case of allylic alcohols, a migratory insertion/β-hydride elimination is the suggested pathway to the alkylated final products (Scheme 130, bottom).

The use of maleimides as coupling partners has been reported by Kim in 2016, leading to succinimide-functionalised methylquino- lines (Scheme 130C).⁷⁸² Although the reported conditions did not prove effective with other α,β-unsaturated carbonyl partners, the reaction proceeded in good yields with a range of N-functionalised maleimides and substituted quinolines (strong EWG substituents gave considerably low yields).

Two papers appeared recently on the alkylation of 8-methyl- quinolines making use of diazocompounds, one under Rh and the other under Co catalysis (Scheme 130D).⁷⁸⁴,⁷⁸⁵ Both protocols are characterised by a good FG tolerance on the quinoline substrate; for instance, strong EWG substituents can still lead to high yields in the Rh-catalysed process,⁷⁸⁴ while a variety of useful functionalisations are tolerated in the Co-catalysed process, such as alkenes, alkynes, free NH₂ and Bpin.⁷⁸⁵

### 15.1.2.3. Alkenylation and alkynylation.
Due to inherently poor reactivity and selectivity, olefination of C(sp³)-H bond is in general rare, and only a few papers have appeared in the literature specifically on the introduction of these functionalities on 8-methylquinolines. Sundararaju reported a Co-catalysed addition to internal alkynes, generating olefins in a stereoselective (syn) manner (Scheme 131A).⁷⁹² The reaction with asymmetric alkynes resulted in varying degrees of regioselectivity, depending on the substituents. Interestingly, one example of addition to a terminal alkyne was also reported, albeit in 30% yield.

The reaction with geminal difluoroalkenes (F as leaving group) under Rh catalysis was developed by Li and Wang, and also occurred with good stereoselectivity for a variety of sub- stituted 8-methylquinolines (Scheme 131B).⁷⁹³ Interestingly, a few examples of heteroaromatic (32–35% yield) and fluoroalkyl- substituted (94%) alkenes were demonstrated. Surprisingly, it was also shown that fluorine can act as a leaving group even in the presence of a tosylate group, which remained unaltered in the product.⁷⁹³

Only one example of alkynylation of 8-methylquinolines has been reported recently (Scheme 131C).⁷⁹⁴ A preformed Pd(II) catalyst was utilised for the coupling with TIPS-substituted

acetylene bromide. A range of differently substituted quinolines (including alkene and ester substituents) could be coupled efficiently under these conditions. The Cu(OAc)₂ in superstoichiometric amounts, despite being mentioned as oxidant, probably has another role, as no oxidant should be required for this transformation.

#### 15.1.2.4. Acylation.
Li reported two protocols for the C(sp³)- H acylation of 8-methylquinolines and 2-ethylpyridines, using relatively reactive ketenes or cyclopropenones with Rh catalysts (Scheme 132A and B).⁷²¹,⁷⁹⁵ In both protocols substituted 8-methylquinolines were well tolerated, even at the C7 position. The acylation with cyclopropenones, although not particularly high-yielding, allows the introduction of enones with a single reactant, and can also be applied to 2-ethylpyridine derivatives.

#### 15.1.2.5. C-N bond formation.
A relatively large number of examples of C(sp³)-N bond formation in 2-ethylpyridine or 8-methylquinoline derivatives have recently appeared in the literature. With a few exceptions, these mostly occur under Rh catalysis, using dioxazolones, amides, azides, hypervalent iodine compounds (amidation), anthranils (amination), and organic nitrites (nitration) as reactants.

<figure><img src="image_252.png" /><figcaption>Scheme 131 Olefination and alkynylation of 8-methylquinolines.</figcaption></figure>

<figure><img src="image_253.png" /></figure>
<figure><img src="image_254.png" /></figure>

<figure><img src="image_255.png" /><figcaption>Scheme 133 Directed amidation on 8-methylquinoline and 2-ethylpyridine derivatives.</figcaption></figure>

**15.1.2.5.1. Amidation.** Amidation reactions have been studied with a range of nitrene precursors, such as azides, dioxazolones, and amidated hypervalent iodine compounds.

The reaction with sulfonazides works efficiently with a variety of substituted coupling partners (Scheme 133A).⁷⁹⁶ Notably, EWG substituents on the quinoline provided better results than EDGs, which rarely occurs. Li and Sundararaju employed dioxazolones for the amidation, using respectively Rh and Co dimers as precatalysts (Scheme 133B).⁷⁹⁷,⁷⁹⁸ Importantly, the reaction with Rh was demonstrated to occur even on 8-ethyl or 8-benzylquinolines, although substitution on the quinoline itself was not investigated. Notably, many examples of C(sp³)-H amidation, including more complex molecules, were reported with this protocol making use of oximes ad DGs.⁷⁹⁷ The protocol under Co catalysis, although being fairly sensitive to the substitution pattern in both coupling partners,⁷⁹⁸ is one of the rare examples of base metal-catalysed C(sp³)-H activation, and is therefore an important advancement.

The use of amidated iodanes, either preformed or formed *in situ*, for the functionalisation of both C(sp²)-H and C(sp³)-H bonds was reported by Loh and You respectively under Rh catalysis (Scheme 133C and D).⁷⁴⁵,⁷⁹⁹ In particular, the amidation of 2-ethylpyridine derivatives can be performed at room temperature, although requiring a long reaction time (48–72 h). Interestingly, this functionalisation seems to require a quaternary

carbon α to the functionalised C–H bond to be effective (Scheme 133C bottom and Scheme 133D). A couple of other procedures have been reported for the amidation of 8-methylquinoline, which proceed *via* a different mechanism (no nitrenes involved). Azodicarboxylates have been used by Kim and Park, while *N*-fluoroarenesulfonimides were utilised by Zheng under Cu catalysis (Scheme 133E and F).⁸⁰⁰,⁸⁰¹ In both cases certain sensitivity to the substitution patterns on the quinoline was observed, resulting in some cases in poor yields.

**15.1.2.5.2. Amination and nitration.** Jiao and Li/Lan reported the amination of 8-methylquinolines and 2-ethylpyridines using anthranils under very similar conditions (Scheme 134A).⁸⁰²,⁸⁰³ A notable point, apart from various functionalities tolerated on both coupling partners, is the possibility to employ 8-ethylquinolines as substrates, which are generally not reactive.

The use of *t*-butylnitrite in combination with oxygen and a Pd catalyst for C(sp³)-H nitration was reported in 2015 by Liu (Scheme 134B).⁸⁰⁴ This protocol is interesting as it avoids the use of stoichiometric AgNO₂ as reactant, often used in C–H nitration. Although proceeding relatively slowly (48 h reactions), variedly substituted 8-methylquinolines, including strong EWG-substituted, could be functionalised in good yields.

