Recent Advances in Molecule Synthesis Involving C-C Bond Cleavage of Ketoxime Esters

Abstract

The synthetic strategies of oxime derivatives participating in radical-type reactions have been rapidly developed in the last few decades. Among them, the N–O bond cleavage of oxime esters leading to formation of nitrogen-centered radicals triggers adjacent C–C bond cleavage to produce carbon-centered free radicals, which has been virtually used in organic synthesis in recent years. Herein, we summarized the radical reactions involving oxime N–O bond and C–C bond cleavage through this special reaction form, including those from acyl oxime ester derivatives and cyclic ketoxime ester derivatives. These contents were systematically classified according to different reaction types. In this review, the free radical reactions involving acyl oxime esters and cyclic ketoxime esters after 2021 were included, with emphasis on the substrate scope and reaction mechanism.

1. Introduction

The nitrogen-containing skeleton widely exists in a large number of natural products, active molecules and functional materials, and various commodities composed of them, such as food, drugs and various other materials that play crucial roles in human life [1,2,3,4,5,6]. The strategy involving nitrogen-centered radicals (NCRs), as a pragmatic strategy to construct a C–N bond rapidly, has always been one of the research hotspots of chemists in the last decades [7,8]. Although a large number of scientists have been committed to developing simpler and more effective paths for C–N bond construction, the development of a nitrogen-centered free radical strategy is still very limited, which is, as concluded by Zard [8], mainly hampered by “a dearth of convenient access to these species and a lack of awareness pertaining to their reactivity” [9].

Ketone-derivated oxime esters have been widely used in the field of organic synthesis [10,11,12,13]. Among them, one of the most important aspects is the application in the construction of nitrogen heterocyclic compounds [14,15]. In the past few decades, the implementation of transition metal catalysis with palladium, rhodium, ruthenium, cobalt, etc. for oxime N–O bond activation has been intensively reported, which exhibited excellent site selectivity and provided effective and convenient methods for the synthesis of aza- compounds [16]. For example, in 2022, the review of O-acyl ketoximes summarized by Huang’s group detailed the cases of the synthesis of nitrogen heterocyclic compounds under various transition-metal-based catalytic systems [16]. In recent years, free radical chemistry has been developed rapidly and has showed featured advantages, among which oxime esters were also widely used in free-radical-type reactions [17,18,19,20,21,22]. Typically, oxime ester derivatives generate imino radicals under the action of photocatalysts or transition metals, and then further convert into carbon-centered radicals (CCRs). The conversion from NCRs to CCRs mainly involves the following methods (Scheme 1a): (1) 1,3-hydrogen transfer process to give α-imidoyl carbon radicals (path I) [23,24]; (2) 1,5-hydrogen transfer process to generate a γ-imidoyl carbon radicals (path II) [25,26]; (3) intramolecular addition of an iminyl radical to a tethered alkene or alkyne in a 5-exo-trig or 5-exo-dig fashion (path III) [27,28,29]; and (4) intramolecular carbon–carbon bond cleavage to generate carbon radicals (path IV) [30,31,32].

Recently, there were many detailed reviews on these topics. In 2019, the Wang group disclosed a review on imino radical-involved reactions [33]. Subsequently, path II and III on photocatalytic cross-couplings via the cleavage of N–O bonds were described in the review by Fu and Zhu [34]. Recently, both the Zhou [31] and Samanta [32] groups presented detailed summaries of the mechanisms, as well as reaction forms, of the various reactions in which cyclic ketoximes are involved. In addition, numerous chemistry groups, including Zard [8], Chen [35], Xu [36], etc., have more or less summarized strategies for the above forms of nitrogen radical centers. However, the use of oxime esters as acylation reagents has only emerged in recent few years, and to our knowledge, there are no related reviews reported; therefore, we mainly focus on this topic to summarize related works. Since acyl oxime esters also belong to the path IV type, we have also added a summary of the work on cyclic ketoximes after 2021. The oxime ester compounds used in this reaction mode all have special structures, one with an o-diketone derivative and the other with a ring structure, which can be obtained by two-step conversion from the corresponding ketones. Meanwhile, they have a similar reaction mode (Scheme 1b) in that oximes undergo single electron transfer with a transition metal or photosensitizer to achieve N–O cleavage and afford imino radicals, which subsequently undergo β-C-C bond cleavage to generate acyl radicals or cyanoalkyl. The nitriles by-products are formed when using acyl oxime esters in reactions. The acyl radicals and cyanoalkyl radicals can be captured by various free radical receptors and participate in various forms of reactions [31,32,37,38,39]. In this review, various free radical reactions involving acyl esters and cyclic ketoxime esters are summarized, and they are classified according to different types of reactions, mainly including radical addition, cross-coupling and radical coupling.

