■ C-H functionalization without cyclisation

<figure><img src="image_291.png" /></figure>

A

+ one pot reaction

good selectivity with asymmetric
iodonium salts

+ atom economic

+ olefins as substrates possible
(yields 40-50%)

+ other DGs: triazoles

+ most yields <70%, but over two
steps

- high cat. loading

- high temperature

- steric hindrance on DG or Ar
needed for monoarylation

<figure><img src="image_292.png" /></figure>

B

+ dialkylation possible

+ some heterocyclic substrates

+ gram scale (53%)

+ TFE used but other solvents are
possible

- some selectivity issues in non
ortho-substituted substrates

- only linear acrylates possible

<figure><img src="image_293.png" /></figure>

C

+ multicomponent reaction

+ diastereoselective (> 90/10)

+ room temperature

+ R = Et, Ph; R' = (hetero)Ar, Alk, vinyl

+ 1 example olefin substrate

+ other DGs possible

- very limited substrate substitution

<figure><img src="image_294.png" /></figure>

D

+ diastereoselective (> 94/6)

+ other DGs: amides, diazene,
triazoles

- only 5 examples

- DCE as solvent

- high cat. loading

- reactant decomposes at temp.
> 60°

<figure><img src="image_295.png" /></figure>

E

+ under air

- exotic Cp ligand needed

- steric hindrance on DG gives
lower yields

- E/Z mixtures (ca. 90/10)

- most yields <70%

- limited substrate substitution

- long reaction time (60h)

<figure><img src="image_296.png" /></figure>

F

+ pyridine and pyrimidine (Indoles)
DG also possible

+ di-n-alkyl groups give allylated
product

- not main DG studied

- all yields < 70%

<figure><img src="image_297.png" /></figure>

G

+ neat reaction, short time (4h),
under air

+ olefination with styrene possible
(3 examples)

+ other DG: oxazoline

+ selective mono or difunct. possible
- few examples, limited substitution

<figure><img src="image_298.png" /></figure>

H

+ other substrates: thiophene

+ difunct. possible (100C, 36h)
- substituent in *ortho*/*meta* on
substrate required for monofunct.

- several yields <70%

- pyridine DG not effective

<caption>Scheme 153 Pyrazole-directed C(sp²)–H functionalisation.</caption>

furnishing phenylglycine derivatives (Scheme 153D).⁹³² It is worth mentioning that the same reaction does not work at all on the corresponding non-fluorinated substrates. A dehydrogenative allylation reaction was reported by Tanaka and Shibata using terminal olefins and Cu/air as oxidant (Scheme 153E). The reaction does not require leaving groups in the olefin, thus increasing the atom economy of the process. However, it has several disadvantages: (i) the exotic CpE ligand [1,3-bis(ethoxycarbonyl)cyclopentadienyl] is necessary for the reaction to proceed; (ii) a large excess of the substrate (3 equiv.) is required to prevent difunctionalisation in non *ortho*-substitutes substrates; (iii) many of the reported yields remain below the 70% threshold; and (iv) the reaction is slow (60 h, Scheme 153E).⁹³³

Addition to 1,1-dialkylallenes under Co catalysis provides olefinated arenes, although only medium yields were obtained using pyrazole as DG (Scheme 153F). Olefination was also performed *via* dehydrogenative coupling with acrylates with a Ru catalyst under aerobic conditions (Scheme 153G).⁹³⁴ Under these conditions, selective mono- or difunctionalisation was possible, only using different (small) excess of acrylates. Few examples were reported, but a similar reaction was demonstrated also for olefination with styrenes.⁹³⁴ Sundararaju published in 2017 a study on the reaction of 1-phenyl-1H-pyrazoles with propargyl alcohols, leading to the corresponding alenylated product (Scheme 153H).⁹³⁵ Whereas mono-functionalised products could be obtained selectively in good yields only on *ortho/meta*-substituted substrates, difunctionalisation was obtained on *para*-substituted arenes.

<figure><img src="image_299.png" /></figure>

I

<figure><img src="image_300.png" /></figure>

J

<figure><img src="image_301.png" /></figure>

K

<figure><img src="image_302.png" /></figure>

L

+ heavily substituted pyrazole DG
(higher yields than unsubstituted)

+ short reaction time (1h)

+ selective monofunctionalisation

+ 1 example C(sp³)-H funct.

+ iodination possible using
ICH₂CO₂H (6 examples)

- EWG-substituted substrates:
lower yields by 30-40%

■ C-H functionalization with cyclisation

<figure><img src="image_303.png" /></figure>

N

<figure><img src="image_304.png" /></figure>

O

GENERAL

+ diaryl and dialkyl alkynes possible

+ different anions possible (X), incl. Cl.

+ the different products are obtained selectively depending on conditions and alkyne used
- no terminal alkynes

- no terminal alkynes

<figure><img src="image_305.png" /></figure>
<figure><img src="image_306.png" /></figure>

Two protocols for the aminocarbonylation of 1-phenyl-1H-pyrazoles, both exploiting Co catalysis and isocyanates as reactants, were reported independently by Ackermann and Ellmann in 2015 (Scheme 153I).⁹³⁶,⁹³⁷ Ackermann's protocol could also be applied to heterocyclic substrates (thiophene and furan) and to olefins, but only aromatic isocyanates were used. Ellman's protocol could instead be used with aliphatic isocyanates (2 examples), and generally provided higher yields, but 2 equiv. of the substrate were required.

Regarding C-heteroatom bond formation, selenation with phenylselenyl chloride was reported by Zhang (Scheme 153J),⁹³⁸ and halogenation by Wang and Hierso. Wang used Na halides and Rh catalysis for iodination, bromination and chlorination of a few 1-phenyl-1H-pyrazoles (Scheme 153K),⁷⁷² while fluorination could be achieved using NFSI with Pd catalysis, as reported by Hierso (Scheme 153L).⁹³⁹ Notably, this functionnalisation proved to be fairly substrate-dependent, requiring varying equivalents of NFSI or leading to mono or difluorinated products depending on the substitution pattern.

Acetoxylation and iodination were finally reported using a heavily functionalised pyrazole as DG. 4-Methyl-1,5-diaryl-1H-pyrazole-3-ethylcarboxylate was used as a model representing a class of pharmaceutically relevant substrates (Scheme 153M).⁹⁴⁰ Selective monoacetoxylation (due to steric hindrance) using Pd(OAc)₂/PIDA/AcOH was achieved in good yields on a number of substrates, including aliphatic substrates (1 example). The corresponding iodinated product was obtained using iodoacetic acid instead under the same conditions.⁹⁴⁰ It is noteworthy that the presence of a EWG substituent on the substrate reduces the yields by 30-40% for both transformations.

Tandem C-H functionalisation/cyclisation processes similar to those reported for pyridine DGs (see Schemes 112 and 115) have also been developed for pyrazoles. Yi and Xu reported the late stage modification of the drug Edaravone *via* alkylation/cyclisation with Meldrum's acid diazo derivative (Scheme 153N).⁹⁴¹ The reaction of 1-phenyl-1H-pyrazole with internal alkynes, apart from giving the typical olefination product, also results in neutral or ionic cyclisation products similar to those observed with pyridines and other heterocycles (Scheme 153O). In this case three different cyclisation products can be obtained, including 'rollover'-derived products, strongly depending on the reaction conditions and the identity of the alkyne.⁹⁴²,⁹⁴³

Interestingly, a couple of C(sp³)-H bond functionalisation studies have been recently reported using pyrazole DGs. Using 3,4,5-trimethyl-1H-pyrazole as DG, Zhao demonstrated that both β and γ arylation is possible using Rh catalysis and aryl boroxines (Scheme 154A).⁹²⁸ While arylation at the β position is to be expected because of the formation of a 5-membered metallacycle intermediate, γ-functionalisation *via* 6-membered metallacycle selectively occurred when a tertiary or quaternary carbon in β was present.⁹²⁸ Another notable feature is the absence of any diarylation products, often observed when multiple functionalisable positions are available. More recently, Daugulis reported a similar arylation, but using Pd(OAc)₂ and aryl iodides (Scheme 154B).⁹²⁶ A notable feature is the possibility to arylate secondary and even tertiary positions (1 example on adamantane substrate).

■ C(sp³)-H functionalization of 1-alkyl-1H-pyrazoles

<figure><img src="image_307.png" /></figure>

<figure><img src="image_308.png" /></figure>

■ C(sp³)-H functionalization of 3-alkyl-1H-pyrazoles

<figure><img src="image_309.png" /><figcaption>Scheme 154 Pyrazole-directed C(sp³)-H functionalisation.</figcaption></figure>

Although a few papers have appeared in the literature about C(sp²)-H functionalisation of 3-aryl-1H-pyrazole derivatives,⁹⁴⁴,⁹⁴⁵ these are mostly related to olefination/cyclisation processes similar to those previously described, and will therefore not explicitly be discussed here. Nonetheless, two reports by Yu's and Stamos' research groups on C(sp³)-H functionalisation have appeared. A domino process was developed where an initial C(sp³)-H functionalisation was promoted by a pyrazole DG, followed by an intramolecular, dehydrogenative, amide-directed C(sp²)-C(sp²) bond formation (Scheme 154C).⁹⁴⁶ The use of two different DGs for two different activations in cascade is a very innovative and useful concept for synthetic applications. The following year a C(sp³)-H olefination of 3-alkyl-1H-pyrazoles was reported by the same authors using ethyl acrylate and analogous reactants (Scheme 154D).⁹⁴⁷ To date this is the only example of pyrazole-directed C(sp³)-H olefination.

### 15.6. 1,2,3-Triazole as DG

Due to the easy access to triazoles, these heterocycles have also been used as DGs. Substrates can be attached to the DG at two different positions: (i) attached to the C4 atom of the DG (1,4-disubstituted triazoles, obtained by click chemistry),
■ 1,4-disubstituted 1,2,3-triazoles

<figure><img src="image_310.png" /></figure>

<figure><img src="image_311.png" /></figure>

■ 2-monosubstituted 1,2,3-triazoles

<figure><img src="image_312.png" /><figcaption>Scheme 155 1,2,3-Triazoles as DGs.</figcaption></figure>

or (ii) attached to the N2 atom (2-monosubstituted triazoles, obtained *via* other methods).

**15.6.1. 1,4-Disubstituted 1,2,3-triazoles.** C(sp²)–H arylation and olefination on the aromatic ring in C4 were reported by Jiang and Wu/Chen *via* Pd-catalysed reaction with aryl iodides and Rh-catalysed Fujiwara–Moritani coupling with acrylates. Although the reported yields are generally good, only difunctionalisation could be obtained (unless *ortho/meta* substituents were present in the substrate) (Scheme 155A and B).⁹⁴⁸,⁹⁴⁹ Acylation was reported using the classical Pd/TBHP method (Scheme 155C),⁹⁵⁰ while acyloxylation and halogenation were disclosed recently by Correa and co-workers, making use of Pd/PIDA and Pd/NBS systems (Scheme 155D and E).⁹⁵¹,⁹⁵² While the acyloxylation gave rise to mixtures of mono- and difunctionalised products in non *ortho/meta* substituted substrates, this was not observed for the halogenation, and selective monofunctionalisation was possible. Notably, in both

cases, C(sp²)–H functionalisation of benzylic substrates (formation of a 6-membered palladacycle) was also demonstrated, and occurred with yields generally comparable to those obtained for aryl substrates.⁹⁵¹,⁹⁵²

The selective functionalisation of the aryl ring in the C4 position of the triazole in the presence of a second aryl substituent in N1 (as for R = aryl in Scheme 155C–E) is suggested to be due to the higher electron density on the N3 in comparison to N2, which promotes selective coordination to this N atom and, consequently, selective functionalisation of the aryl ring in C4.⁹⁵⁰,⁹⁵³

**15.6.2. 2-Monosubstituted 1,2,3-triazoles.** This class of compounds can be prepared using a variety of methods,⁹⁵⁴ and has been subjected to C–H functionalisation studies in a few recent examples.

Acylation in water using Pd/TBHP was reported by Jain (Scheme 155F).⁹⁵⁵ Interestingly, benzyl alcohols were used directly as reactant in this protocol, with oxidation to aldehyde (and formation of the acyl radical) occurring *in situ*. Importantly, heterocyclic-substituted (thiophene, furan) methylalcohols could also be used in this protocol. These substrates were also used in amidation reactions.

One protocol appeared making use of dioxazolones under Co catalysis. (Scheme 155G).⁹⁵⁶ Unfortunately, this reaction resulted in mixtures of mono- and difunctionalised products unless *ortho* or *meta* substituted substrates were employed. The same issue was observed using sulphonyl azides as reactants with Ru catalysts.⁹⁵⁷ In this respect, an interesting contribution came from Wu and Cui, who reported the use of triazole N-oxide as DG (under Ir catalysis) to suppress the undesired difunctionalisation due to the increased steric hindrance (Scheme 155H).⁹⁵⁸

**15.7. 9H-Purines and analogues as DG**

Purine-based compounds are an important class of biologically active molecules, and the modification of purine-containing starting materials has recently been explored in C–H functionalisation chemistry. The state of the art of the use of purines as both substrates and DGs in C–H functionalisation before 2015 has been summarised by Kapdi/Fairlamb.⁹⁵⁹ In this section the use of purine as heterocyclic DGs in the last few years is summarised. As most of the papers included in this section have already appeared in previous chapters (other heterocyclic DGs), the present section has mostly the purpose of collecting all the transformations together from a practical point of view for the reader, given the importance of the core structure, but little further discussion will be added. It is important to note that purines are mostly tested as secondary DG, therefore no specific optimisation and only few examples are typically reported. If not specified in Scheme 156, yields are around 60–70%; in case of considerably different results (higher or lower yields), these are specifically mentioned in the scheme.

Several types of functionalisation have been studied on 6-aryl-9H-purines, where the N1 atom of the pyrimidine ring acts as the coordinating moiety. Arylation with diazonium salts under photoredox catalysis was reported by Guo. The reaction

<figure><img src="image_313.png" /></figure>
■ 6-aryl-9H-purines and analogues (coordinating atom: N1)

<figure><img src="image_314.png" /></figure>

■ 9-aryl-9H-purines and analogues (coordinating atom: N3)

<figure><img src="image_315.png" /><figcaption>Scheme 156 Purine-directed C–H functionalisations.</figcaption></figure>

<figure><img src="image_316.png" /></figure>

worked nicely on a few purines and nucleosides, despite requiring 6 equiv. of the diazonium reactant and the limited substrate substitution investigated (Scheme 156A).⁹⁶⁰ Co-catalysed allylation and olefination were reported by Matsunaga/Yoshino and Yu/Chen respectively (Scheme 156B and C).⁶⁸⁸,⁹⁶¹ Both these processes occurred in higher yields than the average 60–70% for these substrates, but only few examples were reported. Cyanation could be performed using *N*-cyanosuccinimide and Co catalysis, according to a protocol developed by Chang (Scheme 156D).⁷¹¹

Concerning the formation of C–heteroatom bonds in 6-aryl-9H-purines, three amidation methods were reported using electrophilic *N*-Boc *O*-acyl hydroxylamines or dioxazolones (Scheme 156E–G).⁷⁴⁷,⁷⁴⁸,⁷⁵³ This last procedure, in particular, furnished high yields, and offers the possibility of thiophene functionalisation (Scheme 156G). Finally, trifluoromethylthiolation⁷²⁷ and halogenation⁹⁶² were reported by Matsunaga/Yoshino and Pawar, both under Co catalysis (Scheme 156H and I). A good substrate screening was investigated for the halogenation (especially for the iodination), allowing a comparison of the results. This shows that *para* EWG substituents on the aryl ring of the substrate generally result in much lower yields than *para* EDG substituents.⁹⁶²

A rare example of functionalisation on 9-aryl-9H-purines (coordinating atom: N3) was reported by Du. Alkoxylation was studied under Pd catalysis using alcohols as reactants/solvents and PIDA as oxidant. While methoxylation was successfully

achieved on the 8-azapurine analogue (Scheme 156J, product A), ethoxylation did not occur on such substrate, and standard purines had to be used (Scheme 156J, Product B).⁹⁶³

### 15.8. 7-Azaindoles as DG

7-Azaindoles have been used several times as DGs, due to their presence in a number of biologically active compounds. An important aspect of this DG is the relatively broad functional group tolerance on its core, which ranges from halides, alkyl chains, olefins, carbonyls, to (hetero)arenes.