**15.1.2.6. C–O bond formation.** C(sp³)–O bond formation for this class of DG has not been much investigated. Apart from two isolated examples of methoxylation and acetoxylation of 8-methylquinoline (99 and 90% respectively) under heterogeneous Pd catalysis reported by Ellis in 2015,⁷⁶³ Chan demonstrated the coupling of 8-methylquinolines with methylketones catalysed by Cu.⁸⁰⁵ The proposed mechanism for this reaction does not actually involve coordination of the quinoline nitrogen to Cu and is therefore not entirely within the scope of this review. Nonetheless, it has been described in Scheme 135 for completeness. The reaction seems to be initiated by an acid-promoted aerobic oxidation, similar to a reaction developed in the Maes group,⁸⁰⁶,⁸⁰⁷ leading to the corresponding quinoline aldehyde. A subsequent (cascade) condensation with the methylketone results then in the formation of the enone.⁸⁰⁵

<figure><img src="image_256.png" /><figcaption>Scheme 134 Directed amination and nitration on 8-methylquinoline and 2-ethylpyridine derivatives.</figcaption></figure>
<figure><img src="image_257.png" /></figure>

Review Article

<figure><img src="image_258.png" /><figcaption>Scheme 135 C–O bond formation on 8-methylquinolines.</figcaption></figure>

<figure><img src="image_259.png" /><figcaption>Scheme 136 C(sp³)–H borylation and silylation.</figcaption></figure>

15.1.2.7. *C–B and C–Si bond formation.* Few examples have been reported of C(sp³)–B bond formation, investigating cyclic and acyclic amines, rather than the typical 2-ethylpyridines and 8-methylquinolines.<sup>740,808</sup> The functionalisation of cyclic amines is an interesting topic, and has been relatively little explored.<sup>809</sup> The borylation of such compounds are therefore of interest. Ackermann's protocol utilises a preformed, bench-stable Ru-carboxylate catalyst, while Ir catalysis and a complex pre-ligand were used by Li (Scheme 136A and B).<sup>740,808</sup> Although higher yields were obtained in this case, only three examples of C(sp³)–H functionalisation were shown, with the main focus of the paper being C(sp²)–H functionalisation with a number of different DGs.

C(sp³)–Si bond formation has been investigated instead on 2-ethylpyridine derivatives (Scheme 136C).<sup>810</sup> Despite clear disadvantages such as the use of 5 equivalents of silane and 3 of norbornene as additive (hydrogen acceptor), and the high temperature required, the process gave good yields for a variety of substrates, including substituted pyridines and unsubstituted alkyl chains, using a 2% Ru loading (total [Ru]).

## 15.2. Pyrimidine as DG

Pyrimidine is often tested as secondary DG in many protocols developed for pyridine-based strategies, and in many cases works as well in the same or very similar reaction conditions. Nonetheless, there are several cases in the literature where the pyrimidine DG works differently, and many transformations are specific for this DG. In particular, pyrimidine is often the DG of choice for the functionalisation of indoles (and pyrroles) in C2, and in most cases is used only for such substrates.

### Typical pyrimidine cleavage

<figure><img src="image_260.png" /><figcaption>Smiles-type rearrangements (cascade to C–H functionalisation or upon treatment with NaOEt)</figcaption></figure>

<figure><img src="image_261.png" /><figcaption>Scheme 137 Common strategies for pyrimidine DG cleavage or migration.</figcaption></figure>

Because of this, a separate section has been devoted to this DG. Protocols that are very similar to those reported for pyridine will not be reported again in this section (the interested reader can find many information in Section 15.1.1), and more selected literature will be discussed here.

The cleavage of the pyrimidine ring is, as for pyridine, typically not possible when attached *via* a C–C bond, but it is easy when the DG is attached *via* a C–N bond (*e.g.* in indoles, Scheme 137). In this case no quaternisation is necessary (as it is with pyridine), and often simply heating with NaOEt in DMSO is enough to produce the pyrimidine-free substrate (side reactions may occur depending on R, for example in the case of silanes, Scheme 137). Unlike pyridine, however, pyrimidine commonly gives rise to rearrangements, instead of the desired cleavage. In particular, Smiles-type rearrangements (intramolecular nucleophilic aromatic substitution), resulting in 1,4-migration of the pyrimidine ring, have been observed several times when a nucleophilic site is available at a specific position, as shown in Scheme 137. These are specifically reported in the text whenever they were noted in the original publication.

### 15.2.1. Arylation.
As many arylation reactions have been reported before 2015 and many protocols are similar to those developed for pyridine DGs, few examples will be reported here. Li and Cheng reported the naphthylation of indoles using 7-oxabenzonorbornadienes as reactants under Co catalysis (Scheme 138A).<sup>811,812</sup> This class of compounds had been used before with other DGs and under Rh catalysis,<sup>813,814</sup> but the use of base metals constitutes an important improvement. The reaction occurs *via* addition of the indole to the double bond of the alkene, leading to an intermediate cyclic allylation product.<sup>812</sup> Interestingly, Cheng found that the reaction can be stopped at this step if performed at room temperature instead of 90 °C. Arylation with arylboronic acids was reported by Pilarski and Niu/Song
respectively with Ru and Co catalysts under oxidising conditions (Scheme 138B and C).⁸¹⁵,⁸¹⁶ Despite the relatively high amount of Co and the HFIP solvent used in the latter protocol, the use of Co catalysis results in higher tolerance of electron-withdrawing substituents on the indole moiety, which instead result in low yields in the Ru-catalysed reaction (Scheme 138B).

