The green chemistry paradigm in modern organic synthesis

The term ‘green chemistry’, introduced into the chemical lexicon in the early 1990s, means ‘the creation of chemical products and processes without the use or formation of harmful substances’.¹ Development of the green chemistry concept was prompted by the progressive pollution of the environment, to which the chemical industry contributes significantly. To counteract this negative trend, in 1998 Paul Anastas and John Warner formulated 12 principles of green chemistry to make chemical production less harmful to nature and humans.² These principles, which have remained relevant over the years,³ include the following requirements for newly developed chemical processes and products:

— waste prevention;

— atom economy;

— less hazardous chemical processes;

— design of safer chemicals;

— safer solvents and auxiliarities;

— energy efficiency;

— renewable feedstocks;

— step-economy;

— catalysis rather than stoichiometric reactions;

— waste disposal (if any);

— real-time process monitoring;

— safer chemistry for accident (leaks, explosions, fires) prevention.

Historically, the first metrics of the environmental friendliness of chemical reactions were the atom economy (AE) criterion introduced by Barry Trost ⁴ in 1991, and the environmental (E) factor proposed by Roger Sheldon ⁵ in 1992. AE is calculated by dividing the molecular mass of the product by the sum of molecular masses of the substrates involved in the reaction, taking into account their stoichiometric coefficients, whereas the E-factor is the mass ratio of waste generated by the reaction to its product. Subsequently, these metrics were complemented by other sustainability criteria, such as the reaction mass efficiency,⁶ the process mass intensity,⁷ and the catalyst mass efficiency.⁸ These and some other criteria make it possible to quantify various aspects of the efficiency and safety of a chemical process, and its impact on humans and the environment, and provide a theoretical basis for green chemistry in the context of sustainable development.^9 – 11

To date, a number of excellent books and reviews have been published on the important role of chemical sciences in addressing the environmental issues.^{12 – 15} However, recent review publications consider the criteria and principles of green chemistry in relation to specific, rather narrowly defined types of chemical compounds, reactions or processes.^{16 – 20} The purpose of this review is to systematically analyze the complementarity of the green chemistry paradigm to a wide range of state-of-the-art methods of fine and industrial organic synthesis, and to assess the prospects of their application for obtaining practically relevant organic compounds and materials with minimal environmental impact. A special feature of the review is that a significant part of it is focused on green methodologies that meet several principles and criteria of green chemistry. Many of these methodologies involve the use of catalysts that reduce the activation energy of chemical reactions, allowing them to be carried out under milder conditions with less energy consumption. Organic syntheses in the presence of heterogeneous and homogeneous catalysts, including metals, their oxides and complexes, organocatalysts, photocatalysts and other types of catalysts, and their advantages and disadvantages are analyzed using a large number of examples.

The review comprises twelve chapters, and contains 1761 references to original publications, most of which have been published within the last five years. Chapter 2 considers the current metrics of green chemistry. It focuses on a recently proposed methodology for assessing the potential hazard of chemical processes to living organisms, which is based on the use of cytotoxic concentrations of all substances involved in a chemical reaction and its products as sustainability criteria. Taken together, these metrics allow a rapid and adequate assessment of the overall cytotoxicity of the reaction under consideration. Illustrative examples of bio-Profiles and bio-Strips of chemical reactions built on the basis of the obtained data are provided, and the possibilities of their application to assess the hazard of a chemical reaction for the environment and humans are demonstrated.

Chapter 3 consisting of six sections concerns the analysis of promising green methods for organic synthesis. Section 3.1 analyzes green methods of direct activation of carbon-hydrogen bonds in aromatic and non-aromatic systems, which do not require the introduction of auxiliary and protective groups and allow their direct conversion into carbon-carbon or carbon-heteroatom bonds. Such processes are extremely useful in the development of innovative technologies for the production of pharmaceuticals, plant protection chemicals and other practically relevant fine organic chemicals. Among the methods considered are green C(sp²) – H functionalization processes in cyclic systems, including catalytic processes of this type developed in recent years, and reactions of selective catalytic oxidative functionalization of aliphatic C – H groups of complex organic molecules upon treatment with hydrogen peroxide.

The paradigm of green chemistry is clearly seen in the studies aimed at developing modern variants of catalytic cross-coupling reactions of organic molecules, which is a convenient way to directly build carbon – carbon and carbon – heteroatom bonds in organic compounds. Section 3.2 shows that the Suzuki – Miyaura, Sonogashira, Heck, Chan – Evans – Lam and some other processes of this type can be carried out successfully in water (a cheap, safe and non-toxic solvent), in various water – organic mixtures, in other green solvents (ethylene glycol, glycerol, polyethylene glycols, etc.) or under neat conditions. Not only metal complexes (palladium, cobalt, iron, copper, zinc, nickel, etc.) but also their salts, oxides or nanoparticles can act as pre-catalysts, even without ligands. Such reactions can be effectively activated by microwave and ultrasound irradiation.

The asymmetric organocatalysis methodology, which is one of the most dynamically developing areas of modern organic synthesis, is also highly complementary to green chemistry. Metal-free catalysts cannot contaminate pharmacological products. They are generally stable in air and in aqueous media, which is a prerequisite for the development of green technologies suitable for the production of enantiomerically pure drugs without harmful side effects. Three promising directions of asymmetric organocatalysis that fully comply with the criteria and principles of green chemistry are discussed in Section 3.3. They include the development of highly selective, step- and atom-economic organocatalytic syntheses of biologically active compounds, organocatalysis in a continuous flow and the combined use of organo- and photocatalysts in enantioselective reactions using visible light energy.

Electric current is an extremely promising green energy source for organic synthesis. Chemical reactions, including catalytic ones, carried out under electrolytic conditions, avoid the use of traditional, often toxic, chemical oxidants and reducing agents, replacing them with electrodes that transfer or accept the electron — the most environmentally friendly reagent — from reactants. Section 3.4 summarizes the recent findings in the development of electrochemical methods for green organic synthesis. In particular, new approaches to the electrochemical synthesis of diversely functionalized complex organic molecules have been considered and the new possibilities offered by this method for modifying the reactivity of organic substrates and increasing the efficiency and selectivity of chemical transformations, including in the late synthetic stages, have been demonstrated. Much attention is paid to the use of electricity for reduction and utilization of carbon dioxide, a greenhouse gas that accumulates in the atmosphere because of the uncontrolled combustion of hydrocarbon fuels and contributes to global warming. Electroreduction of carbon dioxide converts it into single-carbon molecules necessary for chemical industry, such as carbon monoxide, formic acid, methanol, and methane, or into more complex organic compounds containing CO₂ as a structural unit. The principles of electrochemical conversion of carbon dioxide into useful products, in particular, under catalytic and photoactivation conditions, and instrumentation features of such processes are considered.

A high degree of environmental friendliness is associated with chemical reactions, in which several relatively simple compounds react in series or in parallel to produce highly complex organic products in a single experimental step. Multicomponent reactions not only reduce the number of steps in chemical processes, but also significantly reduce waste related to the separation and purification of intermediate compounds. Section 3.5 presents a number of reactions of this type carried out in green solvents or reagent media using catalysts or electrocatalysis as well as ultrasonic, microwave and mechanical activation.

Heterogeneous catalysts are the most attractive for the chemical industry. Section 3.6 discusses the application of such catalysts in green redox processes of fine chemistry. In particular, the reactions of ‘hydrogen-free’ hydrogenation of multiple bonds using alcohols as hydrogen carriers, reactions of catalytic oxidation under the action of oxygen and hydroperoxides, and photocatalytic transformations of glycerol, a promising natural platform compound for organic synthesis, are highlighted. It is shown that the efficiency of mono- and bimetallic heterogeneous catalysts for such reactions can be improved by preparing them in supercritical fluid media, including carbon dioxide and alcohols.

The key to liquid-phase chemical processes is the solvent, which improve the rate and selectivity of the chemical reaction by solvating the reactants. However, once the reaction is complete the solvent should be recovered and purified, which requires additional energy and resources. In addition, many petroleum-derived solvents are toxic and pollute the atmosphere upon evaporation. It is therefore important to use alternative reaction media that are non-toxic and easily separable from reagents and products. Chapter 4 considers chemical reactions, including catalytic ones, carried out in liquid eutectic mixtures of simple and readily available non-volatile compounds, usually of natural origin, or in the liquid or supercritical carbon dioxide. Eutectic mixtures have low vapour pressures. With the proper choice of components, they are non-flammable and biodegradable. The carbon dioxide can be easily removed from the products via decompression and, being taken from the air itself, it does not contribute to global warming.

A promising trend in modern organic synthesis is the widespread use of biomass, including wood products, as a renewable raw material for the production of a variety of chemical compounds and fuels. The use of bioresources and biowaste reduces the need for petroleum products in the chemical industry and reduces greenhouse gas emissions. In addition, many natural compounds contain elements of chirality, which are essential for the development of highly effective pharmaceuticals. Chapter 5 of the review shows that natural mono- and diterpenes are excellent versatile synthons for the preparation of bioactive substances (anticancer and antibacterial drugs, antioxidants), chemical plant protection agents, chiral organocatalysts and ligands, biocompatible fluorescent markers and other useful compounds.

The application of green chemistry methods to processes providing functional organic materials, such as polymers and energetic products, is discussed in Chapter 6. Section 6.1 analyzes the features of emulsion radical polymerization in aqueous medium in the presence of surfactants as an environmentally friendly method that allows reliable control of process parameters and molecular weight characteristics of the product. The environmental impact of emulsion radical polymerization is considered and the advantages and disadvantages of new approaches proposed in recent years in this practically important field are addressed. Section 6.2 highlights the development of environmentally friendly methods for the synthesis of energetic compounds and materials. Classical nitration processes generate large amounts of waste: spent mixed acids, toxic solvents and other byproducts, the use of which is energy- and resource-consuming. The review discusses promising ‘green’ methods for carrying out these reactions without the use of sulfuric acid. In addition, green methods for producing energy-rich microsized and nanosized modifications of energetic materials in stable gases, such as carbon dioxide and low-molecular freons in liquid or supercritical state, are considered.

The implementation of the green chemistry paradigm is particularly relevant in the chemical industry, where it is necessary to account for a whole range of requirements related to economic efficiency, prevention of hazardous waste, need to increase plant productivity, minimization of fossil fuel consumption, decarbonization, changeover to renewable raw materials and a number of others. Chapter 7 of the review shows that some of these issues can be addressed on an industrial scale, based on the concept of two-phase catalysis, through the use of heterogeneous catalysts, including zeolites and metal oxides, alternative feedstock types (CO₂) and energy sources (electricity or sunlight).

Over the decades, reliable assessment of the toxic potential of chemical reactions has seemed an impossible task, mainly because of the extreme complexity of the processes involved in the interaction of chemicals with living organisms and the environment.^{21 – 24} The increasing popularity of catalytic reactions and the development of the pharmaceutical industry in recent years has spurred the interest to possible harmful effects of the corresponding chemicals on the environment and humans.^{25 – 28} Despite the scientific community’s desire to follow the concepts of sustainable development,^29, 30 the chemical industry continues to cause significant environmental damage.

The introduction of the E factor and the concept of atom-economy helped to re-evaluate the industrial applications of chemical processes.^{31 – 33} Metrics have been developed to calculate material balance, waste, reagent and solvent recovery potentials.^30, 34 Currently, green chemistry metrics represent a specific scientific field with a significant impact on research and industrial projects.^{35 – 37}

The methodologies that have been developed to classify chemicals according to their potential hazard to living organisms typically involve multistep procedures with testing of different biological objects and systems.^{21, 28, 38 – 43} However, obtaining a reliable assessment of the potential environmental impact of a chemical process is extremely challenging. Thus, to assess the systemic effects of a chemical on an organism, many parameters should be considered, including general cytotoxicity, genotoxicity, immunotoxicity, metabolic toxicity, neurotoxicity, reproductive and embryonic toxicity, and more.⁴⁴ Therefore, none of the methodologies developed to date allow for rapid preliminary risk assessment of a wide range of chemicals and processes.

Recently, Ananikov et al.^45, 46 proposed a new methodology for rapid preliminary assessment of potential hazards of chemical processes to living organisms. The idea is to use existing toxicity metrics (e.g., median lethal doses, LD₅₀s) of substances involved in or produced by a given reaction to build diagrams (tox-Profiles) that clearly show the relative contribution of these substances to the ‘overall toxicity’ of the reaction.

The choice of toxicity metric is important. One of the most reliable metrics is considered to be the median lethal doses of substances determined in mammals such as rats and mice, since the results obtained on this basis can be extrapolated to humans with a certain degree of reliability. However, the numerical toxicity indices (LD₅₀, IC₅₀, EC₅₀, etc.) currently available in the scientific literature and databases are often poorly described, and the lack of information on experimental conditions and methods of determination makes it impossible to compare indices obtained by different research groups, even in the experiments performed on the same organism.²³ In addition, chemists synthesize thousands of novel chemical compounds annually, and toxicological studies are simply failing to keep up with the synthetic ones. Ethical standards and the desire to reduce animal testing should also be kept in mind. Even for known substances, toxicity data are often not available from recognized sources such as the NLM PubChem database,⁴⁰ material safety data sheets, etc. As a result, it is currently difficult to assess the overall toxicity of even the simplest chemical reactions using the LD₅₀ values of the compounds involved.

For this reason, we have proposed the use of cytotoxicity data to build tox-Profiles of chemical reactions, namely bio-Profiles and bio-Strips. This concept involves using the values of half-maximal cytotoxic concentrations (CC₅₀) of all substances involved in a chemical reaction or formed during its course to estimate the ‘overall cytotoxicity’ of this reaction.⁴⁶ Cytotoxicity assays are much simpler and faster than laborious animal experiments and allow rapid cytotoxicity screening of a large number of chemicals in different cell lines. To date, this approach has been successfully applied to the analysis of such demanded chemical reactions as the Suzuki, Friedel-Crafts and Heck reactions.^{46 – 49}

The simplest way to build the bio-Profile of a reaction is to equate the area of the sections of a diagram with the mass of compounds involved or formed in the reaction, and to equate the colour of the sectors to the toxicity indices of these substances measured in a particular organism (Fig. 1a). The most toxic substance corresponds to the red colour, the least toxic substance corresponds to the green colour and all the other substances correspond to the intermediate shades of red, orange and yellow. In the given example, the starting materials SM1 and SM2 correspond to sectors of small area according to their quantities. The diagram also includes the target product P, the byproduct BP and the substance R (an auxiliary reagent). The sector with the smallest area corresponds to the catalyst CT, and the sector with the largest area corresponds to the solvent S.

Fig. 1

Exemplary bio-Profiles of a chemical reaction (shown in general form above the table). In diagram a, the area of the sectors corresponds to the mass of substances involved in the reaction, while in diagram b, the area of the sectors corresponds to the ‘normalized cytotoxicity’ (NC) of the substances (the ratio of the amount of a substance to its half-maximal cytotoxic concentration (CC₅₀)). The table shows arbitrary values used for the example. The colours of the sectors correspond to CC₅₀s of the substances in a given cell line; the relative cytotoxicity scales are given below the diagrams. The most toxic substance is shown in red, the least toxic substance is shown in green and all the other substances are shown in the intermediate shades of red, orange and yellow. Reproduced from Ref. 46 with permission from the Royal Society of Chemistry.

When concentration metrics such as half-maximal cytotoxic concentrations (CC₅₀s) are used as indicators of the substance toxicity, the relative contribution of each substance to the ‘overall toxicity’ of the reaction system can be visualized by equating the area of the sectors in the diagram to the ‘normalized cytotoxicity’ (NC) of the compounds (see Eq. (1)):

(1)

where n is the amount of a substance involved in a particular reaction (mmol), and CC₅₀ is a half-maximal cytotoxic concentration (mmol L^–1, mM) measured in a certain cell line. Accordingly, the larger the sector area, the greater the contribution of the substance to the overall cytotoxicity of the process. The colour of the sectors also corresponds to the CC₅₀ values of the substances. Fig. 1b shows a bio-Profile of the same reaction plotted with NC of the substances. It can be seen that in this case the substances with higher cytotoxicity (i.e. lower CC₅₀ values) have larger sectors (see, e.g., starting material SM1, catalyst CT, reagent R and product P). Conversely, the substances with lower cytotoxicity correspond to the sectors of smaller area (starting material SM2, solvent S). The byproduct BP, which has low cytotoxicity and is formed in small amounts, looks the same in both diagrams.

The bio-Strip of a chemical reaction is a compact form of the bio-Profile in which each reaction is represented by a strip consisting of sections.³¹ These sections correspond to the substances involved in a particular chemical reaction and the length of the sections is equal to the ‘normalized cytotoxicity’ of these substances (see Eq. (1)). Therefore, the longer the section, the greater the contribution of the substance to the overall cytotoxicity of the reaction. The colours of the sections correspond to the CC₅₀s of the substances in a given cell line: the substance showing the maximum cytotoxicity (i.e., having the lowest CC₅₀) is shown in red, the substance showing the minimum cytotoxicity (i.e., having the highest CC₅₀) is shown in green, and the remaining substances are shown in the intermediate shades of red, orange, and yellow. An example of bio-Strips for six methods of 1,1'-biphenyl synthesis is given in Fig. 2. The reactions are shown above the bio-Strips, while the common cytotoxicity scale and a list of reaction names and abbreviations are shown at the bottom of the figure. Each bio-Strip is also supplied with a bio-Factor (BF), which shows the change in the overall cytotoxicity of the reaction over time (see Eq. (2)):

(2)

where out and in denote substances leaving the reaction (products, byproducts and reagents that can be regenerated, such as catalysts and solvents) and entering the reaction (starting materials, catalysts, solvents and other reagents), respectively. If BF >1, the overall cytotoxicity of the reaction increases over time; if BF <1, the overall cytotoxicity of the reaction decreases.

Fig. 2

bio-Strips of six methods of synthesis of 1,1'-biphenyl using various catalysts (Pd(OAc)₂ (A), PdCl₂ (B) or Pd(acac)₂ (C)) and solvents (ethanol (A) or N-methylpyrrolidone (NMP) (B)). The reactions are shown above the bio-Strips, while the common cytotoxicity scale and explanations of the reaction names and abbreviations are given at the bottom of the Figure. The lengths of the bio-Strip sections correspond to the NC of the substances, and the colours correspond to the CC₅₀s of these substances determined in a given cell line (here, human colorectal adenocarcinoma CaCo-2 cells). The BF values of the reactions are also given within the bio-Strips. Reproduced from Ref. 49 with permission from Elsevier.

The reactions shown in Fig. 2 differ in the starting materials, catalysts, reagents and solvents, as indicated by the first, second, third and fourth letters of the reaction names. For clarity, the same starting materials (phenylboronic acid (SM1) and iodobenzene (SM2, A), the first letter in the reaction name) and the same reagent (K₂CO₃ (R, A), the third letter in the reaction name) are used in all the reactions. In the case of the catalyst (CT), A = Pd(OAc)₂, B = PdCl₂ and C = Pd(acac)₂; in the case of the solvent (S), A = ethanol and B = N-methylpyrrolidone (NMP). Looking at the bio-Strips of these methods for the synthesis of 1,1'-biphenyl, one can immediately assume that catalysts A (Pd(OAc)₂) and B (PdCl₂) and solvent A (ethanol) are more beneficial in terms of their contribution to the overall cytotoxicity of the reactions. This conclusion is supported by both the length of the corresponding sections of the bio-Strips and their colours.

In addition to bio-Factors, the cytotoxicity potentials of reactions are also used: (1) the initial cytotoxicity potential (CP_i), or the cytotoxicity potential of the substances entering the reaction (see Eq. (3)); (2) the final cytotoxicity potential (CP_f) or the cytotoxicity potential of the substances leaving the reaction (see Eq. (4)); and (3) the relative final cytotoxicity potential (CP_{f_rel}) or the cytotoxicity potential of the substances leaving the reaction except for the target product (see eq. 5).

where out and in denote substances leaving the reaction and entering the reaction, respectively. Thus, CP_i and CP_f essentially quantify the hazard of a specific chemical reaction to a given cell culture, i.e. how many litres of the culture medium can be ‘poisoned’ by the substances entering or leaving the reaction. CP_{f_rel} is a special case of CP_f that does not account for the cyto­toxicity of the target product, but does take into account the byproducts.

Here we analyze in detail the use of bio-Strips to identify the ‘safest’ and ‘most hazardous’ components of chemical reactions, using the synthesis of 1,1'-biphenyl as an example.⁴⁹ We consider 36 methods for the synthesis of 1,1'-biphenyl which differ in the (1) starting materials (iodobenzene, bromobenzene), (2) catalysts (Pd(OAc)₂, PdCl₂, Pd(acac)₂), (3) reagents (K₂CO₃, Na₂CO₃, Cs₂CO₃), and (4) solvents (ethanol, NMP). bio-Strips for these reactions were build by using half-maximal cytotoxic concentrations after 24 hours of incubation (24-h CC₅₀s) measured in three cell lines: CaCo-2 (human colorectal adenocarcinoma), HEK293T (human embryonic kidney) and FRSN (human foreskin mesenchymal stem cells). Summary information on these reactions, including bio-Factors and cytotoxicity potentials, is presented in Table 1; the initial data used in the calculations are given in Table 2. bio-Strips plotted against the CC₅₀ values obtained in the CaCo-2, HEK293T, and FRSN cell lines are shown in Fig. 3, Fig. 4 and Fig. 5, respectively.

Fig. 3

bio-Strips of 36 methods of synthesis of 1,1'-biphenyl built by using CC₅₀ values measured in the CaCo-2 cell line. The letters in the reaction names indicate, correspondingly, the type of starting material (SM2: iodobenzene (A) or bromobenzene (B)), catalyst (CT: Pd(OAc)₂ (A), PdCl₂ (B) or Pd(acac)₂ (C)), reagent (R: K₂CO₃ (A), Na₂CO₃ (B) or Cs₂CO₃ (C)) and solvent (S: ethanol (A) or NMP (B)). The lengths of the sections correspond to the NC values of the substances, and the colours correspond to their CC₅₀ values (see the cytotoxicity scale above the bio-Strips). The bio-Factor values are given within the bio-Strips. Reproduced from Ref. 49 with permission from Elsevier.