A number of functionalisations have been reported using procedures similar to those for other DGs, exclusively under Rh (in one case Ir) catalysis. Among the alkylation and olefination with *α*,*β*-unsaturated moieties (Scheme 157A–C),⁹⁶⁴⁻⁹⁶⁶ an interesting cross-dehydrogenative olefination procedure which does not require the presence of a stoichiometric oxidant (as is usually the case), was reported by Dong (Scheme 157C).⁹⁶⁶ In this reaction the Rh(III) hydride intermediate formed at the final stage of the olefination process reacts with the acid, releasing H₂. This is in turn suggested to react with the excess of unsaturated reactant (2 equiv.), which acts as a hydrogen acceptor.⁹⁶⁶ Another version of this transformation (not shown in scheme), was reported by Miura and Satoh. Despite the use of superstoichiometric Ag as oxidant and DME as solvent, this method allows fast reactions (3–6 h) under mild conditions (40–90 °C), giving generally good to excellent results.⁹⁶⁷
<figure><img src="image_317.png" /></figure>

■ C-H functionalization without cyclisation

<figure><img src="image_318.png" /><figcaption>Scheme 157 C-H functionalisation directed by 7-azaindole moieties.</figcaption></figure>

<figure><img src="image_319.png" /></figure>

■ C-H functionalization with cyclisation

<figure><img src="image_320.png" /></figure>

+ functionalised azaindoles
+ other substrates: thiophene, furan
+ low temperature
+ short reaction time in many cases (<10h)
+ other DG: azaindoline
- steric hindrance at C6 on aryl substrate not well tolerated
- superstoich. Ac₂O used
- DCE as solvent

G

H

I

J

K

L

Reactions with TIPS-EBX, N-cyano-N-phenyl-p-toluenesulfonamide, and anthranils result in ortho alkynylation, cyanation and amination as described in Scheme 157D-F.⁹⁶⁸⁻⁹⁷⁰ Notable is the use of heterocyclic substrates such as (benzo)thiophenes and furans in the cyanation protocol.⁹⁶⁹ One example of C-O bond formation was reported by Deb using PIDA and Rh catalysis. In contrast to many similar procedures employing Pd catalysis, the use of Rh allowed the reaction to run at a low temperature (40 °C) furnishing good yields often in a short time (Scheme 157G).⁹⁷¹

The Dong group reported four procedures for the cascade alkylation-cyclisation or olefination-cyclisation, where a “rollover” mechanism after the initial C-H activation results in the formation of π-conjugated fused systems (see Scheme 115, bottom). The group-directed ortho-alkylation with diazocompounds or *via* addition to alkenyl esters, followed by intramolecular activation of the azaindole C2, and finally by dehydration or β-H elimination, results in the products in Scheme 157H and I.⁹⁷²,⁹⁷³ The reaction with alkynes, occurring as previously reported for other DGs, was also investigated (Scheme 157J and K).⁹⁷⁴,⁹⁷⁵ Interesting in this respect is the reaction with 3 equiv. of alkyne, which results in both *ortho* olefination-cyclisation and arene homologation, ultimately furnishing azahelicenes, interesting compounds for their fluorescent properties.⁹⁷⁵

Finally, the reaction with electron-deficient alkenes resulted in an oxidative olefination, followed by rollover and intramolecular

Michael addition, giving the compounds shown in Scheme 157L.⁹⁷⁶ An interesting aspect is that steric hindrance at the C3 position of the azaindole DG prevents the final intramolecular cyclisation, selectively furnishing the olefination product.⁹⁷⁶

## 15.9. Oxadiazoles and benzisoxazoles as DGs

In the same way that oximes can act as internal oxidants when used as DGs (see Section 12), *via* cleavage of the N-O bond, also 1,2,4-oxadiazoles and 1,2-benzisoxazoles (cyclic oximes equivalents) have been used as DG/internal oxidant combinations, in particular for the synthesis of isoquinoline derivatives upon reaction with alkynes.

Zhu and Miura independently reported in 2017 the use of 1,2,4-oxadiazoles, leading to 1-aminoisoquinolines and 1-acyl-aminoisoquinolines respectively, using Co and Rh catalysis⁹⁷⁷,⁹⁷⁸ (Scheme 158A and B). Either diaryl, dithiophenyl, or dialkyl alkynes could be used as coupling partners, while terminal alkynes seem unsuitable for this reaction.⁹⁷⁸ Interestingly, while in the Co-catalysed reaction the use of unsymmetrical alkynes gave rise to regioisomeric mixtures, under Rh catalysis only one regioisomer was obtained. The mechanism proposed for this transformation involves the insertion of the alkyne into the initial metallacycle formed, followed by a concerted or stepwise C-N bond formation/N-O bond cleavage, leading to the 1-acylaminoisoquinoline product. The presence of TFE in
<figure><img src="image_321.png" /></figure>

<figure><img src="image_322.png" /></figure>

<figure><img src="image_323.png" /></figure>

<figure><img src="image_324.png" /><figcaption>Scheme 158 Oxadiazoles and benzisoxazoles as DGs.</figcaption></figure>

<figure><img src="image_325.png" /><figcaption>Scheme 159 Ring-opening/cyclisation involving oxazoline DGs.</figcaption></figure>

Zhu's protocol provides *in situ* hydrolysis and formation of the
unprotected 1-amino compound.⁹⁷⁷

Zhu also reported analogous reactions employing 1,2,4-
oxadiazolones as DGs. In this case the N–O cleavage results
in the elimination of CO₂ from the reaction product.⁹⁷⁹,⁹⁸⁰

In 2017 the use of 1,2-benzisoxazoles as DGs for a similar
reaction with alkynes, was disclosed by Miura. With this procedure,
isoquinolines functionalised in C1 with a phenolic moiety were
formed (Scheme 158C).⁹⁸¹ The mechanism suggested is analogous
to that proposed above.

**15.10. Oxazolines and benzoxazoles as DGs**

Oxazolines have been used a few times as DGs in C–H func-
tionalisation. One of the reasons is that these functionalities
can be easily introduced from the corresponding carboxylic
acid, *via* condensation with 2-aminoalcohols, and can also be
easily cleaved to return to the original carboxylic acid using a
number of procedures: (i) strongly acidic or basic hydrolysis;
(ii) activation *via* *N*-chlorination, sulphonylation or acylation,
followed by hydrolysis (milder conditions). The oxazoline ring can
also be reductively cleaved to aldehydes using: (i) *N*-quaternization,
followed by reduction with NaBH₄ and hydrolysis; (ii) reduction in
the presence of NiCl₂, followed by acidic hydrolysis.⁹⁸² These and
other methods are nicely summarised in a review by Meyers,⁹⁸³
and will therefore not be discussed in detail here. An interesting
one-pot hydrolysis/cyclisation method, first discovered by Harrity,

for *ortho*-amidated 2-aryloxazolines involves basic hydrolysis of the
amide, and subsequent cyclisation with formamidine acetate, with
consequent opening of the oxazoline ring (Scheme 159).⁷⁵⁴,⁹⁸⁴

Sparse examples of oxazolines as DGs are generally reported
in papers mostly dealing with other DGs, but a few specific
investigations have been recently published. Arylation with aryl
halides or aryl carbamates was reported by Ackermann and
Chatani using Ru, Co or Rh catalysis (Scheme 160A–C),⁶⁵³,⁹⁸⁵,⁹⁸⁶
typically requiring preformed catalysts or the addition of a
ligand to reach good results. An example of intramolecular
alkylation leading to the formation of heterocycles was reported
by Zhu (Scheme 160D).¹⁷⁷ Interestingly, the intramolecular
addition to an unsaturated moiety occurs regiospecifically in
α-position to the carbonyl, instead of β, although the origin
of for such selectivity was not investigated. Olefination by
Fujiwara–Moritani coupling with acrylates and benzoxazoles as
DG was reported by Hou under Rh catalysis (Scheme 160E).⁹⁸⁷
This reaction proved generally substrate- and DG-dependent,
with yields ranging from 33 to 95%, and no monoselectivity
could be achieved in non *ortho*-functionalised substrates. None-
theless, this protocol was efficient for the coupling of different
classes of olefins, including allylbenzene (unusual reactant for
this type of reaction).⁹⁸⁷ Two protocols for amidation were
reported by Harrity and Ackermann, using amides or dioxazo-
lones respectively (Scheme 160F and G).⁷⁵⁴,⁹⁸⁴,⁹⁸⁸ A hydroxylation
reaction on 2-arylbenzoxazoles was demonstrated by Chakraborti
in 2015, where the hydroxy radical was generated *in situ* from
1,4-dioxane, used as solvent (Scheme 160H).⁹⁸⁹ Interestingly,
this protocol only required 2.5% Pd loading, considerably lower
than other analogous procedures. Finally, a C(sp³)–H silylation
on 2-ethyloxazoline derivatives was reported by Murata and
co-workers in 2016 (Scheme 160I).⁹⁹⁰ The reaction was per-
formed at 180 °C with HSi(Me)(OSiMe₃)₂. This reaction did not
require the use of a hydrogen acceptor, probably due to the
high temperature used.

**15.11. Benzothiazoles as DGs**

A handful of papers on the use of benzothiazole DGs have
appeared in the recent literature. The cleavage/ring opening
of 2-functionalised (carbon chains/rings) benzothiazoles have
been reported in a few cases,⁹⁹¹⁻⁹⁹⁵ but these protocols have not
been used in the context of DG cleavage in C–H functionalisation.

Chakraborti investigated the use of benzothiazole DGs
specifically for the olefination of heterocycles with alkynes using
Ru catalysis (Scheme 161A).⁹⁹⁶ This protocol resulted in good
yields of the desired olefinated products, and works efficiently on
2-thienyl, 2-furyl, 2-pyrrolyl and 3-indolyl substrates, and a few
examples of regioselective olefination with unsymmetrical alkynes
were demonstrated as well.⁹⁹⁶ Acylation of benzothiazole-
equipped arenes was reported using classical Pd/oxidant/acyl
radical precursor methods (mechanism in Scheme 118).⁷⁶²,⁹⁹⁷
Of note here, is the use of CAN (ceric ammonium nitrate) as a
new alternative oxidant instead of peroxides or O₂. Patel
reported the use of CAN with α-ketocarboxylic acids for C–H
benzoylation of 2-arylbenzothiazoles and a variety of other
heterocyclic compounds (Scheme 161B).⁷⁶² Another method
<figure><img src="image_326.png" /><figcaption>Scheme 160 Oxazolines and benzoxazoles as DGs.</figcaption></figure>

a (free) radical pathway, as demonstrated by radical trapping experiments, but instead occurs *via* a β-carbon elimination from an alkoxy-coordinated Pd species, which delivers the acyl groups directly to the metal, and a subsequent reductive elimination releases the acylated product.⁹⁹⁸ An example of Cu-catalysed C–H nitration was reported making use of Fe(NO₃)₃ as nitro group source (Scheme 161D).⁹⁹⁹ Although utilising a cheap nitro source, the reaction still requires 2 equiv. of Ag₂O (4 equiv. of Ag in total). With a similar protocol to that shown in Scheme 161B, the benzoylation of 2-aryl benzothiazoles occurs using benzoic acids (Scheme 161E).⁷⁶² Mechanistically, a benzoxy radical is generated by CAN, and subsequently coordinates to the intermediate palladacycle, which ultimately results in its introduction onto the substrate.

<figure><img src="image_327.png" /><figcaption>Scheme 161 Benzothiazoles as DGs.</figcaption></figure>

sees the use of acylperoxycoumarins as acylating agents (Scheme 161C).⁹⁹⁸ Strangely, this reaction does not proceed *via*

## 16. Other DGs employed in C–H functionalisation

The synthetic value of C–H functionalisation chemistry is strongly related to the modularity of the DG used. Ideally, a DG should be traceless or easily convertible into an array of common functionalities. An alternative approach consists in direct utilisation of functionalities naturally present on a molecule of interest to play the role of DG. In such a case particularly sustainable transformations take place as installation and removal of the DG is not required anymore. Following these considerations, over the last decade intensive efforts have been focused on designing DGs based on heteroatoms such as P, S, Si, O, N, etc. Notably, these modern DGs are generally easily cleavable or may also remain present in the final product.
<figure><img src="image_328.png" /></figure>

An additional advantage of these scaffolds is their potentially stereogenic character, and thus diastereoselective C–H functionalisation reactions can be explored, even without the use of external chiral ligands. In the following sections, recent advances on the use of these increasingly important DGs are summarised. Due to their less common nature though, relative to the above reported DGs, important publications from before 2015 will also be included.

## 16.1. Thioether as DG

Due to the strong coordination properties of the sulfur compounds, and in particular thioethers, this motif has been considered, for years, an inefficient DG, leading to catalyst poisoning. However, between 2012 and 2015 few reports have been published showing that the thio unit can be astutely employed in the context of directed functionalisation,¹⁰⁰⁰–¹⁰⁰³ and these pioneering contributions have already been summarized.¹⁷ More recently, due to a widespread presence of thio groups in natural products and biologically active scaffolds, several research groups reported complementary studies.

In 2015, Urriolabeitia expanded the scope of previously known Rh-catalysed direct olefinations of benzylthioethers¹⁰⁰⁰, ¹⁰⁰², ¹⁰⁰³ by developing a related C–H hydroarylation catalysed by the [Ru(*p*-cymene)Cl₂]₂ complex (Scheme 162A).¹⁰⁰⁴ Installation of the thioether motif at the benzylic position is crucial to allow efficient formation of a 5-membered ruthenacyclic intermediate. The optimization study revealed that choice of a protic but not too acidic solvent such as HFIP is essential for a high efficiency. Unfortunately, moderate selectivity between mono- and diarylation is observed, calling for exemplification of this methodology on *ortho*-substituted substrates. Interestingly, the reaction occurs smoothly under microwave heating (100 °C for 30 min), which enables to drastically reduce the reaction time (typically 24 h) required under conventional heating. The reaction well tolerates several aliphatic symmetric alkynes and the coupling occurs as a syn addition, delivering *E*-trisubstituted vinylic fragments (Scheme 162A).¹⁰⁰⁴ Besides, a regioselective transformation was achieved when using 1-phenylpropyne coupling partner (9:1 isomeric ratio) although a significant drop in regioselectivity was witnessed for 2-hexyne. The reaction shows good FG tolerance on the substrate, both on the aromatic ring and the *S*-substituent (aliphatic and aromatic motifs are efficient), delivering the desired vinylic compounds in good to excellent yields (16 examples, 54–96% yield).

To further expand the scope of molecular scaffolds accessible *via* thioether-directed C–H functionalisation Liu and Zhang reported a direct acetoxylation protocol (Scheme 162B).¹⁰⁰⁵ As in the previous example, the reaction requires benzothiophene substrates but the DG may also be installed at homobenzylic position (formation of 6-membered metallacyclic intermediate). Using standard Pd(OAc)₂ catalyst, in combination with Ac₂O, PIDA, and AgOAc, the desired C–O bond formation takes place. Interestingly, this protocol permits selective mono-functionalisation and a remarkable array of FGs is well tolerated, including bromine and chlorine atoms, but also coordinating moieties such as nitrile, ester and OCF₃ moiety. Yields are generally moderate

to good (21 examples, 40–84% yield). Importantly, the DG may be removed from the final product either using RANEY® Ni to furnish the corresponding *o*-tolyl acetate, or by addition of *m*-CPBA to convert the thio-motif into an aldehyde.