### 15.2.2. Alkylation.
Some interesting reports on formal alkylation reactions leading to complex molecules have been recently published. Li showed an alkyne insertion/intramolecular Diels-Alder process between N-pyrimidylindoles and benzoquinonic 1,6-enynes leading to fused and bridged polycyclic compounds (Scheme 139A and B).⁸¹⁷ While with Rh catalysis the fused polycyclic product was obtained almost exclusively, the use of Co allowed preferential formation of the bridged one, although not exclusively. The product switch arises from the different regioselectivities of the initial olefination step (Rh: alkyne 2,1-insertion; Co: 1,2-insertion), in turn due to different steric sensitivities (the Co catalyst is suggested to be more sterically sensitive, giving preferentially the least hindered insertion intermediate). It is worth mentioning that the use of the classical pyrimidine cleavage protocol (NaOEt in DMSO, see Scheme 137) on the fused product did not result in DG cleavage, but in the cleavage of the oxa-cycle, giving the corresponding phenol.⁸¹⁷

<figure><img src="image_262.png" /><figcaption>Scheme 138 Pyrimidine-directed arylation of indoles.</figcaption></figure>

<figure><img src="image_263.png" /><figcaption>Scheme 139 Pyrimidine-directed alkylation of indoles.</figcaption></figure>

<figure><img src="image_264.png" /></figure>
Alkylation with diazo compounds, followed by *in situ* intra-
molecular aldol or Michael-type reactions was reported by Zhou.
In this case, 2,3-fused indoles were obtained (Scheme 139C).⁸¹⁸
Reactants featuring ester, amide, aromatic and heteroaromatic
rings could be successfully employed in the reaction with good
yields. Huang and Wang recently reported a multicomponent
reaction between *N*-pyrimidylindoles, acrolein derivatives and
TEMPO (Scheme 139D).⁸¹⁹ The first step of this reaction is
the addition of indole to the double bond of the acrolein
(Rh-catalysed), followed by Cu-mediated introduction of the
TEMPO radical in α to the carbonyl. Interestingly, MeCN as
solvent proved crucial in suppressing other reaction pathways
(e.g. β-hydride elimination and protonation), despite failing to
do so when acrylic ketones were used instead of aldehydes. Apart
from acyclic derivatives, Li introduced the use of cyclopropanols
as new reactants for the introduction of carbonylethyl chains
(Scheme 139E).⁷⁹⁰ Not being electrophilic compounds, their
use constitutes a challenge and requires oxidising conditions
(superstoichiometric Cu used). The reaction requires low Rh
loadings (2%) and can be performed on arenes as well as
indoles, but the yields obtained do not appear competitive in
comparison to the use of the more common acrylates. Even in
this case, the use of NaOEt in DMSO for pyrimidine cleavage did
not result in the desired product, but in the migration of the
pyrimidine from the indole to the alkyl chain.⁷⁹⁰

The use of acryloyl silanes was reported by Loh and Feng, and resulted in high yields of the corresponding alkylated products (Scheme 139F).⁸²⁰ Li and Ackermann/Li reported the use of sulfoxonium ylides (carbene precursors) and maleimide for the alkylation of indoles (Scheme 139G and H).⁸²¹,⁸²² These reactants have also been used with pyridine DGs, with somewhat different procedures (*cf*. Scheme 110K and Scheme 111A). In the case of Scheme 139H, again the use of NaOEt to cleave the DG resulted in pyrimidine migration. Finally, Shi reported an interesting Ni-catalysed trifluoroethylation of indoles using trifluoroethyl iodide as reactant. Unfortunately, not very high yields were obtained for a range of indoles and other heterocycles, with most yields remaining below the 70% threshold (Scheme 139I).⁸²³

**15.2.3. Allylation.** As previously reported for pyridine DGs, many allylation protocols involve reactions with allyl alcohols, halides, or other activated allylic precursors (strained rings or leaving groups). In this context, a few procedures using different precursors or methodologies have been reported for the allylation of indoles. Li reported the use of both 4- and 6-membered rings as allylic precursors in Rh-catalysed reactions (Scheme 140A and B).⁸²⁴,⁸²⁵ While in the first case the driving force is the opening of the strained 4-membered lactone, the release of CO₂ facilitates the opening of the 6-membered ring. Importantly, both reactions proved to be selective for the *E* isomer. Another interesting procedure was reported by Kim for the synthesis of trifluoromethylallylated indoles and indolines, employing *α*-trifluoromethylallyl carbonates (Scheme 140C).⁸²⁶ The reaction was performed in THF, but *t*AmylOH was found to be a valid alternative. Notably, the allylation of indolines in C7 did not occur with the pyrimidinyl DG, but required

carbonyl-based DGs.⁸²⁶ The use of NaOEt on the allylated
indole did not result in the pyrimidyl cleavage, but in olefin
isomerisation instead, although in modest yields (52%). Moving to
base metals, Li reported the use of vinyloxiranes under Co catalysis
(Scheme 140D),⁸¹¹ allowing allylation of indoles in high yields and at
low temperatures, despite the low stereoselectivity. As vinyloxiranes,
vinyldioxolanones had also been previously reported as allylating
agents, but Yu disclosed their use in a solventless ball-milling
protocol under Co catalysis (Scheme 140E).⁸²⁷ Despite the neat
conditions and only requiring 30 min for completion, mixtures
of isomers were obtained from the reaction, as previously
observed with these reactants (cf. Scheme 113B).

An interesting Mn-catalysed allylation reaction with 1,1-disubstituted allenes was reported by Wang (Scheme 140F).<sup>828</sup> Very high yields were obtained for many examples, and the procedure is applicable to a variety of (hetero)arenes apart from indoles, using either pyrimidine or pyridine DGs. Unfortunately, monosubstituted allenes resulted in isomeric mixtures, and tri- and tetra-substituted ones proved ineffective in the reaction.

**15.2.4. Alkenylation.** Olefination protocols have been investigated on *N*--(2-pyrimidyl)indoles exploiting either oxidative dehydrogenative coupling with alkenes (Fujiwara–Moritani reaction), addition to alkynes or allenes, or *via* cross-coupling type reactions. Loh and Feng reported the reaction with acryloyl silanes for the formation of both alkylated (see Scheme 139F above) and alkenylated products (Scheme 141A).<sup>820</sup> In the case of

<figure><img src="image_265.png" /><figcaption>Scheme 140 Pyrimidine-directed allylation of indoles.</figcaption></figure>

<figure><img src="image_266.png" /></figure>
<figure><img src="image_267.png" /></figure>

<figure><img src="image_268.png" /><figcaption>Scheme 141 Pyrimidine-directed olefinations.</figcaption></figure>

alkenylation, 2 equiv. $Cu(OAc)_2$ were used as oxidant, together with 1 equiv. TEMPO, which was suggested to prevent silane polymerisation and assist in the oxidative turnover of the Rh catalyst. It is noteworthy that this reaction is somewhat sensitive to the steric hindrance on both indole's C3 and C7 (not commonly observed) and on the identity of the silane group.⁸²⁰

Li and Lan reported a rare selective 1,2-insertion of terminal alkynes using Co catalysis, giving α-gem-vinylindoles (Scheme 141B).⁸²⁹ The use of Co and TFE as solvent was crucial for the selectivity, due to the high steric sensitivity of Co and the H-bonding abilities of TFE. Propargylic alcohols, amines and silanes performed well when used as reactants, although yields and selectivity depended on their structure. The use of NaOEt for the cleavage of the DG resulted in the transfer of the heterocycle to the hydroxyl of the propargylic moiety.