2. Acyl Oxime Ester

2.1. Radical Addition

2.1.1. Acyl Addition to Alkenes

In 2019, the Wu and Tung group demonstrated a groundbreaking example of acylation/cyclization of Michael acceptors with acyl radicals derived from acyl oxime esters 1 with C–C bond cleavage. Hence, cyclobutyl ketone derivatives 4 and acylated oxindoles 6 were obtained using fac-Ir(ppy)₃ as a photosensitizer at room temperature (Scheme 2) [40]. The mechanism studies show that the acyl oxime esters 1 are first reduced by a Ir^III catalyst under 3 W blue-light conditions, and then the acyl radicals 7 are produced by C–C bond cleavage. On the one hand, the acyl radical 7 is captured by styrene 3 and oxidized by Ir^IV to remove a proton to produce enone 8, which is sensitized by Ir^III* to further react with another styrene 3 to lead to cross [2 + 2] cyclization and obtain acylated cyclobutanones derivatives 4. Alternatively, acyl radicals 7 could also add to the C–C double bond of the acrylamides 5 to afford structurally useful acylation oxindole skeletons 6.

In the same year, this group reported a novel three-component difunctionalization reaction of acyl oxime esters, olefins and alkane nitriles, which generated a series of β-carbonyl imides 12 with excellent yields (Scheme 3) [41]. The isotope tracking experiment and control experiments revealed the efficient intermolecular reorganization of oxime esters into styrene with the aid of solvent exchange. A possible reaction mechanism is shown in Scheme 3. First, the acyloxime esters 1 are cleaved to nitrile, carboxylate anions 13 and acyl radicals 7 by a single electron transfer (SET) process with the excited state Ir^III*, which is generated from Ir^III under blue-light irradiation. Then, a SET occurs between intermediate 14, which is produced by the addition of an acyl radical 7 to the olefin 3 and Ir^IV to complete the cycle of catalyst Ir and produce the carbocation 15. The intermediate 16, produced by the nucleophilic attack of nitrile to cation 15, undergoes a Mumm rearrangement with carboxylate anions 13 to obtain the amide products 12.

A photocatalytic hydroacylation of alkenes with acyl oximes for the synthesis of valuable ketones was developed by Yang et al. (Scheme 4) [42]. When CF₃-attached styrenes were used, a E1cB-type fluoride elimination pathway was proposed for the obtainment of the 1,1-difluoroolefin products 19. In this difunctionalization reaction, the triphenylphosphine radical cation generated by the reaction of the excited catalyst Ir^III* with triphenyl phosphine combines with the nucleophile acyl oximes 1 to obtain the phosphorus radical intermediate 20. The N–O bond cleavage of the intermediate 20 gives the iminyl radical 21 via β-scission. The imino radical 21 undergoes C–C bond scission to give acyl radical 7 and a molecule of acetonitrile. The acyl radical is added to alkene 17 and reduced by Ir^II to get the carbanion intermediate 23, with the following protonation to generate the desired product 18.

In 2021, Sun and co-workers developed a distinctive carbonylation approach using Ir and DIPEA to access γ-keto acids 24 and cyanocarboxylic acids 25 (Scheme 5) [43]. Mechanistically, this reaction involves the photocatalytic radical addition of acyl radicals and cyanoalkyl radicals to aromatic olefins and then carbon dioxide capture. The valuable dicarbofunctionalization tolerates a wide range of cyclic ketoxime substrates; however, only aliphatic acyl oxime esters proceed smoothly to afford corresponding γ-keto ester products.

Larionov’s group described a N-heterocyclic, carbene-photocatalyzed, three-component regioselective 1,2-diacylation of alkenes, using acyl oxime esters and aldehydes as two different acylating agents (Scheme 6) [44]. In particular, the authors demonstrated the mechanism by density functional theory (DFT) and time-dependent-DFT (TD-DFT), where an EDA intermediate is probably formed in the diacylation, which initiates photoexcitation to mediate charge transfer. The EDA intermediate 33, formed by the complexation of the Breslow intermediate 32 with the acyl oxime ester 1, is excited under light conditions and subsequently cleaved to remove BzO^- and acetonitrile to give the intermediate 34 and acyl radical 7. The intermediate 14 produced by the addition of the acyl radical 7 to the olefin 3 couples with the intermediate 34 and then decomposes to a diketone product 30 and carbene 31.