Fig. 4

bio-Strips of 36 methods of synthesis of 1,1'-biphenyl built by using CC₅₀ values measured in the HEK293T cell line. The letters in the reaction names indicate, correspondingly, the type of starting material (SM2: iodobenzene (A) or bromobenzene (B)), catalyst (CT: Pd(OAc)₂ (A), PdCl₂ (B) or Pd(acac)₂ (C)), reagent (R: K₂CO₃ (A), Na₂CO₃ (B) or Cs₂CO₃ (C)) and solvent (S: ethanol (A) or NMP (B)). The lengths of the sections correspond to the NC values of the substances, and the colours correspond to their CC₅₀ values (see the cytotoxicity scale above the bio-Strips). The bio-Factor values are given within the bio-Strips. Reproduced from Ref. 49 with permission from Elsevier.

Fig. 5

bio-Strips of 36 methods of synthesis of 1,1'-biphenyl built by using CC₅₀ values measured in the FRSN cell line. The letters in the reaction names indicate, in order, the type of starting material (SM2: iodobenzene (A) or bromobenzene (B)), catalyst (CT: Pd(OAc)₂ (A), PdCl₂ (B) or Pd(acac)₂ (C)), reagent (R: K₂CO₃ (A), Na₂CO₃ (B) or Cs₂CO₃ (C)) and solvent (S: ethanol (A) or NMP (B)). The lengths of the sections correspond to the NC values of the substances, and the colours correspond to their CC₅₀ values (see the cytotoxicity scale above the bio-Strips). The bio-Factor values are given within the bio-Strips. Reproduced from Ref. 49 with permission from Elsevier.

Table 1

\[ \]

bio-Factors and cytotoxicity potentials for 36 methods of synthesis of 1,1'-biphenyl.⁴⁹

(1)

Table 2

\[ \]

Experimental data used to build bio-Strips for 36 methods of synthesis of 1,1'-biphenyl.⁴⁹

(2)

Upon looking at the bio-Strips of the 1,1'-biphenyl syntheses analyzed, several immediate assumptions can be made.

1. Catalyst C (Pd(acac)₂) contributes most to the overall cytotoxicity in all the cell lines tested (the effect is particularly evident in FRSN cells where the 24-h CC₅₀ of this compound is as low as 7 mM; see Table 2 and Fig. 5).

2. Of the two solvents tested, solvent A (ethanol) was significantly less cytotoxic than solvent B (NMP).

3. Reagent C (Cs₂CO₃) was more cytotoxic than reagents A and B (K₂CO₃ and Na₂CO₃, respectively).

As for the starting materials, substance B (bromobenzene) contributes less to the overall cytotoxicity than substance A (iodobenzene), but this effect is weaker than that of the catalyst and solvent. However, since the phenyl halide and the reagent determine the byproducts formed, their choice requires further analysis. In the case of phenyl halide, which determines the byproduct salt, KBr has lower cytotoxicity than KI in CaCo-2 cells, whereas the cytotoxicity of these two potassium salts is comparable in HEK293T and FRSN cells. NaI and NaBr as well as CsI and CsBr show comparable cytotoxicity in all the cell lines tested. Therefore, iodobenzene and bromobenzene are similar in terms of the cytotoxicity of the bromides and iodides formed.

Potassium, sodium or cesium tetraborate is also formed as a byproduct during the reaction, depending on the reagent (K₂CO₃, Na₂CO₃ or Cs₂CO₃, respectively). Cs₂B₄O₇ shows higher cytotoxicity than Na₂B₄O₇ in the CaCo-2 and HEK293T cell lines, whereas all three tetraborates show comparable cytotoxicity in FRSN cells. This observation supports the above-discussed suggestion that K₂CO₃ or Na₂CO₃ is preferable in the reaction.

To summarize, reactions with Pd(acac)₂ as a catalyst, NMP as a solvent and Cs₂CO₃ as a reagent seem to be more hazardous approaches in terms of the total cytotoxicity of the reactions.

Regarding the bio-Factors of the considered methods of 1,1'-biphenyl synthesis, it can be seen from Table 1 that in all cases the BF values are below 1, and consequently the overall cytotoxicity decreases during the reaction. The main reason for this decrease is the difference between the cytotoxicity of the products and that of the starting materials: the target product and byproducts, including boric acid, are mostly less cytotoxic than the phenylboronic acid and phenyl halides used as starting materials. Palladium salts, despite their high cytotoxicity, are present in both the numerator and denominator of Eq. (2) and therefore do not contribute significantly to the BF value. Nevertheless, the bio-Factors of the reactions catalyzed by Pd(acac)₂ are higher than those of the reactions using Pd(OAc)₂ or PdCl₂ (see, e.g., reactions A-A-A-A, A-B-A-A and A-C-A-A-A or A-A-A-B, A-B-A-B and A-C-A-B in Table 1). This difference is particularly evident in the case of FRSN cells, where Pd(acac)₂ shows the highest cytotoxicity. NMP as a solvent also increases BFs in some cases, but not as significantly (see, e.g., reactions A-A-A-A and A-A-A-B or A-B-A-A and A-B-A-B in Table 1).

Fig. 6 shows a comparison of CP_i, CP_f and CP_{f_rel} of all the considered routes of synthesis of 1,1'-biphenyl based on the data obtained in three cell lines (see Table 1 for exact values). Such presentation of the data makes it possible to immediately identify the synthetic routes with the highest and lowest cytotoxicity potentials of the initial and final substances. Obviously, the use of Pd(acac)₂ significantly increases CP_i, CP_f and CP_{f_rel} in all the cases (see diagrams labeled N-C-N-N in Fig. 6, where N stands for any possible letter, i.e. A, B or C, depending on the reaction component). The contributions of NMP and Cs₂CO₃ appear to be much smaller or, in the latter case, negligible compared to this catalyst (see the reaction diagrams labelled N-N-N-B and N-N-C-N, respectively, in Fig. 6). Thus, the analysis of the initial and final cytotoxicity potentials of chemical reactions allows suggesting less dangerous synthetic routes from the viewpoint of the cytotoxicity of their components.

Fig. 6

Cytotoxicity potentials of 36 routes of synthesis of 1,1'-biphenyl calculated from CC₅₀ values measured in (a) CaCo-2, (b) HEK293T and (c) FRSN cell lines. Reproduced from Ref. 49 with permission from Elsevier.

The choice of the cell line used to obtain CC₅₀ values for the construction of bio-Profiles and bio-Strips of chemical reactions can be crucial. Three human cell lines of different origin were used in the publication ⁴⁹: CaCo-2 (colorectal adenocarcinoma cells), HEK293T (human embryonic kidney, immortalized non-cancer cells) and FRSN (foreskin mesenchymal stem cells, non-immortalized fibroblast-like cells). Due to genomic differences as well as different origins, these cells were expected to have different sensitivities to chemicals. This assumption was confirmed for at least some components of the reactions studied. A comparison of the 24-h CC₅₀ values measured in the three cell lines is presented in the form of a heat map in Fig. 7. The colour of the cells in the Table corresponds to the given 24-h CC₅₀ values, from the lowest (red) to the highest (green).

Fig. 7

Comparison of cytotoxicity of the studied chemicals in three cell lines (CaCo-2, HEK293T, and FRSN). The colour of the cells in the table corresponds to the 24-h CC₅₀ values given, from lowest (red) to highest (green). The colour legend for each cell line is shown at the bottom, with the midpoint corresponding to the 50th percentile.

It should be noted that FRSN cells were much more sensitive to Pd(acac)₂ than CaCo-2 cells. A similar effect was observed for PdCl₂, 1,1'-biphenyl, KI, NaI, KBr and H₃BO₃: for all these substances, the 24-h CC₅₀ values obtained in FRSN cells were much lower than those obtained in CaCo-2 cells. The opposite effect was observed for ethanol, CsI, CsBr, K₂B₄O₇ and Cs₂B₄O₇ . Comparing the CaCo-2 and HEK293T cells, the latter were more sensitive to phenylboronic acid, Pd(acac)₂, Cs₂CO₃, KI, NaI, KBr, NaBr and H₃BO₃, but less sensitive to iodobenzene, bromobenzene, CsBr and K₂B₄O₇ .

Thus, no clear correlation was observed between the type of cell line and its sensitivity to the substances tested. However, it should be noted that all the cells showed the highest sensitivity to palladium salts (especially Pd(acac)₂) and the lowest sensitivity to ethanol. The sensitivity to the starting materials (phenylboronic acid, iodobenzene and bromobenzene) was also quite high in all the cases. Among the tested salts, the cesium salts (both reagent and byproducts) showed the highest cytotoxicity. Based on these observations, it can be assumed that in this case the choice of cell line was moderately or even slightly reflected in the bio-Strips. Of course, it should be borne in mind that this conclusion concerns the order of cytotoxicity of the substances tested rather than the exact 24-h CC₅₀ values and the corresponding cytotoxicity potentials. In any case, the use of a large number of cell lines of different origins allows a more reliable assessment of the potential hazard of chemical reactions to animals and humans.

The bio-Profile concept is therefore universal and can be used to visually and quantitatively assess the effect of a chemical reaction on any biological object. The choice of object or biochemical process depends entirely on the objectives of the study. For example, in the case of industrial chemical reactions, it is expedient to use the most sensitive organisms in the ecosystems that may be affected by these reactions, whereas for laboratory chemical reactions with narrower applications, it is logical to choose mammals to model the possible harmful effects of reaction components on humans. Suitable microorganisms can be used for bio-Profiles of biocatalytic processes.

Cell cultures are versatile biological systems for rapid screening for cytotoxicity of a large number of chemicals at the first stage of investigation of their toxicity potential. In particular, skin fibroblasts are often used as a simplified model in toxicology.^50, 51 The low cost and relative simplicity of cytotoxicity testing make the cell cultures a suitable biological target for the construction of bio-Profiles, which can be used to pre-evaluate the harmful effects of chemical processes on living organisms and to identify the most toxic substances involved in these processes. The obtained data can subsequently form the basis for more specialized toxicological studies on higher organisms. bio-Profiles will help to select substances and processes in need of such a study.

The key role in the design of green chemical processes belongs to the choice of the method that would provide the most efficient implementation of the process with a minimum environmental impact. According to the basic principles of green chemistry, an ideal method should produce no waste and employ safe reactants, solvents and auxiliary materials that should be mainly obtained from renewable feedstock. The method should exclude the formation of toxic products and also be resource-saving, energy-efficient and safe for humans, flora and fauna. It is clear that while developing a new synthetic approach, chemists have to sacrifice some of the above principles. Nevertheless, the set of these principles as well as the PASE (pot, atom, step economy) concept ⁵² must be necessarily borne in mind as important benchmarks. This chapter of the review addresses synthetic methods that largely comply with the green chemistry requirements and can be recommended for the use in research and teaching chemistry laboratories and as a possible base for the design of new, environmentally benign processes of small-scale chemical production.

The С – Н bond is widely spread in the world of organic compounds and, therefore, it is potentially one of the most important structural groups. Quite naturally, direct C – H functionalization reactions with a variety of mechanisms have always been of interest for organic chemists. The reactions that do not require the introduction of auxiliary groups and allow direct transformation of the carbon–hydrogen bond to C – C or C – Х bond (Х = heteroatom) are especially attractive.⁵³ These strategies markedly reduce the number of steps in the synthesis of a target organic compound (step economy).⁵⁴ In this section, we consider the data published in recent years on the most interesting and promising methods for direct functionalization of the C(sp²) – H and C(sp³) – H bonds in structurally diverse aromatic and non-aromatic systems and analyze the benefits and drawbacks of each method.

First, we will analyze the green strategies for the direct C(sp²) – H functionalization of cyclic systems developed in recent years. These processes receive a great deal of attention, as evidenced by the number of publications, review articles and monographs addressing this topic.^{55 – 65} The nature and the range of reactants suitable for the С – Н functionalization are being expanded and the reaction mechanisms are being studied. Meanwhile, many problems associated with implementation of PASE reactions,⁵² in particular direct C(sp²) – H modification of organic compounds, have not yet been solved.

Herein, we consider characteristic features of non-catalytic approaches to C(sp²) – H-bond functionalization in aromatic and non-aromatic cyclic systems as well as modern protocols for conducting these reactions that include the use of metal catalysts and organocatalysts. The methods based on the catalytic activation of reactants using alternative energy sources (photoredox catalysis, electrocatalysis and mechanocatalysis) are discussed in other parts of this review.

The non-catalytic C(sp²) – H functionalization methods date back to the mid-19th century and are related, first of all, to the development of the electrophilic aromatic substitution (S_EAr) of hydrogen and discovery of nitration, sulfonation, acylation, azo coupling as well as the Vilsmeier, Kolbe – Schmitt, Bischler – Napieralsky reactions and many other name reactions used to introduce halogen atoms, nitro and sulfonic groups, and acyl, chlorosulfonyl, haloform, and other electrophilic residues into the aromatic ring (Scheme 1).

Scheme 1

The reactions of arenes with electrophiles are a widespread and well-studied type of C(sp²) – H functionalization, regarding the reaction mechanism (S_EAr) and scope of applicability. A great contribution to investigation of the S_EAr mechanism and rearrangements of cationic intermediates was made by Novosibirsk chemists V.G.Shubin, V.A.Barkhash and V.D.Shteingarts under the supervision of Academician V.A.Koptyug, who were awarded the Lenin Prize in 1990 for the series of studies entitled Modern Problems of the Chemistry of Arenonium Ions, and by American chemists headed by Professor G.A.Olah, who was awarded the Nobel Prize in chemistry in 1993.

The electrophilic substitution of hydrogen in arenes appears to be quite a natural reaction, because neither the attack of the arene by an electrophilic species nor elimination of the proton from the intermediate arenonium ion is associated with a high energy barrier. A different situation arises when arenes are attacked by nucleophilic reagents to give anionic or neutral σ^H adducts 1 (Scheme 2), which are not prone to eliminate a proton (hydrogen atom) without assistance of an oxidant or auxiliary agent.

Scheme 2

Therefore, the S_EAr reactions receive much less attention in this review than nucleophilic or radical C(sp²) – H functionalization reactions, which have been developed much later. One of the first examples of nucleophilic C(sp²) – H functionalization ^{66 – 68} is the Chichibabin amination, which was first described in 1914. The reaction proceeds under fairly drastic conditions (heating with sodium amide in xylene) and produces molecular hydrogen (Scheme 3); however, the mechanism of this reaction has long been obscure.

Scheme 3

This topic was actively pursued in the 1970s, after O.N.Chupakhin initiated an extensive series of studies dealing with the nucleophilic С – Н functionalization of arenes. Together with Academician I.Ya.Postovskii, O.N.Chupakhin published the first review on the nucleophilic substitution of hydrogen in the Russian Chemical Reviews journal.⁶⁹ These reactions were designated as S_N^H. The Chichibabin reaction has attracted attention of many chemists both in Russia (A.F.Pozharskii,⁷⁰ A.V.Gulevskaya,⁷¹ I.V.Borovlev,⁷² etc.) and abroad (H.van der Plas,⁷³ M.Mąkosza ⁷⁴). The optimal conditions for the reaction were selected, more efficient oxidation systems were proposed, and views on the reaction mechanism were developed for both oxidative and eliminative types.

The mechanism of the nucleophilic aromatic substitution of hydrogen can be considered as a sort of analogue of the S_EAr mechanism, but with the opposite polarity.⁷⁵ Indeed, the key intermediate of the S_N^H reactions is the anionic s^Н adduct 1 (see Scheme 2),⁷⁶ resulting from the addition of a nucleophilic species to the unsaturated ring. Rearomatization can be accomplished by oxidation of the intermediate s^Н adduct with the loss of a proton and two electrons (addition — oxidation, S_N^H[AO], mechanism).

Alternatively, elimination may take place because of the presence of a vicarious leaving group in the substrate or the nucleophilic agent (addition — elimination, S_N^H[AE], mechanism). This accounts for the formation of unusual cine- and tele-substitution products (Scheme 4a,b) and gives rise to the reaction called vicarious nucleophilic substitution of hydrogen (Scheme 4c).^{74 – 77}

Scheme 4

The range of reactions that follow the S_N^H mechanism is still being supplemented with new examples. For instance, in 2022, Mandler et al.⁷⁸ reported successful С – Н amination of nitro-substituted heteroarenes (pyridines, azoles and thiophenes) and nitrobenzene derivatives 2 with (hetero)aromatic amines 3 (Scheme 5).

Scheme 5

This reaction smoothly proceeds in an open flask at room temperature in the presence of lithium bis(trimethylsilyl)amide (LiHMDS). These conditions significantly facilitate conduction of the reaction in comparison with the classic Chichibabin amination, which proceeds in liquid ammonia at low temperatures.⁷⁶ According to the results obtained by the authors, the reaction follows the S_N^H[AO] mechanism, with air oxygen acting as the oxidant.⁷⁸ The obvious advantages of this approach, as regards green chemistry, are the short reaction time (10 min), the use of an environmentally benign oxidant, and the possibility of carrying out the reaction in a relatively low-toxic solvent (THF) at room temperature. The drawbacks of the method include modest yields of products 4, which can be somewhat increased by using a greater excess of the starting nitroheteroarene and LiHMDS.

In the same year of 2022, Chang and co-workers demonstrated the possibility of C – H amination of pyrimidines,⁷⁹ which was distinguished by C(2)-regioselectivity. It was found that pyrimidine N-oxides 5 (Scheme 6) generated in situ by oxidation of appropriate pyrimidines react with N-nucleophile 6 in the presence of trifluoromethanesulfonic anhydride to give mainly the products of C(2)-functionalization of the pyrimidine ring in 7.

Scheme 6

N-Nucleophiles 6 can be represented by imidoyl chlorides or pyridine derivatives containing electron-withdrawing cyano, CF₃ or benzoyl substituents. However, the reaction with 4-dimethylaminopyridine (DMAP) afforded mixtures of C(2)- and C(4)-substituted products. Note that the C(2)-substituted products 7 can be subjected to subsequent one-pot derivatization to give pyrimidine amino derivatives 8.

Another example of the S_N^H reaction unusual from the mechanistic standpoint was reported in 2021 by Jiao, Hao and co-workers ⁸⁰ (Scheme 7). The authors proved the possibility of direct α-alkoxylation of BODIPY derivatives 9 via nucleophilic substitution of hydrogen; furthermore, they found that the reaction can be activated by the preliminary single-electron oxidation of BODIPY 9 to the corresponding radical cation by treatment with copper(I) thiophene-2-carboxylate (CuTc). This radical cation reacts with aliphatic alcohols 10 at one of the α-carbon atoms of the pyrromethene system. The neutral radical resulting from the addition of О-nucleophile undergoes one more single-electron oxidation, resulting in the target product 11.

Scheme 7

It is noteworthy that the S_N^H reaction concept is no longer limited to (hetero)aromatic compounds. Over the last 10 – 15 years, this strategy was extended to non-aromatic unsaturated substrates, in particular aldimine derivatives containing a C(sp²) – H bond at the azomethine moiety.^{81, 82} As an example, consider the reaction (Scheme 8) that is used to introduce a perfluorophenyl moiety into non-aromatic 2H-imidazole 1-oxides 12,⁸³ which can be regarded as cyclic nitrones. In this case, pentafluorophenyllithium 13,⁸⁴ obtained in situ by lithiation of pentafluorobenzene, was used as the C-nucleophile. The nucleophile addition to the imidazole ring gives unstable 𝜎-adduct 14, which is then transformed along both the oxidation and elimination pathways. The synthesized 2H-imidazole derivatives 15 are promising as fluorophores exhibiting the intramolecular charge transfer effect.

Scheme 8

While characterizing the contribution of the nucleophilic C(sp²) – H functionalization to the development of the green chemistry concept, we would like to note that particularly this strategy makes it possible to avoid the introduction of auxiliary groups; if activation is still required, it can often be performed in situ, which markedly simplifies the targeted synthesis. In addition, S_N^H reactions can often proceed as cross-dehydrogenative coupling that increases the atom efficiency of the synthesis. Furthermore, the S_N^H strategy usually does not require the use of transition metal-based reagents, although in some cases, these compounds [e.g., manganese, iron(III), chromium(VI), copper and cerium salts] can be used as oxidants. Generally, an excess of oxidant or other auxiliary reagent in nucleophilic C(sp²) – H-functionalization is one of the major factors that restrict the green potential of the reaction. Fortunately, many S_N^H reactions can be implemented using air oxygen, an almost ideal oxidant, since it gives water as a by-product. Also, electrochemical procedures for aromatization of the relatively stable 𝜎-adducts resistant to aerobic oxidation have been actively developed in recent years.^{85 – 87} In view of the fact that the scope of applicability of nucleophilic C(sp²) – H functionalization is constantly expanding and is no longer restricted to reactions of arenes, and also recalling the active development of the inventory of preparative methods, one can confidently predict further progress in the S_N^H concept and the utility of this reaction as an effective green chemistry method.