A complementary procedure, giving the 2,1-insertion product with terminal alkynes was reported by Li and Lei using Mn as catalyst (Scheme 141C).⁸³⁰ Aryl- and alkyl-substituted alkynes proved efficient reactants in most cases, and the reaction could be performed on internal alkynes as well. A practical downside here is the use of $Et_2O$ at 80 °C.

Rueping and Wang/Li independently reported the Mn-catalysed olefination of indoles with allenic esters. The use of 1,3-disubstituted allenes (Rueping) resulted in the hydroarylation product

(arylation at the C2 position of the allene) in a regio- and stereoselective manner (Scheme 141D).⁸³¹ Interestingly, the reaction with tri- or tetra-substituted allenes (Rueping, Wang/Li) resulted in a cascade hydroarylation/DG migration *via* a Smiles-type rearrangement (see Scheme 137), furnishing the products in Scheme 141E.⁸³¹,⁸³² While Rueping's procedure⁸³¹ resulted in higher yields (often >90%), but required 2 equiv. of NaOAc as additive, Wang/Li's protocol⁸³² gave lower yields in several cases (although a much broader substrate scope was reported), but without the addition of any additive. A number of post-functionalisation reactions were reported by both authors, including: alkene reduction, amide hydrolysis (with consequent pyrimidine migration back to the indole), decarboxylative ring opening, and DG cleavage with $LiAlH_4$ (concomitant carbonyl reduction).⁸³¹,⁸³²

The Co-catalysed hydroarylation of ketenimines resulted in the olefination product depicted in Scheme 141F in generally good yields (lower yields on pyrroles, arenes and indolines).⁸³³ The use of NaOEt on these compounds resulted in a pyrimidine migration similar to that in Scheme 141E, *via* intramolecular nucleophilic attack of the enamine to the pyrimidyne ring.⁸³³ Finally, a couple of substitution procedures for the olefination of indoles were reported using alkenyl acetates or gem-difluoroalkenes. The reaction with cyclic and acyclic alkenyl acetates and similar
presents several advantages, such as the high yields, the use of ethanol as solvent at room temperature, and one example of reaction with tBu-EBX (yield 84%). Finally, Hong reported a Ru- or Rh-catalysed alkynylation of 4-quinolones and isoquinolinones with TIPS-EBX (Scheme 142E).⁸⁴¹ This is a rare example of the use of pyrimidine as DG for the functionalisation of such type of compounds, usually performed using pyridine as DG. The reaction proceeds well in air, but no variation in the reactant (other silyl or carbon groups) was investigated. It is noteworthy that the cleavage of the pyrimidyl DG using basic conditions (NaOEt or NaOMe) when silanes are present in the final product results in the concomitant desilylation (see also Scheme 137), which might constitute an advantage for synthetic purposes.

### 15.2.6. Cyanation, acylation and aminocarbonylation.
An example of cyanation of indoles using NCTS as reactant under Rh catalysis has been reported by Kim (Scheme 143A).⁸⁴² Only a few examples of indole functionalisation were reported in his publication (high yields, mostly >90%), but the same reaction conditions (at 130 °C instead of 110 °C) can be applied to the C7 cyanation of indolines, with carbonyl-based DGs. The pyrimidine DG could be employed for the mono-cyanation of pyrrole and carbazole.

As for the pyridine DG, a number of publications on the use of Pd catalysis in combination with peroxides and acyl radical precursors (aldehydes, α-diketones, toluene) for the introduction of an acyl group onto N-pyrimidinylindoles have been reported.⁸⁴³⁻⁸⁴⁵ The general conditions are: 5–10% Pd(II) catalyst, 3–5 equiv. peroxide, apolar solvent (e.g. toluene, THF), at 90–120 °C, and the reaction follows the general mechanism shown in Scheme 118.

<figure><img src="image_269.png" /></figure>

<figure><img src="image_270.png" /></figure>

<figure><img src="image_271.png" /></figure>

<figure><img src="image_272.png" /><figcaption>**Scheme 143** Pyrimidine-directed cyanation, acylation and aminocarbonylation of indoles.</figcaption></figure>

<figure><img src="image_273.png" /><figcaption>**Scheme 142** Pyrimidine-directed alkynylations.</figcaption></figure>

electrophiles was reported by Ackermann under Co catalysis (Scheme 141G).⁸³⁴ The Mn and Co-catalysed reaction with difluoroalkenes was reported respectively by Loh/Feng and Li (Scheme 141H).⁸³⁵,⁸³⁶ While the substrate scope remains similar, the Co-catalysed process performed much better in terms of reaction temperature, yields and stereoselectivity (Z selective). In this reaction, $Ca(OH)_2$ is suggested to act as a scavenger for the HF produced, pushing the reaction forward.⁸³⁶ It is worth noting though, that the Mn-catalysed reaction shows a certain preference for the less stable E isomer for certain substrates.⁸³⁵

### 15.2.5. Alkynylation.
Concerning alkynylation, although the reactants used are very limited and are the same reported for the pyridine DG, a few reports have appeared on the use of base metal catalysis for these functionalisations (which is not common for pyridine DG), mostly in halogenated solvents. Thus, Ackermann reported both Co- and Mn-catalysed reactions with bromoalkynes for the C2 functionalisation of indoles (Scheme 142A and B).⁸³⁷,⁸³⁸ In particular, the Mn catalyst (Scheme 142B)⁸³⁸ proved very versatile, allowing the use of either silylated (common), and aryl-, alkyl-, alkenyl-functionalised bromoalkynes (rare). The key for the use of non-silylated reactants was the addition of a small amount (0.05%) of $BPh_3$ as Lewis acid, which promoted yields in many cases >80%. This protocol shows an overall good substrate scope, and peptides were tolerated on the indole substrate. Another Co-catalysed protocol was reported by Shi, making use of the hypervalent iodine reactant TIPS-EBX (Scheme 142C).⁸³⁹ This protocol gave generally modest yields and required 3 equivalents of $Mg(OMe)_2$ as additive. Its role in the reaction was not clarified.

