Advances in the Application of Acetonitrile in Organic Synthesis since 2018

Abstract

Acetonitrile is commonly used as an organic solvent and can also be used as an important intermediate in organic synthesis. Its widespread use has led to the development of new methods for the synthesis of a variety of important compounds. In the past decades, the conversion reactions of acetonitrile as a building block have become one of the most-attractive fields in organic synthesis. Especially in the field of electrochemical conversions involving acetonitrile, due to its good conductivity and environmentally friendly features, it has become a powerful and compelling tool to afford nitrogen-containing compounds or nitrile-containing compounds. In this review, we mainly discuss the research progress involving acetonitrile in the past five years, covering both conventional synthesis methods and electrochemical synthesis. Besides, a detailed discussion of the substrate scope and mechanistic pathways is provided.

1. Introduction

Acetonitrile as a small polar molecule and has a high relative permittivity (ε_r = 36), which is conducive to the dissociation of ion pairs into free ions [1]. The bond dissociation energy D (H-CH₂CN) equals 4.03 ± 0.09 eV, and D (CH₃-CN) equals 5.36 ± 0.03 eV [2,3]. Furthermore, the methyl proton of acetonitrile is faintly acidic with pKa = 31.3 in DMSO. This means that acetonitrile can be deprotonated to form nucleophile, and the nitrogen with lone pair electrons can also act as a nucleophile. Additionally, the cleavage of the H₃C-CN bond or H-CH₂CN in CH₃CN generates ^•CN or ^•CH₂CN radicals. Therefore, acetonitrile can be used as an important synthon in many types of organic reactions.

Because of its enrichment, low price, and excellent solvent properties, acetonitrile has been widely applied as a common solvent in organic synthesis [4,5,6,7,8]. Acetonitrile is also an important synthetic intermediate and often used as a source of nitrogen for the preparation of typical nitrogen-containing compounds. For example, nitrile-containing compounds are widely used in medicines [9] and materials [10]. Acetonitrile has been reported as a reliable source of cyanide in chemical compounds [11,12,13,14]. On the other hand, heterocyclic structures are widely present in various natural products or synthetic compounds and are used in organic synthesis, agriculture, animal husbandry, and other fields. Some heterocyclic compounds are also used in medicine due to their biological activity [15,16]. Acetonitrile can also be utilized in the construction of a variety of heterocyclic compounds. Examples include the synthesis of pyridine, oxazole, and tetrazole [17,18,19,20].

Acetonitrile as a building block typically provides three active sites: two carbons and one nitrogen. Up to now, scientists have developed a variety of methodologies with regard to the transformation of acetonitrile, for example cyanomethylation, the Ritter reaction, cyanation, the cyclization reaction, etc. In 2018, Hoff’s group [21] comprehensively reviewed the multifarious reactions using acetonitrile before 2018, including classical approaches and modern strategies. Subsequently, Sawant and colleagues [22] showed that various reaction solvents, such as DMF, DMSO, DMA, MeCN, CHCl₃, and DCM, all can serve as a polyfunctional building block for the organic synthesis reaction, which mainly covers work prior to 2019. Although these reviews have been reported, a comprehensive summary of the reaction development, scope, and mechanism of electrochemical transformations involving acetonitrile is still absent. Moreover, in the past five years, many great advances have been developed in this field, especially in electrochemical synthesis. Therefore, this review summarizes the research progress of acetonitrile as a reagent, including cyanomethylation, the electrochemical oxidative cross-coupling reaction, the heterocyclic reaction, and amidation since 2018. We mainly focused on recent reports (2018 onwards), and previous reports were not included here.

2. Cyanomethylation Reaction

Cyanomethylation is very useful in organic synthesis because the cyano groups can be hydrolyzed to carboxylic acids and reduced to amines, from which other functional groups can be derived [23,24,25,26]. In addition, the cyano group is the structural unit of many drugs, such as piritramide, diphenozlate, and gallopamil [27], while acetonitrile is an ideal source of the cyanomethyl functional group due to the difficulty in breaking the C-CN bond.

2.1. Metal-Catalyzed Cyanomethylation

Transition metal catalysts have been widely used in various reactions. In 2020, Zhu’s group developed the cyanoalkylative aziridination of N-sulfonyl allylamines 1 with alkyl nitriles using Cu catalysts and 2,2’-bipyridine (Scheme 1) [28]. Many N-sulfonyl allylamine derivatives 1 and alkyl nitriles derivative were tolerated, affording the corresponding products 2 in 43–86% yields. Furthermore, enantioenriched N-tosyl-allylamines could also be utilized as substrates, giving the enantioenriched aziridines in moderate to good diastereoselectivity. Five-membered heterocycles including isoindoline and pyrrolidine 2d could be synthetized in yields of 85% and 90%, respectively.

In 2021, Ahmad et al. [29] reported the Cu-catalyzed cyanomethylation of various imines 3 with acetonitrile (Scheme 2). In this process, Cu(OAc)₂ is used as the catalyst, and acetonitrile is used as the solvent and the CN source to synthesize arylacrylonitriles 4. The reaction conditions can tolerate a variety of substrates, including electron-donating groups, strong electron-withdrawing groups, and sterically bulky groups. However, the reaction conditions are harsh, requiring high temperatures and long reaction times. In addition, under conditions where CuCl acts as a catalyst and K₂CO₃ acts as a base, styrene derivatives can react with haloacetonitrile to form β,γ-unsaturated nitriles in 70–94% yields. Ahmad et al. also proposed a possible reaction mechanism (Scheme 2). First, the cyanide group of acetonitrile coordinates with copper. The complex is then attacked by (E)-N-benzylidene-4-Methylbenzenesulfonamide 3a to give intermediate 5. Elimination of methylbenzenesulfonamide 6 from 5 gives phenylacrylonitrile 4.

Iron catalysts have also been used in cyanomethylation. Recently, Yao et al. [30] developed a FeCl₂-catalyzed method for the cyanomethylation of amino-substituted arenes 7, using acetonitrile as the cyanomethyl source and DTBP as the oxidant (Scheme 3). Substrate adaptation studies have shown that yields are higher when substituents on the aminopyridines or anilines have an electron-withdrawing character; conversely, lower yields are obtained with electron-donating groups. In addition, the steric hindrance of the substituents greatly affects the product yields. It is noteworthy that this scheme is the amine-directed cyanomethylation reaction, and the directed amino group plays a decisive role in this reaction. When -NH₂ is replaced by other groups, the cyanomethylation reaction cannot proceed. In addition, the combinations of adjacent amino and cyanomethyl groups can synthesize some valuable nitrogen-containing heterocyclic compounds, which indicates the potential practicability of this reaction. In the control experiments, when 2,2,6,6-tetramethylpiperidine-1-oxyl and butylated hydroxytoluene were added, the corresponding cyanidation products were not generated. These results indicated that a radical process is possibly involved in the reaction. Based on controlled experiments and previous literature, the authors proposed a possible reaction mechanism (Scheme 3). First, DTBP forms a tert-butoxy radical and tert-butoxy anion in the presence of iron. A proton of acetonitrile is removed by the tert-butoxy radical to form cyanomethyl radical 9. Next, the reaction can proceed via one of two ways: (a) 9 attacks the ortho-site of the amino group to afford the free radical 10, from which a proton is subsequently abstracted by the tert-butoxy anion to give 11 and t-BuOH. Finally, 11 is oxidized by Fe(III) to product 8a regenerating Fe(II). (b) FeCl₂ reacts with the amino group to form 12, and 12 reacts with the cyanomethyl radical to give 13. FeCl₂ is then released, and the cyanomethyl group is transferred to the aromatic ring to obtain 10. Finally, product 8a is formed through the same steps as Route (a).