Yet another potent tool of C – H functionalization is the radical substitution reactions, which are actively used to modify not only sp²-hybridized, but also fully saturated systems. The functionalization of C(sp²) – H bonds in unsaturated systems follows two main mechanisms (Scheme 9). The first one is based on proton-coupled electron transfer (PCET),^{88 – 90} which may occur either consecutively [single-electron transfer (SET → proton transfer (PT)] (or in the reverse order) or synchronously [concerted proton – electron transfer (CPET)] (Scheme 9а).^* The latter mechanism can be regarded as a sort of the former one and implies the transfer of a hydrogen atom (HAT) as a unitary species ^{91 – 96} (Scheme 9b). Note that the greater part of PCET and HAT reactions can also occur in the presence of catalysts, in particular using photoredox catalysis.^{91 – 94}

Scheme 9

A useful method of radical C(sp²) – H functionalization is the Minisci reaction used to alkylate electron-deficient heteroarenes by treatment with nucleophilic carbon-centred radicals. Over more than half a century of history of this synthetic approach, various protocols have been found, some of them not requiring the use of transition metal-based catalysts.^{97 – 99} As an example of successful use of the non-catalyzed Minisci reaction, consider direct C(sp²) – H carbamoylation of purine bases 16, particularly adenine, guanine and xanthine derivatives (Scheme 10).¹⁰⁰

Scheme 10

This synthetic protocol involves the generation of active carbon-centred radicals 18 by decarboxylation of N-substituted oxamic acids 17, which, furthermore, increase the electrophilicity of purine substrates 16 via their protonation. The decarboxylation is initiated by the addition of ammonium persulfate, which decomposes to give SO₄^–• radical anions, which in turn trigger the transfer of the unpaired electron from the oxamate molecule with subsequent elimination of CO₂. The resulting carbamoyl radical 18 attacks N-protonated purine, yielding a radical cation adduct; in the presence of persulfate derivatives, the adduct is converted to the final carbamoylation product 19 via the proton and electron loss. According to the authors, this may take place by both the PCET and HAT mechanisms. The benefits of this approach include a broad substrate tolerance, good product yields and no need for transition metal-based reagents. Meanwhile, there are also drawbacks, which include the need to introduce N-protecting groups into adenines and guanines and the use of excess oxamic acids 17 and ammonium persulfate.¹⁰⁰

Another example reported by Melchiorre and co-workers in 2019 ¹⁰¹ is also actually the Minisci reaction; however, the mechanism of this transformation is somewhat different from the canonical mechanism. The authors used 4-acyl-containing Hantzsch esters 21 (Scheme 11) as a source of acyl radicals. The latter were generated under the action of blue light and were trapped by N-protonated (iso)quinolines 20 as the corresponding radical cations, which were converted upon deprotonation to neutral radical intermediates 22. Then, unlike the canonical mechanism of the Minisci reaction, a shift of the spin center and protonation of the acyl oxygen atom took place. The single-electron reduction of the resulting radical intermediate 23 led to the corresponding carbanion, the protonation of which (coupled with the deprotonation of the pyridine nitrogen) gave the final α-hydroxyalkylation product 24.¹⁰¹

Scheme 11

The most popular type of the non-catalyzed radical C – H functionalization implies the use of excess oxidant, which can be represented by peroxides, persulfates, quinones, hypervalent iodine compounds and other agents. These oxidants are rather easily available and are converted to low-toxic products. For example, (diacetoxyiodo)benzene [PIDA, PhI(OAc)₂], was used by Wang and co-workers for the oxidative cross-coupling of azoles 26 with quinoxalinones 25 at room temperature (Scheme 12).¹⁰²

Scheme 12

According to the mechanism proposed by the authors, PIDA is involved in the generation of the azole N-centred radical that adds to a molecule of quinoxalinone 25 to give the corresponding radical intermediate. The subsequent [1,2-H]-shift, single-electron oxidation and deprotonation afford 3-azolyl-substituted quinoxalin-2-one 27. This approach opens up the way to a fairly wide range of compounds; however, it requires the use of a twofold excess of azole 26 and a threefold excess of the oxidant.

* In earlier publications (before 2010), the term ‘proton-coupled electron transfer’ usually meant only the concerted proton and electron transfer; subsequently, this term was extended also to the consecutive SET and PT processes. In this review, the authors adhere to the current meaning of this term.

As noted above, many reactions including the activation of the C(sp²) – H bond proceed in the presence of catalysts and use either air oxygen ^{62 – 64} or an electric anode ^{85 – 87} as the oxidant. According to the green chemistry principles, catalysis considerably increases the green potential of chemical reactions. However, implementation of a reaction with a catalyst does not by itself ensure an advantage over non-catalyzed reactions. The selection of reaction conditions, synthetic availability of catalysts, ligands and reagents, energy and labour costs in organization of the synthesis, as well as productivity and versatility of the process are also significant. Yet, many modern catalytic procedures comply with most, if not with all, of the above requirements, which makes them highly promising.

The history of the use of catalysis in the C(sp²) – H functionalization processes goes back more than a century and a half. One of the first examples is the catalytic benzoin condensation proposed by N.N.Zinin back in 1840 (Scheme 13). The Friedel – Crafts alkylation of arenes and other electrophilic aromatic substitution reactions are also examples of catalytic reactions that occur in the presence of Lewis acids.¹⁰³ In the 20th century, the inventory of catalytic methods was markedly extended by using transition metal catalysis. Reactions such as Cu-catalyzed Meerwein C – H arylation of alkenes (through in situ formation of aryldiazonium salts), Pd-catalyzed Mizoroki – Heck C – H arylation of alkenes (on treatment with aryl halides), and Ag-catalyzed Minisci alkylation of electron-deficient heteroarenes have become a routine practice in modern organic synthesis.¹⁰³ The discovery of the Pd^II-catalyzed Fujiwara–Moritani reaction in the late 1960s was an important milestone in the development of catalytic approaches to oxidative С – Н/С – Н cross-coupling of two unsaturated substrates.¹⁰⁴

Scheme 13

A pioneer of organocatalytic C(sp²) – H functionalization is Professor R. Breslow, whose studies of the mechanism of benzoin condensation in the presence of azolium salts have stimulated the development of numerous reactions catalyzed by N-heterocyclic carbenes (NHCs).^105, 106 In the 1970s, the range of organocatalytic reactions was expanded owing to the discovery of Stetter, Morita – Baylis – Hillman and other reactions.

In the 21st century, the development of the C(sp²) – H functionalization was associated with the success in photoredox catalysis^* and asymmetric organocatalysis and with the development of various hybrid procedures involving two or more interrelated catalytic cycles within one reaction. Some types of catalytic reactions involving the C(sp²) – H bond in aromatic and non-aromatic rings are considered below using selected examples.

* Scheme 13 shows a vivid example reported by Fukuzumi’s research team back in 2011,¹⁰⁷ which demonstrates the formation of phenol from benzene and water in a homogeneous medium, which had long been considered impossible.

Over the past few decades, the use of a variety of transition metal-based catalysts for a wide range of cross-coupling reactions has become a usual practice of modern organic synthesis. Until quite recently, these reactions required catalysts based on palladium, copper or nickel. However, currently it is known that catalytic properties are inherent in many metals. In particular, there is increasing popularity of catalysts based on iridium and ruthenium complexes, which are used in the actively developing photoredox catalysis.¹⁰⁸ Furthermore, in line with the trend towards green chemistry, significant efforts are being made to find approaches that utilize more readily available base-metal catalysts instead of traditional noble metal complexes.^{109 – 111} For procedures that still involve the use of noble metal catalysts, steps are undertaken to minimize the catalyst loading without decreasing the process output and to find ways for repeated regeneration of this reaction component.

While considering the transition metal-catalyzed C(sp²) – H-functionalization reactions, it is necessary to take into account the specific features of activation of certain C – H bonds. A well-known mechanism of activation is oxidative addition according to which the metal complex initiates the C – H bond cleavage with simultaneous formation of M – C and M – H bonds, i.e., the metal complex is actually inserted into the С – Н bond (Scheme 14). This mechanism is typical of electron-rich complexes of late transition metals (Pt, Ru, Ir, Fe, Re, Os) in low oxidation states, for which the increase in the metal oxidation state or a change in the geometry of the complex caused by the potential formation of two new bonds is not a critical obstacle from the energy standpoint.¹¹²

Scheme 14

The reactions of arenes with late transition and post-transition metals possessing Lewis acidity (Pd²⁺, Pt^2+/4+, Hg²⁺) follow a different metalation mechanism, which comprises interaction of the electrophilic metal centre with the π-electron cloud of the aromatic substrate, resulting in the formation of a σ-complex (Scheme 15).^112, 113 The latter, in turn, is prone to deprotonation as a result of spontaneous rearomatization or under the action of a base, which may occur as one of the ligands in the metal coordination sphere.

Scheme 15

One more C – H activation pathway involving electron-deficient metal complexes more resistant to oxidation is the σ-bond metathesis in which cleavage of the M – R and C – H bonds and formation of new M – C and R – H bonds follows a concerted mechanism without a change in the metal oxidation state (Scheme 16). This mechanism is preferable for group 3 and 4 early transition metals, lanthanides and actinides characterized by the d⁰ electronic configuration.¹¹²

Scheme 16

A similar transition state arises in the concerted metalation–deprotonation (CMD) reaction. Despite the fact that in the literature, CMD is sometimes considered to be the same as σ-bond metathesis,¹¹⁴ most often these terms refer to different reactions. In the case of metathesis, one and the same atom (usually carbon) present in the group R (see Scheme 16) simultaneously breaks its own bond with the metal and forms a new bond with hydrogen via a four-centre transition state, thus resembling the [2σ + 2σ]-cycloaddition.¹¹⁵ The transition state of the CMD process may have a larger number of members, since the concerted bond cleavage/formation at group R usually involves various atoms of this group, with the bond of R to the hydrogen atom being necessarily generated through an atom possessing a lone pair of electrons.

Apart from CMD, there is one more type of the C – H-bond activation that does not differ much from the metathesis. The reaction proceeds as concerted 1,2-addition of the C – H bond to the multiple bond of amido, alkoxy, alkylidene or alkylidyne complexes of early and middle transition metals (Scheme 17).¹¹² However, the newly formed X – H bond is not separated from the metal complex, as it utilizes π- rather than σ-electrons (or electrons of the non-bonding orbital) of the M – X bond.

Scheme 17

Besides the above-described inner-sphere pathways of C – H activation, there are a number of outer-sphere mechanisms in which the C – H bond interacts with the ligand environment rather than with the metal. A typical example of the outer-sphere activation is the electron transfer between the substrate and the photoexcited ruthenium polypyridyl complex in a photoredox-catalyzed process (Scheme 18).¹⁰⁸

Scheme 18

The regioselectivity of the transition metal-catalyzed C – H functionalization is influenced by directing groups (DGs) present in the substrate. These groups direct the substrate coordination to a definite site of the metal complex, which becomes preferable owing to the electronic and/or steric effects generated by these groups. The role of directing groups can be performed by either native moieties already present in the substrate molecule or substituents that are deliberately introduced for selective C – H modification and removed afterwards. The latter option is undesirable considering the green chemistry principles, because this elongates the reaction sequence; nevertheless, in some cases, this is necessary to implement the synthesis. The directing groups that can be introduced and removed without much difficulty should be used for this purpose.^116, 117 Among DGs, so-called traceless directing groups that are easily eliminated from the substrate molecule upon metal-catalyzed C – H activation deserve mention.^{117 – 119} The most promising DGs are, perhaps, transient directing groups (TDGs), which are introduced into the substrate molecule, provide the selective activation of the C(sp²) – H bond and are removed from the molecule in a single one-pot process.^{120 – 126} Moreover, the latter option allows the use of reagents for the introduction of DGs in catalytic amounts.

As an example of catalysis involving a transient directing group, consider the Cu-catalyzed ortho-С(sp²) – H sulfonylation of benzylamines 28 with organic sulfinates 29, reported recently by Bull and co-workers ¹²⁷ (Scheme 19).

Scheme 19

In this case, the directing group is attached in situ by the reaction of benzylamines 28 with a catalytic amount of 2-hydroxynicotinic aldehyde 30, which leads to the corresponding imines. Imine moieties are among the most popular TDGs,¹²² owing to the easy introduction, pronounced directing effect, and easy removal via hydrolysis. According to DFT calculations,¹²⁷ the introduction of this directing group substantially reduced the energy barrier for concerted metalation — deprotonation, providing C – H activation of substrate 28. Using the developed approach, a series of 27 sulfonylated benzylamines 31 were synthesized. A benefit of this method is that it does not require complexes of noble metals (such as palladium), which were previously almost necessary components for this type of reactions. However, due to the need for a large amount of the copper catalyst (50 mol.%) and a large excess of the oxidant, manganese dioxide, spent for the catalyst regeneration, there is a room for improvement.

Fagnou and co-workers introduced one more ortho-directing group, N-oxide moiety, into the practice of organic synthesis.^{128 – 131} In the context of green chemistry, a problematic feature of the N-oxide group is that it must be first introduced into the molecule (e.g., by peroxide oxidation of the aza group) and then removed by reduction, which may be incompatible with the presence of functional groups in the substrate molecule. Meanwhile, when N-oxide is a native moiety that is retained in the target product, it can be used for the subsequent derivatization. An example of such potentially useful products are cyclic nitrone derivatives, which are of interest for medicinal and analytical chemistry due to their antiradical and other useful properties. The assistance from the N-oxide moiety enabled, in particular, direct Pd-catalyzed oxidative cross-coupling of imidazole oxides 32 with π-excessive hetarenes 33 (pyrroles and thiophenes), which furnished functionally substituted nitrones 34 (Scheme 20).¹³²

Scheme 20

It is noteworthy that the primary C – H activation in this reaction occurs via coordination of the palladium catalyst to an aromatic heterocycle, which was confirmed by control experiments on hydrogen–deuterium exchange. The subsequent C – H activation in the aldonitrone component is likely to proceed as the concerted metalation – deprotonation, giving rise to target products 34. A benefit of this method is the cross-dehydrogenative reaction pathway. However, the use of surplus amounts of auxiliary reagents, relatively high loading of the palladium catalyst and moderate product yields leave much to be desired.

Most of the known directing groups have an ortho-coordinating effect, thus providing functionalization of the nearest C – H bond in unsaturated systems. Selective conduction of these reactions at one of remote positions may prove to be more challenging.^133, 134 In principle, these transformations can be accomplished by introducing covalently linked directing groups or templates into the substrate, but this may impair the atom economy.^* In this connection, the strategy of undirected C – H functionalization appears to be more interesting;¹³⁵ in this case, the reaction regioselectivity is determined by steric and/or electronic control from native substituents present in the substrate and by the proper tuning of the structure of the catalytic metal complex, the spatial geometry and electronic structure of which can have a crucial effect on the proneness of a distal C – H bond in the substrate molecule to functionalization. An example illustrating this concept is the meta-selective iridium-catalyzed C – H borylation of arenes 35, proposed by Ilies and co-workers.¹³⁶ In this case, the reaction selectivity is achieved by rational design of ligand 36, the geometry of which blocks not only the ortho- but also para-positions, while the access of the inner coordination sphere of the catalyst to the meta-C – H bonds is retained (Scheme 21). This mainly gives meta-borylation products 37. The amount of ligand 36 sufficient for the reaction to occur is only 4 mol.%, which should be regarded as an advantage of the method, even taking into account the fairly complex structure of the ligand. Unfortunately, despite the relatively high regioselectivity of the procedure, the formation of para-substituted and meta-diborylated by-products cannot be completely avoided.¹³⁶

Scheme 21

Generally, transition metal catalysis is still an important tool for direct C – H functionalization of unsaturated compounds, as evidenced by numerous reviews on this topic.^{137 – 144} To increase the green potential of metal-catalyzed reactions, numerous attempts have been made to reduce the amount of chemical oxidants and other auxiliary reagents by combining transition metal catalysis with photoredox catalysis ^{145 – 154} or electrocatalysis.^{149, 155 – 164} The targeted design of ligands and templates can be used to modify С(sp²) – Н bonds both in proximal and distal groups of the substrate, while the development of transient directing groups favours a decrease in the number of chemical steps and in the amounts of reagents required for the introduction of such groups. There is no doubt that success in the field of metal catalysis will strongly facilitate further development and improvement of these methods in the near future.

* There are few examples of selective functionalization of distal C – H bonds in arenes using structurally simple directing groups in the presence of ruthenium catalysts.¹³³ The distal orientation can be implemented due to electronic effects arising upon the arene metalation under the action of a ruthenium derivative.

Organocatalytic methods are finding increasing use in organic synthesis, including functionalization of С(sp²) – Н bonds. Organocatalysts often play an auxiliary role in C – H activation reactions, as they do not directly cleave the C – H bond of the substrate.¹⁶⁵ In this case, their possible function is to promote the activation via the formation of more reactive intermediates upon reactions with the substrate. Examples of organocatalysts are the transient ligands considered above, which are introduced into metal-catalyzed cross-coupling reactions in catalytic amounts. It can be seen that by using chiral organic molecules as ligands, one can attain enantioselectivity of coupling ¹²⁶ (see chapter 3.3).

Organocatalysts (OC) can also directly activate the С(sp²) – Н bond in unsaturated molecules as a result of PCET and HAT events. A well-known class of such compounds are organic photoredox catalysts,^166, 167 which are converted to relatively long-lived excited state upon irradiation, thus becoming potent donors or acceptors for the unpaired electron. This results in redox reaction with the substrate (SET, Scheme 22) or energy transfer from the catalyst to the substrate to bring the latter to the excited state, which predetermines further substrate functionalization.

Scheme 22

Some redox-active organocatalysts are able to initiate the C – H activation when they occur in the ground state rather than in the excited state. In particular, this refers to so-called HAT catalysts: organic radicals able to act as acceptors of a hydrogen atom or an unpaired electron (Scheme 23).¹⁶⁸

Scheme 23

In most cases, these paramagnetic compounds (except for stable nitroxides) are formed in situ upon single-electron oxidation of the corresponding more stable forms. These reduced species are also capable of initiating reverse reactions that can take place during the process, i.e., they can be both HAT donors and single-electron reducing agents. The most frequently used organocatalytic redox pairs include 1-hydroxy-2,2,6,6- tetramethylpiperidine (TEMPOH) and 2,2,6,6-tetramethyl­piperidine-1-oxyl (TEMPO); N-hydroxyphthalimide (NHPI) and phthalimide-N-oxyl (PINO); tertiary amines [e.g., quinuclidine or diazabicyclooctane (DABCO)] and their radical cations; thiols (e.g., thiophenol) and the corresponding thiyl radicals.¹⁶⁸ A similar action is characteristic of organocatalysts that are fairly strong oxidants such as quinones (for example, DDQ and chloranils), organic compounds of hypervalent iodine, and oxoammonium derivatives (for example, 2,2,6,6-tetramethyl-1-oxopiperidinium salts, which result from the oxidation of TEMPO). Note that regeneration of this type of catalysts may require superstoichiometric amounts of a terminal oxidant (or reducing agent) or the reaction with a cooperative catalytic cycle as a part of hybrid procedure. Therefore, it is necessary to compare the expenses and the general environmental footprint inherent in these organocatalytic methods with those of non-catalyzed analogues in which stoichiometric amounts of some auxiliary reagent are used.

As an example, we will consider di- and trifluoromethoxylation of C(sp²) – H bonds in arenes 38 reported in 2020 by Liu, Ngai and co-workers (Scheme 24).¹⁶⁹ This approach is claimed by the authors as a redox-neutral method, since TEMPO used as a catalyst and its oxidized oxoammonium form generated in situ are formally capable of maintaining the catalytic cycle only through redox reactions with substrates (or intermediates); theoretically, this approach does not require additional redox agents. However, the authors noted that successful conduction of this reaction requires the use of a stoichiometric amount of lithium carbonate, which prevents the conversion of TEMPO into a catalytically inactive form via binding to an acidic by-product capable of destructive action on the catalyst. Moreover, it was shown that Li₂CO₃ can reduce the oxoammonium cation back to TEMPO via the SET process, thus promoting the catalyst regeneration. Since lithium carbonate is a cheap and non-toxic reagent, its use does not deteriorate the green potential of the reaction. This approach was used by the authors to prepare a series of 35 (hetero)aromatic compounds 39 in up to 84% yields.

Scheme 24

Special mention should be made of C – C coupling reactions catalyzed by N-heterocyclic carbenes, which proceed via the formation of Breslow intermediates and are based on umpolung,¹⁰⁵ although they cannot be classified as conventional methods for the C(sp²) – H functionalization in cyclic substrates (Scheme 25).^* These reactions are characteristic of aldehydes (Stetter reaction, benzoin condensation) and their azomethine analogues.¹⁷⁰ Surprisingly, no examples of reactions of this type in which NHC-catalyzed umpolung takes place for cyclic aldimines are known to date.

Scheme 25

Biju and co-workers described a rare case of NHC-catalyzed functionalization of the C(sp²) – H bond occurring via an umpolung intermediate (Scheme 26).¹⁷¹ In relation to cyclopent-4-ene-1,3-diones 40, the authors demonstrated the possibility of generation and isolation of pure deoxy-Breslow intermediate 42, which is formed upon the reaction of activated alkene with N-heterocyclic carbene. This intermediate can further react with the C-electrophilic centre of isatin 41 to give coupling products 43 in up to 94% yields. N-Methylmaleimide and 1,4-naphtho­quinone can also be used as alkene-containing components.

Scheme 26

Organic bases and acids are also actively used as organocatalysts in the C(sp²) – H functionalization strategy. For example, Lewis bases catalyze the Morita–Baylis – Hillman ¹⁷² and Rauhut – Currier ¹⁷³ С–С coupling reactions, thus activating the α-C(sp²) – H bonds in α,β-unsaturated carbonyl compounds (Scheme 27) and other Michael acceptors towards subsequent reactions with C-electrophilic reagents.

Scheme 27

The basic catalysts used most often for these reactions are tertiary amines (DABCO, DBU, DMAP) or tertiary phosphines, such as tricyclohexylphosphine and tributylphosphine. The electrophiles used in the Morita–Baylis – Hillman reaction are usually aldehydes and aldimines, which are converted to (α-hydroxy)alkylation and (α-amino)alkylation products, respectively. In the Rauhut – Currier reaction, α,β-unsaturated carbonyl compounds are used as electrophiles. In the context of C(sp²) – H functionalization of cyclic compounds, the above-mentioned reactions can be applied to substrates like cyclic enones, α,β-unsaturated lactones, thiolactones,¹⁷⁴ lactams,¹⁷⁵ maleimide derivatives,¹⁷⁶ pyrones ¹⁷⁷ and chromones.¹⁷⁸ When chiral bases are used, the reactions may proceed enantioselectively.

While discussing optically active organocatalysts, one cannot leave out the class of organic phosphorus-containing Brønsted acids such as commercially available 1,1'-bi-2-naphthol (BINOL) and 1,1'-spirobiindane-7,7'-diol (SPINOL). In recent years, these chiral phosphoric acids (CPA) have been very actively used in the synthesis of bis(hetero)aryls to initiate atroposelective oxidative cross-coupling reactions, the generalized mechanism of which is presented in Scheme 28 .¹⁷⁹

Scheme 28

The scope of application of CPA is far from being exhausted by these reactions. Recently, the research team headed by List ¹⁸⁰ reported that BINOL-based iminodiphosphorimidates 47, which are strong Brønsted acids, can catalyze the Friedel – Crafts reaction involving not only π-excessive (hetero)arenes, but also benzene or alkylbenzenes (Scheme 29). By the alkylation of aromatic substrates 44 with N,O-acetals 45, the authors obtained a series of (hetero)arylglycine esters 46 in up to 98% yields with high regio- and enantioselectivity.

