An array of exceptions

I.5.4.1. Directed CH bond functionalisation via redox neutral process

The well-established CH functionalisation requires a stoichiometric amount of external oxidant. In addition to this, there are exceptional cases where the internal oxidising group present in the substrate enables the entire CH functionalisation process.

These types of oxidising group directed CH functionalisation have un-comparable advantages such as:

 Avoids the use of external oxidant for the whole catalytic cycle.

 Tolerates a broad range of functional group.

 Highly regioselective.

 Requires mild reaction condition.

(a) Intermolecular annulation via redox–neutral process

Very recently, Glorius and coworkers have utilised the α-halo and pseudohalo ketones (Csp³based electrophiles) for the synthesis of diverse N-heterocycles via Rh(III)-catalysed C–H activation under mild and redox-neutral reaction conditions (Scheme I.5.4.1.1). The α-(pseudo)halo ketones were recognised as the oxidised alkyne equivalents to undergo intermolecular redox-neutral annulations with N- methoxybenzamide. Various important N-heterocycles, such as 3-aryl and 3-alkyl- substituted isoquinolones, 2-pyridones, 1,2-benzothiazines, and 2-methylated indole, could be synthesised using this Rh(III) catalysed redox-neutral annulation process.⁶⁹

Scheme I.5.4.1.1. Rhodium-catalysed redox-neutral intermolecular annulation (b) Intramolecular annulation via redox–neutral process

Park and co-workers have reported an efficient Rh(III)-catalysed intramolecular annulation of alkyne tethered hydroxamic esters for the facile synthesis of hydroxyalkyl- substituted isoquinolone/2-pyridone derivatives (Scheme I.5.4.1.2).⁷⁰ The reaction was performed under mild reaction conditions and obviated the use of external oxidants.

Some of the phenanthroindolizidine alkaloids have also been accomplished by using this methodology.

Scheme I.5.4.1.2. Rhodium-catalysed redox-neutral intramolecular annulation

I.5.4.2. Directing group assisted site selectivity beyond ortho CH functionalisation

The selective ortho-functionalisation of proximal CH bonds is well-known strategies where a five or six membered metallacycle is usually involved. Compared to ortho, it is difficult to achieve a meta- or para-CH functionalisation where a large metallacycle is involved. Previously, the meta-selectivity was achieved either by steric⁷¹ control or ligand⁷² promotion. Few meta- and para-CH functionalisation in the presence or absence of copper catalyst has been disclosed by Gaunt et al.⁷³ Inspired by these studies, several new strategies based on meta and para selective CH functionalisation have been successfully developed by other groups which are discussed below.

Meta-C-H functionalisation controlled by electronic effects

A ruthenium-catalysed direct C–H bond sulfonation of 2-phenylpyridines with unusual meta-selectivity was disclosed by Frost and co-workers (Scheme I.5.4.2.1). The mechanistic pathway proposed, involves catalytic chelation assisted cyclometalation.⁷⁴

Scheme I.5.4.2.1. Rutheium-catalysed meta-selective sulfonation of 2-phenyl pyridine

Template based meta-CH functionalisation

The remote control of site selectivity, especially meta-selective CH functionalisation of electron-rich arenes is one of the most challenging task in organic synthesis. In 2012, the first report on the template based meta-CH functionalisation was disclosed by Yu and co-workers (Scheme I.5.4.2.2). They have decorated an easily removable nitrile-based template that can direct the activation of distal meta-C–H bonds (more than ten bonds away) of a tethered arene through the formation of a macropalladacycle. In this unparalleled report, the olefination of the nitrile-containing templates was carried out via meta-selective functionalisation. The nitrile group on the template was weakly chelated to the [Pd(II)–Ar] intermediate and could be successfully displaced by disubstituted olefins, allowing the carbopalladation step. The main advantage is that the template could be easily removed from the meta-alkylated products.⁷⁵

Scheme I.5.4.2.2. Palladium-catalysed template based meta-selective olefination

Later, a number of nitrile group containing templates based meta-selective CH functionalisation reactions such as meta-olefination,^76,77a acetoxylation,^77a hydroxylation,^77b arylation,⁷⁸ silylation and germanylation⁷⁹ have been explored by various research groups. Some of these templates are shown in Figure I.5.4.2.1.

Figure I.5.4.2.1. Nitrile based templates used for meta-selective CH functionalisation Most of the template based meta-selective CH functionalisations involve a weakly coordinating nitrile group. In 2015, Yu group reported a selective meta-C–H functionalisation by replacing the nitrile donor with a 2-fluoropyridine based directing group (Scheme I.5.4.2.3).⁸⁰

Scheme I.5.4.2.3. Palladium-catalysed meta-selective CH olefination Template based para CH functionalisation

After establishing, the template based meta-CH functionalisation, it was then extended to the most challenging approach in this domain i.e. para-CH functionalisation. An efficient and unprecedented strategy was disclosed by Maiti and

co-workers which includes the use of extended templates to deliver para-olefinated and para-acetoxylated products via para CH bond activation (Scheme I.5.4.2.4). They have utilised an easily recyclable Si-containing biphenyl-based template that directs the functionalisation of the distal p-C−H bond of toluene by forming a D-shaped assembly in the presence of Pd(OAc)2 catalyst.^81a Very recently, another remote para CH functionalisation of phenol derivatives has been developed by switching the connectivity of carbon to oxygen atoms in the former silicon-containing biphenyl based template by the same group. Various phenol-based natural products have been accomplished by applying this strategy.^81b

.

Scheme I.5.4.2.4. Palladium-catalysed para-selective CH olefination and acetoxylation

I.5.4.3. Asymmetric CH activation

The enantioselective CH activation leading to the formation of carbon−carbon (C−C) and carbon−heteroatom (C−X) bonds is always a long standing challenge in synthetic organic chemistry. Reactions pertinent to this category are shown below.

Intermolecular stereoselective CH activation

Yu and co-workers disclosed the first report of palladium-catalysed enantioselective C−H activation by incorporating a stereochemistry-generating intermolecular C−H alkylation (Scheme I.5.4.3.1). Here, they have introduced a mono N-protected amino acids (MPAA) as viable chiral ligand for this Pd(II)/ Pd(0)-catalysed highly enantioselective alkylation.⁸²

Scheme I.5.4.3.1. Palladium-catalysed intermolecular alkylation via asymmetric CH activation

Intramolecular stereoselective CH activation

An intramolecular direct arylation of vinyl triflates has been reported by Cramer research group. They have designed a taddol based phosphoramidite ligands which is the key factor for the formation of a quaternary stereocenter based indanes with excellent enantioselectivities.^83a In 2013, Saget and Cramer utilised the same taddol phosphoramidites as chiral ligands for the synthesis of highly functionalised dibenzazepinones possessing a quaternary stereocenter with outstanding enantioselectivities. The reaction proceeds via an enantio-discriminating concerted metalation deprotonation (CMD) step which occurs through an unusual eight membered palladacycle formation (Scheme I.5.4.3.2).^83b

Scheme I.5.4.3.2. Palladium-catalysed intramolecular alkylation via asymmetric CH activation