Liu and Huang’s group reported an intriguing route to 3-acyl-substituted chroman-4-one derivatives 36, which involves SET reduction of acyl oxime esters 1 by fac-Ir(ppy)₃ under thermal and light conditions (Scheme 7) [45]. In this functionalization reaction, the acyl radical generated from the acyl oxime ester first adds to the carbon double bond of the 2-allyloxy benzaldehydes 35, followed by intramolecular cyclization and 1,2-HAT (hydrogen atom transfer) to obtain the alcohol radical intermediate 40. Finally, SET oxidation by Ir^IV and deprotonation occur to obtain the target products 36.

Another acylation/cyclization strategy mediated by a photocatalytic nitrogen-centered radical of acyl oxime esters 1 with activated acrylamides 42 was reported by Liu and Huang’s group (Scheme 8) [46]. The authors screened a variety of acyl oximes with different leaving groups, such as 4-CF₃C₆H₄CO, 4-NO₂C₆H₄CO, C₆F₅CO, CF₃CO, etc., and achieved up to 95% yields with 58 synthetic examples of acylated transformations. The fragmentation of one C–C bond and one N–O bond and the formulation of two new C–C bonds were carried out in one-pot conditions with a low catalyst loading (1 mol%). This protocol represents a simple and green road for the synthesis of acylated indolo/benzimidazo-[2,1,a]isoquinolin-6(5H) ones.

Most recently, the same group uncovered a new acylation reaction of acyl oxime esters with activated N-sulfonyl acrylamides 48, with a broad substrate scope and good functional group compatibility (Scheme 9) [47]. This method provides an effective nitrogen center-mediated approach for the generation of acyl radical intermediates to access acylated oxindole 6. This acylation transformation proceeds through a normal Smiles rearrangement process that involves cascade intramolecular ispo-cyclization (50), de-SO₂ (51) and re-cyclization (52).

2.1.2. Acyl Addition to Alkynes

The heterocyclic skeleton presents in commercial drugs and many naturally occurring compounds; thus, the development of convenient and environmentally friendly methods for the construction of this structural motif is an important and promising research field [48,49,50]. Alkynes with specific substituents, such as alkyne amides [51,52,53], N-propylindoles [54,55,56], alkyne esters [57,58], alkyne amines [59,60,61], etc., are often used as radical acceptors to construct potential heterocyclic compounds by tandem cyclization. Recently, Liu and Zhou have independently developed a multitude of innovative photocatalytic, nitrogen-centered, radical-mediated acylation strategies of reactive alkynes using acyl oxime esters as acyl sources (Scheme 10) [37,39,62,63].

Liu’s group pioneered a radical addition strategy of acyl oxime esters 1 with activated alkynes 54 to construct a series of 3-acylated spiro [4,5]trienones derivatives 55 [37]. The acyl radical generated by the C–C bond breakage of acyl oxime esters attacks the carbon–carbon triple bond of propiolamides 54 to give the radical intermediate 62. The intermediate 62 undergoes intramolecular ispo-cyclization and is oxidized to carbocations 64 by Ir^IV, followed by the combination with hydroxide anion produced in water to obtain the intermediate 65. Finally, a methoxy anion and hydrogen ion are removed to obtain the expected trienone product 55.

Subsequently, Liu’s group developed two pragmatic acylation strategies using N-propynylindoles 56 [63] and alkynoates 58 [62] under photoexcitation conditions. A large quantity of acylated pyrrolo[1,2-a]indole 57 and coumarin 59 derivatives were constructed, and interestingly, both the alkanoyl and aryl groups were well adapted. These studies further developed the application of acyl oxime esters and were of great importance for the development of free radical synthetic chemistry.

Comparably, Zhou’s group has achieved a series of constructions of 3-acyl quinoline skeleton 61 under photocatalytic conditions with N-propargyl aromatic amines 60 as radical acceptors [39]. The mechanism of this acylation reaction states that acyl radicals add to the carbon–carbon triple bond of N-propargyl aromatic amines 60 for intramolecular cyclization and then proceed to dehydroarylation to give the final quinoline product 61.