Scheme 29

A fairly promising type of organocatalysts for the C(sp²) – H activation/functionalization are sterically hindered organic molecules in which two functional moieties possessing Lewis acidity and basicity are separated by a carbon group preventing their interaction (so-called frustrated Lewis pairs; FLP)).^{181 – 183} In particular, using borylation of the C(sp²) – H-bond in π-excessive heterocycles,¹⁸⁴ it was shown that bipolar catalysts of this type can activate the C – H bond by a mechanism similar to the concerted metalation – deprotonation (CMD) mechanism, except that in this case, the borane substituent in FLP acts as the electrophilic pseudometalating agent, while groups possessing Lewis basicity, such as amines or phosphines, are responsible for deprotonation (Scheme 30).

Scheme 30

In the case of FLP in which the acidic and basic sites are located at relatively large distances from each other, the consecutive carbene-associated mechanism, which is more energetically favourable due to distance effects, can also be implemented.¹⁸⁵

In general, it is obvious that direct activation of the C(sp²) – H bond in cyclic systems under the action of metal complex catalysts or organocatalysts is an exceptionally promising green strategy, allowing the introduction of various structural groups to an sp²-hybridized carbon atom in the simplest possible way with high productivity and selectivity, in particular, as late-stage functionalization (LSF).^{17, 57, 186, 187} It is no doubt that further progress in this field can be expected in the coming years.

*Curiously, the formation of the Breslow intermediate upon the reaction of the precatalyst (azolium salt) with a carbonyl compound in the presence of base can be considered as C(sp²)–H functionalization of the precatalyst in which the carbene formation is an intermediate step.

Developing catalytic approaches to the selective activation of aliphatic C – H bonds in organic compounds has been listed among the ‘Holy Grails’ of synthetic chemistry.^188, 189 The main application of such approaches is to provide the insertion of desired functional groups into a particular C – H bond at the ‘late’ stages of multistep synthesis of complex molecules (late-stage functionalization, LSF).^{190 – 193} Such molecules include fine organic synthesis products in demand as agrochemicals, cosmetics, and synthetic pharmaceuticals, many of which are functionalized hydrocarbon frameworks containing several non-equivalent C(sp²) – H and C(sp³) – H groups. In the future, powerful and versatile methods for LSF of aliphatic C – H groups will facilitate the solution of challenges such as the rapid generation of vast chemical libraries of metabolites, tuning of their key pharmacological properties (therapeutic efficacy, bioavailability, pharmacokinetics, etc.) without the need to re-develop or adapt existing multistep procedures.^193, 194 The processes of stereoselective oxidative C(sp³) – H functionalization are of great interest, since the absolute configuration of organic molecules is closely related to their biological activity.¹⁹⁵

Recent advances in the field of selective oxifunctionalization of aliphatic C – H groups are largely due to the application of the biomimetic approach,¹⁹⁶ which aims at modelling the functional properties of natural oxygenase enzymes ^197, 198 using low-molecular-weight (synthetic) metal complexes, mainly those containing iron and manganese.^{199 – 202} In the last two decades, non-heme (non-porphyrin) Mn and Fe complexes have been the most actively studied, offering, as compared to porphyrin complexes, much broader possibilities for structural modification and, consequently, for controlling their reactivity in oxidative catalytic processes. Mn and Fe complexes, like their metalloenzymic prototypes, catalyze direct C‒H functionalization (without forming organometallic intermediate species), which positively affects such green chemistry metrics as atom economy and E-factor.⁹ When designing such systems, there is a steady trend to use cheap and environmentally friendly hydrogen peroxide as an oxidant.

This Section summarizes the state-of-the-art in the field of direct (without intermediate metal – carbon bond formation) selective oxidative functionalization of C(sp³) – H groups of organic molecules with hydrogen peroxide in the presence of non-heme (bis-amino-bis-pyridylmethyl) and similar Fe and Mn complexes. Non-heme systems generally do not require any directing or protecting groups, utilize hydrogen peroxide as an oxidant, producing water as a stoichiometric by-product, which makes them a useful tool for green chemistry.

At the current level of our understanding of the mechanisms of action of catalytic systems based on non-heme metal complex catalysts, activation of the C(sp³) – H bond (via the hydrogen atom abstraction by an active metal oxo species) occurs similarly to the C – H activation mediated by the metalloenzymes of the cytochrome P450 superfamily.²⁰³ As a result of the H atom abstraction, a metal hydroxo species and a C-centered radical are formed (Fig. 8). There are several possibilities for further transformations of this pair in the solvent cage. If the radical is short-lived, it is likely to be captured by the hydroxometal intermediate and bind to the incipient hydroxyl group (pathway a): this option is a direct analogue of the oxygen rebound mechanism proposed by Huang and Groves.²⁰³ Alternatively, the short-lived C-centered radical can be captured by another labile ligand X in the first coordination sphere of the metal (usually X is a residue of the carboxylic acid added to the system as a co-catalytic additive). This pathway is similar to the mechanism of catalytic action of Fe- and α-ketoglutarate-dependent halogenases.²⁰⁴ The implementation of this pathway, referred to as the alternative rebound mechanism (comprising hydrogen abstraction and binding M – X ligand rather than the incipient M – OH group, pathway b),²⁰⁵ makes it possible to obtain compounds with a new C – X bond.

Fig. 8

Alternative routes for oxidative functionalization of C – H groups of organic compounds by metal-oxo species (L is chelate ligand, X is labile ligand).

In both cases, for the C – H functionalization reaction to proceed in a stereospecific manner, the encaged radical pair lifetime must be short enough such that epimerization of the radical does not take place prior to the oxygen rebound/alternative rebound step. Alternatively, the encaged radical pair can undergo formal abstraction of the second hydrogen atom ²⁰³ to give a desaturation product (pathway c).

For relatively long-lived radicals, the probability of their cage escape into the bulk solution increases; this pathway is considered the non-rebound mechanism.²⁰⁶ Further trans­formations of the free C-radical are not necessarily controlled by the catalyst; for example, in the presence of dissolved dioxygen, organic peroxides are formed that are capable of disproportionation to alcohol and ketone (pathway d ).²⁰⁷ The cage escape is often accompanied by stereoinversion, which can lead to complete racemization of the products.

In the oxidation of complex organic molecules containing multiple different C – H groups, the regioselectivity of the overall process is governed by the regioselectivity of the H atom abstraction step. In general, tertiary C – H groups are more nucleophilic than methylenic CH₂ groups and therefore more susceptible to hydrogen abstraction by electrophilic metal-oxo species. This ‘innate substrate reactivity’ can be overcome by either creating steric shielding nearby the active site of the catalyst or by introducing functional groups that allow the active site to ‘recognize’ the substrate, according to the concept of biomimetic control of chemical selectivity.¹⁹⁶

A significant part of recent studies is either directly devoted to, or to a greater or lesser extent concerns the issues of stereoselective oxidative functionalization of C – H groups of complex molecules.²⁰² This situation has developed naturally due to the fact that the main practical motivation of this work is the development of catalytic approaches to biologically active substances, primarily derivatives of natural compounds.

The catalytic activity of non-heme iron and manganese complexes in reactions of selective oxidative functionalization of C – H groups of organic compounds has been explored for more than three decades.^{208, 209} At the same time, the works of Chen and White,^{210, 211} which demonstrated the possibility of selective oxidation of aliphatic C – H groups by hydrogen peroxide in the presence of the non-heme complex (S,S)-I (Fig. 9) and revealed the main regularities responsible for the selectivity of the catalytic reaction, are considered key in this field. Thus, in the oxidation of compounds containing both methine and methylene groups, the more nucleophilic methylene groups, with lower homolytic bond dissociation energies, reacted preferentially, indicating the electrophilic nature of the catalytically active sites.²¹⁰ In such a manner, (+)-artemisinin was selectively oxidized in the presence of (S,S)-I to the C(10)-hydroxy derivative. Using the (S,S)-II catalyst bearing bulky 2,6-bis(trifluoromethyl)phenyl substituents made it possible to overcome the innate reactivity of the substrate and to direct the reaction towards predominant oxidation of the C(9) site.²¹²

Fig. 9

Structures of complexes I – III and examples of their use in catalytic reactions. Hereinafter, the yields of products (%) are given. OTf is OSO₂CF₃ .

(‒)-Ambroxide lacking tertiary C‒H groups was selectively oxidized in the presence of (S,S)-I at the activated (via superconjugation with an adjacent oxygen atom) C(12) position to give the corresponding lactone, (+)-sclareolide, in high yield. (+)-Sclareolide can also be oxidized, preferably to a C(2)-keto derivative.²¹¹ However, in complex substrates such as terpenoids and steroids, diastereotopic hydrogen atoms at the same carbon atom are characterized by different bond strengths (and different steric accessibility). For this reason, the (S,S)-I catalyst enabled the diastereoselective hydroxylation of dihydropleuromutilone 48 at the equatorial C7α position.¹⁹¹ In addition to catalytic activity in selective hydroxylation and ketonization reactions, non-heme iron complexes were able to catalyze lactonization processes under certain conditions: e.g., taxane containing a carboxylic acid group was selectively converted to the corresponding γ-lactone in 49% yield (see Fig. 9).²¹³ Using the isotopic labelling method, it was shown that the reaction proceeds in two steps: the first step involves γ-hydroxylation, followed by intramolecular esterification (lactonization). The high selectivity for the γ-position was explained by the directing effect of the carboxylato group, through which the substrate binds to the catalytically active site. The use of iron complex in combination with strong Brønsted acid (HBF₄) allowed the oxidation of substrates containing nitrogen heterocycles.²¹⁴ In particular, this approach provided the hydroxylation of the steroidal substrate 49 at the C6α position in 42% yield.²¹⁴

It should be noted that the oxidation of methylenic groups initially produces a secondary alcohol with a more electron-rich C(OH) – H bond than in the substrate. It is therefore prone to rapid further oxidation to a ketone. At the same time, in many cases the target product is precisely the secondary alcohol. To halt the reaction at the hydroxylation stage, Costas and co-workers ²¹⁵ proposed to replace acetonitrile, the conventional reaction medium, with Lewis acidic and strongly hydrogen-bond donating poly-β-fluorinated alcohols. Poly-β-fluorinated alcohols are able to deactivate the target product, the secondary alcohol, towards further oxidation by virtue of hydrogen bonding interactions.²¹⁵ Also, the use of poly-β-fluorinated alcohol solvents enables the hydroxylation of substrates that already contain hydroxyl groups. For example, using non-heme iron complex (R,R)-III, Costas and co-workers ²¹⁶ prepared polyhydroxylated steroidal metabolites 50 and 51 in hexafluoroisopropanol (HFIP) without the aid of protecting groups (see Fig. 9).

The emergence of type I – III non-heme iron complexes and the discovery of their catalytic activity was an important milestone in the development of catalytic approaches to the selective oxidative C – H functionalization of organic compounds. At the same time, the inherent disadvantages of such catalysts, such as low productivity and insufficient regio- and stereoselectivity, led to their gradual replacement by catalytically active manganese complexes of similar structure, which proved to be more synthetically promising.

Bryliakov and co-workers ²¹⁷ proposed the use of manganese complexes IV – VIII as catalysts for the selective aliphatic C – H bond oxidation (Fig. 10), which were able to perform up to 100 – 1000 catalytic turnovers. In this way, manganese complexes VI were used to selectively oxidize (–)-ambroxide to (+)-sclareolide ²¹⁸ and tetrahydrofuran to γ-butyrolactone ²¹⁹ at catalyst loadings of 0.1 – 0.2 mol.%. Such high efficiency makes manganese complexes promising catalysts not only for working with valuable complex molecules, but also for obtaining products of relatively low added value, such as the selective oxidation of benzyl alcohol to benzaldehyde.²²⁰ As with non-heme iron complexes, catalysts based on similar manganese complexes are highly sensitive to electronic effects. In the oxidation of methylene groups, this favors the formation of ketones, since the alcohol C(OH) – H bond formed at the first oxidation step is activated by the presence of an adjacent OH group. As in the case of oxidation in the presence of iron complexes, an approach based on the use of β-polyfluoro-substituted alcohol solvents capable of deactivating the newly formed secondary alcohol due to hydrogen bonding has been used to inhibit further oxidation of alcohols to ketones.²¹⁵ Using the oxidation of cyclohexane as an example, it has been demonstrated that increasing the hydrogen bond donating ability of the solvent (in the order acetonitrile < trifluoroethanol < HFIP) improves selectivity for the secondary alcohol.

Fig. 10

Structures of complexes IV–VIII and examples of their use in catalytic reactions. OTf is OSO₂CF₃ , 2,2-DMBA is 2,2-dimethylbutyric acid.

To date, a significant body of information has been accumulated on the catalytic properties of non-heme manganese complexes in chemo-, regio- and stereoselective C – H oxidation reactions.^{200 – 202, 220, 221} In the vast majority of cases, the selectivity of these processes is determined by a more or less successful interplay of electronic and steric properties of the substrate and catalyst. Costas’s research group followed a strategy based on a biomimetic approach,¹⁹⁶ which involves the specific recognition of the substrate by the active site of the supramolecular catalyst (just as it occurs in enzyme-catalyzed biochemical processes). For example, the benzocrown ether-appended catalyst (S,S)-IX allowed the site-selective oxidation of the substrate, undecylammonium tetrafluoroborate, at the C(8) and C(9) positions (Fig. 11).²²² This was achieved by hydrogen bonding between the alkylammonium group and the oxygen atoms of one of the crown ether units. This conclusion is supported by the fact that the oxidation selectivity of substrates lacking ammonium groups did not change when switching from (S,S)-V to (S,S)-IX catalyst. The authors then applied this approach to the oxifunctionalization of the aminosteroid substrate 52 at the C(16) position, with the product being obtained in the acylated form.²²³

Fig. 11

Examples of reactions where selectivity is determined by specific substrate-catalyst interactions. TFE is 2,2,2- trifluoroethanol.

A slightly different version of multi-site hydrogen bonding provided efficient recognition of indane-based substrates in enantioselective hydroxylation reactions (see Fig. 11) catalyzed by the (S)-X complex, where high enantioselectivity (up to 95% ee) was achieved.²²⁴ The hydrogen bonding interactions are thought to involve a solvent molecule CF₃CH₂OH. In the oxidation of substrates not capable of hydrogen bonding (devoid of a ketone group), a sharp decrease in catalytic activity was observed.

Bryliakov and co-workers ²²⁵ found that asymmetric induction in the enantioselective catalytic hydroxylation of benzylic C – H groups in the presence of complex XI stems from two processes: the enantioselective C – H hydroxylation itself and the concomitant stereoconvergent oxidative kinetic resolution of a scalemic mixture of secondary alcohols. Significantly, kinetic resolution did not occur in HFIP medium (due to almost complete suppression of ketonization of the secondary alcohol). As a result, a two-step process was developed, where in the first step, enantioselective hydroxylation was carried out in HFIP, and then the reaction mixture was diluted with an equal volume of acetonitrile. The latter ‘switched on’ the kinetic resolution, which allowed the enantiomeric excess of the secondary alcohol to be increased to 97% at the expense of reducing its yield (Fig. 12).

Fig. 12

Structures of complexes XI and their use in enantioselective benzylic hydroxylation. OTf is OSO₂CF₃

Sun and co-workers ²²⁶ developed a catalytic method for the oxidative desymmetrization of spirocyclic tetralones and indanones in the presence of the chiral manganese complex (S)-X in high yields and enantioselectivities (Fig. 13). The method also proved to be effective in the oxidative desymmetrization of spirocyclic oxindoles and dihydro­quinolinones to afford the corresponding chiral ketones.²²⁷ Moreover, after modification of the reaction conditions, enantioselective hydroxylation of spirocyclic 2,3-dihydro­quinolin-4(1H)-ones was achieved to give the corresponding chiral ketoalcohols in yields up to 41% and enantioselectivities up to 99%.²²⁴

Fig. 13

Oxidative desymetrization of spirocyclic compounds catalyzed by chiral manganese complex (S)-X

In the context of creating libraries of biologically active compounds, substrates of natural origin that already contain one or more asymmetric centres are of considerable practical value. Therefore, the search for not only enantioselective but also diastereoselective methods of C – H functionalization is an urgent task. Bryliakov and co-workers ²²⁸ developed synthetic approaches for the regio- and stereoselective oxidative mono- and polyfunctionalization of the terpenoid substrate (–)-ambroxide (Fig. 14). Three main factors determining the regio- and stereoselectivity of the oxidation were identified including the ligand architecture nearby the active site of the catalyst, the absolute chirality of the catalyst and the nature of the solvent.

Fig. 14

Catalytic oxidation of (–)-ambroxide in the presence of manganese complexes. CAA is chloroacetic acid, N-Boc-D-Pro is N-Boc-D-proline.

The oxidation of a series of steroidal substrates has been studied and approaches to manipulating the selectivity of these processes have been proposed. For example, approaches have been developed for the regio- and stereoselective oxidation of estrone acetate and a number of its derivatives, allowing the oxidation to be directed towards either C9α-hydroxylation or C6α-hydroxylation (Fig. 15).²²⁹ Using HFIP as solvent, high selectivity for the secondary alcohol was achieved, effectively inhibiting further ketonization. A similar approach was applied to the oxidation of a series of fully saturated steroids, derivatives of 5α- and 5β-androstane. The use of catalysts differing in steric demands and chirality provided access to regio- and stereoselective hydroxylation at the C5β, C6α and C12β positions.²³⁰ Using the sterically hindered catalyst XIII, de Lucca and co-workers ²³¹ carried out the hydroxylation of compound 53 at the C(2) position. Varying the temperature and oxidant excess allowed the selective production of C2-ketone or C2β-hydroxy metabolite, an intermediate for the total synthesis of ent-beyerane derivatives.

Fig. 15

Catalytic oxidation of steroids in the presence of chiral manganese complexes. EHA is 2-ethylhexanoic acid.

In recent years, another promising class of selective transformations catalyzed by non-heme manganese complexes — direct C – H acyloxylation — has been identified. It was found that, along with the expected hydroxyl derivative, the oxidation often produces an ester of a carboxylic acid used as a co-catalytic additive (Fig. 16). Acyloxylation has been shown to occur by C-radical rebound to the carboxylato ligand at the metal site in the solvent cage, which competes with the rebound to the incipient OH group: this mechanism was called the ‘alternative rebound mechanism’.²⁰⁵

Fig. 16

‘Alternative rebound mechanism’ on the example of cumene oxidation.

The selectivity for the ester is usually lower than for the hydroxy derivative. However, it increases when the acyloxylation is an intramolecular process. For example, Costas and co-workers ²³² found that manganese complexes can catalyze the γ-lactonization of substituted adamantaneacetic acids with high enantioselectivity (Fig. 17). Isotopic labelling studies witnessed that the lactone formation occurs via two parallel pathways: by rebound of the OH group followed by intramolecular esterification, and by rebound to the carboxylato group. Later, this catalytic method was adapted for the diastereoselective γ-lactonization of a number of natural and synthetic α-amino acids and laid the grounds for a new synthetic approach to chiral α,α-disubstituted α-amino acids.²³³ An insight into the mechanism of this reaction confirmed that the most likely reaction pathway was intramolecular hydrogen abstraction from the γ-carbon atom followed by intramolecular lactonization.²³⁴ The high selectivity for the γ-position was explained by the directing effect of the carboxyl group through which the substrate binds to the catalytically active site. The catalyst (S,S)-XVII can activate even the strongest primary C – H bonds, thus enabling the preparation of diastereoisomeric lactones of camphanic, ketopinic and isoketopinic acids.

Fig. 17

Stereoselective catalytic lactonization of carboxylic acids. dr is diastereomeric ratio.

The use of the sterically hindered catalyst (S,S)-XVIII made it possible to carry out lactonization of fatty acids (Fig. 18).²³⁵ Significantly, by varying the reaction conditions, the regioselectivity of the process can be switched between the γ- and δ-positions. In the latter case, the reaction does not appear to be directed by the carboxyl group. The formation of δ-lactone is probably due to the hydrogen abstraction from the most electron-rich C – H bond, followed by OH group rebound and intramolecular esterification catalyzed by a strong Brønsted acid added to the reaction mixture.

Fig. 18

Regioselective lactonization of fatty acids in the presence of Mn complexes.

Summarizing the above, the development of catalysts and processes for chemo-, regio- and stereoselective oxidative functionalization of C(sp³) – H groups of complex molecules is one of the priority areas of modern synthetic chemistry. The sustainability of this area is determined by the fact that this significantly reduces the step count, thus reducing the amount of byproducts, and allows avoiding the use of toxic or high-molecular-weight oxidants. Until recently, studies on biomimetic catalytic systems for the selective C – H oxidation of organic compounds were mostly fundamental. However, significant advances achieved to date open the gateway to investigations focused on practical synthetic needs, such as late-stage alteration of complex molecules of natural origin, fast generation of chemical libraries of metabolites, production of biologically active compounds and pharmaceuticals.

The discovery of catalytic cross-coupling is a prominent achievement of organic chemistry of the 20th century. Reactions of this type are used for one-step formation of new C(sp²) – C(sp²), C(sp²) – C(sp) and C(sp²) – C(sp³) bonds, which are present in many organic compounds both occurring in nature and synthesized in laboratories.

Historically, the cross-coupling reactions were performed for the first time in Japan (Tamao, Kumada) and France (Corriu) with organolithium and organomagnesium compounds and nickel complexes as catalysts. However, the best results were obtained using a palladium complex (Murahashi). Initially, organotin (Stille, Milstein), organomercury (Beletskaya) and organozinc derivatives (Negishi) and some other compounds served as the organometallic components; however, later they were replaced with readily available, stable and relatively non-toxic (hetero)arylboronic acids (Suzuki, Miyaura). The palladium-catalyzed arylation of activated olefins (Heck, Mizoroki) can also be considered as cross-coupling. For these studies, Suzuki, Negishi and Heck were awarded the Nobel Prize in 2010. The subsequent progress in this research area resulted in the appearance of so-called carbonylative cross-coupling (Tanaka) and the discovery of a method for C(sp²) – E bond formation (E = S, Kosugi and Migita; E = P, Hirao; E = O, Beller; and E = N, Buchwald and Hartwig). The golden age of palladium catalysis was possible thanks to the development of an array of new phosphine ligands and preparation of diverse palladium complexes acting as precursors of active catalysts.

