Transition Metal Catalyzed C-H Functionalization: Construction of C-C, C-O and C-X Bonds

This thesis has been submitted by me to the Department of Chemistry, Indian Institute of Technology Guwahati for the award of the degree of Doctor of Philosophy. I acknowledge the Central Instrument Facility (CIF) and the Chemistry Department for providing instrument facilities.

Abstract

Introduction

Herein, a Pd(II)-catalyzed o-aroylation of 2,3-diarylquinoxalines using aromatic aldehydes or alkylbenzenes in the presence of TBHP oxidant has been reported. A Pd(II)/Pd(0) catalytic cycle has been proposed for this o-halogenation of 2-arylbenzothiazoles (Scheme IVB.1).

Contents

A sketch of Transition Metal Catalyzed CH Functionalizations 01

Ceric Ammonium Nitrate (CAN) Promoted Pd(II)-Catalyzed

Tertiary Alkyl Amines as the Source of Diene for

ACTIVATION

C HAPTER I

A Sketch of Transition Metal Catalyzed CH Functionalizations

Introduction
Traditional Vs Modern Approach
Challenges to CH Functionalizations
Mechanisms of C–H Functionalization
Modern Era of CH Functionalization

Representative Examples of Directed CC Bond Formation
Representative Examples of CO Bond Formation
Representative Examples of CN Bond Formation
Representative Examples of CC Bond Formation
Representative Examples of CO Bond Formation
Representative Examples of Directed CDC Reactions
Directed C–H Bond Functionalization via Redox-Neutral Process
Directing Group Assisted Site Selectivity Beyond ortho Site

Asymmetric CH Activation

Intermolecular Stereoselective CH Activation

References

Thus, the cleavage of the CH bond proceeds with an increase in the oxidation state of the transition metal. All of the above classified CH bond activation mechanisms proceed in the presence of a transition metal complex. Ubiquitous nature and low reactivity of CH bonds make the selective functionalization of the desired C–H bond more challenging.

In the presence of the catalyst Ru-pyrazolidin-3-one caused the C-H annulation reaction via NN bond cleavage.

IIA.1. Introduction

2,3-Diarylquinoxaline-directed mono-ortho-aroylation via cross-dehydrogenative coupling Utilization of aroylation via cross-dehydrogenative coupling using aromatic aldehydes or alkylbenzenes as aroyl surrogate. The modern methods used 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 derivatives thereof; (ii) the carbonylative processes; (iii) the cross-dehydrogenative coupling with various aroyl surrogates and (iv) decarboxylative couplings of -keto acids. Directed o-aroylation via carbonyl insertion. iii) Cross-Dehydrogenative Coupling Approach with Various Aroyl Surrogates The most elegant approach for ortho-aroylation of directed arenes is the CDC reaction.

Some of the recent CDC protocols on ortho-arolation of conducting substrates possessing hetero-donor atoms along with various ArCO substituents are listed below. a) Aldehyde as a source of ArCO. Various directing arenes containing N and O donor atoms have been used for o-arolation using the aromatic aldehyde as the aroyl substituent. Along with aromatic arenes, heretoarenes have also been used for orthoarolation using aldehydes as the aroylation source.

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

IIA.3. Present Work

2,3-Substituted diphenyl-quinoxaline (2) containing an electron-donating group (Me) in its aryl rings gave excellent yield of the desired aroylated product (2a, 80%) when reacted with benzaldehyde under conditions of reaction. In the case of substrate (7) containing two electron-donating substituents (Me and OMe) on one of the phenyl rings, regioisomeric mono-ortho-aroylated products (7a and 7a') are afforded in a 6.7:1 ratio that suggests the preferential oxidn. palladium on the more electron-rich aryl ring. For substrate (8) containing weak electron-withdrawing substituents (Br) on one of the phenyl rings of 2,3-diarylquinoxaline o-aroleation occurs on the other electron-neutral phenyl ring to give the product (8a, 69%) exclusively reconfirming the preferential ortho-arolation at the relatively electron-rich phenyl ring (Scheme IIA.3.2).

