An array of exceptions: Reactions which are not included in the above three classes are exemplified below

C HAPTER I

I.5.4. An array of exceptions: Reactions which are not included in the above three classes are exemplified below

Sulfenylation via Csp3−−H / S−− sp3−−−−H

Recently, Shi group demonstrated the nickel-catalyzed 8-aminoquinoline directed thiolation /sulfenylation of C(sp³)−H bonds to form thioethers (Scheme I.5.1.3.16).^45d

Scheme I.5.3.1.16. Ni(II)-catalyzed sp³ C−H sulfenylation Ortho sp² C–H phosphorylation via CDC

Yu group has reported the first Pd(II)-catalyzed C−H phosphorylation of 2- arylpyridines using both H-phosphonates and diaryl phosphine oxides as suitable coupling partners for this reaction (Scheme I.5.3.1.17).^86a Later on Murakami group reported a similar o-phosphorylation using N-directed substrates such as 2-phenylpyridines, quinolines, isoquinolines, benzo[h]quinolines and pyrimidines.^86b

Scheme I.5.3.1.17. Palladium(II)-catalyzed C−H phosphorylation of 2-phenylpyridine

I.5.4. An array of exceptions: Reactions which are not included in the above three classes

Scheme I.5.4.1.1. Pd(II)-catalyzed C-2 arylation of electron rich arenes

Intermolecular direct arylation of electron-withdrawing perfluorobenzenes was introduced by Fagnou group using a wide variety of arylhalides.The reactions require only a slight excess of the perfluoroarene reagent, and utilize commercially available, air-stable catalyst precursors.Inverse reactivity is observed compared to the common electrophilic aromatic substitution pathway since electron-deficient C−H acidic arenes react preferentially (Scheme I.5.4.1.2).⁸⁸

Scheme I.5.4.1.2. Pd(II)-catalyzed direct arylation of electron deficient arenes

I.5.4.2. Directed C–H bond functionalization using oxidizing groups

Compared with the well-established directed C–H bond functionalization using external stoitiometric oxidants, mainly silver or copper salts, oxidizing group directed redox-neutral C–H bond functionalization presents unparalleled advantages:

(1) No external oxidants required for the catalytic cycle.

(2) Simple and mild reaction conditions.

(3) Very good functional group tolerance.

(4) High regioselectivity.

The oxidizing group directed redox-neutral C–H bond functionalization was pioneered in 2009 by Wu, Cui and co-workers.⁸⁹ They ingeniously employed pyridine N-oxides as substrates cum oxidants in the oxidative Heck reaction. Further progress was made by Hartwig during the synthesis of indole using oxime ester as oxidising directing group (Scheme I.5.4.2.1).⁹⁰

Scheme I.5.4.2.1. Pd-catalyzed redox-neutral intramolecular ortho sp² C−H amination Inspired by previous work in palladium chemistry, the Fagnou group developed first example of Rh(III)-catalyzed redox-neutral C–H bond functionalization of N- methoxybenzamides and C–N bond formation sequence to afford isoquinolone derivatives.(Scheme I.5.4.2.2).⁹¹

Scheme I.5.4.2.2. Rh(III)-catalyzed redox neutral intermolecular ortho sp² C−H annulaion Similar directing group assisted redox-neutral annulation strategies were further extended by Glorius,^92a-b Rovis,^92c-e Cramer^92f-g and others.^92h-o In a conceptual way structures of various oxidizing directing groups are depicted below which are shown in Figure I.5.4.2.1

Fig. I.5.4.2.1. Oxidizing directing groups with internal oxidants

I.5.4.3. Directing group assisted site selectivity beyond ortho site

Comapred to proximity controlled well-established ortho directing groups via five- or six-membered metallacycles, the elusive meta- and para selective C–H transformations may require larger metallacycles, which are often very difficult to generate. Traditionally, meta-selective C–H transformations have been realized initially by steric control⁹³ or

selective C–H functionalizations in the presence or absence of copper catalyst.⁹⁵ Stimulated by these studies, several new meta or para-selective transformations and new strategies appeared very recently.

Meta-C–H bond functionalization controlled by electronic effects

Recently, Frost and co-workers reported a strategy for a meta selective C–H functionalization, namely the sulfonation of 2-phenylpyridines, with the assistance of a ruthenium catalyst (Scheme I.5.4.3.1).⁹⁶ This protocol represents the first example of a catalytic σ-activation process.

Scheme I.5.4.3.1. Ru(II)-catalyzed meta-selective sp² C−H sulfonation

Similarly Ackermann group developed a meta-selective C–H alkylation strategy of N- heterocycle-containing arenes with secondary alkyl bromides where an initial reversible cycloruthenation increased the reactivity of arenes to undergo electrophilic-type substitutions para to carbon-ruthenum (C-Ru) bond (Scheme I.5.4.3.2).⁹⁷

[RuCl₂(p-cymene)]₂(2.5 mol %) MesCO₂H (30 mol %)

K₂CO₃(2.0 equiv) 1,4-dioxane, 100^oC, 20 h DG

H + R²

Br R³ R¹

DG

R¹

R² R³

DG = N HN N

N N

; ;

Scheme I.5.4.3.2. Ru(II)-catalyzed meta-selective alkylation

Template assisted meta-selective C–H functionalization

In contrast to achieving meta-selectivity by controlling the electronic bias, Yu group chose to take advantage of spatial proximity for obtaining challenging meta selectivity by employing an elaborately designed template. In 2012, Yu and co-workers successfully demonstrated a Pd(II)-catalyzed meta-C–H olefination of toluene derivatives using nitrile based removable directing template (Scheme I.5.4.3.3).⁹⁸ In this seminal work, the long- range directing group was thought to coordinate the palladium catalyst via a cyclophane-

type transition state, which could facilitate the approach of the catalyst to induce the meta- C–H functionalization.

Scheme I.5.4.3.3. Pd(II) catalyzed meta-selective olefination of toluene derriavtives

This template-based idea of meta sp² C−H functionalization was further exemplified by Yu and others for meta-selective arylation, acetoxylation and olefination using a range of modified nitrile based removable directing templates.⁹⁹ In a simplified way structures of various meta selective directing templates are depicted below in Figure I.5.4.3.1.

Fig. I.5.4.3.1. Overview of nitrile based removable meta-directing templates

Meta-C–H bond functionalization using norbornene as a transient mediator Yu and co-workers reported an alternative ligand enabled Pd(II) catalyzed meta- selective C–H activation with a simple and common ortho directing group employing norbornene as a transient mediator.¹⁰⁰ The use of a newly developed pyridine-based ligand is crucial for relaying the palladium catalyst to the meta position by norbornene after initial ortho-C–H activation (Scheme I.5.4.3.4).

Scheme I.5.4.3.4. meta-C–H alkylation of phenylacetic amides using norbornene

Para-C–H bond functionalization controlled by directing template

Very recently Maity and coworkers reported a Pd(II) catalyzed novel Si-containing biphenyl-based D-shaped template that directs efficient functionalization of the distal p-C–

H bond of toluene derrivatives (Scheme I.5.4.3.5).¹⁰¹ This DG allows the required flexibility to support the formation of an oversized pre-transition state. By overcoming electronic and steric bias, para-olefination and acetoxylation were successfully performed while undermining o- and m-C–H activation.

Scheme I.5.4.3.5. Pd(II) catalyzed para-selective functionalization of toluene derrivatives