Li and Zhou disclosed a good example of C7 alkynylation of indolines using Ir catalysis (Scheme 142D).⁸⁴⁰ The protocol

<figure><img src="image_274.png" /></figure>
<figure><img src="image_275.png" /></figure>

From these conditions, Noel/Van der Eycken and Jana independently reported a protocol for the group-directed acylation of indoles with aldehydes using a dual photoredox-Pd catalytic strategy which allows functionalisation at room temperature.⁸⁴⁶,⁸⁴⁷ Noel/Van der Eycken reported both a batch and a flow protocol. Although only slightly higher or comparable yields were obtained in flow, and much higher amounts of aldehyde and TBHP were required, the reaction time was drastically decreased using this methodology (2 h instead of 20 h), as well as the photocatalyst loading (Ir) (Scheme 143B).⁸⁴⁶ Jana's protocol (batch), although requiring reaction times up to 48 h, was tested on more variedly functionalised indole substrates, giving overall comparable yields to the Noel/Van der Eyken protocol. An important advantage is the avoidance of the external ligand and the use of a lower excess of aldehyde/TBHP (Scheme 143C).⁸⁴⁷ Both protocols could be applied to benzylic alcohols (oxidised to aldehydes *in situ*), and the DG could be cleaved in basic conditions (NaOEt).

The photoredox catalyst in these procedures facilitates the reaction by promoting the formation of the tBuO radical first, needed to generate the acyl radical, and then the oxidation of the Pd(III) intermediate to Pd(IV), required for the reductive elimination step (see also Scheme 118, bottom). As these activations are not available in the simple Pd(II) catalytic reaction, high temperatures are required to push the reaction forward.

Two very similar procedures for the aminocarbonylation of indoles with aromatic or aliphatic isocyanates were reported by Kim and Van der Eycken in 2015 using a Rh dimer as catalyst (Scheme 143D).⁸⁴⁸,⁸⁴⁹ Both processes required 2.5 to 3 equiv. of isocyanates to perform decently, but the yields remain modest in both cases. Importantly for synthetic purposes, Kim observed the reaction with aromatic isocyanates to be reversible, thus explaining in these case the low yield obtained.⁸⁴⁸ Such reversibility had been observed before for the Rh-catalysed hydroarylation of imines.⁸⁵⁰ Both aliphatic and aromatic amide products could be treated with NaOEt to provide the deprotected indole. Interestingly, Kim showed that the use of EtOH as co-solvent in the process (standard solvent: DMSO) facilitates the reaction.⁸⁴⁸,⁸⁵¹

### 15.2.7. C-N bond formation.
The C-N bond formation still relies mostly on precious metal catalysis, and only few examples are available in the literature on the use of base metals.

Indole phosphoramidation was reported by Kanai and Matsunaga, notably under Co catalysis (Scheme 144A).⁸⁵² Although the process presents some drawbacks, such as the long reaction times and the sensitivity to steric hindrance in the C3 position of the substrate, this is a rare base metal-catalysed example of a C-H phosphoramidation reaction. Substituted dioxazolones were instead employed for the carboxyamidation of indoles at the C7 position at room temperature (or 80 °C for several examples, Scheme 144B).⁸⁵³ The reaction proceeds giving generally good yields. Interestingly, the reaction proved efficient on tetrahydroquinoline as well, a not commonly studied substrate.

Concerning indoline amination, anthranils were used under Rh catalysis by both Kim and Xu/Yang (Scheme 144C).⁸⁵⁴,⁸⁵⁵ The substrate scope investigated and the results are comparable in the two cases. For these substrates, subsequent intramolecular

<figure><img src="image_276.png" /><figcaption>Scheme 144 Phosphoramidation and amination on indoles and indolines.</figcaption></figure>

cyclisation to quinoline fused indoline (as observed in indoles, cf. Scheme 125), did not occur *in situ*, but can be promoted by reaction of the formylaniline product (R¹ = H) with TFA.⁸⁵⁴

### 15.2.8. C-S bond formation.
A few procedures for the C-S bond formation in pyrimidyl-functionalised substrates have appeared. Kambe reported on the use of disulfides and superstoichiometric amounts of Cu(II) salts to promote the thiolation of carbazoles and indoles. Although good yields were obtained in many cases, and both aromatic and aliphatic disulfides could be efficiently employed, temperatures in the range 140–160 °C were used, and difunctionalisation of indoles at the C2 and C3 positions occurs under these conditions.⁸⁵⁶,⁸⁵⁷ The thiolation of indolines was instead reported by Wang using Rh catalysis and stoichiometric amounts of Ag oxidant; even in this case, high temperatures had to be used.⁸⁵⁸ More recently, two interesting reports were released by Ackermann and Glorius for the thiolation of indoles and indolines respectively. Glorius's approach focused on the use of aromatic thiols and Co(III) as catalyst, requiring the combined action of superstoichiometric Cu and BQ as oxidants (Scheme 145A).⁸⁵⁹ Despite these drawbacks, short reaction times, much lower temperatures than usual (60 °C) and a good FG tolerance make this approach stand out. Unfortunately, functionalisation with alkyl or heteroaryl thiols proved unsuccessful. The C7 thiolation of indolines reported by Ackermann is also particularly interesting since no stoichiometric oxidant was used apart from air, requiring

<figure><img src="image_277.png" /><figcaption>Scheme 145 Directed C-S bond formation on indoles and indolines.</figcaption></figure>
<figure><img src="image_278.png" /></figure>

only a catalytic amount of Cu (Scheme 145B).⁸⁶⁰ The same conditions proved effective also for thiolation and selenylation of indoles. Drawbacks of this protocol are the high temperature required and the relatively modest yields obtained for most examples.

### 15.3. N-, O-, S-, and Si-Linked (di)azines as DGs

The pyridine (and pyrimidine) DGs are not easily cleavable when attached *via* a C–C bond. Nonetheless, when attached *via* a C–heteroatom bond, the cleavage becomes relatively easy. This type of bond is found, apart from pyridine- or pyrimidine-functionalised indoles, indolines and pyridones, in a number of other substrates, where the DG is attached *via* a NH₂⁻, O⁻, Si⁻, or SO/SO₂ linker. Apart from their sometimes particular reactivity pattern, the cleavage of these DGs is a very important feature for synthetic purposes. Scheme 146 summarises the different cleavage/modification methods available in the literature for such DGs.

The N-linked pyridine DG is by far the most explored among this family of DGs, and several methods have been developed with time for its cleavage, and routinely used. A common method utilises the “quaternisation-hydrolysis/alcoholysis” strategy,⁸⁶¹ which involves methylation of the pyridine with

MeOTf (no other methylating agent is generally used), followed by hydrolysis or alcoholysis. Other methods are the “quaternisation-hydride reduction”,⁸⁶² where hydrolysis/ alcoholysis is replaced by the reaction with a hydride donor. Alternative cleavage procedures involve a first hydrogenation step, leading to an unstable aminal. The cleavage of the latter can then occur using a hydride donor, or *via* hydrazinolysis.⁸⁶²⁻⁸⁶⁴ The quaternisation-based methods are most commonly encountered in the literature, with little variations from the conditions shown in Scheme 146, and are used for pyridine removal from indoles, pyridone, indolines, aliphatic amines and even anilines.