In recent years, under the influence of green chemistry concepts,^19, 236 the trajectory of development of this synthetic approach has been shifting towards environmentally benign, low-waste and safe methods. In addition to widely known E-factors,³ new criteria have been introduced for evaluation of the greenness of chemical reactions.^10, 237 The need to save energy and the fact that uncontrolled use of natural fuel is no longer possible have started to be regarded as important components of green chemistry paradigm. An organic chemist who performs a catalytic reaction should evaluate the reaction utility not only in terms of TON and TOF, but also by calculating the consumed energy. There appeared the problem of production of ‘clean energy’, ‘green hydrogen’ and many other, which did not come to mind previously. Generally, the theoretical base of green chemistry continues to develop, covering an increasingly broad range of aspects and becoming a truly multidisciplinary discourse within the framework of sustainable development of society.^{30, 238, 239}

Cross-coupling reactions are substitution reactions; therefore, as regards atom economy, they are inferior to addition reactions. Cross-coupling reactions always give salts as by-products, which most often, find no use and end as waste. Recently, toxic organometallic, first of all, organomercury, compounds were excluded from the inventory of reagents for this type of reactions. Although these reagents provide excellent results,^240, 241 they are toxic and hazardous for the environment. Also, aryl halides ArX have different reactivity, cost and toxicity (in particular, considering also the salts formed in reactions) depending on the nature of X.

As regards the classic palladium catalysts, that is, complexes PdX₂*L₂ (L = Ph₃P or other phosphines), which are reduced during the reaction to Pd(0)L₂, efforts of researchers have been mainly directed towards the decrease in the palladium loading due to its high cost. The use of vanishingly low Pd concentrations of approximately 10^–3 – 10^–5 mass % was reported. It is clear that these low quantities of palladium were not isolated and went into waste. This brought about a new problem of palladium scattering, resulting in the inevitable decrease in the reserves of this natural element. This stimulated the development of new approaches based on catalyst immobilization on a support through linkers, use of nanocatalysts supported on soft and hard materials and replacement of noble metals such as Pd, Ru, Rh or Ir by more abundant and less expensive metals like Cu, Ni, Co and Fe.

A considerable role in the cross-coupling reactions, like in any other reactions, belongs to the solvent. Water as a cheap, nontoxic and safe solvent is the most interesting alternative to organic solvents, which have often formed the major part of waste. However, the use of water brings about other problems such as poor water solubility of organic compounds, water purification after the reaction, and the need to prevent contaminated water from getting into the environment. A closed-loop process with water recycling can be implemented in industry, whereas in laboratory, this problem is still to be addressed.

In this Section, we made an attempt to consider the above and some other issues related to cross-coupling reactions taking account of new environmental requirements.

Sheldon, who was one of the first to pay attention to the importance of waste-free methods, emphasized that transition metal catalysis by itself brings a green aspect to a chemical reaction.²⁴² Nevertheless, high temperatures, potentially toxic organic solvents, unsafe organometallic reagents, and the use of considerable amounts of various additives require development of alternative processes that would be markedly safer for the environment. A concise review of the methods that draw cross-coupling reactions closer to green chemistry requirements was published in 2010.²⁴³ The advantages of conducting reactions of this type in water at room temperature without preliminary preparation of organometallic compounds is briefly considered; good prospects of C – H bond activation towards cross-coupling by simple palladium salts, thus avoiding the use of halogenating compounds, were noted.

Extensive literature is devoted to palladium-catalyzed cross-coupling reactions in water and water – organic mixtures. At the Laboratory of Organoelement Compounds of the Department of Chemistry, Moscow State University, it was shown back in the 1980s that the Heck, Suzuki and Sonogashira reactions and carbonylation reaction can be accomplished in water under fairly mild conditions by using ligand-free palladium salts [PdCl₂ , Pd(OAc)₂] as catalyst precursors.²⁴⁴ This resulted in the discovery of palladium nanocatalysis and its wide use in organic synthesis.²⁴⁵ A vivid illustration of the efficiency of this approach is successful synthesis of a wide range of substituted biaryls, which was performed using simple divalent palladium salts in water at room temperature (Scheme 31). This reaction can also be catalyzed by palladium metal (Pd black, which is actually nanopalladium, as was shown previously) also without addition of a ligand.²⁴⁶

Scheme 31

Since palladium is a precious metal and its use in catalysis, even if its amount has been effectively minimized, results in palladium scattering and non-intentional removal from natural resources, studies have been undertaken at catalyst heterogenization by immobilizing the ligand on a support,^{247 – 250} which has blurred the distinction between homogeneous and heterogeneous catalysis. The support itself can act as a ligand that significantly affects the activity of the supported palladium nanoparticles (PdNPs). For example, ligand-free palladium supported on the copolymer of vinylimidazolone (PVI) and vinylcaprolactam (PVC) efficiently catalyzed the Suzuki –Miyaura reaction in aqueous ethanol (Scheme 32). The possibility of recycling the catalyst eight times was demonstrated in relation to the reaction of phenylboronic acid with p-bromoacetophenone.²⁵¹

Scheme 32

The same catalytic system can be used in one more reaction, cyanation, in which the heterogeneous catalyst can be recycled and reused 10 times (Scheme 33).²⁵²

Scheme 33

The well-known Pd/C hydrogenation catalyst is also effective in the Suzuki reaction.²⁵³ The catalyst is easily separated from the reaction mixture by filtering, and high product yield is retained over five cycles.²⁵⁴ The simplest catalysts such as Pd/C and Pd black, without the addition of ligands, enabled industrial synthesis of two medicinal agents of the Lilly pharmaceutical company (Scheme 34). The amounts of reactants were 0.5 – 1 kg, and the product yields were 67 – 93%.

Scheme 34

Reviews on the use of green chemistry principles in cross-coupling reactions have been regularly published in recent years; in some cases, several catalytic processes are considered in one review,²⁵⁵ while other reviews address single reactions, e.g., Suzuki – Miyaura ²⁵⁶ or Sonogashira ²⁵⁷ reaction, or new protocols for known catalytic reactions using microwave or ultrasonic irradiation and mechanochemical procedures.²⁵⁸ Many of these reactions are carried out in water.

The process of hydroformylation in a two-phase system in the presence of water-soluble ligands proposed by the Rhône – Poulenc company back in 1970 ²⁵⁹ proved to be also useful for cross-coupling.²⁶⁰ The suitable ligands include water-soluble phosphines,²⁶¹ hydrophilic N-heterocyclic carbenes ^262, 263 and other hydrophilic nitrogen-containing compounds.²⁶⁴ The reactions are accelerated upon the addition of surfactants. Among recent studies, the following should be mentioned.

Palladium complexes with N-heterocyclic carbenes [NHC · H][Pd(η³-R-allyl)Cl₂] in ethanol (0.3 – 0.5 mol.% Pd) were used as effective catalysts for the cross-coupling reactions involving electron-withdrawing and electron-donating aryl bromides and chlorides and heteroaromatic and sterically hindered aryl halides.²⁶⁵ The phosphine ligand EvanPhos was used to synthesize biaryls by the Suzuki – Miyaura reaction in the presence of 0.5 mol.% palladium. A 2% solution of micelle-forming agent TPGS-750M (Fig. 19) in a 9 : 1 water – toluene mixture served as the reaction medium; in the case of aryl bromides, the yields of biaryls reached 97%.²⁶⁶

Fig. 19

Phosphine ligand EvanPhos and micelle forming agent TPGS-750M.

The fungicides boscalid, fluxapyroxad and bixafen were synthesized in water in the presence of ultralow loading of Pd(OAc)₂ (down to 0.005 mol.%).²⁶⁷ Even aryl chlorides successfully reacted under these conditions (Scheme 35).

Scheme 35

It was shown that aqueous solutions of Kolliphor EL, a well-known surfactant, form nanomicelles, which can serve as ideal nanoreactors for palladium-catalyzed cross-coupling.²⁶⁸ In these systems, the Suzuki – Miyaura reaction proceeds even at room temperature.²⁶⁹ The catalytic cross-coupling in aqueous micelles formed by the PiNap-750M surfactant (naphthalenediimide derivative, 2 mass %) gave rise to organic semiconductors.²⁷⁰ When Pd(dtbpf)Cl₂ [dtbpf = 1,1'-bis(di-tert-butylphosphino)ferrocene (2 mol.%)] was used as the catalyst, the product yields were 80 – 93% (Scheme 36).

Scheme 36

The sonidegib drug was obtained in an aqueous medium in the presence of TPGS-750M micelle-forming surfactant, with the required amount of palladium being only 0.5 mol.% (Scheme 37).²⁷¹

Scheme 37

Model micellar catalysis of the reaction of p-bromoanisole in water in the presence of TPGS-1000 micelles (2 mass %) and palladium (0.5 mol%) as bacteriogenic nanoparticles from Desulfovibrio alaskensis furnished the product in a more than 99% yield.²⁷² Hydrogels formed from 1,3 : 2,4-dibenzylidene­sorbitol modified with acyl hydrazide, agarose and 1 mol.% palladium in aqueous ethanol (1 : 3) ensured quantitative yields of biaryls in the Suzuki–Miyaura reactions and could be recycled and reused up to ten times.²⁷³

The water-soluble C₆₀-TEGs/PdCl₂ catalyst with an average nanoparticle size of ~60 nm obtained by supporting palladium(II) chloride on triethylene glycol (TEG)-modified fullerene (C₆₀-TEGs) proved to be effective in the reaction of phenylboronic acid with aryl halides containing either electron-donating or electron-withdrawing substituents. The target biaryls were formed at room temperature in up to 99% yields in the presence of only 0.01 mol.% catalyst, and the catalyst could be recycled and reused up to five times without a considerable loss of the catalytic activity.²⁷⁴ The use of water-soluble palladium nanoparticles stabilized by phosphinic acids in the Suzuki – Miyaura, Sonogashira and Heck reactions was reported.²⁷⁵

The application of arenes instead of aryl halides is an attractive alternative to the classical Suzuki reaction. However, the methods known to date require fairly harsh conditions and the presence of common organic solvents, which is at variance with the green chemistry principles. Recently, a mild Suzuki oxidation reaction was performed in water using hydrogen peroxide as the oxidant. The efficiency of the oxidative cross-coupling was confirmed for a broad range of substrates, including those containing various functional groups. The applicability of this green strategy for the conduction of Heck and Sonogashira reactions was also demonstrated.²⁷⁶

Nanosized palladium particles immobilized on magnetic graphene oxide modified with poly(2-acrylamido-2-methyl-1-propanesulfonic acid) (GO/Fe₃O₄/PAMPS/Pd) proved to act as effective nanocatalysts for the Suzuki – Miyaura reaction in aqueous ethanol, in particular for aryl chlorides.²⁷⁷

Magnetic palladium nanoparticles supported on a graphene oxide and steel composite efficiently catalyzed the Suzuki–Miyaura and Stille reactions in aqueous ethanol. Cross-coupling products were formed in up to 97% yields.²⁷⁸ Magnetic iron nanoparticles containing a low (0.08 mol.%) amount of palladium combined with the S-Phos ligand (2,6-dimethoxy-2'-dicyclohexylphosphinobiphenyl) were utilized in the Suzuki–Miyaura reaction in a flow reactor. In the synthesis in a water flow containing 2 mass % TPGS-750M surfactant, the yields of products reached 95%.²⁷⁹ The practical value of the method was demonstrated by the synthesis of intermediates for the preparation of drugs in amounts of up to 20 g in one experimental operating cycle (Scheme 38).²⁸⁰

Scheme 38

Palladium nanoparticles immobilized on titanium and zinc oxides taken in sub-stoichiometric amounts were used to catalyze the Suzuki–Miyaura reaction with the possibility of recycling. The reactions were carried out in aqueous ethanol in the presence of 0.3 mol.% palladium, with the yields of biaryls being as high as up to 96%.²⁸¹

A number of reactions catalyzed by palladium-containing metal-organic frameworks (MOFs) have been described. Palladium attached to lanthanum MOF containing Fe₃O₄ nanoparticles via Schiff base was tested in the model Suzuki reaction and provided TOF of 42886 h^–1, which is one of the highest values obtained for this reaction. The catalyst withstood twelve reaction–catalyst recovery cycles without a considerable decrease in the activity.²⁸² Metal-organic frameworks containing bis(N-heterocyclic) palladium complexes were used in the Suzuki, Heck, and Sonogashira reactions.²⁸³ The Fe₃O₄@PDA – Pd@UiO-67 composite (PDA is polydopamine) proved to be an efficient catalyst for the Suzuki reaction in aqueous ethanol reusable up to eight times.²⁸⁴

The catalyst based on palladium nanoparticles (PdNPs) immobilized on reduced graphene oxide (rGO) successfully catalyzed the Suzuki–Miyaura reaction with aryl chlorides in aqueous methanol under microwave irradiation.²⁸⁵ The yields of products reached 95% with the palladium loading being 0.5 mol.%. In this study, the key intermediates for the synthesis of irbesartan and fluxapyroxad drugs were obtained; however, reactions of o-substituted chloroarenes required the use of ethylene glycol or DMF as solvents (Scheme 39).

Scheme 39

The Suzuki – Miyaura reaction involving aryl bromides in water was catalyzed by PdNPs supported on graphene acid.²⁸⁶ The cross-coupling reactions were formed under these conditions in quantitative yields, and immobilized catalyst could be used five times without the loss of activity. The Pd(II) complexes (0.5 mol.%) with N-heterocyclic carbenes efficiently catalyzed the Suzuki – Miyaura reactions involving aryl bromides in water at room temperature.²⁸⁷ Palladium nanoparticles (1.7 mol.%) incorporated in the pores of a covalent framework based on N,N-dimethyldodecyl terphenyldicarboxylic acid dihydrazide derivative (Pd@COF-QA) also proved to actively catalyze these reactions.²⁸⁸

Structure of Pd@COF-QA

Palladium(II) (1 mol.%) chelated by a porous organic polymer (POP) containing 2,2'-bipyridine moieties made possible the Suzuki reaction with aryl bromides in air in aqueous ethanol (EtOH : H₂O = 3 : 2). The catalyst was used five times without decrease in the product yield.²⁸⁹ Palladium-functionalized polyurethane foam also showed high catalytic activity in the Suzuki – Miyaura reaction with bromoarenes in aqueous ethanol.²⁹⁰ In the presence of 1.4 mol.% palladium, the product yields reached 98%. The SBA-15 polymer modified with the N-isopropylacrylamide–methacrylic acid copolymer proved to be a convenient support for the immobilization of PdNPs.²⁹¹ The reactions were carried out in a water – ethanol mixture (4 : 1); the yields of products formed from aryl bromides and aryl iodides differed only slightly (94 – 96%).

There are quite a few recent publications describing unusual supports for immobilization of metal nanoparticles involved in catalysis. For example, PdNPs were supported on a composite in which chitosan and cellulose films were attached to corn stalk biochar. The use of this composite biomaterial in the Suzuki–Miyaura reaction in ethanol with 0.5 mol.% palladium loading gave biaryls in up to 99% yields. The catalyst could be reused many times (up to ten cycles without the loss of activity).²⁹²

Palladium nanoparticles immobilized on a composite comprising cellulose and volcanic pumice magnetic particles effectively catalyzed Suzuki–Miyaura reactions in DMSO, with their activity being retained even after ten regenerations.²⁹³ A dip catalyst prepared by dispersion of PdNPs in the sugarcane bagasse proved to be effective in the cross-coupling reaction where it could be reused many times (up to 15 cycles).²⁹⁴ Agar containing immobilized Pd particles (34 – 45 nm) was used to carry out the Suzuki reaction under microwave irradiation.²⁹⁵

Ultrasonic treatment is an alternative to conventional heating.²⁹⁶ The efficiency of ultrasound was demonstrated in relation to Suzuki–Miyaura reactions catalyzed by Pd/C (5 mass %)²⁹⁷ or Pd nanoparticles immobilized in the KIT-5 – biguanidine mesoporous structure in aqueous ethanol (EtOH : H₂O = 1 : 1).²⁹⁸ In the latter case, bromo- and iodobenzenes were converted to target products in up to 98% yields in the presence of only 0.25 mol.% palladium; the catalyst could be used up to six times without decrease in the performance.

Ethylene glycol, glycerol and polyethylene glycols (PEG) are of obvious interest as green solvents. Glycerol was used as a reaction medium in the Suzuki – Miyaura reaction catalyzed by palladium present in the roots of the Eichhornia crassipes plant commonly known as water hyacinth. In the presence of this plant catalyst, heteroaryl halides and heteroarylboronic acids reacted to give the corresponding bis-heterocycles in good yields.²⁹⁹

A review devoted to the use of polyols as solvents summarizes the data on the use of glycerol- and PEG-stabilized palladium nanoparticles in the Suzuki, Heck and Sonogashira reactions and the Ullmann synthesis of biaryls.³⁰⁰ The reactions with medium-size (4 – 6 nm) PdNPs were noted to smoothly proceed in PEG of various molecular weights (including PEG-400) or using solid supports, for example, styrene and ethylene glycol copolymer.

The presented examples of the Suzuki–Miyaura reaction comply, to an extent, with the green chemistry requirements. Among other C – C bond formation reactions, mention should be made of the Sonogashira reaction, which can also occur in aqueous solutions. The reaction carried out in the presence of Pd(PPh₃)₂Cl₂/PPh₃/CuI (16/33/22 mol.%) in water under microwave irradiation resulted in the synthesis of polyacetylene precursors of porous organic structures (Scheme 40).³⁰¹

Scheme 40

The Sonogashira reaction efficiently proceeds in a flow reactor in the presence of hybrid Si-Gly-CD-PdNPs nanoparticles (the support is silica gel attached to b-cyclodextrin with a glycerol linker) in a flow of a green solvent (cyclopentyl methyl ether/water azeotrope).³⁰² A palladium catalyst immobilized in a styrene – divinyl benzene copolymer containing acidic cation exchange groups (sulfonic acid fragments) was successfully used in the Suzuki reaction (0.5 mol.% Pd, PrⁱOH), Heck reaction (0.2 mol.% Pd, DMA; DMA is dimethylacetamide) and Sonogashira reaction (0.4 mol.% Pd, PrⁱOH-H₂O, 1 : 1) without adding copper as an oxidant.³⁰³ The same behavior in the Sonogashira reaction was inherent in palladium nanoparticles supported on polyaniline (Pd@PANI), obtained by oxidative polymerization of aniline in the presence of PdCl₂ , and in the mesoporous Pd-based catalyst supported on carbon nitride (g-C₃N₄).³⁰⁴

Among a variety of two-dimensional and three-dimensional supramolecular assemblies, Pd₆L₈ type structures in which Pd(II) ions are surrounded by conformationally flexible tripodal pyridine-containing tris-amide ligands proved to be fairly efficient catalysts for the Sonogashira reaction. These catalysts also do not require addition of copper or phosphine ligands to the reaction system.³⁰⁵

Magnetic nanoparticles composed of Pd(II) complexes with N-heterocyclic carbenes supported on Fe₃O₄ successfully catalyzed the Heck reaction in water and could be reused in five cycles.³⁰⁶ Palladium-containing MOFs (PdNPs@ZIF-8,³⁰⁷ Pd@ZIF-67,³⁰⁸ and UiO-67 (Ref. 309)) and microporous metal-organic material based on palladium-containing nanotubes Pd@NH₂-MONFs ³¹⁰ were also effective in catalyzing the Heck reaction.

Due to high cost of palladium and the possible adverse impact of palladium-containing waste on the ecosystems, attempts have been made to replace palladium-based catalysts with catalysts containing other metals. Gold nanoparticles immobilized in the capillary pores of the Sr/Alg/CMC/GO/Au complex composite containing graphene oxide, strontium and cross-linked polymer based on the alginate (Alg) anionic heteropolysaccharide and carboxymethylcellulose (CMC) were exceptionally active in the Suzuki – Miyaura reaction. The standard reaction with aryl iodide required only 0.005 mol.% loading of the catalyst. The possibility of catalyst reuse (six cycles) with biaryl yields of up to 98% was demonstrated.³¹¹

The immobilization of CoCl₂ on magnetic nanoparticles Fe₃O₄@AlO(OH) (boehmite) resulted in the formation of a catalyst active in the Suzuki – Miyaura reaction.³¹² The Co(II) compounds immobilized on chitosan (CS) modified with furfural-based Schiff base was studied in the Suzuki – Miyaura, Heck, Hirao and Hiyama reactions in water (Scheme 41).³¹³ The CoFe₂O₄/asparagine nanocomposite catalyzed the synthesis of diaryl thioethers and could be recycled and reused.³¹⁴

Scheme 41

The α-Fe₂O₃ nanoclusters (1.8 nm) deposited on graphene oxide proved to be effective catalysts for the Suzuki – Miyaura reaction at an ultralow loading (150 ppm). At 80°C, this reaction was performed for bromobenzene derivatives containing electron-donating and electron-withdrawing groups in the para-position. The product yields were as high as 87% and the catalyst was reused four times without a decrease in the activity.³¹⁵ Sonogashira reaction conducted in the presence of iron(III) chloride complex with 1,10-phenanthroline under aerobic conditions in water was reported. Functionalized aryl iodides containing heteroaryl and sterically hindered substituents and terminal heteroarylalkynes were found to be appropriate substrates under these conditions.³¹⁶

The palladium-free Suzuki reaction was carried out using Cu(I) complex supported on polythiophene-functionalized magnetic carbon nanotubes.³¹⁷ The ZnCl₂ – [Bmim]BF₄ (ionic liquid) system served simultaneously as a catalyst and as a solvent in the Suzuki – Pictet – Spengler tandem reaction, which furnished pharmacologically valuable polyfunctional 6-arylphenanthridines.³¹⁸ The zinc-catalyzed reaction of electron-rich aryl iodides with phenylacetylene resulting in the formation of the C(sp²) – C(sp) bond was also reported.³¹⁹

In recent years, nickel-containing catalysts have found wide use for the formation of carbon–carbon and carbon–element bonds.^320, 321 For example, nickel formate derived from food industry waste smoothly catalyzed the Suzuki–Miyaura reaction,³²² while the nickel composite obtained from azide-modified UiO-66 MOF, Ni(cod)₂ and PPh₃ proved to be an efficient reusable (up to seven cycles) catalyst for the Suzuki reaction.³²³

Nickel chloride complex with ferrocene diphosphine successfully catalyzed the Suzuki–Miyaura reaction with diverse aryl halides, including chloroarenes, in an aqueous solution of TPGS-750M. The reactions proceeded at moderate temperature (45 °C) at a nearly stoichiometric ratio of the reactants, including sterically hindered compounds (Scheme 42).³²⁴