Ni-catalyzed cyanomethylation is also important for the construction of nitrile-containing compounds. The enantioselective cyanomethylation catalyzed by Ni(II) was developed by Shibasaki and Kumagai [31,32]. Very recently, Oudeyer and co-workers established a Ni-catalyzed cyanoalkylation of ketone derivatives 14 and acetonitrile derivatives (Scheme 4) [33]. Acetonitrile was added to various isatins or activated ketones with the Ni catalyst C1, affording products 15 in up to a 99% yield. Additionally, the addition of acetonitrile derivatives to ketones required the presence of ⁿBu₄NBF₄ in THF to give good product yields. Preliminary mechanistic studies showed that the Tolman-type complex, Ni^II-complex C1, is the key to the cyanomethylation.

2.2. Transition Metal-Free Cyanomethylation

Transition metal catalysts, which are widely used in organic synthesis, are usually expensive, pollute the environment, and add difficulties to post-treatment. In some areas, such as the pharmaceutical industry, even trace metals are not tolerated in the end product [34]. Developing environmentally friendly and economical synthetic methods is the trend of future development. As a result, metal-free catalyzed reactions have become a popular research topic in organic chemistry.

In the last few years, metal-free catalyzed direct cyanomethylation of C-H bonds, including C(sp2)-H bonds [35,36] and C(sp3)-H bonds [37], has emerged as a powerful tool in organic synthesis, which has the advantages of atom economy. In 2018, Zhang et al. [35] reported the synthesis of cyanomethylcoumarin via a cross-dehydrogenation coupling reaction between coumarin 16 and acetonitrile (Scheme 5). This reaction uses tert-butyl benzoperoxoate (TBPB) as the oxidant and potassium fluoride (KF) as the base over 16 h under a nitrogen atmosphere, with acetonitrile as both the reactant and solvent. The substrates for this methodology are broad, but require an excessive amount of solvent. Zhang et al. also proposed a reasonable mechanism for this reaction. Initially, TBPB is heated to form a benzoate radical and tert-butoxy radical. Next, cyanomethyl radical 18 is formed by abstraction of the acetonitrile proton from either the benzoate radical or the tert-butoxy radical, releasing benzoic acid or tert-butanol. Cyanomethyl radical 18 attacks coumarin 16a to give intermediate 19, which is then deprotonated to produce target product 17a.

Cyanomethylation can also occur in the absence of a base. In 2021, Liu et al. [36] developed a method for the cyanomethylation of 8-aminoquinoline amides 20 (Scheme 6). This method uses only TBPB as an oxidant in the absence of metal catalysts and bases. Under these conditions, a wide range of substituents on the 8-aminoquinoline amides are tolerated, and the electronic effects and steric hindrance of the substituents have little effect on the product yields. The yields of the target products are 50–84%. It is important to note that amide’s functionality is crucial to the smooth progress of the reaction. When simple quinoline or 8-amino quinoline is used in place of 8-aminoquinoline amide, the reaction does not occur smoothly. The possible reaction mechanism proposed by Liu et al. is similar to that proposed by Zhang et al. At first, the tert-butoxy radical and benzoate radical are transferred through the thermal homolytic scission of TBPB. Subsequently, the cyanomethyl radical is generated by the hydrogen abstraction of acetonitrile by the tert-butoxy radical or benzoate radical releasing tert-butanol or benzoic acid. Thereafter, cyanomethyl radical attacks 20a to produce intermediate 22, which further reacts with the tert-butoxy radical or benzoate radical to produce required product 21a. This suggests that cyanomethylation in the absence of metal catalysis may proceed via the same reaction process.

The metal-free catalyzed functionalization of unsaturated hydrocarbons involving acetonitrile is another application of cyanomethylation. Several interesting methods have been developed to provide nitrile-containing products, including the hydrofunctionalization of alkynes [38], cascade radical cyclization of alkynes [39,40], cascade radical cyclization of alkenes [41], etc. A free radical addition of acetonitrile to alkynes was developed by Liu’s group in 2019 (Scheme 7) [38]. In the presence of TBPB, alkynes 23 and acetonitrile reacted in CH₃CN at 130 °C for 3 h, providing β,γ-unsaturated nitriles 24 with up to an 80% yield. The alkynes bearing aryl, alkyl, heteroaryl, cyclopropane, cyclopropane, amide, etc., units showed high compatibility with the addition reaction, affording desired products 24 in moderate to good efficiency.

In 2020, Gao and co-workers reported an efficient cascade radical cyclization of 2-alkynylthio(seleno)anisoles 25 with acetonitrile for the construction of 3-cyanomethylated benzothio(seleno)phenes 26 (Scheme 8) [40]. Under the optimal reaction conditions, a series of desired compounds could be achieved in 45–70% yields. The author proposed a possible reaction mechanism. The DTBP first is heated to give tert-butoxy radical, which assimilates the α-H of acetonitrile to form radical I. Subsequently, generated radical I attacks the α-position of C-C triple bond of 25a to afford vinyl radical II. Finally, target product 26a is formed through a radical 5-exo-trig cyclization with the sulfur atom.

In addition, Lee’s group recently reported an elegant metal-free catalyzed cyanomethylation of acetonitrile with both activated and unactivated amides 27 to afford diversified β-ketonitriles 28 with up to a 99% yield (Scheme 9) [42]. This reaction exhibits high functional group compatibility in the presence of LiHMDS. Benzamides 27 bearing not only electron-donating groups, but also electron-withdrawing groups could be utilized as substrates, giving corresponding β-ketonitriles 28 in moderate to excellent yields. Furthermore, heterocyclic acylamide, such as furan-2-carboxamide 27b and thiophene-2-carboxamide, undergo the reaction smoothly, giving the desired products in an 89% yield and 80% yield, respectively. Notably, alkyl amides 27 also display good tolerance to this method. Under the optimized conditions, benzamides 27 involving various N-substituents react well with acetonitrile and provide corresponding 28 with 25–99% yields.

3. Electrochemical Oxidative Cross-Coupling Reaction

In order to activate the Csp3-H bond of acetonitrile, transition metal catalysts, oxidants, or strong bases and high reaction temperatures are usually required. The harsh reaction conditions not only inconvenience the operation, but also limit the application of the reaction. Therefore, it is urgent to develop an efficient and gentle catalyst-free method to activate the Csp³-H bond of acetonitrile. Electrochemical synthesis has attracted the interest of scientific research workers due to its high efficiency and environmental credentials [43,44,45,46,47,48]. Tetrasubstituted olefins are not only the structural units of many drugs [49], but also important precursors for organic synthesis [50]. Therefore, the electrochemical synthesis of tetrasubstituted olefins has also become a popular topic in recent years.

In 2019, Lu et al. [51] reported the electrochemical oxidative Csp³-H/S-H cross-coupling reaction of acetonitrile and thiophenol 29 to form tetrasubstituted olefins 30 (Scheme 10). In this protocol, KI is used as the electrolyte and medium, cyclohexanecarboxylic is used as the additive, and a series of tetra-substituted alkenes can be obtained in 25–95% yields by reaction under a 12 mA constant current. The results of the substrate range test showed that the reactivity of the thiophenols with electron-neutral substituents (such as methyl, ethyl, isopropyl, or tertiary butyl group) and electron-withdrawing substituents (such as F, Cl, Br, or trifluoromethyl group) substituents is smooth (20a, 82% yield; 20b, 95% yield), but the yields of the thiophenols with strong electron-donating substituent are significantly reduced (20c, 25% yield). Moreover, under standard conditions, the diphenyl disulfide and diphenyl diselenide can also generate the corresponding tetrasubstituted olefins.