Thiol-directed C–H activation can also be astutely used to access benzo-fused thiophenes *via* intramolecular C–H arylation, as illustrated in 2016 by Tobisu and Chatani (Scheme 162C).¹⁰⁰⁶ The authors discovered that biphenylsulfide, in the presence of Pd(OAc)₂ and under carboxylic acid assistance (2,6-Me₂C₆H₃CO₂H used) undergoes a tandem C–H cleavage/intramolecular C–S bond formation/S–C cleavage, delivering the desired heterocyclic products under oxidant-free conditions. This operationally simple and high-yielding protocol using readily accessible starting materials and reactants gives access to a large panel of unsymmetrical dibenzothiophenes, important scaffolds in advanced material science and bioactive molecules. It is noteworthy that this oxidant-free protocol allows the suppression of the usually observed reactivity for this type of compounds, i.e. C–H/C–H intramolecular arylation to give isomeric benzothiophene compounds.¹⁰⁰⁷

In addition to this intramolecular thioether-directed arylation, Shi *et al.* developed a very interesting intermolecular

<figure><img src="image_329.png" /></figure>

<figure><img src="image_330.png" /><figcaption>Scheme 162 C(sp²)–H functionalisation using thioether-based DGs.</figcaption></figure>
<figure><img src="image_331.png" /></figure>

coupling between benzylthioethers and carboxylic acids, yielding dibenzooxepinones (Scheme 162D).¹⁰⁰⁸ This RhCp\*-catalysed transformation involves initial C–H metallation of the thiophene substrate, followed by carboxylate-assisted second C–H activation and reductive elimination, and Rh- or Ag-assisted cyclisation and C–S cleavage. Accordingly, the thio- phene moiety is clearly a traceless DG. Although rather harsh reaction conditions required (use of 4 equivalents of AgNO₃ and reaction temperature of 160 °C) and the relatively low yields (28–75%), the reaction still well tolerates substituents such as Cl, Br, but also strongly electron withdrawing CF₃ or ester moieties.

In 2017 Kuninobu and Kanai designed an interesting *ortho*-selective borylation of arylsulfides.¹⁰⁰⁹ In this case the thioether DG is directly installed on the aromatic ring as, contrary to the previous examples, the S atom does not coordinate directly to the Ir catalyst, but generates a Lewis acid-base intermediate with a bipyridine-ligated boron species (Scheme 162E).¹⁰⁰⁹ Such an unusual interaction directs the borylation highly selectively at the *ortho*-position. Fine-tuning of the catalytic system and ligand design allowed the development of a truly efficient and versatile transformation, occurring under mild reaction conditions and compatible with a range of functionalised substrates. Notably, the reaction is equally efficient at gram scale. As the newly introduced Bpin substituent is a handle for further modification of the molecular scaffolds, this transformation holds great promise for widespread applications. Few months later the authors further expanded the potential of this transformation by conceiving an *ortho*-borylation of phenol and aniline derivatives (Scheme 162F).¹⁰¹⁰ In this case the methylthiomethyl group installed on hydroxy- or amino-moieties allows, *via* the same type of interaction as above, directing the borylation at the *ortho*-position. As previously, the high regioselectivity observed, efficiency and possible post-modifications of the newly obtained scaffolds, render this coupling attractive, as further illustrated by its application in an expedient synthesis of a Ca receptor modulator.¹⁰¹⁰ The removal of the DG (*i.e.* deprotection of hydroxyl group) occurs smoothly using I₂ in MeOH, furnishing the corresponding phenol in high yield.

Drawing inspiration from the standard thioether-directed C–H functionalisation, Satoh and Miura disclosed in 2015 the use of dithiane motifs (commonly used as aldehyde protecting group) as an effective DG for Rh-catalysed Fujiwara-Moritani couplings (Scheme 163A).¹⁰¹¹ This C–C bond forming transformation, occurring under relatively mild conditions

<figure><img src="image_332.png" /><figcaption>Scheme 164 Disulfide-directed C–H hydroxylation.</figcaption></figure>

(60 °C, no need for acidic additives and use of Cu(OAc)₂·H₂O as mild oxidant) is not only highly monoselective but also compatible with an array of functionalised substrates bearing challenging motifs such as nitro, ketone, ether, thioether or halide substituents. The protocol is also compatible with a cyclic sulfide substrate. The synthetic value of this transformation arises from a straightforward post-modification of the dithiane-DG that can be either removed using RANEY¹⁸-Ni or converted into aldehyde in the presence of Dess–Martin periodinane.¹⁰¹¹

Very recently, Li *et al*. used the same DG to achieve an Ir-catalysed *ortho*-borylation (Scheme 163B).¹⁰¹² This ligand-free coupling with B₂pin₂ is effective for the direct functionalisation of both aromatic and heteroaromatic moieties, like thiophene and ferrocene backbones. It is worth noting that the employment of the dithiane motif outcompetes thioether DGs as mono-functionalisation occurs selectively, whereas mixtures of mono- and biarylated products are typically generated when thioethers are used. The cleavage of the 1,3-dithiane was achieved using NaI, Fe(acac)₃ in H₂O₂, delivering the corresponding aldehyde.

Further exploring the potential of the thioether motif as DG and drawing inspiration from the observation that benzylthioethers are effective in C–H activation reactions, Wang and Shi described an elegant example of disulfide-directed C–H hydroxylation (Scheme 164).¹⁰¹³ The optimized Cu-based catalytic system allows a sequential transformation involving: (1) thiophenol oxidation to disulfide, (2) disulfide-directed *ortho*-hydroxylation and (3) *S*-arylation using boronic acid coupling partner, affording otherwise difficult to access 1,2-thio-phenol derivatives. Remarkably, this complex transformation is rather high-yielding and shows good substrate scope, in particular with regard to halogenated substituents at both coupling partners. Besides, applying the same concept for a synthesis of thiophenol-substituted quinones further showcased the potential of this reaction. Few months later, Wang and Li reported a closely related Cu-catalysed disulfide-directed *ortho*-hydroxylation. In this case disulfide substrates were directly employed, and a Cu-bipy complex was selected as the optimal catalyst.¹⁰¹⁴

## 16.2. Sulfoxide as DG

In addition to thioethers, higher oxidation state sulfur moieties also established themselves as powerful DGs. In particular between 2012 and 2014 several research groups employed with success sulfoxide DGs in Pd,¹⁰¹⁵–¹⁰¹⁷ Rh,¹⁰¹⁸ and Ru¹⁰¹⁹-catalysed C–H activation. Since 2015, few additional key contributions have been published,²⁹ mainly relating to the use of enantiopure sulfoxides for stereoselective C–H activation.

<figure><img src="image_333.png" /><figcaption>Scheme 163 Rare examples of dithiane DGs.</figcaption></figure>
<figure><img src="image_334.png" /></figure>

In 2013 Leroux and Colobert reported first example of diastereoselective sulfoxide-directed oxidative olefination of biaryl precursors leading to atropoenriched, axially chiral scaffolds.¹⁰²⁰ This pioneering work clearly showcases the potential of enantiopure sulfinyl, accessible in a large scale from cheap menthol,¹⁰²¹ to play the double role of DG and chiral auxiliary. However, both efficiency and stereoselectivity of the catalytic system were rather moderate. A clear improvement was achieved in 2014 and 2016 by Wencel-Delord and Colobert, who discovered that a much more powerful and general transformation is achieved when changing the reaction medium from DCE to HFIP (Scheme 165A).¹⁰²²,¹⁰²³ Under such modified reaction conditions the Fujiwara–Moritani reaction may be conducted at room temperature and using a significantly lower amount of the Ag oxidant (2 equiv. vs. 6 equiv. initially required), delivering a large panel of axially chiral biaryls with excellent atroposelectivity and high yields. Besides, as the sulfoxide moiety undergoes exchange with Li bases, trapping of the resulting axially chiral Li species with an array of electrophiles could be performed, delivering variety functionallyised biaryls without loss of stereopurity (introduction of functionalities such as aldehydes, Me, OH, CO₂H, etc.).¹⁰²² This methodology was also further used to perform direct acetoxylation and iodination.¹⁰²³ The synthetic potential of this methodology was further illustrated while designing a novel retrosynthetic route towards biologically active, axially chiral Steganacine scaffolds.¹⁰²⁴ Remarkably, the synthesis based on this atropo-diastereoselective transformation delivered the direct precursor of the targeted enantiopure molecule in only 10 steps and in very high total yield (42%).

Very recently the concept of sulfoxide-directed atroposelective C–H functionalisation was employed to build up original tridimensional structures, *i.e.* *ortho*-orientated terphenyl scaffolds with two perfectly controlled chiral axis (Scheme 165B).¹⁰²⁵ These molecules exhibiting “open clam shell architectures” could be obtained *via* direct arylation of the biaryl-sulfoxide precursors with *ortho*-substituted iodoarenes. During this process two chiral Ar–Ar axes, are induced in a single transformation with very high stereocontrol. Importantly, the traceless character of the sulfoxide, combined with the good FG tolerance of the catalytic system

towards the iodoarene partner permits straightforward derivatization into unprecedented bidentate ligands.

Dibenzothiophenes are important molecular motifs in natural products, pharmaceuticals and functional materials. Accordingly, designing of C–H functionalisation-based strategies to access these molecular units has gathered the attention of several research groups. In 2013 Colobert described a Pd-catalysed intramolecular arylation of 2-bromodiarylsulfinyle, delivering dibenzothiophenes S-oxides.¹⁰²⁶ Going one step further, in 2015 Huang and Lin reported an intramolecular two-fold C–H functionalisation of diarylsulfoxides (Scheme 165C).¹⁰²⁷ Interestingly, under this Rh-based protocol deoxygenation of the newly formed dibenzothiophenes S-oxides occurs *in situ*. Unfortunately, the efficiency of the reaction is strongly affected by the nature of the starting material and harsh reaction conditions are required (140 °C).

### 16.3. Sulfones, sulfonamides & sulfoximines DG

In contrast to thioether and sulfoxides that have been regularly employed as DGs, the use of sulfones in this context has remained fairly unexplored till recently, despite the easy access to such molecules *via* electrophilic sulfonylation of aromatic rings. Initially, the sulfone moiety was used as a handle to install other DGs, as in the case to 2-pyridylsulfonate DG.¹⁰²⁸ In this case the heterocycle enhances and dictates the metallation event whereas the SO₂ moiety can be considered as a removable anchor (for examples of such transformations see Section 15.3.4). Satoh and Miura proved however in 2015 that sulfones may act as efficient DGs themselves, allowing *ortho*-selective alkenylation of aromatics (Scheme 166A).¹⁰²⁹ The catalytic system based on Rh complexes, combined with adamantanecarboxylic acid additive gave good results with internal aromatic and aliphatic alkynes, delivering the desired vinylic products in moderate to good yields, but a high reaction temperature was generally required.

An additional attracting example of sulfone-directed intramolecular transformation was reported in 2015 by Zhou (Scheme 166B).¹⁰³⁰ This cascade-type reaction involves sulfone-directed metallation, followed by base-assisted 1,5-H shift affording allene intermediates. Insertion into the C–Rh bond finally delivers seven-membered heteroaromatic products such as benzothiepines. This strategy constitutes an interesting pathway towards molecules of interest despite the complexity of the starting materials used.

Sulfonamide is amongst the most significant pharmaco-phores, frequently encountered in biologically active scaffolds.

<figure><img src="image_335.png" /><figcaption>Scheme 165 Sulfoxide-directed C–H functionalisation.</figcaption></figure>

<figure><img src="image_336.png" /><figcaption>Scheme 166 Sulfone-directed C–H functionalisation.</figcaption></figure>
Review Article

<figure><img src="image_337.png" /><figcaption>Scheme 167 Direct functionalisation using sulfonamides as DG.</figcaption></figure>

However, this weakly coordinating motif has attracted only limited attention from the scientific community working in the field of directed C–H functionalisation. In 2011 Yu *et al*. described a late stage modification of sulfonamide-containing motifs, *via* direct olefination, carboxylation, carbonylation, iodination, arylation and alkylation.¹⁰³¹ The variety of sulfonamide-directed transformations was enlarged in 2016 when Singh developed a Pd-catalysed direct arylation using iodoarenes as coupling partners (Scheme 167A).¹⁰³² This transformation is highly mono-selective, although the products are isolated in moderate to good yields (typically between 60–70%) and prolonged heating at 130 °C in acetic acid is necessary to promote this transformation.

In parallel, Kerr and Tuttle endeavored on designing a catalytic system to regioselectively install deuterium on aromatics (Scheme 167B).¹⁰³³ Following this target they discovered that primary sulfonamides undergo highly selective H/D exchange, when using an Ir–NHC complex. Importantly, D₂ may be employed as deuterium source and this transformation is compatible with an array of functionalities. Unfortunately, the level of deuterium incorporation is highly dependent on the substitution pattern of the substrates, possibly due to their different solubility in DCM. This protocol could however be successfully used to label pharmaceuticals, such as Celecoxib and Mavacoxib.¹⁰³³ In 2017 the synthetic potential and field of application of this methodology was further expanded by conceiving a closely related deuteration of secondary and tertiary sulfonamides. Atzrodt and Derdau established a protocol based on an Ir catalyst bearing either a monodentate NHC or bidentate NHC/oxazoline ligand (commercially available Burgess catalyst), effective in chlorobenzene at higher temperature (typically 100–120 °C) (Scheme 167C).¹⁰³⁴ However, as in the previous example, the outcome of the transformation might be difficult to predict in terms of deuterium incorporation and regioselectivity (in particular if other coordinating moieties are present on the substrate or when tertiary sulfonamides are employed).

Very recently, Yu and coworkers described an astute application for sulfonamide motifs installed at the benzylic position to

promote *meta*-selective functionalisation (Scheme 167D).¹⁰³⁵ The regioselectivity switch was reached using modified norbornene (NBE-CO₂Me: 2-carbomethoxynorbornene) as a transient mediator, while addition of an external isoquinoline ligand was crucial for the efficiency of the catalytic system. Remarkably, both *meta*-arylation and *meta*-alkylations could be performed and the protocol features broad substrate scope as well as excellent FG tolerance. The synthetic value of this reaction was further illustrated by the modularity of the obtained products, which could be easily converted into the corresponding sodium sulfonates, sulfonate esters, other sulfonamides or olefins. Besides, a two-step procedure allows cleavage of the DG under Julia olefination conditions delivering the corresponding styrene.¹⁰³⁵

Finally, sulfoximines further expand the portfolio of S-based DGs. In particular, heterocyclic molecules featuring the sulfoximine group are tempting for drug design. Hence, the development of modern, efficient and straightforward pathways to access them is of great importance. Accordingly, several research groups astutely used sulfoximine-directed C–H functionalisation/cyclisation protocols to access an array of benzothiazines congeners. Amongst pioneering contributions in this field, Bolm described in 2013 the Rh-catalysed oxidative annulation of sulfoximines and internal alkynes, delivering 1,2-benzothiazines with fully substituted heterocyclic cores.¹⁰³⁶ Despite the synthetic value of this methodology, the use of unsymmetrical alkynes raised regioselectivity issues and mixtures of regioisomeric products were generally produced. To tackle this limitation, in 2015 the same research group combined Rh-catalysed sulfoximine-directed C–H alkylation with diazo compounds (Scheme 168A).¹⁰³⁷ Rewardingly, the reaction between NH-sulfoximines and a large variety of alkyl- and phenyl-containing diazo esters occurred smoothly in presence of a Rh catalyst and NaOAc additive, delivering structurally diversified 1,2-benzothiazines in generally excellent yields. Besides, a scale-up of this reaction was achieved and the newly obtained scaffold could be straightforwardly converted into several added-value congeners.