2.2. Radical Cross-Couple

Recently, the development of the photoredox/palladium-catalyzed C-H acylation of 2-arylpyridines 78 with acyl oxime esters 1 using fac-Ir(ppy)₃ as a photosensitizer was reported by the Chen group (Scheme 11) [64]. In order to thoroughly study the reaction mechanism, the author carried out some control experiments, including the radical clock reaction using benzocycloketoxime ester 80 with ethene-1,1-diyldibenzene under standard conditions and TEMPO as a radical inhibitor to test the activity of the reaction. The generation of the target product 83 and the detection of the free radical capture product 84 by the HRMS indicate that this acylation reaction contains a free radical mechanism.

In addition to the above acyl oxime esters, Wu’s group reported the benzyl oxime esters 85 with the same reaction mode, i.e., a single electron transfer followed by carbon–carbon bond cleavage to produce the corresponding radical (Scheme 12) [38]. The resulting benzyl radicals 91 are further oxidized to benzyl carbocation 92, which are then coupled with O and N-nucleophilic reagents to access the target benzyl ethers 88 and benzylamines 89. This benzylation strategy well tolerates various functional groups under mild conditions, where a wide range of nucleophilic substrates, such as primary and secondary alcohols, amines and even H₂O, worked smoothly.

3. Cyclic Ketoxime Esters

3.1. Radical Addition

3.1.1. Ring Opening and Addition to Alkenes

In 2021, Chen and co-workers reported a difunctionalization synthesis of cyanoalkylfluorinated products that exploits a 10-phenyl-10H-phenothiazine (Ph-PTZ) as a photosensitizer approach (Scheme 13) [65]. The three-component cyanoalkylfluorination is initiated by the excitation of Ph-PTZ by 40 W purple LEDs. The cyanoalkyl radical was obtained by the C–C bond cleavage of the imino radical 94 generated by the single electron transfer between the excited-state Ph-PTZ* and the cycloketoxime ester. Oxidation of the intermediate 96 by Ph-PTZ^•+ delivers the carbocation intermediate 97 and Ph-PTZ. The resulting intermediate is then attacked by nucleophilic substances, such as F⁻ and alcohols, to produce corresponding products (93 and 98). This strategy provides a transition-metal-free nitrogen-centered radical pathway for the construction of fluorocyanoalkylation derivatives.

In the same year, Du [66] and Guo [67] independently reported N-heterocyclic, carbene-catalyzed, three-component acylation/cyanoalkylation of alkenes with cyclic ketoxime esters and aldehydes (Scheme 14). The Du group suggested that this radical relay process relied on the SET achieved by the EDA complex 105 bound by Mg, the Breslow intermediate and oxime esters. The EDA complex 105 was subjected to thermally controlled SET and cleaved off the ester group to give the cyanoalkyl radical 95 and the intermediate 103. However, Guo’s group believed that it was the acyl oxime ester that directly undergoes SET with the intermediate bound by the aldehyde and N-heterocyclic carbene to remove the ester group to form the butyl cyano radical and intermediate 103. Subsequently, the addition of cyanoalkyl radicals 95 to olefins 3, followed by the radical-coupling with the intermediate 103, occurred to obtain the intermediate 104, which was further transformed to the final product 99 with the regeneration of the NHC for the next catalytic cycle.

In addition, Du’s group developed N-heterocyclic carbene-catalyzed 1,4-alkylcarbonylation of 1,3-enynes 106 with aldehydes 29 and different alkyl radical precursors, such as CF₃I, alkyl halides, cycloketone oxime esters and redox-active esters derived from aliphatic carboxylic acids, affording a series of tetra-substituted allenyl ketones with excellent yields [68]. Among them, a variety of cyanoalkylated and acylated bianenone derivatives 107 were obtained in yields of 44–94% when cyclic ketoxime esters 2 were involved in this N-heterocyclic carbene-catalyzed system (Scheme 15).

Guo and co-workers reported 1,4-cyanoalkylarylations of 1,3-enynes 106 and aryl boronic acids 108 with a range of cyclobutanone oxime esters 2 to furnish multiple functionalizatized allenes 109. In the presence of [Ir(ppy)₂(bpy)]PF₆ and Cu(CH₃CN)₄PF₆, the reaction completed within 7 minutes to reach 80% yield (Scheme 16) [69]. Cyclic ketoxime esters 2 were smoothly disintegrated and ring-opened to cyanoalkyl radicals with the help of the Ir^III* catalyst, followed by the addition to the olefin of 1,3-enynes to obtain the radical intermediate 110, which underwent a radical shift to give the allene radical species 111. The oxidative addition of Ar-Cu(II) in situ formed by the transmetallation of the Cu(II) species with aryl boronic acids 108 to the diolefin radical 111 gives the intermediate 113, which undergoes reductive elimination to provide the target tetra-substituted allene 109 and the Cu(I) species.