In the same year, He et al. [52] also reported a method for the synthesis of tetrasubstituted olefins 32 using thiophenol 31 and acetonitrile (Scheme 11). The reaction was carried out with KI as the electrolyte and citric acid and 1,2-bis(diphenylphosphino)ethane (DPPE) as the additives at a current of 10 mA. This method has excellent substrate tolerance and can be applied to a variety of substituent phenylthiols/thiols to obtain products at moderate to high yields. Moreover, oxidatively labile functional groups such as amino (32a, 24% yield) and hydroxy (32b, 47% yield) can also tolerate this reaction and obtain the corresponding products. In addition, diphenyl diselenide (32c) and dimethyldiselenide (32d) can also be applied to this condition, and tetrasubstituted olefins can be obtained in high yields. Under this condition, the reaction at the gram-scale is also tolerated, and the product is obtained with good yields. In addition, He et al. further cyclized some of the products to obtain 4H-1,4-benzothiazine scaffolds, which are widely used in pharmaceutical chemistry. This result suggested that the reaction has potential applications in industry.

Organic catalysts have also been used in electrochemical reactions. In 2022, Wan et al. [53] reported the electrochemical synthesis of tetrasubstituted olefins 34 with acetonitrile and heteroaryl thiols 33 catalyzed by a bromide salt (Scheme 12). The reaction is performed with ⁿBu₄NPF₆ as the electrolyte solution, Me₄NBr as the catalyst, and trifluoroacetic acid (TFA) as the additive at a constant current of 10 mA. A series of heteroaryl vinyl sulfides 34 was synthesized using acetonitrile and 2-mercaptobenzoxazoles 33 as substrates. The results showed that the proposed method has wide adaptability. Substitution of 2-mercaptobenzoxazole derivatives by various electron-donating or electron-withdrawing substituents can obtain the corresponding products in high yields. Pyridine rings are also tolerated in this reaction. The same conditions can also be applied to converting the 1,3,4-oxadiazole moiety into heteroaryl vinyl sulfides. The corresponding products can be obtained from substrates with different substituents (electron-donating substituents and electron-withdrawing substituents) on the benzene ring on the C5-benzene ring of the 1,3,4-oxadiazole moiety. In addition, the benzene ring can also be substituted by other aromatic moieties or alkyl substituents, and tetrasubstituted olefins can also be obtained with excellent yields.

The approaches presented all pass through a similar reaction path, on which we propose a possible mechanism for the synthesis of tetrasubstituted olefins 40 by electrochemical oxidation of acetonitrile and thiophenols/thiols (Scheme 13). First, halogen ions (X^-) are anodized to form radicals, which then abstract the hydrogen atoms of acetonitrile to form cyanomethyl radicals. The addition of the cyanomethyl radical to another acetonitrile produces iminoradical 35. Intermediate 36 is then obtained by 1,3-hydrogen transfer. At the same time, the halogen radical attacks the S-H bond to produce the sulfur radical 37, which then dimerizes to form disulfide 38. Finally, intermediate 36 may couple with sulfur radicals 37 to afford tetrasubstituted olefins 40 or it may undergo a substitution reaction with disulfide 38 to give tetrasubstituted olefins 40. Simultaneously, the cathode-reduced proton releases H₂.

4. Cyclization Reaction

4.1. Synthesis of Oxazole

Nitrogen-heterocyclic compounds exist widely in daily life. A considerable number of materials, pesticides, and drug molecules contain nitrogen-heterocyclic structural units. As a result, the development of novel strategies for heterocycle synthesis of nitrogen has been a hot area of organic synthesis. As an ideal nitrogen source, acetonitrile has also been widely used in the synthesis of nitrogen-heterocycles [54].

Oxazole is an important nitrogen-heterocyclic compound. A large number of oxazole compounds and their derivatives are used as drugs to treat various types of diseases. In recent years, a variety of electrochemical synthesis methods of oxazole compounds have been developed. In 2021, Sattler et al. [55] reported the electrochemical synthesis of 1,3-oxazoles 42 from alkynes 41 and acetonitrile (Scheme 14). The good reactivity relies on the symmetric of the substrates. The methodology can tolerate most electron-donating and -withdrawing groups. The yields are reduced when unsymmetrical alkyl-aryl alkynes are used. When dialkyl-substituted alkynes are employed, the yields of the desired products are further lowered. This synthetic method is suitable for symmetric alkynes, but not for unsymmetrical alkyl-aryl alkynes. Sattler et al. proposed a reaction mechanism for this protocol. At the positive electrode, intermediate 43 is formed, which then attacks the Diphenylacetylene 41a to form the nitrile ion 44. Intermediate 45 or intermediate 47 may then be generated. Intermediate 45/47 is then deprotonated with water to give 46/48, and further protons and iodine molecules are removed by 43 to obtain target product 42a.

Inspired by Sattler’s work, Bao et al. [56] proposed an electrochemical synthesis of poly-substituted oxazoles 50 from ketones 49 and acetonitrile in 2022. With TFAA as the ketone activator and Ar₃N as the catalyst, high yields of the desired products can be obtained and a variety of functional groups can be tolerated. Scheme 15 shows the possible mechanism of this reaction. In the presence of anhydride, ketones form vinyl ester 51. Then acid-promoted addition to vinyl ester A and a subsequent Ritter-type reaction deliver intermediate 52. Intermediate 52 is attacked by the carboxylate, and then, the anhydride is removed to afford amide 54. The radical cation produced by Ar₃N at the anode attacks 54 through a single electron transfer (SET) process to give radical cation 55, which is then directly oxidized (a) or undergoes mediated oxidation (b) to form cation 56. Finally, desired product 50a is obtained by intramolecular cyclization and deprotonation, releasing H₂ at the cathode.

4.2. Synthesize Dihydroimidazole and 2-Oxazoline

In addition to the simple photochemical reaction or electrochemical reaction, electrophotocatalysis (EPC) combining the energy of light and electrons has also been developed in recent years. In 2021, Shen et al. [57] reported the electrophotocatalytic diamination of vicinal C-H bonds (Scheme 16). Using alkyl aromatics 59 as the raw materials and acetonitrile as the solvent and nitrogen source, 1,2-diamine derivatives were synthesized via an electrophotocatalytic strategy. Depending on the electrolyte used, either 3,4-dihydroimidazole or 2-oxazoline products can be obtained, of which the yields are moderate to good. Shen et al. also successfully synthesized a series of biologically active molecules such as a 5,7-dibromoisatin analogue (60a, 42% yield) and a celebrex analogue (60b, 56% yield) with pharmacological activity using this method. In addition, this scheme can be used to obtain valuable 1,2-diamines or the free dihydroimidazole adducts after a slight modification of the reaction procedure. Shen et al. also proposed a possible mechanism for the synthesis of 3,4-dihydroimidazoles, which is shown in Scheme 11. First, the trisaminocyclopropenium (TAC) ion acts as a catalyst and undergoes radical attack of 59a, forming radical cation 62 under illumination. Radical cation 62 is then deprotonated and oxidized to give cation 63, which is then converted into amide 64 by the Ritter reaction. The mechanism of the formation of product 60a from amide 64 is not clear. The authors suggested that an elimination reaction of amide 64 produces α-methylstyrene 65, which is then converted into either 3,4-dihydroimidazole or 2-oxazoline by solvent capture and oxidation under the influence of the electrolyte.

4.3. Synthesis of Cyclobutenone

In 2021, Qin et al. [58] reported the first synthesis of cyclobutenone 70 by [2+2] cyclization using acetonitrile as a raw material for C2 cyclization (Scheme 17). The first step of the reaction uses acetonitrile as the raw material and solvent and a proton sponge (PS) as the base, in the presence of catalytic triflic anhydride (Tf₂O); the reaction with an alkyne 69 affords cyclobutene amines 71. Subsequently, H₂O was added to the reaction mixture in order to form cyclobutenone 70. This method is capable of tolerating alkyl- and aryl-substituted alkynes. However, terminal alkynes are not amenable to the reaction conditions. The reaction with enyne substrates proceeds normally without being affected by the C=C bond. A mechanism for this reaction has also been proposed. First, acetonitrile is activated by Tf₂O to form intermediate 72, then 72 is converted to cyclobutene 71 by a [2+2] cyclization reaction. Finally, cyclobutene 71 is hydrolyzed to cyclobutenyl ketone 70.

