IIA.1. Introduction

Functionalizations of ubiquitous CH bonds build complex molecular framework through the construction of CC and CX (X = heteroatoms) bonds.¹ The two most elegant approaches applied for this purpose are the directing group assisted CH functionalization² and the cross-dehydrogenative coupling (CDC).³ In the later approach both the coupling partners are attached through their CH bonds, whereas in the former only ortho CH bonds are functionalized via the chelation of metals through heteroatoms such as nitrogen and oxygen. These two techniques make the protocol highly appreciable due to the requirement of minimal steps and atom economy point of view. However among these transformations, CC bond formation especially installation of carbonyl functional groups into the phenyl system via CH bond cleavage is attractive in organic chemistry. Combination of directing group assisted CH functionalization and the cross-dehydrogenative coupling (CDC) directly installs aroyl functionality at the ortho site of a directing arenes and hence minimized steps and cost. Substrates having different directing groups have been successfully ortho-aroylated using diverse aroyl surrogates viz. aldehyde, alkene, alkyne, benzil, -ketoacid, benzyl alcohol, benzylamine and alkylbenzene.⁴

IIA.2. Strategies for ortho-Aroylation

The most classical approach for ketone synthesis is the Friedel-Craft acylation reaction.⁵ However, the use of stoichiometric amount of reagents and poor regioselectivity, this classical approach has been lately replaced by transition metal catalyzed cross-couplings.⁶ Use of carboxylic acid derivatives, such as nitriles, anhydrides, Weinreb amides or acid chlorides with alkali metals viz. lithium, magnesium or aluminum reagents lead to the formation of corresponding ketones.⁷ However, these processes involve harsh reaction conditions resulting in low compatibility towards various sensitive functional groups. To avoid the substrate pre-functionalization recently cross-coupling reactions involving CH bond functionalizations have come into reclaim as a direct and promising approach to access ketones. The modern methods employed for ortho-aroylation via the cleavage of single or multiple CH bond(s) can be classified into four types, viz. (i) ortho Friedel-Crafts acylation using carboxylic acids or its derivatives; (ii) the carbonylative processes; (iii) the cross-dehydrogenative coupling with various aroyl surrogates and (iv) decarboxylative couplings of -keto acids. Some of the recent advances on each of these categories are summarized below.

(i) o-Friedel-Crafts Acylation Using Carboxylic Acids or its Derivatives

o-Acylations of directing arenes using carboxylic acids or its derivatives are fewer in number. Kakiuchi and co-workers reported a Ru-catalyzed ortho selective acylation of arylpyridines using acyl chlorides via the C–H bond activation under oxidant free conditions.^8a Fu et al. achieved Pd-catalyzed ortho-acylation of same directing arene using readily available carboxylic acids as the aroyl source.^8b Recently, Gooen group has demonstrated a Rh-catalyzed method for the ortho-acylation of benzoic acid with carboxylic anhydrides (Scheme IIA.2.1).^8c

Scheme IIA.2.1. o-Aroylation using carboxylic acids or its derivatives

(ii) The Carbonylative Processes

Beller group reported a Ru-catalyzed carbonylative ortho-acylation of 2- phenylpyridine with aryl halides via direct CH bond activation (Scheme IIA.2.2).^9a Lei et al. developed a Pd-catalyzed double CH oxidative carbonylation of diphenyl ethers to obtain xanthones.^9b

Scheme IIA.2.2. Directed o-aroylation via carbonyl insertion

(iii) Cross-dehydrogenative Coupling Approach with Various Aroyl Surrogates The most elegant approach for ortho-aroylation of directing arenes is the CDC reaction. Some of the recent CDC protocols on ortho-aroylation of directing substrates possessing hetero-donor atoms along with various ArCO surrogates are enlisted below.

(a) Aldehyde as the ArCO Source

Various directing arenes containing N and O donor atoms have been employed for the o-aroylation using aromatic aldehyde as the aroyl surrogate. Cheng et al. reported a Pd(II)-catalyzed ortho-aroylation of 2-arylpyridines, for the installation of carbonyl functional groups from aromatic aldehydes into the phenyl ring via direct sp² CH bond activation.^10a Later Li group demonstrated a similar CDC coupling of 2-arylpyridines with aldehydes in the presence of Pd-catalyst and TBHP.^10b Several ortho-chelating groups such as ketoxime ether, anilide, benzamide, triazole and even azobenzene have also been applied toward similar ortho-aroylation using aldehydes as the ArCO source (Scheme IIA.2.3).⁴

Scheme IIA.2.3. o-Aroylation using aldehydes as ArCO source

Along with aromatic arenes, heretoarenes have also been employed for ortho- aroylation using aldehydes as the aroylating source. Li group has developed a Rh- catalyzed oxidative C-2 acylation of indoles with aryl and alkyl aldehydes,^10c whereas a Pd-catalyzed C-3 acylation of benzofurans and benzothiophenes is reported by Pan group.^10d

(b) Benzyl Alcohol or Ethers as the ArCO Source

Aldehydes can be generated in situ via the oxidation of primary alcohols, thus primary alcohols can be used in various ortho-acylation protocols as a synthetic equivalent of aldehydes. Using primary alcohols various group have reported o- acylation of directing arenes in the presence of Pd-catalyst and suitable oxidant.¹¹ Kim and co-workers have developed a o-aroylation strategy using benzyl ethers as the aroyl surrogate.¹² They showed that benzyl ethers also served as the aroyl surrogate to afford ketones via CO bond cleavage of ethers eventually leading to the formation of CC bond (Scheme IIA.2.4).

Scheme IIA.2.4. o-Aroylation using benzyl alcohols or ethers as ArCO source (c) Alkylbenzenes as the ArCO Source

Our group has demonstrated that inert alkylbenzene to be the synthetic equivalent of an aroyl moiety. A Pd(II)-catalyzed ortho-aroylation protocol via cross- dehydrogenative coupling of directing arenes and alkylbenzenes has been developed in the presence of TBHP (Scheme IIA.2.5).¹³

Scheme IIA.2.5. o-Aroylation using alkylbenzenes as ArCO source

(d) Benzylamine as ArCO Source

Like primary benzyl alcohol, benzyl amine also served as an aroyl unit in Pd- catalyzed ortho-aroylation. Wu group has recently developed an efficient coupling protocol for ortho-aroylation of 2-aryl pyridines with benzylamines in the presence of TBHP (Scheme IIA.2.6).¹⁴

Scheme IIA.2.6. o-Aroylation using benzylamine as ArCO source (iv) Decarboxylative Couplings of -Oxoacids

Besides these strategies for o-aroylations, a number of substrate directed decarboxylation of -keto carboxylic acids strategies has also been achieved. Ge and co- workers have developed a Pd-catalyzed protocol to the direct access of o-aroyl acetanilides via decarboxylative coupling of -oxoacids with acetanilides.^15a Later the same group has also achieved a similar ortho-acylation of 2-arylpyridines^15b and carboxylic acids (Scheme IIA.2.7).^15c

Scheme IIA.2.7. o-Aroylation via decarboxylative coupling

Ongoing progress of the decarboxylative coupling of -ketoacids for o-aroylation, - keto acids have also been implemented on other directing arenes such as 2- aryloxypyridines, ketoxime ether, cyclic enamides, carbamates, acetamide, azobenzene, azoxybenzene and even thioether.¹⁵