Scheme 42

The heterogeneous bimetallic Ni(0) bis(propylmalononitrile) complex (NiFe₂O₄@SiO₂–BPMN – Ni) ³²⁵ and the nickel complex with the tetradentate N,O,O,N-salicylidenethiadiazole ligand ³²⁶ also successfully catalyzed the Suzuki–Miyaura reaction in aqueous methanol. Furthermore, the bimetallic complex was easily isolated with a magnet and could be reused seven times without noticeable loss of activity. The NiCl₂(PPh₃)₂/CuI/PEG-400/H₂O catalytic system was used to prepare various acetylenes by the Sonogashira reaction.³²⁷ When the products were extracted with petroleum ether, this system could be reused up to six times. In the Sonogashira reaction catalyzed by nickel nanoparticles, there was no need to additionally use copper compounds, while the nanocatalyst could be utilized in five cycles.³²⁸

Obviously, reactions using copper as a catalyst form an important step towards green chemistry. The use of nitrogen- and oxygen-containing ligands, most of which are nontoxic and much more readily available than phosphine ligands, allowed the reactions to be performed under fairly mild conditions, which actually created a new Ullmann chemistry.^329, 330 The mechanisms of palladium and copper catalysis have much in common, but there are also quite a few differences.³³¹ However, it is undeniable that copper is an excellent catalyst for the C(sp²) – heteroatom cross-coupling reaction, being especially applicable for the formation of C(sp²) – N bonds, where palladium catalysts would require the presence of expensive ligands that are often difficult to obtain. Currently, there are publications describing copper-catalyzed reactions that give C(sp²) – S(Se), C(sp²) – P and C(sp²) – O bonds using various copper compounds with oxygen- and nitrogen-containing ligands ³³² or ligand-free copper.³³³ The reactions are carried out in green solvents, including water,³³⁴ ethylene glycol ³³⁵ and ethanol.³³⁶ For immobilization of copper complexes and copper nanoparticles (CuNPs), soft and hard supports have been used.³³⁷

Among recent studies, the following ones may be noted. Combination of CuI with surfactants was utilized for the generation of C – S and C – N bonds.³³⁸ A variety of diaryl sulfones were prepared by the reactions of aryl bromides and aryl iodides with benzenesulfinates in water in the presence of N-alkyl-lactosamine. The product yields reached 95% for iodides and 85% in the case of bromides. The same catalytic system proved to be suitable for the arylation of azoles such as imidazole, benzimidazole and indole, with the yields of N-aryl derivatives being as high as 80 – 90%. A polymer based on Cu(II) complex with (E)-N'-(4-(diethylamino)-2-hydroxy­benzylidene)-4-methylbenzohydrazide effectively catalyzed the reaction of aryl iodides with thiophenol giving rise to the C – S bond in water at 90°C in the presence of potassium carbonate as a base (up to 98% yields).³³⁹ The Cu(OAc)₂ (10 mol.%)/Cp*Co(CO)I₂ (1 mol.%) catalyst mixture was used for the amination of aryl chlorides.³⁴⁰ Solvent-free and base-free reactions were carried out for aliphatic and aromatic amines and resulted in the formation of C – N cross-coupling products in 80 – 90% yields (Scheme 43). The authors believed that the cobalt complexes rather than the copper complexes were catalytically active in this case. This work is in line with other studies in which C – N bonds were generated using bimetallic cobalt and iron compounds, e.g., cobalt-containing magnetic nanoparticles ³⁴¹ or nickel ferrite nanoparticles, which were found to be active in the amination reactions and in the amidation of various aryl halides.³⁴²

Scheme 43

Copper(I) oxide nanoparticles can be used for the amination of aryl halides without the use of additional ligands, in some cases, in ionic liquids.³⁴³ The use of Cu₂O nanoparticles formed in situ from Cu(OAc)₂ and a micelle-forming surfactant (hybrid of PEG and aminoglucose) proved to be effective for the formation of the C – S bond in water.³⁴⁴ Under these conditions, aryl iodides and aryl bromides reacted with arenesulfinates to give diaryl sulfones in up to 95 – 96%.

A highly important aspect of the current stage of development of the Ullmann chemistry is the use of copper catalysts immobilized on various supports, which makes them reusable. For example, polymer-supported copper(II) complex successfully catalyzed the reaction of NH-heterocycles with aryl iodides (Scheme 44); the catalyst was recycled and reused several times without a considerable decrease in the yields of products.^345, 346

Scheme 44

The aniline arylation with bromobenzene in the presence of copper(I) complex (0.04 mol.%) with Fe₃O₄-supported guanidine derivative proceeded in glycerol and gave the product in 80% yield.³⁴⁷ After five catalytic cycles, the yield of diphenylamine decreased to 70% (Scheme 45).

Scheme 45

Copper(I) chloride supported on a magnetic material coated by ascorbic acid effectively catalyzed the arylation of NH-heterocycles and aromatic or aliphatic amines.³⁴⁸ These reactions were carried out in water at room temperature in the presence of KOH as a base; the catalyst could be recycled and reused up to six times without a decrease in the performance. Copper(I) iodide supported on the INDION-770 cation exchange resin modified with a sulfonic acid successfully catalyzed the reactions of aryl iodides and aryl bromides with imidazole in DMSO.³⁴⁹ Other polymers were also proposed for immobilization of the copper catalyst. For example, a CuI complex with Schiff base-modified chitosan proved to be an efficient catalyst for the arylation of amines, amides and azoles.³⁵⁰ In the presence of this catalyst in combination with Cs₂CO₃, aryl iodides and aryl bromides reacted with primary and secondary amines in DMSO at 100°C to give amination products in up to 99% yields, while the catalyst retained its activity after recycling and reuse (up to five cycles).

The C – N and C – S bond formation can also be catalyzed by nickel compounds. For example, amination of aryl chlorides and aryl sulfamates takes place in the presence of the NiCl₂/DME complex (DME is dimethoxyethane) in a green solvent, 2-methyl-THF.³⁵¹ The efficiency of amination increases under visible light irradiation in the presence of NaI as an activator. The catalytic reaction does not require the use of an additional photocatalyst and allows the formation of C – N bonds under mild conditions.³⁵² Lipshutz and co-workers ³⁵³ demonstrated that reactions resulting in the C – S bond formation can be performed using micellar catalysis with nickel compounds as catalysts. Aryl and heteroaryl halides were coupled with arene- and alkanethiols in an aqueous solution of TPGS-750M to give valuable compounds. Specifically, an intermediate for the preparation of the anticancer agent axitinib was synthesized in this way (Scheme 46).³⁵³

Scheme 46

Copper catalysts also proved to be effective in the oxidative cross-coupling of arylboronic acids with S-, N- or O-nucleo­philes, discovered independently by three authors, which leads to the formation of C – N, C – S and C – O bonds.^{354 – 356} This reaction, which involves two nucleophiles, unlike the Ullmann reaction, is widely used to synthesize a variety of alkylarylamines, alkylaryl and diaryl sulfides and aromatic ethers. We will consider some recent examples of using this strategy within the framework of green chemistry concept.

Nanomicelles formed from CuBr in the presence of a water-soluble ligand such as PEG-2000-functionalized pyridinetriazole and sodium dodecyl sulfate catalyzed the Chan–Lam reaction of diorganyl diselenides/disulfides with various aryl-, heteroaryl- and styryl-boronic acids in water at room temperature to give cross-coupling products in good yields. The aqueous phase containing the catalyst could be recycled and reused at least seven times. Transmission electron microscopy examination showed that the diameter of nanomicelles was 31.9 ± 8.7 nm in the selenide synthesis and 26.6 ± 5.0 nm in the sulfide synthesis.³⁵⁷

The Chan – Lam reactions are often performed in the presence of copper catalysts supported on various materials. For example, Cu(II) complex with a polyimide organic framework Cu@PI-COF proved to be a fairly efficient catalyst.³⁵⁸ In the presence of this catalyst, the reaction in aqueous methanol (1 : 1) could be performed for aniline derivatives, aliphatic and heteroaromatic amines and azoles. The yields of products containing electron-donating or -withdrawing substituents in the aromatic rings of both reactants reached 90% (Scheme 47).

Scheme 47

Copper nanoparticles immobilized on a modified graphene oxide (N-GO) actively catalyzed the reactions of various amines with phenylboronic acid.³⁵⁹ The expected diarylamines were obtained in 76 – 98% yields, and the catalyst could be reused up to five times (Scheme 48).

Scheme 48

The Cu(II) complex of graphene oxide modified with n-propylsiloxane derivative containing 1-ferrocenylmethyl­imidazole moiety proved to be useful for the syntheses of N-arylsulfonamides.³⁶⁰ A similar complex catalyzed the reactions leading to unsymmetrical diarylamines.³⁶¹ The Cu(II) complex with a Schiff base attached to graphene oxide via the (3-aminopropyl)trialkoxysilane linker was also efficient in these reactions.³⁶² In all cases, heterogeneous catalysts could be reused four to six times without the loss of activity.

Copper(II) oxide nanoparticles proved to be active catalysts for the cross-coupling of arylboronic acids with aniline derivatives and imidazole at room temperature; the product yields exceeded 80%.³⁶³ When spherical CuO nanoparticles (6 nm) were used in the arylation of imidazoles, it was unnecessary to add a base to the reaction mixture.³⁶⁴

The metal-organic framework containing Cu(II) cations as the nodes and terephthalic acid (BDC, benzenedicarboxylic acid) and 4,4´-bipyridine (BPY) as the linkers provided high yields of diarylamines (up to 85%) in the reactions of aniline derivatives with phenylboronic acid in aqueous methanol and could be recycled (Scheme 49).³⁶⁵

Scheme 49

The metal-organic framework based on 4,5-bis(tetrazolyl)-1H-imidazole and Cu(NO₃)₂ was also effective for the arylation of amines with phenylboronic acid,³⁶⁶ while a magnetic nanocatalyst based on Fe₃O₄ encapsulated in the Cu–apatite composite showed high activity in the Chan – Lam reaction involving imidazole and indole.³⁶⁷ In both cases, the catalysts were recyclable and reusable many times.

Other methods for the synthesis of recyclable copper catalysts for the Chan – Lam reactions have also been reported, including, in particular, immobilization of copper(II) sulfate on the montmorillonite K-10 ³⁶⁸ and immobilization of the bimetallic CuPd catalyst on the SiO₂ – TiO₂ support using diamine linkers.³⁶⁹

An important stage in the development of cross-coupling strategy is switching to the reactions involving arenes after their CH-activation. The direct arylation of arenes and elimination of the preliminary metallation step decrease the number of steps and obviously correspond to the green chemistry requirements.^{370 – 372} The reaction includes the metallation of the C – H bond in situ, the reaction of the metal with the partner and the reductive elimination to give the cross-coupling product. The efficiency and selectivity of the reaction are facilitated by the presence of a directing group, while Pd, Ru, Rh, Ir and, more rarely, Cu complexes serve as the catalysts.

Depending on the nature of reactants and conditions, the reaction mechanisms can markedly vary, which accounts for a great variety of reaction products. Copper-catalyzed CH arylation was described in relation to benzoxazole and pentafluorobenzene.³⁷³ The indole arylation with diaryliodonium salt is a regiodivergent reaction yielding products at positions 2 or 3, depending on the substituents at the nitrogen atom.³⁷⁴ Direct arylation of benzene with aryl halides in a photoredox reaction in the presence of iridium complex proceeds as homolytic aromatic substitution.³⁷⁵ In the presence of ruthenium complexes as catalysts, the reaction can be carried out in green solvents.³⁷⁶

The CH arylation of 6-methoxybenzothiophene with p-iodomethoxybenzene catalyzed by the NiCl₂(bipy) complex in a green solvent, 2-methyl-THF, was used to prepare the intermediate of the synthesis of the raloxifene drug (Scheme 50).³⁷⁷ Active studies are carried out into CH alkenylation of, in particular, aromatic compounds with the acetamide directing group, which is catalyzed by Pd/C,³⁷⁸ and quinoline N-oxides, which is catalyzed by iron(II) sulfate.³⁷⁹ The arylation of 2-phenylpyridine (at position 2 of the benzene ring) and some other phenyl derivatives of heteroaromatic compounds was carried out in the presence of cyclometallated Ru(II) complex.³⁸⁰

Scheme 50

The amination reactions with CH-activation are of considerable interest. Most of reported reactions of this type are carried out with copper(II) catalysts; however, the solvents used in this case often cannot be classified as green, e.g., toluene,³⁸¹ xylene,³⁸² DMF ³⁸³ and nitromethane.³⁸⁴ The reactions carried out in DMSO are more complementary to green chemistry principles. Roane and Daugulis ³⁸⁵ used DMSO as the solvent, 8-aminoquinoline as the directing group and oxygen as the oxidant for Cu-catalyzed amination of benzamides with primary and secondary amines and sulfonamide (Scheme 51).

Scheme 51

One more bidentate directing group was used by Yu and co-workers for the amidation of aryl- and heteroarylamides catalyzed by Cu(II) (Scheme 52).³⁸⁶

Scheme 52

Due to the complexity of regioselective CH-amination, noble metal catalysis using metals such as Rh(III)^387, 388 and Ir(III)^389, 390 still plays an important role in this approach to the carbon–nitrogen bond formation, and studies along this line are in progress.

Many examples of cross-coupling reactions conducted in water have been given above. The introduction of other green solvents into the practice of catalytic synthesis is also being investigated. Several recent reviews address different aspects of the possible use of solvents compliant with the green chemistry principles. Thus Sherwood, Clark, et al.³⁹¹ considered various cross-coupling strategies (Suzuki, Stille, Kumada, Negishi, Hiyama, Heck, Sonogashira and Buchwald – Hartwig reactions) and analyzed the possibility of conducting these reactions in new solvents, including sulfolane, propylene carbonate, N-butylpyrrolidone, 2-methyl-THF, g-valerolactone, cyrene (dihydrolevoglucosenone). The last-mentioned solvent, cyrene, prepared from cellulose in two steps and similar to dimethylformamide in the physical properties, was shown to have no adverse impact on human health and to be efficient for the Suzuki – Miyaura reaction, where it provides high product yields and scalability.³⁹²

The use of green solvents in the cross-coupling reactions was considered in a review by Sydnes.³⁹³ The author analyzed a number of solvents, including glycerol, ethyl acetate, 2-methyl-THF, g-valerolactone, glycerol carbonate, cyrene, p-cymene and limonene (Fig. 20), and concluded that most often, the use of these, mostly exotic, reaction media does not reduce the yield of target product in the catalytic reactions provided that the solvent has been appropriately selected. This conclusion echoes the results of a special study that showed that the yield of the product in the Suzuki–Miyaura reaction is generally determined by the nature of reactants but not by the solvent.³⁹⁴

Fig. 20

Promising green solvents.

Finally, in the review by Andrade and Martins,²⁵⁸ the reactants themselves, water, polyethylene glycols, ionic liquids and low-melting eutectics were considered as substitutes for the common organic solvents in the Suzuki – Miyaura reaction. Low-melting eutectics are being actively developed and start, in some cases, to replace ionic liquids. For example, the Suzuki – Miyaura reaction smoothly proceeds in these solvents at 100 °C in the presence of 0.1 – 1.0 mol.% PdCl₂ . Among the considered eutectic mixtures, the best results were obtained for a mixture of choline chloride with ethylene glycol, which can be separated from the products after the reaction, together with the catalyst, and reused in the catalytic process (up to five times).³⁹⁵

Original publications often give other examples of green solvents, which are in some cases quite unusual, such as azeotropic mixture of furfuryl alcohol and water,³⁹⁶ dimethyl sulfone,³¹⁹ ethyl lactate,³⁹⁷ N-hydroxyethylpyrrolidone ³⁹⁸ and numerous technical and edible vegetable oils.³⁹⁹

According to the principles of green chemistry and taking account of the economic and environmental challenges of sustainable development, solvent-free organic reactions are preferred, because they reduce the emission of pollutants. In addition, they are characterized by lower E-factors and mass intensity (the ratio of the total mass of all materials used in the reaction to the mass of the product).⁴⁰⁰ A number of successful examples of C – C, C – N and C – O bond formation under these conditions have been reported.^{401 – 403} The Suzuki–Miyaura reactions can be carried out in a mixture of reagents using an inorganic base (KF – Al₂O₃) and mechanochemical treatment and microwave irradiation of the reaction mixture. The tolerance to atmospheric oxygen, higher yields of products and shorter reaction times make this strategy convenient and attractive. The magnetically isolated palladium catalyst was successfully used to prepare a series of biaryl compounds in the mixture of reagents, and the product yield decreases insignificantly (from 99% to 93%) by the tenth cycle.⁴⁰⁴ Borchardt and co-workers ⁴⁰⁵ showed that the mechanochemical Suzuki polycondensation is an environmentally benign and efficient alternative to the traditional methods of poly(phenylene) preparation in solutions. By using an electromagnetic mill, Li et al.⁴⁰⁶ carried out the Suzuki – Miyaura reaction without a solvent or a dispersant in the presence of a minor amount of palladium (0.05 mol.%).

Thus, the concept of green chemistry plays an important role in the development of new environmentally benign protocols for catalytic cross-coupling reactions. These reactions are performed, more and more often, in the medium of reactants or green solvents using low-toxic, recyclable and low-cost catalysts. There appears new equipment that makes it possible to carry out reactions in the continuous flow mode, under microwave or ultrasonic irradiation or in photochemical or electrochemical cells. Chemists have acquired a potent tool to create new types of bonds and are actively using these opportunities thus changing the adverse environmental impact of chemical synthesis and making chemistry more attractive to the society.

Another essential green chemical process is the enantioselective synthesis of organic compounds under environmentally friendly conditions. The need for such processes arises from the fact that the antipodes of chiral drugs, which make up a large part of the pharmaceutical market,⁴⁰⁷ act differently on the body’s receptors, and the presence of one of the enantiomers can lead to serious side effects.⁴⁰⁸ Enantiomerically-enriched substances are usually synthesized from racemic or prochiral precursors in the presence of chiral catalysts, which can be natural enzymes,^409, 410 metal complexes with chiral ligands ^411, 412 or metal-free enantiomerically pure organic molecules called organocatalysts.⁴¹³

The most recent member of this triad is asymmetric organocatalysis, a method, the creators of which, B.Liszt and D.McMillan, were awarded the 2021 Nobel Prize in Chemistry. This methodology is complementary to green chemistry ⁴¹⁴ and is one of the most dynamically developing areas of modern organic synthesis.⁴¹⁵ With a much simpler structure than the natural enzymes they mimic, organocatalysts can be obtained by convenient synthetic methods,⁴¹⁶ in particular from renewable raw materials.⁴¹⁷ Many catalytic reactions involving them are tolerant to various functional groups present in the reacting molecules and do not contaminate pharmacological products with traces of heavy metals, making them promising tools for medicinal chemistry.^{418 – 420} At the same time, organocatalysts are generally non-toxic and resistant to atmospheric air and moisture, making it possible to carry out many organocatalytic reactions in air and even in water ^{421 – 423} and to create new sustainable chemical technologies on this basis.^424, 425 In 2019, IUPAC listed organocatalysis as one of the 10 most promising chemical technologies for sustainable development of mankind.⁴²⁶ The environmental potential of organocatalysis is further enhanced by modern green chemistry methodologies,⁴²⁷ based on the use of solid-supported organocatalysts,^428, 429 continuous flow processes,^430, 431 photocatalytic ⁴³² or electrochemical ⁴³³ reactions. Tandem organocatalytic reactions are very promising, allowing several process steps to be carried out in a one-pot fashion without the need to isolate and purify intermediate compounds.^{434 – 436} Great hope is placed on the use of green solvents in organocatalysis such as water,^20, 437 compressed carbon dioxide,⁴³⁸ biobased solvents,⁴³⁹ deep eutectic mixtures,⁴⁴⁰ or on performing the reactions under neat conditions.^{441 – 443}

Let us focus on three conceptual directions of green chemistry integrated in modern asymmetric organocatalysis, which include the development of resource-saving cascade and tandem organocatalytic methodologies, carrying out asymmetric continuous flow reactions, and the creation of combined visible-light-induced organophotocatalytic processes. Environmental aspects of asymmetric organocatalysis have already been summarized in one form or another (see, e.g., review ⁴⁴⁴). We will only consider reactions and processes that comply several principles and criteria of green chemistry.⁹ For catalysts, priority is given to the greener and more sustainable chiral amines ⁴⁴⁵ and axially chiral phosphoric acids,⁴⁴⁶ which are structural platforms for solid-supported catalysts. In assessing solvents, we were guided by the recommendations of the European Consortium of Innovative Medicines Initiative (IMI)-CHEM21,³⁴ which take into account several important factors such as safe handling, potential harm to human health and potential negative impact on the environment (ozone depletion, acute ecotoxicity, potential for bioaccumulation, volatility, etc.).

According to the green chemistry paradigm, the most efficient synthetic approach to a chemical compound of high molecular complexity should involve a minimum number of steps, carried out mainly in a single reaction vessel, without isolation and purification of intermediate compounds, thereby reducing labour costs and waste. Below are some examples of how this paradigm is realized in organocatalyst-mediated asymmetric syntheses.

Zhong and co-workers ⁴⁴⁷ proposed an original one-pot method for the enantioselective synthesis of tricyclic compounds containing fused tetrahydronaphthalene and isoxazolidine moieties from ortho-(acrylato)nitrostyrene 55, enolizable aldehydes, and N-substituted hydroxylamine (Scheme 53). The domino reaction proceeds efficiently in aqueous medium in the presence of silylated α,α-diphenylprolinol (S)-XIXa to give the products 56 in good yields and with extremely high diastereo- and enantioselectivities. The plausible mechanism of the process involves the enantioselective addition of an aldehyde activated by the catalyst (enamine activation) to the double bond of nitrostyrene 55 attached to the nitrogroup. The resulting adduct Int₁ reacts with hydroxylamine to generate nitrone Int₂ , which spontaneously cyclizes to the product 56. The addition of benzoic acid appears to facilitate the formation of the key enamine from the catalyst and aldehyde and its subsequent hydrolysis, thereby returning the catalyst to the catalytic cycle.