4.4. Synthesis of 3-Cyanopyridine

3-Cyanopyridines are ubiquitous motifs in pharmaceuticals, natural products, and bioactive molecules. Acetonitrile is a common and abundant precursor for the synthesis of 3-cyanopyridines. In 2019, Doyle and colleagues used α-peroxy-γ,γ-dichloropropanes as the substrate and acetonitrile as the nitrogen source in the presence of KO^tBu to give 3-cyanopyridines in 54–69% yields [59]. Subsequently, Trofimov reported the cyclization of available acylethynylpyrroles with acetonitrile to provide a series of pyrrolyl-pyridines in 63–87% yields [60]. In 2022, Duan et al. reported a new strategy for the synthesis of 2-methylnicotinonitriles 74 through the degenerate ring transformation of N-substituted pyridinium salts 73 (Scheme 18) [61]. The reaction was carried out using potassium hexamethyldisilazide (KHMDS), benzoic acid (BA), and benzyl triethyl ammonium chloride (TEBA) as additives in acetonitrile at 90 °C for 20 h. This reaction is applicable to various phenyl-substituted 4-phenyl-1-vinylpyridin-1-ium tetrafluoroborates and 3-aryl pyridinium salts, while 4-alkyl-substituted pyridinium salts are limited. This strategy may react through the following pathways: First, acetonitrile forms the 3-ACN anion in situ under the action of the base and then conducts nucleophilic attack on the ortho-carbon of pyridinium salt to obtain intermediates (E)-B and (Z)-B. Then, the ring opening of adduct B is triggered by electron transfer to give azapolyenes D1 and D2. Subsequently, dihydropyridine intermediate E is formed via a 6π-aza electrocyclization with the assistance of the CN group. Finally, intermediate E is aromatized to corresponding product 74a.

5. Amidation Reaction

Amide bonds are the structural units of many bioactive molecules and play a crucial role not only in maintaining the life activity of various organisms, but are also widely present in pharmacologically active compounds and organic materials. According to the statistics, about 25% of drugs on the market contain amide bonds, and the construction of amide bonds has become an important link in drug development [62,63,64,65,66].

In recent years, the method of constructing the C-N bond to synthesize amide from acetonitrile by the Ritter reaction has also been developed. In 2021, Shen et al. [67] reported a method for C-H amination via an electrophotocatalytic Ritter-type reaction (Scheme 19). Using trisaminocyclopropenium C7 as a catalyst, acetonitrile was used to attack the benzyl C-H bond of 75, giving corresponding acetamide 76 following irradiation with a compact fluorescent light (CFL) and a 2.2 V current. The yields of the desired products range from 36–88%. Additionally, the reaction can be used to modify complex molecules. For example, sertraline derivatives can be obtained in a 40% yield, and retinoic acid receptor agonist derivatives can be obtained in a 63% yield. In addition, compound 76 was also synthesized on a gram-scale with a yield of 50%. This result further demonstrated the potential use of this reaction in industry. The process of this reaction involves oxidation of C7 to radical 77, which is then irradiated to form intermediate 78. This intermediate attacks the aromatics to form radical cation 80, which is subsequently deprotonated and oxidized to form carbocation 82. Dehydration leads to the formation of an amide through a Ritter-type reaction.

In 2022, our group reported a reaction of aryl isothiocyanate with acetonitrile to form amides 86 (Scheme 20) [68]. This method uses acetonitrile as the raw material and solvent and KOH as the base. The reaction with phenyl isothiocyanate 85 at 120 °C provides a series of acetamides 86 without additional additives. When an aryl isothiocyanate bearing an electron-donating group is used, the yields of the corresponding products are 51–75%. This scheme also tolerates the substitution of aryl isothiocyanates with halogen atoms, but the yields are lower. In addition, when benzonitrile is used instead of acetonitrile, the corresponding amides can also be obtained. For example, N-(4-methylphenyl)benzamide 86c was easily prepared from benzonitrile in a 70% yield. In order to explore the reaction mechanism, a series of control tests was completed. First, deuterated acetonitrile is also suitable for this method to obtain the product deuterated acetanilide (Scheme 20a), which indicates that acetonitrile is involved in this reaction. It also provides a convenient way to synthesize deuterated acetanilide. Second, model reactions of MeCN/H₂O¹⁸ also demonstrate that the carbonyl oxygen atoms may originate from H₂O (Scheme 20b). Through a series of controlled experiments, we proposed possible mechanisms for this reaction (Scheme 20). Acetonitrile is hydrolyzed to the carboxylic acid under basic conditions. Then, the carboxylic acid is added to the phenyl isothiocyanate to form intermediate 87. Next, generated intermediate 87 undergoes the loss of carbonyl sulfide (COS) to give final product 86a.

The difunctionalization of alkenes involving acetonitrile can synchronously form two new chemical bonds. This strategy usually starts with the addition of a radical to an alkene, which then undergo a single electron transfer, affording the carbocation. Finally, the Ritter-type amination of the carbocation and acetonitrile gives the desired difunctionalization product. As far as we know, a variety of reaction systems have been developed in recent years, including Selectfluor and benzoyl peroxide (BPO) as a radical initiator [69,70,71], photocatalysts [72], and electrochemistry [73]. The regioselective aminofluorination of α,β-unsaturated ketones was developed by Li’s group in 2019 (Scheme 21) [69]. Selectfluor as the oxidant and fluorine source could work well in CH₃CN/H₂O to give α-fluoroamides 90 in 37–74% yields. The reaction has a relatively wide substrate scope, and most products have been synthesized without diastereomers. In addition, when the loading of Selectfluor was increased from 1.2 equivalent to 3.0 equivalent, the α-difluoro-β-amidation was obtained in a 55% yield. In 2022, Zhang et al. reported a tandem fluorination/Ritter reaction of α-diazo 2H-benzopyran-4-one compounds using Selectfluor as the fluoride source in MeCN to synthesize β-fluoramides with moderate yields [74].

In 2023, Yu et al. [73] reported the electrochemical synthesis of vicinal azidoacetamides 92 (Scheme 22). The reaction uses substituted styrenes/tetrasubstituted alkenes 91 and TMSN₃ as raw materials. In the MeCN/ⁿBuOH system, the amides can be obtained in 35–63% yields using constant-current electrolysis with ⁿBu₄NHSO₄ as the electrolyte. This approach can tolerate both electron-donating and electron-withdrawing group substitutions of styrene. In addition to acetonitrile, azide amides can also be obtained by this method from other aliphatic nitriles. Possible mechanisms for this reaction have been proposed. Styrene 91a is first oxidized at the anode to form intermediate 93, which is then trapped by TMSN₃ to form radical 94. Radical 94 is then further oxidized at the anode to form benzyl cationic intermediate 95, which undergoes nucleophilic addition with acetonitrile to yield intermediate 96. Finally, 96 is hydrolyzed to form vicinal azidoacetamides 92a. Additionally, benzyl cation 95 can also be trapped by water to generate undesired azidohydroxylation product 97.