Recently, the inert alkylbenzenes have been exploited by us and several others as excellent aroyl surrogates.18 Although the present reaction used alkylbenzene (toluene) as a solvent in the presence of aromatic aldehyde, in no case was an ortho-aroylated product derived from toluene observed. . of the responses. At the end of the reaction (10 hours), the products (le) and (lb) were isolated in the ratio of 7:3 with an overall yield of 68%, showing the higher ortho-aroylating capacity of aromatic aldehyde over alkylbenzene was suggested. This is partly due to the inheterogeneity of the reaction mixture due to the insolubility of p-nitrotoluene.

In order to determine the nature of the mechanisms involved in each of these reactions, a series of experiments was carried out. No di-ortho-aroylation was observed in the second ortho position of the aryl ring or in the two available ortho positions of the second aryl ring, even with an excess of aroylation source, which may be due to the loss of plane of the pendant aryl rings relative to the quinoxaline moiety. The out-of-plane orientation of both aryl rings is clearly seen from one of the mono-ortho-aroylated product (1e), as shown in Fig.

IIB.1. Introduction

Pd(II)-catalyzed peroxide-free orthoaroylation of leading Arenes. ArCO-) group via single decarbonylation22 or to an aryl (Ar-) unit via double decarbonylation.22 A substrate-directed o-aroylation10a or an o-arylation in the presence of a Pd(II)/Cu(II) catalytic combination could therefore be achieved (scheme IIB.1.3).

IIB.3. Present Work

Experimental Section

Crystallographic Description
Mechanistic Investigations

After completion of the reaction (8 h), the reaction mixture was cooled to room temperature and was mixed with water (5 mL). The product was extracted with ethyl acetate (3 x 10 mL) and the combined organic layer was washed with saturated sodium bicarbonate solution (5 mL), dried over anhydrous sodium sulfate (Na 2 SO 4 ) and concentrated under reduced pressure. After completion of the reaction (10 h), the reaction mixture was cooled to room temperature and was mixed with water (5 mL).

After completion of the reaction (12 h) the reaction mixture was cooled to room temperature and the reaction mixture was quenched with ethyl acetate (30 mL). The flask was placed in a condenser and the reaction mixture was stirred in an oil bath preheated to 110 oC for 8 h. The reaction after 8 h afforded the benzoyl-TEMPO adduct 2,2,6,6-tetramethylpiperidin-1-yl benzoate (1A) in 52% yield along with small (~10%) yield of the desired product (1a).

This experiment supports the Pd(OAc)2/TBHP radical-induced formation of the benzoyl radical in the medium from benzaldehyde (a) and also the radical nature of the mechanism. Determine the extrusion of CO from the reaction: To detect the evolution of carbon monoxide (CO), a strip containing PdCl2 and PMA (phosphomolybdic acid) was hung from the neck of the reaction flask as shown in the figure. The initial yellow color of the strip before the reaction (Figure IIB.4.4.1) turned blue after 3 hours of reaction progress (Figure IIB.4.4.2).

Spectral Data

Spectra

Summary: Low-cost cerium ammonium nitrate (CAN) is an efficient oxidant for the Pd-catalyzed substrate-directed o-benzoxylation process.

Ceric Ammonium Nitrate (CAN) Promoted Pd(II)- Catalyzed Substrate Directed o-Benzoxylation

Introduction
Strategies for ortho-Carboxylation
Present Work
Experimental Section

Crystallographic Description

References
Spectral Data
Spectra

The Sanford group reported the first example of Pd-catalyzed ligand-directed sp2 CH acetoxylation using PhI(OAc)2 (DIB) as a stoichiometric amount of reagent (Scheme III.2.1).1s DIB plays a dual role of oxidants and the source of the acetoxy group. The same group also developed a Pd ligand-directed sp3 CH acetoxylation of the ketoxime ether using the hypervalent iodine oxidant DIB (Scheme III.2.2).1s,1w. Further, increasing the amount of catalyst from 5 to 10 mol % the product yield did not change significantly (Table III.3.1, entry 8).