Jiang et al. have established the 100-percent atom utilization, radical, tandem difunctionalization of 1,6-enynes 114 with cycloketone oxime esters 2 for the synthesis of 1-indanones bearing an all-carbon quaternary center by using CuBr as the catalyst, 1,10-phen as the ligand and Na₂CO₃ as the base (Scheme 17) [70]. The alkenyl radical intermediate 118 obtained by cyclization after attacking the alkyne 114 by the cyanoalkyl radical 95 reacted with the carboxylate anions 116 and Cu(II) species, producing all-atom utilization target products 115.

In 2021, a splendent method toward cyanoalkylsulfonylated oxindoles 120 and cyanoalkyl amides 121 was developed by Liang and co-workers (Scheme 18) [71]. Interestingly, the properties of substituent groups on the nitrogen atom in activated alkenes 48 resulted in different products. In particular, when the R⁴ = Me, oxindoles 120 were accessed. More surprisingly, the cyanoalkyl radical in the cyclization process could capture SO₂ from the N-sulfonylated acrylamides 48, thus realizing cyanoalkylation/sulfonylation without an additional sulfur source. On the other hand, when N-arylacrylamides (R⁴ = aryl) were subjected to the system, hydrogenated cyanoalkyl amides were afforded.

A cascade cyanoalkylation/sulfonylation/cyclization of N-arylacrylamides 5 was reported by Gui’s group, which accessed a range of cyanoalkyl sulfonylated oxindole products 120 in good yields (Scheme 19) [72]. Compared to other strategies, this ring-opening sulfonylation transformation avoids the usage of catalysts and oxidants and requires only a 390 nm purple light source to proceed smoothly. The light irradiation was proposed to enable the N–O bond cleavage of ketoximes in the initial step.

Nitrogen-containing heterocycles, especially phenanthridine and quinoxaline derivatives, have been applied extensively in drugs, materials and organic synthesis [73,74]. In 2021, Zhou et al. developed nickel-catalyzed, difunctionalization, oxidative annulation reactions of vinyl azides 128 and cycloketone oxime esters 2 to prepare cyanoalkyl containing quinoxalin-2(1H)-ones 129 (Scheme 20) [73]. One of the highlights of the strategy is that five- and six-membered cyclic ketoxime esters could also react to obtain ring-opening products in moderate yields. In the same year, a similar transition metal-catalyzed system for cyanoalkylation and cyclization of activated alkenes and cyclic ketoxime esters 2 was developed by Xu, Kong and co-workers (Scheme 20) [74]. Compared to Zhou’s work, this reaction replaces the nickel catalyst with a metallic copper catalyst and extends it to 2-(1-azidovinyl)-1,1′-biphenyl derivatives 131. Further, spirocyclic ketone products 132 were obtained when 2-azido-N-(4-methoxyphenyl)acrylamides were used as the substrate. While the origin of the ketone oxygen atom has not been further verified by the authors, it usually comes from the water in the solvent in such a reaction.

Guo, Qiu and co-workers reported a convenient room-temperature synthesis of cyanoalkyl-containing β-enamino ketones from heterocyclic-substituted azidyl homoallylic alcohol precursors under visible-light irradiation (Scheme 21) [75]. The remarkable feature is the short reaction time within 9.3 min; yet, the yields of the substrates are generally low, especially for the cyclic ketoxime substrates, which generally have only 20–50% yields. Mechanistically, the addition of the cyanoalkyl radicals 95 to azide olefins 135, with removal of one molecule of nitrogen, generates the imino radicals 137, which undergo a 5-exo intramolecular radical process to give the key short-lived spiro radical 138. Subsequently, the spirocyclic radical undergoes C–C bond breaking to obtain the alcohol radical intermediate 139, which is oxidized by the Ir^IV to lose a proton to obtain the final product 136.