Amination between C-H bond activation on the benzene ring has also been realized. Strekalova et al. [75] reported the synthesis of N-phenylacetamide 99 by electrochemical oxidation of aromatic compounds 98 under the catalysis of copper salts (Scheme 23). This method uses Cu(OAc)₂ as the catalyst, with no other additives, and reacts for 2–4 h at an 80 mA current to obtain the amides. However, this reaction requires large amounts of acetonitrile as the solvent and reactant (40 mL). The presence of a substituent on the benzene ring will lead to the production of the isomeric amide. When bromobenzene is used, the product is predominantly N-(4-bromophenyl)acetamide (99a), while using trifluoromethylbenzene as the substrate causes N-(2-(triuoromethyl)phenyl)acetamide to be the main product (99b). When the aromatic ring contains a methyl group, the reaction takes place on the methyl fragment. Even if the aromatic ring is substituted by multiple methyl groups (xylene, mesitylene), amidation will also occur on one of the methyl groups, and amidation products with one substituted methyl group are obtained as the main product (85c). Moreover, when benzonitrile is used instead of acetonitrile, the corresponding benzamides can also be obtained with moderate yields (up to 69% yield). The author proposed the possible reaction mechanism of the amidation of benzene (Scheme 16). In addition, according to the nature of the substrate (aromatic or heteroaromatic, presence of methyl or other substituents) and the oxidation potential of the aromatic, the reaction is carried out in different ways under the same conditions. The presence of a methyl substituent on the benzene ring leads to selective amidation of the benzyl fragment, and the reaction has been carried out through the oxidation of the methyl group. However, in the process of the electrooxidation of heteroarenes (e.g., 2-phenylpyridine), dimers are formed instead of acetylamides because heteroarenes can coordinate with metals. Similar to Strekalova’s work, Song’s group developed an electrophilic amidomethylation of the aromatic C-H bond. This strategy using acetonitrile as the NHAc source and DMSO as the CH₂ source could provide various N-benzylic amide derivatives in 31–82% yields [76].

The photocatalytic amidation reaction has also been reported. In 2023, Bao et al. [77] developed a photocatalytic dehydration of alcohol 102 to synthesize amides 103 (Scheme 24). The reaction uses 2,4,6-triphenylpyrylium tetrafluoroborate (PC1) as a catalyst, and benzyl alcohol and acetonitrile can produce amide after 16 h of blue light irradiation in a nitrogen atmosphere. Benzyl alcohols containing electron-donating groups respond well, with yields ranging from 50 to 63%. Substituting benzyl alcohol with an electron-withdrawing group yields a lower-yielding amide. Ortho-, meta-, and, polysubstituted groups in the phenyl ring of benzyl alcohols also react smoothly. Naphthyl methanol can provide amide with a higher yield (103a, 83% yield). The amide can also be obtained from secondary alcohols by this method (103b, 72% yield). This method is also applicable to other alkyl nitriles (103c, 51% yield), but increasing the alkyl chain reduces the activity of the nitriles, resulting in lower yields. Through control experiments and DFT calculations, Bao et al. proposed the possible mechanism of the reaction. The photocatalyst is first excited under light to the excited state (¹TP⁺). The SET process between 102d and ¹TP⁺ then takes place. The resultant 102d⁺ can be used as a Brønsted acid to protonate another 102d to obtain protonated benzyl alcohol 105 and α-hydroxybenzyl radical 104. Subsequently, the protonated 105 undergoes dehydration to obtain the benzyl carbocation (106). Then, the nucleophilic attack of MeCN on 106 occurs, producing iminium carbocation 107. After the generation of 107, the following steps are similar to those of the conventional Ritter reaction. First, H₂O produced from the dehydration step attacks 107 with the support of solvent molecules (MeCN). Finally, obtained imide alcohol intermediate 108 gives rise to product 103d by tautomerism. The intermediates, 104 and MeCNH⁺, participate in the catalytic regeneration of PC1 from ²TP^• and are converted to 102d and MeCN.

6. Conclusions

Acetonitrile has been widely used in organic synthesis and is an important organic substance. This review described the recent synthesis of cyanides, tetrasubstituted olefins, heterocyclic compounds, and amides from acetonitrile, with methodologies involving conventional metal catalysis and electrochemical reactions. It is worth noting that the conditions for the amidation reaction involving acetonitrile are generally applicable to other nitriles. However, some of the new methods require the consumption of large amounts of acetonitrile, which undoubtedly increases the cost of the reaction and also causes a waste of resources. If this problem can be solved, these new methods will be more practical. It is worth noting that electrochemical reactions have the advantage of being mild, having short reaction times, and being more environmentally benign compared with conventional metal catalysis and oxidation reactions. Acetonitrile is well suited for use as a solvent and reactant in electrochemical reactions due to its unique properties. Therefore, more applications that utilize acetonitrile in electrochemistry are worth developing.

Author Contributions

Conceptualization, J.L. and N.L.; writing, J.L. and P.Z.; validation, L.Z. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Footnotes

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Schemes

Scheme 1. Cu-catalyzed cyanoalkylative aziridination of N-sulfonyl allylamines.

Scheme 2. Cu-catalyzed cyanomethylation.

Scheme 3. Fe-catalyzed cyanomethylation.

Scheme 4. Ni-catalyzed cyanomethylation.

Scheme 5. Cyanomethylation with TBPB as the oxidant.

Scheme 6. Cyanomethylation with TBPB as the oxidant.

Scheme 7. Addition of acetonitrile to alkynes.

Scheme 8. Cascade radical cyclization of alkynes with acetonitrile.

Scheme 9. Cyanomethylation of acetonitrile with amides.

Scheme 10. Synthesis of tetrasubstituted olefins by thiophenol and acetonitrile.

Scheme 11. Synthesis of tetrasubstituted olefins via thiophenol and acetonitrile.

Scheme 12. Synthesis of tetrasubstituted olefins by acetonitrile and heteroaryl thiols.

Scheme 13. Mechanism of electrochemical synthesis of tetrasubstituted olefins from acetonitrile and thiols.

Scheme 14. Synthesis of 1,3-oxazoles from alkynes and acetonitrile.

Scheme 15. Synthesis of 1,3-oxazoles from ketones and acetonitrile.

Scheme 16. Synthesis of dihydroimidazoles and 2-oxazolines.

Scheme 17. Synthesis of cyclobutenone.

Scheme 18. Synthesis of 3-cyanopyridine.

Scheme 19. Synthesis of amide by electrophotocatalytic reaction.

Scheme 20. Synthesis of amide by acetonitrile and isothiocyanate.

Scheme 21. Aminofluorination of α,β-unsaturated ketones.

Scheme 22. Electrochemical synthesis of vicinal azidoacetamides.

Scheme 23. Electrochemical synthesis of amides catalyzed by copper.

Scheme 24. Photocatalytic synthesis of amide.

References

1. Kütt, A.; Tshepelevitsh, S.; Saame, J.; Lõkov, M.; Kaljurand, I.; Selberg, S.; Leito, I. Strengths of acids in acetonitrile. Eur. J. Org. Chem.; 2021; 2021, 1407. [DOI: https://dx.doi.org/10.1002/ejoc.202001649]

2. Moran, S.; Ellis, H.B., Jr.; DeFrees, D.J.; McLean, A.D.; Ellison, G.B. Carbanion spectroscopy: Cyanomethide anion (CH₂CN-). J. Am. Chem. Soc.; 1987; 109, 5996. [DOI: https://dx.doi.org/10.1021/ja00254a018]

3. Ashfold, M.N.R.; Simons, J.P. Vacuum ultraviolet photodissociation spectroscopy of CH₃CN, CD₃CN, CF₃CN and CH₃NC. J. Chem. Soc. Faraday Trans.; 1978; 74, 1263. [DOI: https://dx.doi.org/10.1039/f29787401263]

4. Batanero, B.; Sánchez-Sánchez, C.M.; Montiel, V.; Aldaz, A.; Barba, F. Electrochemical synthesis of 3-phenylcinnamonitrile by reduction of benzophenone in acetonitrile. Electrochem. Commun.; 2003; 5, 349. [DOI: https://dx.doi.org/10.1016/S1388-2481(03)00066-3]