Following this idea, Lee and coworkers developed an alternative synthesis of 1,2-benzothiazine derivatives (Scheme 168B).¹⁰³⁸ Using pyridotriazoles as highly reactive diazoimine precursors (see also Scheme 112), pyridine-substituted 1,2-benzothiazines were afforded *via* a domino C–H functionalisation/cyclisation/elimination sequence in good to excellent yields regardless of the substitution pattern of the aromatic substrate. Few months later the same group further expanded the panel of related transformations, now employing 3-diazoindolin-2-imes as coupling partners.¹⁰³⁹ Under Rh catalysis the desired direct coupling/annulation sequence occurred producing an indolo-1,2-benzothiazines with various substituents at both, the substrate and the indole core (Scheme 168C).¹⁰³⁹

An efficient cyclometallation event for sulfoximines substrates combined with the high reactivity of the resulting metallacyclic intermediates towards carbene migratory insertion encouraged further elaboration of innovative synthetic routes towards original heterocycles. Accordingly, in 2017 Chen performed direct C–H amidation of sulfoximines using

<figure><img src="image_338.png" /></figure>
<figure><img src="image_339.png" /></figure>

<figure><img src="image_340.png" /><figcaption>Scheme 168 (Free-NH)-sulfoximine-directed C–H functionalisation.</figcaption></figure>

a Co catalyst and 1,4,2-dioxazol-5-ones as coupling partners (Scheme 168D).¹⁰⁴⁰ Under optimized microwave assisted conditions, the expected aza-heterocycles were delivered, generating only CO₂ and H₂O as waste.

The metallacyclic intermediates can be generally considered as nucleophiles and may hence participate in reactions with various electrophiles, such as Michael acceptors for example. Such reactivity was surveyed by Li and Dong, who synthesized benzoisothiazoles *via* Rh-catalysed coupling between sulfoximines and activated olefins (Scheme 168E).¹⁰⁴¹ Unfortunately, although the original 5-membered heterocyclic products are generally afforded in good yields (typically 70–90%), poor stereo-selectivity was observed (usually 1:1 ratio), clearly hampering the synthetic potential of the reaction. A complementary reaction delivering original heterocyclic scaffolds was achieved by combining C–H activation and coupling with unsaturated ketones (Scheme 168F).¹⁰⁴² The reaction sequence involving formal metal-catalysed functionalisation and subsequent [4+3] annulations produced 7-membered 1,2-benzothiazepines 1-oxides. Broad substrate scope observed for this transformation, quite high efficiency and compatibility with cheap 3d-metal catalysts render this transformation appealing in drug-design science. Finally Bolm illustrated that benzothiazine may also be build-up while performing a Rh(II)-catalysed domino allylation/oxidative cyclisation between sulfoximines and allyl carbonates (Scheme 168G).¹⁰⁴³ This transformation is a synthetic route of choice to prepare 4-unsubstituted 1,2-benzothiazines, scaffolds difficult to access when employing diazo-type coupling partners. Noteworthy, both electron rich and electron poor substituents may be introduced on the aromatic ring of the sulfoximine, and several different alkyl S-substituents are well tolerated. Thus obtained benzothiazine may also

be rapidly diversified into few molecules of interest for pharmaceutical industry. An alternative route towards 4-unsubstituted 1,2-benzothiazines involves coupling between the metallacyclic intermediate and sulfoxonium ylides, used now as novel C2 synths (Scheme 168H).¹⁰⁴⁴ This RhCp\*-catalysed transformation was accelerated in presence of Zn(OTf)₂ additive, is of particular interest if benzothiazines bearing various, aliphatic and aromatic substituents at 3-position are targeted as an array of sulfoxonium yield performed very efficiently in this transformation.

Finally, it should be mentioned that using a standard RhCp\*-catalyst, in combination with NH-Boc oxycarbamates, direct amidation of sulfoximines occurs smoothly for both, electron-poor and electron-rich aromatics (Scheme 168I).¹⁰⁴⁵ Furthermore, as the newly accessed *ortho*-amidated sulfoximines may be converted into few steps into thiadiazine 1-oxides. In addition, still benefitting from efficient metallation of sulfoximine substrates in presence of RhCp\*-catalysts, Bolm *et al.* reported direct C–X coupling (Scheme 168J).¹⁰⁴⁶ Indeed, in presence of NIS or NBS as halogenating agents sulfoximes may be directly converted into *ortho*-halogenated congeners in high to excellent yield. This reaction allows therefore late-stage installation of amenable motifs for further diversifications.

A further key contribution to the field of sulfoximine-directed C–H activation was made by Sahoo who designed a S-methyl-S-phenylsulfoximine (MPS) DG.¹⁶ This motif, straightforwardly installable on carboxylic acids, easily removable (under basic conditions using NaOH in MeOH/H₂O or acidic conditions using aq. HCl at 80 °C) and recyclable, demonstrated excellent reactivity under Ru- and Pd-catalysis, undergoing efficiently direct hydroxylation¹⁰⁴⁷,¹⁰⁴⁸ or amidation¹⁰⁴⁹ reactions.
<figure><img src="image_341.png" /></figure>

<figure><img src="image_342.png" /><figcaption>Scheme 169 (N-Benzoyl)sulfoximine and related DGs.</figcaption></figure>

In 2014 the versatility of this chemistry was further spread by devising a protocol allowing *ortho*- and chemoselective C–H alkenylations (Scheme 169A).1050 This oxidative Heck reaction catalysed by Ru(*p*-cymene) complex was compatible with an array of sulfoximine substrates but activated olefines (typically acrylates) were required. Following this exciting research field Sahoo discovered that MPS-equipped substrates, in presence of the same Ru-complex and N-protected phthalimides, undergo *ortho*-selective C–N bond formation (Scheme 169B).1051 Interestingly, the reaction protocol tolerates several functionalised aromatics (including halo-substituted and N-heteroaroyl ones) and, in presence of a large excess of the phthalimide, double *ortho,ortho'*-C–H activation occurs. Subsequently, intramolecular direct heteroarylation of MPS-sulfoximines was disclosed. Sahoo and coworkers installed on an aromatic substrate a judiciously selected olefin tether (Scheme 169C).1052 After the Ru-catalysed C–H cleavage, spacial proximity between the metallacyclic intermediate and an external double bond enhanced precoordination of a double bond by Ru, to favour migratory insertion into the C–Ru bond and final protodemetallation liberating a cyclised product. Quite remarkably, the same approach may also be used for two-fold unsymmetrical functionalisation. In such a case after initial intramolecular hydroarylation the Ru-catalyst re-enters a new catalytic cycle, inserts into the C–H bond at *ortho'*-position and final intermolecular amidation delivers a large panel of highly decorated scaffolds. MPS-bearing vinylic substrates are equally appealing precursors for this chemistry.1053 Indeed, one-pot double annulation of MPS-acrylamides occurred smoothly using a standard Ru(*p*-cymene)-catalyst in combination with internal alkynes, afforded pyrido-fused isoquinolone scaffolds (Scheme 169D). In course of this reaction both, symmetrical alkynes and two

distinct unsymmetrical coupling partners may be employed. Besides, heteroaromatics substituted by sulfoximine motifs are equally efficient *via* a closely related protocol, delivering π-conjugated polycyclic amides in high yields.1054 Noteworthy, the MPS auxiliary is a traceless DG that can be readily removed after the C–H functionalisation (under basic conditions) or is directly cleaved during the annulation events.

In parallel, Ackermann designed a C–H oxygenation reaction of sulfoximines. As for previous examples, Ru(*p*-cymene) is an optimal catalyst and after fine optimization, an iodine(III) and Ag(I)-free protocol was established to allow direct C–O coupling between sulfoximine benzamides and aromatic carboxylic acids (Scheme 169E).1055 This highly monoselective transformation well tolerates both electron-donating and electron-withdrawing substituents on the carboxylate, delivering the desired products in moderate to good yields (typically 50–70%). Notably, the functionalised sulfoximines may be readily converted into salicylic acids under acidic conditions.

## 16.4. Thioamide, thioketones, alkoxythiocarbonyls and thiocarbamates as DG

Another possibility of employing sulfur in a coordinating group relates to the use of thiocarbonyl motifs. Pioneering work in this challenging field was reported in 2015 by Satoh and Miura who disclosed Rh-catalysed direct coupling of benzothioamides with olefines and alkynes.1056 In this case N,N-diisopropylthioamide was used as DG and the expected functionalisation performed well under standard conditions. Importantly, oxidative Heck reaction with acrylates and styrenes delivers *ortho*-olefinated products while intramolecular cyclisation and desulfurization occur in presence of an alkyne partner, delivering indenone-derived products (Scheme 170A). Both couplings are high yielding and support well both electron-rich and electron-poor substrates. Few months later Yu and co-workers showcased that installation of a thiocarbonyl moiety on heterocycles such as pyrrolidine, piperidine, azapines or N-methyl amine is an efficient approach for α-arylation.1057 The corresponding thioamides undergo smoothly Pd-catalysed metallation and following coupling with boronic acids affords functionalised amine-derivatives (Scheme 170B). Remarkably, this protocol well tolerates a large panel of boronic acids, including sterically demanding *ortho*-substituted ones as well as heteroaromatic partners. High levels of diastereoselectivity are generally reached when substituted pyrrolidine substrates are used and complete diastereoselectivity is observed when one pot, sequential diarylation is performed. Importantly, this thiocarbonyl motif can be removed with methyl lithium as base and the generated amine is protected as the Boc-carbamate. Alternatively, the corresponding amide may also be accessed by oxidation with silver salts. In 2017 the same group reported an enantioselective version of this transformation.1058 Chiral induction (up to 98/2 e.r.) was accessed in presence of a phosphoric acid ligand (Scheme 170C). This arylation reaction is compatible with both cyclic and acyclic amines and as cleavage of the DG might be achieved (2-steps procedure including reduction of the thiocarbonyl in presence of NiCl₂ and NaBH₄, followed by BCl₃-mediated debenzylation)
<figure><img src="image_343.png" /></figure>

<figure><img src="image_344.png" /><figcaption>Scheme 170 Thioamide, thioketones, alkoxythiocarbonyls and thiocarbamates as DG.</figcaption></figure>

it can be considered as an interesting strategy to access stereogenic amines.

Further potential of the thiocarbonyl moiety to enhance C–H activation was illustrated by You who disclosed thioketone-directed arylation of ferrocenes (Scheme 170D).¹⁰⁵⁹ Under reaction conditions close to the one developed by Yu, palladation of thiocarbonylferrocene occurs straightforwardly, delivering either mono- or bi-arylated ferrocenes in generally high yields. The protocol is also applicable for sequential diarylation. The final product could be converted either into the corresponding ketones or a RANEY®-nickel mediated reduction delivered a benzylated congeners.

To further improve the traceless character of a thiocarbonyl based DG, Yu designed in 2017 an alkoxythiocarbonyl auxiliary.¹⁰⁶⁰ This novel sulfur-based DG is particularly appealing in Ir-catalysed C–H activation, affording alkylated compounds in presence of non-activated olefin coupling partners (Scheme 170E). Thanks to a large scope of this coupling and convenient removal of the auxiliary (treatment with ac. solution of TFA

followed by N-protection) an array of original aliphatic amines may be build-up efficiently.

An alternative C≡S type directing group, thiocarbamate, was disclosed by Xia.¹⁰⁶¹ Remarkably, in this case the DG group is truly traceless; in presence of an internal alkyne coupling partner, the C–H activation step and subsequent C–C bond formation event are followed by annulation, delivering coumarins (Scheme 170F).

### 16.5. Phosphine oxides and sulfides as P-based DG

Organophosphorus molecules are key structural motifs in a large panel of pharmaceuticals, agrochemicals and organic materials. Straightforward access to such scaffolds hence presents an appealing synthetic challenge for organic chemists and therefore it is not surprising that diversification of phosphorus-containing molecules by means of C–H activation has been attracting a great deal of attention. The pioneering key contribution in this field were already elegantly summarized elsewhere.¹⁷ The use of auxiliary phosphorus-containing DGs, such as monophosphonic acid phosphonate, presented however a serious drawback related to a low modularity of these DGs. Accordingly, the improvements that were expected in this domain concerned: (1) design of transformations implying generation of the functionalised P-containing molecules where the auxiliary is voluntarily presented in a final product skeleton; (2) conception of innovative, readily transformable or traceless DGs.

Amongst phosphorus-based DGs, phosphine oxides are particularly interesting motifs. Indeed biaryl phosphines are key ligands for both non-asymmetric and stereoselective transformations and thus synthesis of (chiral) biarylphosphine oxides is highly appealing and much work has been already done in this field.¹⁰⁶² This coordinating group exhibits a modular activation mode as coordination of the metal catalyst can be achieved either *via* oxygen or phosphorus atoms, depending on the (1) hard/soft properties of the catalyst used and (2) geometrical considerations and size of a metallacyclic intermediate formed. Accordingly, if functionalisation of biaryl substrates bearing the phosphine oxide-DG is targeted, Pd-based catalytic systems seem particularly suited as a precoordination of this soft metal by the soft P-atom is expected. In accordance with these predictions, a variety of Pd-catalysed functionalisations of phosphine oxides biaryls have been achieved. More recently, this approach was valorized by synthesis of axially chiral phosphine ligands. Initially, a diastereoselective approach has been devised using a chiral phosphine based DG, bearing a menthol substituent as chiral source (Scheme 171A). Rewardingly, direct functionalisation of the corresponding substrates occurred smoothly, delivered atropisomerically highly enriched products *via* C–C, C–O and C–I couplings.¹⁰⁶³ᵃ Subsequently, a closely related acylation of biaryl substrates bearing now a P-chiral DG was disclosed.¹⁰⁶³ᵇ,ᶜ This methodology was further complemented with an enantioselective transformation. Indeed, Yang *et al.* discovered that if a simple diphenylphosphine oxide DG is installed on biaryl substrates, Fujiwara–Moritani coupling catalysed by Pd(OAc)₂ in presence of a chiral amino acid ligand, takes place efficiently in *ortho'*-position with an excellent enantioselectivity (Scheme 171B).¹⁰⁶⁴
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<figure><img src="image_345.png" /></figure>

<figure><img src="image_346.png" /><figcaption>Scheme 171 Phosphine oxide- and sulfide-directed transformations.</figcaption></figure>

The extensive ligand screening revealed that structurally simple Boc-1-Val-OH ligand is optimal in terms of chiral induction, delivering the atropisomeric olefin/phosphineoxides in typically 90% ee. The reaction occurs under relatively mild reaction conditions (60 °C) and probably implies a dynamic transformation such as dynamic kinetic resolution and/or dynamic catalytic asymmetric transformation.

Aside from Pd-catalysed transformations, phosphine oxide DGs are also compatible with Ru, Rh and Ir-based catalysts. Likewise sulfoxide-DGs, as phosphine oxide coordinate these rather hard catalysts *via* the O-atom, a 5-membered metallacyclic intermediates is hence generated when this DG is installed directly on an aromatic ring. Following this analysis, Soulé reported recently direct alkylation of arylphosphine oxides in presence of a Ru-based catalyst (Scheme 171C).¹⁰⁶⁵

This monoselective C–C coupling occurs with moderate to high yields, but the newly accessed scaffolds can be considered as original phosphoros ligand.

Straightforward *ortho*-metallation of arylphosphine oxides may also be performed in presence of a RhCp\*-catalyst, as illustrated by Satoh and Miura (Scheme 171D).¹⁰⁶⁶ The authors discovered that heterocyclic compounds are also suitable coupling partners, allowing direct arylation. This strategy is an interesting alternative to commonly used iodoarenes as coupling partners, delivering biaryl compounds in variable yields ranging from 30 to 91%. Metallacyclic Ir/phosphine oxide intermediates are also prone to undergo migratory insertion of metal carbenes (Scheme 171E).¹⁰⁶⁷ This synthetic route delivers original biaryl scaffolds up to gram scale and their diversification *via* FG interconversion was illustrated.