The unpaired catalytic synthesis of chiral ligands with transition metals is a hot topic, but also a difficult area in the field of organic synthesis. Chen’s group has developed a purple-light-irradiated enantioselective difunctionalization of 1,3-butadienes using cyclic ketoxime ester as a bifunctional reagent under the action of copper catalysis and ligand (R, R)-L1 to generate diversely substituted allylic esters with the ee up to 95% (Scheme 22) [76]. As proposed by the authors, the copper catalyst is combined with the ligand (R, R)-L1 to obtain the [L1Cu(I)X] species, which is subsequently excited by purple light into the excited state [L1Cu(I)X]*. The excited state [L1Cu(I)X]* undergoes electron transfer with the cyclic ketoxime ester 2 to generate an imino radical 94, carboxylate anions and [L1Cu(II)X] species. At the same time, the carboxylate anions combine with [L1Cu(II)X] to obtain a copper–nucleophile complex 143. The imino radical generates the cyanoalkyl radical 95 and then attacks the terminal double bond of 1,3-butadiene 141 to obtain the radical intermediate 144, which is cross-coupled with the above copper–nucleophile complex 143 to provide the intermediate 145. Finally, the enantioselective generation of sp³ C–O bonds provides the expected products 142 and [L1Cu(I)X] species, which then participate in the next catalytic cycle.

The strategy for visible light-mediated synthesis of the 3-cyanoalkyl coumarin skeleton 147 without an external photocatalyst was developed by Yang and co-workers (Scheme 23) [77]. The ortho-hydroxycinnamic esters 146 in the strategy served as both the reactant and photosensitizer. This metal-free cyanoalkylation of cycloketone oxime esters 2 with 2-hydroxyalkenyl esters 146 features a broad substrate scope and good functional group compatibility; especially, the 5-membered oxygen-heterocyclic ketoxime ester could also deliver the target product with a 31% yield.

In 2021, He’s group reported a straightforward approach to synthesize β-lactam derivatives 155 by using cycloketone oxime esters 2 as the cyanoalkyl radical source via Cu-mediated cyclization of inactivated alkenes containing aminoquinoline 154 (Scheme 24) [78]. In particular, the copper catalyst in the cyclization reaction needs the assistance of the aminoquinoline ligand. Mechanistically, as described in Scheme 24, the Cu(II) catalyst chelated with the substrate 154 to obtain the chelated Cu(II) alkene complex 156, which will be nucleophilically added by the cyanoalkyl radical 95 to obtain the five-membered Cu(III)-metallacycle 157. Finally, the β-lactam product and Cu(I) are generated through intramolecular reductive elimination. In addition, the authors further transformed the obtained β-lactam derivatives 155, such as by removing the substituent group on the N atom to obtain β-lactam 158 and opening the quaternary ring to obtain a long-chain amino ester compound 159.

3.1.2. Ring Opening and Addition to Alkynes

The process involving the ring-opening of cyclic ketoxime esters to afford cyanoalkyl radicals and then capturing sulfur dioxide is considered as an effective sulfonylation strategy. Compared with the traditional sulfonylation strategy, it has the advantage of mild and environmentally benign conditions [79,80]. In 2021, Liu’s group demonstrated a cyanoalkyl-radical-triggered cyanoalkylsulfonylation and cyclization transformation of phenyl alkynoates 58 under visible-light conditions to access 3-cyanoalkylsulfonyl-substituted coumarins 160 (Scheme 25) [81]. In this strategy, cyanoalkyl radicals capture sulfur dioxide produced by potassium sulfite to the cyanoalkylsulfonyl radical 125, and then attack the C–C triple bond of the alkynoates 58 to obtain the intermediate 162. Generally, there are two different reaction sequences after the spirane structure 163 is obtained by the ispo-cyclization of the intermediate 164. One is that the helix intermediates will be oxidized directly into carbocations before 1,2-ester migration; the other is that the helix intermediates will be oxidized into carbocation after 1,2-ester migration in the form of free radicals. Both approaches are feasible. It is worth mentioning that in the following year, Liao and co-workers developed a SO₂-free strategy with the same raw material, and the reaction mechanism was believed to be the oxidation after 1,2-ester migration [82].

A visible-light-induced, multi-component cascade cyanoalkylsulfonylation of N-propargyl aromatic amines 60 with cycloketone oxime esters 2 was discovered by Zhou’s group to synthesize cyanoalkylsulfonylated quinolines 166 (Scheme 26) [83]. This methodology provides a facile and mild route for the synthesis of a large number of cyanoalkylsulfonylated quinoline derivatives, with excellent isolated yields ranging from 53% to 99%.

In 2021, Wu et al. established the four-component, free radical, tandem selenosulfonylation of alkynes with cyclobutanone oxime esters 2, DABSO and diphenyl diselenides 172 for the synthesis of β-cyanoalkylsulfonylated vinyl selenides 173 under mild reaction conditions (Scheme 27) [84]. The radical capture experiments demonstrated that the reaction involved a radical course, where cyanoalkylsulfonyl radicals were probably produced. The multicomponent tandem reaction sequentially undergoes the generation of imino radicals 94, C–C bond breaking to produce cyanoalkyl radicals 95, sulfur dioxide capture, addition of cyanoalkylsulfonyl radicals 125 to alkynes 171 and coupling of aryl selenyl radicals 176 with alkenyl radicals 175.