5. Zhao, Q.; Ren, L.; Hou, J.; Yu, W.; Chang, J. Annulation Reactions of In-Situ-Generated N-(Het)aroyldiazenes with Isothiocyanates Leading to 2-Imino-1,3,4-oxadiazolines. Org. Lett.; 2019; 21, 210. [DOI: https://dx.doi.org/10.1021/acs.orglett.8b03663] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30547596]

6. Alanthadka, A.; Maheswari, C.U. N-Heterocyclic carbene-catalyzed oxidative amidation of aldehydes with amines. Adv. Synth. Catal.; 2015; 357, 1199. [DOI: https://dx.doi.org/10.1002/adsc.201400739]

7. Deshidi, R.; Rizvi, M.A.; Shah, B.A. Highly efficient dehydrogenative cross-coupling of aldehydes with amines and alcohols. RSC Adv.; 2015; 5, 90521. [DOI: https://dx.doi.org/10.1039/C5RA17425B]

8. Mohamadighader, N.; Saraei, M.; Nematollahi, D.; Goljani, H. Electrochemical study of 4-chloroaniline in a water/acetonitrile mixture. A new method for the synthesis of 4-chloro-2-(phenylsulfonyl)aniline and N-(4-chlorophenyl)benzenesulfonamide. RSC Adv.; 2020; 10, 31563. [DOI: https://dx.doi.org/10.1039/D0RA05680D] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35520680]

9. Ismail, M.M.F.; Farrag, A.M.; Harras, M.F.; Ibrahim, M.H.; Mehany, A.B.M. Apoptosis: A target for anticancer therapy with novel cyanopyridines. Bioorgan. Chem.; 2020; 94, 103481. [DOI: https://dx.doi.org/10.1016/j.bioorg.2019.103481]

10. Hu, P.; Chai, J.; Duan, Y.; Liu, Z.; Cui, G.; Chen, L. Progress in nitrile-based polymer electrolytes for high performance lithium batteries. J. Mater. Chem. A; 2016; 4, 10070. [DOI: https://dx.doi.org/10.1039/C6TA02907H]

11. Zhao, M.; Zhang, W.; Shen, Z. Cu-catalyzed cyanation of indoles with acetonitrile as a cyano source. J. Org. Chem.; 2015; 80, 8868. [DOI: https://dx.doi.org/10.1021/acs.joc.5b01419] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/26274782]

12. Wang, C.; Li, Y.; Gong, M.; Wu, Q.; Zhang, J.; Kim, J.K.; Huang, M.; Wu, Y. Method for direct synthesis of α-cyanomethyl-β-dicarbonyl compounds with acetonitrile and 1,3-dicarbonyls. Org. Lett.; 2016; 18, 4151. [DOI: https://dx.doi.org/10.1021/acs.orglett.6b01871] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27512940]

13. Su, H.; Wang, L.; Rao, H.; Xu, H. Iron-catalyzed dehydrogenative sp3–sp2 Coupling via Direct Oxidative C–H Activation of Acetonitrile. Org. Lett.; 2017; 19, 2226. [DOI: https://dx.doi.org/10.1021/acs.orglett.7b00678] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28445059]

14. Yu, Y.; Zhuang, S.; Liu, P.; Sun, P. Cyanomethylation and cyclization of aryl alkynoates with acetonitrile under transition-metal-free conditions: Synthesis of 3-cyanomethylated coumarins. J. Org. Chem.; 2016; 81, 11489. [DOI: https://dx.doi.org/10.1021/acs.joc.6b02155] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/27768307]

15. Li, R.; Li, B.; Zhang, H.; Ju, C.-W.; Qin, Y.; Xue, X.-S.; Zhao, D. A ring expansion strategy towards diverse azaheterocycles. Nat. Chem.; 2021; 13, 1006. [DOI: https://dx.doi.org/10.1038/s41557-021-00746-7]

16. Zhang, H.-Z.; Zhao, Z.-L.; Zhou, C.-H. Recent advance in oxazole-based medicinal chemistry. Eur. J. Med. Chem.; 2018; 144, 444. [DOI: https://dx.doi.org/10.1016/j.ejmech.2017.12.044]

17. Facchinetti, V.; Gomes, C.R.B.; de Souza, M.V.N. Application of nitriles on the synthesis of 1,3-oxazoles, 2-oxazolines, and oxadiazoles: An update from 2014 to 2021. Tetrahedron; 2021; 102, 132544. [DOI: https://dx.doi.org/10.1016/j.tet.2021.132544]

18. McIver, A.; Young, D.D.; Deiters, A. A general approach to triphenylenes and azatriphenylenes: Total synthesis of dehydrotylophorine and tylophorine. Chem. Commun.; 2008; 2008, 4750. [DOI: https://dx.doi.org/10.1039/b811068a]

19. Yagyu, T.; Takemoto, Y.; Yoshimura, A.; Zhdankin, V.V.; Saito, A. Iodine(III)-catalyzed formal [2+2+1] cycloaddition reaction for metal-free construction of oxazoles. Org. Lett.; 2017; 19, 2506. [DOI: https://dx.doi.org/10.1021/acs.orglett.7b00742]

20. Hajra, S.; Sinha, D.; Bhowmick, M. Metal triflate catalyzed reactions of alkenes, NBS, nitriles, and TMSN₃:  synthesis of 1,5-disubstituted tetrazoles. J. Org. Chem.; 2007; 72, 1852. [DOI: https://dx.doi.org/10.1021/jo062432j]

21. Hoff, B. Acetonitrile as a building block and reactant. Synthesis; 2018; 50, 2824. [DOI: https://dx.doi.org/10.1055/s-0036-1589535]

22. Kumar Verma, P.; Vishwakarma, R.A.; Sawant, S.D. Reaction medium as the installing reservoir for key functionalities in the molecules. Asian J. Org. Chem.; 2019; 8, 777. [DOI: https://dx.doi.org/10.1002/ajoc.201900223]

23. Chen, H.; Dai, W.; Chen, Y.; Xu, Q.; Chen, J.; Yu, L.; Zhao, Y.; Ye, M.; Pan, Y. Efficient and selective nitrile hydration reactions in water catalyzed by an unexpected dimethylsulfinyl anion generated in situ from CsOH and DMSO. Green Chem.; 2014; 16, 2136. [DOI: https://dx.doi.org/10.1039/C3GC42310G]

24. Ibrahim, A.D.; Entsminger, S.W.; Fout, A.R. Insights into a chemoselective cobalt catalyst for the hydroboration of alkenes and nitriles. ACS Catal.; 2017; 7, 3730. [DOI: https://dx.doi.org/10.1021/acscatal.7b00362]

25. Li, Y.; Chen, H.; Liu, J.; Wan, X.; Xu, Q. Clean synthesis of primary to tertiary carboxamides by CsOH-catalyzed aminolysis of nitriles in water. Green Chem.; 2016; 18, 4865. [DOI: https://dx.doi.org/10.1039/C6GC01565D]

26. Veisi, H.; Maleki, B.; Hamelian, M.; Ashrafi, S.S. Chemoselective hydration of nitriles to amides using hydrated ionic liquid (IL) tetrabutylammonium hydroxide (TBAH) as a green catalyst. RSC Adv.; 2015; 5, 6365. [DOI: https://dx.doi.org/10.1039/C4RA09864A]

27. Fleming, F.F.; Yao, L.; Ravikumar, P.C.; Funk, L.; Shook, B.C. Nitrile-containing pharmaceuticals: Efficacious roles of the nitrile pharmacophore. J. Med. Chem.; 2010; 53, 7902. [DOI: https://dx.doi.org/10.1021/jm100762r]

28. Ha, T.M.; Guo, W.; Wang, Q.; Zhu, J. Copper-catalyzed cyanoalkylative aziridination of N-sulfonyl allylamines. Adv. Synth. Catal.; 2020; 362, 2205. [DOI: https://dx.doi.org/10.1002/adsc.202000276]