The addition of CH3CN was necessary to make the medium homogeneous, thus improving the yield (71%) (Table III.3.1, entry 16). When the reaction was carried out with two equivalents of benzoic acid for a longer period of time (17 h), trace amounts (11%) of the o-dibenzoxylated product (1aa) were observed (Table III.3.1, entry 17). When the benzoxylation of (1) was carried out in the presence of 1, 1.5 and 2 equivalents of the oxidant (CAN) under the same identical conditions, the isolated yields of the product after 12 h were 66%, 71%.

The oxidative addition product is a dimeric Pd(III) intermediate 7II, which was detected by mass spectral analysis of the reaction mixture. After completion of the reaction (12 h), the excess solvent was removed under reduced pressure and the reaction mixture was combined with ethyl acetate (30 mL). This experiment supports the formation of benzoxy radical in the medium from benzoic acid induced by Pd/CAN and also the radical nature of the mechanism.

IVA.1. Introduction

Section-A describes the o-halogenation of 2-arylbenzothiazoles and 2,3-diarylquinoxalines using N-halosuccinamide, whereas Section-B demonstrates the o-halogenation of 2-arylbenzothiazoles using copper(II) halide as the halogenation source.

IVA.3. Present Work

No significant improvement in the product yield was observed, even if the catalyst loading was increased from 5 to 10 mol %, (Table IVA.3.1, entry 11). After screening the reaction with these acidic additives, it was found that using 50 mol % PTSA under otherwise identical conditions provided an improved yield (79%) of the desired o-brominated product (1a) (Table IVA.3.1, entry 12) ). In the presence of other acidic additives such as TFA and AcOH, cleavage of the ester group in (1) was observed together with the formation of o-bromo product (1a) (Table IVA.3.1, entries 13-14) whereby the product yield was effectively reduced.

The ester group survived when PivOH was used as an additive, but was not as effective toward the desired o-bromination (Table IVA.3.1, entry 15). Benzothiazole with naphthyl ester (8) also provided moderate yield of its corresponding o-bromo product (8a, 68%) (Scheme IVA.3.1). Interestingly, no substantial change in product yield was observed even when the reaction was carried out at lower temperature (60 oC).

IVA.3.1 (b)) exactly matches its X-ray crystal structure.12 Thus, this type of periplanar orientation is most favorable for o-palladium leading to o-halogenation. Here too the rates of o-di-halogenation (Scheme IVA.3.2) follow the same order (iodination > bromination > . chlorination) as that of mono-o-halogenation (Scheme IVA.3.1). Keeping the amount (NBS) at 2 equivalents and increasing the reaction temperature to 110 oC a substantial improvement in the yield (76%) of the di-bromo product (20aa) was observed (Scheme IVA.3.3).

IVB.1. Introduction

Copper(II) halide as a halogenating agent in Pd-catalyzed ortho-halogenation of 2-arylbenzothiazoles Catalyzed ortho-halogenation of 2-arylbenzothiazoles.

IVB.3. Present Work

Experimental Section

Synthesis of o-Halogenated 2-Arylbenzothiaoles

The organic layer was washed with saturated sodium bicarbonate solution (2 x 5 mL), dried over anhydrous Na 2 SO 4 , and concentrated under reduced pressure. ESI-MS study to detect reaction intermediates during o-bromination: In order to detect intermediates in the reaction mixture, electrospray mass spectrometry was performed. Different cationic and neutral Pd species were detected in the ESI-MS analysis, as shown below in Figure 1b.

The brominated product, cationic and neutral Pd species observed in the spectrum are as follows: peaks at m/z 411.9857 corresponding to 2-(benzo[d]thiazol-2-yl)-3-bromophenyl benzoate (1a) .

Spectral Data

Spectra