O-Linked 2-pyridyl DGs can also be easily cleaved (Scheme 146). A general procedure is the quaternisation of the pyridine ring, followed by treatment with NaOMe, resulting in the corresponding phenol.⁸⁶⁵ Apart from this traditional cleavage, a few cross coupling methods have been reported by Chatani and Wang to cleave the arene–O bond and introduce a boronic ester (which can be used in subsequent cross couplings)⁸⁶⁶,⁸⁶⁷ or an amino functionality⁸⁶⁸ in its place.

The use of a Si-linked 2-pyridyl and 2-pyrimidyl DG has the great advantage of being very easily cleaved at the arene–Si bond *via* substitution or cross-coupling reactions, as demonstrated in a seminal paper by the Gevorgyan group in 2011 (Scheme 146).⁸⁶⁹

#### ■ NR-linked or NH-linked 2-pyridyl DG

<figure><img src="image_279.png" /></figure>

#### ■ Si-linked 2-pyridyl DG

<figure><img src="image_280.png" /></figure>

#### ■ O-linked 2-pyridyl DG

<figure><img src="image_281.png" /></figure>

#### ■ S-linked 2-pyridyl DG

<figure><img src="image_282.png" /><figcaption>Scheme 146 Protocols for the cleavage/modification of N-, O-, S-, and Si-linked pyridine DGs.</figcaption></figure>
Ir-catalysed reaction with sulfonyl azides adding only catalytic amounts of AgSbF₆ to the reaction. Although resulting in lower yields (max 63%), two examples of alkylsulfonyl amides were also reported, which adds value to the procedure (Scheme 147E).⁸⁸⁰ In this case, the use of aq. HCl on the reaction products results in the cleavage of both DG and amide, giving *ortho*-phenylenediamines. Two procedures for *ortho* nitration were reported with AgNO₃ as nitro source. While Pd catalysis on *N*--(2-pyrimidinyl)anilines using K₂S₂O₈ as oxidant resulted in regioisomeric mixtures in *meta*-substituted anilines (Scheme 147F),⁸⁸¹ this was not observed on the *N*--(2-pyridinyl) analogues using aerobic Co catalysis (Scheme 147H).⁸⁸² Noteworthy in this case is also the range of other N-linked heterocycles effective in the reaction, including pyrimidine, quinolines, pyridazine and benzothiazole. Also two different cleavage protocols were reported, leading to either the *o*-nitroaniline or the *o*-phenylenediamines.⁸⁸² Finally, Schnürch reported the alkylation of benzylic C(sp³)–H bonds in *N*--(2-pyridinyl)benzylamines using Rh catalysis and tetraalkyl-ammonium halides as terminal olefins surrogates (Scheme 147I).⁸⁸³ To our knowledge this is the only case of C(sp³)–H functionalisation with this DG type.

### 15.3.1.2. Functionalisation with cyclisation.
In these reactions the free NH of the DG reacts with an unsaturated moiety, leading to the formation of aza-heterocycles, particularly indole derivatives. In the final compounds the heterocyclic DG can be generally cleaved by the typical methods described in Scheme 146. The reaction with diazo-β-ketoesters or similar results in 3-alkoxycarbonyl-2-alkylindoles (Scheme 147J, cf. Scheme 147A),⁸⁷³⁻⁸⁷⁵,⁸⁸⁴ while the use of Meldrum's acid furnishes 1,3-dihydroindol-2-ones, although the product obtained strongly depends on the substitution pattern on the DG or the aryl ring (Scheme 147K).⁸⁸⁵ 2,3-Diarylated indoles can be obtained by reaction with alkynes, of which Kantam recently reported a heterogeneous version using Pd supported on nanocrystalline Mg oxide [NAP-Mg-Pd(0)] (Scheme 147L).⁸⁸⁶ This heterogeneous catalyst could be recycled and reused for at least 4 runs without considerable changes in yields.

An interesting alternative, reported by Zeng, utilises aryl-alkynylcycloalkanols for the regioselective formation of 2-acyl-3-arylindoles, occurring *via* consequent ring opening of the propargylic alcohol employed (Scheme 147M).⁸⁸⁷ The formation of dihydroquinolinones *via* Rh-catalysed alkylation/cyclisation with unsaturated aldehydes was recently reported by Huang, and to our knowledge this is the only 6-membered ring formation reported for such systems (Scheme 147N).⁸⁸⁸ Finally, an Ir-catalysed amidation/condensation protocol was developed for the synthesis of functionalised benzimidazoles (Scheme 147O).⁸⁸⁹ Unfortunately, the cleavage of the DG in the final product did not succeed using previously reported methods. In all these functionalisations, the heterocyclic DG is maintained unaltered in the final product, and can be exploited for further functionalisation of the heterocycles, e.g. at the C7 in indoles or analogous positions.

### 15.3.2. O-Linked (di)azines.
O-Linked (di)azines, mostly limited to pyridine, have been used less often than the corresponding

N-linked analogues, but in general for different transformations, e.g. acylation, C–O bond formation. The heterocycle can be cleaved at the O-heterocycle bond to give functionalised phenols, or at the arene–O bond (via cross coupling) giving other doubly functionalised arenes (Scheme 146). As before, all the transformations will be treated in one section.

The alkylation with diazocompounds under Rh catalysis occurs in good yields on a variety of substituted phenols, although monofunctionalisation was only possible in somewhat hindered substrates (Scheme 148A).⁸⁹⁰ When known cleavage methods for pyridine/pyrimidine DGs were applied, no cleavage was observed, instead a Smiles-type rearrangement took place (see Scheme 137, unusual for pyridines). Interestingly, this rearrangement proved consistent and occurred in good yields for a number of different products.⁸⁹⁰ Cui reported the aromatic homologation of *O*--(2-pyridinyl)phenols with internal arylalkynes to result in substituted 1-naphthols in good yields using tAmOH as solvent (Scheme 148B). Unfortunately, the reaction with alkyl or heteroarylalkynes did not occur, and asymmetric alkynes resulted in very poor regioselectivity.⁸⁹¹ Acylation reactions were reported by Wu and Huo, using aldehydes and acyl chlorides as reactants. The first method (Scheme 148C)⁸⁹² uses TBHP as oxidant and follows the mechanism depicted in Scheme 118, resulting mostly in monoacylation (difunctionalisation is substrate-dependent), giving low yields for strongly EWG-substituted phenols. The second method (Scheme 148D)⁸⁹³ is a group-directed Friedel-Crafts acylation, and does not require oxidants or additives, but 10% of expensive Pt catalyst was employed for the reaction. The use of PhCl as solvent results in the formation of difunctionalised phenols, while monoacylated ones could be obtained in hindered substrates.