29. Ahmad, M.S.; Ahmad, A. Cu-catalyzed cyanomethylation of imines and alpha, beta-alkenes with acetonitrile and its derivatives. RSC Adv.; 2021; 11, 5427. [DOI: https://dx.doi.org/10.1039/D0RA10693C]

30. Yao, H.; Zhong, X.; Wang, B.; Lin, S.; Yan, Z. Cyanomethylation of the benzene rings and pyridine rings via direct oxidative cross-dehydrogenative coupling with acetonitrile. Org. Lett.; 2022; 24, 2030. [DOI: https://dx.doi.org/10.1021/acs.orglett.2c00498]

31. Saito, A.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric addition of acetonitrile to aldimines. Org. Lett.; 2019; 21, 8187. [DOI: https://dx.doi.org/10.1021/acs.orglett.9b02821]

32. Saito, A.; Adachi, S.; Kumagai, N.; Shibasaki, M. Direct catalytic asymmetric addition of alkylnitriles to aldehydes with designed nickel-carbene complexes. Angew. Chem. Int. Ed.; 2021; 60, 8739. [DOI: https://dx.doi.org/10.1002/anie.202016690] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33528875]

33. Coffinet, A.; Levacher, V.; Gillaizeau, I.; Brière, J.-F.; Oudeyer, S. Nickel-catalyzed cyanoalkylation of ketone derivatives. Adv. Synth. Catal.; 2023; 365, 156. [DOI: https://dx.doi.org/10.1002/adsc.202201147]

34. Csákÿ, A. Metal-free organocatalysis. Catalysts; 2018; 8, 195. [DOI: https://dx.doi.org/10.3390/catal8050195]

35. Zhang, R.; Jin, S.; Liu, Q.; Lin, S.; Yan, Z. Transition metal-free cross-dehydrogenative coupling reaction of coumarins with acetonitrile or acetone. J. Org. Chem.; 2018; 83, 13030. [DOI: https://dx.doi.org/10.1021/acs.joc.8b01508] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30295495]

36. Liu, D.; Xia, Z.; Xiao, Y.; Yu, Y.; Yu, L.; Song, Z.; Wu, Q.; Zhang, J.; Tan, Z. Transition-metal-free cross-dehydrogenative couplings of 8-aminoquinoline amides at C5 position with acetonitrile, ethers or acetone. Eur. J. Org. Chem.; 2021; 2021, 5012. [DOI: https://dx.doi.org/10.1002/ejoc.202100953]

37. Hong, G.; Nahide, P.D.; Kozlowski, M.C. Cyanomethylation of substituted fluorenes and oxindoles with alkyl nitriles. Org. Lett.; 2020; 22, 1563. [DOI: https://dx.doi.org/10.1021/acs.orglett.0c00160]

38. Xiao, Y.; Liu, Z.-Q. Free radical addition of nitrile, ketone, and ester to alkyne and the selectivity discussion. Org. Lett.; 2019; 21, 8810. [DOI: https://dx.doi.org/10.1021/acs.orglett.9b03444] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31633360]

39. Zheng, X.; Zhong, T.; Zhang, L.; Chen, J.; Chen, Z.; Jiang, X.; Yu, C. Radical-triggered cyclization of methylthio-substituted alkynones: Synthesis of diverse 3-alkylthiochromones. Eur. J. Org. Chem.; 2020; 2020, 4534. [DOI: https://dx.doi.org/10.1002/ejoc.202000663]

40. Cai, T.; Shen, F.; Ni, Y.; Xu, H.; Shen, R.; Gao, Y. Cascade radical annulation of 2-alkynylthio(seleno)anisoles with acetone or acetonitrile: Synthesis of 3-acetomethyl- or cyanomethyl-substituted benzothio(seleno)phenes. J. Org. Chem.; 2021; 86, 1002. [DOI: https://dx.doi.org/10.1021/acs.joc.0c02444]

41. Liu, H.; Yang, Z.; Huang, G.; Yu, J.-T.; Pan, C. Cyanomethylative cyclization of unactivated alkenes with nitriles for the synthesis of cyano-containing ring-fused quinazolin-4(3H)-ones. New J. Chem.; 2022; 46, 1347. [DOI: https://dx.doi.org/10.1039/D1NJ05001J]

42. Park, M.S.; Lee, S. Transition-metal-catalyst-free reaction of amides and acetonitriles: Synthesis of β-ketonitriles. Org. Chem. Front.; 2022; 9, 5178. [DOI: https://dx.doi.org/10.1039/D2QO00884J]

43. Qian, P.; Zha, Z.; Wang, Z. Recent advances in C−H functionalization with electrochemistry and various iodine-containing reagents. ChemElectroChem; 2020; 7, 2527. [DOI: https://dx.doi.org/10.1002/celc.202000252]

44. Horn, E.J.; Rosen, B.R.; Baran, P.S. Synthetic organic electrochemistry: An enabling and innately sustainable method. ACS Cent. Sci.; 2016; 2, 302. [DOI: https://dx.doi.org/10.1021/acscentsci.6b00091]

45. Rockl, J.L.; Pollok, D.; Franke, R.; Waldvogel, S.R. A decade of electrochemical dehydrogenative C-C coupling of aryls. Acc. Chem. Res.; 2020; 53, 45. [DOI: https://dx.doi.org/10.1021/acs.accounts.9b00511]

46. Yan, M.; Kawamata, Y.; Baran, P.S. Synthetic organic electrochemical methods since 2000: On the verge of a renaissance. Chem. Rev.; 2017; 117, 13230. [DOI: https://dx.doi.org/10.1021/acs.chemrev.7b00397] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28991454]

47. He, W.-B.; Zhao, S.-J.; Chen, J.-Y.; Jiang, J.; Chen, X.; Xu, X.; He, W.-M. External electrolyte-free electrochemical one-pot cascade synthesis of 4-thiocyanato-1H-pyrazoles. Chin. Chem. Lett.; 2023; 34, 107640. [DOI: https://dx.doi.org/10.1016/j.cclet.2022.06.063]

48. Ding, L.; Niu, K.; Liu, Y.; Wang, Q. Electro-reductive C-H cyanoalkylation of quinoxalin-2(1H)-ones. Chin. Chem. Lett.; 2022; 33, 4057. [DOI: https://dx.doi.org/10.1016/j.cclet.2021.12.053]

49. Pappo, D.; Kashman, Y. β-Turn mimetic:  synthesis of cyclic thioenamino peptides. Org. Lett.; 2006; 8, 1177. [DOI: https://dx.doi.org/10.1021/ol060075t]

50. Kraft, S.; Ryan, K.; Kargbo, R.B. Recent advances in asymmetric hydrogenation of tetrasubstituted olefins. J. Am. Chem. Soc.; 2017; 139, 11630. [DOI: https://dx.doi.org/10.1021/jacs.7b07188]

51. Lu, F.; Yang, Z.; Wang, T.; Wang, T.; Zhang, Y.; Yuan, Y.; Lei, A. Electrochemical oxidative Csp3-H/S-H cross-coupling with hydrogen evolution for synthesis of tetrasubstituted olefins. Chin. J. Chem.; 2019; 37, 547. [DOI: https://dx.doi.org/10.1002/cjoc.201900113]

52. He, T.-J.; Ye, Z.; Ke, Z.; Huang, J.-M. Stereoselective synthesis of sulfur-containing β-enaminonitrile derivatives through electrochemical Csp3–H bond oxidative functionalization of acetonitrile. Nat. Commum.; 2019; 10, 833. [DOI: https://dx.doi.org/10.1038/s41467-019-08762-5] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30783088]

