I.1. Introduction
The extensive exploration of cross coupling strategy in both academics and industries has greatly improved the synthetic routes for the construction of carbon-carbon and carbon-heteroatom bonds.1 Generally, the traditional coupling strategies either require stoichiometric amount of organometallic reagents or the transition metal-catalysed coupling of pre-functionalised hydrocarbons. There was a huge progress in these methods over the decades and the advanced version are fruitfully utilised for the preparation of commercially expedient materials.2 The requirement of pre-functionalised starting materials is a major drawback of these methods as it is not appreciated in a step- economical point of view. In this aspect, the best way to address the aforementioned issues is the direct use of un-functionalised carbon-hydrogen bonds,3 so that it can increase the efficacy of the reaction by reducing the number of synthetic steps.
The carbon-hydrogen bonds are ubiquitous in nature as its availability is realised from small molecules to more elaborated natural products. They are also regarded as un- functional groups having tremendous synthetic utility hidden within them. So, if the dormant reactivity of these CH bonds can be exploited i.e. selectively functionalising the CH bonds would be a most applicable and powerful class of transformation in organic synthesis. Therefore, the direct functionalisation of CH bonds leading to the formation of new CC and Cheteroatom bonds has become the most applicable method in recent organic chemistry. According to the principles of retrosynthetic analysis, the CH activation can drastically shorten the possible synthetic routes to a target molecule by providing unparalleled disconnections in both early and late stages.
I.2. Traditional vs modern approach
The traditional cross-coupling reactions generally involve the installation of a new functional group in place of a pre-existing functional group which is already present in the starting material. For the installation of a new functional group, it needs a pre- functionalised starting material which often decreases its efficiency and atom economy and also increases step and cost of the overall transformation. Moreover, most of the cross coupling reactions terminated with the generation of stoichiometric amount of waste material. On the other hand, the CH bond functionalisation does not require a pre-functionalised starting material and emerged as the most powerful and straightforward strategy for the construction of complex organic frameworks from easily available starting materials with reduced chemical waste (Scheme I.2.1).
Scheme I.2.1. Traditional approach vs modern approach
The development of transition metal-catalysed cross-coupling reaction introduced a new era of modern approach. For the significant contribution in the development of palladium catalysed cross coupling reaction, R. F. Heck, E. Negishi and A. Suzuki were awarded Nobel Prize in 2010.4 Other transition metals are also known to achieve the same. The use of pre-functionalised starting materials was then avoided by the chemists by developing a new approach i.e. transition metal-catalysed CH bond functionalisation. A sketch of different types of transition metal-catalysed cross coupling and CH bond functionalisation reactions are enlisted in Scheme I.2.2.
Scheme I.2.2. Different aspects of cross coupling and CH bond functionalisation It is quite difficult to selectively functionalise a particular CH bond in an organic molecule. But the ability to selectively target a number of different CH bonds in a complex organic scaffold permits direct access to multiple analogues from a common structural precursor. To achieve this target, chemists need to develop suitable reaction conditions importantly, selective catalysts or designed substrates to reach any predictable site selectivity. Below in Scheme I.2.3 is an example of N-protected (alkyl and aryl) amides of 8-aminoquinoline where depending upon the regioselectivity and acidity of various CH bonds, different catalytic routes have been achieved for selective functionalisation (Scheme I.2.3).5,6
Scheme I.2.3. Diverse CH bond functionalisation of amide form of 8-aminoquinoline
In comparison to traditional cross coupling reactions, CH bond functionalisation strategies are advantageous due to the following reasons:
The CH bonds are ubiquitous in organic molecules and could provide new disconnections
No need of the presence of a pre-existing functional group in the starting materials
Step and atom economical
Cost effective
Reduction of chemical waste
I.3. Challenges to achieve CH functionalisation
Although the functionalisation of CH bonds are advantageous in the viewpoint of their ubiquity, step and atom economic, but to use them as a coupling partner is challenging due to the following reasons:
Intrinsic low reactivity
The CH bonds involved in CH bond functionalisation strategies are mostly sp2 or sp3 hybridised and have pKa values more than 3035. In addition to this, these are also associated with high bond dissociation energies (BDE) which clearly indicates their inert nature. So, it is difficult to cleave them either in a homolytic or in a heterolytic pathway.
The bond dissociation energies and pKa values of various CH bonds are listed in Table I.3.1.
Bond BDE (Kcal/mol) pKa (water)
103 48
112 50
133 25
110 43
88 43
85 41
Table I.3.1. Bond dissociation energy and pKa values of different CH bonds
Regioselectivity
Due to the ubiquitous nature of CH bonds, specifically targeting one CH bond for functionalisation in a complex organic molecule keeping all other CH bonds intact, is a very challenging task. For example, N-(quinolin-8-yl)cinnamamide and ethyl acrylate which are shown in Figure I.3.1 possess multiple regionally and electronically distinct CH’s. Thus selective functionalisation of any of the CH bond among all these CH bonds would result a multiple synthetically or biologically important compound from a single moiety.
Figure I.3.1.Ethyl acrylate and N-(quinolin-8-yl)cinnamamide contain multiple unique CH bonds
Chemoselectivity
Chemoselectivity is defined as the selective reactivity of one functional group in the presence of other. In a CH bond functionalisation, if the targeted product is more reactive than the starting material, then there is a possibility to undergo further functional group transformation under the identical reaction condition leading to the undesired product (Scheme I.3.1).
Scheme I.3.1. Chemoselectivity issue in CH bond functionalisation
Stereoselectivity
Many of the CH functionalisation processes require harsh reaction conditions and elevated temperatures to overcome their inertness. Thus, it might have a negative impact on the stability of the chiral complex and the efficiency of asymmetric induction. So it is
more challenging to install a new stereogenic centre with high diastereo- or enantioselectivity during the CH bond functionalisation.
In spite of these four major challenges, CH functionalisation strategy also suffers from certain minor issues such as preservation of the existing functional group that are already present in the starting material and controlling the side reactions such as homo- coupling and hetero-coupling. However, the two major challenges that can minimise these issues and that need to be resolved are reactivity and selectivity.
I.4. Mechanism of CH functionalisation
In CH bond activation, the carbon-metal bond formation is the crucial step. Earlier, two distinct mechanistic paths viz. “inner sphere” and “outer sphere” have been proposed by Sanford.7 In an inner sphere mechanism, the transition metal incorporates into the CH bond and forms a defined CM bond. Then the in situ generated CM bond bearing species can be converted to a new functional group with the reaction of either an external reagent or an organyl ligand attached to the metal center. On the other hand, in an outer sphere mechanism, the CH bond within the substrate reacts with an actively chelated ligand of the metal. But these two mechanisms were limited to saturated alkane CH bonds only. Later, the reactions are classified broadly by Bercaw.8 The classification includes five different mechanisms such as “oxidative addition”, “sigma-bond metathesis”, “electrophilic activation”, “metalloradical activation” and “1,2-addition”.
Among these five mechanisms, three are quite common and the other two are rare.