In the following year, Zhou’s group developed a novel radical tandem cyanoalkylsulfonylation reaction of 3-arylethynyl- [1,10-biphenyl]-2-carbonitriles 177 by using DABSO as the sulfur dioxide source for the synthesis of cyanoalkylsulfonyl-substituted cyclopenta [gh]phenanthridines 178. (Scheme 28) [85]. Mechanistic studies showed that the alkenyl radical intermediate 179, obtained by the addition of a cyanoalkylsulfonyl radical 125 to the carbon–carbon triple bond of substrates 177, undergoes intramolecular cyanogenic cyclization to give the imino radical species 180, which then adds to the benzene ring to get the conjugated radical 181. Finally, the radical 181 could undergo two different pathways to provide the final products, i.e., base-promoted homogeneous aromatic substitution and organometallic-based β-hydride elimination.

Isocyanic compounds are an excellent class of radical acceptors. Some pre-functionalized isocyanic substrates are often used to construct various polycyclic nitrogen-containing heterocyclic compounds. Shao’s group achieved facile construction of a series of 1-cyanoalkyl isoquinolines 183 and 6-cyanoalkyl phenanthridines 185 by cyanoalkylation under iron catalysis using various isocyanines (184 and 186) as substrates and cyclic ketoxime esters 2 as radical precursors (Scheme 29) [86]. As shown in the proposed mechanism, the radical intermediate 188 has two pathways to obtain the final product: oxidation by Fe³⁺ species followed by deprotonation by 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU) or otherwise direct oxidation by oxime ester 2 after deprotonation.

3.2. Radical Cross-Coupling

In 2021, Jiang and co-workers reported an asymmetric deconstructive alkynylation reaction that is facilitated by copper/chiral cinchona alkaloid-based N,N,P-ligand catalysts L1 (Scheme 30) [87]. A variety of chiral molecules with cyanoalkyl groups 191 were successfully obtained under mild conditions, including δ-alkynyl amides, ε-alkenyl carbamate and ζ-keto nitrile, with ee up to 99%. The strategy has good functional group tolerance and substrate adaptability, and a range of cyclic oximes, including five- and six-membered reactants, coupled smoothly in moderate to excellent yields. However, this protocol only applies to aryl-substituted alkynes; other alkynes, including ether-substituted and alkyl alkynes, did not react. In addition, Wu’s group also realized a cyanoalkylation strategy with olefins instead of alkynes under copper catalysis [88]. A range of diverse (E)-cyanoalkylsulfonyl alkenes 192 were accessed with excellent yields by using copper iodide as the catalyst. According to the available literature and control experiments, the cyanoalkyl radical and cyanoalkylsulfonyl radical were believed to be the key intermediates. Also, the protocol has some limitations in that cyclic olefins, alkyl-substituted olefins, 1,2-disubstituted olefins and 1,3-butadiene olefins failed to give the target products, and five- and six-membered cyclic ketoxime esters did not work in the conversion.

In 2022, a radical tandem functionalization of 1,4-quinones 198 through cyanoalkylation was revealed by Akondi and Mainkar’s group to afford a series of cyanoalkylated quinone derivatives 199 at room temperature in the absence of a transition metal catalyst (Scheme 31) [89]. A range of substituted 1,4-quinones 198 smoothly served as the coupling partners with cycloketone oxime esters 2, in the presence of 2 mol% Rose Bengal, affording cyanoalkylated quinone derivatives 199 in moderate yields.

The electrochemical technique has long been touted as an environmentally beneficial method due to its inherent ability to achieve redox reactions in a sustainable manner [90,91]. Very recently, Wang’s group developed a pioneering case of electrocatalytic, quinoxalin-2(1H)-ones 201, C-H direct cyanoalkylation that uses cyclic ketoximes 2 as a cyanoalkyl source to successfully construct a series of 3-cyanoalkyl-substituted quinolones 202 (Scheme 32) [92]. Similar to thermal and photochemistry, cyclic ketoxime esters 2 first undergo a single electron transfer at the anode to remove the ester group, and then β–C–C bond cleavage occurs to give the cyanoalkyl radical, which then attacks the C–N double bond of the quinoxalin-2(1H)-ones to produce the nitrogen radical intermediate 203. Finally, the intermediate 203 undergoes a single electron oxidation at the cathode, followed by deprotonation, to produce the final cyanoalkylated product.