53. Wan, J.L.; Huang, J.M. Bromide-catalyzed electrochemical Csp3−H oxidation of acetonitrile: Stereoselective synthesis of heteroaryl vinyl sulfides. Adv. Synth. Catal.; 2022; 364, 2648. [DOI: https://dx.doi.org/10.1002/adsc.202200247]

54. Igarashi, E.; Sakamoto, K.; Yoshimura, T.; Matsuo, J. Formal [4+2] cycloaddition of 3-phenylcyclobutanones with nitriles. Tetrahedron Lett.; 2019; 60, 13. [DOI: https://dx.doi.org/10.1016/j.tetlet.2018.11.040]

55. Sattler, L.E.; Hilt, G. Iodonium cation-pool electrolysis for the three-component synthesis of 1,3-oxazoles. Chem. Eur. J.; 2021; 27, 605. [DOI: https://dx.doi.org/10.1002/chem.202004140] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33270278]

56. Bao, L.; Liu, C.; Li, W.; Yu, J.; Wang, M.; Zhang, Y. Electrochemical synthesis of polysubstituted oxazoles from ketones and acetonitrile. Org. Lett.; 2022; 24, 5762. [DOI: https://dx.doi.org/10.1021/acs.orglett.2c02252]

57. Shen, T.; Lambert, T.H. Electrophotocatalytic diamination of vicinal C-H bonds. Science; 2021; 371, 620. [DOI: https://dx.doi.org/10.1126/science.abf2798]

58. Qin, Q.; Luo, X.; Wei, J.; Zhu, Y.; Wen, X.; Song, S.; Jiao, N. Acetonitrile activation: An effective two-carbon unit for cyclization. Angew. Chem. Int. Ed.; 2019; 58, 4376. [DOI: https://dx.doi.org/10.1002/anie.201900947]

59. Neff, R.K.; Su, Y.-L.; Liu, S.; Rosado, M.; Zhang, X.; Doyle, M.P. Generation of Halomethyl Radicals by Halogen Atom Abstraction and Their Addition Reactions with Alkenes. J. Am. Chem. Soc.; 2019; 141, 16643. [DOI: https://dx.doi.org/10.1021/jacs.9b05921]

60. Tomilin, D.N.; Sobenina, L.N.; Saliy, I.V.; Ushakov, I.A.; Belogolova, A.M.; Trofimov, B.A. Substituted pyrrolyl-cyanopyridines on the platform of acylethynylpyrroles via their 1 : 2 annulation with acetonitrile under the action of lithium metal. New J. Chem.; 2022; 46, 13149. [DOI: https://dx.doi.org/10.1039/D2NJ02011D]

61. Duan, X.; Sun, R.; Tang, J.; Li, S.; Yang, X.; Zheng, X.; Li, R.; Chen, H.; Fu, H.; Yuan, M. Facile synthesis of 2-methylnicotinonitrile through degenerate ring transformation of pyridinium salts. J. Org. Chem.; 2022; 87, 7975. [DOI: https://dx.doi.org/10.1021/acs.joc.2c00614]

62. Valeur, E.; Bradley, M. Amide bond formation: Beyond the myth of coupling reagents. Chem. Soc. Rev.; 2009; 38, 606. [DOI: https://dx.doi.org/10.1039/B701677H] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19169468]

63. Montalbetti, C.A.G.N.; Falque, V. Amide bond formation and peptide coupling. Tetrahedron; 2005; 61, 10827. [DOI: https://dx.doi.org/10.1016/j.tet.2005.08.031]

64. Nasser, J.; Zhang, L.; Lin, J.; Sodano, H. Aramid nanofiber reinforced polymer nanocomposites via amide–amide hydrogen bonding. ACS Appl. Polym. Mater.; 2020; 2, 2934. [DOI: https://dx.doi.org/10.1021/acsapm.0c00430]

65. Yan, Z.; Sun, B.; Huang, P.; Zhao, H.; Ding, H.; Su, W.; Jin, C. Visible-light-promoted radical alkylation/cyclization of allylic amide with N-hydroxyphthalimide ester: Synthesis of oxazolines. Chin. Chem. Lett.; 2022; 33, 1997. [DOI: https://dx.doi.org/10.1016/j.cclet.2021.09.067]

66. Huang, Y.; Pi, C.; Tang, Z.; Wu, Y.; Cui, X. Cp*Co(III)-catalyzed C-H amidation of azines with dioxazolones. Chin. Chem. Lett.; 2020; 31, 3237. [DOI: https://dx.doi.org/10.1016/j.cclet.2020.08.046]

67. Shen, T.; Lambert, T.H. C-H Amination via electrophotocatalytic Ritter-type reaction. J. Am. Chem. Soc.; 2021; 143, 8597. [DOI: https://dx.doi.org/10.1021/jacs.1c03718]

68. Zhong, P.; Wu, J.; Wu, J.; Liu, K.; Wan, C.; Liu, J.-B. Solvent-controlled selective synthesis of amides and thioureas from isothiocyanates. Tetrahedron Lett.; 2022; 107, 154099. [DOI: https://dx.doi.org/10.1016/j.tetlet.2022.154099]

69. Zhou, J.; Fang, Y.; Wang, F.; Li, J. Catalyst-free regioselective hydroxyfluorination and aminofluorination of α,β-unsaturated ketones. Org. Biomol. Chem.; 2019; 17, 4470. [DOI: https://dx.doi.org/10.1039/C9OB00467J]

70. Liu, S.; Klussmann, M. Acid promoted radical-chain difunctionalization of styrenes with stabilized radicals and (N,O)-nucleophiles. Chem. Commun.; 2020; 56, 1557. [DOI: https://dx.doi.org/10.1039/C9CC09369A]

71. Liu, S.; Klussmann, M. Organo-redox-catalysis for the difunctionalization of alkenes and oxidative Ritter reactions by C–H functionalization. Org. Chem. Front.; 2021; 8, 2932. [DOI: https://dx.doi.org/10.1039/D1QO00259G]

72. Guan, Y.-Q.; Min, X.-T.; He, G.-C.; Ji, D.-W.; Guo, S.-Y.; Hu, Y.-C.; Chen, Q.-A. The serendipitous effect of KF in Ritter reaction: Photo-induced amino-alkylation of alkenes. iScience; 2021; 24, 102969. [DOI: https://dx.doi.org/10.1016/j.isci.2021.102969] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34466792]

73. Yu, Y.; Yuan, Y.; Ye, K.-Y. Electrochemical synthesis of vicinal azidoacetamides. Chem. Commun.; 2023; 59, 422. [DOI: https://dx.doi.org/10.1039/D2CC06246A] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36514900]

74. Zhang, W.; Sun, M.; You, K.; Pang, Y.; Ma, B. Metal-free aminofluorination of α-diazo 2H-benzopyran-4-one: Convenient access to β-fluoramides. Org. Biomol. Chem.; 2022; 20, 7027. [DOI: https://dx.doi.org/10.1039/D2OB01089E]

75. Strekalova, S.; Kononov, A.; Rizvanov, I.; Budnikova, Y. Acetonitrile and benzonitrile as versatile amino sources in copper-catalyzed mild electrochemical C-H amidation reactions. RSC Adv.; 2021; 11, 37540. [DOI: https://dx.doi.org/10.1039/D1RA07650G] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35496383]

76. Zhang, H.; Wang, W.; Wang, B.; Tan, H.; Jiao, N.; Song, S. Electrophilic amidomethylation of arenes with DMSO/MeCN reagents. Org. Chem. Front.; 2022; 9, 2430. [DOI: https://dx.doi.org/10.1039/D2QO00181K]

77. Bao, L.; Zhang, B.-B.; Wang, Z.-X.; Chen, X.-Y. Photocatalytic dehydrations for the Ritter reaction. Org. Chem. Front.; 2023; 10, 1375. [DOI: https://dx.doi.org/10.1039/D2QO02046G]