Outstanding application of the phosphine oxide DG was reported in 2016 by Shi.¹⁰⁶⁸ The authors installed this coordinating motif on the N-atom of indole substrates and observed unexpected regioselectivity during a Pd-catalysed coupling with boronic acids. Indeed, selective arylation at C7, over generally observed C2-functionalisation could be attained in synthetically useful yields when installing bulky phosphine oxide DGs, such as P(O)(tBu)₂ (Scheme 171F). Due to steric reasons, the O-atom is perfectly oriented to perform C–H activation at this specific C7 position. In addition, bulky tBu-substituents on P-atom prevent N–P bond rotation further favouring the observed selectivity. Few months later the same research group succeeded in designing a complementary Cu-catalysed, C6-selective transformation. Drawing inspiration from Gaunt,¹⁰⁶⁹ they reacted the same di-tBu-phosphine oxide substituted indole with iodanes.¹⁰⁷⁰ In line with the expectations, C7 vs. C6 regioselectivity shift occurred *via* transfer of the aromatic ring bound to Cu (resulting from oxidative addition of Cu into iodine) to C6 position *via* the Heck-type four-membered-ring transition state. Accordingly, using the same indol substrate with a judiciously selected DG the functionalisation could be triggered at unusual position, by simple changing the catalyst used and the nature of the arylating agent. Importantly, the DG can be removed by treatment with lithium aluminum hydride to give the unprotected indole derivatives.

In addition to phosphine oxide, phenylphosphine sulfides may also act as efficient DG in RhCp\*-catalysed transformations. Such a P≡S DG was used in 2014 by Satoh and Miura to provide new protocols for direct alkenylation occurring either *via* oxidative Heck reaction or redox-neutral coupling with internal alkynes (Scheme 171G).¹⁰⁷¹ Also thiophosphinamides exhibit a somehow related reactivity as illustrated Satoh and Miura who used this P-DG in Rh-catalysed coupling with heterobicyclic alkenes.¹⁰⁶⁶ The same substrates may also undergo *ortho*-alkenylation and subsequent cyclisation delivering arylthiophosphinamides,¹⁰⁷² compounds of interest due to their intriguing electronic and optical properties (Scheme 171H).

Phosphonic acids constitute another sub-category of P-based DGs. The originality of this DG arises from the presence of an OH-free group on the phosphorus atom and accordingly precoordination of a metal by this motif is expected.
<figure><img src="image_347.png" /></figure>

<figure><img src="image_348.png" /><figcaption>Scheme 172 Other P-based DGs in C–H functionalisation.</figcaption></figure>

Several interesting examples of C–H activation reactions directed by this moiety have been reported before 2015 and they were highlighted elsewhere.¹⁷ More recently, the group of Lee focused on synthesis of phosphaisocoumarins *via* C–H activation strategy directed by P-containing DG (Scheme 172A). The first successful protocol relates to a phosphoannulation reaction of aryl- and benzylphosphonic acids with unactivated alkenes *via* direct C–H coupling/C–O cyclisation step sequence.¹⁰⁷³ This reaction is efficient for both, aryl- and benzylphosphonic acids. The olefination reaction delivers products in moderate to good efficiency. Few months later the same research group provided an alternative approach towards dihydrophosphaisocoumarins *via* C–H activation followed by C–O cyclizing bond formation (Scheme 172B).¹⁰⁷⁴ In this case 1,3-dienes are used as coupling partners and the regioselectivity of this transformation may be arguably attributed to a formation of Pd π-intermediates. Unfortunately, the reaction does not allow diastereoocontrol and the products are obtained as mixture of diastereomeric products albeit in high yields.

Targeting design of transformable/traceless P-containing DGs, several research groups focused on auxiliaries installed on an aromatic substrate *via* a heteroatom like O, or NH motif. Following this idea, enol phosphate DGs have been designed¹⁰⁷⁵⁻¹⁰⁷⁸ and employed them in direct functionalisation of aromatics. In 2015 Loh expanded this reactivity by developing a catalytic system able to functionalise vinyl C–H bonds (Scheme 172C).¹⁰⁷⁹ Cationic RhCp\* catalyst in combination with Cu(OAc)₂ and pivalic acid allowed selective alkenylation of phenylvinyl phosphates. The reaction well tolerates an array of alkene substrates and the diene products are generally obtained in high yields (typically 70–90%) and good E/Z selectivity (approx. 90 : 10). Besides, when using vinyl ketones as coupling partners selective hydroalkenylation occurs and also

unsymmetrical alkynes may be used in this C–C coupling. Finally, in accordance with the general target of devising traceless DGs, efficient removal of this motif using DIBAL-H or TBAF based protocols. In addition, the O-tethered DG may also be considered as a reactive site to perform Ni-catalysed C–C coupling delivering an arylated product.

Besides O-tethered P-containing DGs, use of N-linked directing groups also attracted scientific curiosity. In 2013 Lee developed phosphoramidite-directed arylation.¹⁰⁷⁶ More recently, Oestrich et al. designed phosphinic amides as novel handle for Fujiwara-Moritani reaction (Scheme 172D).¹⁰⁸⁰ Both, NH and NMe aniline derived phosphonic amides performed well. Besides, the oxidative olefination with this DG occurred smoothly at temperature as low as 40 °C, vs. 90 °C required for the activation of substrates bearing an NH-anilide. The transformation well tolerates few electron-donating substituents on the aromatic ring of the substrate as well as few activated olefins.

Alternative, as P-chiral molecules are intriguing motifs, in particular for asymmetric synthesis, design of stereoselective C–H activation reactions directed by P-motifs and delivering chiral molecules is highly appealing. Following this idea Han surmised that if symmetrical phosphinamides are used, a direct activation of one of the aromatic substrates would result in a desymmetrisation of the product, hence delivering P-stereogenic molecules (Scheme 172E).¹⁰⁸¹ As expected, when using a Pd-catalyst in combination with mono protected amino acid ligands, desymmetrization of phosphinamides occurred, delivering the corresponding P-chiral molecules in moderate to good yields and good enantiomeric excess of approx. 90%. Notably, the post-diversifications were performed with little or no loss of chiral information.

In 2017 Cramer reported a complementary catalytic system based on the use of chiral RhCp-derived catalyst bearing an
<figure><img src="image_349.png" /></figure>

atropisomeric Cp-type ligand (Scheme 172F).¹⁰⁸² During this directed alkynylation intramolecular annulation takes place delivering P-chiral cyclic phosphinamides. The reaction shows large scope, good tolerance towards substrates bearing a variety of electron-withdrawing and electron-donating substrates and very high regioselectivity with respect to unsymmetrical alkynes. The yields are moderate to good end ees of roughly 90% were obtained. Subsequently, this chemistry was employed to functionalise racemic dissymmetric phosphinic amides. The same catalytic system was now employed to perform direct stereoselective C–C coupling *via* kinetic resolution.¹⁰⁸³

Finally, the panel of P-based DGs is complemented by using simple phosphines as coordinating motifs. This approach seems highly challenging and counterintuitive as phosphines are excellent ligands and their use in a stoichiometric amount as DG could lead to “catalyst poisoning”. In addition, oxidative conditions frequently applied in C–H activation might lead to the oxidation of this DG. However, in 2014 Clark reported Ir-catalysed phosphine-directed *ortho*-borylation of aromatics (Scheme 172G).¹⁰⁸⁴ Like in a case of thioether (see Section 16.1), the phosphine is installed at the benzylic position to allow generation of 5-membered metallacyclic intermediates. This reactivity could also be extended to diaryl and heteroaryl compounds where a PR₂-motif directs functionalisation at *ortho'*-position. Noteworthy, *in situ* protection of the phosphine as the borane complex takes place, enabling convenient isolation of otherwise air-sensitive boronate esters, and deprotection in presence of Et₂NH can be conducted when requested.

Following this seminal work, in 2017 Shi discovered that direct C–H functionalisation may be applied as an efficient handle to diversify privileged biaryl-monophosphine ligands. Indeed, a PR₂-motif is able to transiently coordinate a Rh(i)-catalyst and *via* formation of a metallacyclic intermediate direct the metallation step at the *ortho'*-position and further promoting C–C coupling with arylbromides (Scheme 172H).¹⁰⁸⁵ Use of an equimolar ratio between a phosphine substrate and Ar–Br partner permits selective mono functionalisation while an increased amount of the coupling partner favours formation of diarylated congeners. Remarkably, this protocol is compatible with an array of commercially available monophosphine ligands such as CyJohnPhos, DavePhos and cataCXium auxiliaries like PinCy or POMeCy. Noteworthy, with enantiopure substrates such as binaphthyl-phosphine H-MOP or Tang’s ligand, the arylation occurs with no loss of the chiral information. Accordingly, this reaction is a unique tool for the late stage diversification of ligands.

Noteworthy, the phosphine motif can also be applied in Cu-mediated alkynylation reactions, delivering, after a cyclisation step, an array of phosphindolium salts.¹⁰⁸⁶ Unfortunately, although this protocol gives straightforwardly access to important heterocyclic motifs, need for 2 equivalents of the metal salt limits its synthetic attractiveness.

## 16.6. Si-Based DGs

One of the major limitations of directed C–H activation relates to the need for preinstalled coordinating motifs, prompt to precoordinate a metal catalyst and thus enhance regioselective metallation.

Although over the last years particular attention has been focused on devising C–H activation reactions benefitting from the functionalities inherently present on a desired product that may play a role of a DG, many catalytic systems still call for the use of non-modular and/or difficult to remove DGs that become static entities. In such a case synthetic value of the C–H activation methodology is clearly reduced. To obviate this serious limitation, the concept of “traceless” DGs emerged recently, enhancing conception of innovative coordinating motifs that are easy to install but also readily cleaved or transformed under mild reaction conditions after the C–H activation step.¹⁰⁸⁷ In this context use of silicone moieties is particularly appealing due to: (1) relative stability and easy access to silicone derivatives; (2) availability of cheap silicone precursors; (3) straightforward Si–X bond cleavage allowing removal of these tethers under mild and often chemoselective protocols, such as the Tamao–Fleming oxidation¹⁰⁸⁸ or the Hiyama coupling.¹⁰⁸⁹ Besides, in intramolecular transformations, if a SiR¹R²H motif is used, this moiety can play a dual role of both DG and reagent.

Following this general concept several research groups entered the field of Si-based DGs in C–H functionalisation.⁷³⁵,¹⁰⁹⁰,¹⁰⁹¹ Already more than one decade ago several research groups questioned the potential of “SiR₂H” to play a double role of a DG to drive the C–H activation event at one specific position and to provide, in an intramolecular fashion, a silicone-based coupling partner. The potential of such reactions holds also a major synthetic value as the newly formed C–Si bonds might be further interconverted into several functionalised motifs.

Following this concept, before 2015 several catalytic systems allowing direct silylation of aromatics and heteroaromatics were reported whereas direct functionalisation of aliphatic substrates remained a less developed field.¹⁰⁹²⁻¹⁰⁹⁴ Besides, design of stereoselective transformations was a challenging goal. Following several pioneering key contributions, Murai and Takai reported in 2015 an improved Rh-based catalytic system for intramolecular silylation of unactivated C(sp³)–H bonds (Scheme 173A).¹⁰⁹⁵ The authors discovered that replacement of the previously employed dppp diphosphine ligand by an axially chiral, structurally well defined SEGPHOS auxiliary in combination with an hydrogen acceptor (such as an olefin) drastically accelerates the desired reaction, enhancing smooth conversion of the starting materials into products at a temperature as low as 50 °C vs. 180 °C previously requested. Importantly, use of a chiral ligand and milder reaction conditions permitted a stereoselective outcome of this transformation, however only moderate chiral induction was observed (ee up to 40% was reached using the BINAP ligand). Highly enantio-selective silylation of aliphatic substrates was achieved two years later, in 2017. Hartwig *et al*. discovered that switching from Rh–diphosphine catalyst towards an Ir complex bearing a chiral N,N-donor ligand, such as indane-fused oxazoline, clearly improved this challenging C–H activation reaction that now delivers the silylated compounds in high yields and good enantio-selectivities (ee of approx. 90%) (Scheme 173B).¹⁰⁹⁶ Importantly, the newly generated stereoenriched dihydrobenzosiloles
<figure><img src="image_350.png" /></figure>

<figure><img src="image_351.png" /><figcaption>Scheme 173 Silanes as DGs (intramolecular silylation).</figcaption></figure>

(accessible also on gram scale using a largely decreased catalyst loading) are a unique platform to access an array of chiral molecules *via* chemoselective functionalisation of each C-Si bond.

In addition to stereoselective silylation of unactivated C(sp³)-H bonds, several research groups applied the same concept to synthesize chiral molecules *via* functionalisation of C(sp²)-H bonds of prochiral substrates. The pioneering key contribution by Takai and Kuninubu provided access to original enantiomerically pure spirosilabifluorenes *via* two-fold intramolecular silylation.¹⁰⁹⁷ Expanding this methodology, He reported in 2017 a tandem transformation involving C-H desymmetrizing silylation, followed by intermolecular dehydrogenative silylation (Scheme 173C). Such a transformation, catalysed by a Rh-SEGPHOS complex, allows the interconversion of silacyclobutanes into chiral tetraorganosilicons in moderate to good yields and ees between 65 and 93%.¹⁰⁹⁸

Intramolecular stereoselective C(sp²)-H silylation was also astutely used to access planar chiral benzosiloloferrocenes. The groups of Shibata,¹⁰⁹⁹ Murai/Takai¹¹⁰⁰ and He¹¹⁰¹ reported simultaneously but independently intramolecular silylation of metallocenes. Although when employing the first protocol (Scheme 173D) based on a Rh-catalyst and a chiral diene ligand only moderate chiral induction was observed (up to 86% ee),¹⁰⁹⁹ clearly more appealing ees were obtained in presence of Rh-SEGPHOS catalyst (Scheme 173E).¹¹⁰⁰,¹¹⁰¹ Notably, using the second protocol either reaction temperature could be decreased to 40 °C or significantly lower catalyst loading (2.5 equiv.) was employed.

An alternative approach to push even further the synthetic value of the above described methodology consists of installing the silicone moiety as a temporary tether such as a silyl ether group.

This elegant concept, developed in 2010 by Hartwig, implies *in situ* generation of silyl ethers from ketones or aldehydes *via* Ir-catalysed hydrosilylation, followed by direct intramolecular silylation catalysed by a second Ir-catalyst.¹¹⁰² Importantly, thus accessed scaffolds may now be chemoselectively converted into an array of functionalised molecules *via* selective O-Si or C-Si cleavage reactions using standard protocols such as Tamao-Fleming oxidation or Hiyama coupling. A further key step forward in this field consisted of designing a related stereo-selective transformation. Following this target, Hartwig described in 2015 a (hydrido)silyl-directed desymmetrisation reaction of benzophenone derived substrates.¹¹⁰³,¹¹⁰⁴ The authors discovered that while conserving the Ir-catalyst for the first step, *i.e.* ketone hydrosilylation, high reactivity and excellent chiral induction for the C-Si bond formation are reached in presence of Rh(i)-catalyst coordinated diphosphine ligand, in particular catASium or Walphos-derivatives and non-bornene as a hydrogen acceptor. The reaction takes place under mild reaction conditions (50 °C). Accordingly, a large panel of highly enantioenriched diarylmethanols is accessed. Noteworthy, when dissymmetric enantiomerically pure diaryketones are used as substrates high catalyst-controlled site-selectivity is observed. Very recently, the same research group designed an alternative catalytic system based on Ir(i) bearing an *N*,*N*-bidentate quinoline-oxazoline ligand.¹¹⁰⁵ The reaction is equally efficient and enantio-selective as the Rh-based protocol but even lower reaction temperature, *i.e.* 35 °C, could be used. In addition, kinetic resolution took place when submitting racemic silyl ethers to the standard reaction protocol, affording the silylated products with high selectivity (Scheme 174).