Scheme 53

Hayashi and co-workers ⁴⁴⁸ have developed an enantioselective one-pot method for the synthesis of the bicyclic Corey lactone, a valuable intermediate in the preparation of synthetic prostaglandin hormones, which regulate important physiological processes in living organisms. The method is based on the domino reaction of ethyl 4-oxo-2-pentenoate (57) with silylated enal 58 catalyzed by (R)-XIXa in PrⁱOH and involves two successive Michael reactions (steps 1 and 2) (Scheme 54). Functionalized cyclopentanone Int₃, formed in 85% yield as a single isomer (>99% ee), was converted to the desired lactone without isolation via functional group transformation (one-pot 5-step synthesis, 50% overall yield). As a result, waste and labour costs were significantly reduced. The total reaction time for the Corey lactone was only 2.5 h, making the developed approach the most environmentally friendly and effective method for the synthesis of this useful compound. A similar methodology was employed by the same authors ⁴⁴⁹ for the enantioselective construction of a functionalized cyclo­pentane motif in the asymmetric syntheses of cis-hydrindane and the neuroprotective agent Clinprost.⁴⁵⁰

Scheme 54

Prolinol catalysts have also been useful in the asymmetric synthesis of polysubstituted derivatives of bicyclo[4.3.0]nonane and bicyclo[4.4.0]decane, motifs found in many natural products, particularly steroids and diterpenes. Hayashi et al.^{451 – 453} proposed efficient methods for the preparation of key bicyclic precursors to natural products via domino reactions of 1,3-diketones 59 containing a 2-positioned nitroethyl group with α,b-enals in green solvents (PrⁱOH or THF). This procedure involves a sequence of asymmetric Michael reaction (step 1) and intramolecular aldol reaction with cyclohexane ring closure (step 2) (Scheme 55). In the presence of (S)-XIXa or (S)-XIXb catalysts, the bicyclic products 60 ^451, 452 and 61,⁴⁵³ containing five contiguous stereocentres, were formed in high yields as almost single enantiomers. The addition of a small (3 equiv.) amount of water significantly accelerated the domino reaction, apparently due to the faster hydrolysis of iminium ions formed from enal and the catalyst. Furthermore, in line with the pot-economy concept,⁴⁵⁴ the authors greatly simplified the conversion of compound 60 to estradiol ether by reducing the number of experimental steps from 12 to 5 and increasing the overall yield of the target product from 6.8% to 15%.

Scheme 55

Appayee and co-workers ⁴⁵⁵ developed a highly selective one-pot cascade synthesis of cyclohexanones 62 containing three contiguous stereogenic carbon atoms from simple precursors: acetone and cinnamaldehydes (Scheme 56). This apparently simple domino reaction involves three stereoselective steps: 1,2-Mannich addition of the enamine Int₄ to the iminium cation Int₅ , 1,4-Michael addition of the resultant enamine Int₆ to the second molecule of the iminium cation Int₅ , and closure of the cyclohexane ring in the adduct Int₇ via an intramolecular Michael reaction. This process features the use of two chiral aminocatalysts (S)-XIXa and (S)-XX, which are capable of forming both enamines and iminium cations with reactants. By changing the absolute configuration of just one of them, the desired isomer of product 62 can be selectively synthesized. The results obtained are well reproduced when scaling up the reaction to several grams. In addition to atom-economy, the method is attractive because it uses isopropanol, an environmentally benign and safe solvent, as the reaction medium.

Scheme 56

Wen and Du ⁴⁵⁶ carried out enantioselective synthesis of bispyrocyclic cyclopropanes via the reaction of 4-arylidene-2,3-dioxopyrrolidines 63 with 3-chloroxindoles 64 catalyzed by a squaramide alkaloid XXIa (Scheme 57). The domino process comprises the asymmetric Michael addition followed by intramolecular cyclization involving the catalyst-generated enolate anion and affords chiral products 65 of high molecular complexity with moderate to high yields and with excellent stereoselectivities. Screening of reaction media carried out by the authors showed that the optimal solvent is ethyl acetate, in which the reaction is easily scalable while maintaining yield and enantiomeric purity of the product.

Scheme 57

In the follow-up study, a cascade reaction of 4-arylidene-2,3-dioxopyrrolidines 63 with 2-isothiocyanato-1-indanones 66 in the presence of a pseudoenantiomeric quinidine XXIb was carried out.⁴⁵⁷ In this case, the asymmetric Michael addition was followed by a diastereoselective cyclization via the isothio­cyanate group of compound 66 to give a dispiro[pyrrolidinethione] 67 containing three contiguous stereocentres (see Scheme 57). Again, the highest stereoselectivity was achieved in ethyl acetate. The above cascade processes provide the easy synthesis of representative libraries of polynuclear heterocyclic compounds containing biogenic motifs for subsequent screening for biological activity.

For the asymmetric synthesis of spiroheterocycles, Li and co-workers ⁴⁵⁸ used another approach based on the ability of functionalized propargylic alcohols to be enantioselectively converted to axially chiral allenes when treated with chiral Brønsted acids. The authors found that 3-alkynyl-3-hydroxyisoindolinones 68 react with 3-substituted-1H-indoles 69 in EtOAc in the presence of BINOL-phosphoric acid (S)-XXIIa to give spiro products 70 in a single step in high yields and with excellent regio- and enantioselectivities (Scheme 58). The catalyst can be recovered by acidifying the reaction mixture and reused in the reaction. The reaction pathway appears to involve the catalyst-induced dehydration of isoindolinone 68 to form an adduct of propargyl-N-acylimine Int₈ with the catalyst. The subsequent enantioselective 1,4-addition of indole 69 releases the catalyst to give allene Int₉ , which further undergoes cyclization to afford spiro-products 70.

Scheme 58

Shi and co-workers ⁴⁵⁹ have developed an interesting method for the deracemization of substituted 3,4-dihydropyrimidin-2-ones (rac-71) containing a diisopropylphosphonate moiety in position 4 of the heterocycle. The method is based on a tandem reaction involving DDQ-mediated oxidation of rac-71 to tautomeric pyrimidinones Int₁₀ and Int₁₁ and asymmetric hydrogenation of the C=N bond in the pyrimidine moieties of the latter compounds (Scheme 59). The best results were obtained using Hantzsch ester 72a, a biomimetic of natural reducing agents, as the hydrogen source, and a BINOL-phosphoric acid derivative (R)-XXIIa as the organocatalyst. Both steps of the one-pot redox process are carried out in the same green solvent, ethyl acetate, without isolation and purification of intermediate compounds, which greatly simplifies the experimental procedure. As a result, enantiomerically enriched products (R)-71 promising for biological studies can be obtained in a gram-scale while maintaining productivity and stereocontrol.

Scheme 59

Zlotin and co-workers ⁴⁶⁰ first performed atom-economical asymmetric domino reactions in supercritical (sc) carbon dioxide, a non-toxic natural compound that is easily removed from the products and does not require disposal. In the presence of a squaramide-containing quinine XXIa, ortho-amino­chalcones 73 added to nitroolefins via a cascade of two asymmetric Michael reactions (a and b) to yield functionalized tetrahydroquinolines 74 with very high diastereo- and enantioselectivities (Scheme 60). However, this was only achieved when the reaction was carried out under rather harsh conditions (20 MPa, 75 °C), providing a high medium density (~14 mol CO₂/L) necessary for an efficient cycloaddition. The use of more lipophilic and better soluble in sub- and sc-CO₂ bifunctional tertiary amines XXIc and XXIIIa with long-chain alkyl groups as catalysts made it possible to reduce the pressure and temperature (7.5 MPa, 35 °C) and make the process more attractive for practical implementation in academic laboratories and industry.⁴⁶¹ This is important because the resultant compounds are precursors to natural alkaloids and some drugs (angustureine, martinelline, etc.).

Scheme 60

Recently, the same research group ⁴⁶² found that one of the basic reactions in organic synthesis, the condensation of carbonyl compounds with arylamines, also proceeds smoothly in scCO₂ , and the resulting imines can be further processed in the same reactor without prior isolation. In particular, the reaction of 4-methoxyaniline with α-ketoester 75 in scCO₂ in the presence of a reducing agent (dihydrobenzothiazole 76a) and chiral BINOL-phosphoric acid (R)-XXIIa affords enantio­selectively the (R)-enantiomer of the N-protected phenylglycinate 77 in a single step in 97% yield and with 96% enantiomeric purity (Scheme 61).

Scheme 61

Šebesta and co-workers ⁴⁶³ performed enantioselective one-pot synthesis of hybrid molecules 78 comprising 2-oxoindoline and pyrazolone motifs. The tandem process involved the asymmetric Mannich addition of pyrazolones 79 to N-Boc-isatinimines 80 and diastereoselective fluorination of the resulting in situ adducts Int₁₂ with N-fluoro-benzenesulphon­imide (NFSI) (Scheme 62). In this case, the high enantio­selectivity of the reaction was provided by using an alkaloid-squaramide catalyst XXId. The required catalyst loading was as low as 1 mol.%. The characteristic feature of the method is that both steps are carried out by mechanical grinding of a mixture of solid reactants wetted with a minimal amount of organic solvent (50 mL) in a ball mill.

Scheme 62

Continuous-flow chemical reactions have a number of advantages over the corresponding batch processes. These include the process intensification ⁴⁶⁴ and the ability to combine multiple reactions/stages into a single process. Moreover, the accuracy of reagent dosing and control over conditions is improved, making the process safer and ensuring good reproducibility of results.⁴⁶⁵ The use of continuous-flow processes fully comply with the principles of green chemistry,^{466 – 469} as they significantly reduces resource, energy and labour costs, avoids isolation and purification of intermediate compounds and consequently reduces waste. These benefits are fully realized in flow systems where the working medium is green solvents that are safe for personnel and the environment.^470, 471 Such systems are very promising for the selective preparation of practically relevant high-purity compounds, including drugs and their precursors.⁴⁷² Let us consider some recent examples of their application in asymmetric organocatalysis using homogeneous and polymer-supported catalysts.

Meng and co-workers ⁴⁷³ carried out enantioselective oxidation of β-dicarbonyl compounds 81 with cumene hydroperoxide (CHP) in a two-phase toluene/1% aqueous Cs₂CO₃ system in a cascade of flow microreactors using cinchonine bromide XXIVa as a chiral phase transfer catalyst (PTC) (Scheme 63). The system components were simultaneously fed into the microreactors by two pumps at a flow rate of 1.5 ml/min: one pump fed a solution of substrate, CHP and catalyst in toluene and the other pump fed an aqueous solution of Cs₂CO₃ . The oxidation products 82 were formed in high yields and enantiomeric enrichment of 78 – 84%. At the same time, the required residence time of the reactants in the flow microreactors (2 h) was much shorter than that for the corresponding batch reactions (24 h).

Scheme 63

Sasai and co-workers ⁴⁷⁴ carried out an atom-economic domino reaction involving enantioselective Rauhut – Currier cycle closure in dienones 83 and [3+2] annulation of bicyclic intermediates Int₁₃ with allene 84 (Scheme 64). The reactions were performed using chiral phosphinamide XXV in a flow system with parameters carefully optimized using artificial intelligence. Under optimal conditions (flow rate 1.7 ml min^–1, temperature 80 °C), the yield of the spirocyclic product 85 (R¹ = Me, R² = Ts) was 76%, significantly higher than in a batch process (20%). Under these conditions, various dienones 83 were converted into the corresponding products 85 as single diastereomers with high enantiomeric purity in less than one minute.

Scheme 64

Recently, Gröger and co-workers ⁴⁷⁵ developed a tandem cascade process comprising the organocatalytic asymmetric aldol reaction and the biocatalytic reduction of the resulting aldol Int₁₄ to diol 86 containing two stereogenic centres. The chemoenzymatic process was carried out in a continuous flow of a mixture of isopropanol and phosphate buffer (Scheme 65). The first-step catalysts were enantiomers of diphenylleucinol-substituted prolinamide XXVI,⁴⁷⁶ and the second-step catalysts were alcohol dehydrogenases ADH030 and ADH270, providing stereoselective formation of a second stereocentre with S or R configuration, respectively. Using different combinations of organo- and biocatalyst enantiomers, the authors were able to synthesize all four possible isomers of diol 86 in optically pure form in 33 – 76% yield and with moderate to high diastereoselectivities. Importantly, the aldol Int₁₄ did not require isolation and purification, which greatly simplified the experimental procedure. The developed process can be used as a basis for the creation of new green technologies for the enantioselective synthesis of pharmaceuticals and other useful organic compounds.

Scheme 65

A common drawback of the above flow processes using low-molecular-weight organocatalysts is the difficulty of their recovery due to ‘washing out’ from the continuous flow unit along with the products. Nakashima and Yamamoto ⁸ proposed an approach to solve this problem by using the simple and accessible (S)-5-(2-pyrrolidinyl)-1H-tetrazole XXVII as a catalyst, which is poorly soluble in many organic solvents. This approach was successfully tested in the asymmetric aldol and Mannich reactions (Scheme 66). When a solution of the reactants in EtOAc or MeCN was passed at a constant rate through a column packed with catalyst XXVII, the corresponding products 87 and 88 were formed in good yields and with high stereo- and enantioselectivities. At the same time, the heterogeneous catalyst was practically insoluble in organic solution and could be used for a long time. In terms of mass efficiency (the number of grams of catalyst required to produce 1 mole of product), the catalyst XXVII is superior to many known catalytic systems.

Scheme 66

Another promising approach to immobilizing chiral organocatalysts intended for usage in flow systems is based on the creation of hybrid molecules in which catalytically active chiral units are grafted to polymers.⁴³¹ For example, Massi and co-workers ⁴⁷⁷ obtained a (S)-5-(2-pyrrolidinyl)-1H-tetrazole-containing polymer XXVII via radical copolymerization of its styryl-substituted analogue XXVII' with styrene and divinylbenzene (DVB). The resulting monolithic copolymer (S)-XXVII/PS, packed into a stainless steel column, continuously catalyzed asymmetric aldol reactions of ketones with aromatic aldehydes in a flow of aqueous ethanol for five days (Scheme 67). Enantiomerically-enriched anti-aldoles 89 were predominantly formed and the productivity of the plant was twice that of the corresponding batch reactions.

Scheme 67

Kobayashi and co-workers ⁴⁷⁸ carried out an asymmetric aldol reaction of trifluoroacetophenone derivatives with methyl ketones under continuous flow conditions. The mixture of reactants (methyl ketone was taken up in excess) was passed through a column packed with a mixture of celite with polystyrene-supported prolinamide catalyst (S,S)-XXVI/PS (Scheme 68). A small amount of water (1 equiv.) was added to the flow system to accelerate the hydrolysis of the iminium intermediates and return the catalyst to the catalytic cycle. Under the above conditions, the reactants were completely converted to fluoromethylated carbinols 90 of high enantiomeric purity. The total catalyst operation time was 195 h. In particular, the developed continuous-flow process was used to prepare a fluorinated chiral analogue 91 of Fenpentadiol, the well-known tranquilizer and antidepressant.

Scheme 68

Smith and co-workers ⁴⁷⁹ performed kinetic resolution (KR) of racemic acyclic alcohols rac-92 containing a quaternary carbon atom by their enantioselective acylation with iso-butyric anhydride as the continuous flow process (Scheme 69). The catalyst was a cyclic isothiourea derivative XXVIII/PS grafted to Merrifield rubber through a spacer group. When a solution of reactants in toluene was passed through a column packed with heterogeneous catalyst (0.05 ml min^–1), the S enantiomer of the alcohol was predominantly acylated to form the enantiomerically enriched ester (S)-93, while the main portion of (R)-92 remained unchanged. The resolution selectivity depended on the substituents R¹ and R² in the α-position to the hydroxyl group and ranged from 21 – 80%. The above method can be used in selective technologies for the preparation of chiral alcohols for pharmacological purposes.

Scheme 69

In some cases, silicon-containing polymers can be used as supports for immobilizing organocatalysts for continuous-flow enantioselective chemical reactions. For example, Massi and co-workers ⁴⁸⁰ compared the catalytic properties of chiral superbasic cyclopropenimines XXIX/Si and XXIX/PS immobilized onto silica and polystyrene, respectively. Asymmetric nucleophilic addition reactions of glycine imine derivatives 94 with acrylic acid esters to afford adducts 95 (Scheme 70) were used as a test system. The catalytic reactions were carried out in ethyl acetate in batch and continuous modes. It was found that the catalysts XXIX/Si and XXIX/PS were almost identical in terms of stereoinduction and efficiency in the batch process. However, in the solvent flow, the catalyst immobilized onto the silicon support was more stable than its polysterene counterpart, maintaining the conversion (90 – 95%) and enantioselectivity (70 – 98% ee) values over 28 h. The activity of the catalyst then decreased, but after reactivation (washing with LiOH solution in anhydrous MeOH) it continued to work efficiently for another 28 h.

Scheme 70

Hayashi et al.⁴⁸¹ carried out in a green solvent flow an asymmetric cascade reaction of a cinnamaldehyde derivative with 2-(b-nitroethyl)-cyclopentane-1,3-dione (59), a key step in the batch synthesis of estradiol esters previously described by the authors (see Refs 451,452 and Scheme 55). The catalyst was an amphiphilic α,α-diphenylprolinol ether XIXc/PEG/PS containing hydrophilic (polyethylene glycol) and hydrophobic (polystyrene) moieties (Scheme 71). A solution of reactants and benzoic acid in a specially selected solvent with an optimal combination of lipophilic and hydrophilic properties was passed through a steel reactor packed with this catalyst at a constant rate. Using the PrⁱOH/THF/H₂O solvent system, the polymer catalyst worked continuously for 60 h, maintaining the enantioselectivity of the process at 91% ee. The overall yield of product 60 was 63% with a catalyst turnover number (TON) = 81.

Scheme 71

Almost at the same time, Pericàs and co-workers ⁴⁸² used the catalyst XIXd/PS immobilized onto polystyrene in the continuous-flow asymmetric addition of dimethyl malonate to α,b-unsaturated aldehydes (Scheme 72). The best results were achieved in the system wherein the excess of dimethyl malonate, easily removable from the product by evaporation at reduced pressure, was used as a solvent. A series of adducts 96 with enantiomeric purity of up to 98% ee were obtained using the same portion of catalyst. At the end of the process (2.5 – 4.5 h), the catalyst was reactivated by successive washing with acetic acid and ethyl acetate and used for the reaction with another substrate. The resulting compounds included intermediates for the synthesis of the antidepressant drugs Paroxetine and Femoxetine and a peptidomimetic inhibitor. They were also diastereoselectively converted to indoloquinolizidine derivatives and δ-lactones using the Pictet – Splengler and reduction reactions, also carried out in continuous flow.

Scheme 72

Ötvös and co-workers ⁴⁸³ reported an innovative method for the continuous asymmetric synthesis of rolipram, a selective cyclic phosphodiesterases type IV inhibitor. The three-step synthesis involved the enantioselective addition of nitromethane to a cinnamaldehyde derivative, oxidative esterification of the enantiomerically enriched γ-nitroaldehyde 97, and reduction of the nitro group in the γ-nitroether 98 to an amino group and concomitant lactamization (Scheme 73). To avoid side transformations of the labile aldehyde 97, the authors combined the first two steps into a single continuous ‘telescopic’ process. A solution of nitroaldehyde 97 in an excess of nitromethane, formed by passing the reactant mixture through a XIXe PS catalyst column, was mixed at the column outlet with solutions of sulfuric acid and hydrogen peroxide in methanol. The resulting mixture was subjected to oxidative esterification to γ-nitroester 98 when treated with persulfuric acid generated in situ in a coil heated to 100 °C. The reductive lactamization of ester 98 under the action of the HSiCl₃ MeN(Prⁱ)₂ system was also carried out in continuous flow mode, in this case in acetonitrile. As a result, (S)-rolipram was obtained in 83% yield and with 94% enantiomeric purity.

Scheme 73

Organocatalytic flow reaction methodology has also been successfully applied to the cost-competitive asymmetric synthesis of (S)-3-aminomethyl-5-methylhexanoic acid, used for the treatment of seizures, neuropathic pain and epilepsy (trade names Lyrica, Pregabalin).⁴⁸⁴

A significant role in the development of asymmetric organocatalysis in recent years has been played by the use of new methods of reagent activation, in particular light activation.⁴⁸⁵ Visible light, sourced from the sun, is the most environmentally friendly, safe and virtually inexhaustible source of energy for sustainable development.^{486 – 488} However, the use of this energy for the enantioselective synthesis of organic compounds is complicated by the high reactivity of the free radicals generated via the homolytic cleavage of the covalent bond, which hampers the stereochemical control of the reaction.^{486 – 488} The problem of selectivity has been solved by combining chiral organocatalysts with achiral photocatalysts, which can be metal (iridium, ruthenium, rhodium, etc.) complexes ^145, 489 or organic chromophores — derivatives of aromatic and heteroaromatic compounds, including polynuclear ones.⁴⁹⁰ The methodology of organophotoredox catalysis is discussed in detail in the review.⁴⁹¹ We will give some conceptual examples of such metal-free green reactions.

Jiang and co-workers ⁴⁹² described a visible light-driven enantioselective cross-coupling reaction between N-aryl­glycines 99 and α-branched 2-vinylpyridines or 2-vinyl­quinolines 100, followed by decarboxylation of the amino acid. The successful implementation of the process was ensured by the combined use of a photochrome, dicyanopyrazine (DPZ), which removes an electron from the amino acid upon light excitation, and an organocatalyst, chiral phosphoric acid XXXa, which is responsible for the enantioselective formation of the product 101 of the photochemical reaction (Scheme 74). The reaction is carried out under mild conditions in tetrahydrofuran. The practical value of the method was demonstrated by the synthesis of the antihistamine pheniramine (R)-enantiomer.

Scheme 74

A similar organophotocatalytic system was then applied to the asymmetric [3 + 2] cycloaddition reaction of N-cyclo­propylamines to N-sulfonyl-3-methylene-isoindolin-1-ones 102.⁴⁹³ Under optimal conditions, the spirocyclic cycloaddition products 103 were produced in near-quantitative yields as single diastereomers with 90 – 95% ee (Scheme 75). The XXXb/DPZ catalyst combination was also useful in the reaction of N-cyclopropylamines with N-protected vinylamines 104 to give 1,2-diaminocyclopentanes 105 of high enantiomeric purity, although the diastereoselectivity of these reactions was lower for some substrates. These methods are of practical value since five-membered cycles, including those contained in spirocyclic units, are key structural motifs in many biologically active compounds.

