IIIA.1. Introduction

CHAPTER III

This chapter is divided into two Sections. Section-A demonstrates Pd(II) catalyzed o- aroylation of 2-arylbenzothiazole and 2-arylbenzoxazole whereas Section-B describes o-aroylation of another directing substrate 3,5-diarylisoxazole.

IIIA. Pd(II)-Catalyzed o-Aroylation of 2-

Arylbenzothiazoles and 2-Arylbenzoxazoles with

Aldehydes

nitriles, Weinreb amides, anhydrides, or acid chlorides with lithium, magnesium, or aluminum reagents are alternative methods for the synthesis of the corresponding ketones.⁷ However, these transformations require harsh reaction conditions such as highly basic and nucleophilic or acidic conditions, which results in low compatibility with various sensitive functional groups. To outwit these drawbacks, in recent years transition metal catalyzed aroylation of arenes via C–H bond cleavage has emerged as a direct and promising approach to access ketones.⁸ The various methods that have been employed can be classified into four types as follows, (i) ortho-selective 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 α-oxoacids. Some of the recent advances on each of these categories are summarized below.

(i) o-Selective Friedel-Crafts acylation using carboxylic acids or its derivatives The direct use of carboxylic acids or its derivatives for ortho-acylation of arenes are scarce in literature. Kakiuchi and co-workers achieved a Ru catalyzed ortho- selective acylation of arylpyridines with acyl chlorides via C–H bond cleavage under oxidant-free conditions.^9a In an analogous Pd-catalyzed reaction, selective aromatic C–H bond acylation with readily available carboxylic acids has also been reported by Fu et al.^9b Recently, Gooβen group has demonstrated a Rh catalyzed method for the ortho-acylation of benzoic acid with carboxylic anhydrides (Scheme IIIA.2.1).^9c

Scheme IIIA.2.1. o-Aroylation using carboxylic acid or its derivatives

(ii) The carbonylative processes

Beller group has reported the synthesis of ketones via the ortho-directed carbonylative coupling reactions of 2-phenylpyridine with aryl halides using Ru catalyzed C−H bond activation (Scheme IIIA.2.2).^10a Apart from this directed ortho- acylation, similar non-directed carbonylative coupling reaction between aryl iodide and heterocycle has also been achieved by the same group in the presence of Pd and Cu.^10b Lei et al. developed an elegant Pd catalyzed process for the double C−H

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

(iii) Cross dehydrogenative coupling approach with various aroyl surrogates There are numbers of CDC based protocols appeared for the directing group assisted ortho-selective aroylation of various directing substrates possessing hetero- donar atoms. Some of the recent protocols on ortho-aroylation using various ArCO−

sources are enlisted below.

(a) Aldehyde as ArCO−−− source −

By using aldehyde as the aroyl source, various directing substrates possessing N and O donor atoms have been employed for the o-aroylation (Scheme IIIA.2.3). In a pioneering study Cheng et al. have developed a Pd catalyzed ortho-aroylaion strategy of 2-arylpyridines with benzaldehydes to give aromatic ketones using dioxygen as oxidant.^11a Using Pd/TBHP combination Li group has demonstrated a similar CDC coupling of 2-arylpyridines with aliphatic aldehydes.^11b A number of other ortho- chelating groups such as ketoxime ether,^11c-d anilide,^11e-i benzamide,^11j triazole^11k and even azobenzene^11l have been studied toward similar ortho-acylation using aldehydes as the ArCO− source (Scheme IIIA.2.3).

Scheme IIIA.2.3. o-Aroylation using aldehydes as ArCO− source

Although a fewer number of ortho-aroylation of heteroarenes have been reported using aldehydes as the aroylating agents. The two precendence that exist are a Rh- catalyzed oxidative C-2 acylation of indoles with aryl and alkyl aldehydes developed by Li group^11m and a Pd catalyzed C-3 acylation of benzofurans and bezothiophenes as reported by Pan group.¹¹ⁿ

(b) Benzyl alcohol or ethers as ArCO−−−− source

Primary alcohols have the ability to generate aldehydes via in situ oxidation, thus they have been used in various ortho-aroylation protocols as aroyl equivalents.

Using alcohols as the latent aldehyde functionality a Pd-catalyzed regioselective o- aroylation of aromatic C−H bonds afforded ketones in good yields in the presence of peroxide (Scheme IIIA.2.4).^12a Later various primary alcohols have been used as the aroyl equivalents for various ortho directing substrates.^12b-e The use of ethers as the aroyl surrogate has also been reported by Kim and co-workers during directing group assisted ortho C−H functionalization. They have shown that not just alcohols but ethers can also act as the acyl surrogate to afford ketones via C−O bond cleavage of ethers eventually leading to the formation of C−C bond (Scheme IIIA.2.4).^12f

Scheme IIIA.2.4. o-Aroylation using benzyl alcohols or ethers as ArCO− source

(c) Alkylbenzenes as ArCO−−−− source

For the first time using inert alkylbenzene as the synthetic equivalent of the aroyl moiety our group has developed a directing group assisted ortho-aroylation through Pd(II)-catalyzed cross dehydrogenative coupling in the presence of TBHP (Scheme IIIA.2.5).¹³

Scheme IIIA.2.5. o-Aroylation using alkylbenzenes as ArCO− source

(d) Benzylamine as ArCO−−−− source

Wu group has recently developed an efficient protocol for Pd-catalyzed ortho- aroylation of 2-aryl pyridines using arylmethyl amines as an aroyl source in presence of TBHP (Scheme IIIA.2.6).¹⁴

Scheme IIIA.2.6. o-Aroylation using benzylamine as ArCO− source

(e) Benzil as ArCO−−−− source

Wang group has achieved an efficient carbo-acylation reaction of 2- arylpyridines with α-diketones via a Pd-catalyzed C−H bond activation and C−C bond cleavage in the presence of TBHP as the radical initiator (Scheme IIIA.2.7).¹⁵

Scheme IIIA.2.7. o-Aroylation using benzil as ArCO− source

(f) Decarboxylative couplings of ααα-oxoacids α

Besides the above strategies, o-aroylation has also been achieved through a substrate-directed decarboxylation of α-keto carboxylic acids. Pertaining to directed ortho-aroylation, Ge and co-workers has demonstrated a novel Pd catalyzed protocol to access o-aroyl acetanilides via decarboxylative coupling of α- oxoacids with acetanilides.^16a Later the same group has achieved a similar ortho- acylation of 2-arylpyridines^16b as well as carboxylic acids (Scheme IIIA.2.8).^16c

DG H DG

COAr

O

[Pd], [Fe] Ar DG =

N

NOR HN R

O DG

H DG

COAr

N O

N N N O O R

R

S

R N O

R R

N N

R O

N N

OH O

R OH

O

[Pd]

CO₂ CO₂

Het

Het

Scheme IIIA.2.8. o-Aroylation via decarboxylative coupling

The decarboxylative coupling of α-oxoacids for ketone synthesis has also been implemented on other directing arenes such as 2-aryloxypyridines,^16d ketoxime ether,^16e-f cyclic enamides,^16g carbamates,^16h acetamide,¹⁶ⁱ azobenzene,^16j-k azoxybenzene^16l and even thioether.^16m Pertinent to such strategy in heteroarenes, C- 2 acylation in indoles has been reported using α-oxoacids as the aroyl source.¹⁶ⁿ