In addition to direct C(sp²)-H activation under mild reaction conditions, the concept of intramolecular silylation using a silyl ether moiety could be expanded to the functionalisation of simple aliphatic substrates. Such a transformation holds great promise for synthetic chemists as, considering high modularity of both C-Si and O-Si bonds, new synthetic routes towards diols could hence be envisioned. Following this inspiration Hartwig described in his pioneering work in 2014 hydroxy-directed silylation of secondary C(sp³)-H bonds (Scheme 175A).¹¹⁰⁶

<figure><img src="image_352.png" /><figcaption>Scheme 174 *In situ* formed silyl ethers as DGs (C(sp²)-H intramolecular silylation).</figcaption></figure>
<figure><img src="image_353.png" /></figure>

<figure><img src="image_354.png" /><figcaption>Scheme 175 In situ formed silyl ethers as DGs (C(sp³)–H intramolecular silylation).</figcaption></figure>

When a (hydrido)silyl ether (obtained *via* dehydrogenative coupling between a ketone and diethylsilane) is reacted with the Ir-catalyst supported by phenanthroline type ligand, formation of a 6-membered metallacyclic intermediate operates furnishing 5-membered oxasilolane. Finally, smooth oxidation of the newly generated oxasilolanes using TBHP, in combination with CsOH monohydrate and *tert*-butyl ammonium delivers the expected 1,3 diols. Accordingly, the overall transformation allows conversion of aliphatic ketones into 1,3-diols, fully validating the initial hypothesis of the project. Very recently, design of protocols devoted to a synthesis of 1,2 and 1,4-diols spread the outlook of this methodology further. The regioselectivity switch towards more distal, δ-position was possible by means of catalyst design (Scheme 175B).¹¹⁰⁷ Hartwig discovered, in accordance with his previous work, that while using a Rh-catalyst with previously employed phenanthroline or common diphosphine ligands, such as BINAP or

SEGPHOS, silylation occurs selectivity at 3-position. However, quite unexpectedly, addition of large bite angle Xanthpos ligand drastically altered the outcome of this C–H activation, directing the metallation event at 4-position and thus providing 6-membered oxasilolanes in good yields (around 70%). Accordingly, a 3-step procedure for direct conversion of aliphatic alcohols into 1,4-diols was devised.

In contrast, 1,2-selectivity for this direct silylation reaction was possible thanks to the substrate designed (Scheme 175C).¹¹⁰⁸ Accordingly, an easy to install and readily cleavable linker needs to be placed between an oxygen atom of a substrate and the silyl-moiety. Detailed investigations revealed that perfluoroacetal is perfectly suited to deliver the silyl DG in close proximity to the targeted δ-position. Accordingly, a reaction sequence including hydrosilylation of a perfluoroalkyl ester, followed by silylation of a C(sp³)–H bond and final Tamao–Fleming oxidation at the C–Si bond provides 1,2-diols. The protocol requires use of the Ir-catalysts in two initial steps and harsher reaction conditions are necessary to favour this short-distance functionalisation.

An additional challenge to be addressed in this field concerns stereoselectivity issues and development of an enantio-selective directed silylation. The first step towards this goal was achieved in 2016 when the same group disclosed enantio-selective synthesis of cyclopropane derivatives (Scheme 175D).¹¹⁰⁹ The authors hypothesized that the hydrosilyl ether of 1-aryl-cyclopropylmethanol may be an effective substrate under Rh(i)-based protocol. Despite significant steric hindrance, the expected C–Si coupling occurs at the more activated (presence of a phenyl substituent), tertiary carbon. Interestingly, the previously employed SEGPHOS type ligand outcompeted other axially chiral diphosphines such as BINAP, MeOBIPHEP and GARPHOS derivatives, delivering the expected cyclised products with high optical purity of approx. 90% yet in moderate to good yields. The reaction well tolerates an array of aromatic substituents on the cyclopropane substrate. Besides, oxidation of the oxasilolanes occurred with no erosion of the enantiopurity.

In his seminal work in 2008 Hartwig reported for the first time the Ir-catalysed *ortho* borylation of aryldimethylsilanes (Scheme 176A).¹¹¹⁰ In this case, the Si moiety acts as a traditional DG, rather than a silylating agent, as in the previous cases in this section (*i.e.* the Si only coordinates to the metal, rather than being involved in a Si–C bond). The desired C–H functionalisation required Ir(i)–dtbpy complex and B₂pin₂ supplemented with a catalytic amount of HBpin, to provide the expected *ortho*-functionalised compounds. This methodology could be further expanded to silyl phenol-ethers. A sequential transformation thus permits direct conversion of phenols into 2-phenyl trifluoroborate salts (Scheme 176A, box). Besides, the structurally related 5-membered metallacyclic intermediates may also be generated when C–H activation occurs at the benzylic position of 2-alkylarylsilanes.¹¹¹¹

In addition, following the same concept, original 7-selective functionalisation of indoles was performed (Scheme 176A). In this example the silyl DG was installed *in situ* on the N-atom and drives the metallation event at C7, suppressing the inherent C2 reactivity of such substrates.¹¹¹² Accordingly, simple indoles
<figure><img src="image_355.png" /></figure>

<figure><img src="image_356.png" /><figcaption>Scheme 176 Silane-directed borylation reactions.</figcaption></figure>

were readily converted into 7-Bpin substituted heterocycles using $[Ir(cod)Cl]_2$ catalyst in combination with dtbpy ligand.

A further major challenge in this field was taken up in 2016, when Hartwig devised a slightly modified catalytic system, sufficiently active to promote directed functionalisation of simple aliphatic substrates (Scheme 176B).¹¹¹³ The strategy proposed by the authors consisted in (1) straightforward installation on the Si-based DG on an olefin *via* alkene hydrosilylation generating highly stable compounds; (2) hydrosilyl-directed Ir-catalysed direct borylation; (3) diversification of the accessed molecules *via* chemoselective cleavage and conversion of the C-Si and C-B bonds. The optimization study revealed that efficient and reproducible C-B coupling occurs when using an isolated Ir-complex bearing a mesityl-substituted phenanthroline ligand in combination with highly reactive Et₃SiBpin boron source, in isooctane and at 80 °C. *Via* this protocol, selective monoborylation occurs selectively at a secondary γ-position generating trans-adducts with high stereoselectivity. Noteworthy, in case of cyclic substrates, geometrical considerations (size of the metallacyclic intermediate formed) override steric issues, as the functionalisation of a secondary carbon at γ-position is favoured over borylation of a primary δ-position.

In 2017, the first example of an enantioselective silyl-directed C-B coupling was disclosed. Drawing inspiration from their previous work on desymmetrization silylation of diarylketones, Hartwig and Shi developed directed borylation of diarylmethylsilanes (Scheme 176C).¹¹¹⁴ As Ir-catalysed borylation are generally milder, the intensive efforts were focused on designing a chiral ligand able to promote this challenging transformation at room temperature. Although enantiopure ligands such as BINAP, various bisoxazolines and bipyridine

derivatives failed, the desired coupling took place in presence of a quinolyl oxazoline auxiliary. Further fine-tuning of the ligand structure led to the design of the optimal chiral inductor, allowing the desired C-H activation to occur smoothly even at 0 °C and with high chiral induction. As previously mentioned, this catalytic system is robust and the reaction performed at 5 mmol scale delivered the product in comparable yield and ee, albeit significantly decreased catalyst loading (0.75% vs. 3% used for small scale reactions). Besides, the enantioenriched borylated products could be further diversified *via* selective FG interconversions.

A complementary application of silyl moieties in the context of C-H activation consists in using these motifs as temporary tethers allowing installation of proper strongly coordinating DGs, like heteroaromatics, or a remote nitrile function. This type of DG is presented in Section 10.2. Alternatively, Si-atom may also be used as linker connecting two moieties of a molecule for an intramolecular coupling initiated by oxidative addition of Pd into a C-X bond.¹¹¹⁵,¹¹¹⁶ Finally, inspired from the recent regain of interest in using weakly coordinating DGs, concerns use of silanols and effective precoordination of a metal *via* hydroxy motif.

Silanols have established themselves as appealing weakly coordinating DGs at the beginning of this decade,¹¹¹⁷ mainly based on key contributions by Gevorgyan¹¹¹⁸,¹¹¹⁹ and Ge.¹¹²⁰ Accordingly, an OH group directly installed on an aromatic ring allowed efficient and selective Pd-catalysed *ortho*-alkenylation¹¹¹⁸ and oxygenation.¹¹¹⁹ More recently, silanol-directed C-H carboxylation has been used to prepare salicylic acid derivatives (Scheme 177A).¹¹²¹ Indeed, this new methodology implying: (i) conversion of an phenol into silanol, (ii) direct C-C bond formation using CO as a coupling partner and (iii) final deprotection of the OH in presence of TBAF delivers an array of salicylic acids in high yields, almost regardless the substitution pattern of the starting material (an array of FGs is well tolerated).

The potential of silanols has been further expanded by Cui and Xu who astutely tethered a second silicone unit on this DG (a siloxane moiety), thus targeting intramolecular C-H silylation (Scheme 177B).¹¹²² Rewardingly, using an Ir-based protocol in combination with phenanthroline ligand they established a general protocol for direct C-Si bond formation. Notably, the reaction is compatible not only with arylsilanols,

<figure><img src="image_357.png" /><figcaption>Scheme 177 Silanols and siloxanes as DGs.</figcaption></figure>
<figure><img src="image_358.png" /></figure>

but also benzylsilanols and aryloxysilanols are efficient substrates. The design of the substrates allows installation of different substituents on the distinct silicone atoms hence chemoselective cleavage of C–Si and C–O bond occurs, ensuring remarkable post-modularity of the unsymmetrical cyclic siloxanes obtained.

## 16.7. OH- and OR-Based DGs

Although initially it was commonly recognized that metal-catalysed C–H functionalisation reactions require strongly coordinating DGs to enhance formation of stable metallacyclic intermediates, key contributions by Yu³³,²⁴⁸ and others¹¹²³ clearly showed the potential of weakly coordinating DGs. This discovery encouraged the scientific community to explore the potential of many different “naturally occurring” DGs, amongst which the hydroxy group has attracted particular attention.¹¹²⁴ Indeed, between 2010 and 2015 many innovative direct C–H activation reactions have been reported, relating mainly to the functionalisation of phenols, benzylic alcohols or biarylphenols and they are already elegantly summarized elsewhere.¹⁷ In 2016 Cheng *et al.* illustrated that OH-directed C–H activation may also be achieved when using CoCp\*-catalyst (Scheme 178A).¹¹²⁵ The authors astutely used the hydroxy-motif to enhance direct metallation of a vinylic C–H bond, located *ortho* to the DG and subsequent reaction with an allene, acting as a one-carbon coupling partner allows [5+1] annulation to occur delivering 2H-chromenes. The reaction occurs under very mild reaction conditions, delivering the targeted heterocyclic products in

moderate to good yields. High regioselectivity is attain when using a simple, mono-substituted allene, however mixtures of products were generally formed when structurally more complex coupling partners were employed.

Alternatively, the OH motif was also used as thether to install temporarily a second, strongly coordinating DG. In this context many examples of O-Py and O-heteroaromatic moieties have been disclosed and these examples are already shown in Section 15.3. Recently, an interesting example of *in situ* conversion of the OH moiety into a potent DG was disclosed by Maleczka, Singleton and Smith (Scheme 178B).¹¹²⁶ These research groups reported an *ortho*-borylation of phenols, a reaction elegantly complementing other C–H borylation protocols, for which regioselectivity is usually imposed by steric factors. The unusual selectivity of this reactions results from *in situ* borylation of the hydroxy group and subsequent electrostatic interactions between the OBpin motif and the bipyridine ligand coordinating the Ir-complex driving the metal catalyst at the *ortho* position. While excellent *ortho*-selectivity was observed for the functionalisation of *para*-substituted phenols (*para*-substituent larger than CN or F) with B₂pin₂, use of less sterically demanding B₂eg₂ was required to induce total regioselectivity for arenes not biased by *para*-substitution.

Although the quite widespread use of the hydroxy motif as DG, ethers are only rarely employed to precoordinate a catalyst and drive the metallation event.¹¹²⁷,¹¹²⁸ Recently, Echavarren addressed this challenge by designing a RhCp\*-based catalytic system promoting highly efficient *ortho*-alkynylation of benzyl ethers (Scheme 178C).¹¹²⁹ When TIPS-protected bromoacetylene is used as a coupling partner, a panel of benzylethers is available, as the reaction well tolerates several substituents on the aromatic ring (mainly halogens). However, for *para*-substituted substrates mono-*vs.* difunctionalisation issues arise. Unfortunately, the reaction is efficient only for methyl-benzylethers. It is important to highlight that other weakly coordinating DGs, such as sulfoxides, thioethers, sulfones, dialkylamines, sulfones, etc also perform well under a very similar protocol.

Another interesting example for the use of a methoxy-group as coordinating motif was disclosed by Hou. The authors devised a catalytic system based on half-sandwich rare earth catalysts to enhance unusual simultaneous chain-growth polymerization (by continuous C=C insertion) and step-growth polymerization (C-H addition of anisole units to vinyl groups).¹¹³⁰ The same catalyst was further exploited in a copolymerization process between 1,4-dimethoxybenzene and 1,4-divinylbenzene or norbornadiene, delivering original polymeric materials (Scheme 178D).¹¹³¹

## 16.8. Amine-based DGs

Amines occupy a particular position in the field of C–H activation. This motif was amongst the first ones to be explored as a DG while studying stoichiometric cyclometallation reactions.¹¹³² Not surprisingly, dialkyl amines have thus been used with some success in catalytic reactions.¹⁷ In recent years, dialkylamine DGs were astutely used to enhance direct functionalisation of the ferrocene scaffold. In presence of Pd-based catalysts in

<figure><img src="image_359.png" /><figcaption>Scheme 178 Hydroxy- and methoxy-directed transformations.</figcaption></figure>
combination with a chiral ligand, powerful protocols for stereo-selective arylation, alkynylation/dehydrogenative annulation and olefination have been designed. These works were already elegantly summarized elsewhere¹¹³³⁻¹¹³⁵ and will not be detailed in this review.

Aside from ferrocene chemistry, the amine moiety is also a handy tool to promote regioselective, direct diversification of biaryl scaffolds. Indeed, much attention has been focused on 2'-functionalisation of biaryl-2-amines as, likewise biarylsulfoxide substrates for example, coordination of a metal catalyst by the N-atom generates a 6-membered metallacyclic intermediate. This general approach was used for both intramolecular couplings (synthesis of carbazoles for instance)¹¹³⁶⁻¹¹³⁹ and intermolecular transformations, like domino olefination/cyclisation,¹¹⁴⁰,¹¹⁴¹ direct carbonylation delivering heterocyclic compounds¹¹⁴²,¹¹⁴³ or C-H arylation.¹¹⁴⁴,¹¹⁴⁵

In 2015 Wang and Ji spread the portfolio of such biaryl functionalisations by developing 2'-selective acylation (Scheme 179).¹¹⁴⁶ The optimized protocol allows selective mono-acylation of the Ts-protected biaryl-2-amines, under Pd-based catalysis and in presence of aldehydes as coupling partners and peroxide oxidants (TBHP). The reaction well tolerates several different FGs, both electron-withdrawing and electron-donating, on the biaryl substrates and a large panel of aldehydes is compatible with this protocol. Besides, in presence of a larger excess of the coupling partner and replacing the AcOH additive by PivOH, difunctionalisation is favoured.

Amine DGs are also a unique handle for one-step carbazole synthesis.¹¹³⁶⁻¹¹³⁹,¹¹⁴⁷⁻¹¹⁴⁹ Biaryls bearing an NH₂-motif in the *ortho* position are indeed potent substrates for Ir-catalysed C–H activation followed by intramolecular C–N bond formation, delivering the heterocyclic product (Scheme 179B).¹¹⁵⁰ This generally high-yielding protocol is compatible with an array of either electron-rich or electron-poor substrates, straightforwardly furnishing dissymmetric carbazoles.