An interesting iron-catalyzed selective functionalization process for the direct C_(sp3)-H cyanoalkylation of glycine derivatives promoted by pyridine-oxazoline ligands was developed by Gong and co-workers (Scheme 33) [93]. A range of substituted glycine derivatives 204 served as cross-coupling partners with cyclobutanone oxime esters 2, in the presence of 1 mol% Fe(NTf₂)₂ and 10 mol% pyridine-oxazoline ligands (L3 or L4), to access cyanoalkylated amino acids and peptides 205 in moderate to high yields. Importantly, this is the first example of C_(sp3)-H cyanoalkylation with cyclic ketoximes, providing a new pathway for the synthesis of unnatural amino acids. The authors demonstrated experimentally that the interaction between the iron-catalyst and glycinate substrates could greatly improve the catalytic efficiency, and the in situ-formed imine intermediates are a key for high chemo-selectivity.

Guo and co-workers reported an alkoxy, radical-triggered, ring-opening halogenation of cyclopentyl hydroperoxides under a simple and effective copper catalytic system involving redox-neutral conditions and green halogen sources [94]. In addition, the authors applied this halogenation reaction system to the ring-opening halogenation of cyclic ketoximes 2, and the structurally diverse halogenated cyanides 209 were constructed in moderate yields (Scheme 34).

Recently, Qin and co-workers utilized transition metal-catalyzed denitrogenative cyanoalkylation of nitroalkenes by a reductive C–C bond formation process (Scheme 35) [95]. The mild method provides convenient catalytic access to cyanoalkylated styrene derivatives with good functional group tolerance. A variety of cyanoalkylated styrenes were synthesized in moderate to excellent yields.

In 2021, Lu and co-workers reported the decarboxylative cross-coupling of α,β-unsaturated carboxylic acids 212 with cycloketone oxime esters 2, exploiting a photo/nickel dual catalysis (Scheme 36) [96]. Different from the previous decarboxylation mechanism of α,β-unsaturated carboxylic acids, this reaction involves the nickelacyclopropane intermediate 215, which then undergoes decarboxylative elimination to access the final product. This method not only constructs a large number of cyanoalkyl olefins with good functional group tolerance, but also has an important role in the modification of complex molecules.

3.3. Radical Coupling

Elements of the group of sulfur, such as S, Se and Te, are often introduced into the skeletons of various organic compounds as a class of heteroatoms, because organic compounds containing such heteroatoms have a wide distribution and application in pharmaceuticals, drug candidates, agrochemicals, catalysis and functional materials [97]. In 2021, Zhao’s group developed two different chalcogenation reactions of cyclic ketoxime esters 2 (Scheme 37). The ring-opening radical coupling of cyclic ketoxime esters 2 with dichalcogenides 217 occurs under additive-free conditions [98]. The mild photocatalysis enabled its coupling with potassium selenocyanate 219 [99].

4. Conclusions

With the increasing requirements for environmental protection, great efforts have been made into advancing green technologies and sustainable chemistry [100,101]. The strategies involving free radical chemistry have been demonstrated as a powerful tool, with features regarding ease of operation, high efficiency, mild conditions and environmental friendliness [21,100,101,102]. Among them, nitrogen-centered radicals are highly versatile reactive intermediates, thus widely exploited for synthetic utility in C–N bond-forming reactions [35]. Readily accessible oxime ester derivatives have gained fame due to their specific N-O structures and their tendency to generate nitrogen-centered radicals with the aid of transition metals or/and photocatalysis.

This paper summarizes related radical reactions of oxime esters through imino radicals, which experience carbon–carbon bond rupture for conversion to carbon-centered radicals (CCRs). Acyl oxime esters and cyclic ketoxime esters are representative substrates of these reactions, which formally include radical addition reactions, cross-couplings, radical couplings, etc. Although the research on oxime esters has been developed rapidly and significant results have been achieved, there are still demands to develop new models of reactivities and expand their applications in related fields. Specifically, the ester group fraction of ketoximes was generally released to form acid by-products, which leads to significant issues of atom economy. Moreover, only a few examples of asymmetric synthesis were disclosed, mostly limited to transition metal catalysis or photocatalysis. In the context of sustainable catalysis, we look forward to further progress in the application of oxime esters with novel reactions and as a multipurpose development in academic and industrial settings.