Comparatively more protocols for C–heteroatom bond formation were reported with this class of DG, although suffering in several cases from low yields (<70%). The reaction with arylsulfonyl azides was reported by Cui (Scheme 148E),⁸⁹⁴ and C–O bond formation can occur *via* reaction with PIDA or carboxylic acids (Scheme 148F and G).⁸⁹⁵,⁸⁹⁶ The DG cleavage on the products obtained results in *ortho*-hydroxyanilines or in catechols. C–S bond formation has been reported making use of sulfonyl chlorides or disulfides (Scheme 148H and I),⁸⁷⁹,⁸⁹⁷ and C–Cl and C–F bonds are formed under Pd catalysis using NCS of NFSI as electrophilic halogen sources (Scheme 148J and K).⁸⁹⁸,⁸⁹⁹

### 15.3.3. Si-Linked (di)azines.
The use of pyridyl- and pyrimidyl-diisopropylsilyl DGs was developed by the Gevorgyan group. These DGs are characterised by a truly unique variety of cleavage options, which makes this DG type synthetically very interesting (Scheme 146). This advantage is, however, somewhat counter-balanced by a lower efficacy of these DGs, which results in long reaction times, or the necessity of a large excess of reactants/reagents.

Alkylation reactions were reported in 2016 by Gevorgyan (pyrimidylsilyl) and Zhang (pyridylsilyl), using very similar protocols: Pd catalysis, alkylboronic acids as reactants, super-stoichiometric amounts of Ag salts as oxidant, an inorganic base and an aminoacid as ligand (Scheme 149A).⁹⁰⁰,⁹⁰¹
<figure><img src="image_283.png" /><figcaption>Scheme 148 Functionalisation with O-linked pyridine and pyrimidine DGs.</figcaption></figure>

Both protocols require long reaction times (48–72 h) and produce yields often in the range of 40–70%. Notable features are the smooth cleavage/substitution of the DG (Gevorgyan), the use of variedly functionalised alkylboronic acids (Zhang) and a single example of C(sp³)-H functionalisation (Zhang). Alkoxycarbonylation was reported by Gevorgyan using CO and hexafluoroisopropanol (HFIP, Scheme 149B).⁹⁰² A good substrate scope and FG tolerance was obtained for this protocol; particularly noteworthy is the use of several heterocyclic substrates (dibenzofuran, thiophene, carbazole, indoline, and tetrahydroquinoline), featuring medium to good yields (47–77%). The same group also reported the C–O and C–halogen bond formation on the same starting materials. Diacyloxylation with hypervalent iodine reactant PhI(OPiv)₂ proved effective on a number of *para*-substituted arenes in good yields, but required up to 120 h (Scheme 149C).⁹⁰³ C–halogen bond formation was achieved using NXS as reactants (X = I, Br, Cl), with different reaction conditions for each halogen (Scheme 149D).⁹⁰³

### 15.3.4. S-Linked (di)azines.
Only a couple of reports on the use of S-linked (di)azines have appeared recently and focused on the use of pyridine. Arylation with benzoyl peroxides was reported by Sun, and halogenation with NXS by Hierso (Scheme 150A and B).⁸⁷¹,⁹⁰⁴ Several yields were <70% for both reports, and product mixtures were obtained in the case of halogenation (mono- + dihalogenated products). Interestingly, modification (oxidation to sulfone, reduction to sulphide),

desulphurisation (to 2-arylpyridines), and cleavage of the DG (obtaining thiols) was demonstrated by Sun (Scheme 146).⁸⁷¹

### 15.4. Quinoline-N-oxide as substrate/DG

While the activation of C–H bonds (either metal-catalysed or metal-free) at the *ortho* position of pyridine-N-oxides has been known for long time, this activation is mostly due to electronic effects.⁹⁰⁵–⁹⁰⁷ These cases will therefore not be treated here. Instead, metal-catalysed reactions where the N-oxide is thought to have a coordinating and directing role will be discussed. It is important to mention that the N-oxide moiety is the DG here, and is therefore limited to the functionalisation of azines. Although, strictly speaking, the coordinating atom is not itself part of a heterocycle, this DG has been considered in the heterocyclic section for simplicity and immediate analogy to its heterocyclic precursors. For the use of different N-oxide moieties in C–H functionalisation see Section 14.3.1 and Section 16.9.

The functionalisation of quinoline-N-oxides at the 8 position is most common in this area. Considering quinolines and their analogues are very common motifs in biologically-active molecules, the simple introduction (e.g. with peroxides) and cleavage (e.g. sulphur or phosphorus reagents)⁹⁰⁷,⁹⁰⁸ of the N-oxide moiety is very convenient for the selective functionalisation of these substrates. The facility of the N-oxide removal or the oxygen-transfer to the quinoline C2 (forming 2-quinolinones)
<figure><img src="image_284.png" /></figure>

<figure><img src="image_285.png" /></figure>

<figure><img src="image_286.png" /><figcaption>Scheme 149 Functionalisation with Si-linked pyridine and pyrimidine DGs.</figcaption></figure>

<figure><img src="image_287.png" /><figcaption>Scheme 150 Functionalisation with S-linked pyridine DGs.</figcaption></figure>

or to an unsaturated moiety in the product (*N*-oxide as internal oxidant), make several of these procedures occur as cascade/tandem processes, leading to interesting compounds. These types of transformation have only been studied from 2014, and all the examples till 2017 have been reported in this section. Due to their limited number, all type or reactions are treated in one single section.

In 2014 Chang reported iodination and amidation with *N*-iodosuccinimide (NIS) and sulfonyl azides (Scheme 151A and B),⁹⁰⁹ also applied to the synthesis of Zinquin ethyl ester (a zinc indicator for biological systems). The only other report on the functionalisation with heteroatoms involved the use of selenyl chlorides for the formation of C–Se bonds. In this case, however, the *N*-oxide was not the main DG investigated and only 5 examples (45–67% yield) were included (Scheme 151C).⁹¹⁰

Two acylation procedures were reported by Wu and Cui, both catalysed by PdCl₂ in similar conditions. The use of TBHP (*tert*-butylhydroperoxide) with benzaldehydes resulted in the 8-acylation followed by *in situ* oxygen transfer from the *N*-oxide to the 2 position of the quinoline, producing 8-benzoyl-2-quinolinones (Scheme 151D).⁹¹¹ The use of α-oxocarboxylic acids as reagents in combination with K₂S₂O₈ as oxidant produced instead 8-benzoylquinoline-*N*-oxides via decarboxylative coupling (Scheme 151E).⁹¹² A Pd-catalysed arylation with aryl iodides was reported by Larionov. Interestingly, this reaction performs best in AcOH/H₂O, and no toxic solvents were required (Scheme 151F).⁹¹³ On the other hand, high amounts of Ag₃PO₄ additive (1.5 equiv. total [Ag]) were used, presumably acting as both base and stoichiometric halide scavenger for the reactant. A similar procedure was later reported by the same authors for the dehydrogenative homocoupling of quinoline-*N*-oxides.⁹¹⁴ 8-Alkynylation can

<figure><img src="image_288.png" /><figcaption>Scheme 151 C8-Functionalisation of quinoline-N-oxides.</figcaption></figure>
<figure><img src="image_289.png" /></figure>

be achieved using TIPS-EBX (Scheme 151G).⁹¹⁵ This reaction, although requiring DCE as solvent and the use of a wasteful reactant, proceeds with good yields at room temperature.