A conceptually different strategy towards amine-directed C–H activation has been developed over the last three years by Gaunt and coworkers. This group recognized a lack of precursors in direct functionalisation of aliphatic substrates, and in particular they were interested in devising transformations showing complementary regioselectivity with respect to commonly observed γ-C–H direct couplings. Following this target, they discovered that aliphatic amines may undergo metallation at unusual β-position (*via* formation of an unprecedented 4-membered metallacycle intermediate) and in presence of an

oxidant, such as PIDA, aziridine-type products are generated (Scheme 180A).¹¹⁵¹ This unusual reaction is possible thanks to the steric hindrance of the amine that prevents formation of inactive bis(amine)–Pd complexes but consequently this transformation is mainly limited to structurally complex secondary cyclic amines, typically aminolactone congeners. Importantly, aziridine ring opening can be performed efficiently on the isolated products, delivering a panel of complex amine congeners, including quaternary amino acids. Moreover replacement of the hypervalent iodine oxidant with carbon monoxide results in a clean carbonylation reaction delivering β-lactams, albeit higher reaction temperatures are necessary to obtain synthetically useful yields (120 °C vs. 70–80 °C required for the aziridation process). Following this pioneering work, in 2017 the same research group reported a stereoselective version of this transformation. High chiral induction was achieved using BINOL-derived phosphoric acid ligands.¹¹⁵² Another major step forward in this field was achieved by modifying the oxidation system.¹¹⁵³ Indeed, replacement of the previously used PIDA-type hypervalent iodine by benziodoxole tosylate in combination with AgOAc alters regioselectivity of the transformation, yet favouring azetidine formation (Scheme 180B). This regioselectivity switch is attributed to the influence of the OTs group. Formation of a 4-membered product is believed to occur *via* a two-step process including initial γ-tosylation followed by internal displacement of OTs by the amine moiety. The broad range of original azetidine compounds could hence be accessed and derivatization of these scaffolds delivers nitrogen-containing original compounds such as diols, amides, hydroxyl acids and hemiaminals.

Following this seminal work, Gaunt expanded also the field of amine-directed C(sp³)–H carbonylation reactions (Scheme 180C). Firstly, a general catalytic system promoting highly selective

<figure><img src="image_360.png" /><figcaption>Scheme 180 Functionalisation of C-sp³ centres directed by aliphatic amines.</figcaption></figure>

<figure><img src="image_361.png" /><figcaption>Scheme 179 Aromatic amines as DGs.</figcaption></figure>

<figure><img src="image_362.png" /></figure>
<figure><img src="image_363.png" /></figure>

β-functionalisation of primary carbons (even in presence of protons at γ-position) was devised thanks to the addition of hindered carboxylic acid derivatives in combination with a quinone oxidant.¹¹⁵⁴ This modified protocol shows exceptional tolerance towards an array of secondary aliphatic amines so that a large panel of 4-membered amides was formed in good to excellent yields, including few biologically active scaffolds. Few months later it was discovered that addition of an external diphosphine ligand and replacement of the Cu-based oxidant by Ag salts generates a much more reactive catalytic system, prompt now to activate methylene β-C–H bonds of aliphatic amines.¹¹⁵⁵ The reaction is highly regioselective and compatible with an ample panel of substrates, bearing not only electron-donating and electron-withdrawing substituents, but also structurally complex motifs such as heterocycles. The reaction proceeds smoothly even when sterically congested α-tertiary amines are selected as starting materials.¹¹⁵⁶ Accordingly, a large panel of β-lactams may now be accessed from simple, non-protected and non-prefunctionalised aliphatic amines. In addition to the carbonylation reactions, Gaunt and coworkers described in 2017 alkenylation reactions (Scheme 180D). This formal dehydrogenative C–C coupling is assisted by an amino acid ligand (under this protocol the metallation step is reversible yet promoting and facilitating the targeted reactivity) and hence the C–H coupling followed by the annulation step leads to formation of complex heterocyclic structures.¹¹⁵⁷ Also a closely related arylation using arylboronic esters as coupling partners takes place under ligand-assistance (Scheme 180E).¹¹⁵⁸ To further illustrate the synthetic value and versatility of the above-presented projects, Gaunt proposed a new retrosynthetic route towards K-252 (stauroeporinone) implying two amine-directed C–H activation events, i.e. Cu-catalysed ortho-arylation of dibenzyl para-toluidinearyl iodane, followed by aromatic carbonylation/intramolecular C–C bond formation.¹¹⁵⁹

In addition to this elegant work on amine-free directed C–H activation, several examples of C–H transformations based on the use of *N*-protected DGs have been reported. In particular, nosyl-protected phenylethylamine, benzylamines and 2-aryl aniline derivatives could be successfully used in Catellani-inspired¹¹⁶⁰ *meta*-selective arylation (Scheme 181A).¹¹⁶¹ The catalytic system combining Pd-catalyst and a pyridine-derived ligand promotes *meta*-functionalisation thanks to the participation of norbornene in a catalytic cycle. The scope of this transformation is rather remarkable, as not only three substrate scaffolds are effective, but also a diversity of both electron-rich and electron-poor arylodanes may be used, although the products are generally isolated in rather modest to good yields.

Quaternary ammonium salts have also met growing interest in the context of direct C–H functionalisation. The cationic nature of this moiety renders it particularly appealing in devising alternative, supramolecular strategies for C–H activation. In 2016 Phipps focused on direct C–B coupling catalysed by Ir-bipyridine type complex (Scheme 181B).¹¹⁶² This research group stipulated that a quaternary ammonium moiety present on a substrate should participate in ion-pairing interactions with a modified bipyridine ligand bearing an anionic substituent. Such DG–ligand interactions should thus direct the Ir-catalyst

to a more distal position, yet allowing remote C–H activation. Rewardingly, it was found that an Ir-catalyst coordinated by a bipyridine ligand with an appended sulfonate tether participates in strong ionic interactions with a quaternized benzylamine DG, consequently validating the initial hypothesis. This catalytic system allowed formation of the expected *meta*-borylated aromatics in high yields and generally high regioselectivity. The reaction is particularly efficient if *ortho*-substituted substrates are used and for unsubstituted precursors double borylation might be expected. In addition, as the ammonium moiety can be further valorized *via* Pd-catalysed C–C couplings, the newly obtained products are highly modular. The concept of ion pair-directed C–H functionalisation is also effective for *meta*-selective borylation of benzylamine, phenylethylamine and phenylpropylamine-derived amides.¹¹⁶³

An alternative approach based on supramolecular recognition between a cationic amine-type DG and a catalyst was disclosed recently by Olivo, Di Stefano and Costas (Scheme 181C). In order to achieve remote and site-selective functionalisation of aliphatic chains, a bioinspired catalyst, *i.e.* Mn complex equipped with 18-benzocrown-6 ether receptors was designed. Reversible pre-association of the crown ether with the protonated aliphatic primary amines approaches C8 and C9 positions of the aliphatic chain to the Mn-atom, yet enhancing regioselective oxidation. Remarkably, the length of the aliphatic chain does not impact the reaction outcome. This conceptually unprecedented transformation is, for the moment, limited to simple, non-substituted substrates and the regioselectivity level still needs improvement.¹¹⁶⁴

Finally we would like to highlight a recent contribution by Suzuki and Yamashita who designed original aluminabenzene-Rh and Ir complexes. Catalytic activity of this new Ir-based complex was evaluated studying C–H borylation of aliphatic tertiary amines and *N*,*N*-diethylbenzylamine.¹¹⁶⁵

## 16.9. Nitrone as DGs

In 2013, the panel of coordinating motifs employed as DG was further expanded, as a potential of nitrones to precoordinate a metal catalyst yet directing its insertion into a particular C–H

<figure><img src="image_364.png" /></figure>

<figure><img src="image_365.png" /></figure>

<figure><img src="image_366.png" /><figcaption>Scheme 181 Amine-directed remote functionalisations.</figcaption></figure>
<figure><img src="image_367.png" /><figcaption>Scheme 182 Nitrone-based DGs.</figcaption></figure>

bond was evidenced by Li.¹¹⁶⁶ Following this pioneering report, several examples of nitrone-directed couplings with alkenes, alkynes, diazo compounds and arenes were reported till 2015. More recently, several research groups astutely used this coordinating motif to build up heterocyclic compounds, and in particular indole derivatives. In 2015 Liu and Lu discovered that nitrone may play the role of an oxidizing DG in RhCp*-catalysed direct coupling with alkynes (Scheme 182A).¹¹⁶⁷ This redox-neutral C–H annulation occurs in absence of an external oxidant affording an array of 2,3-disubstituted indoles with moderate to high yields. Substituents such as CN, F, Br or OMe are well tolerated on the aromatic ring and both aryl–aryl and alkyl–aryl disubstituted alkynes are effective. Targeting more

reliable and industrially appealing transformations, Ackermann and collaborators designed a closely related Co-catalysed transformation (Scheme 182B).¹¹⁶⁸ This redox-neutral coupling between nitrones and alkynes, proceeding via C–H/N–O functionalisation proceeds smoothly when a cationic CoCp*-catalyst is used in combination with either sodium acetate or an amino acid ligand. The reaction displays an excellent site- and regio-selectivity with unsymmetrical nitrones and alkynes, shows outstanding FG tolerance and is easily scalable.

Alternatively, indole synthesis may also be achieved using a RhCp*-catalyst in combination with diazo compounds as coupling partners (Scheme 182C).¹¹⁶⁹ In contrast to the previous examples, this transformation requires a substoichiometric amount of Cu(OAc)₂ as
oxidant but the substituent present on the nitrone is conserved in a final product (as C2-substituent of the indole scaffold). Accordingly, this strategy is of particular interest if indoles bearing an aromatic moiety at C2 position and an ester group at C3 are targeted.

In 2018 Li astutely used nitrone DG to construct fused isoxazolidines (Scheme 182D).1170 The corresponding regio- and diastereoselective C–H coupling of nitrones with perfluoroalkyl-olefines delivers rare heterocyclic compounds with three continuous stereogenic centers and features remarkable atom economy. The reaction proceeds under Ru(ii)-based catalysis and, although rather harsh reaction conditions are required (temperature of 120 °C) it is compatible with an array of functional motifs, delivering the desired products in moderate to good yields.

A traceless character of the nitrone moiety is an additional key advantage, of particular importance for the C–H activation field. This purpose was elegantly illustrated by Li when conceiving a new synthetic route towards 1-naphthols, based on RhCp\*-catalysed coupling of *N*-tert-butyl nitrones with cyclopropenones (Scheme 182E).1171 In this original reaction strained cyclopropenones are used as C3-type coupling partners and the catalytic cycle is believed to be completed by *in situ* removal of the nitrone moiety delivering 2,3-disubstituted naphthols. Besides, an alternative scenario is operative for *ortho*-substituted nitrones; a C–H acylation step is followed by [3+2] dipolar cyclo addition pathway, affording complex bicyclic structures. Noteworthy, the reaction occurs under oxidant free conditions and compounds otherwise difficult to access may now be constructed efficiently and straightforwardly. Naphthols may also be obtained *via* direct coupling between α-carbonyl nitrones and alkynes (Scheme 182H).1172 This redox-neutral RhCp\*-catalysed transformation also implies *in situ* cleavage of the *tert*-butyl nitrone moiety. However, contrary to the previous example, symmetric 3,4-disubstituted naphthols are generated. It should be noted however that in this particular case the carbonyl moiety is rather expected to precoordinate the catalyst and direct the metallation event into the *ortho*-position.

In 2017, a nitrone-directed C–H activation protocol was used to construct indenes (Scheme 182F).1173 This reaction implies a direct coupling with internal nitroalkenes and, likewise previous examples, the *N*-tert-butylnitrone moiety is released *via* a Henry-type reaction delivering an ample selection of nitro-functionalised indenes, convertible *via* reduction into the corresponding ketones.

To complement the portfolio of direct functionalisation reactions compatible with nitrone DGs, Li and Wang developed site-selective amidation (Scheme 182G).1174 This RhCp\*-catalysed transformation implies use of 1,4,2-dioxazol-5-ones as coupling partners and the DG decomposes at the end of the reaction releasing *ortho*-functionalised aldehydes. The optimized protocol allows installation of various amide moieties and several functionalities are also tolerated on the aromatic backbone furnishing the desired products in rather high yields.

## 17. Conclusions and outlook

It can be seen that the field of DG assisted catalytic C–H functionalisation has come a long way since its beginnings

more than two decades ago. Most of the FGs you can think of have been used in one or the other example as DG in one or more transformation. This allows making the statement that most of the compounds which occur in a multistep sequence carry a FG which can be exploited as DG in C–H functionalisation chemistry, at least in principle. The question remains why the methodology is still not explored more frequently in complex synthesis or in R&D processes. The following critical outlook discusses the shortcomings of C–H functionalisation, which need to be addressed in the future.

C–H functionalisation chemistry is very often said to be the future technology replacing cross coupling reactions because of its inherent potential for greenness in comparison to the latter. As green chemistry is a major concern for industry, considerations related to its future application in process chemistry need to be made. Nowadays cross coupling reactions can be performed in a variety of (green) solvents, under air, with catalyst loadings lower than 0.5%, catalytic amounts of ligands and stoichiometric bases. These reactions are now routinely used in chemical development and production of fine chemicals. C–H functionalisation, instead, still requires very often specific cocktails of a number of compounds (as discussed in the introduction), often under inert atmosphere, and additionally necessitate installation and cleavage of a DG, unless already present in the starting materials or found in the target product. The demonstration of the cleavage of a DG was specifically highlighted throughout this review since in most examples DG cleavage has not been investigated. Consequently, progress in the area of cleavable or traceless DGs is highly desirable in the near future.

Apart from these issues, less obvious limitations appear evident from the analysis of the literature in the field of C–H functionalisation. For example, a large number of protocols make use of toxic solvents, in particular DCE and other halogenated solvents are widely used. Although other solvents might be used as replacements in some cases, these are normally not thoroughly investigated, and often result in much lower yields. The efficiency of the reaction in more sustainable solvents is therefore not guaranteed. In a typical process the solvent accounts for 50–60% of the entire mass,1175 and the use of greener media is therefore of major importance in chemical development programs, although still less studied in academia. In case a C–H functionalisation protocol would be of interest to industry, the process chemists will have to spend considerable efforts in finding a valid replacement solvent before even considering using such a protocol. While investigations on green solvents are nowadays common for many type of reactions, this is not yet the practice for C–H functionalisations. Nonetheless, several examples were reported recently of functionalisations in alcoholic media, and some in alkyl acetates. Both these classes of compounds are listed as preferred solvents in solvent guides.1176,1177 In particular, the latter type of solvents has been used in a variety of transition metal-catalysed reactions,908,1178–1182 and EtOAc has for instance been demonstrated by Chang to be an effective replacement of DCE in a larger scale (200 mmol) C–H amidation protocol.751 This will hopefully inspire further research in this direction.
<figure><img src="image_368.png" /></figure>

Regarding the metal catalysts which dominate the field, we still see Pd, Rh, and Ru as the three major players. In a society ever more aware of environmental issues, it is highly desirable to substitute these metals for more abundant ones. Consequently, the number of examples using Fe, Co, Ni, Cu, and Mn are increasing. Not only are these metals less toxic (with the exception of Co, see below), but also their extraction from soil is much simpler and requires less energy or less hazardous chemicals. Hence, as in all fields of metal catalysis, the quest for switching from precious metals to more abundant ones is ongoing and one of the big driving forces of innovation.