Scheme 75

The reductive cross-coupling reactions of α-branched vinyl ketones 106 with 2-vinylazaarenes 107 (Scheme 76), where Hantzsch ethers 72b,c served as reducing agents, proved to be an excellent application of the CPA-DPZ catalytic system.⁴⁹⁴ The above process is interesting in that two stereogenic centres at positions 1 and 4 of the linear carbon chain are formed in the products under LED irradiation as a result of enantioselective reduction/protonation cascade reactions. This gave rise to a series of enantiomerically enriched derivatives of azaheterocycles 108 containing pyridine, benzimidazole or benzothiazole units obtained in 35 – 99% yields with up to 99% ee. The efficiency of the proposed methodology of metal-free organophotoredox catalysis was also demonstrated by the authors in visible light-induced deuteration reactions of α-(chloroalkyl)azaarenes with D₂O.⁴⁹⁵

Scheme 76

Other types of chiral organocatalysts, organic photochromes and reducing agents can also be used in visible light-induced reductive cross-coupling reactions. Recently, Jiang and co-workers ⁴⁹⁶ applied a cooperative system including the bifunctional organocatalyst XXXI based on quinine modified with a thiourea group and the polyfunctional photochrome 3DPAFIPN to the reaction of chalcones 109 with 4-cyanopyridine (Scheme 77). This reaction, accompanied by the cleavage of the cyano group from the heterocyclic substrate, produced adducts 110 in moderate yields but with high enantioselectivities (up to 92% ee). The reducing agent in this case was 2-aryldihydrobenzothiazole (76b), which was oxidized in the reaction to 2-arylbenzothiazole (76b').

Scheme 77

Yang and co-workers ⁴⁹⁷ described the visible-light-induced asymmetric cascade transformation of b-(ortho-aminoaryl)­enones 111 to tetrahydroquinoline derivatives 112, which are widely used as biologically active substances (Scheme 78). The organocatalyst in choice was chiral BINOL-phosphoric acid XXIIb. However, in this case there was no photocatalyst in the reaction system and the light directly induced E/Z isomerization of the double bond in the starting chalcones 111, facilitating their cyclization involving amino and carbonyl moieties. The resulting quinoline derivatives Int₁₅ were further reduced spontaneously to enantiomerically enriched (up to 99% ee) tetrahydroquinolines 112 in the presence of the XXIIb/72d system in up to 98% overall yield. The proposed method can also be used for the stereoselective preparation of cis-isomers of 2,3-disubstituted tetrahydroquinolines 112 (R³ = Me).

Scheme 78

Bach and co-workers ⁴⁹⁸ proposed the use of thioxanthone XXXII, a chiral compound capable of acting as an organocatalyst by forming stereodifferentiating hydrogen bonds with the reactant and simultaneously being excited by visible light, transferring its energy to the reactant, in metal-free organophotocatalysis. This compound was used in particular for deracemization of chiral piperidin-2-one-substituted allenes 113. When irradiated with visible light at a wavelength of 420 nm in MeCN in the presence of sensitizer XXXII, racemate rac-113 was almost completely converted to the enantiomer (R)-113 (Scheme 79), while this did not occur in the absence of the catalyst. This phenomenon was explained by theoretical calculations (DFT), which showed that the distance between the carbonyl carbon atom of thioxanthone and the terminal endocyclic carbon atom of the allene unit of the substrate in complex XXXII/(S)-113 is half as much as that in complex XXXII/(R)-113. As a result, the triplet energy transfer from the light-excited catalyst to the substrate in the first complex and consequently its racemization proceeds faster than in the second complex, leading to the accumulation of the enantiomer (R)-113 in the reaction mixture. The photoinduced asymmetric conversion of achiral 3-allyl-substituted quinolones to enantiomerically enriched 3-cyclopropylquinolones in the presence of photochrome XXXII follows the similar pathway.⁴⁹⁹

Scheme 79

Phipps and co-workers ⁵⁰⁰ carried out the asymmetric oxidative cross-coupling of aza-heterocycles 114 (quinoline, pyridine and pyrimidine derivatives) with N-acetylated primary amines 115 (a Minisci-type reaction) under the action of light in the presence of chiral BINOL-phosphoric acids XXII. The key role in this reaction belongs to diacetyl (116), a simple, cheap and accessible compound that simultaneously acts as a photochrome, oxidant and hydrogen atom acceptor (Scheme 80). The ability of diacetyl to absorb light in the visible region of the spectrum (380 – 460 nm) eliminates the need for more complex photocatalysts. First, the light-excited molecule 116 initiates hydrogen atom transfer from N-acetylamine 115, forming the α-amino radical 115', which is necessary for the reaction to proceed, and the ketyl radical. The ketyl radical is also important: it oxidizes the primary radical cross-coupling products to α-acetylamino derivatives of aza-heterocycles 117 to give acetoin (118). A high degree of stereocontrol in the above organophotocatalytic radical process is provided by chiral phosphoric acid XXII, which forms hydrogen bonds with reactant 114 and α-aminoradical 115' in the transition state of the catalytic reaction.

Scheme 80

In addition to chiral Brønsted acids, chiral amines capable of forming chemically active enamines and iminium ions with carbonyl compounds can be used as organocatalysts in photocatalytic processes. Melchiorre and co-workers ⁵⁰¹ used silylated diarylprolinol XXXIIIa in conjunction with acridinium salt XXXIV to carry out the enantioselective β-functionalization of aliphatic α,β-enals, which is not easily achievable with other photocatalytic systems. The radical sources were organosilicon compounds 119a containing a trimethylsilyl group or an aromatic ring in the α-position to the heteroatom (N or S) (Scheme 81). Light-excited photocatalyst XXXIV abstracts an electron from them, leading to the cleavage of substrate 119a into a SiR³⁺ cation and a C-centered radical. The stereoselective attack of this radical on the iminium cation generated upon condensation of enal with the chiral organocatalyst XXXIIIa in the activated complex Int₁₆ and subsequent hydrolysis of the resulting adduct afford products 120, turning over the organocatalyst and the photochrome XXXIV. The best stereochemical outcome was achieved in the ‘green’ solvent acetonitrile, where branched aldehydes containing b-positioned alkyl, (hetero)aryl and protected amino groups were formed in 35 – 93% yield with up to 98% ee.

Scheme 81

The same catalytic system has proven useful for the enantioselective preparation of 1,7-dicarbonyl compounds with a 3-positioned stereocentre.⁵⁰² These compounds occur in nature and are used as substrates for the preparation of biologically active substances. The photocatalytic process is based on the oxidative ring-opening in cyclobutanols 121 when irradiated with visible light in the presence of photochrome XXXIV. The resulting γ-keto-radicals add enantioselectively to iminium cations generated from enals and organocatalyst XXXIIIa to give 1,7-ketoaldehydes 122 in 30 – 82% yields with up to 95% ee (Scheme 82).

Scheme 82

In contrast to β-alkylenals, cinnamaldehyde derivatives, which have a more extended π-electron system, undergo enantioselective photoinduced reactions catalyzed by chiral prolinol silyl ethers, even in the absence of external photochromes.⁵⁰³ This is due to the ability of β-aryliminium ions to switch to an excited state when exposed to light, similar to what occurs in the organs of vision of higher organisms in nature.

Melchiorre and co-workers ⁵⁰⁴ exploited this ability to perform an asymmetric [3 + 2] annulation of cinnamaldehydes with cyclopropanols 123. The radical photochemical process involves iminium ions in the ground and excited states and allows the one-pot conversion of racemic and prochiral substrates into polysubstituted cyclopentanols 124 of high molecular complexity (Scheme 83). Apparently, the iminium ion derived from aminocatalyst XXXIIIa and enal is light-excited and abstracts an electron from cyclopropanol 123. This result in that the iminium cation is converted to the radical Int₁₇ , and the cyclopropanol, through the opening of the cyclopropane cycle, delivers the cation radical Int₁₈ . Subsequent recombination of the Int₁₇ and Int₁₈ radicals and intramolecular aldol cyclization furnishes functionalized cyclopentanol 124 and releases the aminocatalyst. Efficient control over the geometry of the three stereocentres by the catalyst XXXIIIa in the course of the organophotocatalytic process ensures high diastereo- and enantiomeric purity of the products 124.

Scheme 83

Another example is the visible light-driven enantioselective b-alkylation of cinnamaldehydes, in which 4-alkyl-substituted Hantzsch esters 72e serve as precursors to alkyl radicals.⁵⁰⁵ In this case, diarylprolinol XXXIIIb, containing bulky perfluoroisopropyl groups in the aromatic rings, worked as aminocatalyst and the electron was transferred from the diester 72e to the photoexcited iminium cation (Scheme 84). As a result, a representative series of aldehydes 125 bearing diverse linear and α-branched substituents were obtained with enantioselectivities of up to 94% ee. In the case of α-branched R² substituents, the diastereoselectivity of the reactions was generally not high, except for adduct of cinnamaldehyde with galactose, where the diastereomeric ratio was 9 : 1.

Scheme 84

The same research group ⁵⁰⁶ proposed an original method to generate RCH₂ · radicals from silylated methylamines and employ them in asymmetric addition to cyclic α,β-enones mediated by a chiral carbazole-based primary amine XXXV used as an organic photocatalyst. This catalyst was found to be able to switch to an excited state when irradiated with visible light and transfer an electron from the carbazole moiety to the double bond of the iminium cation derived from the catalyst and the cyclic α,β-enone 126 via the charge transfer π – π interaction. This transfer generates a radical at the β-position of the enone (Scheme 85). Furthermore, in the activated complex Int₁₉ , the carbazole moiety promotes the oxidation of silane 119b to the corresponding cation radical, which is the source of the RCH₂ radical. The recombination of the above radicals affords adducts 127 containing a quaternary carbon atom in β-position to the carbonyl group in good yields with up to 95% ee.

Scheme 85

To conclude, the conceptual ideas and basic principles of green chemistry have had and continue to have a major influence on the development of asymmetric organocatalysis — an innovative field of organic chemistry. The result of their practical implementation can be the creation of highly selective, energy- and resource-saving and environmentally friendly technologies for obtaining enantiomerically pure drugs and other practically useful products of fine organic synthesis.

Electric current is one of the most environmentally benign sources of energy for chemical reactions. Electrification of organic synthesis, that is, the search for alternative eco-effective approaches to the preparation of highly marginal, practically valuable products using methods of electrochemistry is growing exponentially, making up for years of quiet development.^{507 – 530} Advantages of electrochemical methods over conventional approaches can always be demonstrated. If conventional methods are placed on one weighing pan of a balance and electrosynthesis is placed on the other pan to consider the selectivity, efficiency and economic performance of the preparation of the same product or related products, the second pan would undoubtedly outweigh (Fig. 21). The decrease in the number of steps and the atom, time and pot economy are important advantages of electrosynthesis. In addition, elimination of chemical oxidants and reductants, which are replaced by electrodes (an electron is a traceless reagent with a controlled strength), considerably simplifies the reaction system and, hence, isolation of products and eliminates the waste formation.

Fig. 21

Advantages of electrochemistry over conventional chemical processes.

Currently, there are more than 900 known reactions of organic compounds that take place under electrochemical conditions, out of which 7% have already been commercialized as ready industrial processes and 15% have been tested on a pilot scale.⁵¹⁴ However, there is some contradiction between the goals and objectives of industrial electrochemistry and fine organic electrosynthesis (Fig. 22). As a rule, large-scale electrochemical production processes aim at the synthesis of relatively structurally simple and relatively inexpensive molecules (aluminum, chlorine, adiponitrile, formic acid and so on ⁵³¹), but the scale of production and cost effectiveness depend on the cost of electricity, Faraday efficiency (current efficiency), design of the electrolytic cells, etc.

Fig. 22

Goals of the industrial and fine organic electrosynthesis.

In turn, the goals of fine organic electrosynthesis include the search for new, more convenient and selective methods for the synthesis of costly small molecules (drugs, biologically active compounds,^{507, 510 – 522} natural compounds ^523, 524), in particular from natural feedstock ⁵²⁵ or the products of its processing ⁵²⁶ (see Fig. 22). In this case, the cost of electricity is less significant, but particularly these processes take advantage of the benefits of electrochemistry, which provides control over the reactivity of polyfunctional organic substrates by implementing new, more efficient pathways of chemical bond formation and cleavage, in particular at the latest steps of the synthesis.

This Section addresses both fine organic electrosynthesis processes directed towards the preparation of useful molecules of high chemical complexity and industrial electrosynthesis processes for the production of basic organic products containing one or two carbon atoms (liquid fuels, formic acid, etc.) from carbon dioxide, a cheap and readily accessible natural raw material. The attention is focused on the latest achievements in these areas.

The recent advances of electrochemical organic synthesis are largely associated with the design of new types of reactors including flow electrochemical cells, which allow scaling-up of the processes from the laboratory to industrial scale;^{532 – 534} electrochemical cells for original alternating-current electrolysis techniques;⁵³³ reactors combining electrolysis and light activation,^89, 517 including the plasmonic excitation of the electrocatalyst.⁵³⁵ New-generation electrodes with unique composition and porosity were designed; among them, mention should be made of boron-doped diamond electrodes and electrodes with immobilized catalysts.^{507, 508, 526, 532} Organic electrosynthesis makes it possible to produce a wide range of in-demand products ⁵³⁶ with minimized impact on the environment.^537, 538 Machine learning techniques are used more and more actively to predict new electrochemical reactions.⁵³⁹

As noted above (see Sections 3.1 and 3.2), direct С – Н functionalization of molecules, without preliminary replacement of hydrogen by good leaving groups (halogen- or boron containing groups, triflate, etc.) that would increase the amount of waste, meets the green chemistry principles. As an ideal reaction, consider the dehydrating electrochemical cross-coupling of the С – H bond with various proton-containing molecules that takes place without external chemical oxidants or reducing agents (this function is performed by electrodes) and gives hydrogen or protons as by-products (Scheme 86).

Scheme 86

Chupakhin et al.⁵⁴⁰ proposed an atom-economic one-step synthesis of aryl-substituted aza aromatic compounds via an electrochemical oxidation reaction (Scheme 87). The С−С coupling proceeds with high yields by the S_N^H mechanism via the intermediate formation of s-H adducts, which have been successfully isolated and characterized by physicochemical methods, including X-ray diffraction analysis and NMR. The redox properties of these adducts determine the efficiency of the reaction, as they are oxidized before the precursors.

Scheme 87

In recent years, considerable attention has been devoted to electrochemical С – Н phosphorylation, since the conventional methods for the preparation of organophosphorus compounds with the Р – С bonds are among the most hazardous and multistep processes.^{541 – 545} The phosphoryl group improves the hydrophilicity and bioavailability of organic molecules that possess anticancer, antibacterial or antiviral properties, including anti-HIV activity. The choice of phosphorus precursors for these reactions is limited by the fact that many redox-active triorganyl phosphites (RO)₃P and diorganylphosphine oxides R₂P(O)H are not oxidized and are reduced with difficulty in the accessible potential range. Nevertheless, Xu ⁵⁴⁶ and Lei ⁵⁴⁷ and co-workers were able to prepare a broad range of aryl(heteroaryl)phosphonates, including biologically active compounds, by oxidative phosphorylation of aromatic and heteroaromatic compounds with trialkyl phosphites (Scheme 88). Some of these reactions were performed as late stages of the synthesis of biologically active products. The use of undivided and flow cells, mild oxidation conditions, and formally only one by-product, hydrogen, which is released at the cathode, indicate that these processes can be considered as complying with the green chemistry requirements.

Scheme 88

The pathways of these reactions are of separate interest; although reaction mechanisms are proposed in many publications, convincing evidence for a particular mechanism is rarely given. Meanwhile, the knowledge of the key intermediates, their redox properties and reaction pathways is needed to expand the range of substrates, increase the yields of products and scale-up the processes. Presumably, s-H adducts, which were previously observed by Chupakhin,⁵⁴⁰ may be intermediates for the С – Н phosphorylation;⁵⁴⁸ other possible key species are phosphorus-centred radical cations.⁵⁴⁹ The triorganyl phosphite radical cations and s-H adducts (dialkyl dihydroacridine-phosphonates) were isolated and characterized by physicochemical methods (EPR, X-ray diffraction, NMR spectroscopy, voltammetry, etc.) in the controlled-potential phosphorylation of acridine and its derivatives, resulting in the formation of various acridine-phosphonates (Scheme 89). The high yields in this reaction are due to the fact that s-H adducts are oxidized more readily than the precursors.⁵⁴⁸

Scheme 89

Dialkyl H-phosphonates (RO)₂P(O)H and diorganylphosphine oxides R₂P(O)H are not oxidized at an electrode in an accessible potential range; however, they can be involved in the С – Р bond formation with aromatic and heterocyclic compounds that can be oxidized under conditions of electrolysis. Zeng and co-workers ⁵⁵⁰ showed that co-electrolysis of quinoxalin-2(1H)-ones and xanthenes with (RO)₂P(O)H or R₂P(O)H results in phosphorylation of C(sp²) – H or C(sp³) – H bonds (Scheme 90). The benefits of this process include mild reaction conditions, simple design of the undivided cell, formation of hydrogen as a by-product, the absence of chemical oxidants or additives (bases and catalysts needed in the conventional methods), regioselectivity and high product yields (up to 99%).

Scheme 90

Green solvents such as water, ethanol and acetic acid are used more and more often in electrosynthesis, in particular for scaling-up the reactions. For example, a method developed for the synthesis of annulated (isoxazolidine)isoquinolin-1(2H)-ones is based on electrochemical oxidation of arylhydroxamic acid esters containing acetylene groups in aqueous EtOH (95%) (Scheme 91).⁵⁵¹ The reaction proceeds via the formation of amidyl radicals. The advantages of the method include a broad scope of applicability, the absence of metal catalysts or external oxidants, simple design of the undivided cell with carbon sheets as electrodes, environmental friendliness and easy scaling-up.

Scheme 91

Precursors for the synthesis of many biologically active molecules contain thiocyanate groups. Recently, efficient electrochemical thiocyanation of 1,3-dicarbonyl compounds in AcOH was reported (Scheme 92).⁵⁵² The direct-current electrolysis proceeds in an undivided cell without additional halogen-containing electrolytes. Ammonium thiocyanate serves as both the source of the SCN group and the electrolyte. The reaction includes the electrochemical oxidation of the thiocyanate anion to (SCN)₂ and addition of the latter to the double bond of the 1,3-dicarbonyl enol form. Some of the prepared thiocyanates exhibit a high antifungal activity.

Scheme 92

Unlike the reaction of 1,3-dicarbonyl compounds with ammonium thiocyanate, the reaction between benzylic C(sp³) – H groups and trimethylsilyl isocyanate leads to oxidation under mild electrochemical conditions to give the C – N bond.⁵⁵³ The reaction can be easily scaled-up and can be used for the introduction of the isocyanate group into some pharmaceuticals and other biologically active molecules at final stages of a multistep synthesis (Scheme 93). Unfortunately, in this case, the best results were achieved when the electrochemical process was carried out in a binary solvent system containing toxic dichloroethane.

Scheme 93

The С – Н substitution reactions involving metal complexes and salts functioning as homogeneous or heterogeneous catalysts (nanocatalysts) constitute a rapidly developing area of organic electrosynthesis.^{543, 554, 555} The metal is coordinated to the substrate heteroatom and directs the substrate functionalization to the nearest С – Н bond, thus providing the selectivity. The key intermediates of these reactions are usually organometallic compounds (most often, metallacycles with metal – carbon bond), which, in some cases, can be isolated and characterized.^{555 – 560} When this coordination is impossible, the reactions follow a radical mechanism involving phosphorus- or nitrogen-centred radicals, which are detected by EPR spectrscopy.^548, 549 In this case, metals act as redox-mediators of the electrochemical reaction promoting the generation of radicals, although it should be admitted that their role is not always proved.

The oxidative phosphorylation of arenes induced by non-noble metals results in one-step synthesis of dialkyl arylphosphonates in high yields at room temperature (Scheme 94).⁵⁶¹ The 1% Мn^II/Ni^IIbipy bimetallic catalyst proved to be the most active and selective. This reaction was carried out for benzene and its derivatives containing either electron-withdrawing or electron-donating substituents or some coumarins. The efficiency of the process was attributed to fast catalytic cycle and regeneration of the active form of the catalyst at the electrode.

Scheme 94

The electrochemically induced phosphorylation of azole derivatives (benzo-1,3-azoles, 3-methylindole, 4-methyl-2-acetylthiazole) with dialkyl H-phosphonates in the presence of silver salts or silver oxide (1 mol.%) proceeds at room temperature to afford dialkyl azolylphosphonates in up to 75% yields (Scheme 95).⁵⁶² According to the results of cyclic voltammetry, EPR and NMR spectroscopy, the intermediate AgP(O)(OEt)₂ is oxidized before other components of the reaction mixture with elimination of a Р-radical. The EPR spectrum of this radical recorded in the presence of the PBN spin trap corresponds to published data.

Scheme 95

The first studies on the ligand-directed electrochemical С – H substitution involving transition metals appeared about a decade ago.^{557, 559, 560, 563, 564} It was shown that coordination of the metal [Ni(II), Pd(II), etc.] to the nitrogen atom of the substrate ligand (2-phenylpyridine, benzo[h]quinoline or 1-phenyl-1Н-pyrazole) affords the expected metallacycle with the metal–carbon bond, which is electrochemically oxidized much more readily than the starting compound. The oxidation is centred at the metal and is accompanied by the transition of metal M into higher oxidation states +3 and +4.^{556 – 560, 564 – 567} The chemistry and electro­chemistry of these metallacycles, particularly, transmetallation, reductive elimination and pathways for the control of these reactions are very interesting and deserve separate consideration, which is beyond the scope of this review. We would only like to note that in the presence of some metal salts, high regioselectivity of oxidation can be attained, for example, N-heteroarene fluoroalkylation,^557, 563 phosphorylation ^{556 – 560} (Scheme 96) and amidation ⁵⁵⁶ can be carried out.

Scheme 96

The catalyst is readily regenerated at relatively low potentials in the key steps of the reaction such as the metallacycle electrooxidation and reductive elimination of the product. There are few examples of isolated and fully characterized nickel complexes in higher oxidation states. Among them are stable Ni(III) complexes with R_F substituents,^568, 569 the participation of which in catalysis was confirmed by EPR data.⁵⁶⁶ The phosphorylation of aromatic compounds in the presence of palladium salts proceeds, apparently, via Pd(II)/Pd(III)/Pd(IV) redox cycles, since the formation of the final dialkyl arylphosphonate requires two electrons per palladium(II) atom in the intermediate metallacycle.^{559, 563, 565} The easy transition of palladium, nickel and other transition metals to higher oxidation states, needed for C – H functionalization, makes the electrochemical method preferable over conventional organic synthesis, in which only very strong oxidants, undesirable for green chemistry processes, are effective.