Formal alkylation at the 8 position can be achieved with a number of reactants. Chang reported the use of diazomalonates or similar reactants at room temperature (Scheme 151H).⁹¹⁵ Very recently, alkylation *via* reaction with styrenes or aliphatic olefins was reported by Sharma (Scheme 151I).⁹¹⁶ Although the reported yields are relatively low (<70% for styrenes and <50% for aliphatic olefines), even long aliphatic chains could be attached to the quinoline moiety, which is generally quite uncommon. The reaction was suggested to take place *via* the olefinic intermediate, then reduced *in situ* with formic acid, derived from the DMF solvent. The suggested mechanism (only partially) explains the requirement of stoichiometric amounts of both Cu and Ag for an overall non-oxidative coupling.⁹¹⁶ This method was also applied to the total synthesis of an EP4 antagonist. In 2014 the reaction with internal alkynes under Rh catalysis was independently reported by Chang and Li. This reaction occurred *via* formal addition to the alkyne, followed by an intramolecular oxygen transfer from the *N*-oxide to the new functionality, resulting in the ketones shown in Scheme 151J.⁹¹⁷,⁹¹⁸ The same reaction was then reported by Sundararaju under Co catalysis,⁹¹⁹ and showed considerable improvements in terms of coupling partners: diaryl-, dialkyl-, and arylalkyl-alkynes could be easily coupled with good yields. The reaction with allylic alcohols resulted in two different compounds depending on the catalyst. While the use of Rh produced aroylethyl-functionalised compounds, the use of Co in the same conditions only resulted in allylated compounds (Scheme 151K).⁹²⁰ A methylation procedure using MeBF₃K was recently reported by Liu (Scheme 151L);⁹²¹ the same procedure can be applied for C–H arylation using aromatic trifluoroborates, but very few examples with <40% yields were reported in this case.

Two examples of olefination have appeared from 2014. Shibata first reported the Rh(I)-catalysed reaction with internal alkynes, a reaction that was plagued by isomeric mixtures and yields often <70%.⁹²² A second example was reported in 2015 by Sharma *via* reaction with terminal olefins. Although even in this case many yields were low (even <50%), olefination took place with a number of acrylates, styrenes and other linear olefins, also resulting in *N*-oxide cleavage *in situ* (Scheme 151M).⁹²³

### 15.5. Pyrazole as DG

Pyrazoles are the most common 1H-diazole DG type used, and an important pioneering publication by Chatani on the specific use of this DG dates back to 2003.⁹²⁴ As many other heterocycles, in recent years pyrazole DGs are often tested as secondary DGs in procedures mostly developed using pyridine-based groups. In general, in these cases pyrazole performs giving comparable or little lower yields than the corresponding pyridine-directed reaction, and only one or two examples are nowadays generally reported in most publications. It is worth noting that the lower yields obtained in these cases might just be due to a lack of specific optimisation for pyrazole DGs, and do not necessarily mean that pyrazole is a worse

DG than pyridine. In fact, from a practical point of view, there are a few differences that might make pyrazole a much better choice than pyridine depending on the synthetic aim. Most commonly 1-aryl/alkyl-1H-pyrazoles are used as substrates, while 3-aryl/alkyl-1H-pyrazoles are much less explored. In the former substrates, the DG is linked to the substrate *via* a C–N bond, thus making DG introduction easier than with a 2-pyridyl DG requiring a C–C linkage. For example, 1-alkyl/aryl-1H-pyrazole can be easily obtained by: (i) metal-free (or metal-catalysed) nucleophilic substitution/cross coupling; (ii) reaction of functionalised hydrazines with 1,3-diketones or unsaturated carbon moieties, including *in situ* hydrazine formation from amines.⁹²⁵ Moreover, its cleavage/modification, although rarely reported, is easier than with pyridine for arenes or olefins (e.g. ozonolysis/reduction⁹²⁶,⁹²⁷ or elimination reactions,⁹²⁸ Scheme 152), provided that there is FG compatibility with the required reagents.

Although not too many, several C–H functionalisation methods specifically developed for pyrazoles (or with more than 1 or 2 examples anyway) have been published recently. Greaney reported an elegant, atom economic one-pot DG introduction/C–H arylation using diaryliodonium salts. In this procedure, pyrazole is first reacted with the iodonium salt in metal-free conditions (or with catalytic CuI) to provide the 1-phenyl-1H-pyrazole substrate, then a Ru catalyst is added to the reaction to trigger the *ortho* C–H arylation with the aryl iodide formed *in situ* during the first step (Scheme 153A).⁹²⁹ The most notable feature is the possibility to use asymmetric diaryliodonium salts: *N*-arylation of the pyrazole occurs selectively with the less electron-rich arene, or to the more sterically hindered one. The same procedure can be applied to styryl-(phenyl)iodonium salts, giving 1-styryl-1H-pyrazoles, and subsequent arylation of the olefin.⁹²⁹ A number of alkylations have been reported *via* addition to double bonds. Sundararaju demonstrated the Co-catalysed addition to acrylates (Scheme 153B),⁹³⁰ while diastereoselective protocols have been reported by Ellmann. A multicomponent/cascade reaction with 1-phenyl-1H-pyrazoles, α,β-unsaturated ketones, and aldehydes provide access to functionalised branched alkyl chains with two consecutive stereocentres, which could be obtained in good diastereoselectivity (above 90/10, Scheme 153C).⁹³¹

The addition of 1-phenyl-1H-pyrazoles to chiral *N*-perfluorobutanesulfinyl imines also occurs with good diastereoselectivity,

<figure><img src="image_290.png" /><figcaption>Scheme 152 Examples of cleavage/modification of pyrazole DGs.</figcaption></figure>