Sticking to the issue of the catalyst another important aspect is the often high catalyst loading necessary for C–H functionalisation reactions. Although many protocols utilise lower amounts, it is not uncommon to find a loading of 10% [total metal] in Pd, Rh, Ru or Ir catalysed reactions. While such loadings are still acceptable when using base metals, efforts should be devoted to lowering of these amounts when using noble metals. Aside from matters of cost, the accepted residual levels in *e.g.* formulated drugs, based on permitted daily exposure (PDE), are typically higher for base metals (*e.g.* Cu and Fe) than for noble metals.¹¹⁸³ On the other hand, although base metal catalysis is developing quickly in this field, in many cases up to 20% of the metal is used, and several protocols are also reported making use of stoichiometric amounts of metal (*e.g.* for Cu). Catalyst recycling is not often considered in academic publications, but a few interesting examples of heterogeneous catalysts for C–H functionalisation have been reported, which allow easy catalyst recycling and reuse.¹¹⁸⁴ Research in this direction, involving both heterogeneous and homogeneous catalysts, should be developed further.¹¹⁸⁵ Concerning base metals, a very important note has to be made: base metals are not by definition less toxic. In fact, despite the growing use of Co catalysis in C–H functionalisation, Co is not a low-toxicity metal, and the permitted daily exposure for this metal is actually lower than for noble metals used in catalysis such as Pd, Rh, Ru and Ir.¹¹⁸³

Concerning the regioselectivity of C–H functionalisation reactions, most examples of DGs listed in this review are *ortho*-DGs, with respect to aromatic C–H functionalisation. This has been identified as a shortcoming and several groups have started to address this issue. A handful of *meta*- and *para*-DGs have been reported and this area will without doubt see more examples in the near future.

Other selectivity issues have also been identified. It is true that regioselectivity, for example on an aromatic substrate, is achieved using a DG, but monofunctionalisation is often challenging. Many of the protocols included in this review produce in several cases mixtures of mono and difunctionalised compounds. This is common, for example, in arylation and olefination reactions, while with other functionalities this is less of a problem. In the less selective cases, monofunctionalisation is generally achieved by blocking (substitution) one of the reactive positions, or of a contiguous one (*e.g.* in arenes substituted in the 5 position, the DG in position 1 often selectively promotes functionalisation in position 2 based on steric reasons).

Although this might be considered an acceptable solution in academia, this will be more important to tackle when these protocols are used in the synthesis of specific target molecules, where this specific substitution pattern might not be required/desired. Another strategy to deal with difunctionalisation found in the academic literature is the use of an excess of the DG-equipped substrate to avoid difunctionalisation. Although this might not be a big problem *per se* (as the substrate can be easily recovered), the excess substrate is often the most complex and expensive molecule in the mixture (*e.g.* it contains the DG), and therefore this is also not the ideal solution as efficient separation avoiding column chromatography might be tricky.

Furthermore, in some transformations, the applied coupling partners to date leave significant room for improvements. As an example, arylation reactions are often performed with the use of aryl iodides, which the fine chemical industry typically avoids, while relatively few examples currently involve the use of cheaper, widely available and less wasteful aryl chlorides.

At a more general level, stereoselective transformations for the formation of chiral quaternary centres are still quite limited. Enantioselectivity is here achieved using a chiral ligand, and several examples demonstrate that good to excellent selectivity is possible. The mechanism-guided stereoselective formation of alkenes (*e.g.* after Fujiwara–Moritani reactions or hydro-functionalisation of alkynes) is often not achieved and mediocre *E/Z* ratios are obtained in many cases. As alkenylation is one of the most studied transformations, we believe more emphasis should be put in the development of selective strategies. Similarly, the hydrofunctionalisation of unsymmetrical alkynes usually results in regioisomeric mixtures.

Important advancements are being made concerning the use of aerobic conditions for oxidative couplings. Despite the safety issues related to the use of air/O₂ in a chemical process (especially in development and production scale),¹¹⁸⁶ the use of oxygen results in higher atom economy and cheaper processes, especially in comparison to the use of other (super)stoichiometric Ag and Cu salt oxidants (utterly common for group 8–10 metal catalysis, see also introduction). Sometimes O₂/air is used in combination with Cu salt allowing for their use in catalytic amounts. The variety of reported oxidants is anyway limited.

While a huge variety of C(sp²)–H functionalisation protocols have appeared, C(sp³)–H functionalisation still lags behind, due to higher inherent difficulty in activating these bonds. Nonetheless, important developments have been brought forward by a number of groups, mostly using bidentate amides as DGs. These transformation in many cases require external ligands (such as monoprotected amino acids, MPAA), and conformational restraints (aliphatic rings as substrates or Thorpe–Ingold effect) to be efficient. This field is however very promising, due to the many different compounds potentially obtained *via* this strategy.

It has been stated that many of the most frequently occurring FGs have been explored as DGs in C–H activation chemistry. This offers on the one hand great potential in applications, but on the other hand it also raises questions regarding selectivity, in cases a substrate carries more than one potential DG. Hence, research focused on exploring such substrates and eventually developing
<figure><img src="image_369.png" /></figure>

orthogonal sets of conditions in which first DG1 and then DG2 exhibits its directing potential would be highly interesting. However, such reports are scarce¹⁹²,¹⁰³,¹¹⁸⁷⁻¹¹⁹⁰ and much more work in this direction would be highly desirable, since it would increase the number of cases in which C–H functionalisation could be practically applied.

This very critical discussion is not meant to discourage the use or development of this type of chemistry. Quite the contrary in fact! We hope that by critically analysing the weak points of this technology, research groups around the world would realise where important advancements need to be made, and focus their research not just in developing higher-yielding reactions, changing the metal for catalysis, or developing new reagents/reactants, but also in making these protocols more general, selective, and actually greener and industry-appealing.

List of abbreviations

<table><tr><td>@</td><td>Supported on</td></tr><tr><td>acac</td><td>Acetylacetonate</td></tr><tr><td>Ac<sub>2</sub>O</td><td>Acetic anhydride</td></tr><tr><td>AcOH</td><td>Acetic acid</td></tr><tr><td>AdOH</td><td>Adamantane carboxylic acid</td></tr><tr><td>AIBN</td><td>Azobisisobutyronitrile</td></tr><tr><td>Ala</td><td>Alanine</td></tr><tr><td>ampaphos</td><td>tBu<sub>2</sub>PCH<sub>2</sub>P(o-C<sub>6</sub>H<sub>4</sub>OMe)<sub>2</sub></td></tr><tr><td>APAQ</td><td>Acetylprotected aminoethyl quinolone</td></tr><tr><td>Ar<sub>F</sub></td><td>Pentafluorophenyl</td></tr><tr><td>BADME</td><td>Bis(2-dimethylaminoethyl)ether</td></tr><tr><td>B<sub>2</sub>eg<sub>2</sub></td><td>Bis(ethylene glycolato)diboron</td></tr><tr><td>B<sub>2</sub>pin<sub>2</sub></td><td>Bis(pinacolato)diboron</td></tr><tr><td>BarF<sub>4</sub>- or BARF</td><td>Tetrakis[3,5-bis(trifluoromethyl)-phenyl]borate</td></tr><tr><td>9-BBN</td><td>9-Borabicyclo[3.3.1]nonane</td></tr><tr><td>bipy</td><td>2,2'-Bipyridine</td></tr><tr><td>Boc</td><td>tert-Butoxycarbonyl</td></tr><tr><td>BP</td><td>Benzophenone</td></tr><tr><td>BQ</td><td>1,4-Benzoquinone</td></tr><tr><td>Brij 35</td><td>Poly(oxy-1,2-ethanediyl), α-dodecyl-ω-hydroxy-polymer</td></tr><tr><td>BTP</td><td>2-Bromo-3,3,3-trifluoropropene</td></tr><tr><td>CAN</td><td>Ceric ammonium nitrate</td></tr><tr><td>CDC</td><td>Cross dehydrogenative coupling</td></tr><tr><td>cod</td><td>Cyclooctadiene</td></tr><tr><td>Cp*</td><td>1,2,3,4,5-Pentamethylcyclopentadienyl</td></tr><tr><td>CpE</td><td>Diethyl-2,4,5-trimethylcyclopentadienyl-1,3-dicarboxylate</td></tr><tr><td>m-CPBA</td><td>m-Chloroperbenzoic acid</td></tr><tr><td>CPME</td><td>Cyclopentyl methyl ether</td></tr><tr><td>Cy</td><td>Cyclohexyl</td></tr><tr><td>cymene</td><td>p-Cymene</td></tr><tr><td>cym</td><td>p-Cymene</td></tr><tr><td>DABCO</td><td>1,4-Diazabicyclo[2.2.2]octane</td></tr><tr><td>dba</td><td>Dibenzylideneacetone</td></tr><tr><td>DBE</td><td>Dibutylether</td></tr></table>

DCB 1,2-Dichlorobenzene

2,3-DCB 2,3-Dichlorobutane

DCDMH 1,3-Dichloro-5,5-dimethylhydantoin

DCE Dichloroethane

DCP Dicumyl peroxide

DCM Dichloromethane

dcpm Bis(dicyclohexylphosphine)methane

DG Directing group

DIAD Diisopropyl azodicarboxylate

DIBAL-H Diisobutylaluminium hydride

DIOP O-Isopropyliden-2,3-dihydroxy-1,4-bis(diphenylphosphino)butan

DIPEA N,N-Diisopropylethylamine

dippz 1,2-Bis(diisopropylphosphino)benzene

DMAc or DMA Dimethylacetamide

2,6-DMBQ 2,6-Dimethoxy-1,4-benzoquinone

DME 1,2-Dimethoxyethane

DMF Dimethylformamide

DMI 1,3-Dimethyl-2-imidazolidinone

DMPU 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone

dppb 1,4-Bis(diphenylphosphino)butane

dppe 1,2-Bis(diphenylphosphino)ethane

dppen trans-1,2-Bis(diphenylphosphino)ethene

dr Diastereomeric ratio

drs Diastereomeric ratios

DTBEDA N,N'-Di-tert-butylenediamine

dtbpγ 4,4'-Di-tert-butyl-2,2'-dipyridyl

EBX Ethynyl-1,2-benziodoxol-3(1H)-one

EDG Electron donating group

ee Enantiomeric excess

EWG Electron withdrawing group

FG Functional group

Gly Glycine

HBpin Pinacolborane

hfacac Hexafluoroacetylacetone

HFIP Hexafluoroisopropanol

HODmb 2,2-Dimethylbutyric acid

Ile Isoleucine

IPr-HCl 1,3-Bis(2,6-diisopropylphenyl)-imidazolium chloride

LDA Lithium diisopropylamide

LED Light-emitting diode lamp

Leu Leucine

LiHMDS Lithium bis(trimethylsilyl)amide

Men Menthol-OC(O)

Me<sub>2</sub>-TP 4-(Bis(2-(diphenylphosphanyl)phenyl)-phosphanyl)-N,N-dimethylaniline

Mes Mesitylene

MOF Metal-organic framework

MPS Methyl phenylsulfoximine

MTBE Methyl tert-butyl ether

MS Molecular sieves

o-NBA o-Nitrobenzoic acid

nbd Bicyclo[2.2.1]hepta-2,5-dienyl

(= norbornadiene)
<table><tr><td>Tween20</td><td>Sorbitan, monododecanoate, poly(oxy-1,2-ethanediyl) derivatives</td></tr><tr><td>Val</td><td>Valine</td></tr><tr><td>XPhos</td><td>2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl</td></tr></table>

## Conflicts of interest

There are no conflicts to declare.

## Acknowledgements

This work was supported by an Excellence of Science (EOS) project of the Research Foundation Flanders (FWO) under Grant no. G0H0918N and by INSA Rouen, Rouen University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX-0029) and Région Normandie (Crunch Network). CS is grateful to the University of Antwerp for funding (BOF fellowship). TB and RB thank the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 758710). All authors would like to acknowledge the contribution of the COST action CA15106 (CHAOS – C–H Activation in Organic Synthesis). The authors acknowledge the TU Wien University Library for financial support through its Open Access Funding Program.

## References

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<table><tr><td>NBE</td><td>Norbornene</td></tr><tr><td>NBS</td><td>N-Cyano-N-phenyl-p-toluenesulfonamide</td></tr><tr><td>NCTS</td><td>N-Cyano-N-phenyl-p-toluenesulfonamide</td></tr><tr><td>nep</td><td>Neopentyl glycolato</td></tr><tr><td>NFSI</td><td>N-Fluorobenzenesulfonimide</td></tr><tr><td>NHC</td><td>N-Heterocyclic carbene</td></tr><tr><td>NHPI</td><td>N-Hydroxyphthalimide</td></tr><tr><td>NIS</td><td>N-Iodosuccinimide</td></tr><tr><td>NMO</td><td>N-Methylmorpholine-N-oxide</td></tr><tr><td>NMP</td><td>N-Methyl-2-pyrrolidone</td></tr><tr><td>Nphth</td><td>Phthalimide</td></tr><tr><td>NXS</td><td>N-Halosuccinimide (X = halogen)</td></tr><tr><td>ODCB</td><td>1,2-Dichlorobenzene</td></tr><tr><td>o-PBA</td><td>o-Phenylbenzoic acid</td></tr><tr><td>OTf</td><td>Trifluoromethanesulfonate</td></tr><tr><td>PCC</td><td>Pyridinium chlorochromate</td></tr><tr><td>PE</td><td>2-(2-Pyridyl)ethylamine</td></tr><tr><td>PEG</td><td>Poly ethylene glycol</td></tr><tr><td>PEPPSI-IPr</td><td>[1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride</td></tr><tr><td>1,10-phen or phen</td><td>1,10-Phenanthroline</td></tr><tr><td>Phe</td><td>Phenylalanine</td></tr><tr><td>PIDA</td><td>Phenyliodine diacetate</td></tr><tr><td>pin</td><td>Pinacolato</td></tr><tr><td>PivOH</td><td>Pivalic acid</td></tr><tr><td>PM</td><td>2-(Aminomethyl)pyridine</td></tr><tr><td>PTSA</td><td>p-Toluenesulphonic acid</td></tr><tr><td>PyO</td><td>Pyridyl-N-oxide</td></tr><tr><td>rt</td><td>Room temperature</td></tr><tr><td>SDS</td><td>Sodium dodecylsulfate</td></tr><tr><td>SIXyl·HCl</td><td>Bis(2,6-dimethylphenyl)imidazolinium chloride</td></tr><tr><td>SPGS-550-M</td><td>β-Sitosterol methoxypolyethyleneglycol succinate</td></tr><tr><td>TAM</td><td>Triazolyldimethyl</td></tr><tr><td>tAmOH</td><td>tert-Amylalcohol</td></tr><tr><td>TBAA or TBAOAc</td><td>Tetrabutylammonium acetate</td></tr><tr><td>TBAB</td><td>Tetrabutylammonium bromide</td></tr><tr><td>TBAF</td><td>Tetra-n-butylammonium fluoride</td></tr><tr><td>TBAI</td><td>Tetrabutylammonium iodide</td></tr><tr><td>TBHP</td><td>tert-Butylhydroperoxyde</td></tr><tr><td>TBPB</td><td>tert-Butyl peroxybenzoate</td></tr><tr><td>TBS</td><td>tert-Butyldimethylsilyl</td></tr><tr><td>TCC</td><td>Trichloroisocyanuric acid</td></tr><tr><td>TCP</td><td>1,2,3-Trichloropropane</td></tr><tr><td>TEMPO</td><td>(2,2,6,6-Tetramethylpiperidin-1-yl)oxyl</td></tr><tr><td>TFA</td><td>Trifluoroacetic acid</td></tr><tr><td>TFE</td><td>2,2,2-Trifluoroethanol</td></tr><tr><td>THF</td><td>Tetrahydrofurane</td></tr><tr><td>THP</td><td>Tetrahydropyran</td></tr><tr><td>TIPS</td><td>Triisopropylsilyl</td></tr><tr><td>TMBzOH</td><td>2,4,6-Trimethylbenzoic acid</td></tr><tr><td>TMEDA</td><td>Tetramethylethylenediamine</td></tr><tr><td>TMS</td><td>Trimethylsilyl</td></tr><tr><td>TON</td><td>Turn over number</td></tr></table>

<figure><img src="image_370.png" /></figure>
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